WO2024083705A1 - Furoindazole derivatives for the treatment of pain - Google Patents

Furoindazole derivatives for the treatment of pain Download PDF

Info

Publication number
WO2024083705A1
WO2024083705A1 PCT/EP2023/078602 EP2023078602W WO2024083705A1 WO 2024083705 A1 WO2024083705 A1 WO 2024083705A1 EP 2023078602 W EP2023078602 W EP 2023078602W WO 2024083705 A1 WO2024083705 A1 WO 2024083705A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
furo
carboxamide
dihydro
indazole
Prior art date
Application number
PCT/EP2023/078602
Other languages
French (fr)
Inventor
Frank Sacher
Jens Nagel
Hideki MIYATAKE ONDOZABAL
Antje Rottmann
Holger Siebeneicher
Christoph Philipp HETHEY
Original Assignee
Bayer Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Publication of WO2024083705A1 publication Critical patent/WO2024083705A1/en

Links

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • 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
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • the present invention covers the use of furoindazole compounds of general formula (I) as described and defined herein, for the treatment or prophylaxis of diseases in particular of inflammatory-driven pain diseases such as neuropathic pain diseases like diabetic neuropathic pain, and chemotherapy induced pain, and post-breast surgery pain, cancer bone pain, trigeminal neuralgia, post-mastectomy pain, fibromyalgia, multiple sclerosis pain, post-herpetic neuralgia, Fabry disease, gout, and bladder pain syndrome in humans and animals.
  • inflammatory-driven pain diseases such as neuropathic pain diseases like diabetic neuropathic pain, and chemotherapy induced pain
  • post-breast surgery pain cancer bone pain
  • trigeminal neuralgia post-mastectomy pain
  • fibromyalgia multiple sclerosis pain
  • post-herpetic neuralgia Fabry disease
  • gout gout
  • the furoindazole compounds of general formula (I) are antagonists of the G-protein coupled receptor 84 (also known as GPR84).
  • GPR84 G-protein coupled receptor 84
  • MFFAs Medium-chain free fatty acids
  • MCFFAs stimulate release of IL6 from fibroblasts (Smith and Tasi, Nat. Prod. Rep.2007 Oct, 24(5): 1041-72) and myristic acid increases IL6 and IL8 levels in human coronary arterial smooth muscle (HCASM) and endothelial (HCEC) cells (Soto-Vaca A. et al., J. Agric. Food Chem.2013 Oct 23, 61(42): 10074-9).
  • GPR84 belongs to the group of Free Fatty Acid (FFA) receptors (Wang J. et al., J. Biol. Chem. 2006 Nov 10, 281(45): 34457-64).
  • FFA receptors The group of FFA receptors consists of 4 GPCRs (FFA1-FFA2) and the new members GPR42 and GPR84.
  • FFA receptors are involved in biological processes such as metabolic and immune function receptors (Wang J. et al., J. Biol. Chem.2006 Nov 10, 281(45): 34457-64).
  • GPR84 has been described to be expressed primarily in various leukocyte populations and adipocytes (Wang J. et al., J. Biol. Chem.2006 Nov 10, 281(45): 34457-64; Lattin J.E. et al., Immunome Res. 2008 Apr 29, 4: 5; Nagasaki H.
  • GPR84 promotes a comprehensive fibrotic and inflammatory cellular response, exerted by enhanced migration of macrophages and neutrophils, promoted pro-inflammatory M1 macrophage polarization and response and secretion of key inflammatory cytokines such as IL1beta and TNFalpha (Gagnon L. et al., Am. J. Pathol. 2018 May, 188(5): 1132-1148; Muredda L. et al., Arch. Physiol. Biochem. 2018 May, 124(2): 97-108; Huang Q. et al., Dev. Comp. Immunol.2014, 45(2): 252-258).
  • IL1beta and TNFalpha key inflammatory cytokines
  • GPR84 as microglia-associated protein is expressed in neuroinflammatory conditions and is described as a potential target for the treatment of multiple sclerosis (Bouchard C. et al., Glia 2007 Jun, 55(8): 790-800) and for endometriosis associated and inflammatory pain (Sacher F. et al.2018, Conference Abstract SRI 2018). Furthermore, inhibition of activity and/or the knockout of GPR84 are also effective in the treatment of neuropathic pain in several preclinical models (Roman et al. 2010, 7th Forum of European Neuroscience (FENS)).
  • GPR84 for inflammatory kidney diseases has been shown in experiments using Gpr84-knockout mice or GPR84 antagonist in models of kidney fibrosis and models for inflammatory liver diseases like non-alcoholic, alcoholic- and toxic fatty liver diseases (Puengel et al.2018, 2018 International Liver Congress (ILC) of the European Association for the Study of the Liver (EASL); Thibodeau J.F. et al.2018, 51st Annual Meeting and Exposition of the American Society of Nephrology (ASN): Kidney Week 2018).
  • inflammatory changes in adipose tissue enhance expression of GPR84 in adipocytes and modulation of GPR84 regulates adipocyte immune response capabilities (Muredda et al., Archives of Physiology and Biochemistry 2017 Aug, 124(2): 1-12) indicating the relevance of GPR84 in metabolic and metabolic-endocrine disorders like metabolic syndrome, insulin resistance, diabetes mellitus type I and type II, and polycystic ovary syndrome (PCOS) through normalization of adipose tissue inflammation.
  • PCOS polycystic ovary syndrome
  • GPR84 idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease
  • lung diseases like asthma, idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease
  • GPR84 antagonists for example the patent applications WO2013092791 and WO2014095798 disclose dihydropyrimidinoisoquinolinones having activity as GPR84 antagonists. Such compounds find utility in several therapeutic applications including inflammatory conditions.
  • the patent applications WO2015197550 and WO2016169911 disclose related dihydropyridoisoquinolinones as GPR84 antagonists.
  • the patent application WO2018161831 discloses dibenzoannulen hydrogen phosphates as GPR84 antagonists.
  • the patent application WO2009023773 discloses galactokinase inhibitors that were identified by a high throughput screening approach. Among the identified hits were two furoindazole compounds.
  • the patent application US20090163545 discloses compounds for altering the lifespan of eukaryotic organisms that were identified by a cell-based phenotypic high throughput screening approach. Among the identified hits were two furoindazole compounds.
  • the patent applications US6245796B1, WO2001083487 and WO2011071136 disclose aromatic tricyclic pyrrole or pyrazole derivatives as 5-HT2c ligands.
  • the patent application WO2016085990 discloses compounds inhibiting serine hydroxy- methyltransferase 2 activity that were identified by a high throughput screening approach. Among the identified hits were nine furoindazole compounds.
  • the patent application WO2019084271 discloses compounds inhibiting the non- canonical poly(A) RNA polymerase associated domain containing protein 5 (PAPD5) originating from diverse compound classes that were identified by a high throughput screening approach. Among the identified hits were eight furoindazole compounds.
  • the compounds according to WO2021122415 have surprising and advantageous properties for the use in the treatment or prophylaxis of diseases, in particular of inflammatory-driven pain diseases such as neuropathic pain, more specifically for diseases like diabetic neuropathic pain, and chemotherapy induced pain, and post-breast surgery pain, cancer bone pain, trigeminal neuralgia, post-mastectomy pain, fibromyalgia, multiple sclerosis pain, post-herpetic neuralgia, Fabry disease, gout, and bladder pain syndrome.
  • inflammatory-driven pain diseases such as neuropathic pain, more specifically for diseases like diabetic neuropathic pain, and chemotherapy induced pain
  • post-breast surgery pain cancer bone pain
  • trigeminal neuralgia post-mastectomy pain
  • fibromyalgia multiple sclerosis pain
  • post-herpetic neuralgia Fabry disease
  • gout gout
  • the present invention covers the use of compounds of general formula (I): in which: R 1 represents hydrogen, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl; R 2 represents hydrogen, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl; or R 1 and R 2 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring; R 3 represents C 3 -C 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, heterocycloalkyl fused with phenyl or heteroaryl, or heteroaryl, wherein said groups are optionally substituted, one or more times, independently of each other, with R 8 , or R 3 represents phenyl, which is optionally substituted, one or more times, independently of each other, with R 8 , and additionally R 7a and R 7b represent de
  • substituted means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.
  • optionally substituted means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, it is possible for the number of optional substituents, when present, to be 1, 2, 3, 4, or 5, in particular 1, 2, or 3.
  • the term “one or more”, e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means 1, 2, 3, 4, or 5, particularly 1, 2, 3, or 4, more particularly 1, 2, or 3, even more particularly 1 or 2.
  • an oxo substituent represents an oxygen atom, which is bound to a carbon atom via a double bond. Should a composite substituent be composed of more than one parts, e.g. (C 1 -C 4 -alkoxy)-(C 1 -C 4 -alkyl)-, it is possible for the position of a given part to be at any suitable position of said composite substituent, i.e.
  • the C 1 -C 4 -alkoxy part can be attached to any carbon atom of the C 1 -C 4 -alkyl part of said (C 1 -C 4 -alkoxy)-(C 1 -C 4 -alkyl)- group.
  • a hyphen at the beginning or at the end of such a composite substituent indicates the point of attachment of said composite substituent to the rest of the molecule.
  • a ring comprising carbon atoms and optionally one or more heteroatoms, such as nitrogen, oxygen or sulphur atoms for example, be substituted with a substituent, it is possible for said substituent to be bound at any suitable position of said ring, be it bound to a suitable carbon atom and/or to a suitable heteroatom.
  • halogen atom means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.
  • C 1 -C 4 -alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, or 4 carbon atoms, e.g.
  • said group has 1, 2, or 3 carbon atoms (“C 1 -C 3 -alkyl”), e.g. a methyl, ethyl, propyl, or isopropyl group, more particularly 1 or 2 carbon atoms (“C 1 -C 2 -alkyl”), e.g. a methyl or ethyl group.
  • C 2 -C 4 -hydroxyalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C 2 -C 4 -alkyl” is defined supra, and in which one hydrogen atom is replaced with a hydroxy group, e.g. a 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1-hydroxy-2-methyl-propyl group.
  • a hydroxy group e.g. a 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1-hydroxy-2-methyl-propyl group.
  • C 1 -C 4 -haloalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C 1 -C 4 -alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom.
  • Said C 1 -C 4 -haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoropropan-2-yl.
  • C 1 -C 4 -alkoxy means a linear or branched, saturated, monovalent group of formula (C 1 -C 4 -alkyl)-O-, in which the term “C 1 -C 4 -alkyl” is as defined supra, e.g.
  • C 1 -C 4 -haloalkoxy means a linear or branched, saturated, monovalent C 1 -C 4 -alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine atom.
  • Said C 1 -C 4 -haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.
  • C 3 -C 6 -cycloalkyl means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5, or 6 carbon atoms (“C 3 -C 6 -cycloalkyl”).
  • Said C 3 -C 6 -cycloalkyl group is for example, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.
  • C 3 -C 6 -halocycloalkyl means a saturated, monovalent, monocyclic hydrocarbon ring in which the term “C 3 -C 6 -halocycloalkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine atom.
  • 4- to 6-membered heterocycloalkyl means a monocyclic, saturated heterocycle with 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S, it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • Said heterocycloalkyl group can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3-thiazolidinyl, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-
  • “4- to 6-membered heterocycloalkyl” means a 4- to 6-membered heterocycloalkyl as defined supra containing one ring nitrogen or oxygen atom and optionally one further ring heteroatom from the series: N, O, S. More particularly, “5- or 6-membered heterocycloalkyl” means a monocyclic, saturated heterocycle with 5 or 6 ring atoms in total, containing one ring nitrogen or oxygen atom and optionally one further ring heteroatom from the series: N, O.
  • heterocycloalkyl fused with phenyl or heteroaryl means a bicyclic heterocycle with 8, 9 or 10 ring atoms in total, in which the two rings share two adjacent ring atoms, and in which the “heterocycloalkyl” part contains one or two identical or different ring heteroatoms from the series: N, O and/or S
  • heteroaryl means a monocyclic aromatic ring having 5 or 6 ring atoms (a “5- to 6-membered heteroaryl” group), which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series N, O and/or S; it being possible for said fused heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • heterospirocycloalkyl means a bicyclic, saturated heterocycle with 6, 7, 8, 9, 10 or 11 ring atoms in total, in which the two rings share one common ring carbon atom, which “heterospirocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterospirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom.
  • Said heterospirocycloalkyl group is, for example, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxaazaspiro[3.3]heptyl, thiaazaspiro[3.3]heptyl, oxaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, azaspiro[4,5]decyl, oxazaspiro [5.5]undecyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, azaspiro[5.5]undecyl, or one of the further homologous scaffolds such as spiro[3.4]-, spiro[4.4]-, spiro[2.4]-, spiro[2.5]-,
  • heteroaryl means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 8, 9, or 10 ring atoms (a “5- to 10-membered heteroaryl” group), particularly 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).
  • Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, such as, for example, carbazolyl, acridinyl or phenazinyl; or a 9- membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl,
  • the heteroaryl groups include all possible isomeric forms thereof, e.g.: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule.
  • the term pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
  • the heteroaryl group is a pyridinyl group.
  • C 1 -C 6 -alkyl in the context of the definition of “C 1 -C 6 -alkyl”, “C 1 -C 6 -haloalkyl”, “C 1 -C 6 -hydroxyalkyl”, “C 1 -C 6 -alkoxy” or “C 1 -C 6 -haloalkoxy” means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e.1, 2, 3, 4, 5 or 6 carbon atoms.
  • C 3 -C 8 as used in the present text, e.g.
  • C 3 -C 8 -cycloalkyl in the context of the definition of “C 3 -C 8 -cycloalkyl”, means a cycloalkyl group having a finite number of carbon atoms of 3 to 8, i.e.3, 4, 5, 6, 7 or 8 carbon atoms. When a range of values is given, said range encompasses each value and sub-range within said range.
  • C 1 -C 6 encompasses C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 2 -C 6 , C 2 - C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 - C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 ;
  • C 2 -C 6 encompasses C 2 , C 3 , C 4 , C 5 , C 6 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C
  • the term “leaving group” means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons.
  • a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphen
  • the invention therefore includes the use of one or more isotopic variant(s) of the compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).
  • the term “Isotopic variant” of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • the term “Isotopic variant of the compound of general formula (I)” is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • the expression “unnatural proportion” means a proportion of such isotope which is higher than its natural abundance.
  • isotopes to be applied in this context are described in “Isotopic Compositions of the Elements 1997”, Pure Appl. Chem., 70(1), 217-235, 1998.
  • isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, respectively.
  • the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium (“deuterium-containing compounds of general formula (I)”).
  • deuterium-containing compounds of general formula (I) Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as 3 H or 14 C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability.
  • Positron emitting isotopes such as 18 F or 11 C may be incorporated into a compound of general formula (I). These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications.
  • Deuterium-containing and 13 C- containing compounds of general formula (I) can be used in mass spectrometry analyses in the context of preclinical or clinical studies.
  • Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent.
  • a reagent for an isotopic variant of said reagent preferably for a deuterium-containing reagent.
  • deuterium from D2O can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds.
  • Deuterium gas is also a useful reagent for incorporating deuterium into molecules.
  • Catalytic deuteration of olefinic bonds and acetylenic bonds is a rapid route for incorporation of deuterium.
  • Metal catalysts i.e. Pd, Pt, and Rh
  • Pd, Pt, and Rh metal catalysts in the presence of deuterium gas can be used to directly exchange deuterium for hydrogen in functional groups containing hydrocarbons.
  • a variety of deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.
  • deuterium-containing compound of general formula (I) is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than the natural abundance of deuterium, which is about 0.015%. Particularly, in a deuterium-containing compound of general formula (I) the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s).
  • the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).
  • the selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J.
  • deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102).
  • the major effect of deuteration is to reduce the rate of systemic clearance. As a result, the biological half-life of the compound is increased.
  • the potential clinical benefits would include the ability to maintain similar systemic exposure with decreased peak levels and increased trough levels.
  • Deuterated drugs showing this effect may have reduced dosing requirements (e.g. lower number of doses or lower dosage to achieve the desired effect) and/or may produce lower metabolite loads.
  • a compound of general formula (I) may have multiple potential sites of attack for metabolism. To optimize the above-described effects on physicochemical properties and metabolic profile, deuterium-containing compounds of general formula (I) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected.
  • the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P450.
  • metabolizing enzymes such as e.g. cytochrome P450.
  • the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds intended for the use according to the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds. Preferred compounds are those which produce the more desirable biological activity.
  • Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • Preferred isomers are those which produce the more desirable biological activity.
  • These separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful.
  • the optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials. In order to distinguish different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).
  • the compounds intended for the use according to the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g.
  • the compounds intended for the use according to the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the compounds intended for the use according to the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised.
  • the present invention includes all such possible N-oxides.
  • the present invention also covers the use of useful forms of the compounds, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co-precipitates.
  • the compounds intended for the use according to the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non-stoichiometric ratio.
  • polar solvents in particular water
  • stoichiometric solvates e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • the compounds intended for the use according to the present invention may exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.
  • a suitable pharmaceutically acceptable salt of the compounds intended for the use according tothe present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or “mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphtho
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt
  • acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.
  • the present invention includes the use of all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds intended for the use according to the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • the compounds intended for the use according to the present invention also include prodrugs of the compounds.
  • prodrugs here designates compounds which themselves can be biologically active or inactive but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body.
  • the present invention covers the use of compounds of general formula (I), supra, in which: R 1 represents hydrogen, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl; R 2 represents hydrogen, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl; or R 1 and R 2 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring; R 3 represents C 3 -C 6 -cycloalkyl, 3- to 6-membered heterocycloalkyl, heterocycloalkyl fused with phenyl or heteroaryl, or heteroaryl, wherein said groups are optionally substituted, one or more times, independently of each other, with R 8 , or R 3 represents phenyl, which is optionally substituted, one or more times, independently of each other, with R 8 , and additionally R 7a and R 7b represent
  • the present invention covers the use of compounds of general formula (I), supra, in which: R 1 represents hydrogen, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl; R 2 represents hydrogen or C 1 -C 4 -alkyl; or R 1 and R 2 together with the carbon atom to which they are attached form a 3- to 4-membered cycloalkyl or heterocycloalkyl ring; R 3 represents C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocycloalkyl, heterocycloalkyl fused with heteroaryl, or heteroaryl, wherein said groups are optionally substituted, one or more times, independently of each other, with R 8 , or R 3 represents phenyl, which is optionally substituted, one or more times, independently of each other, with R 8 , and additionally R 7a and R 7b represent deuterium; R 4 represents hydrogen, C 1 -C 4 -alkyl or C 1 -C 4 -halo
  • the present invention covers the use of compounds of general formula (I), supra, in which: R 1 represents hydrogen, methyl or trifluoromethyl; R 2 represents hydrogen or methyl; or R 1 and R 2 together with the carbon atom to which they are attached form a 3- to 4-membered cycloalkyl ring; R 3 represents cyclopropyl, 4- to 6-membered heterocycloalkyl, 2,3- dihydro[1,4]dioxino[2,3-b]pyridin-2-yl, or heteroaryl, wherein said groups are optionally substituted, one or more times, independently of each other, with R 8 , or R 3 represents phenyl, which is optionally substituted, one or more times, independently of each other, with R 8 , and additionally R 7a and R 7b represent deuterium; R 4 represents hydrogen, methyl, C 1 -haloalkyl or cyclopropyl; R 5 represents hydrogen; R 6 represents methoxy-ethyl
  • the present invention covers the use of compounds of general formula (I), supra, in which: R 1 represents hydrogen or methyl; R 2 represents hydrogen or methyl; or R 1 and R 2 together with the carbon atom to which they are attached form a 3- to 4-membered cycloalkyl ring; R 3 represents cyclopropyl, 2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-yl, oxetan-3-yl, oxolan-3-yl, oxolan-2-yl, 3-methyloxetan-3-yl, 3-fluorooxetan-3-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, oxan-4-yl, 1,4-dioxan-2-yl, 6-methylpyridin-3-yl, 5- methylpyridin-2-yl, 3-methylpyridin
  • R 3 represents phenyl, and additionally R 7a and R 7b represent deuterium;
  • R 4 represents methyl, difluoromethyl, trifluoromethyl, or cyclopropyl;
  • R 5 represents hydrogen;
  • R 6 represents (oxolan-2-yl)methyl, (1,3-oxazol-4-yl)methyl, (1,2-oxazol-3-yl)methyl, (4-methyloxolan-2-yl)methyl, (pyrimidin-2-yl)methyl, (pyrazin-2-yl)methyl, (5- methyloxolan-2-yl)methyl, (5-methyloxolan-2-yl)methyl, (1,4-dioxan-2-yl)methyl, (4-methylphenyl)methyl, (5-methylpyrimidin-2-yl)methyl, (5-methylpyrazin-2- yl)methyl, (5-chloropyrazin-2-yl)methyl, (5-cyclopropyl-pyrazin-2-yl)methyl, 2,3- dihydro[1,4]dioxino[2,3-b]pyridin-2
  • the invention refers to the use of one of the following compounds: 1 2-(pyridin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 2 8-methyl-N-[(4-methylphenyl)methyl]-2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 3 8-methyl-2-(pyridin-2-ylmethyl)-N-[(2R/S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 3 8-methyl-2-(pyridin-2-ylmethyl)-N-[(2R)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro- 2H-furo[2,
  • the invention refers to the use of (4R)-N-[(5-cyclopropylpyrazin-2- yl)methyl]-2- ⁇ [(2S)-1,4-dioxan-2-yl]methyl ⁇ -4-methyl-8-(trifluoromethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide for the treatment or prophylaxis of diseases, in particular of inflammatory-driven pain diseases such as neuropathic pain, more specifically for diseases like diabetic neuropathic pain, and chemotherapy induced pain, and post-breast surgery pain, cancer bone pain, trigeminal neuralgia, post-mastectomy pain, fibromyalgia, multiple sclerosis pain, post-herpetic neuralgia, Fabry disease, gout, and bladder pain syndrome.
  • inflammatory-driven pain diseases such as neuropathic pain, more specifically for diseases like diabetic neuropathic pain, and chemotherapy induced pain
  • the compounds of general formula (I) can be prepared according to the schemes 1, 2, 3, and 4 according to WO2021122415 page 40, 43, 45, and 47 which are incorporated herein as a reference and are part of the present application. Furthermore, the preparation of the compounds of general formula (I) according to WO2021122415, reported on page 39, line 21 to page 47, line 11 is also incorporated herein as a reference and is part of the present application. Compounds of general formula (I) demonstrate a valuable pharmacological spectrum of action which could not have been predicted.
  • Compounds of the present invention have surprisingly been found to be effective antagonists of GPR84 and it is possible therefore that said compounds be used for the treatment or prophylaxis of diseases, in particular of inflammatory-driven pain diseases such as neuropathic pain diseases like diabetic neuropathic pain, and chemotherapy induced pain, and post-breast surgery pain, cancer bone pain, trigeminal neuralgia, post-mastectomy pain, fibromyalgia, multiple sclerosis pain, post-herpetic neuralgia, Fabry disease, gout, and bladder pain syndrome.
  • Compounds of general formula (I) can be utilized to inhibit, antagonize, block, reduce, decrease GPR84 signal transduction, activity and cellular function.
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of general formula (I), or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; which is effective to treat the disorder.
  • a mammal in need thereof, including a human, an amount of a compound of general formula (I), or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; which is effective to treat the disorder.
  • inflammatory-driven pain diseases such as neuropathic pain diseases like diabetic neuropathic pain, and chemotherapy induced pain, and post-breast surgery pain, cancer bone pain, trigeminal neuralgia, post-mastectomy pain, fibromyalgia, multiple sclerosis pain, post-herpetic neuralgia, Fabry disease, gout, and bladder pain syndrome in humans and animals.
  • treating or “treatment” as used in the present text is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as PCOS or IPF.
  • the present invention covers the use of a compound of formula (I), described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of diseases, in particular of inflammatory-driven pain diseases such as neuropathic pain diseases like diabetic neuropathic pain, and chemotherapy induced pain, and post-breast surgery pain, cancer bone pain, trigeminal neuralgia, post- mastectomy pain, fibromyalgia, multiple sclerosis pain, post-herpetic neuralgia, Fabry disease, gout, and bladder pain syndrome in humans and animals.
  • diseases in particular of inflammatory-driven pain diseases such as neuropathic pain diseases like diabetic neuropathic pain, and chemotherapy induced pain, and post-breast surgery pain, cancer bone pain, trigeminal neuralgia, post- mastectomy pain, fibromy
  • the compounds of general formula (I) can have systemic and/or local activity.
  • they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
  • a suitable manner such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
  • the compounds of general formula (I) can be administered in suitable administration forms.
  • the compounds intended for the use according to the invention for oral administration, it is possible to formulate the compounds intended for the use according to the invention to dosage forms known in the art that deliver the compounds rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally-disintegrating tablets, films/wafers, films/lyophilizates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds intended for the use according to the invention in crystalline and/or amorphized and/or dissolved form into said dosage forms.
  • Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • absorption step for example intravenous, intraarterial, intracardial, intraspinal or intralumbal
  • absorption for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal.
  • Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.
  • Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
  • inhalation inter alia powder inhalers, nebulizers
  • nasal drops nasal solutions, nasal sprays
  • tablets/films/wafers/capsules for lingual, sublingual or buccal
  • compositions of general formula (I) can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients.
  • Pharmaceutically suitable excipients include, inter alia, • fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel ® ), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos ® )), • ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), • bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), • solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffin
  • the present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
  • a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
  • the synthesis of the compounds 1 to 323, the required intermediates for said synthesis and the methods for their identification were described in the patent application WO2021122415, Experimental section, page 58 to 479 which is incorporated herein as a reference and is part of the present application.
  • the compounds 1 to 323 are numbered in accordance with the examples described in WO2021122415 and in case of stereoisomers one single example number was assigned.
  • cAMP HTRF® Assay for identification of cellular GPR84 antagonists
  • HTRF® Homogenous Time-Resolved Fluorescence
  • CHO-K1 cells stably expressing human GPR84 receptor purchased from DiscoveRx, now Eurofins were used and treated with Forskolin (F6886, Sigma, Germany) to stimulate membrane adenylyl cyclases and thereby unspecific cAMP formation.
  • Activation of the Gi-coupled GPR84 by a natural or small molecule agonist results in inhibition of cellular cAMP formation which can be released again by antagonists to this receptor.
  • Detection and quantification of cellular cAMP levels in this HTRF assay is achieved by interaction between a fluorescent cAMP tracer (cAMP-d2) and an Eu-cryptate labelled anti-cAMP antibody. Following excitation at 337 nm this pairing allows for the generation of a fluorescence resonance energy transfer (FRET) between the partners and results in FRET induced emissions at 665 nm and 620 nm, the latter representing background signal by Eu- cryptate labelled anti-cAMP antibody.
  • FRET fluorescence resonance energy transfer
  • CHO-K1 cells expressing hGPR84 prepared by acCELLerate, Hamburg, Germany
  • cell suspension (1.67E+06 cells/mL) in assay media (Ham’s F12 Nutrient Mix, Thermo Fisher Scientific, Waltham, USA; 5% fetal calf serum, Biomol, Hamburg, Germany) containing cAMP-d2 (dilution 1:20, supplied with the kit #62AM5PEJ, Cisbio, Condolet, France) was prepared.
  • 3 ⁇ L/well cell suspension including cAMP-d2 were added to a pre-dispensed assay plate (Greiner Bio-One, Kremsmuenster, Austria) containing 50nl/well test compound in 100% DMSO or 100% DMSO as control. This was followed by a 30 minutes incubation step at room temperature. The stimulation time was started by addition of 2 ⁇ L/well assay media containing 2.5xEC 80 agonist 6-OAU and 2.5xEC 9 0 Forskolin (negative control: 2.5xEC 90 Forskolin in assay media) and was continued for 30 minutes at room temperature.
  • cAMP Eu-Cryptate antibody (dilution 1:20) (both supplied with the kit #62AM5PEJ, Cisbio, Condolet, France).
  • cAMP Eu-Cryptate antibody both supplied with the kit #62AM5PEJ, Cisbio, Condolet, France.
  • plates were incubated for 60 minutes at room temperature before measurement in an HTRF reader, e.g. a PHERAstar (BMG Labtech, Ortenberg, Germany).
  • Example GPR84 IC 50 [ ⁇ M] Example GPR84 IC 50 [ ⁇ M] Table 6 (continued)
  • Example GPR84 IC 50 [ ⁇ M] Example GPR84 IC 50 [ ⁇ M] 53 0.032 80 0.057 Table 6 (continued)
  • Example GPR84 IC 50 [ ⁇ M] Example GPR84 IC 50 [ ⁇ M] 113 0.091 146 0.047 Table 6 (continued)
  • Example GPR84 IC 50 [ ⁇ M] Example GPR84 IC 50 [ ⁇ M] 179 6.41 216 0.006 Table 6 (continued)
  • Example GPR84 IC 50 [ ⁇ M] Example GPR84 IC 50 [ ⁇ M] 246 0.075 273 0.009 Table 6 (continued)
  • Example GPR84 IC 50 [ ⁇ M] 306 0.027 The suitability of the compounds of general formula (I) for the treatment pain disorders can be demonstrated in the following animal models
  • Example 3-2 Efficacy of GPR84 antagonist in the rat DHT-PCOS model
  • In vivo assay 2 Effects of Example 3-2 in the CFA pain model The efficacy of Example 3-2 in vivo on inflammatory pain was measured in inflamed paws after administration of complete Freund’s adjuvant (CFA) (24 h) in the dynamic weight- bearing (DWB) model. The effects of repeated preventive treatment with Example 3-2 on pain following repeated oral administration (3x) in the mouse CFA model of inflammation were investigated using a preventive setting.
  • Example 3-2 (20 or 60 mg/kg, 3x doses) was administered 2 h before injection of CFA and 6-8 h later at day 0. At 24 h after CFA application, the third dose of Example 3-2 was given 2 h before DWB testing. Statistical analysis was performed with one-way analysis of variance, followed by Bonferroni’s multiple comparison test against vehicle control groups using the GraphPad PRISM software, *p ⁇ 0.05.
  • Table 8 Effects of GPR84 antagonist in the CFA pain model
  • In vivo assay 3 Effects in the Oxaliplatin induced pain model
  • the efficacy of example 320 in vivo on chemotherapy (Oxaliplatin; OPNP) induced pain was measured in a rat Oxaliplatin-induced 6 weeks neuropathic pain model.
  • the GPR84 antagonist example 320 was administered with the first application at d1.
  • Rats were habituated to the circumstances for 30 min before starting with behavioral test.
  • von Frey test was conducted on all animals for baseline measurement.
  • paw withdrawal thresholds was measured by applying the von Frey filaments (with ascending weights; 0.4, 0.6, 1.4, 2, 4, 6, 8, 15 g) on the center of the right hind paw.
  • Von Frey tests were conducted prior to test article administration (baseline) and once per week, 1 hr, 2 hr and 4 hr post dosing until the end of the experiment.
  • Statistical analysis was performed with one-way analysis of variance, followed by Dunnett multiple comparison test against vehicle control group using the GraphPad PRISM software, *p ⁇ 0.05.
  • Table 9 Effects of GPR84 antagonist in Oxaliplatin induced pain model Example mg/kg/d Threshold to von Frey Stimulation (g) on day 28 E l 10
  • In vivo assay 4 Effects in the Streptozotocin (STZ)-induced diabetic neuropathic pain model The efficacy of example 320 in vivo on diabetic neuropathic pain was studied in the Streptozotocin (STZ)-induced neuropathic pain model. Diabetes was induced in Sprague Dawley male rats by dosing of Streptozotocin (STZ, 60 mg/kg) on study day 0. The development of diabetes was confirmed by the measurement of blood glucose levels on study day 3.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Rheumatology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present invention covers the use of furoindazole compounds of general formula (I): (I) in which R1, R2, R3, R4, R5, R6, R7a, and R7b are as defined herein, for the treatment or prophylaxis of diseases, in particular of inflammatory-driven pain diseases such as neuropathic pain diseases like diabetic neuropathic pain, and chemotherapy induced pain, and post-breast surgery pain, cancer bone pain, trigeminal neuralgia, post- mastectomy pain, fibromyalgia, multiple sclerosis pain, post-herpetic neuralgia, Fabry disease, gout, and bladder pain syndrome in humans and animals.

Description

USE OF FUROINDAZOLE DERIVATIVES The present invention covers the use of furoindazole compounds of general formula (I) as described and defined herein, for the treatment or prophylaxis of diseases in particular of inflammatory-driven pain diseases such as neuropathic pain diseases like diabetic neuropathic pain, and chemotherapy induced pain, and post-breast surgery pain, cancer bone pain, trigeminal neuralgia, post-mastectomy pain, fibromyalgia, multiple sclerosis pain, post-herpetic neuralgia, Fabry disease, gout, and bladder pain syndrome in humans and animals. BACKGROUND The furoindazole compounds of general formula (I) are antagonists of the G-protein coupled receptor 84 (also known as GPR84). The relevance of GPR84 for human disease has been described and studied in several publications. Medium-chain free fatty acids (MCFFAs) are fatty acids with tails of 6 to 12 carbons and can activate GPR84 (Wang J et al., J. Biol. Chem. 2006 Nov 10, 281(45): 34457-64). There are two sources of FAs for animal metabolism, exogenously-derived (dietary) FAs and endogenously-synthesized FAs. The biosynthesis of the latter is catalysed by FASN. MCFFAs stimulate release of IL6 from fibroblasts (Smith and Tasi, Nat. Prod. Rep.2007 Oct, 24(5): 1041-72) and myristic acid increases IL6 and IL8 levels in human coronary arterial smooth muscle (HCASM) and endothelial (HCEC) cells (Soto-Vaca A. et al., J. Agric. Food Chem.2013 Oct 23, 61(42): 10074-9). GPR84 belongs to the group of Free Fatty Acid (FFA) receptors (Wang J. et al., J. Biol. Chem. 2006 Nov 10, 281(45): 34457-64). The group of FFA receptors consists of 4 GPCRs (FFA1-FFA2) and the new members GPR42 and GPR84. FFA receptors are involved in biological processes such as metabolic and immune function receptors (Wang J. et al., J. Biol. Chem.2006 Nov 10, 281(45): 34457-64). In contrast to all other FFA receptors which have a broader expression pattern, GPR84 has been described to be expressed primarily in various leukocyte populations and adipocytes (Wang J. et al., J. Biol. Chem.2006 Nov 10, 281(45): 34457-64; Lattin J.E. et al., Immunome Res. 2008 Apr 29, 4: 5; Nagasaki H. et al., FEBS Lett. 2012 Feb 17, 586(4): 368-72). Activation of GPR84 promotes a comprehensive fibrotic and inflammatory cellular response, exerted by enhanced migration of macrophages and neutrophils, promoted pro-inflammatory M1 macrophage polarization and response and secretion of key inflammatory cytokines such as IL1beta and TNFalpha (Gagnon L. et al., Am. J. Pathol. 2018 May, 188(5): 1132-1148; Muredda L. et al., Arch. Physiol. Biochem. 2018 May, 124(2): 97-108; Huang Q. et al., Dev. Comp. Immunol.2014, 45(2): 252-258). Based on the involvement of GPR84 in fibrotic and inflammatory cellular response several diseases have been suggested to be GPR84 dependent. GPR84 as microglia-associated protein is expressed in neuroinflammatory conditions and is described as a potential target for the treatment of multiple sclerosis (Bouchard C. et al., Glia 2007 Jun, 55(8): 790-800) and for endometriosis associated and inflammatory pain (Sacher F. et al.2018, Conference Abstract SRI 2018). Furthermore, inhibition of activity and/or the knockout of GPR84 are also effective in the treatment of neuropathic pain in several preclinical models (Roman et al. 2010, 7th Forum of European Neuroscience (FENS)). The relevance of GPR84 for inflammatory kidney diseases has been shown in experiments using Gpr84-knockout mice or GPR84 antagonist in models of kidney fibrosis and models for inflammatory liver diseases like non-alcoholic, alcoholic- and toxic fatty liver diseases (Puengel et al.2018, 2018 International Liver Congress (ILC) of the European Association for the Study of the Liver (EASL); Thibodeau J.F. et al.2018, 51st Annual Meeting and Exposition of the American Society of Nephrology (ASN): Kidney Week 2018). As described previously for macrophages and monocytes, inflammatory changes in adipose tissue enhance expression of GPR84 in adipocytes and modulation of GPR84 regulates adipocyte immune response capabilities (Muredda et al., Archives of Physiology and Biochemistry 2017 Aug, 124(2): 1-12) indicating the relevance of GPR84 in metabolic and metabolic-endocrine disorders like metabolic syndrome, insulin resistance, diabetes mellitus type I and type II, and polycystic ovary syndrome (PCOS) through normalization of adipose tissue inflammation. Regulation of neutrophil activity and general inflammation by GPR84 was also described to be relevant for lung diseases like asthma, idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease (Nguyen et al.2018; Annual Congress Scientific Sessions of the American Heart Association (AHA 2018); Saniere L. et al.2019; 2019 International Conference of the American Thoracic Society (ATS)). Few compounds are known as GPR84 antagonists, for example the patent applications WO2013092791 and WO2014095798 disclose dihydropyrimidinoisoquinolinones having activity as GPR84 antagonists. Such compounds find utility in several therapeutic applications including inflammatory conditions. The patent applications WO2015197550 and WO2016169911 disclose related dihydropyridoisoquinolinones as GPR84 antagonists. The patent application WO2018161831 discloses dibenzoannulen hydrogen phosphates as GPR84 antagonists. The patent application WO2009023773 discloses galactokinase inhibitors that were identified by a high throughput screening approach. Among the identified hits were two furoindazole compounds. The patent application US20090163545 discloses compounds for altering the lifespan of eukaryotic organisms that were identified by a cell-based phenotypic high throughput screening approach. Among the identified hits were two furoindazole compounds. The patent applications US6245796B1, WO2001083487 and WO2011071136 disclose aromatic tricyclic pyrrole or pyrazole derivatives as 5-HT2c ligands. The patent application WO2016085990 discloses compounds inhibiting serine hydroxy- methyltransferase 2 activity that were identified by a high throughput screening approach. Among the identified hits were nine furoindazole compounds. The patent application WO2019084271 discloses compounds inhibiting the non- canonical poly(A) RNA polymerase associated domain containing protein 5 (PAPD5) originating from diverse compound classes that were identified by a high throughput screening approach. Among the identified hits were eight furoindazole compounds. The patent application WO2021122415 discloses furoindazole compounds intended for the use according to the present invention. However, the state of the art does not describe the use of the furoindazole compounds of general formula (I) according to WO2021122415 as described and defined herein. It has now been found, and this constitutes the basis of the present invention, that the compounds according to WO2021122415 have surprising and advantageous properties for the use in the treatment or prophylaxis of diseases, in particular of inflammatory-driven pain diseases such as neuropathic pain, more specifically for diseases like diabetic neuropathic pain, and chemotherapy induced pain, and post-breast surgery pain, cancer bone pain, trigeminal neuralgia, post-mastectomy pain, fibromyalgia, multiple sclerosis pain, post-herpetic neuralgia, Fabry disease, gout, and bladder pain syndrome. DESCRIPTION In accordance with a first aspect, the present invention covers the use of compounds of general formula (I): in which:
Figure imgf000005_0001
R1 represents hydrogen, C1-C4-alkyl or C1-C4-haloalkyl; R2 represents hydrogen, C1-C4-alkyl or C1-C4-haloalkyl; or R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring; R3 represents C3-C6-cycloalkyl, 3- to 6-membered heterocycloalkyl, heterocycloalkyl fused with phenyl or heteroaryl, or heteroaryl, wherein said groups are optionally substituted, one or more times, independently of each other, with R8, or R3 represents phenyl, which is optionally substituted, one or more times, independently of each other, with R8, and additionally R7a and R7b represent deuterium; R4 represents hydrogen, C1-C4-alkyl, C1-C4-haloalkyl or C3-C6-cycloalkyl; R5, R6 represent, independently of each other, hydrogen, C1-C4-alkyl, C2-C4-hydroxyalkyl, (C1-C4-alkoxy)-( C2-C4-alkyl)-, C3-C6-cycloalkyl, C1-C4-haloalkyl, C3-C6-halocycloalkyl, 3- to 6-membered heterocycloalkyl, heterospirocycloalkyl, phenyl, heteroaryl, heterocycloalkyl fused with phenyl or heteroaryl, 3- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-, heterospirocycloalkyl-(C1-C3-alkyl)-, (heterocycloalkyl fused with phenyl or heteroaryl)-(C1-C3-alkyl)-, phenyl-(C1-C3-alkyl)- or heteroaryl-(C1-C3-alkyl)-, wherein said 3- to 6-membered heterocycloalkyl, heterospirocycloalkyl, heterocycloalkyl fused with phenyl or heteroaryl, phenyl or heteroaryl groups are optionally substituted, one or more times, independently of each other, with R9, or R5 and R6 together with the nitrogen atom to which they are attached form a 3- to 6-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom or heteroatom containing group selected from O, NH and S, and which may be optionally substituted, one or more times, independently of each other, with R9; R7a represents hydrogen, deuterium, or C1-C4-alkyl; R7b represents hydrogen, deuterium, or C1-C4-alkyl; R8 represents halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C3-C6-cycloalkyl, C3-C6-cycloalkyl-(C1-C3-alkyl)-, R13-(C=O)-, R10-O-(C=O)-, R11-NH-(C=O)-, or R12-(SO2)-; R9 represents halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, H2N-C1-C4-alkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C3-C6-cycloalkyl, R10-O-(C=O)-, oxo, 5- to 6- membered heterocycloalkyl-, 5- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-, phenyl, or heteroaryl, wherein said phenyl or heteroaryl group is optionally substituted, one or more times, independently of each other, with halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, or C1-C3-haloalkoxy; R10 represents hydrogen, C1-C4-alkyl, or phenyl-CH2-; R11 represents hydrogen, C1-C4-alkyl, or 5- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-; R12 represents C1-C4-alkyl or phenyl; R13 represents C1-C4-alkyl, C1-C4-haloalkyl, (C1-C4-alkoxy)-(C1-C4-alkyl)-, C1-C4-alkyl-(C=O)-, C3-C6-cycloalkyl, or phenyl, wherein said C3-C6-cycloalkyl group is optionally substituted with C1-C4-alkyl or hydroxy and said phenyl group is optionally substituted, one or more times, independently of each other, with halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, or C1-C3-haloalkoxy; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, for the treatment or prophylaxis of diseases. DEFINITIONS The term “substituted” means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible. The term “optionally substituted” means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen atom. Commonly, it is possible for the number of optional substituents, when present, to be 1, 2, 3, 4, or 5, in particular 1, 2, or 3. As used herein, the term “one or more”, e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means 1, 2, 3, 4, or 5, particularly 1, 2, 3, or 4, more particularly 1, 2, or 3, even more particularly 1 or 2. As used herein, an oxo substituent represents an oxygen atom, which is bound to a carbon atom via a double bond. Should a composite substituent be composed of more than one parts, e.g. (C1-C4-alkoxy)-(C1-C4-alkyl)-, it is possible for the position of a given part to be at any suitable position of said composite substituent, i.e. the C1-C4-alkoxy part can be attached to any carbon atom of the C1-C4-alkyl part of said (C1-C4-alkoxy)-(C1-C4-alkyl)- group. A hyphen at the beginning or at the end of such a composite substituent indicates the point of attachment of said composite substituent to the rest of the molecule. Should a ring, comprising carbon atoms and optionally one or more heteroatoms, such as nitrogen, oxygen or sulphur atoms for example, be substituted with a substituent, it is possible for said substituent to be bound at any suitable position of said ring, be it bound to a suitable carbon atom and/or to a suitable heteroatom. The term “comprising” when used in the specification includes “consisting of”. If within the present text any item is referred to as “as mentioned herein”, it means that it may be mentioned anywhere in the present text. The terms as mentioned in the present text have the following meanings: The term “halogen atom” means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom. The term C1-C4-alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, or 4 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, tert-butyl. Particularly, said group has 1, 2, or 3 carbon atoms (“C1-C3-alkyl”), e.g. a methyl, ethyl, propyl, or isopropyl group, more particularly 1 or 2 carbon atoms (“C1-C2-alkyl”), e.g. a methyl or ethyl group. The term “C2-C4-hydroxyalkyl” means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C2-C4-alkyl” is defined supra, and in which one hydrogen atom is replaced with a hydroxy group, e.g. a 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1-hydroxy-2-methyl-propyl group. The term “C1-C4-haloalkyl” means a linear or branched, saturated, monovalent hydrocarbon group in which the term “C1-C4-alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. Said C1-C4-haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoropropan-2-yl. The term “C1-C4-alkoxy” means a linear or branched, saturated, monovalent group of formula (C1-C4-alkyl)-O-, in which the term “C1-C4-alkyl” is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or tert-butoxy group. The term “C1-C4-haloalkoxy” means a linear or branched, saturated, monovalent C1-C4-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. Said C1-C4-haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy. The term “C3-C6-cycloalkyl” means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5, or 6 carbon atoms (“C3-C6-cycloalkyl”). Said C3-C6-cycloalkyl group is for example, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. The term “C3-C6-halocycloalkyl” means a saturated, monovalent, monocyclic hydrocarbon ring in which the term “C3-C6-halocycloalkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. The term 4- to 6-membered heterocycloalkyl means a monocyclic, saturated heterocycle with 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S, it being possible for said heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom. Said heterocycloalkyl group, without being limited thereto, can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxidothiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl or 1,3-thiazolidinyl, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl or 1,2-oxazinanyl, for example. Particularly, “4- to 6-membered heterocycloalkyl” means a 4- to 6-membered heterocycloalkyl as defined supra containing one ring nitrogen or oxygen atom and optionally one further ring heteroatom from the series: N, O, S. More particularly, “5- or 6-membered heterocycloalkyl” means a monocyclic, saturated heterocycle with 5 or 6 ring atoms in total, containing one ring nitrogen or oxygen atom and optionally one further ring heteroatom from the series: N, O. The term “heterocycloalkyl fused with phenyl or heteroaryl” means a bicyclic heterocycle with 8, 9 or 10 ring atoms in total, in which the two rings share two adjacent ring atoms, and in which the “heterocycloalkyl” part contains one or two identical or different ring heteroatoms from the series: N, O and/or S, and the term “heteroaryl” means a monocyclic aromatic ring having 5 or 6 ring atoms (a “5- to 6-membered heteroaryl” group), which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series N, O and/or S; it being possible for said fused heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom. The term “heterospirocycloalkyl” means a bicyclic, saturated heterocycle with 6, 7, 8, 9, 10 or 11 ring atoms in total, in which the two rings share one common ring carbon atom, which “heterospirocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterospirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom. Said heterospirocycloalkyl group is, for example, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxaazaspiro[3.3]heptyl, thiaazaspiro[3.3]heptyl, oxaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, azaspiro[4,5]decyl, oxazaspiro [5.5]undecyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, azaspiro[5.5]undecyl, or one of the further homologous scaffolds such as spiro[3.4]-, spiro[4.4]-, spiro[2.4]-, spiro[2.5]-, spiro[2.6]-, spiro[3.5]-, spiro[3.6]-, spiro[4.5]- and spiro[4.6]-. The term “heteroaryl” means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 8, 9, or 10 ring atoms (a “5- to 10-membered heteroaryl” group), particularly 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency). Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, such as, for example, carbazolyl, acridinyl or phenazinyl; or a 9- membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolizinyl or purinyl; or a 10-membered heteroaryl group, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl or pteridinyl. In general, and unless otherwise mentioned, the heteroaryl groups include all possible isomeric forms thereof, e.g.: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule. Thus, for some illustrative non-restricting examples, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl. Particularly, the heteroaryl group is a pyridinyl group. The term “C1-C6”, as used in the present text, e.g. in the context of the definition of “C1-C6-alkyl”, “C1-C6-haloalkyl”, “C1-C6-hydroxyalkyl”, “C1-C6-alkoxy” or “C1-C6-haloalkoxy” means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e.1, 2, 3, 4, 5 or 6 carbon atoms. Further, as used herein, the term “C3-C8”, as used in the present text, e.g. in the context of the definition of “C3-C8-cycloalkyl”, means a cycloalkyl group having a finite number of carbon atoms of 3 to 8, i.e.3, 4, 5, 6, 7 or 8 carbon atoms. When a range of values is given, said range encompasses each value and sub-range within said range. For example: "C1-C6" encompasses C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2- C5, C2-C4, C2-C3, C3-C6, C3-C5, C3- C4, C4-C6, C4-C5, and C5-C6; " C2-C6" encompasses C2, C3, C4, C5, C6, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6; "C3-C10" encompasses C3, C4, C5, C6, C7, C8, C9, C10, C3- C10, C3-C9, C3-C8, C3- C7, C3-C6, C3-C5, C3-C4, C4-C10, C4-C9, C4-C8, C4-C7, C4-C6, C4-C5, C5-C10, C5- C9, C5-C8, C5-C7, C5-C6, C6-C10, C6-C9, C6- C8, C6-C7, C7-C10, C7-C9, C7-C8, C8-C10, C8-C9 and C9-C10; "C3-C8" encompasses C3, C4, C5, C6, C7, C8, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C8, C4- C7, C4-C6, C4-C5, C5-C8, C5-C7, C5-C6, C6-C8, C6-C7 and C7-C8; "C3-C6" encompasses C3, C4, C5, C6, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6; "C4-C8" encompasses C4, C5, C6, C7, C8, C4-C8, C4-C7, C4-C6, C4-C5, C5-C8, C5-C7, C5-C6, C6-C8, C6-C7 and C7-C8; "C4-C7" encompasses C4, C5, C6, C7, C4-C7, C4-C6, C4-C5, C5-C7, C5-C6 and C6-C7; "C4-C6" encompasses C4, C5, C6, C4-C6, C4-C5 and C5-C6; "C5-C10" encompasses C5, C6, C7, C8, C9, C10, C5-C10, C5-C9, C5-C8, C5-C7, C5-C6, C6-C10, C6-C9, C6-C8, C6-C7, C7-C10, C7-C9, C7-C8, C8-C10, C8-C9 and C9-C10; "C6-C10" encompasses C6, C7, C8, C9, C10, C6-C10, C6-C9, C6-C8, C6-C7, C7-C10, C7-C9, C7- C8, C8-C10, C8-C9 and C9-C10. As used herein, the term “leaving group” means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons. In particular, such a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy and [(4-methoxyphenyl)sulfonyl]oxy. It is possible for the compounds of general formula (I) to exist as isotopic variants. The invention therefore includes the use of one or more isotopic variant(s) of the compounds of general formula (I), particularly deuterium-containing compounds of general formula (I). The term “Isotopic variant” of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound. The term “Isotopic variant of the compound of general formula (I)” is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound. The expression “unnatural proportion” means a proportion of such isotope which is higher than its natural abundance. The natural abundances of isotopes to be applied in this context are described in “Isotopic Compositions of the Elements 1997”, Pure Appl. Chem., 70(1), 217-235, 1998. Examples of such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), 3H (tritium), 11C, 13C, 14C, 15N, 17O, 18O, 32P, 33P, 33S, 34S, 35S, 36S, 18F, 36Cl, 82Br, 123I, 124I, 125I, 129I and 131I, respectively. With respect to the treatment and/or prophylaxis of the disorders specified herein the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium (“deuterium-containing compounds of general formula (I)”). Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as 3H or 14C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability. Positron emitting isotopes such as 18F or 11C may be incorporated into a compound of general formula (I). These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications. Deuterium-containing and 13C- containing compounds of general formula (I) can be used in mass spectrometry analyses in the context of preclinical or clinical studies. Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent. Depending on the desired sites of deuteration, in some cases deuterium from D2O can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds. Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic bonds and acetylenic bonds is a rapid route for incorporation of deuterium. Metal catalysts (i.e. Pd, Pt, and Rh) in the presence of deuterium gas can be used to directly exchange deuterium for hydrogen in functional groups containing hydrocarbons. A variety of deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA. The term “deuterium-containing compound of general formula (I)” is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than the natural abundance of deuterium, which is about 0.015%. Particularly, in a deuterium-containing compound of general formula (I) the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s). The selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271]) and/or the metabolic profile of the molecule and may result in changes in the ratio of parent compound to metabolites or in the amounts of metabolites formed. Such changes may result in certain therapeutic advantages and hence may be preferred in some circumstances. Reduced rates of metabolism and metabolic switching, where the ratio of metabolites is changed, have been reported (A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in the exposure to parent drug and metabolites can have important consequences with respect to the pharmacodynamics, tolerability and efficacy of a deuterium-containing compound of general formula (I). In some cases, deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). In other cases, the major effect of deuteration is to reduce the rate of systemic clearance. As a result, the biological half-life of the compound is increased. The potential clinical benefits would include the ability to maintain similar systemic exposure with decreased peak levels and increased trough levels. This could result in lower side effects and enhanced efficacy, depending on the particular compound’s pharmacokinetic/ pharmacodynamic relationship. ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208) and Odanacatib (K. Kassahun et al., WO2012/112363) are examples for this deuterium effect. Still other cases have been reported in which reduced rates of metabolism result in an increase in exposure of the drug without changing the rate of systemic clearance (e.g. Rofecoxib: F. Schneider et al., Arzneim. Forsch. / Drug. Res., 2006, 56, 295; Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993). Deuterated drugs showing this effect may have reduced dosing requirements (e.g. lower number of doses or lower dosage to achieve the desired effect) and/or may produce lower metabolite loads. A compound of general formula (I) may have multiple potential sites of attack for metabolism. To optimize the above-described effects on physicochemical properties and metabolic profile, deuterium-containing compounds of general formula (I) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected. Particularly, the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P450. Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like. By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The compounds intended for the use according to the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds. Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art. Preferred isomers are those which produce the more desirable biological activity. These separated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials. In order to distinguish different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976). The compounds intended for the use according to the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)- isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as hromatography, especially chiral chromatography, for example. Further, it is possible for the compounds to exist as tautomers. For example, any compound of the present invention which contains an indazole moiety can exist as a 1H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, namely:
Figure imgf000016_0001
1H tautomer 2H tautomer
The compounds intended for the use according to the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
Further, the compounds intended for the use according to the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides.
The present invention also covers the use of useful forms of the compounds, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co-precipitates.
The compounds intended for the use according to the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.
Further, it is possible for the compounds intended for the use according to the present invention to exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
The term “pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.
A suitable pharmaceutically acceptable salt of the compounds intended for the use according tothe present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or “mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, 3-phenylpropionic, pivalic, 2-hydroxyethanesulfonic, itaconic, trifluoromethanesulfonic, dodecylsulfuric, ethanesulfonic, benzenesulfonic, para- toluenesulfonic, methanesulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, or thiocyanic acid, for example. Further, another suitably pharmaceutically acceptable salt of a compound intended for the use according tothe present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt, or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, 1,2-ethylenediamine, N-methylpiperidine, N-methyl-glucamine, N,N- dimethyl-glucamine, N-ethyl-glucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or a salt with a quarternary ammonium ion having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n- butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline or benzalkonium. Those skilled in the art will further recognise that it is possible for acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods. The present invention includes the use of all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio. For the synthesis of intermediates and of examples of the compounds intended for the use according to the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown. Unless specified otherwise, suffixes to chemical names or structural formulae relating to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCl", "x CF3COOH", "x Na+", for example, mean a salt form, the stoichiometry of which salt form not being specified. This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates, with (if defined) unknown stoichiometric composition. Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds intended for the use according to the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio. Moreover, the compounds intended for the use according to the present invention also include prodrugs of the compounds. The term “prodrugs” here designates compounds which themselves can be biologically active or inactive but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body. In accordance with a second embodiment of the first aspect, the present invention covers the use of compounds of general formula (I), supra, in which: R1 represents hydrogen, C1-C4-alkyl or C1-C4-haloalkyl; R2 represents hydrogen, C1-C4-alkyl or C1-C4-haloalkyl; or R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring; R3 represents C3-C6-cycloalkyl, 3- to 6-membered heterocycloalkyl, heterocycloalkyl fused with phenyl or heteroaryl, or heteroaryl, wherein said groups are optionally substituted, one or more times, independently of each other, with R8, or R3 represents phenyl, which is optionally substituted, one or more times, independently of each other, with R8, and additionally R7a and R7b represent deuterium; R4 represents hydrogen, C1-C4-alkyl, C1-C4-haloalkyl or C3-C6-cycloalkyl; R5, R6 represent, independently of each other, hydrogen, C1-C4-alkyl, C2-C4- hydroxyalkyl, (C1-C4-alkoxy)-(C2-C4-alkyl)-, C3-C6-cycloalkyl, C1-C4-haloalkyl, C3-C6-halocycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, heteroaryl, heterocycloalkyl fused with phenyl or heteroaryl, 3- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-, (heterocycloalkyl fused with phenyl or heteroaryl)-(C1-C3-alkyl)-, phenyl-(C1-C3-alkyl)- or heteroaryl-(C1-C3-alkyl)-, wherein said 3- to 6-membered heterocycloalkyl, phenyl or heteroaryl group is optionally substituted, one or more times, independently of each other, with R9, or R5 and R6 together with the nitrogen atom to which they are attached form a 3- to 6-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom or heteroatom containing group selected from O, NH and S, and which may be optionally substituted, one or more times, independently of each other, with R9; R7a represents hydrogen, deuterium, or C1-C4-alkyl; R7b represents hydrogen, deuterium, or C1-C4-alkyl; R8 represents halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C3-C6-cycloalkyl, C1-C4-alkyl-(C=O)-, R10-O-(C=O)-, R11-NH-(C=O)-, or R12-(SO2)-; R9 represents halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, H2N-C1-C4-alkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C3-C6-cycloalkyl, R10-O-(C=O)-, oxo, 5- to 6- membered heterocycloalkyl-, 5- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-, phenyl, or heteroaryl, wherein said phenyl or heteroaryl group is optionally substituted, one or more times, independently of each other, with halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, or C1-C3-haloalkoxy; R10 represents hydrogen, C1-C4-alkyl, or phenyl-CH2-; R11 represents hydrogen, C1-C4-alkyl, or 5- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-; R represents C1-C4-alkyl or phenyl; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, for the treatment or prophylaxis of diseases. In accordance with a third embodiment of the first aspect, the present invention covers the use of compounds of general formula (I), supra, in which: R1 represents hydrogen, C1-C4-alkyl or C1-C4-haloalkyl; R2 represents hydrogen or C1-C4-alkyl; or R1 and R2 together with the carbon atom to which they are attached form a 3- to 4-membered cycloalkyl or heterocycloalkyl ring; R3 represents C3-C6-cycloalkyl, 4- to 6-membered heterocycloalkyl, heterocycloalkyl fused with heteroaryl, or heteroaryl, wherein said groups are optionally substituted, one or more times, independently of each other, with R8, or R3 represents phenyl, which is optionally substituted, one or more times, independently of each other, with R8, and additionally R7a and R7b represent deuterium; R4 represents hydrogen, C1-C4-alkyl, C1-C4-haloalkyl or C3-C6-cycloalkyl; R5, R6 represent, independently of each other, hydrogen, C2-C4-hydroxyalkyl, (C1-C4-alkoxy)-(C2-C4-alkyl)-, 3- to 6-membered heterocycloalkyl, heterospirocycloalkyl, phenyl, heteroaryl, 4- to 6-membered heterocycloalkyl- (C1-C3-alkyl)-, heterospirocycloalkyl-(C1-C3-alkyl)-, (heterocycloalkyl fused with heteroaryl)-(C1-C3-alkyl)-, or heteroaryl-(C1-C3-alkyl)-, wherein said 3- to 6- membered heterocycloalkyl, phenyl or heteroaryl groups are optionally substituted, one or more times, independently of each other, with R9, or R5 and R6 together with the nitrogen atom to which they are attached form a 5-membered nitrogen containing heterocyclic ring, which may be optionally substituted, once with R9; R7a represents hydrogen, deuterium, or methyl; R7b represents hydrogen, deuterium, or methyl; R8 represents halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, C3-C6-cycloalkyl, C3-C6-cycloalkyl-(C1-C3-alkyl)-, R13-(C=O)-, R10-O-(C=O)-, R11-NH-(C=O)-, or R12-(SO2)-; R9 represents halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, H2N-C1-C4-alkyl, C3-C6-cycloalkyl, R10-O-(C=O)-, oxo, 6-membered heterocycloalkyl- (C1-C3-alkyl)-, phenyl, or heteroaryl, wherein said phenyl or heteroaryl group is optionally substituted, one or more times, independently of each other, with halogen, C1-C4-haloalkyl, or C1-C3-alkoxy; R10 represents hydrogen, C1-C4-alkyl, or phenyl-CH2-; R11 represents 5- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-; R12 represents C1-C4-alkyl; R13 represents C1-C4-alkyl, (C1-C4-alkoxy)-(C1-C4-alkyl)-, C1-C4-alkyl-(C=O)-, C3-C6-cycloalkyl, or phenyl, wherein said C3-C6-cycloalkyl group is optionally substituted with methyl or hydroxy; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, for the treatment or prophylaxis of diseases. In accordance with a fourth embodiment of the first aspect, the present invention covers the use of compounds of general formula (I), supra, in which: R1 represents hydrogen, methyl or trifluoromethyl; R2 represents hydrogen or methyl; or R1 and R2 together with the carbon atom to which they are attached form a 3- to 4-membered cycloalkyl ring; R3 represents cyclopropyl, 4- to 6-membered heterocycloalkyl, 2,3- dihydro[1,4]dioxino[2,3-b]pyridin-2-yl, or heteroaryl, wherein said groups are optionally substituted, one or more times, independently of each other, with R8, or R3 represents phenyl, which is optionally substituted, one or more times, independently of each other, with R8, and additionally R7a and R7b represent deuterium; R4 represents hydrogen, methyl, C1-haloalkyl or cyclopropyl; R5 represents hydrogen; R6 represents methoxy-ethyl, 5-membered heteroaryl, 4- to 6-membered heterocycloalkyl-( C1-C2-alkyl)-, heterospirocycloalkyl-methyl, 2,3- dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl, or 5- to 6-membered heteroaryl-(C1- C2-alkyl)-, wherein said 4- to 6-membered heterocycloalkyl or heteroaryl groups are optionally substituted, one or more times, independently of each other, with R9; R7a represents hydrogen, deuterium, or methyl; R7b represents hydrogen, deuterium, or methyl; R8 represents fluoro, chloro, C1-C2-alkyl, trifluoromethyl, C1-C3-alkoxy, cyclopropyl, cyclopropylmethyl, R13-(C=O)-, R10-O-(C=O)-, R11-NH-(C=O)-, or R12-(SO2)-; R9 represents fluoro, chloro, C1-C3-alkyl, trifluoromethyl, cyclopropyl, or oxo; R10 represents C1-C4-alkyl, or phenyl-CH2-; R11 represents 5- to 6-membered heterocycloalkyl-methyl; R12 represents methyl; R13 represents methyl, methoxymethyl, ethyl-(C=O)-, cyclopropyl, or phenyl, wherein said cyclopropyl group is optionally substituted with methyl or hydroxy; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, for the treatment or prophylaxis of diseases. In accordance with a fifth embodiment of the first aspect, the present invention covers the use of compounds of general formula (I), supra, in which: R1 represents hydrogen or methyl; R2 represents hydrogen or methyl; or R1 and R2 together with the carbon atom to which they are attached form a 3- to 4-membered cycloalkyl ring; R3 represents cyclopropyl, 2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-yl, oxetan-3-yl, oxolan-3-yl, oxolan-2-yl, 3-methyloxetan-3-yl, 3-fluorooxetan-3-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, oxan-4-yl, 1,4-dioxan-2-yl, 6-methylpyridin-3-yl, 5- methylpyridin-2-yl, 3-methylpyridin-2-yl, 2-methylpyridin-4-yl, 6-methylpyridin-2- yl, 3-chloropyridin-2-yl, 6-ethylpyridin-3-yl, 1 -acetylpiperidin-4-yl, 3-chloro-5- ethoxypyridin-2-yl, 1 -benzoylpiperidin-4-yl, or a group selected from:
5
Figure imgf000023_0001
R3 represents phenyl, and additionally R7a and R7b represent deuterium;
R4 represents methyl, difluoromethyl, trifluoromethyl, or cyclopropyl; R5 represents hydrogen; R6 represents (oxolan-2-yl)methyl, (1,3-oxazol-4-yl)methyl, (1,2-oxazol-3-yl)methyl, (4-methyloxolan-2-yl)methyl, (pyrimidin-2-yl)methyl, (pyrazin-2-yl)methyl, (5- methyloxolan-2-yl)methyl, (5-methyloxolan-2-yl)methyl, (1,4-dioxan-2-yl)methyl, (4-methylphenyl)methyl, (5-methylpyrimidin-2-yl)methyl, (5-methylpyrazin-2- yl)methyl, (5-chloropyrazin-2-yl)methyl, (5-cyclopropyl-pyrazin-2-yl)methyl, 2,3- dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl, 1,3-oxazol-2-ylmethyl, 1,3-thiazol-2- ylmethyl, (1-methyl-1H-pyrazol-3-yl)methyl, (1-methyl-1H-imidazol-4-yl)methyl, (5-isopropyl-1,2-oxazol-3-yl)methyl, (5-cyclopropyl-1,2-oxazol-3-yl)methyl, (5,5- dimethyltetrahydrofuran-2-yl)methyl, (4,4-difluorotetrahydrofuran-2-yl)methyl, (6,6-dimethyl-1,4-dioxan-2-yl)methyl, 5-oxaspiro[2.4]heptan-6-ylmethyl, or 2,6- dioxaspiro[3.4]octan-7-ylmethyl; R7a represents hydrogen; R7b represents hydrogen; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, for the treatment or prophylaxis of diseases. More particularly the invention refers to the use of one of the following compounds: 1 2-(pyridin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 2 8-methyl-N-[(4-methylphenyl)methyl]-2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 3 8-methyl-2-(pyridin-2-ylmethyl)-N-[(2R/S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 3 8-methyl-2-(pyridin-2-ylmethyl)-N-[(2R)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 3 8-methyl-2-(pyridin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 4 8-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-2-(pyridin-2-ylmethyl)-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 5 8-methyl-N-[(1,2,4-oxadiazol-3-yl)methyl]-2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 6 8-methyl-N-(1,2-oxazol-3-ylmethyl)-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 7 N-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]-8-methyl-2-(pyridin-2-ylmethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8 8-methyl-N-[(5-methyl-1,2-oxazol-3-yl)methyl]-2-(pyridin-2-ylmethyl)-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 9 N-[(2R/S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-2-(pyridin-2- ylmethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 9 N-[(2R)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-2-(pyridin-2- ylmethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 9 N-[(2S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-2-(pyridin-2- ylmethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 10 N-(2-hydroxy-2-methylpropyl)-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 11 8-methyl-N-{[5-(morpholin-4-ylmethyl)-1,2-oxazol-3-yl]methyl}-2-(pyridin-2- ylmethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 12 8-methyl-2-(pyridin-2-ylmethyl)-N-(2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin- 1-yl}ethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 13 8-methyl-2-(pyridin-2-ylmethyl)-N-(2-{4-[3-(trifluoromethyl)phenyl]piperazin-1- yl}ethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 14 N-{[5-(3-methoxyphenyl)-1,2-oxazol-3-yl]methyl}-8-methyl-2-(pyridin-2-ylmethyl)- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 15 8-methyl-N-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-2-(pyridin-2-ylmethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 16 N-[(5-cyclopropyl-1,2-oxazol-4-yl)methyl]-8-methyl-2-(pyridin-2-ylmethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 17 N-{[5-(2-chlorophenyl)-1,2-oxazol-3-yl]methyl}-8-methyl-2-(pyridin-2-ylmethyl)- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 18 N-[(5-isopropyl-1,2-oxazol-3-yl)methyl]-8-methyl-2-(pyridin-2-ylmethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 19 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 19 N-{[(2S)-1,4-dioxan-2-yl]methyl}-8-methyl-2-[(pyridin-2-yl)methyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 20 8-methyl-2-(pyridin-2-ylmethyl)-N-(4H-1,2,4-triazol-3-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 21 8-methyl-N,2-bis(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide 22 8-methyl-N-(1H-pyrazol-3-ylmethyl)-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 23 8-methyl-2-(pyridin-2-ylmethyl)-N-(1,3-thiazol-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 24 8-methyl-N-(1,2-oxazol-4-ylmethyl)-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 25 8-methyl-2-(pyridin-2-ylmethyl)-N-{[5-(trifluoromethyl)-1,2-oxazol-3-yl]methyl}- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 26 8-methyl-N-[(4-methyl-1,2-oxazol-3-yl)methyl]-2-(pyridin-2-ylmethyl)-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 27 N-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-8-methyl-2-(pyridin-2-ylmethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 28 N-[2-(3,3-dimethyl-2-oxoazetidin-1-yl)ethyl]-8-methyl-2-(pyridin-2-ylmethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 29 N-(2-methoxyethyl)-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 30 [(2R/S)-2-(aminomethyl)pyrrolidin-1-yl][8-methyl-2-(pyridin-2-ylmethyl)-4,5- dihydro-2H-furo[2,3-g]indazol-7-yl]methanone 30 [(2R)-2-(aminomethyl)pyrrolidin-1-yl][8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro- 2H-furo[2,3-g]indazol-7-yl]methanone 30 [(2S)-2-(aminomethyl)pyrrolidin-1-yl][8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro- 2H-furo[2,3-g]indazol-7-yl]methanone 31 3-[({[8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3-g]indazol-7- yl]carbonyl}amino)methyl]-1,2-oxazole-4-carboxylic acid 32 8-methyl-N-(1,3-oxazol-2-ylmethyl)-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 33 8-methyl-2-(pyridin-2-ylmethyl)-N-[(3S)-tetrahydrofuran-3-ylmethyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 33 8-methyl-2-(pyridin-2-ylmethyl)-N-[(3R)-tetrahydrofuran-3-ylmethyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 34 8-methyl-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-2-(pyridin-2-ylmethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 35 8-methyl-N-[(2R/S)-oxetan-2-ylmethyl]-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 35 8-methyl-N-[(2R)-oxetan-2-ylmethyl]-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 35 8-methyl-N-[(2S)-oxetan-2-ylmethyl]-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 36 8-methyl-N-(oxetan-3-ylmethyl)-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 37 N-[(3-fluorooxetan-3-yl)methyl]-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 38 8-methyl-N-{[(2R/S)-4-methylmorpholin-2-yl]methyl}-2-(pyridin-2-ylmethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 38 8-methyl-N-{[(2R)-4-methylmorpholin-2-yl]methyl}-2-(pyridin-2-ylmethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 38 8-methyl-N-{[(2S)-4-methylmorpholin-2-yl]methyl}-2-(pyridin-2-ylmethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 39 8-methyl-N-{[(2R/S)-5-oxotetrahydrofuran-2-yl]methyl}-2-(pyridin-2-ylmethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 39 8-methyl-N-{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-2-(pyridin-2-ylmethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 39 8-methyl-N-{[(2S)-5-oxotetrahydrofuran-2-yl]methyl}-2-(pyridin-2-ylmethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 40 8-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 41 8-methyl-N-(pyridin-3-yl)-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 42 8-methyl-N-(2-phenylethyl)-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 43 N-(4-cyanophenyl)-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 44 8-methyl-2-(pyridin-3-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 45 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-(pyridin-3-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 46 8-methyl-2-(pyridin-4-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 47 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-(pyridin-4-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 48 2-(cyclopropylmethyl)-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 49 2-(cyclopropylmethyl)-N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 50 N-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]-2-[(2R/S)-2,3-dihydro[1,4]dioxino[2,3- b]pyridin-2-ylmethyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 50 N-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]-2-[(2R)-2,3-dihydro[1,4]dioxino[2,3- b]pyridin-2-ylmethyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 50 N-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]-2-[(2S)-2,3-dihydro[1,4]dioxino[2,3- b]pyridin-2-ylmethyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 51 2-[(2R/S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-[(2R/S)- tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 51 2-[(2R)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-[(2R/S)- tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 51 2-[(2S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-[(2R/S)- tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 52 2-[(2R/S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-[(2S)- tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 52 2-[(2R)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-[(2S)- tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 52 2-[(2S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-[(2S)- tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 53 2-[(2R/S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-(4- methylbenzyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 53 2-[(2R)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-(4- methylbenzyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 53 2-[(2S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-(4- methylbenzyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 54 2-[(2R/S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-[2-(4- methylpiperazin-1-yl)ethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 54 2-[(2R)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-[2-(4- methylpiperazin-1-yl)ethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 54 2-[(2S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-[2-(4- methylpiperazin-1-yl)ethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 55 2-[(2R/S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-(1,2- oxazol-3-ylmethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 55 2-[(2R)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-(1,2-oxazol- 3-ylmethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 55 2-[(2S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-(1,2-oxazol- 3-ylmethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 56 8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2-{[6-(trifluoromethyl)pyridin-2- yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 57 8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2-{[5-(trifluoromethyl)pyridin-2- yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 58 2-[(3-chloro-5-fluoropyridin-2-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran-2- ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 59 2-[(3-chloro-5-ethoxypyridin-2-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran-2- ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 60 2-[(3-chloropyridin-2-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 61 2-[(3-chloropyridin-2-yl)methyl]-N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 62 8-methyl-2-[(3-methylpyridin-2-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 63 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(3-methylpyridin-2-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 64 8-methyl-2-[(5-methylpyridin-2-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 65 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(5-methylpyridin-2-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 66 8-methyl-2-[(6-methylpyridin-2-yl)methyl]-N-[(2R/S)-tetrahydrofuran-2-ylmethyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 66 8-methyl-2-[(6-methylpyridin-2-yl)methyl]-N-[(2R)-tetrahydrofuran-2-ylmethyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 66 8-methyl-2-[(6-methylpyridin-2-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 67 N-[2-(azetidin-1-yl)ethyl]-8-methyl-2-[(6-methylpyridin-2-yl)methyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 68 N-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]-8-methyl-2-[(6-methylpyridin-2- yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 69 8-methyl-2-[(6-methylpyridin-2-yl)methyl]-N-[2-(pyrrolidin-1-yl)ethyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 70 N-[(2R/S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-2-[(6- methylpyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 70 N-[(2R)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-2-[(6- methylpyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 70 N-[(2S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-2-[(6- methylpyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 71 8-methyl-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-2-[(6-methylpyridin-2-yl)methyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 72 8-methyl-2-[(6-methylpyridin-2-yl)methyl]-N-(1,3-oxazol-2-ylmethyl)-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 73 8-methyl-2-[(2-methylpyridin-3-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 74 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(2-methylpyridin-3-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 75 8-methyl-2-[(6-methylpyridin-3-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 76 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(6-methylpyridin-3-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 77 2-[(2,6-dimethylpyridin-3-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran-2- ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 78 2-[(2,6-dimethylpyridin-3-yl)methyl]-N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 79 8-methyl-2-[(2-methylpyridin-4-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 80 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(2-methylpyridin-4-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 81 2-[(2,6-dimethylpyridin-4-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran-2- ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 82 2-[(2,6-dimethylpyridin-4-yl)methyl]-N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 83 8-methyl-2-(pyrimidin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 84 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-(pyrimidin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 85 8-methyl-2-(pyrimidin-5-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 86 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-(pyrimidin-5-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 87 2-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 88 N,2-bis[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole- 7-carboxamide 89 2-[(2S)-1,4-dioxan-2-ylmethyl]-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 90 N-[(2R)-1,4-dioxan-2-ylmethyl]-2-[(2S)-1,4-dioxan-2-ylmethyl]-8-methyl-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 91 8-methyl-2-(oxetan-3-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 92 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-(oxetan-3-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 93 8-methyl-2-[(3-methyloxetan-3-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 94 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(3-methyloxetan-3-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 95 2-[(3-fluorooxetan-3-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 96 N-[(2R)-1,4-dioxan-2-ylmethyl]-2-[(3-fluorooxetan-3-yl)methyl]-8-methyl-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 97 8-methyl-2-[(2R)-oxetan-2-ylmethyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 98 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(2R)-oxetan-2-ylmethyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 99 8-methyl-2-[(2S)-oxetan-2-ylmethyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 100 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(2S)-oxetan-2-ylmethyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 101 8-methyl-2-{[(2R)-4-methylmorpholin-2-yl]methyl}-N-[(2S)-tetrahydrofuran-2- ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 102 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-{[(2R)-4-methylmorpholin-2- yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 103 8-methyl-2-{[(2S)-4-methylmorpholin-2-yl]methyl}-N-[(2S)-tetrahydrofuran-2- ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 104 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-{[(2S)-4-methylmorpholin-2- yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 105 8-methyl-2-[(2R)-tetrahydrofuran-2-ylmethyl]-N-[(2S)-tetrahydrofuran-2- ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 106 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(2R)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 107 8-methyl-N,2-bis[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 108 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 109 tert-butyl 3-[(8-methyl-7-{[(2S)-tetrahydrofuran-2-ylmethyl]carbamoyl}-4,5- dihydro-2H-furo[2,3-g]indazol-2-yl)methyl]azetidine-1-carboxylate 110 tert-butyl 3-[(7-{[(2R)-1,4-dioxan-2-ylmethyl]carbamoyl}-8-methyl-4,5-dihydro-2H- furo[2,3-g]indazol-2-yl)methyl]azetidine-1-carboxylate 111 8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2-[(3R)-tetrahydrofuran-3- ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 112 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(3R)-tetrahydrofuran-3-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 113 8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2-[(3S)-tetrahydrofuran-3-ylmethyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 114 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(3S)-tetrahydrofuran-3-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 115 2-(pyridin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-8-(trifluoromethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 116 N-[(2R)-1,4-dioxan-2-ylmethyl]-2-(pyridin-2-ylmethyl)-8-(trifluoromethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 117 N-[(1-methyl-1H-pyrazol-3-yl)methyl]-2-(pyridin-2-ylmethyl)-8-(trifluoromethyl)- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 118 N-(1,3-oxazol-2-ylmethyl)-2-(pyridin-2-ylmethyl)-8-(trifluoromethyl)-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 119 8-cyclopropyl-2-(pyridin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 120 8-cyclopropyl-N-[(2R)-1,4-dioxan-2-ylmethyl]-2-(pyridin-2-ylmethyl)-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 121 8-cyclopropyl-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-2-(pyridin-2-ylmethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 122 8-cyclopropyl-N-(1,3-oxazol-2-ylmethyl)-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 123 8'-methyl-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-2'-(pyridin-2-ylmethyl)-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 124 8'-methyl-N-(1,3-oxazol-2-ylmethyl)-2'-(pyridin-2-ylmethyl)-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 125 2'-[(2S)-1,4-dioxan-2-ylmethyl]-8'-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]- 2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 126 N-[(2R)-1,4-dioxan-2-ylmethyl]-2'-[(2S)-1,4-dioxan-2-ylmethyl]-8'-methyl-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 127 2'-[(2S)-1,4-dioxan-2-ylmethyl]-8'-methyl-N-[(1-methyl-1H-pyrazol-3-yl)methyl]- 2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 128 2'-[(2S)-1,4-dioxan-2-ylmethyl]-8'-methyl-N-(1,3-oxazol-2-ylmethyl)-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 129 2'-(cyclopropylmethyl)-8'-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 130 2'-(cyclopropylmethyl)-N-[(2S)-1,4-dioxan-2-ylmethyl]-8'-methyl-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 131 2'-(cyclopropylmethyl)-N-[(2R)-1,4-dioxan-2-ylmethyl]-8'-methyl-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 132 8'-methyl-2'-(pyridin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2',5'- dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 133 N-[(2S)-1,4-dioxan-2-ylmethyl]-8'-methyl-2'-(pyridin-2-ylmethyl)-2',5'- dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 134 N-[(2R)-1,4-dioxan-2-ylmethyl]-8'-methyl-2'-(pyridin-2-ylmethyl)-2',5'- dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 135 8-methyl-2-[phenyl(2H2)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 136 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[phenyl(2H2)methyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 137 2-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran- 2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 138 2-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]-N-[(2R)-1,4-dioxan-2-ylmethyl]-8- methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 139 tert-butyl [2-(8-methyl-7-{[(2S)-tetrahydrofuran-2-ylmethyl]carbamoyl}-4,5- dihydro-2H-furo[2,3-g]indazol-2-yl)ethyl]carbamate 140 tert-butyl [2-(7-{[(2R)-1,4-dioxan-2-ylmethyl]carbamoyl}-8-methyl-4,5-dihydro-2H- furo[2,3-g]indazol-2-yl)ethyl]carbamate 141 tert-butyl 4-[2-(8-methyl-7-{[(2S)-tetrahydrofuran-2-ylmethyl]carbamoyl}-4,5- dihydro-2H-furo[2,3-g]indazol-2-yl)ethyl]piperazine-1-carboxylate 142 tert-butyl 4-[2-(7-{[(2R)-1,4-dioxan-2-ylmethyl]carbamoyl}-8-methyl-4,5-dihydro- 2H-furo[2,3-g]indazol-2-yl)ethyl]piperazine-1-carboxylate 143 2'-[(2S)-1,4-dioxan-2-ylmethyl]-8'-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]- 2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 144 N,2'-bis[(2S)-1,4-dioxan-2-ylmethyl]-8'-methyl-2',5'-dihydrospiro[cyclobutane- 1,4'-furo[2,3-g]indazole]-7'-carboxamide 145 N-[(2R)-1,4-dioxan-2-ylmethyl]-2'-[(2S)-1,4-dioxan-2-ylmethyl]-8'-methyl-2',5'- dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 146 8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2-[(6-{[(2S)-tetrahydrofuran-2- ylmethyl]carbamoyl}pyridin-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide 147 N-[(2R)-1,4-dioxan-2-ylmethyl]-2-[(6-{[(2R)-1,4-dioxan-2- ylmethyl]carbamoyl}pyridin-3-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 148 4,4,8-trimethyl-2-(pyridin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 149 8'-methyl-2'-(pyridin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 150 N-[(2R)-1,4-dioxan-2-ylmethyl]-8'-methyl-2'-(pyridin-2-ylmethyl)-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 151 8'-methyl-2'-(pyridin-3-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 152 N-[(2R)-1,4-dioxan-2-ylmethyl]-8'-methyl-2'-(pyridin-3-ylmethyl)-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 153 N2',N2',8'-trimethyl-N7'-[(2S)-tetrahydrofuran-2-ylmethyl]spiro[cyclopropane-1,4'- furo[2,3-g]indazole]-2',7'(5'H)-dicarboxamide 154 N7'-[(2R)-1,4-dioxan-2-ylmethyl]-N2',N2',8'-trimethylspiro[cyclopropane-1,4'- furo[2,3-g]indazole]-2',7'(5'H)-dicarboxamide 155 benzyl 3-fluoro-3-[(8-methyl-7-{[(2S)-tetrahydrofuran-2-ylmethyl]carbamoyl}-4,5- dihydro-2H-furo[2,3-g]indazol-2-yl)methyl]azetidine-1-carboxylate 156 benzyl 3-[(8-methyl-7-{[(2S)-tetrahydrofuran-2-ylmethyl]carbamoyl}-4,5-dihydro- 2H-furo[2,3-g]indazol-2-yl)methyl]azetidine-1-carboxylate 157 2-[(3-fluoroazetidin-3-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 158 2-(azetidin-3-ylmethyl)-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 159 2-(azetidin-3-ylmethyl)-N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 160 2-(2-aminoethyl)-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 161 2-(2-aminoethyl)-N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 162 8-methyl-2-[2-(piperazin-1-yl)ethyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 163 N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[2-(piperazin-1-yl)ethyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 164 2-[(1-acetylazetidin-3-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 165 2-[(1-acetyl-3-fluoroazetidin-3-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran-2- ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 166 2-{[3-fluoro-1-(methylsulfonyl)azetidin-3-yl]methyl}-8-methyl-N-[(2S)- tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 167 methyl 3-fluoro-3-[(8-methyl-7-{[(2S)-tetrahydrofuran-2-ylmethyl]carbamoyl}-4,5- dihydro-2H-furo[2,3-g]indazol-2-yl)methyl]azetidine-1-carboxylate 168 2'-[(2S)-1,4-dioxan-2-ylmethyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-8'- (trifluoromethyl)-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'- carboxamide 169 N-{[(2R)-1,4-dioxan-2-yl]methyl}-2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'- (trifluoromethyl)-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'- carboxamide 170 N-{[(2±)-5,5-dimethyloxolan-2-yl]methyl}-8-methyl-2-[(pyridin-2-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 171 8-methyl-N-[(oxan-4-yl)methyl]-2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 172 8-methyl-N-{[(2±)-oxan-2-yl]methyl}-2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 173 8-methyl-N-{[(2±)-2-methyloxolan-2-yl]methyl}-2-[(pyridin-2-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 174 N-{[(2±)-4,4-difluorooxolan-2-yl]methyl}-8-methyl-2-[(pyridin-2-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 175 8-methyl-N-[(4-methyltetrahydrofuran-2-yl)methyl]-2-(2-pyridylmethyl)-4,5- dihydrofuro[2,3-g]indazole-7-carboxamide 176 8-methyl-N-{[(2±,5±)-5-methyloxolan-2-yl]methyl}-2-[(pyridin-2-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 177 2,5-anhydro-1,3,4-trideoxy-3-methyl-1-({8-methyl-2-[(pyridin-2-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carbonyl}amino)-D-threo-pentitol (Racemate) 178 8-methyl-N-{[(6±)-5-oxaspiro[2.4]heptan-6-yl]methyl}-2-[(pyridin-2-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 179 N-{[(2±)-3,3-dimethyloxolan-2-yl]methyl}-8-methyl-2-[(pyridin-2-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 180 N-{[(6±)-2,5-dioxaspiro[3.4]octan-6-yl]methyl}-8-methyl-2-[(pyridin-2-yl)methyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 181 N-{[(2±)-6,6-dimethyl-1,4-dioxan-2-yl]methyl}-8-methyl-2-[(pyridin-2-yl)methyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 182 2-[(4-fluoropyridin-2-yl)methyl]-8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 183 2-[(5-fluoropyridin-3-yl)methyl]-8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 184 8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-2-[(pyridazin-3-yl)methyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 185 N-{[(2R)-1,4-dioxan-2-yl]methyl}-8-methyl-2-[(pyridazin-3-yl)methyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 186 2-[(6-ethylpyridin-3-yl)methyl]-8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 187 N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-[(6-ethylpyridin-3-yl)methyl]-8-methyl-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 188 8-methyl-2-[(1,3-oxazol-2-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 189 8-methyl-2-[(oxan-4-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 190 8-methyl-2-{[(2±)-oxan-2-yl]methyl}-N-{[(2S)-oxolan-2-yl]methyl}-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 191 N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-[(6-methylpyridin-3-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 192 2-[(6-methylpyridin-3-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8-(trifluoromethyl)- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 193 8-cyclopropyl-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 194 8-cyclopropyl-2-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(2S)-oxolan-2-yl]methyl}-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 195 N-{[(2±)-5,5-dimethyloxolan-2-yl]methyl}-2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'- methyl-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 196 N-{[(2±)-6,6-dimethyl-1,4-dioxan-2-yl]methyl}-2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'- methyl-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 197 N-{[(2±)-4,4-difluorooxolan-2-yl]methyl}-2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'- methyl-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 198 2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'-methyl-N-{[(2±,5±)-5-methyloxolan-2- yl]methyl}-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'- carboxamide 199 2-[[(2S)-1,4-dioxan-2-yl]methyl]-8-methyl-N-[(4-methyltetrahydrofuran-2- yl)methyl]spiro[5H-furo[2,3-g]indazole-4,1'-cyclopropane]-7-carboxamide 200 2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'-methyl-N-{[(6±)-5-oxaspiro[2.4]heptan-6- yl]methyl}-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'- carboxamide 201 2'-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(6±)-2,5-dioxaspiro[3.4]octan-6-yl]methyl}- 8'-methyl-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'- carboxamide 201 2'-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(6R)-2,5-dioxaspiro[3.4]octan-6-yl]methyl}- 8'-methyl-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'- carboxamide 201 2'-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(6S)-2,5-dioxaspiro[3.4]octan-6-yl]methyl}- 8'-methyl-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'- carboxamide 202 8'-Methyl-2'-(pyridin-4-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2',5'- dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 203 8'-Methyl-2'-[(5-methylpyridin-2-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]- 2',5'-dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 210 N-{[(2R)-1,4-dioxan-2-yl]methyl}-8'-methyl-2'-[(6-methylpyridin-3-yl)methyl]-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 211 8'-methyl-2'-[(6-methylpyridin-3-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 212 N-{[(2R)-1,4-dioxan-2-yl]methyl}-2'-[(6-methylpyridin-3-yl)methyl]-8'- (trifluoromethyl)-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'- carboxamide 213 2'-[(6-methylpyridin-3-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8'-(trifluoromethyl)- 2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 214 2'-[(5-methylpyridin-2-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8'-(trifluoromethyl)- 2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 215 N-{[(2R)-1,4-dioxan-2-yl]methyl}-2'-[(5-methylpyridin-2-yl)methyl]-8'- (trifluoromethyl)-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'- carboxamide 216 N-[(2R)-1,4-Dioxan-2-ylmethyl]-2'-(pyridin-4-ylmethyl)-8'-(trifluormethyl)-2',5'- dihydrospiro[cyclopropan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 217 2'-(Pyridin-4-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-8'-(trifluormethyl)- 2',5'-dihydrospiro[cyclopropan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 218 N-{[(2S)-oxolan-2-yl]methyl}-2'-[(pyridin-2-yl)methyl]-8'-(trifluoromethyl)-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 219 N-[(2R)-1,4-Dioxan-2-ylmethyl]-2'-(pyridin-2-ylmethyl)-8'-(trifluormethyl)-2',5'- dihydrospiro[cyclopropan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 220 N,2-bis{[(2R)-1,4-dioxan-2-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 221 2-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(2S)-oxolan-2-yl]methyl}-8-(trifluoromethyl)- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 222 N-{[(2±)-4,4-difluorooxolan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 222 N-{[(2R)-4,4-difluorooxolan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 222 N-{[(2S)-4,4-difluorooxolan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 223 N-{[(2±)-5,5-dimethyloxolan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 223 N-{[(2R)-5,5-dimethyloxolan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 223 N-{[(2S)-5,5-dimethyloxolan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 224 2-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(2±, 5±)-5-methyloxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 224 2-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(2R, 5R)-5-methyloxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 224 2-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(2S, 5R)-5-methyloxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 224 2-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(2R, 5S)-5-methyloxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 224 2-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(2S, 5S)-5-methyloxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 226 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-(1,3-thiazol-2-ylmethyl)-8-(trifluormethyl)-4,5- dihydro-2H-furo[2,3-g]indazol-7-carboxamide 227 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[(5-methylpyrazin-2-yl)methyl]-8- (trifluormethyl)-4,5-dihydro-2H-furo[2,3-g]indazol-7-carboxamide 228 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-(pyrazin-2-ylmethyl)-8-(trifluormethyl)-4,5- dihydro-2H-furo[2,3-g]indazol-7-carboxamide 230 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[(1-methyl-1H-imidazol-4-yl)methyl]-8- (trifluormethyl)-4,5-dihydro-2H-furo[2,3-g]indazol-7-carboxamide 231 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-(1,3-thiazol-5-ylmethyl)-8-(trifluormethyl)-4,5- dihydro-2H-furo[2,3-g]indazol-7-carboxamide 232 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[2-(4-methylpyridin-2-yl)ethyl]-8-(trifluormethyl)- 4,5-dihydro-2H-furo[2,3-g]indazol-7-carboxamide 233 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[2-(pyridin-2-yl)ethyl]-8-(trifluormethyl)-4,5- dihydro-2H-furo[2,3-g]indazol-7-carboxamide 234 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[2-(3-methyl-1H-pyrazol-1-yl)ethyl]-8- (trifluormethyl)-4,5-dihydro-2H-furo[2,3-g]indazol-7-carboxamide 235 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[2-(1H-imidazol-4-yl)ethyl]-8-(trifluormethyl)- 4,5-dihydro-2H-furo[2,3-g]indazol-7-carboxamide 236 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[2-(pyridin-3-yl)ethyl]-8-(trifluormethyl)-4,5- dihydro-2H-furo[2,3-g]indazol-7-carboxamide 237 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[2-(1,3-thiazol-2-yl)ethyl]-8-(trifluormethyl)-4,5- dihydro-2H-furo[2,3-g]indazol-7-carboxamide 238 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[(6-methylpyridin-2-yl)methyl]-8-(trifluormethyl)- 4,5-dihydro-2H-furo[2,3-g]indazol-7-carboxamide 239 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-(1,3-oxazol-4-ylmethyl)-8-(trifluormethyl)-4,5- dihydro-2H-furo[2,3-g]indazol-7-carboxamide 240 2-{[(2S)-1,4-dioxan-2-yl]methyl}-N-[2-(pyrazin-2-yl)ethyl]-8-(trifluoromethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 242 N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-[(oxan-4-yl)methyl]-8-(trifluoromethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 243 2-[(oxan-4-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 244 8-(difluoromethyl)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2- yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 245 8-(difluoromethyl)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(2S)-oxolan-2-yl]methyl}- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 246 (4±)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4,8-dimethyl-2-[(pyridin-2-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 247 (4±)-4,8-dimethyl-N-{[(2S)-oxolan-2-yl]methyl}-2-[(pyridin-2-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 248 (4±)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4,8- dimethyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 249 (4±)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4,8-dimethyl-N-{[(2S)-oxolan-2-yl]methyl}- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 250 (4±)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl-2-[(pyridin-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 251 (4±)-4-methyl-2-[(5-methyl-2-pyridyl)methyl]-N-[[(2S)-tetrahydrofuran-2- yl]methyl]-8-(trifluoromethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide 252 (4±)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl-2-[(6-methylpyridin-3-yl)methyl]- 8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 253 (4±)-4-methyl-2-[(6-methylpyridin-3-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 254 (4±)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl- 8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 254 (4R)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl- 8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 254 (4S)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl- 8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 255 (4±)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 255 (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 255 (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 256 (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1,3-oxazol-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 256 (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1,3-oxazol-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 257 (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1-methyl-1H-pyrazol-3- yl)methyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 257 (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1-methyl-1H-pyrazol-3- yl)methyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 258 (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(5-methylpyrazin-2-yl)methyl]- 8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 258 (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(5-methylpyrazin-2-yl)methyl]- 8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 259 (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1,3-thiazol-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 259 (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1,3-thiazol-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 260 (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(pyrazin-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 260 (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(pyrazin-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 261 (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1,3-oxazol-4-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 261 (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1,3-oxazol-4-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 262 (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-8-(trifluoromethyl)-N-{[2- (trifluoromethyl)pyrimidin-5-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide 262 (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-8-(trifluoromethyl)-N-{[2- (trifluoromethyl)pyrimidin-5-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide 263 (4R)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl-2-[(oxan-4-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 263 (4S)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl-2-[(oxan-4-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 264 (4R)-4-methyl-2-[(oxan-4-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 264 (4S)-4-methyl-2-[(oxan-4-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 265 (4±)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8-methyl- 4-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 265 (4R)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8-methyl- 4-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 265 (4S)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8-methyl- 4-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 266 (4±)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-4- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 266 2-{[(2S)-1,4-dioxan-2-yl]methyl}-8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-(4R)-4- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 266 2-{[(2S)-1,4-dioxan-2-yl]methyl}-8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-(4S)-4- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 267 N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4,4-dimethyl-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 268 2-{[(2S)-1,4-dioxan-2-yl]methyl}-4,4-dimethyl-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 269 N-[(2R)-1,4-dioxan-2-ylmethyl]-2'-[(2S)-1,4-dioxan-2-ylmethyl]-8'-(trifluormethyl)- 2',5'-dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 270 2'-[(2S)-1,4-dioxan-2-ylmethyl]-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-8'- (trifluormethyl)-2',5'-dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'- carboxamide 271 2'-[(2S)-1,4-dioxan-2-ylmethyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-8'- (trifluormethyl)-2',5'-dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'- carboxamide 272 2'-{[(2S)-1,4-dioxan-2-yl]methyl}-N-[(1,3-oxazol-2-yl)methyl]-8'-(trifluoromethyl)- 2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 273 N-[(2R)-1,4-Dioxan-2-ylmethyl]-2'-(pyridin-2-ylmethyl)-8'-(trifluormethyl)-2',5'- dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 274 2'-(Pyridin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-8'-(trifluormethyl)- 2',5'-dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 275 N-(1,3-Oxazol-2-ylmethyl)-2'-(pyridin-2-ylmethyl)-8'-(trifluormethyl)-2',5'- dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 276 N-[(1-Methyl-1H-pyrazol-3-yl)methyl]-2'-(pyridin-2-ylmethyl)-8'-(trifluormethyl)- 2',5'-dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 277 2'-[(5-Methylpyridin-2-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-8'- (trifluormethyl)-2',5'-dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'- carboxamide 278 N-[(2R)-1,4-Dioxan-2-ylmethyl]-2'-[(5-methylpyridin-2-yl)methyl]-8'- (trifluormethyl)-2',5'-dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'- carboxamide 279 N-[(1-Methyl-1H-pyrazol-3-yl)methyl]-2'-[(5-methylpyridin-2-yl)methyl]-8'- (trifluormethyl)-2',5'-dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'- carboxamide 280 2'-(Pyridin-4-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-8'-(trifluormethyl)- 2',5'-dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 281 N-[(2R)-1,4-Dioxan-2-ylmethyl]-2'-(pyridin-4-ylmethyl)-8'-(trifluormethyl)-2',5'- dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 282 2-(cyclopropylmethyl)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-8-(trifluoromethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 283 N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[1-(methoxyacetyl)piperidin-4-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 284 2-{[1-(methoxyacetyl)piperidin-4-yl]methyl}-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 285 2-{[1-(cyclopropanecarbonyl)piperidin-4-yl]methyl}-N-{[(2R)-1,4-dioxan-2- yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 286 2-{[1-(cyclopropanecarbonyl)piperidin-4-yl]methyl}-N-{[(2S)-oxolan-2-yl]methyl}- 8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 287 2-[(1-benzoylpiperidin-4-yl)methyl]-N-{[(2R)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 288 2-[(1-benzoylpiperidin-4-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 289 8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-2-[2-(pyridin-3-yl)propan-2-yl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 290 (4R)-2-{[1-(cyclopropanecarbonyl)piperidin-4-yl]methyl}-4-methyl-N-{[(2S)- oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide 290 (4S)-2-{[1-(cyclopropanecarbonyl)piperidin-4-yl]methyl}-4-methyl-N-{[(2S)- oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide 291 (4R)-2-{[1-(cyclopropanecarbonyl)piperidin-4-yl]methyl}-N-{[(2R)-1,4-dioxan-2- yl]methyl}-4-methyl-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide 291 (4S)-2-{[1-(cyclopropanecarbonyl)piperidin-4-yl]methyl}-N-{[(2R)-1,4-dioxan-2- yl]methyl}-4-methyl-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide 292 (4R)-2-[(1-acetylpiperidin-4-yl)methyl]-4-methyl-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 292 (4S)-2-[(1-acetylpiperidin-4-yl)methyl]-4-methyl-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 293 (4R)-2-{[1-(1-hydroxycyclopropane-1-carbonyl)piperidin-4-yl]methyl}-4-methyl-N- {[(2S)-oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole- 7-carboxamide 293 (4S)-2-{[1-(1-hydroxycyclopropane-1-carbonyl)piperidin-4-yl]methyl}-4-methyl-N- {[(2S)-oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole- 7-carboxamide 294 (4R)-2-[(1-acetylpiperidin-4-yl)methyl]-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl- 8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 294 (4S)-2-[(1-acetylpiperidin-4-yl)methyl]-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl- 8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 295 (4R)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[1-(1-hydroxycyclopropane-1- carbonyl)piperidin-4-yl]methyl}-4-methyl-8-(trifluoromethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 295 (4S)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[1-(1-hydroxycyclopropane-1- carbonyl)piperidin-4-yl]methyl}-4-methyl-8-(trifluoromethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 296 (4R)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl-2-{[1-(2-oxobutanoyl)piperidin-4- yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 296 (4S)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl-2-{[1-(2-oxobutanoyl)piperidin-4- yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 297 (4R)-4-methyl-2-{[1-(2-oxobutanoyl)piperidin-4-yl]methyl}-N-{[(2S)-oxolan-2- yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 297 (4S)-4-methyl-2-{[1-(2-oxobutanoyl)piperidin-4-yl]methyl}-N-{[(2S)-oxolan-2- yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 298 (4R)-4-methyl-2-{[1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl]methyl}-N- {[(2S)-oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole- 7-carboxamide 298 (4S)-4-methyl-2-{[1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl]methyl}-N- {[(2S)-oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole- 7-carboxamide 299 (4R)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl-2-{[1-(1-methylcyclopropane-1- carbonyl)piperidin-4-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 299 (4S)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl-2-{[1-(1-methylcyclopropane-1- carbonyl)piperidin-4-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 300 N,2-bis{[(2S)-1,4-dioxan-2-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 301 2-{[(2R)-1,4-dioxan-2-yl]methyl}-N-{[(2S)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 302 (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(2-methylpyrimidin-5- yl)methyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 302 (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(2-methylpyrimidin-5- yl)methyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 303 (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(5-methylpyrimidin-2- yl)methyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 303 (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(5-methylpyrimidin-2- yl)methyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 304 (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(pyrimidin-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 304 (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(pyrimidin-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 305 2-[(1-acetylpiperidin-4-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8-(trifluoromethyl)- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 306 2-[(1-acetylpiperidin-4-yl)methyl]-N-{[(2R)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 307 2-{[1-(cyclopropylmethyl)piperidin-4-yl]methyl}-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 308 2-[(1-methylpiperidin-4-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 309 N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-[(1-methylpiperidin-4-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 310 2-{[1-(cyclopropylmethyl)piperidin-4-yl]methyl}-N-{[(2R)-1,4-dioxan-2-yl]methyl}- 8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 311 2-[(1-ethylpiperidin-4-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8-(trifluoromethyl)- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 312 N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-[(1-ethylpiperidin-4-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 313 2,5-anhydro-1,3,4-trideoxy-1-{[(4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carbonyl]amino}-4- methylpentitol 313 2,5-anhydro-1,3,4-trideoxy-1-{[(4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carbonyl]amino}-4- methylpentitol 314 (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1-methyl-1H-imidazol-4- yl)methyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 314 (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1-methyl-1H-imidazol-4- yl)methyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 315 (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(6-methylpyridin-2-yl)methyl]- 8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 315 (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(6-methylpyridin-2-yl)methyl]- 8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 316 (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1,3-thiazol-5-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 316 (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1,3-thiazol-5-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 317 8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-2-[(1±)-1-(pyridin-2-yl)ethyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 317 8-methyl-2-[(5-methylpyridin-2-yl)methyl]-N-[(3R)-oxolan-3-yl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 317 2-[(5-cyanopyridin-2-yl)methyl]-8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 318 N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 319 N-[(5-cyclopropylpyrazin-2-yl)methyl]-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 320 (4R)-N-[(5-cyclopropylpyrazin-2-yl)methyl]-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4- methyl-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 321 (4S)-N-[(5-cyclopropylpyrazin-2-yl)methyl]-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4- methyl-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 322 (4R)-N-[(5-chloropyrazin-2-yl)methyl]-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl- 8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 323 (4S)-N-[(5-chloropyrazin-2-yl)methyl]-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl- 8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide The compounds 1 to 323 are numbered in accordance with the examples described in WO2021122415 and in case of stereoisomers one single example number was assigned. More particularly the invention refers to the use of (4R)-N-[(5-cyclopropylpyrazin-2- yl)methyl]-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-8-(trifluoromethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide for the treatment or prophylaxis of diseases, in particular of inflammatory-driven pain diseases such as neuropathic pain, more specifically for diseases like diabetic neuropathic pain, and chemotherapy induced pain, and post-breast surgery pain, cancer bone pain, trigeminal neuralgia, post-mastectomy pain, fibromyalgia, multiple sclerosis pain, post-herpetic neuralgia, Fabry disease, gout, and bladder pain syndrome. The compounds of general formula (I) can be prepared according to the schemes 1, 2, 3, and 4 according to WO2021122415 page 40, 43, 45, and 47 which are incorporated herein as a reference and are part of the present application. Furthermore, the preparation of the compounds of general formula (I) according to WO2021122415, reported on page 39, line 21 to page 47, line 11 is also incorporated herein as a reference and is part of the present application. Compounds of general formula (I) demonstrate a valuable pharmacological spectrum of action which could not have been predicted. Compounds of the present invention have surprisingly been found to be effective antagonists of GPR84 and it is possible therefore that said compounds be used for the treatment or prophylaxis of diseases, in particular of inflammatory-driven pain diseases such as neuropathic pain diseases like diabetic neuropathic pain, and chemotherapy induced pain, and post-breast surgery pain, cancer bone pain, trigeminal neuralgia, post-mastectomy pain, fibromyalgia, multiple sclerosis pain, post-herpetic neuralgia, Fabry disease, gout, and bladder pain syndrome. Compounds of general formula (I) can be utilized to inhibit, antagonize, block, reduce, decrease GPR84 signal transduction, activity and cellular function. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of general formula (I), or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; which is effective to treat the disorder. In particular of inflammatory-driven pain diseases such as neuropathic pain diseases like diabetic neuropathic pain, and chemotherapy induced pain, and post-breast surgery pain, cancer bone pain, trigeminal neuralgia, post-mastectomy pain, fibromyalgia, multiple sclerosis pain, post-herpetic neuralgia, Fabry disease, gout, and bladder pain syndrome in humans and animals. These disorders have been well characterized in humans, but also exist with a similar aetiology in other mammals and can be treated by administering pharmaceutical compositions of the present invention. The term “treating”, or “treatment” as used in the present text is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as PCOS or IPF. The present invention covers the use of a compound of formula (I), described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the prophylaxis or treatment of diseases, in particular of inflammatory-driven pain diseases such as neuropathic pain diseases like diabetic neuropathic pain, and chemotherapy induced pain, and post-breast surgery pain, cancer bone pain, trigeminal neuralgia, post- mastectomy pain, fibromyalgia, multiple sclerosis pain, post-herpetic neuralgia, Fabry disease, gout, and bladder pain syndrome in humans and animals. It is possible for the compounds of general formula (I) to have systemic and/or local activity. For this purpose, they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent. For these administration routes, it is possible for the compounds of general formula (I) to be administered in suitable administration forms. For oral administration, it is possible to formulate the compounds intended for the use according to the invention to dosage forms known in the art that deliver the compounds rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally-disintegrating tablets, films/wafers, films/lyophilizates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds intended for the use according to the invention in crystalline and/or amorphized and/or dissolved form into said dosage forms. Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders. Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents. The compounds of general formula (I) can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia, • fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos®)), • ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), • bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), • solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins), • surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®), • buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), • isotonicity agents (for example glucose, sodium chloride), • adsorbents (for example highly-disperse silicas), • viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®); alginates, gelatine), • disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol®)), • flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)), • coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®)), • capsule materials (for example gelatine, hydroxypropylmethylcellulose), • synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers), • plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate), • penetration enhancers, stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate), • preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), • colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide), • flavourings, sweeteners, flavour- and/or odour-masking agents. The present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention. The synthesis of the compounds 1 to 323, the required intermediates for said synthesis and the methods for their identification were described in the patent application WO2021122415, Experimental section, page 58 to 479 which is incorporated herein as a reference and is part of the present application. The compounds 1 to 323 are numbered in accordance with the examples described in WO2021122415 and in case of stereoisomers one single example number was assigned. EXPERIMENTAL SECTION – BIOLOGICAL ASSAYS The in vitro activity of the compounds of the present invention can be demonstrated in the following assay: cAMP HTRF® Assay for identification of cellular GPR84 antagonists By using a Homogenous Time-Resolved Fluorescence (HTRF®) based assay (#62AM5PEJ, Cisbio, Condolet, France) the inhibition of the Gi-coupled GPR84 receptor can be detected. CHO-K1 cells stably expressing human GPR84 receptor (purchased from DiscoveRx, now Eurofins) were used and treated with Forskolin (F6886, Sigma, Germany) to stimulate membrane adenylyl cyclases and thereby unspecific cAMP formation. Activation of the Gi-coupled GPR84 by a natural or small molecule agonist (e.g. 6-n-octyl aminouracile, inhouse) results in inhibition of cellular cAMP formation which can be released again by antagonists to this receptor. Detection and quantification of cellular cAMP levels in this HTRF assay is achieved by interaction between a fluorescent cAMP tracer (cAMP-d2) and an Eu-cryptate labelled anti-cAMP antibody. Following excitation at 337 nm this pairing allows for the generation of a fluorescence resonance energy transfer (FRET) between the partners and results in FRET induced emissions at 665 nm and 620 nm, the latter representing background signal by Eu- cryptate labelled anti-cAMP antibody. Maximal signal is obtained in the absence of any cellular cAMP (no competition for the binding of the tracer to the antibody). Given the combination of the Gi coupling properties of GPR84 and the competitive nature of the detection system agonist treatment should result in an increase in the HTRF signal due to lowered cAMP levels. Any signal decrease in the presence of Forskolin, agonist and compound is indicative of antagonist mediated abrogation of GPR84 signalling. For the assay, frozen aliquots of CHO-K1 cells expressing hGPR84 (prepared by acCELLerate, Hamburg, Germany) were thawed and a cell suspension (1.67E+06 cells/mL) in assay media (Ham’s F12 Nutrient Mix, Thermo Fisher Scientific, Waltham, USA; 5% fetal calf serum, Biomol, Hamburg, Germany) containing cAMP-d2 (dilution 1:20, supplied with the kit #62AM5PEJ, Cisbio, Condolet, France) was prepared. After recovery of cells for 20 minutes at 37 °C, 3 µL/well cell suspension including cAMP-d2 were added to a pre-dispensed assay plate (Greiner Bio-One, Kremsmuenster, Austria) containing 50nl/well test compound in 100% DMSO or 100% DMSO as control. This was followed by a 30 minutes incubation step at room temperature. The stimulation time was started by addition of 2 µL/well assay media containing 2.5xEC80 agonist 6-OAU and 2.5xEC90 Forskolin (negative control: 2.5xEC90 Forskolin in assay media) and was continued for 30 minutes at room temperature. The reaction was stopped by addition of 3 µL/well lysis buffer containing cAMP Eu-Cryptate antibody (dilution 1:20) (both supplied with the kit #62AM5PEJ, Cisbio, Condolet, France). To enable complete lysis, plates were incubated for 60 minutes at room temperature before measurement in an HTRF reader, e.g. a PHERAstar (BMG Labtech, Ortenberg, Germany). From the fluorescence emissions at 665 nm (FRET) and at 620 nm (background signal of Eu-cryptate) the ratio (emission at 665 nm divided by emission at 620 nm x 10000) was calculated and the data were normalized (reaction without test compound, only 100% DMSO = 0% inhibition; all other assay components except agonist = 100% inhibition). For dose response testing on the same microtiter plate, compounds were tested at 11 different concentrations in the range of 20 µM to 0.07 nM (20 µM, 5.7 µM, 1.6 µM, 0.47 µM, 0.13 µM, 38 nM, 11 nM, 3.1 nM, 0.89 nM, 0.25 and 0.07 nM; dilution series prepared before the assay at the level of the 100-fold conc. stock solutions by serial 1:3.5 dilutions in 100% DMSO) in duplicate values for each concentration. IC50 values were calculated by 4-parameter fitting using a commercial software package (Genedata Screener, Basel, Switzerland). Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein • the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and • the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values. Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.
Table 6: Potency in GPR84 cAMP HTRF® assay, the potency is given as IC50 [µM]. Example GPR84 IC50 [µM] Example GPR84 IC50 [µM]
Figure imgf000062_0001
Table 6 (continued) Example GPR84 IC50 [µM] Example GPR84 IC50 [µM] 53 0.032 80 0.057
Figure imgf000063_0001
Table 6 (continued) Example GPR84 IC50 [µM] Example GPR84 IC50 [µM] 113 0.091 146 0.047
Figure imgf000064_0001
Table 6 (continued) Example GPR84 IC50 [µM] Example GPR84 IC50 [µM] 179 6.41 216 0.006
Figure imgf000065_0001
Table 6 (continued) Example GPR84 IC50 [µM] Example GPR84 IC50 [µM] 246 0.075 273 0.009
Figure imgf000066_0001
Table 6 (continued) Example GPR84 IC50 [µM] 306 0.027
Figure imgf000067_0001
The suitability of the compounds of general formula (I) for the treatment pain disorders can be demonstrated in the following animal models: In vivo assay 1: GPR84 ligand and antagonist characterization in metabolic PCOS model The efficacy of Example 3-2 in vivo on the treatment of the metabolic disease POCS was measured in the DHT driven rat PCOS model. At 3 weeks of age, Han-Wistar rats were randomly divided into three experimental groups [control (n =10), DHT (n=10), and DHT plus Example 3-2 (n=10)] and implanted s.c. with 60-d continuous-DHT-release pellets (80 µg/d, Bayer AG, Germany). The dose of DHT was chosen to mimic the hyperandrogenic state in women with PCOS. Controls received identical pellets lacking the bioactive DHT molecule. Animal received a standard chow, only for the last week standard show was replaced by a high fat diet. Rats were weighted bi-weekly from 21 d of age. The study was concluded after 26 days of drug administration. Example 3-2 treated animal gained less weight compared to the untreated control. Statistical analysis was performed with one-way analysis of variance, followed by Bonferroni’s multiple comparison test against vehicle control groups using the GraphPad PRISM software, *p<0.05. Table 7: Efficacy of GPR84 antagonist in the rat DHT-PCOS model
Figure imgf000068_0001
In vivo assay 2: Effects of Example 3-2 in the CFA pain model The efficacy of Example 3-2 in vivo on inflammatory pain was measured in inflamed paws after administration of complete Freund’s adjuvant (CFA) (24 h) in the dynamic weight- bearing (DWB) model. The effects of repeated preventive treatment with Example 3-2 on pain following repeated oral administration (3x) in the mouse CFA model of inflammation were investigated using a preventive setting. The GPR84 antagonist Example 3-2 (20 or 60 mg/kg, 3x doses) was administered 2 h before injection of CFA and 6-8 h later at day 0. At 24 h after CFA application, the third dose of Example 3-2 was given 2 h before DWB testing. Statistical analysis was performed with one-way analysis of variance, followed by Bonferroni’s multiple comparison test against vehicle control groups using the GraphPad PRISM software, *p<0.05. Table 8: Effects of GPR84 antagonist in the CFA pain model Example mg/kg Weight distribution (% weight on injected paw)
Figure imgf000069_0001
In vivo assay 3: Effects in the Oxaliplatin induced pain model The efficacy of example 320 in vivo on chemotherapy (Oxaliplatin; OPNP) induced pain was measured in a rat Oxaliplatin-induced 6 weeks neuropathic pain model. Sprague Dawley male rats at the age of about 9 weeks were used for the experiment. Rats were randomly divided into experimental groups (e.g. n=10). Pain was induced by oxaliplatin application (2 mg/kg) once per day for 5 days. The GPR84 antagonist example 320 was administered with the first application at d1. Rats were habituated to the circumstances for 30 min before starting with behavioral test. Prior to treatment, von Frey test was conducted on all animals for baseline measurement. To assess mechanical allodynia, paw withdrawal thresholds was measured by applying the von Frey filaments (with ascending weights; 0.4, 0.6, 1.4, 2, 4, 6, 8, 15 g) on the center of the right hind paw. Von Frey tests were conducted prior to test article administration (baseline) and once per week, 1 hr, 2 hr and 4 hr post dosing until the end of the experiment. Statistical analysis was performed with one-way analysis of variance, followed by Dunnett multiple comparison test against vehicle control group using the GraphPad PRISM software, *p<0.05. Table 9: Effects of GPR84 antagonist in Oxaliplatin induced pain model Example mg/kg/d Threshold to von Frey Stimulation (g) on day 28
Figure imgf000069_0002
E l 10
Figure imgf000070_0001
In vivo assay 4: Effects in the Streptozotocin (STZ)-induced diabetic neuropathic pain model The efficacy of example 320 in vivo on diabetic neuropathic pain was studied in the Streptozotocin (STZ)-induced neuropathic pain model. Diabetes was induced in Sprague Dawley male rats by dosing of Streptozotocin (STZ, 60 mg/kg) on study day 0. The development of diabetes was confirmed by the measurement of blood glucose levels on study day 3. On study day 10 the sensitivity of all animals to von Frey filaments was tested and diabetic animals (>300 mg/dL) that show a decrease in the withdrawal force threshold (average pain threshold of ≤ 15 g for both hind paws) are included in the study. Animals were treated with the compound example 320 or the vehicle from study day 10 until day 28. Mechanical pain sensitivity was tested using the von Frey test, which measures the withdrawal force threshold of the animals. Statistical analysis is performed with one-way analysis of variance, followed by Dunnett multiple comparison test against vehicle control group using the GraphPad PRISM software, *p<0.05. Table 10: Effects in the Streptozotocin (STZ)-induced diabetic neuropathic pain model Example mg/kg/d Threshold to von Frey Stimulation (g) on day 26 p)
Figure imgf000070_0002
Figure imgf000071_0001

Claims

CLAIMS 1. Use of a compound of general formula (I): in which:
Figure imgf000072_0001
R1 represents hydrogen, C1-C4-alkyl or C1-C4-haloalkyl; R2 represents hydrogen, C1-C4-alkyl or C1-C4-haloalkyl; or R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring; R3 represents C3-C6-cycloalkyl, 3- to 6-membered heterocycloalkyl, heterocycloalkyl fused with phenyl or heteroaryl, or heteroaryl, wherein said groups are optionally substituted, one or more times, independently of each other, with R8, or R3 represents phenyl, which is optionally substituted, one or more times, independently of each other, with R8, and additionally R7a and R7b represent deuterium; R4 represents hydrogen, C1-C4-alkyl, C1-C4-haloalkyl or C3-C6-cycloalkyl; R5, R6 represent, independently of each other, hydrogen, C1-C4-alkyl, C2-C4- hydroxyalkyl, (C1-C4-alkoxy)-(C2-C4-alkyl)-, C3-C6-cycloalkyl, C1-C4-haloalkyl, C3-C6-halocycloalkyl, 3- to 6-membered heterocycloalkyl, heterospirocycloalkyl, phenyl, heteroaryl, heterocycloalkyl fused with phenyl or heteroaryl, 3- to 6- membered heterocycloalkyl-(C1-C3-alkyl)-, heterospirocycloalkyl-(C1-C3-alkyl)-, (heterocycloalkyl fused with phenyl or heteroaryl)-(C1-C3-alkyl)-, phenyl-(C1-C3-alkyl)- or heteroaryl-(C1-C3-alkyl)-, wherein said 3- to 6-membered heterocycloalkyl, heterospirocycloalkyl, heterocycloalkyl fused with phenyl or heteroaryl, phenyl or heteroaryl groups are optionally substituted, one or more times, independently of each other, with R9, or R5 and R6 together with the nitrogen atom to which they are attached form a 3- to 6-membered nitrogen containing heterocyclic ring, optionally containing one additional heteroatom or heteroatom containing group selected from O, NH and S, and which may be optionally substituted, one or more times, independently of each other, with R9; R7a represents hydrogen, deuterium, or C1-C4-alkyl; R7b represents hydrogen, deuterium, or C1-C4-alkyl; R8 represents halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C3-C6-cycloalkyl, C3-C6-cycloalkyl-(C1-C3-alkyl)-, R13-(C=O)-, R10-O-(C=O)-, R11-NH-(C=O)-, or R12-(SO2)-; R9 represents halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, H2N-C1-C4-alkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C3-C6-cycloalkyl, R10-O-(C=O)-, oxo, 5- to 6- membered heterocycloalkyl-, 5- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-, phenyl, or heteroaryl, wherein said phenyl or heteroaryl group is optionally substituted, one or more times, independently of each other, with halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, or C1-C3-haloalkoxy; R10 represents hydrogen, C1-C4-alkyl, or phenyl-CH2-; R11 represents hydrogen, C1-C4-alkyl, or 5- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-; R12 represents C1-C4-alkyl or phenyl; R13 represents C1-C4-alkyl, C1-C4-haloalkyl, (C1-C4-alkoxy)-(C1-C4-alkyl)-, C1-C4-alkyl-(C=O)-, C3-C6-cycloalkyl, or phenyl, wherein said C3-C6-cycloalkyl group is optionally substituted with C1-C4-alkyl or hydroxy and said phenyl group is optionally substituted, one or more times, independently of each other, with halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, or C1-C3-haloalkoxy; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, for the treatment or prophylaxis of inflammatory-driven pain diseases and/or neuropathic pain diseases.
2. Use of the compound according to claim 1, wherein R1 represents hydrogen, C1-C4-alkyl or C1-C4-haloalkyl; R2 represents hydrogen or C1-C4-alkyl; or R1 and R2 together with the carbon atom to which they are attached form a 3- to 4-membered cycloalkyl or heterocycloalkyl ring; R3 represents C3-C6-cycloalkyl, 4- to 6-membered heterocycloalkyl, heterocycloalkyl fused with heteroaryl, or heteroaryl, wherein said groups are optionally substituted, one or more times, independently of each other, with R8, or R3 represents phenyl, which is optionally substituted, one or more times, independently of each other, with R8, and additionally R7a and R7b represent deuterium; R4 represents hydrogen, C1-C4-alkyl, C1-C4-haloalkyl or C3-C6-cycloalkyl; R5, R6 represent, independently of each other, hydrogen, C2-C4-hydroxyalkyl, (C1-C4-alkoxy)-(C2-C4-alkyl)-, 3- to 6-membered heterocycloalkyl, heterospirocycloalkyl, phenyl, heteroaryl, 4- to 6-membered heterocycloalkyl- (C1-C3-alkyl)-, heterospirocycloalkyl-(C1-C3-alkyl)-, (heterocycloalkyl fused with heteroaryl)-(C1-C3-alkyl)-, or heteroaryl-(C1-C3-alkyl)-, wherein said 3- to 6- membered heterocycloalkyl, phenyl or heteroaryl groups are optionally substituted, one or more times, independently of each other, with R9, or R5 and R6 together with the nitrogen atom to which they are attached form a 5-membered nitrogen containing heterocyclic ring, which may be optionally substituted, once with R9; R7a represents hydrogen, deuterium, or methyl; R7b represents hydrogen, deuterium, or methyl; R8 represents halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, C3-C6-cycloalkyl, C3-C6-cycloalkyl-(C1-C3-alkyl)-, R13-(C=O)-, R10-O-(C=O)-, R11-NH-(C=O)-, or R12-(SO2)-; R9 represents halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, H2N-C1-C4-alkyl, C3-C6-cycloalkyl, R10-O-(C=O)-, oxo, 6-membered heterocycloalkyl-(C1-C3-alkyl)- , phenyl, or heteroaryl, wherein said phenyl or heteroaryl group is optionally substituted, one or more times, independently of each other, with halogen, C1-C4-haloalkyl, or C1-C3-alkoxy; R10 represents hydrogen, C1-C4-alkyl, or phenyl-CH2-; R11 represents 5- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-; R12 represents C1-C4-alkyl; R13 represents C1-C4-alkyl, (C1-C4-alkoxy)-(C1-C4-alkyl)-, C1-C4-alkyl-(C=O)-, C3-C6-cycloalkyl, or phenyl, wherein said C3-C6-cycloalkyl group is optionally substituted with methyl or hydroxy; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, for the treatment or prophylaxis of diseases. 3. Use of the compound according to claim 1 or 2, wherein: R1 represents hydrogen, methyl or trifluoromethyl; R2 represents hydrogen or methyl; or R1 and R2 together with the carbon atom to which they are attached form a 3- to 4-membered cycloalkyl ring; R3 represents cyclopropyl, 4- to 6-membered heterocycloalkyl, 2,3- dihydro[1,4]dioxino[2,3-b]pyridin-2-yl, or heteroaryl, wherein said groups are optionally substituted, one or more times, independently of each other, with R8, or R3 represents phenyl, which is optionally substituted, one or more times, independently of each other, with R8, and additionally R7a and R7b represent deuterium; R4 represents hydrogen, methyl, C1-haloalkyl or cyclopropyl; R5 represents hydrogen; R6 represents methoxy-ethyl, 5-membered heteroaryl, 4- to 6-membered heterocycloalkyl-(C1-C2-alkyl)-, heterospirocycloalkyl-methyl, 2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl, or 5- to 6-membered heteroaryl- (C1-C2-alkyl)-, wherein said 4- to 6-membered heterocycloalkyl or heteroaryl groups are optionally substituted, one or more times, independently of each other, with R9; R7a represents hydrogen, deuterium, or methyl; R7b represents hydrogen, deuterium, or methyl; R8 represents fluoro, chloro, C1-C2-alkyl, trifluoromethyl, C1-C3-alkoxy, cyclopropyl, cyclopropylmethyl, R13-(C=O)-, R10-O-(C=O)-, R11-NH-(C=O)-, or R12-(SO2)-; R9 represents fluoro, chloro, C1-C3-alkyl, trifluoromethyl, cyclopropyl, or oxo; R10 represents C1-C4-alkyl, or phenyl-CH2-; R11 represents 5- to 6-membered heterocycloalkyl-methyl; R12 represents methyl; R13 represents methyl, methoxymethyl, ethyl-(C=O)-, cyclopropyl, or phenyl, wherein said cyclopropyl group is optionally substituted with methyl or hydroxy; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, for the treatment or prophylaxis of diseases. 4. Use of the compound according to claim 1, 2, or 3, wherein: R1 represents hydrogen or methyl; R2 represents hydrogen or methyl; or R1 and R2 together with the carbon atom to which they are attached form a 3- to 4-membered cycloalkyl ring; R3 represents cyclopropyl, 2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-yl, oxetan-3-yl, oxolan-3-yl, oxolan-2-yl, 3-methyloxetan-3-yl, 3-fluorooxetan-3-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, oxan-4-yl, 1,4-dioxan-2-yl, 6-methylpyridin-3-yl, 5- methylpyridin-2-yl, 3-methylpyridin-2-yl, 2-methylpyridin-4-yl, 6-methylpyridin-2- yl, 3-chloropyridin-2-yl, 6-ethylpyridin-3-yl, 1-acetylpiperidin-4-yl, 3-chloro-5- ethoxypyridin-2-yl, 1-benzoylpiperidin-4-yl, or a group selected from:
Figure imgf000077_0001
R3 represents phenyl, and additionally R7a and R7b represent deuterium;
R4 represents methyl, difluoromethyl, trifluoromethyl, or cyclopropyl;
R5 represents hydrogen; R6 represents (oxolan-2-yl)methyl, (1,3-oxazol-4-yl)methyl, (1,2-oxazol-3-yl)methyl, (4-methyloxolan-2-yl)methyl, (pyrimidin-2-yl)methyl, (pyrazin-2-yl)methyl, (5- methyloxolan-2-yl)methyl, (5-methyloxolan-2-yl)methyl, (1,4-dioxan-2-yl)methyl, (4-methylphenyl)methyl, (5-methylpyrimidin-2-yl)methyl, (5-methylpyrazin-2- yl)methyl, (5-chloropyrazin-2-yl)methyl, (5-cyclopropyl-pyrazin-2-yl)methyl, 2,3- dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl, 1,3-oxazol-2-ylmethyl, 1,3-thiazol-2- ylmethyl, (1-methyl-1H-pyrazol-3-yl)methyl, (1-methyl-1H-imidazol-4-yl)methyl, (5-isopropyl-1,2-oxazol-3-yl)methyl, (5-cyclopropyl-1,2-oxazol-3-yl)methyl, (5,5- dimethyltetrahydrofuran-2-yl)methyl, (4,4-difluorotetrahydrofuran-2-yl)methyl, (6,6-dimethyl-1,4-dioxan-2-yl)methyl, 5-oxaspiro[2.4]heptan-6-ylmethyl, or 2,6- dioxaspiro[3.4]octan-7-ylmethyl; R7a represents hydrogen; R7b represents hydrogen; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, for the treatment or prophylaxis of diseases. 5. Use of the compound according to claim 1, 2, 3, or 4 which is selected from the group consisting of: 2-(pyridin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8-methyl-N-[(4-methylphenyl)methyl]-2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8-methyl-2-(pyridin-2-ylmethyl)-N-[(2R/S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-2-(pyridin-2-ylmethyl)-N-[(2R)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-2-(pyridin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-N-[(1,2,4-oxadiazol-3-yl)methyl]-2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-N-(1,2-oxazol-3-ylmethyl)-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide N-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-N-[(5-methyl-1,2-oxazol-3-yl)methyl]-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-[(2R/S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-2-(pyridin-2- ylmethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(2R)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-2-(pyridin-2-ylmethyl)- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(2S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-2-(pyridin-2-ylmethyl)- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-(2-hydroxy-2-methylpropyl)-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8-methyl-N-{[5-(morpholin-4-ylmethyl)-1,2-oxazol-3-yl]methyl}-2-(pyridin-2-ylmethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-2-(pyridin-2-ylmethyl)-N-(2-{4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1- yl}ethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-2-(pyridin-2-ylmethyl)-N-(2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-{[5-(3-methoxyphenyl)-1,2-oxazol-3-yl]methyl}-8-methyl-2-(pyridin-2-ylmethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-N-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-2-(pyridin-2-ylmethyl)-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide N-[(5-cyclopropyl-1,2-oxazol-4-yl)methyl]-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide N-{[5-(2-chlorophenyl)-1,2-oxazol-3-yl]methyl}-8-methyl-2-(pyridin-2-ylmethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(5-isopropyl-1,2-oxazol-3-yl)methyl]-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide N-{[(2S)-1,4-dioxan-2-yl]methyl}-8-methyl-2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-2-(pyridin-2-ylmethyl)-N-(4H-1,2,4-triazol-3-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8-methyl-N,2-bis(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-N-(1H-pyrazol-3-ylmethyl)-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8-methyl-2-(pyridin-2-ylmethyl)-N-(1,3-thiazol-2-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8-methyl-N-(1,2-oxazol-4-ylmethyl)-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8-methyl-2-(pyridin-2-ylmethyl)-N-{[5-(trifluoromethyl)-1,2-oxazol-3-yl]methyl}-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-N-[(4-methyl-1,2-oxazol-3-yl)methyl]-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-[2-(3,3-dimethyl-2-oxoazetidin-1-yl)ethyl]-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide N-(2-methoxyethyl)-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3-g]indazole- 7-carboxamide [(2R/S)-2-(aminomethyl)pyrrolidin-1-yl][8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazol-7-yl]methanone [(2R)-2-(aminomethyl)pyrrolidin-1-yl][8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazol-7-yl]methanone [(2S)-2-(aminomethyl)pyrrolidin-1-yl][8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazol-7-yl]methanone 3-[({[8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3-g]indazol-7- yl]carbonyl}amino)methyl]-1,2-oxazole-4-carboxylic acid 8-methyl-N-(1,3-oxazol-2-ylmethyl)-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8-methyl-2-(pyridin-2-ylmethyl)-N-[(3S)-tetrahydrofuran-3-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-2-(pyridin-2-ylmethyl)-N-[(3R)-tetrahydrofuran-3-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-N-[(2R/S)-oxetan-2-ylmethyl]-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8-methyl-N-[(2R)-oxetan-2-ylmethyl]-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8-methyl-N-[(2S)-oxetan-2-ylmethyl]-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8-methyl-N-(oxetan-3-ylmethyl)-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide N-[(3-fluorooxetan-3-yl)methyl]-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8-methyl-N-{[(2R/S)-4-methylmorpholin-2-yl]methyl}-2-(pyridin-2-ylmethyl)-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-N-{[(2R)-4-methylmorpholin-2-yl]methyl}-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-N-{[(2S)-4-methylmorpholin-2-yl]methyl}-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-N-{[(2R/S)-5-oxotetrahydrofuran-2-yl]methyl}-2-(pyridin-2-ylmethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-N-{[(2R)-5-oxotetrahydrofuran-2-yl]methyl}-2-(pyridin-2-ylmethyl)-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-N-{[(2S)-5-oxotetrahydrofuran-2-yl]methyl}-2-(pyridin-2-ylmethyl)-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8-methyl-N-(pyridin-3-yl)-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide 8-methyl-N-(2-phenylethyl)-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide N-(4-cyanophenyl)-8-methyl-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide 8-methyl-2-(pyridin-3-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-(pyridin-3-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8-methyl-2-(pyridin-4-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-(pyridin-4-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 2-(cyclopropylmethyl)-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 2-(cyclopropylmethyl)-N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide N-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]-2-[(2R/S)-2,3-dihydro[1,4]dioxino[2,3- b]pyridin-2-ylmethyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]-2-[(2R)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2- ylmethyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]-2-[(2S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2- ylmethyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2R/S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-[(2R/S)- tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2R)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-[(2R/S)- tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-[(2R/S)- tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2R/S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-[(2S)- tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2R)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-[(2S)- tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-[(2S)- tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2R/S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-(4-methylbenzyl)- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2R)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-(4-methylbenzyl)- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-(4-methylbenzyl)- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2R/S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-[2-(4- methylpiperazin-1-yl)ethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2R)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-[2-(4- methylpiperazin-1-yl)ethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-[2-(4- methylpiperazin-1-yl)ethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2R/S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-(1,2-oxazol-3- ylmethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2R)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-(1,2-oxazol-3- ylmethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-N-(1,2-oxazol-3- ylmethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2-{[6-(trifluoromethyl)pyridin-2-yl]methyl}- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2-{[5-(trifluoromethyl)pyridin-2-yl]methyl}- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(3-chloro-5-fluoropyridin-2-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(3-chloro-5-ethoxypyridin-2-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(3-chloropyridin-2-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(3-chloropyridin-2-yl)methyl]-N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-2-[(3-methylpyridin-2-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(3-methylpyridin-2-yl)methyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-2-[(5-methylpyridin-2-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(5-methylpyridin-2-yl)methyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-2-[(6-methylpyridin-2-yl)methyl]-N-[(2R/S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-2-[(6-methylpyridin-2-yl)methyl]-N-[(2R)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-2-[(6-methylpyridin-2-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[2-(azetidin-1-yl)ethyl]-8-methyl-2-[(6-methylpyridin-2-yl)methyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-[(5-cyclopropyl-1,2-oxazol-3-yl)methyl]-8-methyl-2-[(6-methylpyridin-2-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-2-[(6-methylpyridin-2-yl)methyl]-N-[2-(pyrrolidin-1-yl)ethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-[(2R/S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-2-[(6-methylpyridin- 2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(2R)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-2-[(6-methylpyridin-2- yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(2S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl]-8-methyl-2-[(6-methylpyridin-2- yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-2-[(6-methylpyridin-2-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-2-[(6-methylpyridin-2-yl)methyl]-N-(1,3-oxazol-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-2-[(2-methylpyridin-3-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(2-methylpyridin-3-yl)methyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-2-[(6-methylpyridin-3-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(6-methylpyridin-3-yl)methyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 2-[(2,6-dimethylpyridin-3-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2,6-dimethylpyridin-3-yl)methyl]-N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-2-[(2-methylpyridin-4-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(2-methylpyridin-4-yl)methyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 2-[(2,6-dimethylpyridin-4-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2,6-dimethylpyridin-4-yl)methyl]-N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-2-(pyrimidin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-(pyrimidin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-2-(pyrimidin-5-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-(pyrimidin-5-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 2-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N,2-bis[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide 2-[(2S)-1,4-dioxan-2-ylmethyl]-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-2-[(2S)-1,4-dioxan-2-ylmethyl]-8-methyl-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-2-(oxetan-3-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-(oxetan-3-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8-methyl-2-[(3-methyloxetan-3-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(3-methyloxetan-3-yl)methyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 2-[(3-fluorooxetan-3-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-2-[(3-fluorooxetan-3-yl)methyl]-8-methyl-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-2-[(2R)-oxetan-2-ylmethyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(2R)-oxetan-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-2-[(2S)-oxetan-2-ylmethyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(2S)-oxetan-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-2-{[(2R)-4-methylmorpholin-2-yl]methyl}-N-[(2S)-tetrahydrofuran-2-ylmethyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-{[(2R)-4-methylmorpholin-2-yl]methyl}-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-2-{[(2S)-4-methylmorpholin-2-yl]methyl}-N-[(2S)-tetrahydrofuran-2-ylmethyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-{[(2S)-4-methylmorpholin-2-yl]methyl}-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-2-[(2R)-tetrahydrofuran-2-ylmethyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(2R)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-N,2-bis[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide tert-butyl 3-[(8-methyl-7-{[(2S)-tetrahydrofuran-2-ylmethyl]carbamoyl}-4,5-dihydro-2H- furo[2,3-g]indazol-2-yl)methyl]azetidine-1-carboxylate tert-butyl 3-[(7-{[(2R)-1,4-dioxan-2-ylmethyl]carbamoyl}-8-methyl-4,5-dihydro-2H- furo[2,3-g]indazol-2-yl)methyl]azetidine-1-carboxylate 8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2-[(3R)-tetrahydrofuran-3-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(3R)-tetrahydrofuran-3-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2-[(3S)-tetrahydrofuran-3-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[(3S)-tetrahydrofuran-3-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-(pyridin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-8-(trifluoromethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-2-(pyridin-2-ylmethyl)-8-(trifluoromethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-[(1-methyl-1H-pyrazol-3-yl)methyl]-2-(pyridin-2-ylmethyl)-8-(trifluoromethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-(1,3-oxazol-2-ylmethyl)-2-(pyridin-2-ylmethyl)-8-(trifluoromethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-cyclopropyl-2-(pyridin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-cyclopropyl-N-[(2R)-1,4-dioxan-2-ylmethyl]-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-cyclopropyl-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-2-(pyridin-2-ylmethyl)-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 8-cyclopropyl-N-(1,3-oxazol-2-ylmethyl)-2-(pyridin-2-ylmethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8'-methyl-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-2'-(pyridin-2-ylmethyl)-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 8'-methyl-N-(1,3-oxazol-2-ylmethyl)-2'-(pyridin-2-ylmethyl)-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 2'-[(2S)-1,4-dioxan-2-ylmethyl]-8'-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-2'-[(2S)-1,4-dioxan-2-ylmethyl]-8'-methyl-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 2'-[(2S)-1,4-dioxan-2-ylmethyl]-8'-methyl-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 2'-[(2S)-1,4-dioxan-2-ylmethyl]-8'-methyl-N-(1,3-oxazol-2-ylmethyl)-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 2'-(cyclopropylmethyl)-8'-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 2'-(cyclopropylmethyl)-N-[(2S)-1,4-dioxan-2-ylmethyl]-8'-methyl-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 2'-(cyclopropylmethyl)-N-[(2R)-1,4-dioxan-2-ylmethyl]-8'-methyl-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 8'-methyl-2'-(pyridin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2',5'- dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N-[(2S)-1,4-dioxan-2-ylmethyl]-8'-methyl-2'-(pyridin-2-ylmethyl)-2',5'- dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8'-methyl-2'-(pyridin-2-ylmethyl)-2',5'- dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 8-methyl-2-[phenyl(2H2)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[phenyl(2H2)methyl]-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 2-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran-2- ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]-N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide tert-butyl [2-(8-methyl-7-{[(2S)-tetrahydrofuran-2-ylmethyl]carbamoyl}-4,5-dihydro-2H- furo[2,3-g]indazol-2-yl)ethyl]carbamate tert-butyl [2-(7-{[(2R)-1,4-dioxan-2-ylmethyl]carbamoyl}-8-methyl-4,5-dihydro-2H- furo[2,3-g]indazol-2-yl)ethyl]carbamate tert-butyl 4-[2-(8-methyl-7-{[(2S)-tetrahydrofuran-2-ylmethyl]carbamoyl}-4,5-dihydro-2H- furo[2,3-g]indazol-2-yl)ethyl]piperazine-1-carboxylate tert-butyl 4-[2-(7-{[(2R)-1,4-dioxan-2-ylmethyl]carbamoyl}-8-methyl-4,5-dihydro-2H- furo[2,3-g]indazol-2-yl)ethyl]piperazine-1-carboxylate 2'-[(2S)-1,4-dioxan-2-ylmethyl]-8'-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2',5'- dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N,2'-bis[(2S)-1,4-dioxan-2-ylmethyl]-8'-methyl-2',5'-dihydrospiro[cyclobutane-1,4'- furo[2,3-g]indazole]-7'-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-2'-[(2S)-1,4-dioxan-2-ylmethyl]-8'-methyl-2',5'- dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2-[(6-{[(2S)-tetrahydrofuran-2- ylmethyl]carbamoyl}pyridin-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-2-[(6-{[(2R)-1,4-dioxan-2-ylmethyl]carbamoyl}pyridin-3- yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 4,4,8-trimethyl-2-(pyridin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 8'-methyl-2'-(pyridin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8'-methyl-2'-(pyridin-2-ylmethyl)-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 8'-methyl-2'-(pyridin-3-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8'-methyl-2'-(pyridin-3-ylmethyl)-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N ,N ,8-trimethyl-N7'-[(2S)-tetrahydrofuran-2-ylmethyl]spiro[cyclopropane-1,4-furo[2,3- g]indazole]-2',7'(5'H)-dicarboxamide N7'-[(2R)-1,4-dioxan-2-ylmethyl]-N2',N2',8'-trimethylspiro[cyclopropane-1,4'-furo[2,3- g]indazole]-2',7'(5'H)-dicarboxamide benzyl 3-fluoro-3-[(8-methyl-7-{[(2S)-tetrahydrofuran-2-ylmethyl]carbamoyl}-4,5-dihydro- 2H-furo[2,3-g]indazol-2-yl)methyl]azetidine-1-carboxylate benzyl 3-[(8-methyl-7-{[(2S)-tetrahydrofuran-2-ylmethyl]carbamoyl}-4,5-dihydro-2H- furo[2,3-g]indazol-2-yl)methyl]azetidine-1-carboxylate 2-[(3-fluoroazetidin-3-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-(azetidin-3-ylmethyl)-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 2-(azetidin-3-ylmethyl)-N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 2-(2-aminoethyl)-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 2-(2-aminoethyl)-N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8-methyl-2-[2-(piperazin-1-yl)ethyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-8-methyl-2-[2-(piperazin-1-yl)ethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 2-[(1-acetylazetidin-3-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(1-acetyl-3-fluoroazetidin-3-yl)methyl]-8-methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-{[3-fluoro-1-(methylsulfonyl)azetidin-3-yl]methyl}-8-methyl-N-[(2S)-tetrahydrofuran-2- ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide methyl 3-fluoro-3-[(8-methyl-7-{[(2S)-tetrahydrofuran-2-ylmethyl]carbamoyl}-4,5-dihydro- 2H-furo[2,3-g]indazol-2-yl)methyl]azetidine-1-carboxylate 2'-[(2S)-1,4-dioxan-2-ylmethyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-8'-(trifluoromethyl)- 2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8-(trifluoromethyl)- 2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N-{[(2±)-5,5-dimethyloxolan-2-yl]methyl}-8-methyl-2-[(pyridin-2-yl)methyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-N-[(oxan-4-yl)methyl]-2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8-methyl-N-{[(2±)-oxan-2-yl]methyl}-2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8-methyl-N-{[(2±)-2-methyloxolan-2-yl]methyl}-2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-{[(2±)-4,4-difluorooxolan-2-yl]methyl}-8-methyl-2-[(pyridin-2-yl)methyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-N-[(4-methyltetrahydrofuran-2-yl)methyl]-2-(2-pyridylmethyl)-4,5- dihydrofuro[2,3-g]indazole-7-carboxamide 8-methyl-N-{[(2±,5±)-5-methyloxolan-2-yl]methyl}-2-[(pyridin-2-yl)methyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 2,5-anhydro-1,3,4-trideoxy-3-methyl-1-({8-methyl-2-[(pyridin-2-yl)methyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carbonyl}amino)-D-threo-pentitol (Racemate) 8-methyl-N-{[(6±)-5-oxaspiro[2.4]heptan-6-yl]methyl}-2-[(pyridin-2-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-{[(2±)-3,3-dimethyloxolan-2-yl]methyl}-8-methyl-2-[(pyridin-2-yl)methyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide N-{[(6±)-2,5-dioxaspiro[3.4]octan-6-yl]methyl}-8-methyl-2-[(pyridin-2-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-{[(2±)-6,6-dimethyl-1,4-dioxan-2-yl]methyl}-8-methyl-2-[(pyridin-2-yl)methyl]-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(4-fluoropyridin-2-yl)methyl]-8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 2-[(5-fluoropyridin-3-yl)methyl]-8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-2-[(pyridazin-3-yl)methyl]-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide N-{[(2R)-1,4-dioxan-2-yl]methyl}-8-methyl-2-[(pyridazin-3-yl)methyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 2-[(6-ethylpyridin-3-yl)methyl]-8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-[(6-ethylpyridin-3-yl)methyl]-8-methyl-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-2-[(1,3-oxazol-2-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-2-[(oxan-4-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 8-methyl-2-{[(2±)-oxan-2-yl]methyl}-N-{[(2S)-oxolan-2-yl]methyl}-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-[(6-methylpyridin-3-yl)methyl]-8-(trifluoromethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(6-methylpyridin-3-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-cyclopropyl-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-cyclopropyl-2-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(2S)-oxolan-2-yl]methyl}-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide N-{[(2±)-5,5-dimethyloxolan-2-yl]methyl}-2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'-methyl-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N-{[(2±)-6,6-dimethyl-1,4-dioxan-2-yl]methyl}-2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'-methyl- 2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N-{[(2±)-4,4-difluorooxolan-2-yl]methyl}-2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'-methyl-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'-methyl-N-{[(2±,5±)-5-methyloxolan-2-yl]methyl}-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 2-[[(2S)-1,4-dioxan-2-yl]methyl]-8-methyl-N-[(4-methyltetrahydrofuran-2- yl)methyl]spiro[5H-furo[2,3-g]indazole-4,1'-cyclopropane]-7-carboxamide 2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'-methyl-N-{[(6±)-5-oxaspiro[2.4]heptan-6-yl]methyl}- 2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 2-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(6±)-2,5-dioxaspiro[3.4]octan-6-yl]methyl}-8- methyl-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 2'-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(6R)-2,5-dioxaspiro[3.4]octan-6-yl]methyl}-8'- methyl-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 2'-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(6S)-2,5-dioxaspiro[3.4]octan-6-yl]methyl}-8'- methyl-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 8'-Methyl-2'-(pyridin-4-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2',5'- dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 8'-Methyl-2'-[(5-methylpyridin-2-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2',5'- dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide N-{[(2R)-1,4-dioxan-2-yl]methyl}-8'-methyl-2'-[(6-methylpyridin-3-yl)methyl]-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 8'-methyl-2'-[(6-methylpyridin-3-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N-{[(2R)-1,4-dioxan-2-yl]methyl}-2'-[(6-methylpyridin-3-yl)methyl]-8'-(trifluoromethyl)- 2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 2'-[(6-methylpyridin-3-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8'-(trifluoromethyl)-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 2'-[(5-methylpyridin-2-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8'-(trifluoromethyl)-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N-{[(2R)-1,4-dioxan-2-yl]methyl}-2'-[(5-methylpyridin-2-yl)methyl]-8'-(trifluoromethyl)- 2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N-[(2R)-1,4-Dioxan-2-ylmethyl]-2'-(pyridin-4-ylmethyl)-8'-(trifluormethyl)-2',5'- dihydrospiro[cyclopropan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 2'-(Pyridin-4-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-8'-(trifluormethyl)-2',5'- dihydrospiro[cyclopropan-1,4'-furo[2,3-g]indazol]-7'-carboxamide N-{[(2S)-oxolan-2-yl]methyl}-2'-[(pyridin-2-yl)methyl]-8'-(trifluoromethyl)-2',5'- dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N-[(2R)-1,4-Dioxan-2-ylmethyl]-2'-(pyridin-2-ylmethyl)-8'-(trifluormethyl)-2',5'- dihydrospiro[cyclopropan-1,4'-furo[2,3-g]indazol]-7'-carboxamide N,2-bis{[(2R)-1,4-dioxan-2-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 2-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(2S)-oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-{[(2±)-4,4-difluorooxolan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-{[(2R)-4,4-difluorooxolan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-{[(2S)-4,4-difluorooxolan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-{[(2±)-5,5-dimethyloxolan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-{[(2R)-5,5-dimethyloxolan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-{[(2S)-5,5-dimethyloxolan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(2±, 5±)-5-methyloxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(2R, 5R)-5-methyloxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(2S, 5R)-5-methyloxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(2R, 5S)-5-methyloxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(2S, 5S)-5-methyloxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-(1,3-thiazol-2-ylmethyl)-8-(trifluormethyl)-4,5-dihydro- 2H-furo[2,3-g]indazol-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[(5-methylpyrazin-2-yl)methyl]-8-(trifluormethyl)-4,5- dihydro-2H-furo[2,3-g]indazol-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-(pyrazin-2-ylmethyl)-8-(trifluormethyl)-4,5-dihydro-2H- furo[2,3-g]indazol-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[(1-methyl-1H-imidazol-4-yl)methyl]-8-(trifluormethyl)- 4,5-dihydro-2H-furo[2,3-g]indazol-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-(1,3-thiazol-5-ylmethyl)-8-(trifluormethyl)-4,5-dihydro- 2H-furo[2,3-g]indazol-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[2-(4-methylpyridin-2-yl)ethyl]-8-(trifluormethyl)-4,5- dihydro-2H-furo[2,3-g]indazol-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[2-(pyridin-2-yl)ethyl]-8-(trifluormethyl)-4,5-dihydro-2H- furo[2,3-g]indazol-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[2-(3-methyl-1H-pyrazol-1-yl)ethyl]-8-(trifluormethyl)- 4,5-dihydro-2H-furo[2,3-g]indazol-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[2-(1H-imidazol-4-yl)ethyl]-8-(trifluormethyl)-4,5- dihydro-2H-furo[2,3-g]indazol-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[2-(pyridin-3-yl)ethyl]-8-(trifluormethyl)-4,5-dihydro-2H- furo[2,3-g]indazol-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[2-(1,3-thiazol-2-yl)ethyl]-8-(trifluormethyl)-4,5-dihydro- 2H-furo[2,3-g]indazol-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[(6-methylpyridin-2-yl)methyl]-8-(trifluormethyl)-4,5- dihydro-2H-furo[2,3-g]indazol-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-(1,3-oxazol-4-ylmethyl)-8-(trifluormethyl)-4,5-dihydro- 2H-furo[2,3-g]indazol-7-carboxamide 2-{[(2S)-1,4-dioxan-2-yl]methyl}-N-[2-(pyrazin-2-yl)ethyl]-8-(trifluoromethyl)-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-[(oxan-4-yl)methyl]-8-(trifluoromethyl)-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide 2-[(oxan-4-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-(difluoromethyl)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-(difluoromethyl)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-N-{[(2S)-oxolan-2-yl]methyl}-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4±)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4,8-dimethyl-2-[(pyridin-2-yl)methyl]-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide (4±)-4,8-dimethyl-N-{[(2S)-oxolan-2-yl]methyl}-2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide (4±)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4,8-dimethyl-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4±)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4,8-dimethyl-N-{[(2S)-oxolan-2-yl]methyl}-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4±)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl-2-[(pyridin-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4±)-4-methyl-2-[(5-methyl-2-pyridyl)methyl]-N-[[(2S)-tetrahydrofuran-2-yl]methyl]-8- (trifluoromethyl)-4,5-dihydrofuro[2,3-g]indazole-7-carboxamide (4±)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl-2-[(6-methylpyridin-3-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4±)-4-methyl-2-[(6-methylpyridin-3-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4±)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4±)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1,3-oxazol-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1,3-oxazol-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(5-methylpyrazin-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(5-methylpyrazin-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1,3-thiazol-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1,3-thiazol-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(pyrazin-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(pyrazin-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1,3-oxazol-4-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1,3-oxazol-4-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-8-(trifluoromethyl)-N-{[2- (trifluoromethyl)pyrimidin-5-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-8-(trifluoromethyl)-N-{[2- (trifluoromethyl)pyrimidin-5-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide (4R)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl-2-[(oxan-4-yl)methyl]-8-(trifluoromethyl)- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl-2-[(oxan-4-yl)methyl]-8-(trifluoromethyl)- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-4-methyl-2-[(oxan-4-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-4-methyl-2-[(oxan-4-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4±)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8-methyl-4- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8-methyl-4- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8-methyl-4- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4±)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-4- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-{[(2S)-1,4-dioxan-2-yl]methyl}-8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-(4R)-4- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-{[(2S)-1,4-dioxan-2-yl]methyl}-8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-(4S)-4- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4,4-dimethyl-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-{[(2S)-1,4-dioxan-2-yl]methyl}-4,4-dimethyl-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-2'-[(2S)-1,4-dioxan-2-ylmethyl]-8'-(trifluormethyl)-2',5'- dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 2'-[(2S)-1,4-dioxan-2-ylmethyl]-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-8'-(trifluormethyl)- 2',5'-dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 2'-[(2S)-1,4-dioxan-2-ylmethyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-8'-(trifluormethyl)- 2',5'-dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 2'-{[(2S)-1,4-dioxan-2-yl]methyl}-N-[(1,3-oxazol-2-yl)methyl]-8'-(trifluoromethyl)-2',5'- dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N-[(2R)-1,4-Dioxan-2-ylmethyl]-2'-(pyridin-2-ylmethyl)-8'-(trifluormethyl)-2',5'- dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 2'-(Pyridin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-8'-(trifluormethyl)-2',5'- dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide N-(1,3-Oxazol-2-ylmethyl)-2'-(pyridin-2-ylmethyl)-8'-(trifluormethyl)-2',5'- dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide N-[(1-Methyl-1H-pyrazol-3-yl)methyl]-2'-(pyridin-2-ylmethyl)-8'-(trifluormethyl)-2',5'- dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 2'-[(5-Methylpyridin-2-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-8'-(trifluormethyl)- 2',5'-dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide N-[(2R)-1,4-Dioxan-2-ylmethyl]-2-[(5-methylpyridin-2-yl)methyl]-8-(trifluormethyl)-2,5- dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide N-[(1-Methyl-1H-pyrazol-3-yl)methyl]-2'-[(5-methylpyridin-2-yl)methyl]-8'-(trifluormethyl)- 2',5'-dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 2'-(Pyridin-4-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-8'-(trifluormethyl)-2',5'- dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide N-[(2R)-1,4-Dioxan-2-ylmethyl]-2'-(pyridin-4-ylmethyl)-8'-(trifluormethyl)-2',5'- dihydrospiro[cyclobutan-1,4'-furo[2,3-g]indazol]-7'-carboxamide 2-(cyclopropylmethyl)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro- 2H-furo[2,3-g]indazole-7-carboxamide N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[1-(methoxyacetyl)piperidin-4-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-{[1-(methoxyacetyl)piperidin-4-yl]methyl}-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-{[1-(cyclopropanecarbonyl)piperidin-4-yl]methyl}-N-{[(2R)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-{[1-(cyclopropanecarbonyl)piperidin-4-yl]methyl}-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(1-benzoylpiperidin-4-yl)methyl]-N-{[(2R)-1,4-dioxan-2-yl]methyl}-8-(trifluoromethyl)- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(1-benzoylpiperidin-4-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-2-[2-(pyridin-3-yl)propan-2-yl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide (4R)-2-{[1-(cyclopropanecarbonyl)piperidin-4-yl]methyl}-4-methyl-N-{[(2S)-oxolan-2- yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-2-{[1-(cyclopropanecarbonyl)piperidin-4-yl]methyl}-4-methyl-N-{[(2S)-oxolan-2- yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-2-{[1-(cyclopropanecarbonyl)piperidin-4-yl]methyl}-N-{[(2R)-1,4-dioxan-2- yl]methyl}-4-methyl-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide (4S)-2-{[1-(cyclopropanecarbonyl)piperidin-4-yl]methyl}-N-{[(2R)-1,4-dioxan-2- yl]methyl}-4-methyl-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide (4R)-2-[(1-acetylpiperidin-4-yl)methyl]-4-methyl-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-2-[(1-acetylpiperidin-4-yl)methyl]-4-methyl-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-2-{[1-(1-hydroxycyclopropane-1-carbonyl)piperidin-4-yl]methyl}-4-methyl-N-{[(2S)- oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide (4S)-2-{[1-(1-hydroxycyclopropane-1-carbonyl)piperidin-4-yl]methyl}-4-methyl-N-{[(2S)- oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide (4R)-2-[(1-acetylpiperidin-4-yl)methyl]-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-2-[(1-acetylpiperidin-4-yl)methyl]-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[1-(1-hydroxycyclopropane-1- carbonyl)piperidin-4-yl]methyl}-4-methyl-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide (4S)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[1-(1-hydroxycyclopropane-1- carbonyl)piperidin-4-yl]methyl}-4-methyl-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide (4R)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl-2-{[1-(2-oxobutanoyl)piperidin-4- yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl-2-{[1-(2-oxobutanoyl)piperidin-4- yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-4-methyl-2-{[1-(2-oxobutanoyl)piperidin-4-yl]methyl}-N-{[(2S)-oxolan-2-yl]methyl}- 8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-4-methyl-2-{[1-(2-oxobutanoyl)piperidin-4-yl]methyl}-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-4-methyl-2-{[1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl]methyl}-N-{[(2S)- oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide (4S)-4-methyl-2-{[1-(1-methylcyclopropane-1-carbonyl)piperidin-4-yl]methyl}-N-{[(2S)- oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide (4R)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl-2-{[1-(1-methylcyclopropane-1- carbonyl)piperidin-4-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide (4S)-N-{[(2R)-1,4-dioxan-2-yl]methyl}-4-methyl-2-{[1-(1-methylcyclopropane-1- carbonyl)piperidin-4-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7- carboxamide N,2-bis{[(2S)-1,4-dioxan-2-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 2-{[(2R)-1,4-dioxan-2-yl]methyl}-N-{[(2S)-1,4-dioxan-2-yl]methyl}-8-(trifluoromethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(2-methylpyrimidin-5-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(2-methylpyrimidin-5-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(5-methylpyrimidin-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(5-methylpyrimidin-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(pyrimidin-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(pyrimidin-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(1-acetylpiperidin-4-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(1-acetylpiperidin-4-yl)methyl]-N-{[(2R)-1,4-dioxan-2-yl]methyl}-8-(trifluoromethyl)- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-{[1-(cyclopropylmethyl)piperidin-4-yl]methyl}-N-{[(2S)-oxolan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(1-methylpiperidin-4-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-[(1-methylpiperidin-4-yl)methyl]-8-(trifluoromethyl)- 4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-{[1-(cyclopropylmethyl)piperidin-4-yl]methyl}-N-{[(2R)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(1-ethylpiperidin-4-yl)methyl]-N-{[(2S)-oxolan-2-yl]methyl}-8-(trifluoromethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-[(1-ethylpiperidin-4-yl)methyl]-8-(trifluoromethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2,5-anhydro-1,3,4-trideoxy-1-{[(4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carbonyl]amino}-4-methylpentitol 2,5-anhydro-1,3,4-trideoxy-1-{[(4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carbonyl]amino}-4-methylpentitol (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1-methyl-1H-imidazol-4-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1-methyl-1H-imidazol-4-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(6-methylpyridin-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(6-methylpyridin-2-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1,3-thiazol-5-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-N-[(1,3-thiazol-5-yl)methyl]-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-2-[(1±)-1-(pyridin-2-yl)ethyl]-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide 8-methyl-2-[(5-methylpyridin-2-yl)methyl]-N-[(3R)-oxolan-3-yl]-4,5-dihydro-2H-furo[2,3- g]indazole-7-carboxamide 2-[(5-cyanopyridin-2-yl)methyl]-8-methyl-N-{[(2S)-oxolan-2-yl]methyl}-4,5-dihydro-2H- furo[2,3-g]indazole-7-carboxamide N-{[(2R)-1,4-dioxan-2-yl]methyl}-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8-(trifluoromethyl)-4,5- dihydro-2H-furo[2,3-g]indazole-7-carboxamide N-[(5-cyclopropylpyrazin-2-yl)methyl]-2-{[(2S)-1,4-dioxan-2-yl]methyl}-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-N-[(5-cyclopropylpyrazin-2-yl)methyl]-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4S)-N-[(5-cyclopropylpyrazin-2-yl)methyl]-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-N-[(5-chloropyrazin-2-yl)methyl]-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4-methyl-8- (trifluoromethyl)-4,5-dihydro-2H-furo[2,
3-g]indazole-7-carboxamide (4S)-N-[(5-chloropyrazin-2-yl)methyl]-2-{[(2S)-1,
4-dioxan-2-yl]methyl}-4-methyl-8- (trifluoromethyl)-4,
5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, for the treatment or prophylaxis of diseases.
6. Use of a compound of formula (I) according to claims 1-5 for the treatment or prophylaxis of diabetic neuropathic pain.
7. Use of a compound of formula (I) according to claims 1-5 for the treatment or prophylaxis of chemotherapy induced neuropathic pain.
8. Use of a compound of formula (I) according to claims 1-5 for the treatment or prophylaxis of post-breast surgery pain.
9. Use of a compound of formula (I) according to claims 1-5 for the treatment or prophylaxis of cancer bone pain.
10. Use of a compound of formula (I) according to claims 1-5 for the treatment or prophylaxis of trigeminal neuralgia.
11. Use of a compound of formula (I) according to claims 1-5 for the treatment or prophylaxis of post-mastectomy pain.
12. Use of a compound of formula (I) according to claims 1-5 for the treatment or prophylaxis of fibromyalgia.
13. Use of a compound of formula (I) according to claims 1-5 for the treatment or prophylaxis of multiple sclerosis pain diseases.
14. Use of a compound of formula (I) according to claims 1-5 for the treatment or prophylaxis of post-herpetic neuralgia.
15. Use of a compound of formula (I) according to claims 1-5 for the treatment or prophylaxis of Fabry, gout, or bladder pain syndrome.
PCT/EP2023/078602 2022-10-18 2023-10-16 Furoindazole derivatives for the treatment of pain WO2024083705A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP22202234.5 2022-10-18
EP22202234 2022-10-18

Publications (1)

Publication Number Publication Date
WO2024083705A1 true WO2024083705A1 (en) 2024-04-25

Family

ID=83903248

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2023/078602 WO2024083705A1 (en) 2022-10-18 2023-10-16 Furoindazole derivatives for the treatment of pain

Country Status (1)

Country Link
WO (1) WO2024083705A1 (en)

Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6245796B1 (en) 1997-06-13 2001-06-12 Yamanouchi Pharmaceutical Co., Ltd. Tricyclic pyrrole or pyrazole derivative
WO2001083487A1 (en) 2000-04-28 2001-11-08 Yamanouchi Pharmaceutical Co., Ltd. Froindazole derivative
WO2005050225A2 (en) * 2003-10-31 2005-06-02 Bayer Healthcare Ag Diagnostics and therapeutics for diseases associated with g protein-coupled receptor 84 (gpr84)
WO2009023773A2 (en) 2007-08-15 2009-02-19 University Of Miami Galactokinase inhibitors
US20090163545A1 (en) 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms
WO2011071136A1 (en) 2009-12-11 2011-06-16 アステラス製薬株式会社 Therapeutic agent for fibromyalgia
WO2012112363A1 (en) 2011-02-14 2012-08-23 Merck Sharp & Dohme Corp. Cathepsin cysteine protease inhibitors
WO2013092791A1 (en) 2011-12-22 2013-06-27 Galapagos Nv Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
WO2014095798A1 (en) 2012-12-20 2014-06-26 Galapagos Nv Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders (gpr84 antagonists)
WO2015197550A1 (en) 2014-06-25 2015-12-30 Galapagos Nv Novel dihydropyridoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
WO2016085990A1 (en) 2014-11-24 2016-06-02 The Regents Of The University Of Michigan Compositions and methods relating to inhibiting serine hyrdoxymethyltransferase 2 activity
WO2016169911A1 (en) 2015-04-23 2016-10-27 Galapagos Nv Novel dihydropyridoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
WO2018161831A1 (en) 2017-03-06 2018-09-13 中国科学院上海药物研究所 Gpr84 receptor antagonist and use thereof
WO2019084271A1 (en) 2017-10-25 2019-05-02 Children's Medical Center Corporation Papd5 inhibitors and methods of use thereof
WO2021122415A1 (en) 2019-12-19 2021-06-24 Bayer Aktiengesellschaft Furoindazole derivatives
WO2022179940A1 (en) * 2021-02-23 2022-09-01 Bayer Aktiengesellschaft Furoindazole derivatives as gpr84 antagonists
WO2022229061A1 (en) * 2021-04-29 2022-11-03 Bayer Aktiengesellschaft Furoindazole derivatives as antagonists or inhibitors of gpr84

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6245796B1 (en) 1997-06-13 2001-06-12 Yamanouchi Pharmaceutical Co., Ltd. Tricyclic pyrrole or pyrazole derivative
WO2001083487A1 (en) 2000-04-28 2001-11-08 Yamanouchi Pharmaceutical Co., Ltd. Froindazole derivative
WO2005050225A2 (en) * 2003-10-31 2005-06-02 Bayer Healthcare Ag Diagnostics and therapeutics for diseases associated with g protein-coupled receptor 84 (gpr84)
WO2009023773A2 (en) 2007-08-15 2009-02-19 University Of Miami Galactokinase inhibitors
US20090163545A1 (en) 2007-12-21 2009-06-25 University Of Rochester Method For Altering The Lifespan Of Eukaryotic Organisms
WO2011071136A1 (en) 2009-12-11 2011-06-16 アステラス製薬株式会社 Therapeutic agent for fibromyalgia
WO2012112363A1 (en) 2011-02-14 2012-08-23 Merck Sharp & Dohme Corp. Cathepsin cysteine protease inhibitors
WO2013092791A1 (en) 2011-12-22 2013-06-27 Galapagos Nv Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
WO2014095798A1 (en) 2012-12-20 2014-06-26 Galapagos Nv Novel dihydropyrimidinoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders (gpr84 antagonists)
WO2015197550A1 (en) 2014-06-25 2015-12-30 Galapagos Nv Novel dihydropyridoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
WO2016085990A1 (en) 2014-11-24 2016-06-02 The Regents Of The University Of Michigan Compositions and methods relating to inhibiting serine hyrdoxymethyltransferase 2 activity
WO2016169911A1 (en) 2015-04-23 2016-10-27 Galapagos Nv Novel dihydropyridoisoquinolinones and pharmaceutical compositions thereof for the treatment of inflammatory disorders
WO2018161831A1 (en) 2017-03-06 2018-09-13 中国科学院上海药物研究所 Gpr84 receptor antagonist and use thereof
WO2019084271A1 (en) 2017-10-25 2019-05-02 Children's Medical Center Corporation Papd5 inhibitors and methods of use thereof
WO2021122415A1 (en) 2019-12-19 2021-06-24 Bayer Aktiengesellschaft Furoindazole derivatives
WO2022179940A1 (en) * 2021-02-23 2022-09-01 Bayer Aktiengesellschaft Furoindazole derivatives as gpr84 antagonists
WO2022229061A1 (en) * 2021-04-29 2022-11-03 Bayer Aktiengesellschaft Furoindazole derivatives as antagonists or inhibitors of gpr84

Non-Patent Citations (29)

* Cited by examiner, † Cited by third party
Title
"Isotopic Compositions of the Elements 1997", PURE APPL. CHEM., vol. 70, no. 1, 1998, pages 217 - 235
"IUPAC Rules Section E", PURE APPL CHEM, vol. 45, 1976, pages 11 - 30
A. E. MUTLIB ET AL., TOXICOL. APPL. PHARMACOL., vol. 169, 2000, pages 102
A. M. SHARMA ET AL., CHEM. RES. TOXICOL., vol. 26, 2013, pages 410
B. TESTA ET AL., INT. J. PHARM., vol. 19, no. 3, 1984, pages 271
BOUCHARD C. ET AL., GLIA, vol. 55, no. 8, June 2007 (2007-06-01), pages 790 - 800
C. J. WENTHUR ET AL., J. MED. CHEM., vol. 56, 2013, pages 5208
C. L. PERRIN ET AL., J. AM. CHEM. SOC., vol. 127, 2005, pages 9641
C. L. PERRIN ET AL., J. AM. CHEM. SOC., vol. 129, 2007, pages 4490
DATABASE EMBASE [online] ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL; 1 March 2018 (2018-03-01), SACHER F ET AL: "The medium-chain free fatty acid receptor GPR84 in endometriosis associated pain", XP002808817, Database accession no. EMB-621267647 *
F. MALTAIS ET AL., J. MED. CHEM., vol. 52, 2009, pages 7993
F. SCHNEIDER ET AL., ARZNEIM. FORSCH. / DRUG. RES., vol. 56, 2006, pages 295
GAGNON L. ET AL., AM. J. PATHOL., vol. 188, no. 5, May 2018 (2018-05-01), pages 1132 - 1148
HUANG Q. ET AL., DEV. COMP. IMMUNOL., vol. 45, no. 2, 2014, pages 252 - 258
LATTIN J.E. ET AL., IMMUNOME RES, vol. 4, 29 April 2008 (2008-04-29), pages 5
MUREDDA ET AL., ARCHIVES OF PHYSIOLOGY AND BIOCHEMISTRY, vol. 4, no. 2, 12 August 2017 (2017-08-12), pages 1 - 12
MUREDDA L. ET AL., ARCH. PHYSIOL. BIOCHEM., vol. 4, no. 2, 12 May 2018 (2018-05-12), pages 97 - 108
NAGASAKI H. ET AL., FEBS LETT., vol. 586, no. 4, 17 February 2012 (2012-02-17), pages 368 - 72
NGUYEN ET AL., ANNUAL CONGRESS SCIENTIFIC SESSIONS OF THE AMERICAN HEART ASSOCIATION (AHA 2018, 2018
NICOL L. S. C. ET AL: "The Role of G-Protein Receptor 84 in Experimental Neuropathic Pain", THE JOURNAL OF NEUROSCIENCE, vol. 35, no. 23, 10 June 2015 (2015-06-10), US, pages 8959 - 8969, XP093031266, ISSN: 0270-6474, DOI: 10.1523/JNEUROSCI.3558-14.2015 *
PUENGEL ET AL., 2018 INTERNATIONAL LIVER CONGRESS (ILC) OF THE EUROPEAN ASSOCIATION FOR THE STUDY OF THE LIVER (EASL, 2018
ROMAN ET AL., 7TH FORUM OF EUROPEAN NEUROSCIENCE (FENS, 2010
S. M. BERGE ET AL.: "Pharmaceutical Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104
SACHER F ET AL: "The medium-chain free fatty acid receptor GPR84 in endometriosis associated pain", REPRODUCTIVE SCIENCES 20180301 SAGE PUBLICATIONS INC. NLD, vol. 25, no. 1, 1 March 2018 (2018-03-01), pages 290A CONF 20180306 to 20180310 San Diego, CA - 65th Annu, ISSN: 1933-7205 *
SACHER F. ET AL., CONFERENCE ABSTRACT SRI, 2018
SANIERE L ET AL., 2019 INTERNATIONAL CONFERENCE OF THE AMERICAN THORACIC SOCIETY (ATS, 2019
SMITHTASI, NAT. PROD. REP., no. 5, 24 October 2007 (2007-10-24), pages 1041 - 72
SOTO-VACA A. ET AL., J. AGRIC. FOOD CHEM., vol. 61, no. 42, 23 October 2013 (2013-10-23), pages 10074 - 9
WANG J ET AL., J. BIOL. CHEM., vol. 281, no. 45, 10 November 2006 (2006-11-10), pages 34457 - 64

Similar Documents

Publication Publication Date Title
TW201840567A (en) PYRROLO[1,2-b]PYRIDAZINE DERIVATIVES
US20230227441A1 (en) 2-oxo-oxazolidine-5-carboxamides as nav1.8 inhibitors
KR20170106452A (en) 4h-pyrrolo[3,2-c]pyridin-4-one derivatives
JP7357617B2 (en) Modulators of beta-3 adrenergic receptors useful in the treatment or prevention of heart failure and related disorders
EA017952B1 (en) PYRROLO[2,3-d]PYRIDINES AND USE THEREOF AS TYROSINE KINASE INHIBITORS
EA024123B1 (en) Tetrahydro-pyrido-pyrimidine derivatives
US20230112499A1 (en) Furoindazole derivatives
WO2011149874A2 (en) N-phenyl imidazole carboxamide inhibitors of 3-phosphoinositide-dependent protein kinase-1
US11319324B2 (en) Pyrazolo-pyrrolo-pyrimidine-dione derivatives as P2X3 inhibitors
WO2020260463A1 (en) Analogues of 3-(5-methyl-1,3-thiazol-2-yl)-n-{(1r)-1-[2-(trifluoro-methyl)pyrimidin-5-yl]ethyl}benzamide
JP2022539208A (en) Tyrosine kinase non-receptor 1 (TNK1) inhibitors and uses thereof
BR112021008995A2 (en) heterocyclic derivatives like nav1.7 and nav1.8 blockers
US10196383B2 (en) Substituted quinazoline compounds and preparation and uses thereof
WO2022229061A1 (en) Furoindazole derivatives as antagonists or inhibitors of gpr84
WO2024083705A1 (en) Furoindazole derivatives for the treatment of pain
JP2022130716A (en) PYRROLO[1,2-b]PYRIDAZINE DERIVATIVE AS IRAK4 INHIBITOR
CA3211437A1 (en) Furoindazole derivatives as gpr84 antagonists
WO2023118092A1 (en) Pyrazolo[1,5-a]pyrido[3,2-e]pyrimidines and pyrazolo[1,5-a][1,3]thiazolo[5,4-e]pyrimidines as p2x3 inhibitors for the treatment of neurogenic disorders
CN117624187A (en) Efficient HPK1 degradation agent compound and preparation method and application thereof
WO2023239846A1 (en) Heterocyclic compounds as pi3kα inhibitors
JP2023519605A (en) Compounds active against nuclear receptors
EP4017858A1 (en) Organic compounds
EP3782997A1 (en) Fused pyrimidine compounds and pharmaceutical compositions thereof for the treatment of fibrotic diseases