furoindazole derivatives

Abstract

The present invention relates to a compound of general formula (I): [Formula 1] TIFF2023508908000648.tif64170, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7a , and R 7b as defined herein, methods for preparing said compounds, intermediate compounds useful in preparing said compounds, pharmaceutical compositions comprising said compounds, and the use of said compounds to manufacture pharmaceutical compositions for the treatment or prevention of diseases in humans and animals, particularly autoimmune diseases such as multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, primary and secondary autoimmune uveitis, inflammatory disorders such as endometriosis, inflammatory eye diseases, inflammatory kidney diseases, inflammatory liver diseases such as non-alcoholic, alcoholic, and toxic fatty liver, pulmonary diseases such as asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and metabolic and metabolic endocrine disorders such as metabolic syndrome, insulin resistance, type I and type II diabetes, and polycystic ovary syndrome (PCOS) disorders, neuropathic and inflammatory pain disorders.

Description

[Technical Field]

[0001] The present invention is directed to furoindazole compounds of general formula (I) as described and defined herein, to processes for preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions comprising said compounds, and to the use of said compounds for the manufacture of pharmaceutical compositions for the treatment or prevention of diseases, in particular autoimmune diseases such as multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, primary and secondary autoimmune uveitis, inflammatory disorders such as endometriosis, inflammatory eye diseases, inflammatory kidney diseases, inflammatory liver diseases such as non-alcoholic, alcoholic, and toxic fatty liver, lung diseases such as asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and metabolic and metabolic endocrine disorders such as metabolic syndrome, insulin resistance, type I and type II diabetes, and polycystic ovarian syndrome (PCOS) disorders, neuropathic and inflammatory pain disorders, etc. [Background technology]

[0002] The present invention covers furoindazole compounds of general formula (I), which are antagonists of G protein-coupled receptor 84 (also known as GPR84). The relevance of GPR84 to human diseases has been described and studied in several publications.

[0003] Medium-chain free fatty acids (MCFFAs) are fatty acids with a tail of 6 to 12 carbon atoms that can activate GPR84 (Wang J et al., J.Biol.Chem. 2006 Nov 10, 281(45): 34457-64). Animal metabolism has two sources of FAs: exogenous (dietary) and endogenously synthesized FAs. The biosynthesis of the latter is catalyzed by FASN. MCFFA stimulates the release of IL-6 from fibroblasts (Smith and Tasi, Nat. Prod. Rep. 2007 Oct., 24(5): 1041-72), and myristic acid increases IL-6 and IL-8 levels in human coronary artery smooth muscle (HCASM) and endothelial (HCEC) cells (Soto-Vaca A. et al., J. Agric. Food Chem. 2013 Oct., 61(42): 10074-9).

[0004] GPR84 belongs to the free fatty acid (FFA) receptor family (Wang J. et al., J. Biol. Chem. 2006 Nov 10, 281(45): 34457-64). The FFA receptor family consists of four GPCRs (FFA1-FFA2) and two 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).

[0005] GPR84 has been described to be predominantly expressed in various leukocyte populations and adipocytes, in contrast to all other FFA receptors, which have a broader expression pattern (Wang J. et al., J.Biol.Chem. 2006 Nov 10, 281(45): 34457-64; Lattin JE et al., Immunome Res. 2008 Apr 29, 4: 5; Nagasaki H. et al., FEBS Lett. 2012 Feb 17, 586(4): 368-72).

[0006] Activation of GPR84 promotes comprehensive fibrotic and inflammatory cellular responses, including promoting macrophage and neutrophil migration, promoting proinflammatory M1 macrophage polarization and responses, and secreting key inflammatory cytokines such as IL-1 beta and TNF alpha (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 responses, several diseases have been suggested to be GPR84-dependent.

[0007] GPR84, a microglia-associated protein, is expressed in neuroinflammatory conditions and has been described as a potential target for the treatment of multiple sclerosis (Bouchard C. et al., Glia 2007 Jun, 55(8): 790-800), and related endometriosis and inflammatory pain (Sacher F. et al. 2018, Conference Abstract SRI 2018). Furthermore, inhibition and / or knockout of GPR84 activity is effective in treating neuropathic pain in several preclinical models (Roman et al. 2010, 7th Forum of European Neuroscience (FENS)).

[0008] The relevance of GPR84 to inflammatory kidney disease has been demonstrated in experiments using Gpr84 knockout mice or GPR84 antagonists in models of renal fibrosis and inflammatory liver diseases such as non-alcoholic, alcoholic, and toxic fatty liver disease (Puengel et al. 2018, 2018 International Liver Congress (ILC) of the European Association for the Study of the Liver (EASL); Thibodeau JF et al. 2018, 51st Annual Meeting and Exposition of the American Society of Nephrology (ASN): Kidney Week 2018).

[0009] As previously described for macrophages and monocytes, inflammatory changes in adipose tissue promote the expression of GPR84 in adipocytes, and modulation of GPR84 regulates the immune response capacity of adipocytes (Muredda et al., Archives of Physiology and Biochemistry 2017 Aug, 124(2): 1-12), demonstrating the relevance of GPR84 in metabolic and metabolic endocrine disorders such as metabolic syndrome, insulin resistance, type I and type II diabetes, and polycystic ovary syndrome (PCOS) through normalization of adipose tissue inflammation.

[0010] Regulation of neutrophil activity and general inflammation by GPR84 has also been described to be associated with lung diseases such as 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)).

[0011] A few compounds are known as GPR84 antagonists, for example, International Patent Applications WO2013092791 and WO2014095798 disclose dihydropyrimidinoisoquinolinones that have activity as GPR84 antagonists, and such compounds have found utility in several therapeutic applications, including inflammatory conditions.

[0012] International Patent Applications WO2015197550 and WO2016169911 disclose related dihydropyridoisoquinolinones as GPR84 antagonists.

[0013] International Patent Application No. WO2018161831 discloses dibenzoannulene hydrogen phosphates as GPR84 antagonists.

[0014] International Patent Application No. WO2009023773 discloses galactokinase inhibitors identified by a high-throughput screening approach, with two of the identified hits being furoindazole compounds.

[0015] US Patent Application No. US20090163545 discloses compounds that alter the lifespan of eukaryotic organisms, identified by a cell-based phenotypic high-throughput screening approach. Two of the identified hits were furoindazole compounds.

[0016] US Patent Application No. US6245796B1, International Patent Application Nos. WO2001083487, and WO2011071136 disclose aromatic tricyclic pyrrole or pyrazole derivatives as 5-HT2c ligands.

[0017] International Patent Application No. WO2016085990 discloses compounds that were identified by a high-throughput screening approach and inhibit the activity of serine hydroxymethyltransferase 2. Nine of the identified hits were furoindazole compounds.

[0018] International Patent Application No. WO2019084271 discloses compounds that inhibit non-classical poly(A) RNA polymerase-associated domain-containing protein 5 (PAPD5), derived from diverse compound classes identified by high-throughput screening techniques. Eight of the identified hits were furoindazole compounds.

[0019] However, the state of the art does not describe the furoindazole compounds of general formula (I) of the present invention as described and defined herein.

[0020] It has now been found that the compounds of the invention have surprising and advantageous properties, which form the basis of the present invention.

[0021] In particular, the compounds of the present invention have surprisingly been found to be effective antagonists of human GPR84 and may be used to treat or prevent diseases, in particular autoimmune diseases such as multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, primary and secondary autoimmune uveitis, inflammatory disorders such as endometriosis, inflammatory eye diseases, inflammatory kidney diseases, inflammatory liver diseases such as non-alcoholic, alcoholic, and toxic fatty liver, lung diseases such as asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and metabolic and metabolic endocrine disorders such as metabolic syndrome, insulin resistance, type I and type II diabetes, and polycystic ovary syndrome (PCOS) disorders, neuropathic and inflammatory pain disorders, and the like. DISCLOSURE OF THE INVENTION

[0022] According to a first aspect, the present invention provides a compound of general formula (I):

[0023] [ka]

[0024] A compound of the formula: R 1 represents hydrogen, C1-C4-alkyl or C1-C4-haloalkyl; R 2 represents hydrogen, C1-C4-alkyl or C1-C4-haloalkyl; or R 1 and R 2 combine with the carbon atoms to which they are attached to form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring; R 3 represents C3-C6-cycloalkyl, 3- to 6-membered heterocycloalkyl, heterocycloalkyl fused with phenyl or heteroaryl, or heteroaryl, and said groups may be one or more times, independently of one another, R 8 optionally substituted with; or R 3represents phenyl, and may occur one or more times, independently of one another, as R 8 and optionally substituted with R 7a and R 7b represents deuterium; R 4 represents hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, or C3-C6-cycloalkyl; R 5 , R 6 are, independently of one another, 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 to phenyl or heteroaryl, 3- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-, heterospirocycloalkyl-(C 1- and wherein said 3- to 6-membered heterocycloalkyl, heterospirocycloalkyl, heterocycloalkyl fused with phenyl or heteroaryl, phenyl, or heteroaryl group may occur one or more times, independently of one another, as R 9 optionally substituted with; or R 5 and R 6 are joined to the nitrogen atom to which they are attached to 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, which may occur one or more times, independently of each other, as R 9 may be optionally substituted with; R 7a represents hydrogen, deuterium, or C1-C4-alkyl; R 7b represents hydrogen, deuterium, or C1-C4-alkyl; R8 is halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, C1-C 3- Haloalkoxy, C3-C6-cycloalkyl, C3-C6-cycloalkyl-(C1-C3-alkyl)-, R 13 -(C=O)-, R 10 -O-(C=O)-, R 11 -NH-(C=O)-, or R 12 -(SO2)- represents; R 9 is halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, H2N-C1-C4-alkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C3-C6-cycloalkyl, R 10 -O-(C=O)-, oxo, 5- to 6-membered heterocycloalkyl-, 5- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-, phenyl, or heteroaryl, wherein the phenyl or heteroaryl group is optionally substituted one or more times, independently of one another, with halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, or C1-C3-haloalkoxy; R 10 represents hydrogen, C1-C4-alkyl, or phenyl-CH2-; R 11 represents hydrogen, C1-C4-alkyl, or 5- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-; R 12 represents C1-C4-alkyl or phenyl; R 13 represents C1-C4-alkyl, C1-C4-haloalkyl, (C1-C4-alkoxy)-(C1-C4-alkyl)-, C1-C4-alkyl-(C=O)-, C3-C6-cycloalkyl, or phenyl, wherein the C3-C6-cycloalkyl group is optionally substituted by C1-C4-alkyl or hydroxy, and the phenyl group is optionally substituted one or more times, independently of one another, by halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, or C1-C3-haloalkoxy; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0025] definition The term "substituted" means that one or more hydrogen atoms on the specified atom or group are replaced with options selected from the indicated group, provided that the replacement does not exceed the normal valence of the specified atom under the existing circumstances. Combinations of substituents and / or variable substituents are permitted.

[0026] The term "optionally substituted" means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, an optionally substituted group can be substituted on any available carbon or nitrogen atom with as many optional substituents as is acceptable by replacing a hydrogen atom with a non-hydrogen substituent. Typically, the number of optional substituents, if present, can be 1, 2, 3, 4, or 5, particularly 1, 2, or 3.

[0027] As used herein, the term "one or more" means 1, 2, 3, 4, or 5, particularly 1, 2, 3, or 4, more particularly 1, 2, or 3, and even more particularly 1 or 2, for example in the definition of substituents in compounds of general formula (I) of the present invention.

[0028] As used herein, an oxo substituent refers to an oxygen atom that is attached to a carbon atom via a double bond.

[0029] When a composite substituent is composed of multiple moieties, such as (C-C-alkoxy)-(C-C-alkyl), the position of a given moiety can be any suitable position of the composite substituent, i.e., the C-C-alkoxy moiety can be attached to any carbon atom of the C-C-alkyl moiety of the (C-C-alkoxy)-(C-C-alkyl) group. A hyphen at the beginning or end of such a composite substituent indicates the point of attachment of the composite substituent to the rest of the molecule. When a ring comprising carbon atoms and optionally one or more heteroatoms, such as nitrogen, oxygen, or sulfur atoms, is substituted with a substituent, the substituent may be attached to any suitable position of the ring, provided that it is attached to a suitable carbon atom and / or a suitable heteroatom.

[0030] As used herein, the term "comprising" includes "consisting of."

[0031] In the text, when any item is referred to as "as mentioned in this specification", it means that it may be mentioned anywhere in the text.

[0032] Terms referred to in this text have the following meanings: The term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, in particular a fluorine atom, a chlorine atom, or a bromine atom.

[0033] The term "C1-C4-alkyl" means a linear or branched, saturated monovalent hydrocarbon radical having 1, 2, 3, or 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl. In particular, said radical has 1, 2, or 3 carbon atoms ("C1-C3-alkyl"), such as a methyl, ethyl, propyl, or isopropyl radical, and more particularly has 1 or 2 carbon atoms ("C1-C2-alkyl"), such as a methyl or ethyl radical.

[0034] The term "C2-C4-hydroxyalkyl" means a linear or branched saturated monovalent hydrocarbon radical, as the term "C2-C4-alkyl" is defined above, in which one hydrogen atom has been replaced by a hydroxy group, such as 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 radicals.

[0035] The term "C1-C4-haloalkyl" refers to a linear or branched, saturated, monovalent hydrocarbon radical, as the term "C1-C4-alkyl" is defined above, in which one or more hydrogen atoms are simultaneously or independently replaced by halogen atoms. In particular, the halogen atoms are fluorine atoms. The C1-C4-haloalkyl radical 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.

[0036] The term "C-C-alkoxy" means a linear or branched, saturated monovalent radical of the formula (C-C-alkyl)-O-, where the term "C-C-alkyl" is defined as above, such as a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or tert-butoxy radical.

[0037] The term "C1-C4-haloalkoxy" refers to a linear or branched, saturated, monovalent C1-C4-alkoxy group as defined above, in which one or more hydrogen atoms are simultaneously or independently replaced by a halogen atom. In particular, the halogen atom is a fluorine atom. The C1-C4-haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, or pentafluoroethoxy.

[0038] The term "C3-C6-cycloalkyl" means a saturated monovalent monocyclic hydrocarbon ring ("C3-C6-cycloalkyl") containing 3, 4, 5, or 6 carbon atoms. The C3-C6-cycloalkyl group is, for example, a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

[0039] The term "C3-C6-halocycloalkyl" means a saturated monovalent monocyclic hydrocarbon ring, as the term "C3-C6-halocycloalkyl" is defined above, in which one or more hydrogen atoms are simultaneously or independently replaced by halogen atoms. In particular, said halogen atoms are fluorine atoms.

[0040] The term "4- to 6-membered heterocycloalkyl" means a monocyclic saturated heterocycle having a total of 4, 5, or 6 ring atoms and containing one or two identical or different ring heteroatoms from the series N, O, and S, wherein the heterocycloalkyl group can be attached to the remainder of the molecule through any one of the carbon atoms or, if present, the nitrogen atom.

[0041] The heterocycloalkyl group may be, but is not limited to, a four-membered ring such as azetidinyl, oxetanyl, or thietanyl; or a five-membered ring such as tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,1-dioxythiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, or 1,3-thiazolidinyl; or a six-membered ring such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl, or 1,2-oxazinyl.

[0042] Specifically, "4- to 6-membered heterocycloalkyl" means a 4- to 6-membered heterocycloalkyl as defined above containing one ring nitrogen or oxygen atom and, optionally, one additional ring heteroatom from the series of N, O, and S. More specifically, "5- or 6-membered heterocycloalkyl" means a monocyclic saturated heterocycle having a total of 5 or 6 ring atoms, containing one ring nitrogen or oxygen atom and, optionally, one additional ring heteroatom from the series of N, O, and S.

[0043] The term "heterocycloalkyl fused to phenyl or heteroaryl" means a bicyclic heterocycle having a total of 8, 9, or 10 ring atoms, where the two rings share two adjacent ring atoms and the "heterocycloalkyl" portion contains one or two identical or different ring heteroatoms from the series: N, O, and / or S; the term "heteroaryl" means a monocyclic aromatic ring having 5 or 6 ring atoms (a "5- to 6-membered heteroaryl" group) containing at least one ring heteroatom and, optionally, one, two, or three additional ring heteroatoms from the series N, O, and / or S; said fused heterocycloalkyl group can be attached to the remainder of the molecule through any one of the carbon atoms or, if present, the nitrogen atom.

[0044] The term "heterospirocycloalkyl" means a bicyclic saturated heterocycle having a total of 6, 7, 8, 9, 10, or 11 ring atoms, wherein the two rings share one common ring carbon atom, and wherein the "heterospirocycloalkyl" contains one, two identical or different ring heteroatoms from the series: N, O, S; said heterospirocycloalkyl group can be attached to the remainder of the molecule through any one of the carbon atoms excluding the spiro carbon atom or, if present, the nitrogen atom.

[0045] Examples of the heterospirocycloalkyl group include azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, oxaspiro[3.3]heptyl, oxaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, azaspiro[4,5]decyl, oxazaspiro[5.5]undecyl, dia ... It is one of the further homologous skeletons such as pyro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, azaspiro[5.5]undecyl, or 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]-.

[0046] 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 having 5, 6, 9, or 10 ring atoms, containing at least one ring heteroatom and optionally 1, 2, or 3 additional ring heteroatoms from the series: N, O, and / or S, bonded via a ring carbon atom or, optionally, a ring nitrogen atom (where allowed by valence).

[0047] The heteroaryl group may be a 5-membered heteroaryl group, such as thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, or tetrazolyl; or a 6-membered heteroaryl group, such as pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl; or a tricyclic heteroaryl group, such as carbazolyl, acridinyl, or or phenazinyl, or a 9-membered heteroaryl group such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, isoindolyl, indolizinyl, or purinyl; or a 10-membered heteroaryl group such as quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxaline, or pteridinyl.

[0048] In general, and unless otherwise stated, a heteroaryl group includes all its possible isomeric forms, such as tautomers and positional isomers with respect to the point of attachment to the remainder of the molecule. Thus, for some illustrative, non-limiting 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.

[0049] Particularly, the heteroaryl group is a pyridinyl group.

[0050] The term "C1-C6", as used herein, for example in the context of the definitions "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 from 1 to 6, i.e., 1, 2, 3, 4, 5 or 6 carbon atoms.

[0051] Furthermore, as used herein, for example in the context of the definition of "C3-C8-cycloalkyl", the term "C3-C8" means a cycloalkyl group having a finite number of carbon atoms from 3 to 8, i.e., 3, 4, 5, 6, 7, or 8 carbon atoms.

[0052] When a range of values ​​is given, the range includes each value and subrange within the range.

[0053] for example: "C1-C6" means 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" includes 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-C 10 ” is C3, C4, C5, C6, C7, C8, C9, C 10 , C3-C 10 , C3-C9, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C 10 , C4-C9, C4-C8, C4-C7, C4-C6, C4-C5, C5-C 10 , C5-C9, C5-C8, C5-C7, C5-C6, C6-C 10 , C6-C9, C6-C8, C6-C7, C7-C 10 , C7-C9, C7-C8, C8-C 10 , C8-C9, and C9-C 10 encompasses; "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" includes C3, C4, C5, C6, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6; "C4-C8" includes 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" includes C4, C5, C6, C7, C4-C7, C4-C6, C4-C5, C5-C7, C5-C6, and C6-C7; "C4-C6" includes C4, C5, C6, C4-C6, C4-C5, and C5-C6; "C5-C 10 ” is C5, C6, C7, C8, C9, C 10 , C5-C 10 , C5-C9, C5-C8, C5-C7, C5-C6, C6-C 10 , C6-C9, C6-C8, C6-C7, C7-C 10 , C7-C9, C7-C8, C8-C 10 , C8-C9, and C9-C 10 encompasses; "C6-C 10 " is C6, C7, C8, C9, C 10 , C6-C 10 , C6-C9, C6-C8, C6-C7, C7-C 10 , C7-C9, C7-C8, C8-C 10 , C8-C9, and C9-C 10 Includes.

[0054] As used herein, the term "leaving group" refers to an atom or group of atoms that, during a chemical reaction, is removed as a stable species while retaining its bonding electrons. Specifically, such leaving groups are selected from the group comprising: halide, particularly 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.

[0055] Compounds of general formula (I) may exist as isotopic variations. Thus, the present invention includes one or more isotopic variations of compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).

[0056] The term "isotopic variant" of a compound or reagent is defined as a compound that exhibits a non-naturally occurring proportion of one or more isotopes that constitute such compound.

[0057] The term "isotopic variant of a compound of general formula (I)" is defined as a compound of general formula (I) that exhibits a non-naturally occurring proportion of one or more isotopes that constitute such compound.

[0058] The expression "non-naturally occurring proportion" means a proportion of such isotope that is higher than its natural abundance. The natural abundance of an isotope that will apply in this context is described in "Isotopic Compositions of the Elements 1997", Pure Appl. Pure Appl. Chem., 70(1), 217-235, 1998.

[0059] Examples of such isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, e.g. 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, etc. are listed.

[0060] For the treatment and / or prevention of disorders as defined herein, isotopic variants of compounds of general formula (I) preferably contain deuterium ("deuterium-containing compounds of general formula (I)"). One or more radioactive isotopes, e.g. 3 H or 14 Isotopic variations of compounds of general formula (I) incorporating C are useful, for example, in drug and / or substrate tissue distribution studies. These isotopes are particularly preferred for their ease of incorporation and detectability. 18 F or 11Positron-emitting isotopes, such as C, may be incorporated into the compounds of general formula (I). These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications. Deuterium-containing compounds of general formula (I) and 13 C-containing compounds can be used for mass spectrometry in preclinical or clinical research settings.

[0061] Isotopic variants of compounds of general formula (I) can generally be prepared by methods known to those skilled in the art, such as those described in the schemes and / or examples herein, by substituting a reagent for an isotopic variant of the reagent, preferably a deuterium-containing reagent. Depending on the desired site of deuteration, deuterium from DO can optionally be incorporated directly into the compound or into a reagent useful for synthesizing such a compound. Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic and acetylenic bonds is a rapid route for incorporating deuterium. Direct exchange of hydrogen for deuterium in hydrocarbon-containing functional groups can be achieved using metal catalysts (e.g., Pd, Pt, Rh) in the presence of deuterium gas. A variety of deuterated reagents and synthesis building blocks are commercially available from companies such as C / D / N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, Massachusetts, USA; and CombiPhos Catalysts, Inc., Princeton, New Jersey, USA.

[0062] The term "deuterium-containing compound of general formula (I)" is defined as a compound of general formula (I) in which one or more hydrogen atoms have been replaced with one or more deuterium atoms, and the abundance of deuterium at each deuterated position of the compound of general formula (I) is greater than the natural abundance of deuterium, about 0.015%. Specifically, 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 greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% at said position, preferably greater than 90%, 95%, 96%, or 97%, and more preferably greater than 98% or 99%. It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated positions.

[0063] Selective incorporation of one or more deuterium atoms into compounds of general formula (I) may alter the physicochemical properties of the molecule (e.g., acidity [CL Perrin, et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [CL Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271]) and / or metabolic profile, resulting in changes in the ratio of parent compound to metabolites or the amount of metabolites formed. Such changes may confer certain therapeutic advantages and may therefore be desirable in certain circumstances. Decreased metabolic rates and metabolic switching, resulting in altered metabolite ratios, have been reported (A.E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102). These changes in exposure to parent drugs and metabolites can have important consequences for the pharmacodynamics, tolerability, and maximal efficacy of deuterium-containing compounds of general formula (I). In some cases, deuterium substitution reduces or eliminates the formation of undesirable or toxic metabolites and promotes the formation of desirable metabolites (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 primary effect of deuteration is to reduce the rate of systemic clearance, thereby extending the biological half-life of the compound. Potential clinical advantages may include maintaining similar systemic exposure by increasing peak levels and decreasing trough levels, which may result in reduced side effects and / or increased maximal efficacy depending on the pharmacokinetic / pharmacodynamic relationship of the particular compound.ML-337 (CJ Wenthur et al., J. Med. Chem., 2013, 56, 5208) and odanacatib (K. Kassahun et al., WO2012 / 112363) are examples of this deuterium effect. Other examples have reported increased drug exposure without altering the rate of systemic clearance due to a decreased metabolic rate (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 that exhibit this effect may result in reduced dosing requirements (e.g., fewer doses or lower dosages to achieve the desired effect) and / or may result in a reduced metabolic burden.

[0064] A compound of general formula (I) may have multiple potential attack sites for metabolism. To optimize the above effects on physicochemical properties and metabolic profiles, a deuterium-containing compound of general formula (I) can be selected that has one or more specific patterns of deuterium-hydrogen exchange. In particular, the deuterium atoms of a deuterium-containing compound of general formula (I) are bonded to carbon atoms and / or their deuterium atoms are bonded to, for example, cytochrome P 450 The compound of general formula (I) is located at the site of attack for metabolic enzymes such as

[0065] When the plural of compounds, salts, polymorphs, hydrates, solvates, and the like is used herein, this is intended to mean also a single compound, salt, polymorph, isomer, hydrate, solvate, or the like.

[0066] By "stable compound" or "stable structure" is intended 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.

[0067] The compounds of the present invention optionally contain one or more asymmetric centers, depending on the location and nature of the various substituents desired. One or more asymmetric carbon atoms can be in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric center and diastereomeric mixtures in the case of multiple asymmetric centers. In some cases, asymmetry can exist due to restricted rotation around a given bond, for example, around the central bond adjacent to two substituted aromatic rings in a specified compound.

[0068] Preferred compounds are those that produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers, or racemic mixtures or diastereomeric mixtures of the compounds of the invention, are also within the scope of the present invention. Purification and separation of such materials can be accomplished by standard techniques known in the art.

[0069] Preferred isomers are those which result in the more desirable biological activity. These separated, pure or partially purified isomers, or racemic mixtures of the compounds of the invention, are also within the scope of the present invention. Purification and separation of such materials can be accomplished by standard techniques known in the art.

[0070] Optical isomers can be obtained by separating racemic mixtures according to conventional processes, for example, by forming diastereomeric salts using optically active acids or bases, or by forming covalent diastereomers. Examples of suitable acids are tartaric acid, diacetyltartaric acid, ditoluoyltartaric acid, and camphorsulfonic acid. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical and / or chemical differences by methods known in the art, for example, by chromatography or fractional crystallization. The optically active base or acid is then liberated from the separated diastereomeric salts. Different processes for separating optical isomers include the use of chiral chromatography (e.g., an HPLC column using a chiral phase) optimally selected to maximize the separation of enantiomers, with or without conventional derivatization. Suitable HPLC columns using chiral phases are commercially available, for example, those manufactured by Daicel, such as Chiracel OD and Chiracel OJ, among many others, all of which are routinely selectable. Enzymatic resolutions, with or without derivatization, are also useful.The optically active compounds of this invention can also be obtained by chiral syntheses utilizing optically active starting materials.

[0071] To distinguish different types of isomers from one another, reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

[0072] The present invention includes all possible stereoisomers of the compounds of the present invention, either as a single stereoisomer or as any mixture of said stereoisomers, e.g., (R)- or (S)-isomers, in any ratio. Isolation of a single stereoisomer of a compound of the present invention, e.g., a single enantiomer or a single diastereomer, is achieved by any suitable method in the art, such as chromatography, in particular chiral chromatography.

[0073] Furthermore, compounds of the invention may exist as tautomers. For example, any compound of the invention containing an indazole moiety may exist as a 1H tautomer, or a 2H tautomer, i.e.:

[0074] [ka] , or furthermore may exist as a mixture of any amount of the two tautomers.

[0075] The present invention includes all possible tautomers of the compounds of the present invention, either as single tautomers or as any mixture of said tautomers, in any ratio.

[0076] Additionally, the compounds of 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 oxidized, and the present invention includes all such possible N-oxides.

[0077] The present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, particularly pharmaceutically acceptable salts, and / or coprecipitates.

[0078] The compounds of the present invention can exist as hydrates or solvates, and the compounds of the present invention contain polar solvents, particularly water, methanol, or ethanol, as structural elements of the crystalline lattice of the compounds. The amount of polar solvent, particularly water, may be present in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, such as hydrates, hemi-, semi-, mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates are possible. The present invention includes all such hydrates or solvates.

[0079] Furthermore, the compounds of the present invention may exist in free form, for example as a free base, or as a free acid, or as a zwitterion, or may exist in the form of a salt, which may be any salt, either an organic or inorganic addition salt, in particular a pharmaceutically acceptable organic or inorganic addition salt, conventionally used in pharmacy or, for example, an addition salt used to isolate or purify the compounds of the present invention.

[0080] The term "pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present invention. See, for example, SM Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.

[0081] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, sufficiently basic, acid addition salts of compounds of the present invention bearing a nitrogen atom, such as linear or cyclic, with, for example, inorganic acids, or "mineral acids", such as hydrochloric acid, hydrobromic acid, valeric acid, sulfuric acid, sulfamic acid, bisulfuric acid, phosphoric acid, or nitric acid, or with organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, The acid addition salts may also be those with pamoic acid, pectinic acid, 3-phenylpropionic acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, or thiocyanic acid.

[0082] Furthermore, other suitable pharmaceutically acceptable salts of the compounds of the invention that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium, magnesium or strontium salts, or aluminum or zinc salts, or salts derived from ammonia or organic primary, secondary or tertiary amines having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N-methylmonomethyl ... Ammonium salts derived from ammonium phosphate, 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 salts with quaternary ammonium ions having 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N-trimethylammonium, choline, or benzalkonium ions.

[0083] Those skilled in the art will further recognize that acid addition salts of the claimed compounds may be prepared by reacting the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali metal and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.

[0084] The present invention includes all possible salts of the compounds of the present invention, either as single salts or as any mixture of said salts in any ratio.

[0085] When compounds are mentioned in the present text, and in particular in the experimental section, for the synthesis of intermediates and examples of the present invention in the form of salts with the corresponding bases or acids, the exact stoichiometric composition of said salt forms as obtained by the respective preparation and / or purification processes is in most cases unknown.

[0086] Unless otherwise specified, the suffix of the chemical name or structural formula for the salt, e.g., "hydrochloride," "trifluoroacetate," "sodium salt," or "x HCl," "x CF3COOH," "x Na + " and the like refer to a salt form, the stoichiometry of which is not specified.

[0087] This also applies analogously if the synthetic intermediates or example compounds or their salts are obtained by the preparation and / or purification processes described as solvates of unknown stoichiometry (if defined), e.g. hydrates.

[0088] Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as a single polymorph or as a mixture of two or more polymorphs in any ratio.

[0089] Moreover, the present invention also includes prodrugs of compounds according to the invention, where the term "prodrug" designates a compound which may itself be biologically active or inactive, and which is converted (e.g., by metabolism or hydrolysis) into a compound according to the invention during its residence in the body.

[0090] According to a second embodiment of the first aspect, the present invention provides a compound of general formula (I) above, wherein: R 1 represents hydrogen, C1-C4-alkyl or C1-C4-haloalkyl; R 2 represents hydrogen, C1-C4-alkyl or C1-C4-haloalkyl; or R 1 and R 2 combine with the carbon atoms to which they are attached to form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring; R 3 represents C3-C6-cycloalkyl, 3- to 6-membered heterocycloalkyl, heterocycloalkyl fused with phenyl or heteroaryl, or heteroaryl, and said groups may be one or more times, independently of one another, R 8 optionally substituted with; or R 3 represents phenyl, and may occur one or more times, independently of one another, as R 8 and optionally substituted with R 7a and R 7b represents deuterium; R 4 represents hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, or C3-C6-cycloalkyl; R 5 , R 6 represent, independently of one another, hydrogen, C-C-alkyl, C-C-hydroxyalkyl, (C-C-alkoxy)-(C-C-alkyl)-, C-C-cycloalkyl, C-C-haloalkyl, C-C-halocycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, heteroaryl, heterocycloalkyl fused to phenyl or heteroaryl, 3- to 6-membered heterocycloalkyl-(C-C-alkyl)-, (heterocycloalkyl fused to phenyl or heteroaryl)-(C-C-alkyl)-, phenyl-(C-C-alkyl)-, or heteroaryl-(C-C-alkyl)-, and said 3- to 6-membered heterocycloalkyl, phenyl, or heteroaryl group may, one or more times, independently of one another, be selected from R 9 optionally substituted with; or R 5 and R 6are joined to the nitrogen atom to which they are attached to 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, which may occur one or more times, independently of each other, as R 9 may be optionally substituted with; R 7a represents hydrogen, deuterium, or C1-C4-alkyl; R 7b represents hydrogen, deuterium, or C1-C4-alkyl; R 8 is halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C3-C6-cycloalkyl, C1-C4-alkyl-(C=O)-, R 10 -O-(C=O)-, R 11 -NH-(C=O)-, or R 12 -(SO2)- represents; R 9 is halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, H2N-C1-C4-alkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C3-C6-cycloalkyl, R 10 -O-(C=O)-, oxo, 5- to 6-membered heterocycloalkyl-, 5- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-, phenyl, or heteroaryl, wherein the phenyl or heteroaryl group is optionally substituted one or more times, independently of one another, with halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, or C1-C3-haloalkoxy; R 10 represents hydrogen, C1-C4-alkyl, or phenyl-CH2-; R 11 represents hydrogen, C1-C4-alkyl, or 5- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-; R 12 represents C1-C4-alkyl or phenyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0091] According to a third embodiment of the first aspect, the present invention provides a compound of the above general formula (I), wherein: R 1 represents hydrogen, C1-C4-alkyl or C1-C4-haloalkyl; R 2 represents hydrogen, C1-C4-alkylalkyl; or R 1 and R 2 combine with the carbon atoms to which they are attached to form a 3- to 4-membered cycloalkyl or heterocycloalkyl ring; R 3 represents C3-C6-cycloalkyl, 4- to 6-membered heterocycloalkyl, heterocycloalkyl fused with heteroaryl, or heteroaryl, and said groups may be one or more times, independently of one another, R 8 optionally substituted with; or R 3 represents phenyl, and may occur one or more times, independently of one another, as R 8 and optionally substituted with R 7a and R 7b represents deuterium; R 4 represents hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, or C3-C6-cycloalkyl; R 5 , R 6represent, independently of one another, hydrogen, C2-C4-hydroxyalkyl, (C1-C4-alkoxy)-(C2-C4-alkyl)-, 3- to 6-membered heterocycloalkyl, heterocycloalkyl, phenyl, heteroaryl, 4- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-, heterospirocycloalkyl-(C1-C3-alkyl)-, (heterocycloalkyl fused to heteroaryl)-(C1-C3-alkyl)-, or heteroaryl-(C1-C3-alkyl)-, and said 3- to 6-membered heterocycloalkyl, phenyl, or heteroaryl group may, one or more times, independently of one another, be selected from R 9 optionally substituted with, or R 5 and R 6 are joined to the nitrogen atom to which they are attached to form a five-membered nitrogen-containing heterocyclic ring, which heterocyclic ring is joined once by R 9 may be optionally substituted with; R 7a represents hydrogen, deuterium, or methyl; R 7b represents hydrogen, deuterium, or methyl; R 8 is halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, C3-C6-cycloalkyl, C3-C6-cycloalkyl-(C1-C3-alkyl)-, R 13 -(C=O)-, R 10 -O-(C=O)-, R 11 -NH-(C=O)-, or R 12 -(SO2)- represents; R 9 is halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, H2N-C1-C4-alkyl, C3-C6-cycloalkyl, R 10 -O-(C=O)-, oxo, 6-membered heterocycloalkyl-(C1-C3-alkyl)-, phenyl, or heteroaryl, wherein the phenyl or heteroaryl group is optionally substituted one or more times, independently of one another, with halogen, C1-C4-haloalkyl, or C1-C3-alkoxy; R10 represents hydrogen, C1-C4-alkyl, or phenyl-CH2-; R 11 represents a 5- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-; R 12 represents C1-C4-alkyl; R 13 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 by methyl or hydroxy; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0092] According to a fourth embodiment of the first aspect, the present invention provides a compound of general formula (I) above, wherein: R 1 represents hydrogen, methyl, or trifluoromethyl; R 2 represents hydrogen or methyl; or R 1 and R 2 combine with the carbon atoms to which they are attached to 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, and said groups may occur one or more times, independently of one another, as R 8 optionally substituted with, or R 3 represents phenyl, and may occur one or more times, independently of one another, as R 8 and optionally substituted with R 7a and R 7b represents deuterium; R 4 represents hydrogen, methyl, C1-haloalkyl, or cyclopropyl; R 5represents hydrogen; R 6 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)-, and said 4- to 6-membered heterocycloalkyl or heteroaryl group may, one or more times, independently of one another, be R 9 optionally substituted with; R 7a represents hydrogen, deuterium, or methyl; R 7b represents hydrogen, deuterium, or methyl; R 8 is fluoro, chloro, C1-C2-alkyl, trifluoromethyl, C1-C3-alkoxy, cyclopropyl, cyclopropylmethyl, R 13 -(C=O)-, R 10 -O-(C=O)-, R 11 -NH-(C=O)-, or R 12 -(SO2)- represents; R 9 represents fluoro, chloro, C1-C3-alkyl, trifluoromethyl, cyclopropyl, or oxo; R 10 represents C1-C4-alkyl, or phenyl-CH2-; R 11 represents a 5- to 6-membered heterocycloalkyl-methyl; R 12 represents methyl; R 13 represents methyl, methoxymethyl, ethyl-(C═O)—, cyclopropyl, or phenyl, said cyclopropyl group being optionally substituted with methyl or hydroxy; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0093] According to a fifth embodiment of the first aspect, the present invention provides a compound of general formula (I) above, wherein: R 1 represents hydrogen or methyl; R 2 represents hydrogen or methyl; or R 1 and R 2 combine with the carbon atoms to which they are attached to form a 3- to 4-membered cycloalkyl ring; R 3 is 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

[0094] [ka]

[0095] [ka]

[0096] [ka]

[0097] [ka]

[0098] [ka]

[0099] [ka]

[0100] [ka]

[0101] [ka]

[0102] [ka]

[0103] [ka]

[0104] [ka]

[0105] [ka]

[0106] [ka]

[0107] [ka]

[0108] or R 3 represents phenyl, and R 7a and R7b represents deuterium; R 4 represents methyl, difluoromethyl, trifluoromethyl, or cyclopropyl; R 5 represents hydrogen; R 6 but (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]pyridine -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; R 7a represents hydrogen; R 7b represents hydrogen; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0109] Further embodiments of the first aspect of the present invention: In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 1 represents hydrogen, C1-C4-alkyl or C1-C4-haloalkyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0110] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 1 represents hydrogen, methyl, or trifluoromethyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0111] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 1 represents hydrogen, C1-C4-alkyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0112] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 1 represents hydrogen, C1-C3-alkyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0113] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 1 represents hydrogen or methyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0114] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 2 represents hydrogen, C1-C4-alkyl or C1-C4-haloalkyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0115] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 2 represents hydrogen, C1-C4-alkyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0116] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 2 represents hydrogen, C1-C3-alkyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0117] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 2 represents hydrogen or methyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0118] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 1 and R 2 combine with the carbon atom to which they are attached to form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0119] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 1 and R 2 combine with the carbon atom to which they are attached to form a 3- to 6-membered cycloalkyl ring; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0120] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 1 and R 2 combine with the carbon atom to which they are attached to form a 3- to 5-membered cycloalkyl ring; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0121] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 1 and R 2 combine with the carbon atom to which they are attached to form a 3- to 4-membered cycloalkyl ring; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0122] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 3 represents C3-C6-cycloalkyl, 3- to 6-membered heterocycloalkyl, heterocycloalkyl fused with phenyl or heteroaryl, or heteroaryl, and said groups may be one or more times, independently of one another, R 8 optionally substituted with; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0123] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 3 represents C3-C6-cycloalkyl, 4- to 6-membered heterocycloalkyl, heterocycloalkyl fused with phenyl or heteroaryl, or 5- to 6-membered heteroaryl, and said groups may occur one or more times, independently of one another, as R 8 optionally substituted with; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0124] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 3 represents C3-C6-cycloalkyl, 4- to 6-membered heterocycloalkyl, heterocycloalkyl fused to heteroaryl, or 5- to 6-membered heteroaryl, and said groups may occur one or more times, independently of one another, as R 8 optionally substituted with; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0125] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 3 represents cyclopropyl, 4- to 6-membered heterocycloalkyl, 2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-yl, or 5- to 6-membered heteroaryl, and said groups may occur one or more times, independently of one another, as R 8 optionally substituted with; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0126] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 3 represents C3-C6-cycloalkyl, 4- to 6-membered heterocycloalkyl, heterocycloalkyl fused with heteroaryl, or heteroaryl, and said groups may be one or more times, independently of one another, R 8 optionally substituted with; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0127] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 3 represents cyclopropyl, 4- to 6-membered heterocycloalkyl, 2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-yl, or heteroaryl, and said groups may occur one or more times, independently of one another, as R 8 optionally substituted with; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0128] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 3is 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

[0129] [ka]

[0130] [ka]

[0131] [ka]

[0132] [ka]

[0133] [ka]

[0134] [ka]

[0135] [ka]

[0136] [ka]

[0137] [ka]

[0138] [ka]

[0139] [ka]

[0140] [ka]

[0141] [ka]

[0142] [ka]

[0143] represents a group selected from: The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0144] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 3 represents phenyl, and may occur one or more times, independently of one another, as R 8 and optionally substituted with R 7a and R 7b represents deuterium; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0145] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 3 represents phenyl and may occur one or two times, independently of each other, as R 8 and optionally substituted with R 7a and R 7b represents deuterium; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0146] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 3 represents phenyl, and R 7a and R 7b represents deuterium; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0147] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 4 represents hydrogen, C1-C4-alkyl, C1-C4-haloalkyl, or C3-C6-cycloalkyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0148] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 4 represents hydrogen, C1-C3-alkyl, C1-C3-haloalkyl, or C3-C6-cycloalkyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0149] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 4 represents hydrogen, C1-C3-alkyl, C1-C3-haloalkyl or C3-C5-cycloalkyl, The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0150] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 4 represents hydrogen, methyl, C1-haloalkyl, or cyclopropyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0151] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 4 represents hydrogen, methyl, trifluoromethyl, or cyclopropyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0152] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 5 , R 6are, independently of one another, 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 to phenyl or heteroaryl, 3- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-, hetero and wherein the 3- to 6-membered heterocycloalkyl, heterospirocycloalkyl, heterocycloalkyl fused with phenyl or heteroaryl, phenyl, or heteroaryl group may, one or more times, independently of each other, be selected from the group consisting of R 9 optionally substituted with; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0153] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 5 , R 6 represent, independently of one another, 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 to a heteroaryl)-(C1-C3-alkyl)-, or heteroaryl-(C1-C3-alkyl)-, and said 3- to 6-membered heterocycloalkyl, phenyl, or heteroaryl group may, one or more times, independently of one another, be R 9 optionally substituted with; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0154] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 5 , R 6 represent, independently of one another, hydrogen, C-C-alkyl, C-C-hydroxyalkyl, (C-C-alkoxy)-(C-C-alkyl)-, C-C-cycloalkyl, C-C-haloalkyl, C-C-halocycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, heteroaryl, heterocycloalkyl fused to phenyl or heteroaryl, 3- to 6-membered heterocycloalkyl-(C-C-alkyl)-, (heterocycloalkyl fused to phenyl or heteroaryl)-(C-C-alkyl)-, phenyl-(C-C-alkyl)-, or heteroaryl-(C-C-alkyl)-, and said 3- to 6-membered heterocycloalkyl, phenyl, or heteroaryl group may, one or more times, independently of one another, be selected from R 9 optionally substituted with; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0155] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 5 and R 6 are joined to the nitrogen atom to which they are attached to 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, which may occur one or more times, independently of each other, as R 9 may be optionally substituted with; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0156] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 5 and R 6 are joined to the nitrogen atom to which they are attached to form a 5- to 6-membered nitrogen-containing heterocyclic ring, optionally containing one additional heteroatom or heteroatom-containing group selected from O, NH, and S, which may occur one or more times, independently of each other, as R 9 may be optionally substituted with; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0157] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 5 and R 6 are joined to the nitrogen atom to which they are attached to form a 5- to 6-membered nitrogen-containing heterocyclic ring, which heterocyclic ring may be one or more times selected from the group consisting of R 9 may be optionally substituted with; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0158] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 5 and R 6 combine with the nitrogen atom to which they are attached to form a 5-membered nitrogen-containing heterocyclic ring, which heterocycle is substituted with aminomethyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0159] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 5 represents hydrogen; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0160] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 6 represents methoxy-ethyl, 5-membered heteroaryl, 4- to 5-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)-, and said 4- to 5-membered heterocycloalkyl or heteroaryl group may, one or more times, independently of one another, be R 9 optionally substituted with; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0161] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 6but (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]pyridine -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; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0162] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 6represent hydrogen, C-C-alkyl, C-C-hydroxyalkyl, (C-C-alkoxy)-(C-C-alkyl)-, C-C-cycloalkyl, C-C-haloalkyl, C-C-halocycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, heteroaryl, heterocycloalkyl fused to phenyl or heteroaryl, 3- to 6-membered heterocycloalkyl-(C-C-alkyl)-, (heterocycloalkyl fused to phenyl or heteroaryl)-(C-C-alkyl)-, phenyl-(C-C-alkyl)-, or heteroaryl-(C-C-alkyl)-, and said 3- to 6-membered heterocycloalkyl, phenyl, or heteroaryl group may, one or more times, independently of one another, be selected from the group consisting of R 9 optionally substituted with; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0163] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 6 represents C1-C3-alkyl, C2-C4-hydroxyalkyl, (C1-C3-alkoxy)-(C2-C4-alkyl)-, C3-C5-cycloalkyl, C1-C3-haloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, heterocycloalkyl fused to a heteroaryl, 4- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-, (heterocycloalkyl fused to a heteroaryl)-(C1-C3-alkyl), phenyl-(C1-C3-alkyl)-, or 5- to 6-membered heteroaryl-(C1-C3-alkyl)-, and said 4- to 6-membered heterocycloalkyl, phenyl, or heteroaryl group may, one or more times, independently of one another, be selected from the group consisting of R 9 optionally substituted with; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0164] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 6 represents C2-C4-hydroxyalkyl, methoxy-(C2-C4-alkyl)-, phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl-(C1-C2-alkyl)-, (2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-yl)-methyl, phenyl-(C1-C2-alkyl)-, or 5- to 6-membered heteroaryl-methyl, and said 4- to 6-membered heterocycloalkyl, phenyl, or heteroaryl group may, one or more times, independently of one another, be selected from the group consisting of R 9 optionally substituted with; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0165] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 7a represents hydrogen, deuterium, or C1-C4-alkyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0166] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 7b represents hydrogen, deuterium, or C1-C4-alkyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0167] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 7a represents hydrogen, deuterium, or methyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0168] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 7b represents hydrogen, deuterium, or methyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0169] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 7a represents hydrogen or deuterium; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0170] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 7b represents hydrogen or deuterium; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0171] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 7a represents hydrogen; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0172] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 7b represents hydrogen; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0173] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 8 is halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, C1-C 3- Haloalkoxy, C3-C6-cycloalkyl, C3-C6-cycloalkyl-(C1-C3-alkyl)-, R 13 -(C=O)-, R 10 -O-(C=O)-, R 11 -NH-(C=O)-, or R 12 -(SO2)-represents; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0174] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 8 is halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, C3-C6-cycloalkyl, C3-C6-cycloalkyl-(C1-C3-alkyl)-, R 13 -(C=O)-, R 10 -O-(C=O)-, R 11 -NH-(C=O)-, or R 12 -(SO2)-represents; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0175] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 8 is fluoro, chloro, C1-C2-alkyl, trifluoromethyl, C1-C3-alkoxy, cyclopropyl, cyclopropylmethyl, R 13 -(C=O)-, R 10 -O-(C=O)-, R 11 -NH-(C=O)-, or R 12 -(SO2)-represents; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0176] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 8 is halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C3-C6-cycloalkyl, C1-C4-alkyl-(C=O)-, R 10 -O-(C=O)-, R 11 -NH-(C=O)-, or R 12 -(SO2)-represents; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0177] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 8 is halogen, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, C3-C6-cycloalkyl, C1-C3-alkyl-(C=O)-, R 10 -O-(C=O)-, R 11 -NH-(C=O)-, or R 12 -(SO2)-represents; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0178] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 8 is fluoro, chloro, methyl, trifluoromethyl, ethoxy, cyclopropyl, methyl-(C=O)-, R 10 -O-(C=O)-, R 11 -NH-(C=O)-, or R 12 -(SO2)-represents; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0179] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 9 is halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, H2N-C1-C4-alkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, C3-C6-cycloalkyl, R 10 -O-(C=O)-, oxo, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-, phenyl, or heteroaryl, wherein the phenyl or heteroaryl group is optionally substituted one or more times, independently of one another, with halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, or C1-C3-haloalkoxy; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0180] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 9 is halogen, cyano, C1-C4-alkyl, C1-C4-haloalkyl, H2N-C1-C4-alkyl, C3-C6-cycloalkyl, R 10 -O-(C=O)-, oxo, 6-membered heterocycloalkyl-(C1-C3-alkyl)-, phenyl, or heteroaryl, wherein the phenyl or heteroaryl group is optionally substituted one or more times, independently of one another, with halogen, C1-C4-haloalkyl, or C1-C3-alkoxy; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0181] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 9 is halogen, cyano, C1-C3-alkyl, C1-C3-haloalkyl, H2N-C1-C3-alkyl, C1-C3-alkoxy, C3-C6-cycloalkyl, R 10 represents -O-(C=O)-, oxo, 5- to 6-membered heterocycloalkyl-, 5- to 6-membered heterocycloalkyl-(C1-C2-alkyl)-, phenyl, or 5- to 6-membered heteroaryl, wherein the phenyl or heteroaryl group is optionally substituted one or more times, independently of one another, by halogen, C1-C3-alkyl, C1-C3-haloalkyl, or C1-C3-alkoxy; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0182] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 9 is fluoro, cyano, C1-C3-alkyl, trifluoromethyl, aminomethyl, ethoxy, cyclopropyl, R 10 -O-(C=O)-, oxo, 6-membered heterocycloalkyl-methyl, phenyl, or 5- to 6-membered heteroaryl, wherein said phenyl or heteroaryl group is optionally substituted with chloro, trifluoromethyl, or methoxy; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0183] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 9 represents fluoro, chloro, C1-C3-alkyl, trifluoromethyl, cyclopropyl, or oxo; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0184] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 10 represents hydrogen, C1-C4-alkyl, or phenyl-CH2-; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0185] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 10 represents C1-C4-alkyl, or phenyl-CH2-; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0186] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 11 represents hydrogen, C1-C4-alkyl, or 5- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0187] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 11 represents C1-C4-alkyl or 5- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0188] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 11 represents C1-C3-alkyl or 5- to 6-membered heterocycloalkyl-(C1-C2-alkyl)- The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0189] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 11 represents C1-C3-alkyl or 5- to 6-membered heterocycloalkyl-methyl The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0190] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 11 represents a 5- to 6-membered heterocycloalkyl-(C1-C3-alkyl)-; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0191] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 11 represents a 5- to 6-membered heterocycloalkyl-methyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0192] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 11 represents tetrahydrofuran-2-yl-methyl, or 1,4-dioxan-2-yl-methyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0193] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 12 represents C1-C4-alkyl or phenyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0194] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 12 represents C1-C3-alkyl or phenyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0195] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 12 represents C1-C4-alkyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0196] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 12 represents methyl; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0197] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 13represents C1-C4-alkyl, C1-C4-haloalkyl, (C1-C4-alkoxy)-(C1-C4-alkyl)-, C1-C4-alkyl-(C=O)-, C3-C6-cycloalkyl, or phenyl, wherein the C3-C6-cycloalkyl group is optionally substituted by C1-C4-alkyl or hydroxy, and the phenyl group is optionally substituted one or more times, independently of one another, by halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C3-alkoxy, or C1-C3-haloalkoxy; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0198] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 13 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 by methyl or hydroxy; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0199] In a further embodiment of the first aspect, the present invention provides a compound of formula (I) above, wherein: R 13 represents methyl, methoxymethyl, ethyl-(C═O)—, cyclopropyl, or phenyl, said cyclopropyl group being optionally substituted with methyl or hydroxy; The compounds and their stereoisomers, tautomers, N-oxides, hydrates, solvates, salts, and mixtures thereof are covered.

[0200] In certain further embodiments of the first aspect, the present invention covers combinations of two or more of the above-described embodiments under the heading "Further embodiments of the first aspect of the invention".

[0201] The present invention covers any subcombination within any embodiment or aspect of the invention of compounds of general formula (I) above.

[0202] The present invention covers any subcombination within any embodiment or aspect of the invention of intermediate compounds of general formula (II).

[0203] The present invention covers compounds of general formula (I) disclosed in the Examples section herein below.

[0204] The compounds of the present invention of general formula (I) can be prepared according to the following schemes 1, 2, 3, and 4. The schemes and procedures described below are illustrative of the synthetic routes of the compounds of general formula (I) of the present invention, and are not intended to be limiting. It will be apparent to those skilled in the art that the order of the transformations illustrated in schemes 1, 2, 3, and 4 can be modified in various ways. Therefore, the order of the transformations illustrated in these schemes is not intended to be limiting. In addition, the substituent R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7a , or R 7b Interconversion of any of the following can be accomplished before and / or after the exemplified transformations. These modifications can be the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution, or other reactions known to those skilled in the art. These transformations include those that introduce functional groups that allow further interconversion of substituents. Suitable protecting groups, and their introduction and cleavage, are well known to those skilled in the art. Specific examples are described in the following paragraphs.

[0205] Routes for preparing compounds of general formula (I) and corresponding intermediates are described in Schemes 1, 2, 3, and 4. Scheme 1

[0206] [ka]

[0207] Scheme 1: X is a leaving group, R is methyl, ethyl, or tert-butyl, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7a , and R 7b has the meaning as given for general formula (I) above.

[0208] Tetrahydrobenzofurans of general formula (3) can be obtained through the aldol condensation of (1) and (2) followed by an intramolecular cyclization reaction according to the procedure described by Stetter at al. (Chem. Ber. 1960, 93, 603-607), as illustrated in Scheme 1. Compounds (1) and (2) can be purchased or prepared according to procedures available in the public domain, as will be understood by those skilled in the art. Depending on the reactivity of the centers involved [i.e., when nucleophilic displacement of the leaving group of (2) by the acidic methylene unit of (1) occurs prior to the intramolecular condensation with the ketone moiety of (2)], regioisomers of (3) can be obtained.

[0209] Generally, 1,3-diketones of formula (1) can be reacted with alpha-carbonyl esters of general formula (2) in a protic solvent, such as methanol, ethanol, or water, or a mixture thereof, preferably a mixture of the alcohol incorporated in ester (2) and water, in the presence of an inorganic base, such as sodium hydroxide or potassium hydroxide, preferably potassium hydroxide, at a temperature between 0°C and the boiling point of the solvent (mixture), preferably between room temperature and 50°C. The reaction time varies from 15 hours to several days. Usually, it is necessary to isomerize the primary cyclization product to tetrahydrobenzofurans of general formula (3) by treating with an acid, such as hydrochloric acid at a pH of 1-4, at a temperature between 0°C and the boiling point of the solvent (mixture), preferably at room temperature, for 1-6 hours.

[0210] Alternatively, (1) and (2) may be reacted in an aprotic solvent such as dichloromethane, dichloroethane, or tetrahydrofuran, preferably dichloromethane or dichloroethane, in the presence of an organic base such as triethylamine at a temperature between room temperature and the boiling point of the solvent, preferably at 40 to 60°C (pressure tube), for 12 to 72 hours, followed by treatment with an acid such as hydrochloric acid at pH 1 to 4 at a temperature between 0°C and the boiling point of the solvent (mixture), preferably at room temperature, for 3 to 24 hours.

[0211] Alternatively, (1) and (2) may be reacted in toluene without any further additives at a temperature between room temperature and 120°C, preferably 80 to 120°C, for 12 to 20 hours.

[0212] Enamines of general formula (4a) can be synthesized from tetrahydrobenzofurans of general formula (3) by alpha-methylation with electrophiles such as 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (Bredereck's reagent) or 1,1-dimethoxy-N,N-dimethylmethanamine, preferably 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine, in an aprotic solvent such as benzene, toluene, or dioxane, preferably toluene, at a temperature between room temperature and the boiling point of the solvent, preferably 100-110°C, for 15 hours up to several days.

[0213] Alternatively, the tetrahydrobenzofurans of general formula (3) can be converted to α-hydroxymethylene ketones of general formula (4b) by formylation with a formic acid derivative such as ethyl formate or methyl formate in the presence of a base such as sodium methylate, sodium ethylate, potassium tert-butoxide, or sodium hydride in a solvent such as methanol, ethanol, toluene, tetrahydrofuran, or a mixture thereof, at a temperature between 0°C and the boiling point of the solvent (mixture), preferably between room temperature and 50°C, for 1 to 18 hours.

[0214] The furoindazoles of general formula (5) can be obtained by starting from either enamines of general formula (4a) or α-hydroxymethylene ketones of general formula (4b), and reacting (4a) or (4b) with hydrazine or a hydrazine derivative such as hydrazine hydrate or a hydrazine salt, preferably hydrazine hydrate or hydrazine dihydrochloride, in a polar protic solvent such as ethanol, water, or a mixture thereof, preferably an ethanol / water mixture, at a temperature between room temperature and the boiling point of the solvent (mixture), preferably at 70 to 80°C, for 4 to 18 hours.

[0215] The disubstituted furoindazole esters of general formula (8) can be synthesized from the furoindazoles of general formula (5) by the Mitsunobu reaction with the alcohols of general formula (6) in an aprotic solvent such as tetrahydrofuran or toluene, preferably toluene, in the presence of an activator such as diisopropyl azodicarboxylate (DIAD) or N,N,N',N'-tetramethylazodicarboxamide (TMAD) and a tertiary phosphine such as triphenylphosphine or tri-n-butylphosphine, preferably a combination of TMAD and tri-n-butylphosphine, at a temperature between room temperature and the boiling point of the solvent, preferably at room temperature, for 12 to 48 hours. Alternatively, disubstituted furoindazoles of general formula (8) can be synthesized from furoindazoles of general formula (5) by reacting them with electrophiles of general formula (7), such as alkyl halides, alkyl tosylates, or alkyl mesylates, preferably alkyl bromides, in a polar aprotic solvent such as acetonitrile or ethyl acetate, preferably acetonitrile, in the presence of an inorganic base such as potassium carbonate or an organic base such as triethylamine or N,N-diisopropylethylamine, preferably potassium carbonate, at temperatures between room temperature and the boiling point of the solvent, preferably 60-75°C. It is advantageous to add a catalyst such as 4-dimethylaminopyridine (DMAP) to the mixture. Generally, depending on the reactivity of the centers involved, monosubstituted regioisomers of (8) can also be obtained in some cases.

[0216] Carboxylic acids of general formula (9) may be obtained from carboxylic acid esters of formula (8) by saponification using an inorganic base such as lithium hydroxide, potassium hydroxide, or sodium hydroxide, preferably lithium hydroxide, in a suitable solvent such as methanol, ethanol, tetrahydrofuran, water, or a mixture thereof, preferably a mixture of the alcohol to be incorporated into ester (8), THF, and water, at a temperature between 0°C and the boiling point of the solvent (mixture), typically 70°C, for 4 to 48 hours.

[0217] Furoindazoles of general formula (I) can be prepared from suitably functionalized carboxylic acids of general formula (9) by the addition of suitable amines HN(R 5 )(R 6 ) (III). However, for amide formation, all processes known to those skilled in the art from peptide chemistry may be applied. The acids of general formula (9) can be reacted with the appropriate amines in aprotic polar solvents such as DMF, acetonitrile, or N-methylpyrrolidin-2-one through activated acid derivatives, which can be obtained using, for example, hydroxybenzotriazole and carbodiimides, such as diisopropylcarbodiimide, or alternatively, preformed reagents, such as O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (see, for example, Chem. Comm. 1994, 201-203), or alternatively, activating agents such as dicyclohexylcarbodiimide / N,N-dimethylaminopyridine or N-ethyl-N',N'-dimethylaminopropylcarbodiimide / N,N-dimethylaminopyridine. Addition of a suitable base, such as N-methylmorpholine, triethylamine, or DIPEA, may be necessary. In some cases, the activated acid derivative may be isolated before reacting with the appropriate amine. Amide formation may also be achieved through an acid halide (which can be formed from a carboxylic acid by reaction with, for example, oxalyl chloride, thionyl chloride, or sulfuryl chloride), a mixed acid anhydride (which can be formed from a carboxylic acid by reaction with, for example, isobutyl chloroformate), an imidazolide (which can be generated from a carboxylic acid by reaction with, for example, carbonyldiimidazole), or an azide (which can be generated from a carboxylic acid by reaction with, for example, diphenylphosphoryl azide). Scheme 2

[0218] [ka]

[0219] Scheme 2: Intermediates of general formula (3), wherein Hal is a halogen atom, R is methyl, ethyl, or tert-butyl, and R 1 , R 2 , and R 4 has the meaning as given for general formula (I) above.

[0220] An alternative route to prepare tetrahydrobenzofuran intermediates of general formula (3) is illustrated in Scheme 2. 1,3-Diketones of general formula (1) may be converted to diazodicarbonyl compounds of general formula (11) by diazo group rearrangement as described in Synthesis 2011, 16, 2549-2552 or Synlett 2009, 18, 2943-2944.

[0221] Bicyclic furan esters of general formula (13) can be synthesized from diazodicarbonyl compounds of general formula (11) and terminal alkynes of general formula (12) in the presence of a metal catalyst such as Ru(PPh3)3Cl2 via a [3+2] cycloaddition reaction according to the procedure described by Lee, et al. (Eur. J. Org. Chem. 2014, 3430-3442).

[0222] Halogenated furans of general formula (14) can be obtained from furans of general formula (13) by any aromatic halogenation reaction known to those skilled in the art. For example, compounds of formula (13) may be reacted with a halogen electrophile such as N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS), preferably NBS, in a polar solvent such as pyridine or N,N-dimethylformamide, preferably pyridine, at a temperature between 0°C and the boiling point of the solvent, preferably at room temperature. The reaction time varies from 2 hours to several days.

[0223] Tetrahydrobenzofuran intermediates of general formula (3) can subsequently be obtained from halogenated furans of general formula (14) by radical processes such as Suzuki reaction or photoinduced reactions applying photocatalysis.

[0224] An alternative route to prepare 8-methyl-furoindazoles of general formula (Ia) is illustrated in Scheme 3. 3-Methyl-tetrahydrobenzofurans of general formula (16) can be synthesized from 1,3-dicarbonyls of general formula (1) by a two-step procedure involving the reaction of the enolate of (1) with allenylsulfonium salt (15) [prepared in situ by reacting propargyl bromide with dimethyl sulfide], followed by acid-catalyzed isomerization to (16) according to the procedure described by Kanematsu et al. (J. Org. Chem. 1993, 58, 3960-3968 and Heterocycles 1990, 31, 6, 1003-1006).

[0225] Brominated furans of general formula (17) may be obtained from furans of general formula (16) by any aromatic bromination reaction known to those skilled in the art. For example, compounds of formula (16) may be reacted with a bromoelectrophile such as N-bromosuccinimide (NBS) in a polar solvent such as pyridine or N,N-dimethylformamide, preferably pyridine, at a temperature between 0°C and the boiling point of the solvent, preferably at room temperature. The reaction time varies from 2 hours to several days.

[0226] Enamines of general formula (18a) and α-hydroxymethylene ketones of general formula (18b) can be synthesized starting from compounds of general formula (17) according to the procedures described for (4a) and (4b) in Scheme 1.

[0227] 8-Methyl-furindazoles of general formula (19) can be obtained from either (18a) or (18b) by reaction with hydrazine derivatives as described for the synthesis of (5) in Scheme 1. Scheme 3

[0228] [ka]

[0229] Scheme 3: Compounds of general formula (Ia) in which R 4 =CH3, and R 1 , R 2 , R 3 , R 5 , R 6 , R 7a , and R 7b An alternative route to prepare compounds in which:

[0230] Disubstituted furoindazoles of general formula (20) can be synthesized from compounds of general formula (19) and alcohols (6) or electrophiles (7), as described for the synthesis of (8) from (5) in Scheme 1.

[0231] Carboxylic acids of general formula (21) can be obtained from bromofuroindazoles (20) by carbonylation. Bromides of general formula (20) can be reacted in the presence of a carbon monoxide source such as molybdenum hexacarbonyl or under a carbon monoxide atmosphere at a pressure between 1 bar and 20 bar (autoclave), preferably 15 bar (autoclave), in the presence of a suitable palladium catalyst such as palladium acetate or bis(triphenylphosphine)palladium(II) dichloride, preferably palladium acetate, in a polar solvent such as dimethyl sulfoxide, in the presence of a ligand such as 1,1'-bis(diphenylphosphino)ferrocene, and a suitable base such as potassium acetate, at a temperature between room temperature and 180°C, preferably 100°C, for 12 to 24 hours.

[0232] 8-Methyl-furindazoles of general formula (Ia) can be prepared from suitably functionalized carboxylic acids of general formula (21) by the addition of suitable amines HN(R 5 )(R 6 ) (III) by amide coupling reaction.

[0233] Alternatively, 8-methyl-furoindazoles of general formula (Ia) can be prepared from aryl bromides of general formula (20) by palladium catalyzed carbonylation of the appropriate amines HN(R 5 )(R 6 ) (III). For this carbonylation, any process known to those skilled in the art may be applied. Bromides of formula (20) can be reacted with the appropriate amine (III) in the presence of a carbon monoxide source, such as molybdenum hexacarbonyl, or under a carbon monoxide atmosphere at a pressure between 1 and 20 bar (autoclave), in a polar aprotic solvent, such as dioxane, in the presence of a palladium catalyst, such as palladium(II) acetate, and a base, such as sodium carbonate, at a temperature between room temperature and the boiling point of the solvent, preferably at 110-140 °C (pressure tube). It may be necessary to add a ligand, such as tri-tert-butylphosphonium tetrafluoroborate, to the mixture.

[0234] An alternative approach to 8-methyl-furindazoles of general formula (Ia) is illustrated in Scheme 4. 8-Methyl-furindazoles of general formula (24) can be obtained in four steps starting from 1,3-dicarbonyl compounds of general formula (1) via (16), and (22a) or (22b), and (23) according to the corresponding procedures described in Scheme 1 and Scheme 3.

[0235] Compounds of general formula 24 can subsequently be formylated to give aldehydes of general formula 25 by any formylation process known to those skilled in the art. Furans of general formula 24 can be reacted under Vilsmeier-Haack conditions with a mixture of N,N-dimethylformamide and phosphoryl chloride at temperatures between 0 °C and room temperature for 1-18 hours.

[0236] Carboxamides of general formula (Ia) can be obtained directly from aldehydes of general formula (24) by the procedure described in Synthesis 2003, 7, 1055-1064. Aldehydes of general formula (24) can be reacted with the appropriate amine (III) in the presence of a cyanide salt such as sodium cyanide or potassium cyanide and an oxidizing agent such as manganese dioxide in a solvent such as tetrahydrofuran, dichloromethane, or dimethyl sulfoxide, preferably tetrahydrofuran, at a temperature between 0°C and the boiling point of the solvent, preferably at room temperature, for 24 to 96 hours. Scheme 4

[0237] [ka]

[0238] Scheme 4: Compounds of general formula (Ia) in which R 4 =CH3, and R 1 , R 2 , R 3 , R 5 , R 6 , R 7a , and R 7b An alternative route to prepare compounds in which:

[0239] Specific examples are given in the experimental section.

[0240] According to a second aspect, the present invention provides a method for preparing a compound of general formula (I) as defined above, comprising the step of reacting a compound of general formula (II):

[0241] [ka]

[0242] wherein R is H or OH or OMe or OEt, and R 1 , R 2 , R 3 , R 4 , R 7a , and R 7b is as defined for compounds of general formula (I) as defined above, by reacting an intermediate compound with a compound of general formula (III):

[0243] [ka]

[0244] wherein R 5 and R 6 is as defined for compounds of general formula (I) as defined above, Thereby, the general formula (I):

[0245] [ka]

[0246] wherein R 1 , R 2 , R 3 , R 5 , R 6 , R 7a , and R 7b is as defined above.

[0247] According to a third aspect, the present invention provides a method for preparing a compound of general formula (I) as defined above, comprising the step of:

[0248] [ka]

[0249] wherein R is H, OH, OMe, or OEt, and R 1 , R 2 , R 3 , R 4 , R 7a , and R 7b is as defined for compounds of general formula (I) as defined above, General formula (III):

[0250] [ka]

[0251] wherein R 5 and R 6 is as defined for compounds of general formula (I) as defined above, Thereby, the general formula (I):

[0252] [ka]

[0253] wherein R 1 , R 2 , R 3 , R 5 , R 6 , R 7a , and R 7b is as defined above, Then, optionally, converting said compound into a solvate, salt, and / or solvate of such salt using a corresponding (i) solvent and / or (ii) base or acid is covered.

[0254] The present invention is directed to a method for preparing the compounds of the invention of general formula (I), comprising the steps as described in the experimental section herein.

[0255] In accordance with a fourth aspect, the present invention covers intermediate compounds useful in the preparation of compounds of general formula (I) above.

[0256] In particular, the present invention provides a compound of general formula (II):

[0257] [ka]

[0258] wherein R is H or OH or OMe or OEt, and R 1 , R 2 , R 3 , R 4 , R 7a , and R 7b is as defined for compounds of general formula (I) above.

[0259] According to a fifth aspect, the present invention covers the use of said intermediate compounds for preparing compounds of general formula (I) as defined above.

[0260] In particular, the present invention provides a compound of general formula (II):

[0261] [ka]

[0262] wherein R is H or OH or OMe or OEt, and R 1 , R 2 , R 3 , R 4 , R 7a , and R 7bis as defined for compounds of general formula (I) as defined above, using intermediate compounds wherein

[0263] The present invention covers the intermediate compounds disclosed in the Examples section herein below.

[0264] The present invention covers any subcombination within any embodiment or aspect of the invention of intermediate compounds of general formula (II) above.

[0265] The compounds of general formula (I) of the present invention can be converted into any salt, preferably a pharmaceutically acceptable salt, as described herein, by any method known to those skilled in the art.Similarly, any salt of the compounds of general formula (I) of the present invention can be converted into the free compound by any method known to those skilled in the art.

[0266] The compounds of general formula (I) of the present invention demonstrate an unexpectedly useful pharmacological spectrum of action.It has surprisingly been found that the compounds of the present invention are effective antagonists of GPR84, and therefore can be used for the treatment or prevention of diseases in humans and animals, particularly autoimmune diseases such as multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, primary and secondary autoimmune uveitis, inflammatory disorders such as endometriosis, inflammatory eye disease, inflammatory kidney disease, inflammatory liver diseases such as non-alcoholic, alcoholic and toxic fatty liver, pulmonary diseases such as asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and metabolic and metabolic endocrine disorders such as metabolic syndrome, insulin resistance, type I and type II diabetes and polycystic ovarian syndrome (PCOS), neuropathic and inflammatory pain disorders, etc.

[0267] The compounds of the present invention can be used to inhibit, antagonize, block, reduce, or decrease GPR84 signaling, activity, and cellular function, which method comprises administering to a mammal, including a human, in need thereof, an amount of a compound of the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate, or ester thereof, effective to treat the disorder.

[0268] In particular, autoimmune diseases such as multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, primary and secondary autoimmune uveitis, inflammatory disorders such as endometriosis, inflammatory eye diseases, inflammatory kidney diseases, inflammatory liver diseases such as non-alcoholic, alcoholic, and toxic fatty liver, lung diseases such as asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and metabolic and metabolic endocrine disorders such as metabolic syndrome, insulin resistance, type I and type II diabetes, and polycystic ovarian syndrome (PCOS) disorders, neuropathic and inflammatory pain disorders in humans and animals.

[0269] The present invention also provides methods for treating PCOS and symptoms, which are well characterized in humans but also exist with similar etiologies in other mammals, and can be treated by administering the pharmaceutical compositions of the present invention.

[0270] As used herein, the terms "treat" or "treatment" are used conventionally and refer to the management or care of a subject for the purpose of combating, alleviating, reducing, ameliorating, or improving the condition of a disease or disorder, such as PCOS or IPF.

[0271] The compounds of the present invention can be used in the therapy and prevention, i.e., prophylaxis and treatment, in humans and animals of autoimmune diseases such as multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, primary and secondary autoimmune uveitis, inflammatory disorders such as endometriosis, inflammatory eye diseases, inflammatory kidney diseases, inflammatory liver diseases such as non-alcoholic, alcoholic, and toxic fatty liver, lung diseases such as asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and metabolic and metabolic endocrine disorders such as metabolic syndrome, insulin resistance, type I and type II diabetes, and polycystic ovarian syndrome (PCOS) disorders, neuropathic and inflammatory pain disorders, and the like.

[0272] In accordance with a further aspect, the present invention covers compounds of general formula (I) as described above, or stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures thereof, for use in the treatment or prevention of diseases in humans and animals, particularly autoimmune diseases such as multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, primary and secondary autoimmune uveitis, inflammatory disorders such as endometriosis, inflammatory eye diseases, inflammatory kidney diseases, inflammatory liver diseases such as non-alcoholic, alcoholic and toxic fatty liver, lung diseases such as asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and metabolic and metabolic endocrine disorders such as metabolic syndrome, insulin resistance, type I and type II diabetes, and polycystic ovary syndrome (PCOS) disorders, neuropathic and inflammatory pain disorders, etc.

[0273] The pharmaceutical activity of the compounds according to the invention can be explained by their activity as GPR84 antagonists.

[0274] According to a further aspect, the present invention covers the use of compounds of general formula (I) as described above, or stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures thereof, for the treatment or prevention of diseases in humans and animals, particularly autoimmune diseases such as multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, primary and secondary autoimmune uveitis, inflammatory disorders such as endometriosis, inflammatory eye diseases, inflammatory kidney diseases, inflammatory liver diseases such as non-alcoholic, alcoholic and toxic fatty liver, lung diseases such as asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and metabolic and metabolic endocrine disorders such as metabolic syndrome, insulin resistance, type I and type II diabetes, and polycystic ovarian syndrome (PCOS) disorders, neuropathic and inflammatory pain disorders, etc.

[0275] According to a further aspect, the present invention covers the use of compounds of general formula (I) as described above, or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures thereof, for the treatment or prevention of diseases in humans and animals, particularly autoimmune diseases such as multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, primary and secondary autoimmune uveitis, inflammatory disorders such as endometriosis, inflammatory eye diseases, inflammatory kidney diseases, inflammatory liver diseases such as non-alcoholic, alcoholic and toxic fatty liver, lung diseases such as asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and metabolic and metabolic endocrine disorders such as metabolic syndrome, insulin resistance, type I and type II diabetes, and polycystic ovarian syndrome (PCOS) disorders, neuropathic and inflammatory pain disorders, etc.

[0276] According to a further aspect, the present invention covers the use of compounds of general formula (I) as described above, or stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures thereof, in a method for the treatment or prevention of diseases in humans and animals, particularly autoimmune diseases such as multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, primary and secondary autoimmune uveitis, inflammatory disorders such as endometriosis, inflammatory eye diseases, inflammatory kidney diseases, inflammatory liver diseases such as non-alcoholic, alcoholic and toxic fatty liver, lung diseases such as asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and metabolic and metabolic endocrine disorders such as metabolic syndrome, insulin resistance, type I and type II diabetes, and polycystic ovarian syndrome (PCOS) disorders, neuropathic and inflammatory pain disorders, etc.

[0277] In accordance with a further aspect, the present invention covers the use of compounds of general formula (I) as described above, or stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, particularly pharmaceutically acceptable salts thereof, or mixtures thereof, to prepare pharmaceutical compositions, preferably medicaments, for the treatment or prevention of diseases in humans and animals, particularly autoimmune diseases such as multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, primary and secondary autoimmune uveitis, inflammatory disorders such as endometriosis, inflammatory eye diseases, inflammatory kidney diseases, inflammatory liver diseases such as non-alcoholic, alcoholic and toxic fatty liver, lung diseases such as asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and metabolic and metabolic endocrine disorders such as metabolic syndrome, insulin resistance, type I and type II diabetes, and polycystic ovarian syndrome (PCOS) disorders, neuropathic and inflammatory pain disorders, etc.

[0278] In accordance with a further aspect, the present invention is directed to a method for treating or preventing diseases, particularly autoimmune diseases such as multiple sclerosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, primary and secondary autoimmune uveitis, inflammatory disorders such as endometriosis, inflammatory eye diseases, inflammatory kidney diseases, inflammatory liver diseases such as non-alcoholic, alcoholic, and toxic fatty liver, pulmonary diseases such as asthma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and metabolic and metabolic endocrine disorders such as metabolic syndrome, insulin resistance, type I and type II diabetes, and polycystic ovary syndrome (PCOS) disorders, neuropathic and inflammatory pain disorders, and the like, in humans and animals using an effective amount of a compound of general formula (I) as described above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts, particularly pharmaceutically acceptable salts thereof, or mixtures thereof.

[0279] In accordance with a further aspect, the present invention is directed to pharmaceutical compositions, particularly medicaments, comprising a compound of general formula (I) as described above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts, particularly pharmaceutically acceptable salts thereof, or mixtures thereof, and one or more excipients), particularly one or more pharmaceutically acceptable excipients. Conventional procedures for preparing such pharmaceutical compositions in suitable dosage forms may be utilized.

[0280] The present invention further covers pharmaceutical compositions, in particular medicaments, comprising at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipients, and their use for the above-mentioned purposes.

[0281] The compounds according to the invention may be systemically and / or locally active, and for this purpose they may be administered in any suitable manner, for example via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, cutaneous, transdermal, conjunctival, auricular route, or as an implant or stent.

[0282] For these administration routes, the compounds according to the invention may be administered in suitable dosage forms.

[0283] For oral administration, the compounds according to the invention may be formulated into dosage forms known in the art that deliver the compounds of the invention rapidly and / or in a modified manner, such as tablets (uncoated or coated, e.g., with enteric or controlled-release coatings that dissolve slowly or are insoluble), orally disintegrating tablets, films / wafers, films / lyophilisates, capsules (e.g., hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols, or solutions. The compounds according to the invention may be incorporated into said dosage forms in crystalline and / or amorphous and / or dissolved form.

[0284] Parenteral administration can be carried out in such a way as to avoid the absorption step (e.g., intravenously, intraarterially, intramyocardially, intraspinally, or intrapulmonary) or to include absorption (e.g., intramuscularly, subcutaneously, intradermally, transdermally, or intraperitoneally). Suitable dosage forms for parenteral administration are, in particular, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates, or sterile powders.

[0285] Examples of suitable other administration routes are drug forms for inhalation (especially 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, eye inserts, ear drops, ear sprays, ear powders, ear washes, ear tampons; vaginal capsules, aqueous suspensions (lotions, agitated mixtures), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (e.g. patches), milks, pastes, foams, dusting powders, implants or stents.

[0286] The compounds according to the invention can be incorporated into the described dosage forms. This can be done in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, in particular: fillers and carriers (e.g., cellulose, microcrystalline cellulose (e.g., Avicel®), lactose, mannitol, starch, calcium phosphate (e.g., Di-Cafos®), Ointment bases (e.g., petrolatum, paraffin, triglycerides, wax, wool wax, wool wax alcohols, lanolin, hydrophilic ointments, polyethylene glycols), suppository bases (e.g., polyethylene glycols, cocoa butter, hard fats), Solvents (e.g., water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglyceride fatty oils, liquid polyethylene glycols, paraffins), surfactants, emulsifiers, dispersants or wetting agents (e.g. sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (e.g. Lanette®), sorbitan fatty acid esters (e.g. Span®), polyoxyethylene sorbitan fatty acid esters (e.g. Tween®), polyoxyethylene fatty acid glycerides (e.g. Cremophor®), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerin fatty acid esters, poloxamers (e.g. Pluronic®), buffers, acids, and bases (e.g., phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine); Tonicity agents (e.g., glucose, sodium chloride), Adsorbents (e.g., highly dispersed silica), viscosity-increasing agents, gel-forming agents, thickeners, and / or binders (e.g., polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, starch, carbomers, polyacrylic acids (e.g., Carbopol®); alginates, gelatin); disintegrants (e.g., modified starch, sodium carboxymethylcellulose, sodium starch glycolate (e.g., Explotab®), cross-linked polyvinylpyrrolidone, croscarmellose sodium (e.g., AcDiSol®), etc.); Flow control agents, lubricants, glidants, release agents (magnesium stearate, stearic acid, talc, highly dispersed silica (e.g. Aerosil®), etc.), coating materials (e.g. sugar, shellac) and film-forming agents for rapidly or modified dissolving films or diffusion membranes (e.g. polyvinylpyrrolidone (e.g. Kollidon®), polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as Eudragit®), capsule materials (e.g., gelatin, hydroxypropyl methylcellulose), synthetic polymers (e.g. polylactides, polyglycolides, polyacrylates, polymethacrylates (e.g. Euragit®, etc.), polyvinylpyrrolidones (e.g. Kollidon®, etc.), polyvinyl alcohols, vinyl acetates, polyethylene oxides, polyethylene glycols, and copolymers and block copolymers thereof); Plasticizers (e.g. polyethylene glycols, propylene glycols, glycerol, triacetin, triacetyl citrate, dibutyl phthalate), penetration enhancers, stabilizers (e.g., antioxidants such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, and propyl gallate); Preservatives (e.g., parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate, etc.), coloring agents (e.g. inorganic pigments such as iron oxides, titanium dioxide, etc.); Flavorings, sweeteners, taste masking agents, and / or odor masking agents.

[0287] The present invention further relates to pharmaceutical compositions comprising at least one compound according to the invention together with one or more conventional pharmaceutically suitable excipients, and to their uses according to the invention.

[0288] Experimental Chapter NMR peak forms are given as they appear in the spectra and possible higher order effects are not taken into account.

[0289] of selected compounds 1 H-NMR data is 1 The information is given in the form of a H-NMR peak list, where for each signal peak, the δ value in ppm is given, followed by the signal intensity reported in parentheses. δ value-signal intensity pairs from different peaks are separated by commas. Thus, the peak list has the general format: δ1(intensity 1), δ2(intensity 2), ..., δ i (intensity i),..., δ n It is written as (intensityn).

[0290] The intensity of a sharp signal correlates to its height (cm) in the printed NMR spectrum. When compared to other signals, this data can be correlated to the actual ratio of signal intensities. In the case of broad signals, multiple peaks or signal centers are displayed along with their relative intensities compared to the most intense signal appearing in the spectrum. 1 The list of H-NMR peaks is given by the classical 1 The H-NMR readout is similar and therefore usually contains all the peaks listed in a classical NMR interpretation. 1 Similar to a H-NMR printout, the peak list includes solvent signals, signals due to stereoisomers of a particular target compound, impurity peaks, 13 The peaks of the target compound may show C satellite peaks and / or spinning side bands. The peaks of stereoisomers and / or impurities typically appear at lower intensities compared to the peaks of the target compound (e.g., purity >90%). Such stereoisomers and / or impurities may be typical for a particular manufacturing process, and therefore their peaks may be useful for identifying the reproducibility of the manufacturing process based on the "by-product fingerprint". Experts who calculate the peaks of the target compound by known methods (MestReC, ACD simulation, or using empirically evaluated expectation values) can optionally use additional intensity filters to separate the peaks of the target compound as needed. Such operations are performed in the classical 1This is similar to peak picking in H-NMR interpretation. A detailed description of the reporting of NMR data in the form of a peak list can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (see: http: / / www.researchdisclosure.com / searching-disclosures, Research Disclosure Database Number 605005, 2014, 01 Aug 2014). In the peak picking routine described in Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1% and 4%. However, depending on the chemical structure and / or the concentration of the measured compound, it may be appropriate to set the parameter "MinimumHeight" to <1%.

[0291] Chemical names were generated using ACD / Name software from ACD / Labs. In some cases, accepted names of commercially available reagents were used in place of ACD / Name-generated names.

[0292] Table 1 below lists the abbreviations used in this paragraph and in the Examples section unless explained within the text. Other abbreviations have their customary meanings to those skilled in the art.

[0293] The following table lists the abbreviations used in this specification.

[0294] [Table 1-1] [Table 1-2] [Table 1-3]

[0295] Various aspects of the invention described in this application are illustrated by the following examples, which are not intended to limit the invention in any way.

[0296] The exemplary validation experiments described herein serve to illustrate the invention, and the invention is not limited to the given examples.

[0297] Experimental Chapter - General Section All reagents whose synthesis is not described in the experimental section are commercially available, are known compounds, or may be formed from known compounds by known methods by one skilled in the art.

[0298] The compounds and intermediates produced according to the methods of the present invention may require purification. Purification of organic compounds is well known to those skilled in the art, and there may be several methods for purifying the same compound. In some cases, purification may not be necessary. In some cases, the compound may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compound may be purified by chromatography, particularly flash column chromatography, using, for example, a prepacked silica gel cartridge, such as Biotage SNAP cartridges KP-Sil® or KP-NH®, in conjunction with a Biotage automated purification system (SP4® or Isonera Four®) and an eluent such as a hexane / ethyl acetate or DCM / methanol gradient. In some cases, compounds may be purified by preparative HPLC using, for example, a Waters automated purification system equipped with a diode array detector and / or an online electrospray ionization mass spectrometer, in conjunction with a suitable pre-packed reverse phase column and an eluent such as a gradient of water and acetonitrile, which may contain additives such as trifluoroacetic acid, formic acid, or aqueous ammonia.

[0299] In some cases, the above purification method can provide those compounds of the present invention having sufficiently basic or acidic functional groups in the form of a salt, for example, a trifluoroacetate salt or a formate salt in the case of a sufficiently basic compound of the present invention, or an ammonium salt in the case of a sufficiently acidic compound of the present invention. Such salts can be converted to their free base or free acid forms, respectively, by various methods known to those skilled in the art, or used as salts in subsequent biological assays. It should be understood that the specific form (e.g., salt, free base, etc.) of the compound of the present invention isolated and described herein is not necessarily the only form in which the compound can be applied to a biological assay to determine a specific biological activity.

[0300] Standard procedure for UPLC-MS Analytical UPLC-MS was performed as described below. Masses (m / z) are reported from positive mode electrospray ionization unless negative mode (ESI-) is indicated. In most cases, method 1 was used. If not, this is indicated.

[0301] Method 1: Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 μm, 50 × 2.1 mm; Eluent A: water + 0.2 vol% ammonia, Eluent B: acetonitrile; Gradient: 0–1.6 min 1–99% B; 1.6–2.0 min 99% B; Flow rate: 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210–400 nm; ELSD.

[0302] Method 2: Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 μm, 50 × 2.1 mm; Eluent A: water + 0.1 vol% formic acid, Eluent B: acetonitrile; Gradient: 0–1.6 min 1–99% B; 1.6–2.0 min 99% B; Flow rate: 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210–400 nm.

[0303] Standard LC-MS procedure

[0304] Method A: Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 μm, 50 × 2.1 mm; Eluent A: water + 0.2 vol% aqueous ammonia (32%), Eluent B: acetonitrile; Gradient: 0–1.6 min 1–99% B, 1.6–2.0 min 99% B; Flow rate: 0.8 mL / min; Temperature: 60 °C; DAD scan: 210–400 nm.

[0305] Method B: 5-95AB, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Chromolith@Flash RP-18E 25-2 MM; Eluent A: water + 0.0375 vol% trifluoroacetic acid, Eluent B: acetonitrile + 0.01875 vol% trifluoroacetic acid; Gradient: 0–0.8 min, 5–95% B, 0.8–1.2 min, 95% B; Flow rate: 1.5 mL / min; Temperature: 50°C; PDA: 220 nm & 254 nm.

[0306] Method C:5-95AB, Agilent Instrument: Agilent 1100 / G1956A SingleQuad; Column: Kinetex@ 5μm EVO C18 30×2.1mm; Eluent A: water + 0.0375vol% trifluoroacetic acid, Eluent B: acetonitrile + 0.01875vol% trifluoroacetic acid; Gradient: 0-0.8min 5-95% B, 0.8-1.2min 95% B; Flow rate: 1.5mL / min; Temperature: 50℃; PDA: 220nm & 254nm.

[0307] Method D:5-95CD, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C18 2.1 × 30 mm, 5 μm; Eluent A: water + 0.025 vol% ammonium hydroxide; Eluent B: acetonitrile; Gradient: 0–0.8 min, 5–95% B, 0.8–1.2 min, 95% B; Flow rate: 1.5 mL / min; Temperature: 40°C; PDA: 220 nm & 254 nm.

[0308] Method E: 5-95CD, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex EVO C18 2.1×30 mm, 5 μm; Eluent A: water + 0.025 vol% ammonium hydroxide, Eluent B: acetonitrile; Gradient: 0–0.8 min, 5–95% B, 0.8–1.2 min, 95% B; Flow rate: 1.5 ml / min; Temperature: 40°C; PDA: 220 nm & 254 nm.

[0309] Analytical characterization of the enantiomers was carried out by analytical chiral HPLC. In the description of the individual examples, reference is made to the HPLC procedure applied.

[0310] Purification method: Biotage's Isolella™ chromatography system (http: / / www.biotage.com / product-area / flash-purification) uses prepacked silica and prepacked modified silica cartridges.

[0311] Preparative HPLC, Method A: Equipment: Pump: Labomatic HD-5000 or HD-3000, Head HDK 280, Low Pressure Gradient Module ND-B1000; Manual Injection Valve: Rheodyne 3725i038; Detector: Knauer Azura UVD 2.15, Collector: Labomatic Labocol Vario-4000; Column: Chromatorex RP C-18 10 μm, 125 × 30 mm; Eluent A: water + 0.2 vol% ammonia (32%), Eluent B: acetonitrile; Gradient A: 0–15 min 1–25% B; flow rate: 60 ml / min; Gradient B: 0-15 min 10-50% B; Flow rate: 60 ml / min; Gradient C: 0–15 min 15–55% B; flow rate: 60 ml / min; Gradient D: 0–15 min 30–70% B; flow rate: 60 ml / min; Gradient E: 0–15 min 40–80% B; flow rate: 60 ml / min; Gradient F: 0–15 min 65–100% B; flow rate: 60 ml / min; Temperature: 25°C; Solution: max. 250 mg / 2 ml dimethyl sulfoxide; Injection: 1 x 2 ml; Detection: UV 254 nm; Software: SCPA PrepCon5.

[0312] Preparative HPLC, Method B: Equipment: Pump: Labomatic HD-5000 or HD-3000, Head HDK 280, Low Pressure Gradient Module ND-B1000; Manual Injection Valve: Rheodyne 3725i038; Detector: Knauer Azura UVD 2.15, Collector: Labomatic Labocol Vario-4000; Column: Chromatorex RP C-18 10 μm, 125 × 30 mm; Eluent A: water + 0.1 vol% formic acid (99%), Eluent B: acetonitrile; Gradient A: 0–15 min 1–25% B; flow rate: 60 ml / min; Gradient B: 0-15 min 10-50% B; Flow rate: 60 ml / min; Gradient C: 0–15 min 15–55% B; flow rate: 60 ml / min; Gradient D: 0–15 min 30–70% B; flow rate: 60 ml / min; Gradient E: 0–15 min 40–80% B; flow rate: 60 ml / min; Gradient F: 0–15 min 65–100% B; flow rate: 60 ml / min; Temperature: 25°C; Solution: max. 250 mg / 2 ml dimethyl sulfoxide; Injection: 1 x 2 ml; Detection: UV 254 nm; Software: SCPA PrepCon5.

[0313] Experimental Section - General Procedure General Procedure A (GP A): Alpha-formylation reaction (3 → 4a / b, Scheme 1, or 17 → 18a / b, Scheme 3, or 16 → 22a / b, Scheme 4) (Condition A: enamine formation); similar to H. Bredereck et al., Liebigs Ann. Chem. 1980, 3, 344-357 and International Publication No. WO2010 / 078427, p. 222.

[0314] To a solution of the respective ketone (1 equivalent) in toluene at room temperature, add 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (Bredereck's reagent, CAS number [5815-08-7]; 1.2-5 equivalents) or 1,1-dimethoxy-N,N-dimethylmethanamine (1.2-5 equivalents), and stir the reaction mixture at 100-120 °C until TLC and / or LCMS indicate complete consumption of the starting material (overnight or up to 6 days). The reaction mixture is concentrated under reduced pressure and used in subsequent reactions without further purification.

[0315] Alpha-formylation reaction (3 → 4a / b, Scheme 1, or 17 → 18a / b, Scheme 3, or 16 → 22a / b, Scheme 4) (Condition B: enol formation); similar to M. L. Hammond et al., J. Med. Chem. 1989, 32, 1006-1020, and D. J. Goldsmith et al., J. Org. Chem. 1980, 45, 3989-3993, and G. Grandolini et al., Gazzetta Chimica Italiana 1976, 106, 1083-1094.

[0316] To a solution of ethyl formate (CAS number [109-94-4]; 2.0-6.0 equiv.) in toluene is added sodium hydride (3.0 equiv., 60% purity) at 0°C. After stirring for 0.5 h, a solution of the respective ketone (1.0 equiv.) in toluene is added to the above mixture. The reaction mixture is stirred at room temperature or 45°C until TLC and / or LCMS indicate complete consumption of the starting material (typically 2 h or up to overnight). The reaction mixture is quenched with 2N hydrochloric acid and the phases are separated. The aqueous phase is extracted with ethyl acetate, and the combined organic phases are washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The desired crude product obtained is used in subsequent reactions without further purification steps.

[0317] General Procedure B (GP B): Formation of furoindazole (4a / b → 5, Scheme 1, or 18a / b → 19, Scheme 3, or 22a / b → 23, Scheme 4); similar to G. Grandolini et al., Gazzetta Chimica Italiana 1976, 106, 1083-1094, and Waremers et al., J. Heterocycl. Chem. 1975, 12, 421-422.

[0318] To a solution of the enamine or enol (1.0 equiv.) in ethanol, respectively, is added a solution of hydrazine hydrate 1:1 (CAS No. [7803-57-8]; 5.0 equiv.) or hydrazine dihydrochloride (CAS No. [5341-61-7]; 2.0 equiv.) in water or ethanol at room temperature. The reaction mixture is stirred at 60-70 °C until TLC and / or LCMS indicate complete consumption of the starting material (typically 2 h or up to overnight). After quenching with sodium hypochlorite at 0 °C, the biphasic mixture is concentrated under reduced pressure. The residue is either subjected directly to column chromatography (SiO2) or partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate, and the combined organic layers are washed with brine, filtered, and concentrated under reduced pressure to give the crude title compound, which is purified by column chromatography (SiO2) as appropriate.

[0319] General Procedure C (GP C): Alkylation of furoindazole (5 → 8, Scheme 1, or 19 → 20, Scheme 3, or 23 → 24, Scheme 4) (Condition A: Mitsunobu reaction; similar to DL Selwood et al., J. Med. Chem. 2009, 52, 2694-2707) To a solution of furoindazole (1.0 equiv.) and alcohol (1–2 equiv.), respectively, in toluene, tri-n-butylphosphine (CAS No. [998-40-3]; 1.5–3 equiv.) and N,N,N',N'-tetramethylazodicarboxamide (TMAD, CAS No. [10465-78-8]; 1.5–3 equiv.) are added at room temperature. The reaction mixture is stirred at room temperature until TLC and / or LCMS indicate complete consumption of the starting material (typically overnight). The reaction mixture is diluted with water, and the phases are separated. The aqueous phase is extracted with dichloromethane (2–3 times), and the combined organic phases are dried over MgSO4 or Na2SO4, filtered, and concentrated. The resulting crude material is subjected to column chromatography (SiO2) to obtain the desired alkylation product. Disubstituted indazoles are typically obtained as the major product.

[0320] Alkylation of furoindazole (5 → 8, Scheme 1, or 19 → 20, Scheme 3, or 23 → 24, Scheme 4) (Condition B: Reaction with alkyl (pseudo)halides) A solution of furoindazole (1.0 equiv.) and alkyl (pseudo)halide (1.5–3 equiv.) in acetonitrile or ethyl acetate, respectively, is treated with potassium carbonate (5–15 equiv.) and N,N-dimethylpyridin-4-amine (DMAP, CAS number [1122-58-3]; 2.5 mol%) at room temperature. The reaction mixture is stirred at 60–70°C until TLC and / or LCMS indicate complete consumption of the starting material (typically overnight, or up to several days). The reaction mixture is cooled to room temperature and filtered. The filtrate is concentrated under reduced pressure, and the residue is subjected to column chromatography (SiO2) to obtain the desired alkylated product.

[0321] General Procedure D (GP D): Saponification of furoindazole ester (8→9, Scheme 1) A solution of each furoindazole ester (1.0 equiv.) in a 1:1 mixture of tetrahydrofuran and ethanol is treated with aqueous lithium hydroxide (2 M, 15 equiv.) at room temperature. In some cases, aqueous sodium hydroxide (30 equiv.) in THF is used instead. The reaction mixture is stirred at 60-70 °C until TLC and / or LCMS indicate complete consumption of the starting material (typically overnight). The reaction mixture is cooled to room temperature, acidified to pH 3-5 with hydrochloric acid, and extracted with ethyl acetate. The desired carboxylic acid precipitates in the aqueous phase (possibly as the HCl salt) and can be isolated by filtration and drying, which is used in subsequent reactions without further purification. Alternatively, the phases are separated, and the organic phase is washed with brine, dried over Na2SO2, filtered, and concentrated under reduced pressure to give the desired carboxylic acid, which is used in subsequent reactions without further purification.

[0322] General Procedure E (GP E): Carboxylation of furoindazole bromide (20→21, Scheme 3) Furindazole bromide (1.0 equiv.) was placed in a steel autoclave under an argon atmosphere and dissolved in dimethyl sulfoxide (approximately 15 mL / mmol). Palladium(II) acetate (5.0 mol%), 1,1'-bis(diphenylphosphino)ferrocene (CAS No. [12150-46-8]; 0.20 equiv.), and potassium acetate (4.0 equiv.) were added, and the mixture was purged with carbon monoxide three times. The mixture was stirred at 20°C under approximately 11 bar of carbon monoxide pressure for 30 minutes. The autoclave was evacuated again, and then approximately 15 bar of carbon monoxide pressure was applied. The mixture was heated to 100°C, generating a maximum pressure of approximately 18 bar, until TLC and / or LCMS indicated complete consumption of the starting material (typically 23 hours). The reaction was cooled to room temperature, the pressure was released, and the reaction mixture was added to ice water. The mixture is acidified with 1 M aqueous HCl (pH approx. 2.5) and stirred for 20 minutes before diluting with dichloromethane or ethyl acetate. The phases are separated and the aqueous phase is extracted with dichloromethane or ethyl acetate. The combined organic phases are dried, filtered, and concentrated under reduced pressure. The crude carboxylic acid obtained is carried on to the next step without further purification.

[0323] General Procedure F (GP F): Vilsmeier-Haack formylation of furoindazoles (24→25, Scheme 4) Phosphoryl chloride (10 equiv.) is added dropwise to N,N-dimethylformamide (10 equiv.) under ice-cooling and stirred for 15 min. A solution of furoindazole (1.0 equiv.) in N,N-dimethylformamide is added dropwise, and the mixture is warmed to room temperature and stirred until TLC and / or LCMS indicate complete consumption of the starting material (usually 1-2 h). The reaction mixture is added to ice water, and aqueous sodium hydroxide (4 M) is added to adjust the pH to approximately 9. The mixture is extracted with dichloromethane, the phases are separated, and the combined organic phase is dried, filtered, and concentrated under reduced pressure. The resulting crude aldehyde is purified by column chromatography (SiO2), as appropriate.

[0324] General Procedure G (GP G): Amide formation (9 → (I), Scheme 1 or 21 → (Ia), Scheme 3) (Condition A: Amide Coupling) A solution of the carboxylic acid or corresponding salt (1.0 equiv.) in DMF is treated with HATU (1.5 equiv.) and DIPEA (3.0 equiv.) and stirred at room temperature for several minutes. After this, the amine component (1–1.5 equiv.) is added and stirring at room temperature is continued until TLC and / or LCMS indicate complete consumption of the starting material (usually overnight). In most cases, the reaction mixture is filtered and purified by preparative HPLC to give the desired amide. In some cases, the reaction mixture is diluted with water and extracted with ethyl acetate. The organic phase is dried, filtered, and purified by column chromatography (SiO2) to give the desired amide.

[0325] Alternatively, to a solution of the carboxylic acid or corresponding salt (1.0 equiv.) in DMF, add 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P, 50 wt% solution in DMF, 1.5-3 equiv.), DIPEA (3-5 equiv.), and the amine component (1-1.5 equiv.). The reaction mixture is stirred at room temperature until TLC and / or LCMS indicate complete consumption of the starting material (usually overnight). The reaction mixture is filtered and purified by preparative HPLC to give the desired amide.

[0326] Amide formation (20 → (Ia), Scheme 3) (Condition B: Direct formation of amides by carbonylation of bromides) A solution of furoindazole bromide (1.0 equiv.) in 1,4-dioxane (containing approximately 1% water) is treated with the corresponding amine (3–5 equiv.), molybdenum hexacarbonyl (CAS No. [13939-06-5]; 2.0 equiv.), sodium carbonate (CAS No. [497-19-8]; 3.0 equiv.), tri-tert-butylphosphonium tetrafluoroborate (CAS No. [131274-22-1]; 0.10 equiv.), and palladium(II) acetate (CAS No. [3375-31-3]; 0.20 equiv.). The reaction mixture is stirred at 120–140 °C until TLC and / or LCMS indicate complete consumption of the starting material (typically 18 h). The mixture is cooled to room temperature, and the solid is isolated by filtration over Celite and washed with ethyl acetate. The filtrate is concentrated under reduced pressure and the resulting crude product is purified by preparative HPLC.

[0327] Amide formation (25 → (Ia), Scheme 4) (Condition C: Conversion of aldehydes to amides); similar to JK Taylor et al., Synthesis 2003, 7, 1055-1064.

[0328] A solution of furoindazole aldehyde (1.0 equiv.) in DMSO or THF is treated with the corresponding amine (5.0 equiv.), sodium cyanide (1.0 equiv.), and manganese dioxide (15 equiv.) and stirred at room temperature for 30 minutes. An additional amount of manganese dioxide (15 equiv.) is added, and stirring at room temperature is continued until TLC and / or LCMS indicate complete consumption of the starting material (24 hours or up to several days). The reaction mixture is filtered over Celite, the filtrate is concentrated under reduced pressure, and the resulting crude product is purified by preparative HPLC to give the desired amide.

[0329] General Procedure H (GP H): Amide formation (9 → (I), Scheme 1 or 21 → (Ia), Scheme 3) (Condition A: Amide Coupling) A solution of the carboxylic acid or corresponding salt (1.0 equiv.) in DMF is treated with HATU (1.5 equiv.) and DIPEA (3–6 equiv.) and stirred at room temperature for several minutes. After this, the amine component (1–1.5 equiv.) is added and stirring at room temperature is continued until TLC and / or LCMS indicate complete consumption of the starting material (usually overnight). In most cases, the reaction mixture is diluted with saturated ammonium chloride and extracted with ethyl acetate. The combined organic phases are washed with water, dried by hydrophobic filtration, and purified by preparative HPLC to give the desired amide. In some cases, the reaction mixture is filtered and purified by preparative HPLC to give the desired amide.

[0330] Amide formation (9 → (I), Scheme 1 or 21 → (Ia), Scheme 3) (Condition B: Amide Coupling) A solution of the carboxylic acid or corresponding salt (1.0 equiv.) in DMF is treated with HATU (1.5 equiv.) and DIPEA (3–6 equiv.) and stirred at room temperature for several minutes. After this, the amine component (1–2 equiv.) is added and stirring at room temperature is continued until TLC and / or LCMS indicate complete consumption of the starting material (usually overnight). In most cases, the reaction mixture is diluted with ethyl acetate and water. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine, dried over Na2SO4, filtered or hydrophobic filtered, and purified by preparative HPLC to give the desired amide. In some cases, the reaction mixture is filtered and purified by preparative HPLC to give the desired amide.

[0331] (Condition C: Amide Coupling) A solution of the carboxylic acid or corresponding salt (1.0 equiv.) in THF (and sometimes DMF for dissolution) is treated with HATU (1.5 equiv.) and DIPEA (3–6 equiv.). After stirring at room temperature for several minutes, the amine component (1–2 equiv.) is added, and stirring at room temperature is continued until TLC and / or LCMS indicate complete consumption of the starting material (usually 72 h). In most cases, the reaction mixture is diluted with saturated NaHCO3 / water (1:5) and ethyl acetate and stirred for 30 min. The phases are separated, and the ethyl acetate phase is extracted with water. The combined organic phases are dried over Na2SO4, filtered or hydrophobically filtered, and purified by preparative HPLC to give the desired amide. In some cases, the reaction mixture is filtered and purified by preparative HPLC to give the desired amide.

[0332] (Condition D: Amide Coupling) A solution of the carboxylic acid or corresponding salt (1.0 equiv.) in DMF or THF is treated with HATU (1.5 equiv.) and DIPEA (3–6 equiv.) and stirred at room temperature for several minutes. After this, the amine component (1–1.5 equiv.) is added and stirring at room temperature is continued until TLC and / or LCMS indicate complete consumption of the starting material (usually overnight). In most cases, the reaction mixture is diluted with saturated sodium bicarbonate / water and extracted with ethyl acetate. The combined organic phases are washed with brine, hydrophobic filtration, or dried over sodium sulfate, and purified by preparative HPLC to give the desired amide. In some cases, the reaction mixture is filtered and purified by preparative HPLC to give the desired amide.

[0333] Experimental Chapter - Intermediates Intermediate 1: Step 1 (5E / Z)-5-[(dimethylamino)methylidene]-6,7-dihydro-1-benzofuran-4(5H)-one

[0334] [ka]

[0335] According to GP A (Condition A), 6,7-dihydro-1-benzofuran-4(5H)-one (commercially available, CAS number [16806-93-2]; 5.00 g, 36.7 mmol) was reacted with 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (Bredereck's reagent, CAS number [5815-08-7]; 1.20 equiv., 7.68 g, 44.1 mmol) in toluene (100 mL) at 100 °C for 2 h. An additional amount of 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (1.20 equiv., 7.68 g, 44.1 mmol) was added, and stirring at 100 °C was continued for an additional 6 h. The reaction mixture was concentrated under reduced pressure, and the resulting crude title compound was used in the subsequent reaction without further purification. UPLC-MS (Method 1): R t = 0.83 min; MS (ESIpos): m / z = 192 [M+H] + .

[0336] Step 2 4,5-Dihydro-1H-furo[2,3-g]indazole

[0337] [ka]

[0338] Following GP B, crude (5E / Z)-5-[(dimethylamino)methylidene]-6,7-dihydro-1-benzofuran-4(5H)-one (1.0 equiv, 7.0 g, 37 mmol) from Step 1 was reacted with hydrazine hydrate 1:1 (5.0 equiv, 8.9 mL, 180 mmol) in ethanol (100 mL) at 70 °C for 3 h, followed by column chromatography (SiO, DCM / MeOH) to give the title compound (5.6 g, 35% over two steps). UPLC-MS (Method 1): R t = 0.80 min; MS (ESIpos): m / z = 161 [M+H] + .

[0339] Step 3 2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole

[0340] [ka]

[0341] According to GP C (Condition B), 4,5-dihydro-1H-furo[2,3-g]indazole from Step 2 (1.0 equiv., 5.6 g, 35 mmol) was reacted with 2-(bromomethyl)pyridine (1.2 equiv., 7.2 g, 42 mmol), potassium carbonate (15 equiv., 73 g, 530 mmol), and DMAP (2.5 mol%, 110 mg, 880 μmol) in EtOAc (150 mL) at 75 °C for 3 days to give the title compound (6.0 g, 52%) after column chromatography (SiO, DCM / MeOH).

[0342] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.86 (s, 4H), 5.34 (s, 2H), 6.62 (d, 1H), 7.03-7.05 (m, 1H), 7.27-7.31 (m, 1H), 7.57-7.60 (m, 2H), 7.76 (dt, 1H), 8.52-8.53 (m, 1H). UPLC-MS (Method 1): R t = 0.96 min; MS (ESIpos): m / z = 252 [M+H] + .

[0343] Step 4 2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carbaldehyde

[0344] [ka]

[0345] Following GP F, 2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole (1.00 equiv., 1.00 g, 3.98 mmol) from Step 3 was reacted with phosphorus trichloride (CAS number [10025-87-3]; 5.0 equiv., 1.9 mL, 20 mmol) and DMF (5.0 equiv., 1.5 mL, 20 mmol) at room temperature for 1 h to afford the title compound (63 mg, 5%) after column chromatography (SiO, DCM / MeOH) followed by preparative HPLC.

[0346] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.91-2.95 (m, 2H), 3.00-3.04 (m, 2H), 5.39 (s, 2H), 7.09 (d, 1H), 7.31 (ddd, 1H), 7.67 (s, 1H), 7.70 (s, 1H), 7.77 (dt, 1H), 8.52-8.54 (m, 1H), 9.52 (s, 1H). UPLC-MS (Method 1): R t = 0.83 min; MS (ESIpos): m / z = 280 [M+H] + .

[0347] Intermediate 2: Step 1 Ethyl 8-methyl-2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0348] [ka]

[0349] According to GP C (Condition B), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.0 equiv., 3.0 g, 12 mmol) was reacted with 2-(bromomethyl)pyridine (1.6 equiv., 3.4 g, 20 mmol), potassium carbonate (15.0 equiv., 25.3 g, 183 mmol), and DMAP (2.5 mol%, 37 mg, 300 μmol) in EtOH (200 mL) at 75 °C for 44 h. Additional amounts of 2-(bromomethyl)pyridine (1.3 equiv, 2.7 g, 16 mmol) and DMAP (2.5 mol%, 37 mg, 300 μmol) were added and stirring at 75 °C was continued for another 3 days to afford the title compound (3.7 g, 71%) after column chromatography (SiO, hexane / DCM).

[0350] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.46 (s, 3H), 2.85-2.95 (m, 4H), 4.26 (q, 2H), 5.39 (s, 2H), 7.07 (d, 1H), 7.31 (ddd, 1H), 7.65 (s, 1H), 7.77 (dt, 1H), 8.53-8.55 (m, 1H). UPLC-MS (Method 1): R t = 1.15 min; MS (ESIpos): m / z = 338 [M+H] + .

[0351] Step 2 8-Methyl-2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0352] [ka]

[0353] Following GP D, ethyl 8-methyl-2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (3.68 g, 10.9 mmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 82 mL, 160 mmol) in a 1:1 mixture of ethanol and THF (40 mL) at 70 °C overnight. After acidification (pH 2–3) with 6 N hydrochloric acid and dilution with EtOAc, a precipitate formed, which was isolated by filtration. The precipitate was dissolved in EtOAc, dried over Na2SO2, filtered, and concentrated under reduced pressure to give the desired carboxylic acid (1.9 g, 54%).

[0354] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.44 (s, 3H), 2.84-2.93 (m, 4H), 5.39 (s, 2H), 7.07 (d, 1H), 7.32 (dd, 1H), 7.65 (s, 1H), 7.78 (dt, 1H), 8.53-8.55 (m, 1H), 12.80 (br. s., 1H). UPLC-MS (Method 1): R t = 0.50 min; MS (ESIpos): m / z = 310 [M+H] + .

[0355] Intermediate 3: Step 1 Ethyl 8-methyl-2-[(pyridin-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0356] [ka]

[0357] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.0 equiv., 1.0 g, 4.1 mmol) was reacted with (pyridin-3-yl)methanol (1.10 equiv., 487 mg, 4.47 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 1.6 mL, 6.5 mmol), and TMAD (CAS No. [10465-78-8]; 1.6 equiv., 1.1 g, 6.5 mmol) in toluene (30 mL) at room temperature overnight. Column chromatography (Si-NH SiO 2 , DCM / MeOH) and trituration with hexane gave the title compound (1.6 g, 75% purity, 70%).

[0358] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.48 (s, 3H), 2.83-2.93 (m, 4H), 4.26 (q, 2H), 5.35 (s, 2H), 7.36-7.39 (m, 1H), 7.64 (t, 1H), 7.66 (s, 1H), 8.50 (dd, 1H), 8.52 (d, 1H). UPLC-MS (Method 1): R t = 1.10 min; MS (ESIpos): m / z = 338 [M+H] + .

[0359] Step 2 8-Methyl-2-[(pyridin-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0360] [ka]

[0361] Following GP D, ethyl 8-methyl-2-[(pyridin-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.50 g, 75% purity, 3.33 mmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 82 mL, 160 mmol) in a 1:1 mixture of ethanol and THF (20 mL) at 70° C. overnight. Upon acidification (pH 4) with 4 N hydrochloric acid, a precipitate formed, which was isolated by filtration and dried to give the desired carboxylic acid (331 mg, 77% purity, 25%).

[0362] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.46 (s, 3H), 2.82-2.91 (m, 4H), 5.34 (s, 2H), 7.38 (ddd, 1H), 7.64-7.67 (m, 2H), 8.50 (dd, 1H), 8.52 (d, 1H), 12.83 (br. s., 1H). UPLC-MS (Method 1): R t = 0.47 min; MS (ESIpos): m / z = 310 [M+H] + .

[0363] Intermediate 4: Step 1 Ethyl 8-methyl-2-[(pyridin-4-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0364] [ka]

[0365] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.0 equiv., 1.0 g, 4.1 mmol) was reacted with (pyridin-4-yl)methanol (1.10 equiv., 487 mg, 4.47 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 1.6 mL, 6.5 mmol), and TMAD (CAS No. [10465-78-8]; 1.6 equiv., 1.1 g, 6.5 mmol) in toluene (30 mL) at room temperature overnight. Additional amounts of (pyridin-4-yl)methanol (0.40 equiv., 175 mg, 1.6 mmol), tri-n-butylphosphine (0.4 equiv., 0.4 mL, 1.6 mmol), and TMAD (0.4 equiv., 0.3 g, 1.6 mmol) were added and stirring was continued for 2 days to afford the title compound (3 g, 20% purity, 44%) after column chromatography (Si-NH SiO, DCM / MeOH).

[0366] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.47 (s, 3H), 2.87-2.97 (m, 4H), 4.26 (q, 2H), 5.37 (s, 2H), 7.13-7.15 (m, 2H), 7.68 (s, 1H), 8.52-8.53 (m, 2H). UPLC-MS (Method 1): R t = 1.09 min; MS (ESIpos): m / z = 338 [M+H] + .

[0367] Step 2 8-Methyl-2-[(pyridin-4-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0368] [ka]

[0369] Following GP D, ethyl 8-methyl-2-[(pyridin-4-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (3 g, 20% purity, 4 mmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 31 mL, 61 mmol) in a 1:1 mixture of ethanol and THF (22 mL) overnight at 70° C. Upon acidification (pH 4) with 4 N hydrochloric acid, a precipitate formed, which was isolated by filtration and dried to give the desired carboxylic acid (467 mg, 35%).

[0370] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.45 (s, 3H), 2.85-2.94 (m, 4H), 5.37 (s, 2H), 7.13-7.15 (m, 2H), 7.67 (s, 1H), 8.52-8.53 (m, 2H), 12.81 (br. s., 1H). UPLC-MS (Method 1): R t = 0.50 min; MS (ESIpos): m / z = 310 [M+H] + .

[0371] Intermediate 5: Step 1 Ethyl 2-(cyclopropylmethyl)-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0372] [ka]

[0373] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.0 equiv., 1.0 g, 4.1 mmol) was reacted with cyclopropylmethanol (1.5 equiv., 490 μL, 6.1 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 1.6 mL, 6.5 mmol), and TMAD (CAS No. [10465-78-8]; 1.6 equiv., 1.1 g, 6.5 mmol) in toluene (20 mL) at room temperature overnight, and column chromatography (Si-HP SiO, hexane / EtOAc) afforded the title compound (957 mg, 75%) along with the corresponding N1-isomer (155 mg, 12%).

[0374] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.33-0.37 (m, 2H), 0.49-0.54 (m, 2H), 1.18-1.26 (m, 1H), 1.30 (t, 3H), 2.83-2.93 (m, 4H), 3.92 (d, 2H), 4.27 (q, 2H), 7.56 (s, 1H). UPLC-MS (Method 1): R t = 1.31 min; MS (ESIpos): m / z = 301 [M+H] + .

[0375] Step 2 2-(Cyclopropylmethyl)-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0376] [ka]

[0377] Following GP D, ethyl 2-(cyclopropylmethyl)-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 955 mg, 3.18 mmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 24 mL, 48 mmol) in a 1:1 mixture of ethanol and THF (22 mL) at 70° C. overnight. Upon acidification (pH 4) with 6 N hydrochloric acid, a precipitate formed, which was isolated by filtration, washed with water, and dried to give the desired carboxylic acid (945 mg, 100%).

[0378] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.33-0.37 (m, 2H), 0.49-0.54 (m, 2H), 1.17-1.27 (m, 1H), 2.48 (s, 3H), 2.82-2.91 (m, 4H), 3.91 (d, 2H), 7.54 (s, 1H), 12.81 (br. s., 1H). UPLC-MS (Method 1): R t = 0.55 min; MS (ESIpos): m / z = 273 [M+H] + .

[0379] Intermediate 6: Step 1 Ethyl 2-{[(2R / S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-yl]methyl}-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0380] [ka]

[0381] According to GP C (condition B), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.0 equiv., 930 mg, 3.78 mmol) was reacted with [(2R / S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-yl]methyl 4-methylbenzene-1-sulfonate (G. Guillaumet et al., Tetrahedron 2004, 60, 6461-6473, cpd.) in MeCN (50 mL). Prepared as described in 16B; reacted with 1.5 equiv. (1.8 g, 5.7 mmol), potassium carbonate (15 equiv. (7.8 g, 57 mmol), and DMAP (0.30 equiv. (140 mg, 1.1 mmol) at 60 °C for 9 days, followed by two-step column chromatography (SiHP SiO, hexane / EtOAc) to give the title compound (443 mg, 28%).

[0382] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.84-2.94 (m, 4H), 4.18-4.29 (m, 3H), 4.36-4.48 (m, 2H), 4.53 (dd, 1H), 4.62-4.66 (m, 1H), 6.96 (dd, 1H), 7.31 (dd, 1H), 7.56 (s, 1H), 7.77 (dd, 1H). UPLC-MS (Method 1): R t = 1.17 min; MS (ESIpos): m / z = 396 [M+H] + .

[0383] Step 2 2-{[(2R / S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-yl]methyl}-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0384] [ka]

[0385] In the modification of GP D, ethyl 2-{[(2R / S)-2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-yl]methyl}-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 418 mg, 1.06 mmol) from Step 1 was reacted with aqueous sodium hydroxide (4 M; 30 equiv., 7.9 mL, 32 mmol) in THF (6 mL) at 70 °C overnight. After acidification (pH 2) with 6 N hydrochloric acid and dilution with EtOAc, a precipitate formed, which was isolated by filtration. The filtrate was saved. The precipitate was dissolved in EtOAc, dried over Na2SO2, filtered, and concentrated under reduced pressure to give the first crop of the desired carboxylic acid (190 mg, 47%). The filtrate obtained above was separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a second crop of the desired carboxylic acid (160 mg, 39%).

[0386] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.48 (s, 3H), 2.83-2.92 (m, 4H), 4.20 (dd, 1H), 4.36-4.47 (m, 2H), 4.52 (dd, 1H), 4.62-4.67 (m, 1H), 6.96 (dd, 1H), 7.31 (dd, 1H), 7.55 (s, 1H), 7.76 (dd, 1H), 12.83 (br. s., 1H). UPLC-MS (Method 1): R t = 0.51 min; MS (ESIpos): m / z = 368 [M+H] +

[0387] Intermediate 7: Step 1 Ethyl 8-methyl-2-{[6-(trifluoromethyl)pyridin-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0388] [ka]

[0389] According to GP C (Condition B), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 500 mg, 2.03 mmol) was reacted with 2-(chloromethyl)-6-(trifluoromethyl)pyridine (1.5 equiv., 596 mg, 3.05 mmol), potassium carbonate (15.0 equiv., 4.21 g, 30.5 mmol) in MeCN (10 mL) at 60 °C for 3 days to give the title compound (493 mg, 57%) after column chromatography (SiO, hexane / EtOAc).

[0390] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.46 (s, 3H), 2.87-2.96 (m, 4H), 4.26 (q, 2H), 5.52 (s, 2H), 7.27 (d, 1H), 7.72 (s, 1H), 7.84 (d, 1H), 8.08 (t, 1H). UPLC-MS (Method 1): R t = 1.36 min; MS (ESIpos): m / z = 406 [M+H] + .

[0391] Step 2 8-Methyl-2-{[6-(trifluoromethyl)pyridin-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0392] [ka]

[0393] Following GP D, ethyl 8-methyl-2-{[6-(trifluoromethyl)pyridin-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (438 mg, 1.19 mmol) from Step 1 was reacted with aqueous lithium hydroxide (1 M; 15 equiv., 18 mL, 18 mmol) in a 1:1 mixture of ethanol and THF (35 mL) at 70 °C overnight. The reaction mixture was acidified (pH 4) with 4 N aqueous HCl and diluted with EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to the desired carboxylic acid (405 mg, 87%).

[0394] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.44 (s, 3H), 2.86-2.94 (m, 4H), 5.51 (s, 2H), 7.26 (d, 1H), 7.71 (s, 1H), 7.84 (d, 1H), 8.08 (t, 1H), 12.84 (br. s., 1H). UPLC-MS (Method 1): R t = 0.66 min; MS (ESIpos): m / z = 378 [M+H] + .

[0395] Intermediate 8: Step 1 Ethyl 8-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0396] [ka]

[0397] In the modification of GP C (Condition B), an ice-cold solution of ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 171 mg, 694 μmol) in DMF (6 mL) was treated with sodium hydride (CAS No. [7646-69-7]; 55% purity, 1.2 equiv., 36 mg, 830 μmol) for 30 minutes, at which point 2-(bromomethyl)-5-(trifluoromethyl)pyridine (1.20 equiv., 200 mg, 833 μmol) was added, the reaction mixture was allowed to warm to room temperature, and stirring was continued for 45 minutes. The reaction mixture was diluted with saturated aqueous ammonium chloride and EtOAc, the phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered, concentrated under reduced pressure and the resulting material was subjected to column chromatography (Si-NH4SiO2, DCM / MeOH) to afford the title compound (81 mg, 24%).

[0398] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.46 (s, 3H), 2.87-2.96 (m, 4H), 4.26 (q, 2H), 5.54 (s, 2H), 7.25 (d, 1H), 7.71 (s, 1H), 8.21 (dd, 1H), 8.95 (d, 1H). UPLC-MS (Method 1): R t = 1.34 min; MS (ESIpos): m / z = 406 [M+H] + .

[0399] Step 2 8-Methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0400] [ka]

[0401] Following GP D, ethyl 8-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (76.0 mg, 187 μmol) from Step 1 was reacted with aqueous lithium hydroxide (1 M; 30 equiv., 5.6 mL, 5.6 mmol) in a 1:1 mixture of ethanol and THF (20 mL) at 70 °C overnight. The reaction mixture was acidified (pH 4) with 4 N aqueous HCl and diluted with EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to the desired carboxylic acid (71 mg, 84%).

[0402] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.44 (s, 3H), 2.86-2.94 (m, 4H), 5.53 (s, 2H), 7.25 (d, 1H), 7.70 (s, 1H), 8.21 (d, 1H), 8.95 (d, 1H), 12.80 (br. s., 1H). UPLC-MS (Method 1): R t = 0.62 min; MS (ESIpos): m / z = 378 [M+H] + .

[0403] Intermediates 9-1 and 9-2: Step 1 Ethyl 2-[(3-chloro-5-fluoropyridin-2-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0404] [ka]

[0405] According to GP C (Condition B), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 500 mg, 2.03 mmol) was reacted with 2-(bromomethyl)-3-chloro-5-fluoropyridine (1.5 equiv., 684 mg, 3.05 mmol), potassium carbonate (15.0 equiv., 4.21 g, 30.5 mmol) in MeCN (10 mL) at 60 °C for 3 days to give the title compound (364 mg, 44%) after column chromatography (SiO, hexane / EtOAc).

[0406] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.44 (s, 3H), 2.83-2.93 (m, 4H), 4.26 (q, 2H), 5.51 (s, 2H), 7.56 (s, 1H), 8.16 (dd, 1H), 8.58 (d, 1H). UPLC-MS (Method 1): R t = 1.33 min; MS (ESIpos): m / z = 390 / 392 [M+H] + (Cl isotope pattern).

[0407] Step 2 2-[(3-chloro-5-fluoropyridin-2-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid (Intermediate 9-1) and 2-[(3-chloro-5-ethoxypyridin-2-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid (Intermediate 9-2)

[0408] [ka]

[0409] Following GP D, ethyl 2-[(3-chloro-5-fluoropyridin-2-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 355 mg, 911 μmol) from Step 1 was reacted with aqueous lithium hydroxide (1 M; 15 equiv., 14 mL, 14 mmol) in a 1:1 mixture of ethanol and THF (27 mL) at 70 °C overnight. The reaction mixture was acidified (pH 4) with 4 N aqueous HCl and diluted with EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure to give a 1:1 mixture of the title compounds (405 mg).

[0410] 9-1: UPLC-MS (Method 1): R t = 0.60 min; MS (ESIpos): m / z = 362 / 364 [M+H] + (Cl isotope pattern).

[0411] 9-2: UPLC-MS (Method 1): R t = 0.67 min; MS (ESIpos): m / z = 388 / 390 [M+H] + (Cl isotope pattern).

[0412] Intermediate 10: Step 1 Ethyl 2-[(3-chloropyridin-2-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0413] [ka]

[0414] According to GP C (Condition B), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 250 mg, 1.02 mmol) was reacted with 3-chloro-2-(chloromethyl)pyridine (1.50 equiv., 247 mg, 1.52 mmol), potassium carbonate (15 equiv., 2.1 g, 15 mmol) in MeCN (5 mL) at 60° C. overnight to give, after filtration, the crude title compound (388 mg, 95%), which was not further purified.

[0415] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.44 (s, 3H), 2.84-2.94 (m, 4H), 4.26 (q, 2H), 5.53 (s, 2H), 7.42 (dd, 1H), 7.56 (s, 1H), 7.98 (dd, 1H), 8.50 (dd, 1H). UPLC-MS (Method 1): R t = 1.29 min; MS (ESIpos): m / z = 372 / 374 [M+H] + (Cl isotope pattern).

[0416] Step 2 2-[(3-chloropyridin-2-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0417] [ka]

[0418] Following GP D, ethyl 2-[(3-chloropyridin-2-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 382 mg, 1.03 mmol) from Step 1 was reacted with aqueous lithium hydroxide (1 M; 15 equiv., 7.7 mL, 15 mmol) in a 1:1 mixture of ethanol and THF (10 mL) at 70 °C for 3 days. After acidification (pH 4) with 4 N hydrochloric acid and dilution with EtOAc, a precipitate formed, which was isolated by filtration, washed with water, and dried to give the first crop of the desired carboxylic acid (204 mg, 57%). The filtrate was separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure to give the second crop of the desired carboxylic acid (123 mg, 31%).

[0419] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.42 (s, 3H), 2.83-2.91 (m, 4H), 5.52 (s, 2H), 7.42 (dd, 1H), 7.55 (s, 1H), 7.98 (dd, 1H), 8.50 (dd, 1H), 12.81 (br. s., 1H). UPLC-MS (Method 1): R t = 0.56 min; MS (ESIpos): m / z = 344 / 346 [M+H] + (Cl isotope pattern).

[0420] Intermediate 11: Step 1 Ethyl 8-methyl-2-[(3-methylpyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0421] [ka]

[0422] According to GP C (Condition B), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 264 mg, 1.07 mmol) was reacted with 2-(chloromethyl)-3-methylpyridine hydrochloride (1 / 1) (1.50 equiv., 286 mg, 1.61 mmol), potassium carbonate (15 equiv., 2.2 g, 16 mmol) in MeCN (5 mL) at 60° C. for 2 days to give, after filtration, the crude title compound (413 mg, 100%), which was not further purified.

[0423] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.39 (s, 3H), 2.46 (s, 3H), 2.82-2.92 (m, 4H), 4.26 (q, 2H), 5.39 (s, 2H), 7.25 (dd, 1H), 7.47 (s, 1H), 7.62 (dd, 1H), 8.35 (dd, 1H). UPLC-MS (Method 1): R t = 1.23 min; MS (ESIpos): m / z = 352 [M+H] + .

[0424] Step 2 8-Methyl-2-[(3-methylpyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0425] [ka]

[0426] Following GP D, ethyl 8-methyl-2-[(3-methylpyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 400 mg, 1.14 mmol) from Step 1 was reacted with aqueous lithium hydroxide (1 M; 15 equiv., 17 mL, 17 mmol) in a 1:1 mixture of ethanol and THF (10 mL) at 70 °C overnight. After acidification (pH 4) with 4 N hydrochloric acid and dilution with EtOAc, a precipitate formed, which was isolated by filtration, washed with water, and dried to give the first crop of the desired carboxylic acid (209 mg, 56%). The filtrate was separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the second crop of the desired carboxylic acid (54 mg, 12%).

[0427] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.39 (s, 3H), 2.44 (s, 3H), 2.81-2.90 (m, 4H), 5.38 (s, 2H), 7.25 (dd, 1H), 7.46 (s, 1H), 7.62 (dd, 1H), 8.35 (dd, 1H), 12.79 (br. s., 1H). UPLC-MS (Method 1): R t = 0.50 min; MS (ESIpos): m / z = 324 [M+H] + .

[0428] Intermediate 12: Step 1 Ethyl 8-methyl-2-[(5-methylpyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0429] [ka]

[0430] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 300 mg, 1.22 mmol) was reacted with (5-methylpyridin-2-yl)methanol (1.50 equiv., 225 mg, 1.83 mmol), tri-n-butylphosphine (CAS no. [998-40-3]; 1.6 equiv., 490 μL, 1.9 mmol), and TMAD (CAS no. [10465-78-8]; 1.60 equiv., 336 mg, 1.95 mmol) in toluene (8 mL) at room temperature overnight, followed by column chromatography (SiO, hexane / EtOAc) to give the title compound (395 mg, 88%).

[0431] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.27 (s, 3H), 2.46 (s, 3H), 2.84-2.94 (m, 4H), 4.26 (q, 2H), 5.34 (s, 2H), 7.01 (dd, 1H), 7.58 (dd, 1H), 7.62 (s, 1H), 8.37 (dd, 1H). UPLC-MS (Method 1): R t = 1.18 min; MS (ESIpos): m / z = 352 [M+H] + .

[0432] Step 2 8-Methyl-2-[(5-methylpyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0433] [ka]

[0434] Following GP D, ethyl 8-methyl-2-[(5-methylpyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 388 mg, 1.10 mmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 17 mL, 8.3 mmol) in a 1:1 mixture of ethanol and THF (16 mL) at 70 °C overnight. The reaction mixture was acidified (pH 4) with 6 N aqueous HCl and diluted with EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired carboxylic acid (328 mg, 85%).

[0435] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.27 (s, 3H), 2.44 (s, 3H), 2.83-2.92 (m, 4H), 5.33 (s, 2H), 7.01 (dd, 1H), 7.59 (dd, 1H), 7.61 (s, 1H), 8.37 (dd, 1H), 12.78 (br. s., 1H). UPLC-MS (Method 1): R t = 0.54 min; MS (ESIpos): m / z = 324 [M+H] + .

[0436] Intermediate 13: Step 1 Methyl (5E / Z)-5-[(dimethylamino)methylidene]-3-methyl-4-oxo-4,5,6,7-tetrahydro-1-benzofuran-2-carboxylate

[0437] [ka]

[0438] Following GP A (Condition A), methyl 3-methyl-4-oxo-4,5,6,7-tetrahydro-1-benzofuran-2-carboxylate (commercially available, CAS number [40200-70-2]; 10.0 g, 48.0 mmol) was reacted with 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (Bredereck's reagent, CAS number [5815-08-7]; 1.2 equivalents, 12 mL, 58 mmol) in toluene (100 mL) at 100 °C overnight. An additional amount of 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (0.50 equivalents, 5.0 mL, 24 mmol) was added, and stirring at 100 °C was continued for an additional 5 days. The reaction mixture was concentrated under reduced pressure, and the resulting crude title compound was used in subsequent reactions without further purification. UPLC-MS (Method 1): R t = 0.95 / 1.01 min; MS (ESIpos): m / z = 264 [M+H] + .

[0439] Step 2 Methyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate

[0440] [ka]

[0441] Following GP B, crude methyl (5E / Z)-5-[(dimethylamino)methylidene]-3-methyl-4-oxo-4,5,6,7-tetrahydro-1-benzofuran-2-carboxylate (1.0 equiv., 13 g, 48 mmol) from Step 1 was reacted with 1:1 hydrazine hydrate (4.0 equiv., 9.5 mL, 195 mmol) in ethanol (150 mL) at 70 °C for 4 h and at room temperature overnight, followed by column chromatography (SiO, hexane / EtOAc) to afford the title compound (771 mg, 27% over two steps).

[0442] 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.51 (s, 3H; partially covered by solvent peak), 2.84-2.93 (m, 4H), 3.80 (s, 3H), 7.52 (s, 1H), 12.49 (s, 1H). UPLC-MS (Method 1): R t = 0.88 min; MS (ESIpos): m / z = 233 [M+H] + .

[0443] Step 3 Methyl 8-methyl-2-[(6-methylpyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0444] [ka]

[0445] Following GP C (Condition B), methyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate from Step 2 (1.0 equiv., 770 mg, 3.3 mmol) was reacted with 2-(bromomethyl)-6-methylpyridine (1.50 equiv., 926 mg, 4.98 mmol), potassium carbonate (10 equiv., 4.6 g, 33 mmol) in MeCN (10 mL) at 60° C. overnight to give, after filtration, the crude title compound (1.27 g, 100%), which was not further purified.

[0446] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.46-2.46 (m, 6H), 2.85-2.94 (m, 4H), 3.79 (s, 3H), 5.33 (s, 2H), 6.79 (d, 1H), 7.16 (d, 1H), 7.62-7.66 (m, 2H). UPLC-MS (Method 1): R t = 1.14 min; MS (ESIpos): m / z = 338 [M+H] +.

[0447] Step 4 8-Methyl-2-[(6-methylpyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0448] [ka]

[0449] In the modification of GP D, methyl 8-methyl-2-[(6-methylpyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.0 equiv., 1.2 g, 2.2 mmol) from Step 3 was reacted with aqueous sodium hydroxide (4 M; 30 equiv., 17 mL, 66 mmol) in THF (14 mL) at 70 °C for 2 days. The reaction mixture was acidified (pH 4-5) with 2 N aqueous HCl and diluted with EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired carboxylic acid (980 mg, 85% purity, 100%).

[0450] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.45-2.46 (m, 6H), 2.84-2.92 (m, 4H), 5.33 (s, 2H), 6.79 (d, 1H), 7.16 (d, 1H), 7.62-7.66 (m, 2H)., 12.52 (br. s., 1H). UPLC-MS (Method 1): R t = 0.55 min; MS (ESIpos): m / z = 324 [M+H] + .

[0451] Intermediates 14-1 and 14-2: Step 1 Ethyl 8-methyl-2-[(2-methylpyridin-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0452] [ka]

[0453] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 300 mg, 1.22 mmol) was reacted with (2-methylpyridin-3-yl)methanol (1.50 equiv., 225 mg, 1.83 mmol), tri-n-butylphosphine (CAS no. [998-40-3]; 1.6 equiv., 490 μL, 1.9 mmol), and TMAD (CAS no. [10465-78-8]; 1.60 equiv., 336 mg, 1.95 mmol) in toluene (8 mL) at room temperature overnight, followed by column chromatography (SiO, hexane / EtOAc) to afford the title compound (315 mg, 71%).

[0454] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.47 (s, 3H), 2.54 (s, 3H), 2.84-2.94 (m, 4H), 4.26 (q, 2H), 5.35 (s, 2H), 7.17-7.25 (m, 2H), 7.59 (s, 1H), 8.36 (dd, 1H). UPLC-MS (Method 1): R t = 1.12 min; MS (ESIpos): m / z = 352 [M+H] + .

[0455] Step 2 8-Methyl-2-[(2-methylpyridin-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid hydrogen chloride (1 / 1) and 8-Methyl-2-[(2-methylpyridin-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0456] [ka]

[0457] Following GP D, ethyl 8-methyl-2-[(2-methylpyridin-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 313 mg, 891 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 6.7 mL, 13 mmol) in a 1:1 mixture of ethanol and THF (14 mL) at 70 °C overnight. After acidifying (pH 4) with 6 N hydrochloric acid and diluting with EtOAc, a precipitate formed, which was isolated by filtration and dried to afford the hydrochloride salt of the desired carboxylic acid (Intermediate 14-1, 225 mg, 67%). The filtrate was separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired carboxylic acid (Intermediate 14-2, 47 mg, 15%).

[0458] 14-1: 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.44 (s, 3H), 2.79 (s, 3H), 2.86-2.94 (m, 4H), 5.52 (s, 2H), 7.68 (s, 1H), 7.73-7.77 (m, 1H), 7.83-7.85 (m, 1H), 8.65 (dd, 1H), 12.84 (br. s., 1H).

[0459] 14-1: UPLC-MS (Method 1): R t = 0.50 min; MS (ESIpos): m / z = 324 [M-Cl - ] + .

[0460] Intermediates 15-1 and 15-2: Step 1 Ethyl 8-methyl-2-[(6-methylpyridin-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0461] [ka]

[0462] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 300 mg, 1.22 mmol) was reacted with (6-methylpyridin-3-yl)methanol (1.50 equiv., 225 mg, 1.83 mmol), tri-n-butylphosphine (CAS no. [998-40-3]; 1.6 equiv., 490 μL, 1.9 mmol), and TMAD (CAS no. [10465-78-8]; 1.60 equiv., 336 mg, 1.95 mmol) in toluene (8 mL) at room temperature overnight, followed by column chromatography (SiO, hexane / EtOAc) to give the title compound (299 mg, 66%).

[0463] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.43 (s, 3H), 2.48 (s, 3H), 2.83-2.92 (m, 4H), 4.26 (q, 2H), 5.28 (s, 2H), 7.22 (d, 1H), 7.56 (dd, 1H), 7.63 (s, 1H), 8.40 (d, 1H). UPLC-MS (Method 1): R t = 1.17 min; MS (ESIpos): m / z = 352 [M+H] + .

[0464] Step 2 8-Methyl-2-[(6-methylpyridin-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid hydrogen chloride (1 / 1) and 8-Methyl-2-[(6-methylpyridin-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0465] [ka]

[0466] Following GP D, ethyl 8-methyl-2-[(6-methylpyridin-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 291 mg, 828 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 6.2 mL, 12 mmol) in a 1:1 mixture of ethanol and THF (12 mL) at 70 °C overnight. After acidifying with 6 N hydrochloric acid (pH 3) and diluting with EtOAc, a precipitate formed, which was isolated by filtration and dried to afford the hydrochloride salt of the desired carboxylic acid (Intermediate 15-1, 195 mg, 63%). The filtrate was separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired carboxylic acid (Intermediate 15-2, 44 mg, 15%).

[0467] 15-1: 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.46 (s, 3H), 2.57 (s, 3H), 2.82-2.91 (m, 4H), 5.39 (s, 2H), 7.57 (d, 1H), 7.67 (s, 1H), 7.94 (d, 1H), 8.59 (d, 1H), 12.84 (br. s., 1H).

[0468] 15-1: UPLC-MS (Method 1): R t = 0.51 min; MS (ESIpos): m / z = 324 [M-Cl- ] + .

[0469] Intermediates 16-1 and 16-2: Step 1 Ethyl 2-[(2,6-dimethylpyridin-3-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0470] [ka]

[0471] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 300 mg, 1.22 mmol) was reacted with (2,6-dimethylpyridin-3-yl)methanol (1.50 equiv., 251 mg, 1.83 mmol), tri-n-butylphosphine (CAS no. [998-40-3]; 1.6 equiv., 490 μL, 1.9 mmol), and TMAD (CAS no. [10465-78-8]; 1.60 equiv., 336 mg, 1.95 mmol) in toluene (8 mL) at room temperature overnight, followed by column chromatography (SiO, hexane / EtOAc) to give the title compound (312 mg, 63%).

[0472] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.39 (s, 3H), 2.47 (s, 3H), 2.83-2.93 (m, 4H), 4.26 (q, 2H), 5.29 (s, 2H), 7.04 (d, 1H), 7.20 (d, 1H), 7.55 (s, 1H). UPLC-MS (Method 1): R t = 1.23 min; MS (ESIpos): m / z = 366 [M+H] + .

[0473] Step 2 2-[(2,6-dimethylpyridin-3-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid hydrogen chloride (1 / 1) and 2-[(2,6-dimethylpyridin-3-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0474] [ka]

[0475] Following GP D, ethyl 2-[(2,6-dimethylpyridin-3-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 305 mg, 835 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 6.3 mL, 13 mmol) in a 1:1 mixture of ethanol and THF (12 mL) at 70 °C overnight. After acidifying with 6 N hydrochloric acid (pH 3) and diluting with EtOAc, a precipitate formed, which was isolated by filtration and dried to afford the hydrochloride salt of the desired carboxylic acid (Intermediate 16-1, 86 mg, 27%). The filtrate was separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired carboxylic acid (Intermediate 16-2, 91 mg, 24%).

[0476] 16-1: 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.44 (s, 3H), 2.62 (br. s., 3H), 2.74 (br. s., 3H), 2.84-2.93 (m, 4H), 5.45 (s, 2H), 7.57 (br. s., 2H), 7.65 (s, 1H), 7.81 (br. s., 1H), 12.83 (br. s., 1H).

[0477] 16-1: UPLC-MS (Method 1): R t= 0.58 min; MS (ESIpos): m / z = 338 [M-Cl - ] + .

[0478] Intermediates 17-1 and 17-2: Step 1 Ethyl 8-methyl-2-[(2-methylpyridin-4-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0479] [ka]

[0480] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 300 mg, 1.22 mmol) was reacted with (2-methylpyridin-4-yl)methanol (1.10 equiv., 165 mg, 1.34 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 490 μL, 1.9 mmol), and TMAD (CAS No. [10465-78-8]; 1.60 equiv., 336 mg, 1.95 mmol) in toluene (12 mL) at room temperature overnight, followed by column chromatography (SiO, CHCl / hexane) to give the title compound (524 mg, 44% purity, 54%).

[0481] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.43 (s, 3H), 2.47 (s, 3H), 2.85-2.95 (m, 4H), 4.26 (q, 2H), 5.31 (s, 2H), 6.94 (d, 1H), 7.05 (s, 1H), 7.66 (s, 1H), 8.38 (d, 1H). UPLC-MS (Method 1): R t = 1.15 min; MS (ESIpos): m / z = 352 [M+H] + .

[0482] Step 2 8-Methyl-2-[(2-methylpyridin-4-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid hydrogen chloride (1 / 1) and 8-methyl-2-[(2-methylpyridin-4-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid and

[0483] [ka]

[0484] Following GP D, ethyl 8-methyl-2-[(2-methylpyridin-4-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 522 mg, 1.22 mmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 17 equiv., 10 mL, 21 mmol) in a 1:1 mixture of ethanol and THF (12 mL) at 70 °C overnight and then at room temperature for 2 days. After acidifying with 4 N hydrochloric acid (pH 3.5) and diluting with EtOAc, a precipitate formed, which was isolated by filtration and dried to afford the hydrochloride salt of the desired carboxylic acid (Intermediate 17-1, 168 mg, 61%). The filtrate was separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give the desired carboxylic acid (Intermediate 17-2, 285 mg, 50% purity, 36%).

[0485] 17-1: 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.44 (s, 3H), 2.66 (s, 3H), 2.87-2.95 (m, 4H), 5.57 (s, 2H), 7.39 (d, 1H), 7.53 (s, 1H), 7.73 (s, 1H), 8.65 (d, 1H), 12.84 (br. s., 1H).

[0486] 17-1: UPLC-MS (Method 1): R t = 0.51 min; MS (ESIpos): m / z = 324 [M-Cl - ] + .

[0487] Intermediates 18-1 and 18-2: Step 1 Ethyl 2-[(2,6-dimethylpyridin-4-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0488] [ka]

[0489] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 300 mg, 1.22 mmol) was reacted with (2,6-dimethylpyridin-4-yl)methanol (1.50 equiv., 251 mg, 1.83 mmol), tri-n-butylphosphine (CAS no. [998-40-3]; 1.6 equiv., 490 μL, 1.9 mmol), and TMAD (CAS no. [10465-78-8]; 1.60 equiv., 336 mg, 1.95 mmol) in toluene (8 mL) at room temperature overnight, followed by column chromatography (SiO, hexane / EtOAc) to give the title compound (419 mg, 83%).

[0490] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.22 (s, 3H), 2.41 (s, 3H), 2.47 (s, 3H), 2.85-2.95 (m, 4H), 4.26 (q, 2H), 5.28 (s, 2H), 6.71 (s, 1H), 7.00 (s, 1H), 7.62 (s, 1H). UPLC-MS (Method 1): R t= 1.29 min; MS (ESIpos): m / z = 366 [M+H] + .

[0491] Step 2 2-[(2,6-dimethylpyridin-4-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid hydrogen chloride (1 / 1) and 2-[(2,6-dimethylpyridin-4-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0492] [ka]

[0493] Following GP D, ethyl 2-[(2,6-dimethylpyridin-4-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 408 mg, 1.12 mmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 8.4 mL, 17 mmol) in a 1:1 mixture of ethanol and THF (16 mL) at 70 °C overnight. After acidifying (pH 3) with 6 N hydrochloric acid and diluting with EtOAc, a precipitate formed, which was isolated by filtration and dried to afford the hydrochloride salt of the desired carboxylic acid (Intermediate 18-1, 94 mg, 22%). The filtrate was separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired carboxylic acid (Intermediate 18-2, 161 mg, 32%).

[0494] 18-1: 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.35 (br. s., 3H), 2.45 (s, 3H), 2.55 (br. s., 3H), 2.85-2.94 (m, 4H), 5.46 (s, 2H), 6.97 (br. s., 1H), 7.33 (br. s., 1H), 7.69 (s, 1H), 12.83 (br. s., 1H).

[0495] 18-1: UPLC-MS (Method 1): R t = 0.58 min; MS (ESIpos): m / z = 338 [M-Cl - ] + .

[0496] Intermediate 19: Step 1 Ethyl 8-methyl-2-[(pyrimidin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0497] [ka]

[0498] According to GP C (Condition B), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 260 mg, 1.06 mmol) was reacted with 2-(chloromethyl)pyrimidine (1.50 equiv., 204 mg, 1.58 mmol) and potassium carbonate (15 equiv., 2.2 g, 16 mmol) in MeCN (5 mL) overnight at 60° C. DMAP (5 mol%, 6.5 mg, 53 μmol) was added and stirring at 60° C. was continued for 4 days to give the crude title compound (332 mg, 79%) after filtration, which was not further purified.

[0499] 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.44 (s, 3H), 2.86-2.95 (m, 4H), 4.26 (q, 2H), 5.51 (s, 2H), 7.45 (t, 1H), 7.63 (s, 1H), 8.79-8.80 (m, 2H). UPLC-MS (Method 1): R t = 1.03 min; MS (ESIpos): m / z = 339 [M+H] + .

[0500] Step 2 8-Methyl-2-[(pyrimidin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0501] [ka]

[0502] Following GP D, ethyl 8-methyl-2-[(pyrimidin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 332 mg, 834 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 6.3 mL, 13 mmol) in a 1:1 mixture of ethanol and THF (8 mL) overnight at 70° C. The reaction mixture was acidified (pH 4) with 4 N aqueous HCl and concentrated under reduced pressure to give the crude title compound (1.8 g) along with salts, which was not further purified. UPLC-MS (Method 1): R t = 0.44 min; MS (ESIpos): m / z = 311 [M+H] + .

[0503] Intermediate 20: Step 1 Ethyl 8-methyl-2-[(pyrimidin-5-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0504] [ka]

[0505] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 300 mg, 1.22 mmol) was reacted with (pyrimidin-5-yl)methanol (1.50 equiv., 201 mg, 1.83 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 490 μL, 1.9 mmol), and TMAD (CAS No. [10465-78-8]; 1.60 equiv., 336 mg, 1.95 mmol) in toluene (8 mL) at room temperature overnight, followed by column chromatography (Si-NH SiO 2 , hexane / CHCl 2 / MeOH) to give the title compound (483 mg, 52% purity, 61%).

[0506] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.47 (s, 3H), 2.83-2.93 (m, 4H), 4.26 (q, 2H), 5.39 (s, 2H), 7.70 (s, 1H), 8.74 (s, 2H), 9.13 (s, 1H). UPLC-MS (Method 1): R t = 1.02 min; MS (ESIpos): m / z = 339 [M+H] + .

[0507] Step 2 8-Methyl-2-[(pyrimidin-5-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0508] [ka]

[0509] Following GP D, ethyl 8-methyl-2-[(pyrimidin-5-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 480 mg, 52% purity, 738 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 5.5 mL, 11 mmol) in a 1:1 mixture of ethanol and THF (5.2 mL) at 70 °C overnight. The reaction mixture was acidified (pH 4) with 6 N aqueous HCl and diluted with EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired carboxylic acid (439 mg, 37% purity, 71%).

[0510] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.46 (s, 3H), 2.83-2.92 (m, 4H), 5.38 (s, 2H), 7.70 (s, 1H), 8.74 (s, 2H), 9.13 (s, 1H), 12.73 (br. s., 1H). UPLC-MS (Method 1): R t = 0.44 min; MS (ESIpos): m / z = 311 [M+H] + .

[0511] Intermediate 21: Step 1 Ethyl 2-{[(2R)-1,4-dioxan-2-yl]methyl}-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0512] [ka]

[0513] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 250 mg, 1.02 mmol) was reacted with [(2R)-1,4-dioxan-2-yl]methanol (1.50 equiv., 180 mg, 1.52 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 410 μL, 1.6 mmol), and TMAD (CAS No. [10465-78-8]; 1.60 equiv., 280 mg, 1.62 mmol) in toluene (8 mL) at room temperature overnight. Additional amounts of tri-n-butylphosphine (0.30 equiv., 76 μL, 300 μmol) and TMAD (0.30 equiv., 52 mg, 0.31 mmol) were added, stirring at room temperature was continued for 4 days, and two successive column chromatography runs (SiO, CHCl / MeOH) afforded the title compound (739 mg, 35–40% purity, 74%). UPLC-MS (Method 1): R t = 1.12 min; MS (ESIpos): m / z = 347 [M+H] + .

[0514] Step 2 2-{[(2R)-1,4-dioxan-2-yl]methyl}-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0515] [ka]

[0516] Following GP D, ethyl 2-{[(2R)-1,4-dioxan-2-yl])methyl}-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 739 mg, 40% purity, 850 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 6.4 mL, 13 mmol) in a 1:1 mixture of ethanol and THF (6 mL) at 70 °C overnight. The reaction mixture was acidified (pH 3) with 4 N aqueous HCl and diluted with EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired carboxylic acid (712 mg, 41% purity, 100%). UPLC-MS (Method 1): R t = 0.49 min; MS (ESIpos): m / z = 319 [M+H] + .

[0517] Intermediate 22: Step 1 Ethyl 2-{[(2S)-1,4-dioxan-2-yl]methyl}-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0518] [ka]

[0519] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 347 mg, 1.41 mmol) was reacted with [(2S)-1,4-dioxan-2-yl]methanol (CAS No. [406913-93-7]; 1.50 equiv., 250 mg, 2.12 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 560 μL, 2.3 mmol), and TMAD (CAS No. [10465-78-8]; 1.60 equiv., 389 mg, 2.26 mmol) in toluene (8 mL) at room temperature for 4 days, followed by column chromatography (Si-NH SiO2, hexane / CH2Cl2) to give the title compound (483 mg, 65% purity, 64%).

[0520] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.30 (t, 3H), 2.82-2.93 (m, 4H), 3.26 (dd, 1H), 3.45 (dt, 1H), 3.54 (dt, 1H), 3.62-3.64 (m, 1H), 3.72-3.76 (m, 2H), 3.80-3.87 (m, 1H), 4.05-4.14 (m, 2H), 4.27 (q, 2H), 7.48 (s, 1H). UPLC-MS (Method 1): R t = 1.13 min; MS (ESIpos): m / z = 347 [M+H] + .

[0521] Step 2 2-{[(2S)-1,4-dioxan-2-yl]methyl}-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0522] [ka]

[0523] Following GP D, ethyl 2-{[(2S)-1,4-dioxan-2-yl])methyl}-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 480 mg, 65% purity, 900 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 23 equiv., 10 mL, 21 mmol) in a 1:1 mixture of ethanol and THF (10 mL) at 70 °C overnight. The reaction mixture was acidified (pH 4) with 4 N aqueous HCl and diluted with EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired carboxylic acid (422 mg, 64% purity, 61%).

[0524] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.47 (s, 3H), 2.81-2.91 (m, 4H), 3.26 (dd, 1H), 3.44 (dt, 1H), 3.54 (dt, 1H), 3.62-3.64 (m, 1H), 3.72-3.75 (m, 2H), 3.82-3.87 (m, 1H), 4.05-4.14 (m, 2H), 7.47 (s, 1H), 12.73 (br. s., 1H). UPLC-MS (Method 1): R t = 0.48 min; MS (ESIpos): m / z = 319 [M+H] + .

[0525] Intermediate 23: Step 1 Ethyl 8-methyl-2-[(oxetan-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0526] [ka]

[0527] According to GP C (Condition B), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 270 mg, 1.10 mmol) was reacted with 3-(bromomethyl)oxetane (1.50 equiv., 248 mg, 1.64 mmol) and potassium carbonate (15 equiv., 2.3 g, 16 mmol) in MeCN (8 mL) overnight at 60° C. DMAP (5 mol%, 6.7 mg, 55 μmol) was added and stirring at 60° C. was continued for 4 days to give the crude title compound (509 mg, 68% purity, 100%) after filtration, which was not further purified.

[0528] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.48 (s, 3H), 2.81-2.85 (m, 2H), 2.88-2.92 (m, 2H), 3.36-3.40 (m, 1H), 4.26 (q, 2H), 4.35-4.43 (m, 3H), 4.49 (d, 1H), 4.64 (dd, 2H), 7.55 (s, 1H). UPLC-MS (Method 1): R t = 1.07 min; MS (ESIpos): m / z = 317 [M+H] + .

[0529] Step 2 8-Methyl-2-[(oxetan-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0530] [ka]

[0531] Following GP D, ethyl 8-methyl-2-[(oxetan-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 510 mg, 68% purity, 1.1 mmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 8.2 mL, 16 mmol) in a 1:1 mixture of ethanol and THF (10 mL) at 70° C. overnight. The reaction mixture was made neutral (pH 6) with 4 N aqueous HCl and concentrated under reduced pressure to give the crude title compound (1.9 g) along with salts, which was not further purified. UPLC-MS (Method 1): R t = 0.44 min; MS (ESIpos): m / z = 289 [M+H] + .

[0532] Intermediate 24: Step 1 Ethyl 8-methyl-2-[(3-methyloxetan-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0533] [ka]

[0534] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 300 mg, 1.22 mmol) was reacted with (3-methyloxetan-3-yl)methanol (1.5 equiv., 190 μL, 1.8 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 490 μL, 1.9 mmol), and TMAD (CAS No. [10465-78-8]; 1.60 equiv., 336 mg, 1.95 mmol) in toluene (8 mL) at room temperature overnight, followed by column chromatography (Si-NH SiO 2 , hexane / CHCl 2 ) to give the title compound (529 mg, 52% purity, 68%).

[0535] 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.17 (s, 3H), 1.29 (t, 3H), 2.48 (s, 3H), 2.83-2.93 (m, 4H), 4.21-4.29 (m, 6H), 4.60 (d, 2H), 7.55 (s, 1H). UPLC-MS (Method 1): R t = 1.17 min; MS (ESIpos): m / z = 331 [M+H] + .

[0536] Step 2 8-Methyl-2-[(3-methyloxetan-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0537] [ka]

[0538] Following GP D, ethyl 8-methyl-2-[(3-methyloxetan-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 527 mg, 52% purity, 829 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 6.2 mL, 12 mmol) in a 1:1 mixture of ethanol and THF (6 mL) at 70 °C overnight. The reaction mixture was acidified (pH 3) with 4 N aqueous HCl and diluted with EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired carboxylic acid (500 mg, 42% purity, 84%).

[0539] 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.16 (s, 3H), 2.45 (s, 3H), 2.81-2.89 (m, 4H), 4.22 (d, 2H), 4.26 (s, 2H), 4.60 (d, 2H), 7.52 (s, 1H), 12.75 (br. s., 1H). UPLC-MS (Method 1): R t = 0.49 min; MS (ESIpos): m / z = 303 [M+H] + .

[0540] Intermediate 25: Step 1 Ethyl 2-[(3-fluorooxetan-3-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0541] [ka]

[0542] According to GP C (Condition B), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 270 mg, 1.10 mmol) was reacted with 3-(bromomethyl)-3-fluorooxetane (1.50 equiv., 278 mg, 1.64 mmol) and potassium carbonate (15 equiv., 2.3 g, 16 mmol) in MeCN (8 mL) overnight at 60° C. DMAP (5 mol%, 6.7 mg, 55 μmol) was added and stirring at 60° C. was continued for 4 days. After filtration, the crude title compound (433 mg, 85% purity, 100%) was obtained without further purification.

[0543] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.83-2.94 (m, 4H), 4.27 (q, 2H), 4.59-4.68 (m, 4H), 4.75-4.85 (m, 2H), 7.55 (s, 1H). UPLC-MS (Method 1): R t = 1.13 min; MS (ESIpos): m / z = 335 [M+H] + .

[0544] Step 2 2-[(3-fluorooxetan-3-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0545] [ka]

[0546] Following GP D, ethyl 2-[(3-fluorooxetan-3-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 433 mg, 85% purity, 1.1 mmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 8.3 mL, 17 mmol) in a 1:1 mixture of ethanol and THF (10 mL) overnight at 70° C. The reaction mixture was made neutral (pH 6) with 4 N aqueous HCl and concentrated under reduced pressure to give the crude title compound (1.8 g) along with salts, which was not further purified. UPLC-MS (Method 1): R t = 0.46 min; MS (ESIpos): m / z = 307 [M+H] + .

[0547] Intermediate 26: Step 1 Ethyl 8-methyl-2-{[(2R)-oxetan-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0548] [ka]

[0549] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 330 mg, 1.34 mmol) was reacted with [(2R)-oxetan-2-yl]methanol (1.50 equiv., 177 mg, 2.01 mmol), tri-n-butylphosphine (CAS no. [998-40-3]; 1.6 equiv., 540 μL, 2.1 mmol), and TMAD (CAS no. [10465-78-8]; 1.60 equiv., 369 mg, 2.14 mmol) in toluene (5 mL) at room temperature overnight, followed by column chromatography (SiO, hexane / EtOAc) to give the title compound (197 mg, 46%).

[0550] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.37-2.46 (m, 1H), 2.60-2.68 (m, 1H), 2.83-2.93 (m, 4H), 4.24-4.37 (m, 5H), 4.46-4.51 (m, 1H), 4.94-5.00 (m, 1H), 7.52 (s, 1H). UPLC-MS (Method 1): R t = 1.00 min; MS (ESIpos): m / z = 317 [M+H] + .

[0551] Step 2 8-Methyl-2-{[(2R)-oxetan-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0552] [ka]

[0553] Following GP D, ethyl 8-methyl-2-{[(2R)-oxetan-2-yl])methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 190 mg, 601 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 4.5 mL, 9.0 mmol) in a 1:1 mixture of ethanol and THF (8 mL) at 70 °C for 3 days. The reaction mixture was acidified (pH 4) with 6 N aqueous HCl and diluted with EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired carboxylic acid (198 mg, 91%). UPLC-MS (Method 1): R t = 0.50 min; MS (ESIpos): m / z = 289 [M+H] + .

[0554] Intermediate 27: Step 1 Ethyl 8-methyl-2-{[(2S)-oxetan-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0555] [ka]

[0556] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 330 mg, 1.34 mmol) was reacted with [(2S)-oxetan-2-yl]methanol (1.50 equiv., 177 mg, 2.01 mmol), tri-n-butylphosphine (CAS no. [998-40-3]; 1.6 equiv., 540 μL, 2.1 mmol), and TMAD (CAS no. [10465-78-8]; 1.60 equiv., 369 mg, 2.14 mmol) in toluene (5 mL) at room temperature overnight, followed by column chromatography (SiO, hexane / EtOAc) to give the title compound (233 mg, 53%).

[0557] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.37-2.46 (m, 1H), 2.60-2.68 (m, 1H), 2.83-2.94 (m, 4H), 4.24-4.37 (m, 5H), 4.47-4.51 (m, 1H), 4.94-5.00 (m, 1H), 7.52 (s, 1H). UPLC-MS (Method 1): R t = 1.11 min; MS (ESIpos): m / z = 317 [M+H] + .

[0558] Step 2 8-Methyl-2-{[(2S)-oxetan-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0559] [ka]

[0560] Following GP D, ethyl 8-methyl-2-{[(2S)-oxetan-2-yl])methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 228 mg, 721 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 5.4 mL, 11 mmol) in a 1:1 mixture of ethanol and THF (10 mL) at 70 °C for 3 days. The reaction mixture was acidified (pH 4) with 4 N aqueous HCl and diluted with EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired carboxylic acid (198 mg, 86%).

[0561] 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.38-2.45 (m, 1H), 2.47 (s, 3H), 2.60-2.68 (m, 1H), 2.82-2.91 (m, 4H), 4.24-4.36 (m, 3H), 4.46-4.51 (m, 1H), 4.94-5.00 (m, 1H), 7.50 (s, 1H), 12.80 (br. s., 1H). UPLC-MS (Method 1): R t = 0.50 min; MS (ESIpos): m / z = 289 [M+H] + .

[0562] Intermediate 28: Step 1 Ethyl 8-methyl-2-{[(2R)-4-methylmorpholin-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0563] [ka]

[0564] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 313 mg, 1.27 mmol) was reacted with [(2R)-4-methylmorpholin-2-yl]methanol (CAS No. [1159598-35-2]; 1.50 equiv., 250 mg, 1.91 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 510 μL, 2.0 mmol), and TMAD (CAS No. [10465-78-8]; 1.60 equiv., 350 mg, 2.03 mmol) in toluene (8 mL) at room temperature overnight. Additional amounts of tri-n-butylphosphine (0.30 equiv., 95 μL, 0.38 mmol) and TMAD (0.30 equiv., 66 mg, 0.38 mmol) were added, and stirring at room temperature was continued for 3 days. Column chromatography (Si-NH SiO, CH Cl / MeOH) afforded the title compound (921 mg, 44% purity, 88%).

[0565] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.30 (t, 3H), 1.72-1.78 (m, 1H), 1.96 (dt, 1H), 2.16 (s, 3H), 2.54-2.57 (m, 1H), 2.63-2.66 (m, 1H), 2.82-2.86 (m, 3H), 2.89-2.93 (m, 2H), 3.45 (dt, 1H), 3.74-3.80 (m, 2H), 4.10 (d, 2H), 4.27 (q, 2H), 7.48 (s, 1H). UPLC-MS (Method 1): R t = 1.10 min; MS (ESIpos): m / z = 360 [M+H] + .

[0566] Specific rotation: [α] D 20 = -7.2° + / - 0.49° (C = 10.0 mg / mL, methanol).

[0567] Step 2 8-methyl-2-{[(2R)-4-methylmorpholin-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0568] [ka]

[0569] Following GP D, ethyl 8-methyl-2-{[(2R)-4-methylmorpholin-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 912 mg, 44% purity, 1.12 mmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 8.4 mL, 17 mmol) in a 1:1 mixture of ethanol and THF (12 mL) at 70° C. overnight. The reaction mixture was acidified (pH 4) with 4 N aqueous HCl and concentrated under reduced pressure to give the crude title compound (1.15 g) along with salts, which was not further purified. UPLC-MS (Method 1): R t = 0.50 min; MS (ESIpos): m / z = 332 [M+H] + .

[0570] Intermediate 29: Step 1 Ethyl 8-methyl-2-{[(2S)-4-methylmorpholin-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0571] [ka]

[0572] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 313 mg, 1.27 mmol) was reacted with [(2S)-4-methylmorpholin-2-yl]methanol (CAS No. [1159598-33-0]; 1.50 equiv., 250 mg, 1.91 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 510 μL, 2.0 mmol), and TMAD (CAS No. [10465-78-8]; 1.60 equiv., 350 mg, 2.03 mmol) in toluene (8 mL) at room temperature overnight. Additional amounts of tri-n-butylphosphine (0.30 equiv., 95 μL, 0.38 mmol) and TMAD (0.30 equiv., 66 mg, 0.38 mmol) were added, and stirring at room temperature was continued for 3 days. Column chromatography (Si-NH SiO, CH Cl / MeOH) afforded the title compound (192 mg, 85% purity, 36%).

[0573] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.30 (t, 3H), 1.72-1.77 (m, 1H), 1.96 (dt, 1H), 2.16 (s, 3H), 2.54-2.57 (m, 1H), 2.63-2.67 (m, 1H), 2.82-2.86 (m, 3H), 2.89-2.93 (m, 2H), 3.45 (dt, 1H), 3.75-3.80 (m, 2H), 4.10 (d, 2H), 4.27 (q, 2H), 7.48 (s, 1H). UPLC-MS (Method 1): R t = 1.10 min; MS (ESIpos): m / z = 360 [M+H] + .

[0574] Step 2 8-Methyl-2-{[(2S)-4-methylmorpholin-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0575] [ka]

[0576] Following GP D, ethyl 8-methyl-2-{[(2S)-4-methylmorpholin-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 192 mg, 85% purity, 534 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 4.0 mL, 8.0 mmol) in a 1:1 mixture of ethanol and THF (6 mL) at 70° C. overnight. The reaction mixture was acidified (pH 4) with 4 N aqueous HCl and concentrated under reduced pressure to give the crude title compound (691 mg) along with salts, which was not further purified. UPLC-MS (Method 1): R t = 0.50 min; MS (ESIpos): m / z = 332 [M+H] + .

[0577] Intermediate 30: Step 1 Ethyl 8-methyl-2-[(2R)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0578] [ka]

[0579] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 300 mg, 1.22 mmol) was reacted with (2R)-tetrahydrofuran-2-ylmethanol (CAS No. [22415-59-4]; 1.1 equiv., 130 μL, 1.3 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 490 μL, 1.9 mmol), and TMAD (CAS No. [10465-78-8]; 1.60 equiv., 336 mg, 1.95 mmol) in toluene (8 mL) at room temperature overnight, followed by column chromatography (Si-NH SiO 2 , CHCl 2 / MeOH) to give the title compound (470 mg, 68% purity, 79%).

[0580] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.54-1.57 (m, 1H), 1.75-1.82 (m, 2H), 1.90-1.97 (m, 1H), 2.82-2.93 (m, 4H), 3.60-3.65 (m, 1H), 3.72-3.78 (m, 1H), 4.03-4.17 (m, 3H), 4.27 (q, 2H), 7.49 (s, 1H). UPLC-MS (Method 1): R t = 1.22 min; MS (ESIpos): m / z = 331 [M+H] + .

[0581] Step 2 8-Methyl-2-[(2R)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0582] [ka]

[0583] Following GP D, ethyl 8-methyl-2-[(2R)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 470 mg, 68% purity, 967 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 18 equiv., 8.5 mL, 17 mmol) in a 1:1 mixture of ethanol and THF (8 mL) at 70 °C for 24 h and then at room temperature for 2 days. The reaction mixture was acidified (pH 4) with 4 N aqueous HCl and diluted with EtOAc. The combined organic phases were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give the desired carboxylic acid (380 mg, 69% purity, 76%).

[0584] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.54-1.57 (m, 1H), 1.75-1.82 (m, 2H), 1.88-1.97 (m, 1H), 2.47 (s, 3H), 2.81-2.90 (m, 4H), 3.60-3.65 (m, 1H), 3.72-3.78 (m, 1H), 4.02-4.17 (m, 3H), 7.47 (s, 1H), 12.73 (br. s., 1H). UPLC-MS (Method 1): R t = 0.52 min; MS (ESIpos): m / z = 303 [M+H] + .

[0585] Intermediate 31: Step 1 Ethyl 8-methyl-2-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0586] [ka]

[0587] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 300 mg, 1.22 mmol) was reacted with (2S)-tetrahydrofuran-2-ylmethanol (CAS No. [57203-01-4]; 1.1 equiv., 130 μL, 1.3 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 490 μL, 1.9 mmol), and TMAD (CAS No. [10465-78-8]; 1.60 equiv., 336 mg, 1.95 mmol) in toluene (8 mL) at room temperature overnight, followed by column chromatography (Si-NH SiO 2 , CHCl 2 / MeOH) to give the title compound (437 mg, 72% purity, 78%).

[0588] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.54-1.57 (m, 1H), 1.75-1.82 (m, 2H), 1.90-1.97 (m, 1H), 2.82-2.93 (m, 4H), 3.60-3.65 (m, 1H), 3.72-3.78 (m, 1H), 4.03-4.16 (m, 3H), 4.27 (q, 2H), 7.48 (s, 1H). UPLC-MS (Method 1): R t = 1.22 min; MS (ESIpos): m / z = 331 [M+H] + .

[0589] Step 2 8-Methyl-2-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0590] [ka]

[0591] Following GP D, ethyl 8-methyl-2-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 435 mg, 72% purity, 948 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 21 equiv., 9.9 mL, 20 mmol) in a 1:1 mixture of ethanol and THF (10 mL) at 70 °C for 24 h and then at room temperature for 2 days. The reaction mixture was acidified (pH 4) with 4 N aqueous HCl and diluted with EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired carboxylic acid (373 mg, 78% purity, 73%).

[0592] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.54-1.57 (m, 1H), 1.75-1.82 (m, 2H), 1.88-1.96 (m, 1H), 2.47 (s, 3H), 2.81-2.90 (m, 4H), 3.60-3.65 (m, 1H), 3.72-3.78 (m, 1H), 4.02-4.16 (m, 3H), 7.47 (s, 1H), 12.72 (br. s., 1H). UPLC-MS (Method 1): R t = 0.51 min; MS (ESIpos): m / z = 303 [M+H] + .

[0593] Intermediate 32: Step 1 Ethyl 2-{[1-(tert-butoxycarbonyl)azetidin-3-yl]methyl}-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0594] [ka]

[0595] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 330 mg, 1.34 mmol) was reacted with tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (CAS no. [142253-56-3]; 1.50 equiv., 376 mg, 2.01 mmol), tri-n-butylphosphine (CAS no. [998-40-3]; 1.6 equiv., 540 μL, 2.1 mmol), and TMAD (CAS no. [10465-78-8]; 1.60 equiv., 369 mg, 2.14 mmol) in toluene (9 mL) at room temperature overnight, followed by column chromatography (SiO, hexane / EtOAc) to afford the title compound (420 mg, 69%).

[0596] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.35 (s, 9H), 2.81-2.98 (m, 5H), 3.66-3.69 (m, 2H), 3.88 (br. s., 2H), 4.24-4.29 (m, 4H), 7.58 (s, 1H). UPLC-MS (Method 1): R t = 1.34 min; MS (ESIpos): m / z = 416 [M+H] + .

[0597] Step 2 2-{[1-(tert-butoxycarbonyl)azetidin-3-yl]methyl}-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0598] [ka]

[0599] Following GP D, ethyl 2-{[1-(tert-butoxycarbonyl)azetidin-3-yl]methyl}-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 417 mg, 1.00 mmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 7.5 mL, 15 mmol) in a 1:1 mixture of ethanol and THF (8 mL) at 70 °C for 24 h and then at room temperature for 2 days. The reaction mixture was acidified (pH 4) with 4 N aqueous HCl and diluted with EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired carboxylic acid (327 mg, 76%).

[0600] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.35 (s, 9H), 2.47 (s, 3H), 2.80-2.96 (m, 5H), 3.66-3.69 (m, 2H), 3.85-3.94 (m, 2H), 4.26 (d, 2H), 7.56 (s, 1H), 12.85 (br. s., 1H). UPLC-MS (Method 1): R t = 0.65 min; MS (ESIpos): m / z = 388 [M+H] + .

[0601] Intermediate 33: Step 1 Ethyl 8-methyl-2-[(3R)-tetrahydrofuran-3-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0602] [ka]

[0603] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 300 mg, 1.22 mmol) was reacted with (3R)-tetrahydrofuran-3-ylmethanol (CAS No. [124506-31-6]; 1.5 equiv., 187 mg, 1.83 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 490 μL, 1.9 mmol), and TMAD (CAS No. [10465-78-8]; 1.60 equiv., 336 mg, 1.95 mmol) in toluene (8 mL) at room temperature overnight, followed by column chromatography (SiO, hexane / EtOAc) to afford the title compound (465 mg, 100%).

[0604] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.56-1.65 (m, 1H), 1.88-1.96 (m, 1H), 2.65-2.74 (m, 1H), 2.81-2.94 (m, 4H), 3.49 (dd, 1H), 3.59-3.68 (m, 2H), 3.73-3.80 (m, 1H), 4.00-4.09 (m, 2H), 4.27 (q, 2H), 7.56 (s, 1H). UPLC-MS (Method 1): R t = 1.17 min; MS (ESIpos): m / z = 331 [M+H] + .

[0605] Step 2 8-Methyl-2-[(3R)-tetrahydrofuran-3-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0606] [ka]

[0607] Following GP D, ethyl 8-methyl-2-[(3R)-tetrahydrofuran-3-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 458 mg, 1.39 mmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 10 mL, 21 mmol) in a 1:1 mixture of ethanol and THF (20 mL) at 70 °C overnight and then at room temperature for 2 days. The reaction mixture was acidified (pH 3) with 6 N aqueous HCl and diluted with EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired carboxylic acid (166 mg, 38%).

[0608] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.56-1.65 (m, 1H), 1.88-1.96 (m, 1H), 2.47 (s, 3H), 2.63-2.72 (m, 1H), 2.81-2.91 (m, 4H), 3.49 (dd, 1H), 3.59-3.68 (m, 2H), 3.74-3.78 (m, 1H), 3.99-4.08 (m, 2H), 7.54 (s, 1H), 12.78 (br. s. ,1H). UPLC-MS (Method 1): R t = 0.48 min; MS (ESIpos): m / z = 303 [M+H] + .

[0609] Intermediate 34: Step 1 Ethyl 8-methyl-2-[(3S)-tetrahydrofuran-3-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0610] [ka]

[0611] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 402 mg, 1.63 mmol) was reacted with (3S)-tetrahydrofuran-3-ylmethanol (CAS no. [124391-75-9]; 1.5 equiv., 250 mg, 2.45 mmol), tri-n-butylphosphine (CAS no. [998-40-3]; 1.6 equiv., 650 μL, 2.6 mmol), and TMAD (CAS no. [10465-78-8]; 1.60 equiv., 450 mg, 2.61 mmol) in toluene (8 mL) at room temperature overnight, followed by column chromatography (SiO, hexane / EtOAc) to give the title compound (365 mg, 67%).

[0612] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.56-1.65 (m, 1H), 1.88-1.96 (m, 1H), 2.65-2.74 (m, 1H), 2.82-2.93 (m, 4H), 3.49 (dd, 1H), 3.59-3.68 (m, 2H), 3.73-3.79 (m, 1H), 4.00-4.09 (m, 2H), 4.26 (q, 2H), 7.56 (s, 1H). UPLC-MS (Method 1): R t = 1.11 min; MS (ESIpos): m / z = 331 [M+H] + .

[0613] Step 2 8-Methyl-2-[(3S)-tetrahydrofuran-3-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0614] [ka]

[0615] Following GP D, ethyl 8-methyl-2-[(3S)-tetrahydrofuran-3-ylmethyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 357 mg, 1.08 mmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 8.1 mL, 16 mmol) in a 1:1 mixture of ethanol and THF (16 mL) at 70 °C overnight. The reaction mixture was acidified (pH 4) with 6 N aqueous HCl and diluted with EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired carboxylic acid (311 mg, 86%).

[0616] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.56-1.65 (m, 1H), 1.88-1.96 (m, 1H), 2.48 (s, 3H), 2.63-2.72 (m, 1H), 2.81-2.92 (m, 4H), 3.49 (dd, 1H), 3.59-3.68 (m, 2H), 3.74-3.78 (m, 1H), 4.00-4.09 (m, 2H), 7.55 (s, 1H), 12.78 (br. s. ,1H). UPLC-MS (Method 1): R t = 0.47 min; MS (ESIpos): m / z = 303 [M+H] + .

[0617] Intermediate 35: Step 1 Ethyl 2-chloro-4,4,4-trifluoro-3-oxobutanoate

[0618] [ka]

[0619] To a solution of ethyl 4,4,4-trifluoro-3-oxobutanoate (1.00 equiv., 500 mmol, 92.0 g) in dichloromethane (100 mL) was added a solution of sulfuryl chloride (CAS number [7791-25-5]; 1.10 equiv., 550 mmol, 44 mL) in dichloromethane (50 mL) at -5 to 0 °C. The reaction mixture was warmed to room temperature and stirred at this temperature for 12 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and concentrated under reduced pressure. The resulting material was purified by column chromatography (100-200 mesh, petroleum ether:ethyl acetate = 50:1, then 5:1) to give ethyl 2-chloro-4,4,4-trifluoro-3-oxobutanoate (66.0 g, 60%) as a yellow oil.

[0620] 1 H NMR (400 MHz, CDCl3) δ [ppm]: 1.34 (t, 3H), 4.33 (q, 2H), 4.48 (s, 1H).

[0621] Step 2 Ethyl 4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1-benzofuran-2-carboxylate

[0622] [ka]

[0623] To a solution of cyclohexane-1,3-dione (1.00 equiv., 44.6 mmol, 5.00 g) in toluene (15 mL) was added ethyl 2-chloro-4,4,4-trifluoro-3-oxobutanoate (2.20 equiv., 98.1 mmol, 21.4 g) from Step 1 at 20 °C, and the reaction mixture was then stirred at 100 °C for 36 h. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine and concentrated under reduced pressure. The resulting material was purified by column chromatography (100-200 mesh, petroleum ether:ethyl acetate = 50:1, then 20:1) to give ethyl 4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1-benzofuran-2-carboxylate as a yellow oil (7.2 g, 57%).

[0624] 1 H NMR (400 MHz, CDCl3) δ [ppm]: 1.40 (t, 3H), 2.23 (quint, 2H), 2.59-2.62 (m, 2H), 2.99 (t, 2H), 4.43 (q, 2H), 4.48 (s, 1H).

[0625] LC-MS (Method B): R t = 0.89 min; MS (ESIpos): m / z = 277 [M+H] + .

[0626] Step 3 (5E / Z)-Ethyl 5-(hydroxymethylene)-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1-benzofuran-2-carboxylate

[0627] [ka]

[0628] According to GP A (Condition B), a solution of ethyl formate (CAS No. [109-94-4]; 6.0 equiv., 87 mmol, 7.0 mL) in toluene (40 mL) was treated with sodium hydride (CAS No. [7646-69-7]; 3.00 equiv., 43.4 mmol, 1.74 g, 60% purity) at 0 °C. After stirring the mixture for 0.5 h, a solution of ethyl 4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1-benzofuran-2-carboxylate (1.00 equiv., 14.5 mmol, 4.00 g) from Step 2 in toluene (10 mL) was added. The reaction mixture was stirred at room temperature for 2 h and quenched with 2 N aqueous HCl (pH ∼3). The phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give crude (5E / Z)-ethyl 5-(hydroxymethylene)-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1-benzofuran-2-carboxylate (4.4 g, 100%) as a brown oil, which was not further purified.

[0629] 1 H NMR (400 MHz, CDCl3) δ [ppm]: 1.41 (t, 3H), 2.70 (t, 2H), 2.97 (t, 2H), 4.44 (q, 2H), 4.48 (s, 1H), 7.37-7.40 (m, 1H), 13.48-13.50 (m, 1H).

[0630] LC-MS (Method B): R t = 0.73 min; MS (ESIpos): m / z = 305 [M+H] + .

[0631] Step 4 Ethyl 8-(trifluoromethyl)-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate

[0632] [ka]

[0633] Following GP B, a solution of crude (5E / Z)-ethyl 5-(hydroxymethylene)-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1-benzofuran-2-carboxylate (1.0 equiv., 15 mmol, 4.4 g) from Step 3 in ethanol (60 mL) was treated with a solution of hydrazine dihydrochloride (CAS number [5341-61-7]; 2.0 equiv., 29 mmol, 3.0 g) in water (20 mL) at room temperature. The reaction mixture was stirred at 60 °C for 2 h, quenched with saturated aqueous sodium carbonate (pH ∼9), and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting material was purified by column chromatography (100-200 mesh, petroleum ether:ethyl acetate = 20:1, then 2:1) and dissolved in methanol. The mixture was concentrated again to give ethyl 8-(trifluoromethyl)-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (2.2 g, 51%) as a yellow solid.

[0634] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.31 (t, 3H), 2.86-2.90 (m, 2H), 2.97-3.01 (m, 2H), 4.34 (q, 2H), 7.58 (s, 1H), 12.64 (br s, 1H).

[0635] LC-MS (Method B): R t = 0.70 min; MS (ESIpos): m / z = 301 [M+H] + .

[0636] Step 5 Ethyl 2-[(pyridin-2-yl)methyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0637] [ka]

[0638] According to GP C (Condition A), ethyl 8-(trifluoromethyl)-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 500 mg, 1.67 mmol) from Step 4 was reacted with (pyridin-2-yl)methanol (1.1 equiv., 200 mg, 1.83 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 660 μL, 2.7 mmol), and TMAD (CAS No. [10465-78-8]; 1.60 equiv., 459 mg, 2.66 mmol) in toluene (21 mL) at room temperature overnight, followed by column chromatography (SiO, hexane / EtOAc) to afford the title compound (322 mg, 48%; together with another 264 mg product fraction containing approximately 15% of the corresponding N1-isomer).

[0639] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.30 (t, 3H), 2.87-2.91 (m, 2H), 2.98-3.02 (m, 2H), 4.34 (q, 2H), 5.40 (s, 2H), 7.09 (d, 1H), 7.31 (ddd, 1H), 7.71 (s, 1H), 7.78 (dt, 1H), 8.54 (ddd, 1H). UPLC-MS (Method 1): R t = 1.34 min; MS (ESIpos): m / z = 392 [M+H] + .

[0640] Step 6 2-[(pyridin-2-yl)methyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0641] [ka]

[0642] Following GP D, ethyl 2-[(pyridin-2-yl)methyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 320 mg, 818 μmol) from Step 5 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 6.1 mL, 12 mmol) in a 1:1 mixture of ethanol and THF (12 mL) at 70 °C for 2.5 h. The reaction mixture was acidified (pH 4) with 2 N aqueous HCl, and the precipitate that formed was filtered off. The solid was washed with water and EtOAc and dried to give the desired carboxylic acid (255 mg, 83%).

[0643] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.86-2.90 (m, 2H), 2.95-2.99 (m, 2H), 5.39 (s, 2H), 7.08 (d, 1H), 7.31 (dd, 1H), 7.69 (s, 1H), 7.78 (dt, 1H), 8.54 (ddd, 1H), 13.89 (br. s., 1H).

[0644] 19 F NMR (377 MHz, DMSO-d6) δ [ppm]: -54.73 (s, 3F). UPLC-MS (Method 1): R t = 0.52 min; MS (ESIpos): m / z = 364 [M+H] + .

[0645] Intermediate 36: Step 1 Methyl 2-chloro-3-cyclopropyl-3-oxopropanoate

[0646] [ka]

[0647] A solution of methyl 3-cyclopropyl-3-oxopropanoate (1.00 equivalent, 20.0 g, 141 mmol) in dichloromethane (150 mL) was added sulfuryl chloride (0.99 equivalent, 12 mL, 140 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. Water (200 mL) was added to the mixture, and the organic layer was separated. The organic layer was washed with saturated sodium bicarbonate and brine, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 50:1, then 20:1) to obtain methyl 2-chloro-3-cyclopropyl-3-oxopropanoate (27.0 g, 98%) as a yellow oil.

[0648] 1 1H NMR (400 MHz, CDCl3): δ [ppm] = 1.07-1.11 (m, 2H), 1.17-1.21 (m, 2H), 2.27-2.33 (m, 1H), 3.86 (s, 3H), 4.95 (s, 1H).

[0649] LC-MS (method C): R t = 0.55 min; MS (ESIpos): m / z = 177 [M+H] + .

[0650] Step 2 Methyl 3-cyclopropyl-4-oxo-4,5,6,7-tetrahydro-1-benzofuran-2-carboxylate

[0651]

Chemical formula

[0652] To a mixture of methyl 2-chloro-3-cyclopropyl-3-oxopropanoate (1.00 equiv., 17.0 g, 96.3 mmol) from Step 1 in 1,2-dichloroethane (100 mL) was added cyclohexane-1,3-dione (1.00 equiv., 10.8 g, 96.3 mmol) and triethylamine (1.2 equiv., 16 mL, 120 mmol) at room temperature. The mixture was stirred at 50 °C under nitrogen protection for 60 h. The pH was adjusted to ~1 with hydrochloric acid (12 M), and the mixture was stirred for an additional 16 h. Water was added to the mixture, and the organic layer was separated. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium carbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=1:0 to 5:1) to give methyl 3-cyclopropyl-4-oxo-4,5,6,7-tetrahydro-1-benzofuran-2-carboxylate (8.0 g, 35%) as a pale yellow solid.

[0653] 1 H NMR (400 MHz, DMSO-d6): δ [ppm] = 0.86-0.91 (m, 2H), 1.20-1.23 (m, 2H), 2.01-2.07 (m, 2H), 2.41-2.44 (m, 2H), 2.65-2.72 (m, 1H), 2.90 (t, 2H), 3.81 (s, 3H).

[0654] LC-MS (Method C): R t = 0.80 min; MS (ESIpos): m / z = 235 [M+H] + .

[0655] Step 3 (5E / Z)-Methyl 3-cyclopropyl-5-(hydroxymethylene)-4-oxo-4,5,6,7-tetrahydro-1-benzofuran-2-carboxylate

[0656] [ka]

[0657] According to GP A (Condition B), a mixture of sodium hydride (2.00 equiv., 1.02 g, 60% purity, 25.6 mmol) in toluene (60 mL) was treated with methyl formate (3.0 equiv., 2.4 mL, 38 mmol) and methyl 3-cyclopropyl-4-oxo-4,5,6,7-tetrahydro-1-benzofuran-2-carboxylate (1.00 equiv., 3.00 g, 12.8 mmol) from Step 2 at 0° C. The mixture was stirred at 40° C. for 12 h, then quenched with saturated aqueous ammonium chloride and diluted with water. The mixture was extracted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give (5E / Z)-methyl 3-cyclopropyl-5-(hydroxymethylene)-4-oxo-4,5,6,7-tetrahydro-1-benzofuran-2-carboxylate (3.50 g), which was used directly without further purification.

[0658] LC-MS (Method C): R t = 0.84 min; MS (ESIpos): m / z = 263 [M+H] + .

[0659] Step 4 Methyl 8-cyclopropyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate

[0660] [ka]

[0661] Following GP B, to a solution of crude (5E / Z)-methyl 3-cyclopropyl-5-(hydroxymethylene)-4-oxo-4,5,6,7-tetrahydro-1-benzofuran-2-carboxylate (3.50 g, 13.3 mmol) from Step 3 in methanol (50 mL) and water (5.0 mL) was added hydrazine dihydrochloride (3.00 equiv., 4.20 g, 40.0 mmol) at 25 °C. The mixture was stirred at 50 °C for 1 h. The mixture was slowly added to saturated aqueous sodium carbonate at 0 °C. The precipitate was collected and purified by flash column chromatography (petroleum ether:ethyl acetate = 1:0 to 1:1) to give methyl 8-cyclopropyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (1.50 g, 42% over two steps) as a yellow solid.

[0662] 1 H NMR (400 MHz, DMSO-d6): δ [ppm] = 0.88-0.93 (m, 2H), 1.52-1.54 (m, 2H), 2.74-2.87 (m, 5H), 3.80 (s, 3H), 7.51 (s, 1H), 12.46 (br s, 1H).

[0663] LC-MS (Method D): R t = 0.89 min; MS (ESIpos): m / z = 259 [M+H] + .

[0664] Step 5 Methyl 8-cyclopropyl-2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0665] [ka]

[0666] According to GP C (Condition A), methyl 8-cyclopropyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate from Step 4 (commercially available; 1.00 equiv., 400 mg, 1.55 mmol) was reacted with (pyridin-2-yl)methanol (1.1 equiv., 186 mg, 1.70 mmol), tri-n-butylphosphine (CAS no. [998-40-3]; 1.6 equiv., 620 μL, 2.5 mmol), and TMAD (CAS no. [10465-78-8]; 1.60 equiv., 427 mg, 2.48 mmol) in toluene (20 mL) at room temperature overnight, followed by column chromatography (SiO, hexane / EtOAc) to afford the title compound (391 mg, 69%).

[0667] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.83-0.88 (m, 2H), 1.43-1.47 (m, 2H), 2.68-2.75 (m, 1H), 2.78-2.89 (m, 4H), 3.79 (s, 3H), 5.36 (s, 2H), 7.04 (d, 1H), 7.31 (ddd, 1H), 7.64 (s, 1H), 7.78 (dt, 1H), 8.54 (ddd, 1H). UPLC-MS (Method 1): R t = 1.18 min; MS (ESIpos): m / z = 350 [M+H] + .

[0668] Step 6 8-Cyclopropyl-2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0669] [ka]

[0670] Following GP D, methyl 8-cyclopropyl-2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 385 mg, 1.10 mmol) from Step 5 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 8.3 mL, 17 mmol) in a 1:1 mixture of ethanol and THF (18 mL) at 70 °C for 4 h. The reaction mixture was concentrated under reduced pressure, and the concentrate was acidified (pH 3) with 2 N aqueous HCl. The precipitate that formed was filtered off. The solid was washed with water and EtOAc and dried to give the desired carboxylic acid (360 mg, 93%).

[0671] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.79-0.84 (m, 2H), 1.41-1.45 (m, 2H), 2.73-2.87 (m, 5H), 5.37 (s, 2H), 7.06 (d, 1H), 7.33 (dd, 1H), 7.64 (s, 1H), 7.80 (dt, 1H), 8.54-8.56 (m, 1H), 12.83 (br. s., 1H). UPLC-MS (Method 1): R t = 0.55 min; MS (ESIpos): m / z = 336 [M+H] + .

[0672] Intermediate 37: Step 1 3,6,6-trimethyl-6,7-dihydro-1-benzofuran-4(5H)-one

[0673] [ka]

[0674] Similar to K. Kanematsu et al., Heterocycles 1990, 31, 6, 1003-1006 and J. Org. Chem. 1993, 58, 3960-3968: To a solution of 3-bromoprop-1-yne (CAS No.: [106-96-7]; 2.00 equiv., 25 mL, 290 mmol) in anhydrous acetonitrile (20 mL), dimethyl sulfide (CAS No.: [75-18-3]; 0.57 equiv., 6.0 mL, 82 mmol) was added, and the reaction mixture was stirred overnight at room temperature in a light-shielded flask. Sodium ethoxide (1.1 equiv., 37 mL of a 21% solution in ethanol, 160 mmol) and a solution of 5,5-dimethylcyclohexane-1,3-dione (CAS No. [126-81-8]; 1.00 equiv., 20.0 g, 143 mmol) in ethanol (365 mL) were added, and the mixture was heated to reflux for 1.5 hours. The reaction mixture was diluted with water and concentrated under reduced pressure, and the resulting residue was extracted with dichloromethane. The combined organic layers were concentrated under reduced pressure, and the residue was dissolved in toluene (150 mL) and treated with 4-methylbenzenesulfonic acid (CAS number [104-15-4]; 1.11 equiv., 27.3 g, 159 mmol) at room temperature overnight. The reaction mixture was quenched with saturated aqueous NaHCO, the layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were filtered through a hydrophobic filter and concentrated under reduced pressure, and the resulting crude product was subjected to column chromatography (SiO, hexane / EtOAc) to give the title compound (9.4 g, 34%).

[0675] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.04 (s, 6H), 2.09 (d, 3H), 2.30 (s, 2H), 2.74 (s, 2H), 7.43-7.44 (m, 1H). UPLC-MS (Method 1): R t = 1.11 min; MS (ESIpos): m / z = 179 [M+H] + .

[0676] Step 2 2-Bromo-3,6,6-trimethyl-6,7-dihydro-1-benzofuran-4(5H)-one

[0677] [ka]

[0678] Similar to US Pat. No. 6,048,880; Example 2, Step 2 (page 20): A solution of 3,6,6-trimethyl-6,7-dihydro-1-benzofuran-4(5H)-one (1.00 equiv., 7.64 g, 42.9 mmol) from Step 1 in pyridine (60 mL) was treated with 1-bromopyrrolidine-2,5-dione (NBS, CAS number [128-08-5]; 1.01 equiv., 7.71 g, 43.3 mmol) and stirred at room temperature for 2 days. An additional amount of 1-bromopyrrolidine-2,5-dione (1.00 equiv., 7.63 g, 42.9 mmol) was added, and stirring at room temperature was continued overnight. The reaction mixture was acidified (pH 4) with 2 N aqueous HCl and diluted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure, and the crude product was subjected to column chromatography (SiO2, hexane / EtOAc) to give the title compound (5.7 g, 52%).

[0679] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.05 (s, 6H), 2.05 (s, 3H), 2.32 (s, 2H), 2.76 (s, 2H). UPLC-MS (Method 1): R t = 1.32 min; MS (ESIpos): m / z = 257 / 259 [M+H] + (Br isotope pattern).

[0680] Step 3 (5E / Z)-2-Bromo-5-[(dimethylamino)methylidene]-3,6,6-trimethyl-6,7-dihydro-1-benzofuran-4(5H)-one

[0681] [ka]

[0682] Following GP A (Condition A), 2-bromo-3,6,6-trimethyl-6,7-dihydro-1-benzofuran-4(5H)-one (1.00 equiv., 3.50 g, 13.6 mmol) from Step 2 was reacted with 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (Bredereck's reagent, CAS number [5815-08-7]; 1.20 equiv., 3.37 mL, 16.3 mmol) in toluene (35 mL) at 100° C. for 3 h. An additional amount of 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (1.20 equiv., 3.37 mL, 16.3 mmol) was added, and stirring at 100° C. was continued for an additional 24 h. An additional amount of 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (1.20 equiv, 3.37 mL, 16.3 mmol) was added and stirring at 100°C was continued for 10 h, followed by 3 days at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude title compound obtained was used in the subsequent reaction without further purification. UPLC-MS (Method 1): R t = 1.33 / 1.37 min; MS (ESIpos): m / z = 312 / 314 [M+H] + (Br isotope pattern).

[0683] Step 4 7-Bromo-4,4,8-trimethyl-4,5-dihydro-1H-furo[2,3-g]indazole

[0684] [ka]

[0685] Following GP B, crude (5E / Z)-2-bromo-5-[(dimethylamino)methylidene]-3,6,6-trimethyl-6,7-dihydro-1-benzofuran-4(5H)-one (1.0 equiv., 4.3 g, 14 mmol) from Step 3 was reacted with 1:1 hydrazine hydrate (5.0 equiv., 3.3 mL, 68 mmol) in ethanol (50 mL) at 70 °C overnight, followed by column chromatography (SiO, hexane / EtOAc) to give the title compound (1.38 g, 35% over two steps).

[0686] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.22 (s, 6H), 2.13 (s, 3H), 2.66 (s, 2H), 7.53 (s, 1H), 12.39 (s, 1H). UPLC-MS (Method 1): R t = 1.25 min; MS (ESIpos): m / z = 281 / 283 [M+H] + (Br isotope pattern).

[0687] Step 5 7-Bromo-4,4,8-trimethyl-2-[(pyridin-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole

[0688] [ka]

[0689] According to GP C (Condition B), 7-bromo-4,4,8-trimethyl-4,5-dihydro-1H-furo[2,3-g]indazole (1.0 equiv., 5.6 g, 35 mmol) from Step 4 was reacted with 2-(bromomethyl)pyridine (1.5 equiv., 1.2 g, 6.9 mmol), potassium carbonate (15 equiv., 9.6 g, 69 mmol), and DMAP (14 mg, 120 μmol, 2.5 mol%) in EtOAc (75 mL) at 75° C. overnight. An additional amount of 2-(bromomethyl)pyridine (0.75 equiv., 600 mg, 3.5 mmol) was added, and stirring at 75° C. was continued for an additional 3 days to afford the title compound (200 mg, 7%) after column chromatography (SiO 2 , hexane / EtOAc).

[0690] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.26 (s, 6H), 2.08 (s, 3H), 2.69 (s, 2H), 5.36 (s, 2H), 7.04 (d, 1H), 7.31 (ddd, 1H), 7.69 (s, 1H), 7.78 (dt, 1H), 8.53-8.55 (m, 1H). UPLC-MS (Method 1): R t = 1.39 min; MS (ESIpos): m / z = 371 / 373 [M+H] + (Br isotope pattern).

[0691] Intermediate 38: Step 1 3-Methyl-5H-spiro[[1]benzofuran-6,1'-cyclopropan]-4(7H)-one

[0692] [ka]

[0693] Similar to K. Kanematsu et al., Heterocycles 1990, 31, 6, 1003-1006 and J. Org. Chem. 1993, 58, 3960-3968: To a solution of 3-bromoprop-1-yne (CAS No.: [106-96-7]; 2.00 equiv., 12 mL, 145 mmol) in anhydrous acetonitrile (10 mL), dimethyl sulfide (CAS No.: [75-18-3]; 0.57 equiv., 3.0 mL, 41 mmol) was added, and the reaction mixture was stirred overnight at room temperature in a light-shielded flask. Sodium ethoxide (1.1 equiv., 19 mL of a 21% solution in ethanol, 81 mmol) and a solution of spiro[2.5]octane-5,7-dione (CAS No. [893411-52-4]; 1.00 equiv., 10.0 g, 72.4 mmol) in ethanol (190 mL) were added, and the mixture was heated to reflux for 1.5 hours. The reaction mixture was diluted with water, concentrated under reduced pressure, and the resulting residue was extracted with dichloromethane. The combined organic layers were concentrated under reduced pressure, and the residue was dissolved in toluene (75 mL) and treated with 4-methylbenzenesulfonic acid (CAS number [104-15-4]; 4 mol%, 0.50 g, 2.9 mmol) at room temperature overnight. The reaction mixture was quenched with saturated aqueous NaHCO, the layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were filtered through a hydrophobic filter and concentrated under reduced pressure, and the resulting crude product was subjected to column chromatography (SiO, hexane / EtOAc) to give the title compound (3.8 g, 29%).

[0694] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.42-0.44 (m, 2H), 0.47-0.50 (m, 2H), 2.11 (d, 3H), 2.28 (s, 2H), 2.75 (s, 2H), 7.44 (m, 1H). UPLC-MS (Method 1): R t = 1.07 min; MS (ESIpos): m / z = 177 [M+H] + .

[0695] Step 2 2-Bromo-3-methyl-5H-spiro[[1]benzofuran-6,1'-cyclopropan]-4(7H)-one

[0696] [ka]

[0697] A solution of 3-methyl5H-spiro[[1]benzofuran-6,1'-cyclopropane]-4(7H)-one (1.00 equiv., 3.80 g, 21.6 mmol) from Step 1 in pyridine (30 mL) was treated with 1-bromopyrrolidine-2,5-dione (NBS, CAS number [128-08-5]; 1.01 equiv., 3.88 g, 21.8 mmol) and stirred at room temperature overnight. An additional amount of 1-bromopyrrolidine-2,5-dione (1.00 equiv., 3.84 g, 21.6 mmol) was added, and stirring at room temperature was continued overnight. The reaction mixture was acidified (pH 4) with 2 N aqueous HCl and extracted with dichloromethane. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered, concentrated under reduced pressure, and the crude product was subjected to column chromatography (SiO.sub.2, hexane / EtOAc) to afford the title compound (2.68 g, 46%).

[0698] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.42-0.46 (m, 2H), 0.48-0.52 (m, 2H), 2.07 (s, 3H), 2.31 (s, 2H), 2.78 (s, 2H). UPLC-MS (Method 1): R t = 1.28 min; MS (ESIpos): m / z = 255 / 257 [M+H] + (Br isotope pattern).

[0699] Step 3 (5E / Z)-2-Bromo-5-[(dimethylamino)methylidene]-3-methyl-5H-spiro[[1]benzofuran-6,1'-cyclopropan]-4(7H)-one

[0700] [ka]

[0701] According to GP A (Condition A), 2-bromo-3-methyl-5H-spiro[[1]benzofuran-6,1′-cyclopropane]-4(7H)-one (1.00 equiv., 2.00 g, 7.84 mmol) from Step 2 was reacted with 1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (Bredereck's reagent, CAS number [5815-08-7]; 1.2 equiv., 1.9 mL, 9.4 mmol) in toluene (20 mL) at 100° C. overnight. The reaction mixture was concentrated under reduced pressure, and the resulting crude title compound was used in the subsequent reaction without further purification. UPLC-MS (Method 1): R t = 1.33 min; MS (ESIpos): m / z = 310 / 312 [M+H] + (Br isotope pattern).

[0702] Step 4 7'-Bromo-8'-methyl-1',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]

[0703] [ka]

[0704] Following GP B, crude (5E / Z)-2-bromo-5-[(dimethylamino)methylidene]-3-methyl-5H-spiro[[1]benzofuran-6,1'-cyclopropane]-4(7H)-one (1.0 equiv., 2.5 g, 8.1 mmol) from Step 3 was reacted with 1:1 hydrazine hydrate (5.0 equiv., 2.0 mL, 40 mmol) in ethanol (35 mL) at 70 °C for 5 h, followed by column chromatography (SiO, hexane / EtOAc) to give the title compound (1.3 g, 59% over two steps).

[0705] 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.78-0.80 (m, 2H), 0.82-0.85 (m, 2H), 2.14 (s, 3H), 2.78 (s, 2H), 7.29 (s, 1H), 12.33 (s, 1H). UPLC-MS (Method 1): R t = 1.20 min; MS (ESIpos): m / z = 279 / 281 [M+H] + (Br isotope pattern).

[0706] Step 5 7'-Bromo-8'-methyl-2'-[(pyridin-2-yl)methyl]-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]

[0707] [ka]

[0708] According to GP C (Condition A), 7'-bromo-8'-methyl-1',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole] (1.00 equiv., 300 mg, 1.22 mmol) from Step 4 was reacted with (pyridin-2-yl)methanol (1.1 equiv., 376 mg, 3.45 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 1.2 mL, 5.0 mmol), and TMAD (CAS No. [10465-78-8]; 1.60 equiv., 864 mg, 5.02 mmol) in toluene (40 mL) at room temperature for 2 days, followed by column chromatography (SiO, hexane / EtOAc) to give the title compound (933 mg, 72%).

[0709] 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.78-0.82 (m, 2H), 0.84-0.88 (m, 2H), 2.09 (s, 3H), 2.80 (s, 2H), 5.34 (s, 2H), 7.03 (d, 1H), 7.33 (ddd, 1H), 7.44 (s, 1H), 7.80 (dt, 1H), 8.54 (ddd, 1H). UPLC-MS (Method 1): R t = 1.33 min; MS (ESIpos): m / z = 370 / 372 [M+H] + (Br isotope pattern).

[0710] Step 6 8'-Methyl-2'-[(pyridin-2-yl)methyl]-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxylic acid

[0711] [ka]

[0712] According to GP E, 7'-bromo-8'-methyl-2'-[(pyridin-2-yl)methyl]-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole] (1.00 equiv., 500 mg, 1.35 mmol) from Step 5 was dissolved in bis(diphenylphosphino)ferrocene (CAS no. [12150-46-8]; 0.200 equiv.) in DMSO (20 mL) in a steel autoclave (50 mL). Carbonylation in the presence of 1.0 mol%, 15 mg, 271 μmol), palladium(II) acetate (5.0 mol%, 15 mg, 68 μmol), and potassium acetate (4.0 equiv., 530 mg, 5.40 mmol) at 100° C. under approximately 15 bar carbon monoxide pressure for 23 h afforded the crude title compound (0.9 g, 32% purity, 65%), which was used in the subsequent reaction without further purification steps after workup. UPLC-MS (Method 1): R t= 0.64 min; MS (ESIpos): m / z = 336 [M+H] + .

[0713] Intermediate 39: 7'-Bromo-8'-methyl-2'-[(pyridin-3-yl)methyl]-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]

[0714] [ka]

[0715] According to GP C (Condition A), intermediate 38, 7'-bromo-8'-methyl-1',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole] (1.00 equiv., 200 mg, 716 μmol) from Step 4, was reacted with (pyridin-3-yl)methanol (1.10 equiv., 86.0 mg, 788 μmol), tri-n-butylphosphine (CAS no. [998-40-3]; 1.60 equiv., 286 μmL, 1.15 mmol), and TMAD (CAS no. [10465-78-8]; 1.60 equiv., 197 mg, 1.15 mmol) in toluene (10 mL) at room temperature overnight, followed by column chromatography (SiO, CHCl / MeOH) to afford the title compound (430 mg, 38% purity, 62%).

[0716] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.77-0.81 (m, 2H), 0.83-0.87 (m, 2H), 2.11 (s, 3H), 2.79 (s, 2H), 5.28 (s, 2H), 7.38 (dd, 1H), 7.44 (s, 1H), 7.60-7.62 (m, 1H), 8.48-8.50 (m, 2H). UPLC-MS (Method 1): R t = 1.31 min; MS (ESIpos): m / z = 370 / 372 [M+H] + (Br isotope pattern).

[0717] Intermediate 40-1: Step 1 7'-Bromo-2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'-methyl-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]

[0718] [ka]

[0719] According to GP C (Condition A), intermediate 38, 7'-bromo-8'-methyl-1',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole] from step 4 (1.00 equiv., 700 mg, 2.51 mmol) was reacted with [(2S)-1,4-dioxan-2-yl]methanol (CAS no. [406913-93-7]; 1.10 equiv., 326 mg, The reaction mixture was reacted with tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 1.0 mL, 4.0 mmol), and TMAD (CAS No. [10465-78-8]; 1.60 equiv., 691 mg, 4.01 mmol) at room temperature for 2 days, and purified by column chromatography (SiO, hexane / EtOAc) to give the title compound (595 mg, 65% purity, 41%).

[0720] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.76-0.80 (m, 2H), 0.82-0.85 (m, 2H), 2.12 (s, 3H), 2.77-2.78 (m, 2H), 3.24 (dd, 1H), 3.43 (dt, 1H), 3.53 (dt, 1H), 3.61-3.64 (m, 1H), 3.69-3.73 (m, 2H), 3.78-3.84 (m, 1H), 3.97-4.07 (m, 2H), 7.25 (s, 1H). UPLC-MS (Method 1): R t= 1.31 min; MS (ESIpos): m / z = 379 / 381 [M+H] + (Br isotope pattern).

[0721] Step 2 2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'-methyl-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxylic acid

[0722] [ka]

[0723] According to GP E, 7'-bromo-2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'-methyl-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole] (1.00 equiv., 989 mg, 2.61 mmol) from step 1 was dissolved in bis(diphenylphosphino)ferrocene (CAS no. [12150-46-8]; 0.01) in DMSO (40 mL) in a steel autoclave (90 mL). Carbonylation in the presence of palladium(II) acetate (5.0 mol%, 29 mg, 130 μmol), palladium(II) acetate (5.0 mol%, 201 equiv., 300 mg, 524 μmol), palladium(II) acetate (5.0 mol%, 29 mg, 130 μmol), and potassium acetate (4.00 equiv., 1.02 g, 10.4 mmol) at 100° C. under approximately 16 bar carbon monoxide pressure for 23 hours gave, after workup, the crude title compound (0.67 g, 60% purity, 45%), which was used in the subsequent reaction without further purification steps.

[0724] 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.78-0.87 (m, 4H), 2.85-2.86 (m, 2H), 3.25 (dd, 1H), 3.44 (dt, 1H), 3.54 (dt, 1H), 3.61-3.64 (m, 1H), 3.70-3.74 (m, 2H), 3.80-3.86 (m, 1H), 4.00-4.06 (m, 2H), 7.29 (s, 1H), 12.86 (br. s., 1H). UPLC-MS (Method 1): R t = 0.51 min; MS (ESIpos): m / z = 345 [M+H] + .

[0725] Intermediate 40-2: 7'-Bromo-N,N,8'-trimethylspiro[cyclopropane-1,4'-furo[2,3-g]indazole]-2'(5'H)-carboxamide

[0726] [ka]

[0727] Intermediate 40-1, isolated from the reaction mixture of Step 1 (166 mg, 18%).

[0728] Intermediate 41: Step 1 Ethyl 3-methyl-4-oxo-4,7-dihydro-5H-spiro[[1]benzofuran-6,1'-cyclopropane]-2-carboxylate

[0729] [ka]

[0730] To a mixture of spiro[2.5]octane-5,7-dione (CAS number [893411-52-4]; 1.00 equiv., 5.00 g, 36.2 mmol) in 1,2-dichloroethane (80 mL), ethyl 2-chloro-3-oxobutanoate (CAS number [609-15-4]; 1.0 equiv., 5.0 mL, 36 mmol) and triethylamine (1.2 equiv., 6.1 mL, 43 mmol) were added at room temperature, and the mixture was stirred at 50 °C for 15 h. The pH was adjusted to ~2 with 2 N aqueous HCl, and stirring at room temperature was continued for an additional 7 h. Water was added to the mixture, and the organic layer was separated. The organic layer was washed with water, filtered through a hydrophobic filter, and concentrated under reduced pressure. The resulting crude product was subjected to column chromatography (SiO, hexane / EtOAc) to afford the title compound (3.5 g, 36%).

[0731] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.44-0.48 (m, 2H), 0.50-0.54 (m, 2H), 1.29 (t, 3H), 2.35 (s, 2H), 2.47 (s, 3H), 2.86 (s, 2H), 4.29 (q, 2H). UPLC-MS (Method 1): R t = 1.14 min; MS (ESIpos): m / z = 249 [M+H] + .

[0732] Step 2 Ethyl (5E / Z)-5-[(dimethylamino)methylidene]-3-methyl-4-oxo-4,7-dihydro-5H-spiro[[1]benzofuran-6,1'-cyclopropane]-2-carboxylate

[0733] [ka]

[0734] According to GP A (Condition A), ethyl 3-methyl-4-oxo-4,7-dihydro-5H-spiro[[1]benzofuran-6,1'-cyclopropane]-2-carboxylate (1.00 equiv., 3.40 g, 13.7 mmol) from Step 1 was reacted with 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (Bredereck's reagent, CAS number [5815-08-7]; 1.2 equiv., 3.4 mL, 16 mmol) in toluene (35 mL) at 100°C for 5 days. The reaction mixture was concentrated under reduced pressure, and the resulting crude title compound was used in the subsequent reaction without further purification. UPLC-MS (Method 1): R t = 1.16 / 1.23 min; MS (ESIpos): m / z = 304 [M+H] + .

[0735] Step 3 Ethyl 8'-methyl-1',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxylate

[0736] [ka]

[0737] Following GP B, crude ethyl (5E / Z)-5-[(dimethylamino)methylidene]-3-methyl-4-oxo-4,7-dihydro-5H-spiro[1]benzofuran-6,1′-cyclopropane]-2-carboxylate (1.0 equiv., 4.2 g, 14 mmol) from Step 2 was reacted with 1:1 hydrazine hydrate (5.0 equiv., 3.3 mL, 68 mmol) in ethanol (35 mL) at 70 °C for 5 h, followed by column chromatography (SiO, hexane / EtOAc) to give the title compound (1.49 g, 84% purity, 34% over two steps).

[0738] 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.80-0.82 (m, 2H), 0.85-0.88 (m, 2H), 1.30 (t, 3H), 2.53 (s, 3H), 2.87 (s, 2H), 4.27 (q, 2H), 7.34 (s, 1H), 12.44 (s, 1H). UPLC-MS (Method 1): R t = 1.03 min; MS (ESIpos): m / z = 273 [M+H] + .

[0739] Step 4 Ethyl 2'-(cyclopropylmethyl)-8'-methyl-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxylate

[0740] [ka]

[0741] According to GP C (Condition A), ethyl 8'-methyl-1',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxylate (1.00 equiv., 400 mg, 1.47 mmol) from Step 3 was reacted with cyclopropylmethanol (1.5 equiv., 180 μL, 2.2 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 590 μL, 2.4 mmol), and TMAD (CAS No. [10465-78-8]; 1.60 equiv., 405 mg, 2.35 mmol) in toluene (7 mL) at room temperature overnight, followed by column chromatography (SiO, hexane / EtOAc) to afford the title compound (263 mg, 49%).

[0742] 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.31-0.35 (m, 2H), 0.48-0.53 (m, 2H), 0.79-0.83 (m, 2H), 0.85-0.89 (m, 2H), 1.16-1.24 (m, 1H), 1.29 (t, 3H), 2.52 (s, 3H), 2.87 (s, 2H), 3.88 (d, 2H), 4.27 (q, 2H), 7.37 (s, 1H). UPLC-MS (Method 1): R t = 1.40 min; MS (ESIpos): m / z = 327 [M+H] + .

[0743] Step 5 2'-(Cyclopropylmethyl)-8'-methyl-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxylic acid

[0744] [ka]

[0745] Following GP D, ethyl 2'-(cyclopropylmethyl)-8'-methyl-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxylate (1.00 equiv., 260 mg, 797 μmol) from Step 4 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 6.0 mL, 12 mmol) in a 1:1 mixture of ethanol and THF (12 mL) at 70 °C for 4 h and then at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and the concentrate was acidified (pH 3) with 2 N aqueous HCl. The precipitate that formed was filtered off. The solid was washed with water and EtOAc and dried to give the desired carboxylic acid (146 mg, 55%).

[0746] 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.33-0.34 (m, 2H), 0.50-0.52 (m, 2H), 0.80-0.86 (m, 4H), 1.17-1.23 (m, 1H), 2.83 (s, 2H), 3.87 (d, 2H), 7.34 (s, 1H). UPLC-MS (Method 1): R t = 0.59 min; MS (ESIpos): m / z = 299 [M+H] + .

[0747] Intermediate 42: Step 1 Ethyl 3-methyl-4-oxo-4,7-dihydro-5H-spiro[[1]benzofuran-6,1'-cyclobutane]-2-carboxylate

[0748] [ka]

[0749] To a mixture of spiro[3.5]nonane-6,8-dione (CAS number [221342-48-9]; 1.00 equiv., 2.00 g, 13.1 mmol) in 1,2-dichloroethane (30 mL) was added ethyl 2-chloro-3-oxobutanoate (CAS number [609-15-4]; 1.0 equiv., 1.8 mL, 13 mmol) and triethylamine (1.2 equiv., 2.2 mL, 16 mmol) at room temperature. The mixture was stirred at 50 °C for 3 days and then allowed to stand at room temperature for an additional 3 days. The pH was adjusted to ~2 with 2 N aqueous HCl, and stirring at room temperature was continued for an additional 2 hours. Water was added to the mixture, and the organic layer was separated. The organic layer was washed with water, filtered through a hydrophobic filter, and concentrated under reduced pressure. The resulting crude product was subjected to column chromatography (SiO, hexane / EtOAc) to afford the title compound (955 mg, 26%).

[0750] 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.77-1.94 (m, 6H), 2.44 (s, 3H), 2.62 (s, 2H), 3.09 (s, 2H), 4.28 (q, 2H). UPLC-MS (Method 1): R t = 1.23 min; MS (ESIpos): m / z = 263 [M+H] + .

[0751] Step 2 Ethyl (5E / Z)-5-[(dimethylamino)methylidene]-3-methyl-4-oxo-4,7-dihydro-5H-spiro[[1]benzofuran-6,1'-cyclobutane]-2-carboxylate

[0752] [ka]

[0753] According to GP A (Condition A), ethyl 3-methyl-4-oxo-4,7-dihydro-5H-spiro[[1]benzofuran-6,1'-cyclobutane]-2-carboxylate (1.00 equiv., 500 mg, 1.91 mmol) from Step 1 was reacted with 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (Bredereck's reagent, CAS number [5815-08-7]; 1.2 equiv., 470 μL, 2.3 mmol) in toluene (5 mL) at 100° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and the resulting crude title compound was used in the subsequent reaction without further purification. UPLC-MS (Method 1): R t = 1.23 / 1.25 min; MS (ESIpos): m / z = 318 [M+H] + .

[0754] Step 3 Ethyl 8'-methyl-1',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxylate

[0755] [ka]

[0756] Following GP B, crude ethyl (5E / Z)-5-[(dimethylamino)methylidene]-3-methyl-4-oxo-4,7-dihydro-5H-spiro[[1]benzofuran-6,1'-cyclobutane]-2-carboxylate (1.0 equiv., 600 mg, 1.9 mmol) from Step 2 was reacted with 1:1 hydrazine hydrate (5.0 equiv., 460 μL, 9.5 mmol) in ethanol (5 mL) at 70 °C for 13 h, followed by column chromatography (SiO, hexane / EtOAc) to give the title compound (134 mg, 25% over two steps).

[0757] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.30 (t, 3H), 1.93-2.13 (m, 6H), 3.05 (s, 2H), 4.27 (q, 2H), 7.79 (s, 1H), 12.54 (s, 1H). UPLC-MS (Method 1): R t = 1.12 min; MS (ESIpos): m / z = 287 [M+H] + .

[0758] Step 4 Ethyl 8'-methyl-2'-[(pyridin-2-yl)methyl]-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxylate

[0759] [ka]

[0760] According to GP C (Condition A), ethyl 8'-methyl-1',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxylate (1.00 equiv., 130 mg, 454 μmol) from Step 3 was reacted with (pyridin-2-yl)methanol (1.1 equiv., 55 mg, 500 μmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 180 μL, 730 μmol), and TMAD (CAS No. [10465-78-8]; 1.60 equiv., 125 mg, 726 μmol) in toluene (7.5 mL) at room temperature for 2 days, followed by column chromatography (SiO, hexane / EtOAc) to give the title compound (111 mg, 58%).

[0761] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.89-2.13 (m, 6H), 2.45 (s, 3H), 3.08 (s, 2H), 4.26 (q, 2H), 5.41 (s, 2H), 7.06 (d, 1H), 7.31 (ddd, 1H), 7.78 (dt, 1H), 7.94 (s, 1H), 8.55 (ddd, 1H). UPLC-MS (Method 1): R t = 1.27 min; MS (ESIpos): m / z = 378 [M+H] + .

[0762] Step 5 8'-Methyl-2'-[(pyridin-2-yl)methyl]-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxylic acid

[0763] [ka]

[0764] Following GP D, ethyl 8'-methyl-2'-[(pyridin-2-yl)methyl]-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxylate (1.00 equiv., 100 mg, 265 μmol) from Step 4 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 2.0 mL, 4.0 mmol) in a 1:1 mixture of ethanol and THF (4 mL) at 70 °C for 4 h and then at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the concentrate was acidified (pH 3) with 2 N aqueous HCl. The precipitate that formed was filtered off. The solid was washed with water and EtOAc and dried to give the desired carboxylic acid (70 mg, 64%).

[0765] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.91-2.05 (m, 2H), 2.06-2.13 (m, 4H), 2.42 (s, 3H), 3.03 (s, 2H), 5.40 (s, 2H), 7.05 (d, 1H), 7.31 (ddd, 1H), 7.78 (dt, 1H), 7.92 (s, 1H), 8.54 (ddd, 1H). UPLC-MS (Method 1): R t = 0.63 min; MS (ESIpos): m / z = 350 [M+H] + .

[0766] Intermediate 43: 8-Methyl-N-[(2S)-tetrahydrofuran-2-ylmethyl]-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxamide

[0767] [ka]

[0768] To an ice-cooled solution of 1-[(2S)-tetrahydrofuran-2-yl]methanamine (CAS No. [7175-81-7]; 3.0 equiv., 1.3 mL, 12 mmol) in dichloromethane (20 mL) under an argon atmosphere, trimethylaluminum (CAS No. [75-24-1]; 3.0 equiv., 2.0 M solution in toluene, 6.1 mL, 12 mmol) was added dropwise, and stirring was continued for 5 min. To this mixture was added dropwise a suspension of ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 1.00 g, 4.06 mmol) in dichloromethane (10 mL). The reaction mixture was allowed to warm to room temperature and stirred for 1 h, at which point it was warmed to 40° C. and stirring at 40° C. was continued for 4 days. The reaction mixture was quenched with a saturated aqueous solution of sodium potassium tartrate, the phases were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over MgSO, filtered, and concentrated under reduced pressure. The resulting crude material was subjected to column chromatography (Si-NH SiO, EtOAc / MeOH) and subsequent trituration with acetonitrile afforded the title compound (453 mg, 35%).

[0769] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.54-1.62 (m, 1H), 1.73-1.92 (m, 3H), 2.83-2.92 (m, 4H), 3.18-3.28 (m, 2H), 3.58-3.64 (m, 1H), 3.74-3.79 (m, 1H), 3.91-3.98 (m, 1H), 7.50 (s, 1H), 7.97 (t, 1H), 12.41 (s, 1H). UPLC-MS (Method 1): R t = 0.82 min; MS (ESIpos): m / z = 302 [M+H] + .

[0770] Intermediate 44: Step 1 Ethyl 8-methyl-2-[phenyl( 2H2) Methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0771] [ka]

[0772] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 304 mg, 1.23 mmol) was added to phenyl ( 2 H2) The reaction mixture was reacted with methanol (CAS No. [21175-64-4]; 1.5 equiv., 190 μL, 1.9 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 490 μL, 2.0 mmol), and TMAD (CAS No. [10465-78-8]; 1.60 equiv., 340 mg, 1.98 mmol) at room temperature for 3 days, followed by column chromatography (SiO2, hexane / EtOAc) to give the title compound (364 mg, 83%).

[0773] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.48 (s, 3H), 2.83-2.93 (m, 4H), 4.26 (q, 2H), 7.22-7.36 (m, 5H), 7.61 (s, 1H). UPLC-MS (Method 1): R t = 1.33 min; MS (ESIpos): m / z = 339 [M+H] + .

[0774] Step 2 8-methyl-2-[phenyl( 2 H2) Methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0775] [ka]

[0776] Following GP D, ethyl 8-methyl-2-[phenyl( 2 [H2)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 355 mg, 1.05 mmol) was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 7.9 mL, 16 mmol) in a 1:1 mixture of ethanol and THF (14 mL) at 70 °C overnight and then at room temperature for 2 days. The reaction mixture was acidified (pH 3-4) with 6 N aqueous HCl, resulting in the formation of a precipitate. The precipitate was isolated by filtration, washed with water, and dried under reduced pressure to give the desired carboxylic acid (214 mg, 64%).

[0777] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 2.46 (s, 3H), 2.82-2.91 (m, 4H), 7.23-7.30 (m, 3H), 7.33-7.37 (m, 2H), 7.59 (s, 1H), 12.80 (br. s., 1H). UPLC-MS (Method 1): R t = 0.58 min; MS (ESIpos): m / z = 311 [M+H] + .

[0778] Intermediate 45: Step 1 Ethyl 2-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0779] [ka]

[0780] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 300 mg, 1.22 mmol) was reacted with (5-cyclopropyl-1,2,4-oxadiazol-3-yl)methanol (CAS no. [915920-06-8]; 1.5 equiv., 256 mg, 1.83 mmol), tri-n-butylphosphine (CAS no. [998-40-3]; 1.6 equiv., 490 μL, 1.9 mmol), and TMAD (CAS no. [10465-78-8]; 1.60 equiv., 336 mg, 1.95 mmol) in toluene (8 mL) at room temperature for 3 days, followed by column chromatography (SiO, hexane / EtOAc) to give the title compound (363 mg, 73%).

[0781] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.06-1.10 (m, 2H), 1.21-1.25 (m, 2H), 1.29 (t, 3H), 2.29-2.36 (m, 1H), 2.46 (s, 3H), 2.84-2.94 (m, 4H), 4.26 (q, 2H), 5.41 (s, 2H), 7.62 (s, 1H). UPLC-MS (Method 1): R t = 1.19 min; MS (ESIpos): m / z = 369 [M+H] + .

[0782] Step 2 2-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0783] [ka]

[0784] Following GP D, ethyl 2-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 354 mg, 961 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 7.2 mL, 14 mmol) in a 1:1 mixture of ethanol and THF (14 mL) at 70 °C overnight. The reaction mixture was acidified (pH 3-4) with 6 N aqueous HCl and diluted with EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired carboxylic acid (275 mg, 76%).

[0785] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.06-1.10 (m, 2H), 1.20-1.25 (m, 2H), 2.29-2.36 (m, 1H), 2.44 (s, 3H), 2.82-2.92 (m, 4H), 5.41 (s, 2H), 7.61 (s, 1H), 12.81 (br. s., 1H). UPLC-MS (Method 1): R t = 0.51 min; MS (ESIpos): m / z = 341 [M+H] + .

[0786] Intermediate 46: Step 1 Ethyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0787] [ka]

[0788] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate ethyl (commercially available; 1.00 equiv., 350 mg, 1.42 mmol) was reacted with tert-butyl(2-hydroxyethyl)carbamate (CAS no. [26690-80-2]; 1.50 equiv., 344 mg, 2.13 mmol), tri-n-butylphosphine (CAS no. [998-40-3]; 1.6 equiv., 570 μL, 2.3 mmol), and TMAD (CAS no. [10465-78-8]; 1.60 equiv., 392 mg, 2.27 mmol) in toluene (8 mL) at room temperature overnight, followed by column chromatography (SiO, hexane / EtOAc) and subsequent trituration with acetonitrile to give the title compound (285 mg, 46%).

[0789] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.36 (s, 9H), 2.81-2.92 (m, 4H), 3.25-3.30 (m, 2H), 4.08 (t, 2H), 4.27 (q, 2H), 6.95 (t, 1H), 7.47 (s, 1H). UPLC-MS (Method 1): R t = 1.21 min; MS (ESIpos): m / z = 390 [M+H] + .

[0790] Step 2 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0791] [ka]

[0792] Following GP D, ethyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 280 mg, 719 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 5.4 mL, 11 mmol) in a 1:1 mixture of ethanol and THF (9 mL) at 70 °C overnight. The reaction mixture was acidified (pH 4) with 6 N aqueous HCl and diluted with EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired carboxylic acid (301 mg, 100%).

[0793] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.36 (s, 9H), 2.47 (s, 3H), 2.80-2.89 (m, 4H), 3.25-3.30 (m, 2H), 4.08 (t, 2H), 6.94 (t, 1H), 7.45 (s, 1H), 12.68 (br. s., 1H). UPLC-MS (Method 1): R t = 0.54 min; MS (ESIpos): m / z = 362 [M+H] + .

[0794] Intermediate 47: Step 1 Ethyl 2-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethyl}-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0795] [ka]

[0796] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate ethyl (commercially available; 1.00 equiv., 350 mg, 1.42 mmol) was reacted with tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (CAS no. [77279-24-4]; 1.50 equiv., 491 mg, 2.13 mmol) in toluene (8 mL). Reaction with tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 570 μL, 2.3 mmol) and TMAD (CAS No. [10465-78-8]; 1.60 equiv., 392 mg, 2.27 mmol) at room temperature overnight, column chromatography (SiO, hexane / EtOAc), and subsequent trituration with acetonitrile afforded the title compound (567 mg, 83%).

[0797] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 1.39 (s, 9H), 2.37-2.39 (m, 4H), 2.49 (s, 3H), 2.70 (t, 2H), 2.82-2.92 (m, 4H), 3.27-3.30 (m, 4H), 4.18 (t, 2H), 4.26 (q, 2H), 7.54 (s, 1H). UPLC-MS (Method 1): R t = 1.32 min; MS (ESIpos): m / z = 459 [M+H] + .

[0798] Step 2 2-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethyl}-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid hydrogen chloride (1 / 1)

[0799] [ka]

[0800] Following GP D, ethyl 2-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethyl}-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 560 mg, 1.22 mmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 9.2 mL, 18 mmol) in a 1:1 mixture of ethanol and THF (18 mL) at 70 °C overnight. The reaction mixture was acidified (pH 3-4) with 6 N aqueous HCl and diluted with EtOAc. The phases were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired carboxylic acid as the HCl salt (518 mg, 86%).

[0801] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.41 (s, 9H), 2.84-2.93 (m, 4H), 3.05-3.20 (m, 4H), 3.50-3.57 (m, 4H), 4.01 (br. s., 2H), 4.53 (br. ., 2H), 7.61 (s, 1H), 10.35 (br. s., 1H), 12.85 (br. s., 1H). UPLC-MS (Method 1): R t = 0.62 min; MS (ESIpos): m / z = 431 [M-Cl - ] + .

[0802] Intermediate 48: Step 1 Ethyl 2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'-methyl-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxylate

[0803] [ka]

[0804] According to GP C (Condition A), ethyl 8'-methyl-1',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxylate (prepared according to Intermediate 42, Step 3; 1.00 equiv., 500 mg, 1.75 mmol) was dissolved in [(2S)-1,4-dioxan-2-yl]methanol (CAS no. [406913-93-7]; 1.10 equiv.) in toluene (30 mL). The resulting mixture was reacted with tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equivalents, 700 μL, 2.8 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equivalents, 700 μL, 2.8 mmol), and TMAD (CAS No. [10465-78-8]; 1.60 equivalents, 481 mg, 2.79 mmol) at room temperature for 2 days, and purified by column chromatography (SiO2, hexane / ethyl acetate) to give the title compound (291 mg, 86% purity, 34%).

[0805] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.30 (t, 3H), 2.06-2.13 (m, 6H), 2.49 (s, 3H), 3.05-3.06 (m, 2H), 3.28 (dd, 1H), 3.46 (dt, 1H), 3.56 (dt, 1H), 3.62-3.65 (m, 1H), 3.73-3.76 (m, 2H), 3.85-3.91 (m, 1H), 4.10-4.12 (m, 2H), 4.27 (q, 2H), 7.76 (s, 1H). UPLC-MS (Method 1): R t = 1.26 min; MS (ESIpos): m / z = 387 [M+H] + .

[0806] Step 2 2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'-methyl-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxylic acid

[0807] [ka]

[0808] Following GP D, ethyl 2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'-methyl-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxylate (1.00 equiv., 240 mg, 621 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 4.7 mL, 9.3 mmol) in a 1:1 mixture of ethanol and THF (10 mL) at 70 °C for 4 h and then at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the concentrate was acidified (pH 3) with 2 N aqueous HCl. The precipitate that formed was filtered off. The solid was washed with water and EtOAc and dried to give the desired carboxylic acid (209 mg, 60% purity, 56%). UPLC-MS (Method 1): R t = 0.56 min; MS (ESIpos): m / z = 359 [M+H] + .

[0809] Intermediate 49: Step 1 Ethyl 2-[(6-cyanopyridin-3-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0810] [ka]

[0811] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 245 mg, 994 μmol) was reacted with 5-(hydroxymethyl)pyridine-2-carbonitrile (CAS No. [58553-48-3]; 1.50 equiv., 200 mg, 1.49 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 400 μL, 1.6 mmol), and TMAD (CAS No. [10465-78-8]; 1.60 equiv., 274 mg, 1.59 mmol) in toluene (8 mL) at room temperature overnight and at 40° C. for 1 day. Additional amounts of tri-n-butylphosphine (1.0 equiv, 250 μL, 1.0 mmol) and TMAD (1.0 equiv, 170 mg, 1.0 mmol) were added, and stirring at 40 °C was continued for 10 days. Column chromatography (SiO, hexane / EtOAc) afforded the title compound (72 mg, 18%).

[0812] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.47 (s, 3H), 2.86-2.94 (m, 4H), 4.26 (q, 2H), 5.48 (s, 2H), 7.71 (s, 1H), 7.82 (dd, 1H), 8.03 (dd, 1H), 8.86-8.87 (m, 1H). UPLC-MS (Method 1): R t = 1.20 min; MS (ESIpos): m / z = 363 [M+H] + .

[0813] Step 2 2-[(6-carboxypyridin-3-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0814] [ka]

[0815] Following GP D, ethyl 2-[(6-cyanopyridin-3-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.00 equiv., 72.0 mg, 199 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 1.5 mL, 3.0 mmol) in a 1:1 mixture of ethanol and THF (2 mL) at 70° C. overnight and at room temperature for 2 days. The reaction mixture was acidified (pH 3) with 6 N aqueous HCl and concentrated under reduced pressure, and the resulting crude dicarboxylic acid (268 mg) was used without further purification. UPLC-MS (Method 1): R t = 0.18 min; MS (ESIpos): m / z = 354 [M+H] + .

[0816] Intermediate 50: Step 1 Ethyl 4-oxo-3-(trifluoromethyl)-4,7-dihydro-5H-spiro[[1]benzofuran-6,1'-cyclopropane]-2-carboxylate

[0817] [ka]

[0818] To a solution of spiro[2.5]octane-5,7-dione (CAS number [893411-52-4]; 1.00 equiv., 67.5 mmol, 9.33 g) in toluene (30 mL), ethyl 2-chloro-4,4,4-trifluoro-3-oxobutanoate (see Intermediate 35, Step 1; 2.2 equiv., 150 mmol, 23 mL) was added, and the reaction mixture was stirred at 100 °C for 43 h. The mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The resulting material was purified by column chromatography (Si-NH SiO, hexane / EtOAc) to give the title compound (3.2 g, 15%).

[0819] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.48-0.51 (m, 2H), 0.54-0.57 (m, 2H), 1.30 (t, 3H), 2.45 (s, 2H), 2.96 (s, 2H), 4.36 (q, 2H). UPLC-MS (Method 1): R t = 1.22 min; MS (ESIpos): m / z = 303 [M+H] + .

[0820] Step 2 Ethyl (5E / Z)-5-[(dimethylamino)methylidene]-4-oxo-3-(trifluoromethyl)-4,7-dihydro-5H-spiro[[1]benzofuran-6,1'-cyclopropane]-2-carboxylate

[0821] [ka]

[0822] According to GP A (Condition A), ethyl 4-oxo-3-(trifluoromethyl)-4,7-dihydro-5H-spiro[[1]benzofuran-6,1′-cyclopropane]-2-carboxylate (1.00 equiv., 1.53 g, 5.06 mmol) from Step 1 was reacted with 1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (Bredereck's reagent, CAS number [5815-08-7]; 1.2 equiv., 1.1 mL, 6.1 mmol) in toluene (30 mL) at 100° C. for 29 h. An additional amount of 1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (1.5 equiv., 1.4 mL, 7.6 mmol) was added, and stirring at 100° C. was continued for an additional 19 h. The reaction mixture was concentrated under reduced pressure and the crude title compound obtained was used in the subsequent reaction without further purification steps. UPLC-MS (Method 1): R t = 1.23 / 1.29 min; MS (ESIpos): m / z = 358 [M+H] + .

[0823] Step 3 Ethyl 8'-(trifluoromethyl)-1',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxylate

[0824] [ka]

[0825] Following GP B, crude ethyl (5E / Z)-5-[(dimethylamino)methylidene]-4-oxo-3-(trifluoromethyl)-4,7-dihydro-5H-spiro[[1]benzofuran-6,1'-cyclopropane]-2-carboxylate (1.00 equiv., 1.81 g, 5.06 mmol) from Step 2 was reacted with hydrazine dihydrochloride (CAS number [5341-61-7]; 2.0 equiv., 1.1 g, 10 mmol) in a mixture of ethanol (13 mL) and water (2 mL) at 70 °C for 1 h, followed by column chromatography (SiO, hexane / EtOAc) to give the title compound (192 mg, 11% over two steps).

[0826] 1 H NMR (500 MHz, DMSO-d6) δ [ppm]: 0.83-0.86 (m, 2H), 0.88-0.91 (m, 2H), 1.31 (t, 3H), 2.97 (s, 2H), 4.35 (q, 2H), 7.42 (s, 1H), 12.62 (s, 1H). 19 F NMR (470 MHz, DMSO-d6) δ [ppm]: -55.0 (s). UPLC-MS (Method 1): R t = 1.15 min; MS (ESIpos): m / z = 327 [M+H] + .

[0827] Step 4 Ethyl 2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'-(trifluoromethyl)-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxylate

[0828] [ka]

[0829] According to GP C (Condition A), ethyl 8'-(trifluoromethyl)-1',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxylate (1.00 equiv., 142 mg, 435 μmol) from Step 3 was dissolved in toluene (5 mL) with [(2S)-1,4-dioxan-2-yl]methanol (CAS no. [406913-93-7]; 1.1 equiv. , 77 mg, 650 μmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equivalents, 170 μL, 700 μmol), and TMAD (CAS No. [10465-78-8]; 1.60 equivalents, 120 mg, 696 μmol) at room temperature for 5 days, and column chromatography (SiO2, hexane / ethyl acetate) gave the title compound (97 mg, 52%).

[0830] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.79-0.91 (m, 4H), 1.31 (t, 3H), 2.92-3.02 (m, 2H), 3.25 (dd, 1H), 3.43 (dt, 1H), 3.53 (dt, 1H), 3.61-3.64 (m, 1H), 3.71-3.75 (m, 2H), 3.79-3.85 (m, 1H), 4.10-4.11 (m, 2H), 4.35 (q, 2H), 7.38 (s, 1H). UPLC-MS (Method 1): R t = 1.29 min; MS (ESIpos): m / z = 427 [M+H] + .

[0831] Step 5 2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'-(trifluoromethyl)-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxylic acid

[0832] [ka]

[0833] Following GP D, ethyl 2'-{[(2S)-1,4-dioxan-2-yl]methyl}-8'-(trifluoromethyl)-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxylate (1.0 equiv., 97 mg, 230 μmol) from Step 4 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 1.7 mL, 3.4 mmol) in a 1:1 mixture of ethanol and THF (4 mL) at 70 °C for 4 h. The reaction mixture was acidified (pH 2) with 2 N aqueous HCl, and the precipitate that formed was filtered off. The solid was washed with water and EtOAc and dried to give the first crop of the desired carboxylic acid (57 mg, 60%). The combined filtrate and washings were re-extracted with ethyl acetate (twice), and the combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure to give a second crop of the desired carboxylic acid (34 mg, 87% purity, 33%).

[0834] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 0.79-0.92 (m, 4H), 2.90-2.99 (m, 2H), 3.25 (dd, 1H), 3.43 (dt, 1H), 3.53 (dt, 1H), 3.61-3.64 (m, 1H), 3.70-3.75 (m, 2H), 3.80-3.85 (m, 1H), 4.00-4.11 (m, 2H), 7.37 (s, 1H), 13.94 (br. s., 1H). UPLC-MS (Method 1): R t= 0.55 min; MS (ESIpos): m / z = 399 [M+H] + .

[0835] Intermediate 51: Step 1 Ethyl 2-[(4-fluoropyridin-2-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0836] [ka]

[0837] Ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.0 equiv., 100 mg, 406 μmol), 2-(chloromethyl)-4-fluoropyridine (1.5 equiv., 88.7 mg, 609 μmol), and cesium carbonate (CAS No. [534-17-8], 3.0 equiv., 397 mg, 1.22 mmol) were added to DMF (3.0 mL) and stirred overnight at room temperature under nitrogen for 24 hours. 2,2-(chloromethyl)-4-fluoropyridine (1.5 equiv., 88.7 mg, 609 μmol) and cesium carbonate (CAS No. [534-17-8], 3.0 equiv., 397 mg, 1.22 mmol) were added again and stirred overnight at room temperature under nitrogen. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was evaporated and purified by column chromatography (SiO2, hexane / ethyl acetate) to give the product (53.1 mg, 37% yield).

[0838] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.27 - 1.31 (m, 3 H) 2.46 (s, 3 H) 2.85 - 2.94 (m, 4 H) 4.23 - 4.29 (m, 2 H) 5.40 (s, 2 H) 7.19 - 7.22 (m, 1H) 7.65 (s, 1H) 7.71 (td, 1H) 8.55 (d, 1H) LC-MS (Method 1): R t = 1.22 min; MS (ESIpos): m / z = 356 [M+H] +

[0839] Step 2 2-[(4-fluoropyridin-2-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0840] [ka]

[0841] According to GP D, ethyl 2-[(4-fluoropyridin-2-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.0 equiv., 53.0 mg, 149 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 5 equiv., 370 μL, 750 μmol) in a 1:1 mixture of ethanol and THF (2.0 mL) at 70 °C overnight. The mixture was acidified (pH 2) with 6 N hydrochloric acid and then evaporated. The residue was added with DCM (20 ml) and i-PrOH (1 ml) and stirred at room temperature. The DCM phase was decanted and evaporated. THF (20 ml) was then added and co-evaporated. This crude material (75 mg) was used in the subsequent reaction without further purification.

[0842] LC-MS (Method 1): R t = 0.52 min; MS (ESIpos): m / z = 328 [M+H] +

[0843] Intermediate 52: Step 1 Ethyl 8-methyl-2-[(pyridazin-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0844] [ka]

[0845] A solution of ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.0 equiv., 180 mg, 731 μmol) and 3-(chloromethyl)pyridazine chloride (CAS No. [27349-66-2], 1.5 equiv., 180 mg, 1096 μmol) in DMF (24.0 mL) under nitrogen was treated with cesium carbonate (CAS No. [534-17-8], 20.0 equiv., 4.76 g, 14.6 mmol) and stirred at 80 °C overnight. The solid was filtered, washed with ethyl acetate, and evaporated. The residue was purified by column chromatography (SiO, hexane / ethyl acetate) to give the product (87 mg, 35% yield).

[0846] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.27 - 1.31 (m, 3 H) 2.46 (s, 3 H) 2.85 - 2.95 (m, 4 H) 4.21 - 4.30 (m, 2 H) 5.63 (s, 2 H) 7.38 - 7.43 (m, 1 H), 7.67 - 7.71 (m, 1 H) 7.72 (s, 1 H) 9.13 - 9.22 (m, 1 H) LC-MS (Method 1): R t = 1.02 min; MS (ESIpos): m / z = 339 [M+H] +

[0847] Step 2 8-Methyl-2-[(pyridazin-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0848] [ka]

[0849] According to GP D, ethyl 8-methyl-2-[(pyridazin-3-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.0 equiv., 87.0 mg, 257 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 5 equiv., 640 μL, 1.3 mmol) in a 1:1 mixture of ethanol and THF (5.0 mL) at 70 °C overnight. The mixture was acidified (pH 2) with 6 N hydrochloric acid and evaporated. To the residue was added DCM (50 mL) and i-PrOH (4 × 5 mL) and stirred at room temperature for 30 minutes. Hexane was added until a precipitate formed, filtered, washed with hexane / DCM (1:1), and evaporated. To the residue was added DCM and brine (2 mL) and stirred. The phases were separated and the DCM phase was evaporated to give the product (35.0 mg, 44% yield).

[0850] LC-MS (Method 2): R t = 0.72 min; MS (ESIpos): m / z = 311 [M+H] +

[0851] Intermediate 53: Step 1 Ethyl 2-[(6-chloropyridin-3-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0852] [ka]

[0853] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 250 mg, 1.05 mmol) was reacted with (6-chloropyridin-3-yl)methanol (1.5 equiv., 218 mg, 1.52 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 0.4 mL, 1.6 mmol), and TMAD (CAS No. [10465-81-3]; 1.6 equiv., 279 mg, 1.6 mmol) in toluene (5.8 mL) overnight at room temperature. The reaction mixture was filtered and extracted with water. The aqueous phase was extracted twice with DCM. The combined organic layers (DCM and toluene phases) were dried on a hydrophobic filter paper and evaporated to give the crude material. This was purified by column chromatography (SiO2, hexane / EtOAc) to give the title compound (140 mg, 36% yield).

[0854] LC-MS (Method 1): R t = 1.28 min; MS (ESIpos): m / z = 372 [M+H] +

[0855] Step 2 Ethyl 2-[(6-ethylpyridin-3-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0856] [ka]

[0857] Ethyl 2-[(6-chloropyridin-3-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.0 equiv., 350 mg, 941 μmol) from Step 1 was dissolved in dioxane (22 mL) and flushed with nitrogen. 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (76.8 mg, 94.1 μmol; CAS Registry Number: [72287-26-4]) was added first, followed by the dropwise addition of diethylzinc in hexane (CAS Registry Number [557-20-0], 4.5 equiv., 4.2 mL, 1.0 M, 4.2 mmol). The resulting reaction mixture was stirred at 100 °C for 4 hours. Water and DCM were added to the reaction mixture. The layers were separated, and the aqueous layer was extracted with DCM and then with ethyl acetate. The organic layer was dried by hydrophobic filtration and evaporated. The crude material was purified by silica gel column chromatography (hexane / DCM) to give the title compound (187 mg, 55% yield).

[0858] LC-MS (Method 1): R t = 1.26 min; MS (ESIpos): m / z = 366 [M+H] +

[0859] Step 3 2-[(6-ethylpyridin-3-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0860] [ka]

[0861] According to GP D, ethyl 2-[(6-ethylpyridin-3-yl)methyl]-8-methyl-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.0 equiv., 94.0 mg, 257 μmol) from Step 2 was reacted with aqueous lithium hydroxide (2 M; 5 equiv., 640 μL, 1.3 mmol) in a 1:1 mixture of ethanol and THF (3.0 mL) at 70 °C overnight. The mixture was acidified (pH 2) with 6 N hydrochloric acid and evaporated. To the residue were added DCM (30 mL), water (20 mL), and i-PrOH (2 mL). The aqueous phase was extracted with DCM / i-PrOH (9:1). The combined organic phases were dried on a hydrophobic filter and evaporated to give the crude product (55 mg, 63% yield), which was used in the next step without further purification.

[0862] LC-MS (Method 1): R t = 0.56 min; MS (ESIpos): m / z = 338 [M+H] +

[0863] Intermediate 54: Step 1 Ethyl 8-methyl-2-[(1,3-oxazol-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0864] [ka]

[0865] Ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 100 mg, 406 μmol) was reacted with (1,3-oxazol-2-yl)methanol (CAS No. [14774-37-9]; 1.5 equiv., 60.4 mg, 609 μmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 160 μL, 650 μmol), and 1,1'-(azodicarbonyl)dipiperidine (CAS No. [10465-81-3]; 1.6 equiv., 112 mg, 650 μmol) in toluene (3.0 mL) at room temperature overnight. The same amounts of reagents were added, and the mixture was again stirred at room temperature overnight. The reaction mixture was filtered and extracted with water. The aqueous phase was re-extracted with DCM. The organic layers were combined, dried on a hydrophobic filter paper, and evaporated to give the crude material, which was then purified by column chromatography (NH, SiO, hexane / DCM) to give the title compound (60 mg), which was used in the next step without further purification.

[0866] LC-MS (Method 1): R t = 1.10 min; MS (ESIpos): m / z = 328 [M+H] +

[0867] Step 2 8-Methyl-2-[(1,3-oxazol-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0868] [ka]

[0869] According to GP D, ethyl 8-methyl-2-[(1,3-oxazol-2-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.0 equiv., 60 mg, 183 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 1.4 mL, 2.7 mmol) in a 1:1 mixture of ethanol and THF (1.3 mL) at 70 °C overnight. After acidification (pH 2) with 6 N hydrochloric acid, the resulting mixture was evaporated. The crude material obtained was used in the subsequent reaction without further purification (90 mg).

[0870] LC-MS (Method 1): R t = 0.47 min; MS (ESIpos): m / z = 300 [M+H] +

[0871] Intermediate 55: Step 1 Ethyl 8-methyl-2-[(oxan-4-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0872] [ka]

[0873] Ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 1.00 equiv., 100 mg, 406 μmol) was reacted with (oxan-4-yl)methanol (CAS No. [14774-37-9]; 1.5 equiv., 70.8 mg, 609 μmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 160 μL, 650 μmol), and 1,1'-(azodicarbonyl)dipiperidine (CAS No. [10465-81-3]; 1.6 equiv., 112 mg, 650 μmol) in toluene (3.0 mL) at room temperature overnight. The same amounts of reagents were added, and the mixture was again stirred at room temperature overnight. The reaction mixture was filtered and extracted with water. The aqueous phase was extracted with DCM. The combined organic layers were dried on a hydrophobic filter paper and evaporated to give the crude material, which was then purified by column chromatography (NH, SiO, hexane / DCM) to give the title compound (314 mg), which was used in the next step without further purification.

[0874] LC-MS (Method 1): R t = 1.21 min; MS (ESIpos): m / z = 345 [M+H] +

[0875] Step 2 8-Methyl-2-[(oxan-4-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0876] [ka]

[0877] Following GP D, ethyl 8-methyl-2-[(oxan-4-yl)methyl]-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.0 equiv., 210 mg, 610 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 15 equiv., 4.6 mL, 9.1 mmol) in a 1:1 mixture of ethanol and THF (4.3 mL) overnight at 70° C. Upon acidification (pH 2) with 6 N hydrochloric acid, the resulting mixture was evaporated and the crude material was used in the subsequent reaction without further purification (350 mg).

[0878] LC-MS (Method 1): R t = 0.53 min; MS (ESIpos): m / z = 317 [M+H] +

[0879] Intermediate 56: Step 1 Ethyl 8-methyl-2-{[(2R and 2S)-oxan-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (racemic)

[0880] [ka]

[0881] According to GP C (Condition A), ethyl 8-methyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (commercially available; 100 mg, 406 μmol) and [(2R and 2S)-oxan-2-yl]methanol (racemic, 70.8 mg, 609 μmol, CAS Registry Number: [100-72-1]) were suspended in toluene (3 mL) along with TMAD (112 mg, 650 μmol, CAS Registry Number: [10465-78-8]). Tri-n-butylphosphine (160 μL, 650 μmol, CAS Registry Number: [998-40-3]) was carefully added, and the reaction mixture was stirred at room temperature for 18 h. Additional TMAD (112 mg, 650 μmol) and tri-n-butylphosphine (160 μL, 650 μmol) were then added, and stirring was continued for 18 hours at room temperature and 4 hours at 45°C. After additional tri-n-butylphosphine (160 μL, 650 μmol) was added, stirring was continued for an additional 3 days at room temperature. After filtration, water was added to the filtrate, and the aqueous phase was extracted with dichloromethane. After evaporation of the organic layer, the crude material was purified by Biotage Isorella® chromatography (SNAP KP-NH - 28 g) eluting with hexane-dichloromethane (1:0 to 3:2) to give the title compound (100 mg, 72% yield).

[0882] LC-MS (Method 1): R t = 1.33 min; MS (ESIpos): m / z = 345 [M+H] +

[0883] Step 2 8-Methyl-2-{[(2R and 2S)-oxan-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid (racemic)

[0884] [ka]

[0885] According to GP D, ethyl 8-methyl-2-{[(2R and 2S)-oxan-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (racemic, 100 mg, 290 μmol) from Step 1 was reacted with aqueous lithium hydroxide (15 equiv., 2.2 mL, 2.0 M, 4.4 mmol) in a 1:1 mixture of ethanol and THF (4.1 mL) at 70 °C overnight. The reaction mixture was acidified (pH 4) with 6 N aqueous HCl and concentrated in vacuo. The resulting crude product (140 mg) was used in the next step without further purification.

[0886] LC-MS (Method 1): R t = 0.59 min; MS (ESIpos): m / z = 317 [M+H] +

[0887] Intermediate 57: Step 1 Ethyl 2-[(6-methylpyridin-3-yl)methyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0888] [ka]

[0889] According to GP C (Condition A), ethyl 8-(trifluoromethyl)-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (1.0 equiv., 325 mg, 1.08 mmol) from Intermediate 35, Step 4, was reacted with (6-methylpyridin-3-yl)methanol (CAS No. [34107-46-5], 1.7 equiv., 227 mg, 1.84 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 430 μL, 1.7 mmol), and TMAD (CAS No. [10465-78-8]; 1.6 equiv., 298 mg, 1.73 mmol) in toluene (10 mL) at room temperature overnight. The reaction mixture was filtered and extracted with water. The aqueous phase was re-extracted with DCM. The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure to give a crude material, which was then purified by column chromatography (NH, SiO2, hexane / DCM) to give the title product (460.5 mg), which was used in the next step without further purification.

[0890] LC-MS (Method 1): R t = 1.24 min; MS (ESIpos): m / z = 406 [M+H] +

[0891] Step 2 2-[(6-methylpyridin-3-yl)methyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0892] [ka]

[0893] Following GP D, ethyl 2-[(6-methylpyridin-3-yl)methyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.0 equiv., 460 mg, 1.13 mmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 5 equiv., 2.8 mL, 5.7 mmol) in a 1:1 mixture of ethanol and THF (9.2 mL) at 70 °C overnight. After acidification (pH 2) with 6 N hydrochloric acid, the resulting mixture was evaporated. The crude material was added with DCM (75 mL) and i-PrOH (2 × 0.5 mL) and stirred at room temperature. The DCM phase was decanted and the remaining solid was dissolved in DCM (75 ml) and i-PrOH (5 ml), stirred at room temperature, the resulting DCM phase was decanted and the solution was evaporated to give the product as a solid (226 mg, 53% yield).

[0894] LC-MS (Method 1): R t = 0.56 min; MS (ESIpos): m / z = 378 [M+H] +

[0895] Intermediate 58: Step 1 Methyl 8-cyclopropyl-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate

[0896] [ka]

[0897] According to GP C (Condition A), intermediate 36, methyl 8-cyclopropyl-4,5-dihydro-1H-furo[2,3-g]indazole-7-carboxylate (1.0 equiv., 250 mg, 968 μmol) from Step 4, was reacted with [(2S)-1,4-dioxan-2-yl]methanol (CAS No. [406913-93-7], 1.5 equiv., 172 mg, 1.45 mmol), tri-n-butylphosphine (CAS No. [998-40-3]; 1.6 equiv., 380 μL, 1.5 mmol), and TMAD (CAS No. [10465-78-8]; 1.6 equiv., 267 mg, 1.55 mmol) in toluene (5.5 mL) at room temperature overnight. The reaction mixture was filtered and extracted with water. The combined aqueous phases were re-extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated. The crude material was purified by column chromatography (SiO2, hexane / DCM) to give the title compound (350 mg).

[0898] LC-MS (Method 1): R t = 1.19 min; MS (ESIpos): m / z = 359 [M+H] +

[0899] Step 2 8-Cyclopropyl-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylic acid

[0900] [ka]

[0901] According to GP D, methyl 8-cyclopropyl-2-{[(2S)-1,4-dioxan-2-yl]methyl}-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxylate (1.0 equiv., 350 mg, 977 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2 M; 5 equiv., 2.4 mL, 4.9 mmol) in a 1:1 mixture of ethanol and THF (5.0 mL) at 70 °C overnight. The mixture was acidified (pH 2) with 6 N hydrochloric acid, and the resulting mixture was evaporated under reduced pressure. The residue was added with DCM (40 mL) and i-PrOH (1 mL) and stirred at room temperature for 30 minutes. The organic phase was separated and evaporated under reduced pressure to give the title compound (400 mg), which was used in the subsequent step without further purification.

[0902] LC-MS (Method 1): R t = 0.51 min; MS (ESIpos): m / z = 345 [M+H] +

[0903] Intermediate 59: Step 1 Ethyl 8'-methyl-2'-[(pyridin-4-yl)methyl]-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxylate

[0904] [ka]

[0905] According to GP C (Condition A), ethyl 8'-methyl-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxylate (190 mg, 664 μmol, Intermediate 42 (Step 3)) and pyridin-4-yl)methanol (109 mg, 995 μmol, CAS Registry Number: [586-95-8]) were suspended in toluene (3.8 mL) along with TMAD (183 mg, 1.06 mmol, CAS Registry Number [10465-78-8]). Tri-n-butylphosphine (260 μL, 1.1 mmol, CAS Registry Number [998-40-3]) was carefully added, and the reaction mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, which was then concentrated in vacuo. The residue was diluted with 3 mL of acetonitrile and purified by preparative HPLC (Method A, Gradient D). Product fractions were pooled and concentrated in vacuo to give 18.0 mg (6% yield, 79% purity) of the title compound.

[0906] 1 H NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 2.01-2.15 (m, 6H), 2.46 (s, 3H), 3.01-3.15 (m, 2H), 4.26 (q, 2H), 5.39 (s, 2H), 7.13-7.16 (m, 2H), 7.97 (s, 1H), 8.52-8.55 (m, 2H) LC-MS (Method 1): R t = 1.27 min; MS (ESIpos): m / z = 378 [M+H] +

[0907] Step 2 8'-Methyl-2'-[(pyridin-4-yl)methyl]-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxylic acid

[0908] [ka]

[0909] Following GP D, ethyl 8'-methyl-2'-[(pyridin-4-yl)methyl]-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxylate (18.0 mg, 79% purity, 37.7 μmol) from Step 1 was reacted with aqueous lithium hydroxide (2190 μL, 2.0 M, 380 μmol) in THF (430 μL) overnight at room t...

Claims

1. General formula (I): 【Chemistry 1】 A compound of the formula: R １ But hydrogen, C １ -C ４ - alkyl or C １ -C ４ - represents haloalkyl; R ２ But hydrogen, C １ -C ４ - alkyl or C １ -C ４ -haloalkyl; or R １ and R ２ combine with the carbon atoms to which they are attached to form a 3- to 6-membered cycloalkyl or heterocycloalkyl ring; R ３ But C ３ -C ６ -cycloalkyl, 3- to 6-membered heterocycloalkyl, heterocycloalkyl fused with phenyl or heteroaryl, or heteroaryl, wherein said groups are, one or more times, independently of one another, R ８ and optionally substituted with R ７ａ is hydrogen, deuterium, or C １ -C ４ represents alkyl; and R ７ｂ is hydrogen, deuterium, or C １ -C ４ represents alkyl; or R ３ represents phenyl, and one or more times, independently of one another, R ８ and optionally substituted with R ７ａ and R ７ｂ represents deuterium; R ４ But hydrogen, C １ -C ４ -Alkyl, C １ -C ４ -haloalkyl, or C ３ -C ６ represents cycloalkyl; R ５ , R ６ are independently hydrogen, C １ -C ４ -Alkyl, C ２ -C ４ -hydroxyalkyl, (C １ -C ４ -alkoxy)-(C ２ -C ４ -alkyl)-, C ３ -C ６ -cycloalkyl, C １ -C ４ -haloalkyl, C ３ -C ６ -halocycloalkyl, 3- to 6-membered heterocycloalkyl, heterospirocycloalkyl, phenyl, heteroaryl, heterocycloalkyl fused to phenyl or heteroaryl, 3- to 6-membered heterocycloalkyl-(C １ -C ３ -alkyl)-, heterospirocycloalkyl-(C １ -C ３ -alkyl)-, (heterocycloalkyl fused with phenyl or heteroaryl)-(C １ -C ３ -alkyl)-, phenyl-(C １ -C ３ -alkyl)-, or heteroaryl-(C １ -C ３ -alkyl)-, and the heterocycloalkyl, phenyl, or heteroaryl group fused to said 3- to 6-membered heterocycloalkyl, heterospirocycloalkyl, phenyl, or heteroaryl may be one or more times, independently of each other, R ９ optionally substituted with; or R ５ and R ６ are joined to the nitrogen atom to which they are attached to 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, which may occur one or more times, independently of each other, as R ９ may be optionally substituted with; R ８ But halogen, cyano, C １ -C ４ -Alkyl, C １ -C ４ -haloalkyl, C １ -C ３ -alkoxy, C １ -C ３ -haloalkoxy, C ３ -C ６ -cycloalkyl, C ３ -C ６ -cycloalkyl-(C １ -C ３ -alkyl)-, R １３ -(C=O)-, R １０ -O-(C=O)-, R １１ —NH—(C═O)—, or R １２ - (SO ２ )- represents; R ９ But halogen, cyano, C １ -C ４ -Alkyl, C １ -C ４ -haloalkyl, H ２ N-C １ -C ４ -Alkyl, C １ -C ３ -alkoxy, C １ -C ３ -haloalkoxy, C ３ -C ６ -cycloalkyl, R １０ -O-(C=O)-, oxo, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkyl-(C １ -C ３ -alkyl)-, phenyl, or heteroaryl, wherein the phenyl or heteroaryl group may be one or more times independently of each other selected from halogen, C １ -C ４ -Alkyl, C １ -C ４ -haloalkyl, C １ -C ３ -alkoxy, or C １ -C ３ -optionally substituted with haloalkoxy; R １０ But hydrogen, C １ -C ４ -alkyl, or phenyl-CH ２ represents -; R １１ But hydrogen, C １ -C ４ -alkyl, or 5- to 6-membered heterocycloalkyl-(C １ -C ３ -alkyl)-; R １２ But C １ -C ４ represents alkyl or phenyl; R １３ But C １ -C ４ -Alkyl, C １ -C ４ -haloalkyl, (C １ -C ４ -alkoxy)-(C １ -C ４ -alkyl)-, C １ -C ４ -alkyl-(C═O)-, C ３ -C ６ -cycloalkyl, or phenyl, ３ -C ６ - the cycloalkyl group is C １ -C ４ - optionally substituted by alkyl or hydroxy, and the phenyl groups may be one or more times, independently of one another, by halogen, C １ -C ４ -Alkyl, C １ -C ４ -haloalkyl, C １ -C ３ -alkoxy, or C １ -C ３ -optionally substituted with haloalkoxy; The compound, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

2. R １ But hydrogen, C １ -C ４ - alkyl or C １ -C ４ - represents haloalkyl; R ２ But hydrogen, C １ -C ４ represents alkyl; or R １ and R ２ combine with the carbon atoms to which they are attached to form a 3- to 4-membered cycloalkyl or heterocycloalkyl ring; R ３ But C ３ -C ６ -cycloalkyl, 4- to 6-membered heterocycloalkyl, heterocycloalkyl fused to heteroaryl, or heteroaryl, wherein said groups are, one or more times, independently of each other, R ８ and optionally substituted with R ７ａ represents hydrogen, deuterium, or methyl; and R ７ｂ represents hydrogen, deuterium, or methyl; or R ３ represents phenyl, and one or more times, independently of one another, R ８ and optionally substituted with R ７ａ and R ７ｂ represents deuterium; R ４ But hydrogen, C １ -C ４ -Alkyl, C １ -C ４ -haloalkyl, or C ３ -C ６ - represents cycloalkyl; R ５ , R ６ are independently hydrogen, C ２ -C ４ -hydroxyalkyl, (C １ -C ４ -alkoxy)-(C ２ -C ４ -alkyl)-, 3- to 6-membered heterocycloalkyl, heterospirocycloalkyl, phenyl, heteroaryl, 4- to 6-membered heterocycloalkyl-(C １ -C ３ -alkyl)-, heterospirocycloalkyl-(C １ -C ３ -alkyl)-, (heterocycloalkyl fused with heteroaryl)-(C １ -C ３ -alkyl)-, or heteroaryl-(C １ -C ３ -alkyl)-, wherein said 3- to 6-membered heterocycloalkyl, phenyl, or heteroaryl groups may occur one or more times, independently of each other, as R ９ optionally substituted with, or R ５ and R ６ are joined to the nitrogen atom to which they are attached to form a five-membered nitrogen-containing heterocyclic ring, which heterocycle is joined once by R ９ may be optionally substituted with; R ８ But halogen, cyano, C １ -C ４ -Alkyl, C １ -C ４ -haloalkyl, C １ -C ３ -alkoxy, C ３ -C ６ -cycloalkyl, C ３ -C ６ -cycloalkyl-(C １ -C ３ -alkyl)-, R １３ -(C=O)-, R １０ -O-(C=O)-, R １１ —NH—(C═O)—, or R １２ - (SO ２ )- represents; R ９ But halogen, cyano, C １ -C ４ -Alkyl, C １ -C ４ -haloalkyl, H ２ N-C １ -C ４ -Alkyl, C ３ -C ６ -cycloalkyl, R １０ -O-(C=O)-, oxo, 6-membered heterocycloalkyl-(C １ -C ３ -alkyl)-, phenyl, or heteroaryl, and the phenyl or heteroaryl groups may be one or more times independently selected from halogen, C １ -C ４ -haloalkyl, or C １ -C ３ -optionally substituted with alkoxy; R １０ But hydrogen, C １ -C ４ -alkyl, or phenyl-CH ２ represents -; R １１ is a 5- to 6-membered heterocycloalkyl-(C １ -C ３ -alkyl)-; R １２ But C １ -C ４ represents alkyl; R １３ But C １ -C ４ - alkyl, (C １ -C ４ -alkoxy)-(C １ -C ４ -alkyl)-, C １ -C ４ -alkyl-(C═O)-, C ３ -C ６ -cycloalkyl, or phenyl, ３ -C ６ - the cycloalkyl group is optionally substituted with methyl or hydroxy; 2. The compound of claim 1, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

3. R １ represents hydrogen, methyl, or trifluoromethyl; R ２ represents hydrogen or methyl; or R １ and R ２ combine with the carbon atoms to which they are attached to 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, and said groups occur one or more times, independently of one another, as R ８ optionally substituted with R ７ａ represents hydrogen, deuterium, or methyl; and R ７ｂ represents hydrogen, deuterium, or methyl; or R ３ represents phenyl, and one or more times, independently of one another, R ８ and optionally substituted with R ７ａ and R ７ｂ represents deuterium; R ４ is hydrogen, methyl, C １ -haloalkyl, or cyclopropyl; R ５ represents hydrogen; R ６ is methoxy-ethyl, 5-membered heteroaryl, 4- to 6-membered heterocycloalkyl-(C １ -C ２ -alkyl)-, heterospirocycloalkyl-methyl, 2,3-dihydro[1,4]dioxino[2,3-b]pyridin-2-ylmethyl, or 5- to 6-membered heteroaryl-(C １ -C ２ -alkyl)-, wherein said 4- to 6-membered heterocycloalkyl or heteroaryl groups may occur one or more times, independently of each other, as R ９ optionally substituted with; R ８ But fluoro, chloro, C １ -C ２ - alkyl, trifluoromethyl, C １ -C ３ -alkoxy, cyclopropyl, cyclopropylmethyl, R １３ -(C=O)-, R １０ -O-(C=O)-, R １１ —NH—(C═O)—, or R １２ - (SO ２ )- represents; R ９ But fluoro, chloro, C １ -C ３ - alkyl, trifluoromethyl, cyclopropyl, or oxo; R １０ But C １ -C ４ -alkyl, or phenyl-CH ２ represents -; R １１ represents a 5- to 6-membered heterocycloalkyl-methyl; R １２ represents methyl; R １３ represents methyl, methoxymethyl, ethyl-(C═O)—, cyclopropyl, or phenyl, said cyclopropyl group being optionally substituted with methyl or hydroxy; 3. The compound according to claim 1 or 2, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

4. R １ represents hydrogen or methyl; R ２ represents hydrogen or methyl; or R １ and R ２ combine with the carbon atoms to which they are attached to form a 3- to 4-membered cycloalkyl ring; R ３ is 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: 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 represents a group selected from R ７ａ represents hydrogen; and R ７ｂ represents hydrogen; or R ３ represents phenyl, and R ７ａ and R ７ｂ represents deuterium; R ４ represents methyl, difluoromethyl, trifluoromethyl, or cyclopropyl; R ５ represents hydrogen; R ６ (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]pyridine -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; 4. The compound according to any one of claims 1 to 3, which is a compound, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

5. 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)-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 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 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-[(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 (racemic form) 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[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 8'-Methyl-2'-[(5-methylpyridin-2-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-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'-(trifluoromethyl)-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 2'-(pyridin-4-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-8'-(trifluoromethyl)-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-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'-(trifluoromethyl)-2',5'-dihydrospiro[cyclopropane-1,4'-furo[2,3-g]indazole]-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-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2S)-1,4-dioxan-2-ylmethyl]-N-[(5-methylpyrazin-2-yl)methyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-(pyrazin-2-ylmethyl)-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[(1-methyl-1H-imidazol-4-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-thiazole -5-ylmethyl)-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2S)-1,4-dioxan-2-ylmethyl]-N-[2-(4-methylpyridin-2-yl)ethyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[2-(pyridin-2-yl)ethyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[2-(3-methyl-1H-pyrazol-1-yl)ethyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[2-(1H-imidazol-4-yl)ethyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[2-(pyridin-3-yl)ethyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[2-(1,3-thiazol-2-yl)ethyl]-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide 2-[(2S)-1,4-dioxan-2-ylmethyl]-N-[(6-methylpyridin-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-oxazol-4-ylmethyl)-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-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'-(trifluoromethyl)-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 2'-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-8'-(trifluoromethyl)-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 2'-[(2S)-1,4-Dioxan-2-ylmethyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-8'-(trifluoromethyl)-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-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'-(trifluoromethyl)-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 2'-(pyridin-2-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-8'-(trifluoromethyl)-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N-(1,3-oxazol-2-ylmethyl)-2'-(pyridin-2-ylmethyl)-8'-(trifluoromethyl)-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N-[(1-methyl-1H-pyrazol-3-yl)methyl]-2'-(pyridin-2-ylmethyl)-8'-(trifluoromethyl)-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 2'-[(5-methylpyridin-2-yl)methyl]-N-[(2S)-tetrahydrofuran-2-ylmethyl]-8'-(trifluoromethyl)-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-2'-[(5-methylpyridin-2-yl)methyl]-8'-(trifluoromethyl)-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N-[(1-methyl-1H-pyrazol-3-yl)methyl]-2'-[(5-methylpyridin-2-yl)methyl]-8'-(trifluoromethyl)-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide 2'-(pyridin-4-ylmethyl)-N-[(2S)-tetrahydrofuran-2-ylmethyl]-8'-(trifluoromethyl)-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-7'-carboxamide N-[(2R)-1,4-dioxan-2-ylmethyl]-2'-(pyridin-4-ylmethyl)-8'-(trifluoromethyl)-2',5'-dihydrospiro[cyclobutane-1,4'-furo[2,3-g]indazole]-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-oxobutanol)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-oxobutanol)piperidin-4-yl]methyl}-8-(trifluoromethyl)-4,5-dihydro-2H-furo[2,3-g]indazole-7-carboxamide (4R)-4-methyl-2-{[1-(2-oxobutanol)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-oxobutanol)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, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof.

6. 2. The compound of claim 1, which is 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, or a stereoisomer, tautomer, hydrate, or salt thereof, or a mixture thereof.

7. General formula (II): 【Chemistry 15】 wherein R is H, OH, OMe or OEt, and R １ , R ２ , R ３ , R ４ , R ７ａ , and R ７ｂ is as defined for the compounds of general formula (I) according to any one of claims 1 to 4, 【Chemistry 16】 wherein R ５ and R ６ is as defined for the compounds of general formula (I) according to any one of claims 1 to 4, Thereby, the general formula (I): 【Chemistry 17】 wherein R １ , R ２ , R ３ , R ５ , R ６ , R ７ａ , and R ７ｂ is as defined for compounds of general formula (I) according to any one of claims 1 to 4.

8. General formula (II): [Chemistry 18] wherein R is H, OH, OMe or OEt, and R １ , R ２ , R ３ , R ４ , R ７ａ , and R ７ｂ is as defined for the compounds of general formula (I) according to any one of claims 1 to 4.

9. General formula (II): 【Chemistry 19】 wherein R is H, OH, OMe or OEt, and R １ , R ２ , R ３ , R ４ , R ７ａ , and R ７ｂ is as defined for compounds of general formula (I) according to any one of claims 1 to 4, for the preparation of compounds of general formula (I) according to any one of claims 1 to 5.

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