IRAK4 inhibitors

Abstract

To provide compounds that inhibit IRAK4 and consequently have potential utility in medicine.SOLUTION: The present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Specifically, for example, 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridine-3-yl)-2-((1r,4r)-4-(N-methylacetamide)cyclohexyl)-2H-indazole-5-carboxamide is illustrated.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to chemical compounds and their pharma- ceutical acceptable salts that inhibit IRAK4 and may be useful as pharmaceuticals.The present disclosure also relates to the use of these IRAK4 inhibitors in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), cancer, inflammatory diseases and autoinflammatory / autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjogren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis and psoriasis.The present disclosure also relates to the process and intermediate compounds involved in the preparation of the IRAK4 inhibitors and pharmaceutical compositions containing them. [Background technology]

[0002] Interleukin-1 receptor (IL-1R)-associated kinase 4 (IRAK4) is a key regulator of immune signaling. IRAK4 is expressed by multiple cell types and mediates signaling from Toll-like receptors (TLRs) and the interleukin-1 (IL-1) family of receptors, including IL-1R, IL-18R, and the IL-33 receptor ST2. TLRs recognize and respond to microbial-derived ligands such as lipopolysaccharide (LPS) or microbial RNA or DNA, whereas IL-1 family receptors are activated by endogenous ligands produced by TLR-activated cells (IL-1β and IL-18) or tissue injury (IL-1α and IL-33). Upon ligand activation of TLRs or IL-1 receptors, the adaptor protein myeloid differentiation primary response 88 (MyD88) is recruited to the receptor and forms a multimeric protein complex, termed the "myddosome," with proteins from the IRAK family (IRAK1, IRAK2, and IRAK4). The mydosome serves as a signaling platform that induces the nuclear factor kappa B (NF-kappa B) and mitogen-activated protein kinase (MAPK) signaling pathways, ultimately activating the transcription factors NF-kappa B, activator protein 1 (AP1), c-AMP response element binding protein (CREB) and interferon regulatory factor 5 (IRF5), inducing the transcription of inflammatory cytokines and chemokines. Mice lacking IRAK4 are viable but lack inflammatory cytokine responses to IL-1β, IL-18 and LPS. Humans with loss-of-function mutations in IRAK4 display an immunodeficient phenotype, with immune cells exhibiting abrogated cytokine responses to TLR agonists and IL-1 receptor ligands.

[0003] IRAK4 is characterized by an N-terminal death domain that mediates interaction of the central kinase domain with MyD88. Mymidosome formation promotes IRAK4 autophosphorylation, which regulates mymidosome stability and downstream signaling. The kinase activity of IRAK4 is required for cytokine induction by TLRs and IL-1R, as shown by studies in knock-in mice expressing kinase-dead IRAK4 and using small molecule IRAK4 kinase inhibitors.

[0004] Given its important role in eliciting inflammatory responses, IRAK4 constitutes a target for drugs that exert anti-inflammatory effects.

[0005] Asthma and COPD (chronic obstructive pulmonary disease) are chronic lung diseases that constitute a large unmet medical need worldwide. Asthma and COPD are characterized by chronic airway inflammation involving aberrant cytokine release, dysregulated immune cell activation and airway remodeling. In asthma, airway insults such as allergenic, viral and bacterial insults activate TLR receptors via pathogen-associated molecular patterns (PAMPs) and IL-1R and ST2 receptors via alarmin release including IL-33 and IL-1α and by IL-1β released by inflammasome activation. TLR and IL-1 family receptors are present on multiple cell types in the airways including macrophages, dendritic cells, mast cells, monocytes and epithelial cells and respond to ligands by releasing inflammatory cytokines (TNF-α, IL-6, IL-8, GM-CSF, IL-5), leading to airway inflammation, recruitment of inflammatory cells such as neutrophils and eosinophils, airway hyperresponsiveness and mucus production. IRAK4 inhibition has the potential to suppress these inflammatory pathways in the airways. Gene expression analysis of lung samples from asthma and COPD patients has confirmed upregulation of expression of genes associated with the IL-1R and TLR2 / 4 inflammatory pathways in a subset of severely ill patients. Although IRAK4 inhibitors have not, to our knowledge, been explored in the clinic for the treatment of respiratory disease, preclinical data from several research groups indicate that disruption of IRAK4-regulated pathways attenuates airway inflammation in animal models of both asthma and COPD. For example, mice lacking MyD88, a central component of the mydosome, are protected from allergen- or IL-33-induced airway inflammation, as are mice treated with a small molecule mimic that blocks the interaction between IRAK2 and IRAK4. Blockade of IL-1β with monoclonal antibodies has also been found to suppress allergen- and bacteria-induced airway inflammation in a steroid-resistant mouse model of asthma. Furthermore, treatment of mice with the IL-1R antagonist anakinra upon allergen challenge reduces asthma-like symptoms in a mouse model of allergic asthma.Chronic exposure to tobacco smoke is a major contributing factor in the development of COPD.In cigarette smoke-exposed mice, IL-1 signaling is central in mediating neutrophilic airway inflammation, and blockade of IL-1 signaling with antibodies against IL-1α, IL-1β, or IL-1R can attenuate neutrophilic inflammation in the lungs and reduce bacterial- or viral-induced exacerbations in cigarette smoke-exposed mice. Collectively, IRAK4 inhibition may provide broad anti-inflammatory effects in inflammatory respiratory diseases by simultaneously blocking several disease-related signaling pathways.

[0006] As a central regulator of the myosinosome, IRAK4 is also a promising therapeutic target for other inflammatory diseases driven by IL-1R, TLR or ST2-mediated mechanisms. As previously disclosed, IRAK4 plays a role in autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus (SLE) (see, for example, WO2017207386 and WO2015150995). In SLE, immune complexes consisting of autoantibodies and autoantigens can drive TLR-dependent pathological signaling. In SLE pathogenesis, IRAK4 inhibition has been reported to block the release of type I interferon and proinflammatory cytokines mediated by TLR7 and TLR9 activation in plasmacytoid dendritic cells. Mice expressing kinase-deactivated mutants of IRAK4 or treated with IRAK4 kinase inhibitor compounds are resistant to experimentally induced arthritis and lupus (see, for example, WO2017207386). The approved use of anakinra (an IL-1 receptor antagonist) for the treatment of rheumatoid arthritis also supports the role of pathogenic IL-1R signaling in this disease. In Sjögren's syndrome, TLRs are upregulated in PBMCs (peripheral blood mononuclear cells) and salivary glands, and TLR activation can stimulate the release of interferon and other inflammatory cytokines, suggesting an involvement in Sjögren's pathogenesis. MyD88 knockout mice also show reduced disease manifestation in an experimental mouse model of Sjögren's syndrome. Systemic sclerosis is a severe autoimmune disorder in which IL-1R, TLR4, TLR8 and ST2-signaling may drive pathogenic mechanisms including microvascular injury and fibrosis. IRAK4 inhibition as a treatment for systemic sclerosis may therefore simultaneously block multiple disease-related pathways. In myositis, elevated levels of IL-1α and IL-1β may contribute to muscle tissue inflammation. Myositis patients are also characterized by a high type I interferon gene signature that may be driven in part by TLR7 / 9 activation, and the relevance of IL-1R signaling was also supported by the improved clinical outcomes of myositis patients treated with anakinra in a small mechanistic clinical trial. As a central regulator of the IL-1R pathway, IRAK4 is also a promising target for the treatment of gout.Sodium urate crystals, characteristically formed in gout sufferers, can trigger inflammasome activation and IL-1β release. The use of both anti-IL-1β monoclonal antibodies, canakinumab or anakinra, has shown clinical efficacy in treating gout attacks. Elevated levels of IL-1β and IL-33 have also been found in endometriosis patients. The importance of IRAK4 in the disease process of endometriosis was shown in a mouse model in which oral administration of an IRAK4 inhibitor suppressed lesion formation. MyD88 knockout mice were also protected against the development of endometriosis in the same mouse model. IL-33 / ST2 signaling is a key mechanism in atopic dermatitis and is involved in the control of skin inflammation, epithelial barrier integrity, and eosinophil recruitment. IL-33 triggers eczema and dermatitis in mice in a MyD88-dependent manner. As a regulator of ST2 signaling and a central component of the mydosome, IRAK4 inhibition has the potential to inhibit pathogenic IL-33 / ST2 signaling in atopic dermatitis. Both TLR7 and IL-1R-mediated mechanisms have been suggested to be involved in psoriasis. Imiquimod, a TLR / 8 agonist, can induce psoriasis-like disease in mice in a MyD88-dependent manner. IL-1β is upregulated in psoriatic skin lesions, and the IL-1β / IL-1R axis has been suggested to contribute to skin inflammation and control the production of IL-17, a key cytokine released by T17 cells in psoriasis pathogenesis. IRAK4 kinase activity has further been shown to be required for T17 differentiation and control of T17-mediated disease in vivo.

[0007] Several IRAK4 kinase inhibitors are known and being developed, mainly for use in tumors or inflammatory diseases (see, for example, WO2015150995, WO2017207386, WO2017009806, WO2016174183, WO2018234342, WO2020263967, WO2020263980). Among the known IRAK4 kinase inhibitors, PF-06650833 has recently completed a Phase II clinical trial for the treatment of rheumatoid arthritis (see clinicaltrials.gov entry NCT02996500). Summary of the Invention [Problem to be solved by the invention]

[0008] In summary, IRAK4 inhibitors have potential for the treatment of several diseases and conditions, even though to date such inhibitors have not been approved for clinical use. It is an object of the present disclosure to provide novel IRAK4 inhibitors with physicochemical and selectivity profiles that make them suitable for clinical use in the treatment of inflammatory diseases associated with IRAK4-mediated pathway activation, such as cancer, asthma, COPD, and chronic autoimmune / autoinflammatory diseases.

[0009] In a first aspect, the present disclosure provides a compound of formula (I): [ka] [During the ceremony, R 1 i) H, Me, Et, Pr, i-Pr, cyclopropyl, CH 2 CN, CH 2 F and oxetane or ii) in each case optionally Me, F, Cl, CN, OMe and C 1 -C 3 C substituted with one or more substituents selected from alkyl 1 -C 6 Alkyl group, C 3 -C 6 selected from a cycloalkyl group or a 5-membered N-heterocycle; R 2 is selected from H, F, Cl, D and Me; R 3 and R 4 each independently represents H, Me, Et, F, Cl, optionally substituted C 1 -C 3 Alkyl and C 1 -C 3 haloalkyl; Y is N(Me)COMe, N(R 5 )COMe, N(Me)COR 6, N(Me)COCH(OH)Me, N(Me)COCH(OR 5 )R 6 , N(R 5 )COR 6 , CONMe 2 ,CONR 5 R 6 , 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole, 2-pyrrolidinone, 2-imidazolidinone, imidazole or pyrazole, or a 6-membered N-heterocycle such as 1-pyridone or pyridazine, in which the 5- or 6-membered N-heterocycle can optionally be replaced by a group R 5 or C to group R 6 and Z is H, Me, Et or an optionally substituted C 1 -C 6 is alkyl; or Y and Z together form an optionally substituted 4-, 5-, or 6-membered ring; X is OR 7 and N.R. 8 R 9 Selected from; R 5 is H, Me, optionally substituted C 1 -C 6 Alkyl and optionally substituted C 3 -C 6 cycloalkyl; R 6 is Me, optionally substituted C 1 -C 6 Alkyl and optionally substituted C 3 -C 6 cycloalkyl; R 7 is Me, Et, i-propyl, n-propyl, cyclopropyl, cyclobutyl, optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, -CH 2 (C 3 -C 6cycloalkyl) or a 4-, 5- or 6-membered ring containing one heteroatom selected from O and N; R 8 and R 9 are independently H, Me and optionally substituted C 1 -C 6 alkyl, or together optionally substituted C 3 -C 6 forming an optionally substituted 4-, 5- or 6-membered ring containing cycloalkyl or one further heteroatom selected from O and N; Here, Z, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 The optional substituents, when present, are OH, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C(O)Me, amino, NHMe, NMe 2 , F or Cl. or a pharma- ceutically acceptable salt thereof.

[0010] This specification also describes a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient.

[0011] This specification also describes a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for use as a pharmaceutical.

[0012] This specification also describes a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment of respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD).

[0013] This specification also describes a compound of formula (I), or a pharma- ceutically acceptable salt thereof, for use in the treatment of inflammatory diseases.

[0014] The present specification also describes a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment of autoinflammatory / autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjogren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis and psoriasis.

[0015] This specification also describes a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment of cancer, e.g., for use in combination with a BTK inhibitor.

[0016] The present specification also describes the compound of formula (I) or its pharmacologic acceptable salt for use in the treatment of cancer.In such use, for example, for the treatment of hematological malignancies, the compound of formula (I) is used as a monotherapy or in combination with additional therapeutic agents.The hematological malignancies to be treated can be selected from Waldenstrom's macroglobulinemia (WM), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), primary central nervous system lymphoma (PCNSL), splenic marginal zone lymphoma (SMZL), small lymphocytic lymphoma (SLL), leukemia (chronic lymphocytic leukemia (CLL)) and monoclonal gammopathy of undetermined significance (MGUS-IgM+).Furthermore, the use can be for the treatment of hematological malignancies with MYD88 mutation, B-cell receptor (BCR) mutation, or both MYD88 and BCR mutation. When the compound is used in combination with a further therapeutic agent, the second agent may be selected from the group consisting of BCR inhibitors, such as BTK inhibitors (examples include ibrutinib, acalabrutinib, zanubrutinib or tirabrutinib), PI3Kδ inhibitors and SYK inhibitors or immunotherapy.

[0017] The present specification also describes the use of a compound of formula (I) in the manufacture of a medicament, for example where the medicament is for use in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), or for use in the treatment of cancer, or for use in the treatment of autoinflammatory / autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjogren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis and psoriasis, or for use in the treatment of an inflammatory disease.

[0018] Also described herein is a method of treatment comprising the administration of an effective amount of a compound of formula (I) to a patient in need thereof, wherein the patient in need thereof has a respiratory disease such as asthma and chronic obstructive pulmonary disease (COPD), cancer, systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjogren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis and psoriasis, or an autoinflammatory / autoimmune disease or an inflammatory disease.

[0019] The present disclosure also relates to methods for making the compounds of formula (I).

[0020] Further aspects of the present disclosure will be apparent to those skilled in the art from reading this specification.

[0021] As mentioned above, it has been found that the compound of formula (I) or its pharma-ceutically acceptable salt is a potent inhibitor of IRAK4 kinase.In addition, the preferred compound of formula (I) has excellent selectivity over other kinases and provides a profile that avoids off-target effects and toxicity.This desirable combination of IRAK4 inhibitory activity and lack of harmful off-target effects indicates the suitability of the compounds of the present disclosure for use as medicines.

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press provide those skilled in the art with a general dictionary of many of the terms used in this disclosure.

[0023] In order that the present disclosure may be more readily understood, certain terms are expressly defined below. Further definitions will be provided throughout the detailed description, as appropriate.

[0024] Units, prefixes and symbols are in their International System of Units (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range.

[0025] The term "pharmaceutical composition" refers to a formulation that is in such a form that allows the biological activity of active ingredient and does not contain additional ingredients that are unacceptably toxic to the subject to which the composition is administered.Such compositions can be sterile.The pharmaceutical composition of the present disclosure comprises a compound of formula (I) or its pharmaceutical acceptable salt and at least one pharmaceutical acceptable additive.

[0026] The terms "treat" or "treatment" or "to treat" or "alleviate" or "to alleviate" and the like refer to both (1) therapeutic measures that cure, slow, reduce symptoms and / or halt progression of a diagnosed condition or disorder, and (2) prophylactic or preventative measures that prevent and / or delay the onset of the targeted condition or disorder. Thus, those in need of treatment include those already with the disorder; those susceptible to having or developing the disorder; and those in whom the disorder is to be prevented. In some embodiments, a subject is sufficiently "treated" for a respiratory disorder by the methods of the present disclosure if the patient exhibits, e.g., a complete, partial or transient alleviation of the symptoms of the respiratory disorder.

[0027] The term "subject" refers to any animal (e.g., mammal), including but not limited to humans, non-human primates, rodents, etc., that is the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to human subjects.

[0028] Symbols used here * is used to indicate the site of attachment of one component of a compound of formula (I) to another component of the compound.

[0029] The term "alkyl" as used herein refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms. The term deuteroalkyl as used herein refers to an alkyl group in which one or more, optionally all, hydrogens have been replaced with deuterium atoms. The term cycloalkyl as used herein refers to a saturated cyclic hydrocarbon. The term haloalkyl as used herein refers to an alkyl group in which one or more, optionally all, hydrogens have been replaced with halogen atoms, where for example, the halogen atoms are fluorine or chlorine atoms. An embodiment of a haloalkyl group is CF 3 , C.F. 2 CF 3 Fully fluorinated ones such as CH 2 F, C.H. 2 Cl, CF 2 CH 3 , C.H. 2 CF 3 , C.H. 2 CH2 F and CH 2 CH 2 These include those having fluorine or chlorine replacing one or more hydrogens attached to the same carbon atom of an alkyl group, such as Cl.

[0030] In this specification, C x -C y The prefix "C" used in terms such as alkyl x -C y " (where x and y are integers) indicates the range of carbon atoms present in the group. For example, C 1 -C 4 Alkyl includes methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl and t-butyl, while C 1 -C 3 Examples of alkyl groups include methyl, ethyl, n-propyl and i-propyl. 1 -C 4 Alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy. 1 -C 3 Examples of alkoxy groups include methoxy, ethoxy, n-propoxy and i-propoxy.

[0031] Unless otherwise specified, the bond to an atom or group may be to any suitable atom of the group; for example, propyl includes prop-1-yl and prop-2-yl.

[0032] As used herein, the term "cycloalkyl" refers to a cyclic saturated hydrocarbon radical having the specified number of carbon atoms. 3 -C 6 Cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

[0033] The term "alkoxy" as used herein refers to a group with an oxygen atom attached to an alkyl chain, where the alkyl chain is a straight and branched chain saturated hydrocarbon radical having the specified number of carbon atoms, as defined above. 1 -C3 Alkoxy is methoxy, ethoxy, O n Pr and O i This refers to the Pr group.

[0034] The group R 1 is optionally Me, F, Cl, CN, OMe and C 1 -C 3 In some embodiments, the 5-membered N-heterocycle may be an aromatic heterocycle containing 1, 2 or 3 ring nitrogens, such as pyrrole, imidazole, pyrazole, 1,2,3-triazole or 1,2,4-triazole. In some embodiments, the ring nitrogen of the 5-membered N-heterocycle may be C 1 -C 3 It is substituted with an alkyl group, for example a methyl group.

[0035] As described herein and above, the cyclohexyl group is represented by the group R 4 In such cases, the group R 4 may be attached to any available ring carbon. In certain embodiments, R 4 is attached to the carbon atom adjacent to the carbon atom attached to the indazole ring, as shown below. [ka]

[0036] The term "acetyl" as used herein and above refers to a group of formula -C(O)Me. The description of an N-acylated group herein refers to a small alkyl side chain, i.e., an optionally substituted C(O)Me. 1 -C 6 Alkyl side chain or optionally substituted C 3 -C 6 In each case, the optional substituents are OH, C 1 -C 3 Alkoxy, C(O)Me, amino, NHMe, NMe 2, F or Cl. In certain embodiments, the N-acylation group is an N-acetyl group, i.e., the group -NRC(O)Me.

[0037] As described herein and above, the compounds of formula (I) contain a cyclohexyl ring substituted with two groups Y and Z which together may form a 4-, 5- or 6-membered ring. In such cases, the 4-, 5- or 6-membered ring is a saturated hydrocarbon ring system in which one or two ring carbons are optionally replaced with a heteroatom selected from O and N. When two ring carbons are replaced with heteroatoms, the heteroatoms are not directly bonded, i.e., the heteroatoms replace non-adjacent ring carbons or are not bonded within the ring as CH. 2 The hydrocarbon rings are not separated by groups, but are linked, for example, by a carbonyl group, resulting in, for example, a carbonate or carbamate motif. The hydrocarbon rings may incorporate a carbonyl group, such as when Y and Z together form a cyclic amide. In some embodiments, the 4-, 5- or 6-membered ring is a cyclic amide or carbamate, such as pyrrolidin-2-one, oxazolidin-2-one, piperidin-2-one, and 1,3-oxazinan-2-one. Alternatively, the groups Y and Z may together form an azetidine substituted at the nitrogen by an acyl group. Additionally, the 4-, 5- or 6-membered ring may be joined by OH, C, or OH groups. 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C(O)Me, amino, NHMe, NMe 2 , F or Cl. These optional substituents may be advantageously used to adjust the physicochemical properties of the molecule, such as solubility, or to further optimize the interaction with IRAK4 kinase, e.g., versus other kinases, thus resulting in more potent and selective IRAK4 kinase inhibitors.

[0038] As described herein, the compounds of formula (I) include N(Me)COMe, N(R 5 )COMe, N(Me)COR 6 , N(Me)COCH(OH)Me, N(Me)COCH(OR5 )R 6 , N(R 5 )COR 6 , CONMe 2 ,CONR 5 R 6 , 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole, 2-pyrrolidinone, 2-imidazolidinone, 5-membered N-heterocycle such as imidazole or pyrazole or 6-membered N-heterocycle such as 1-pyridone or pyridazine, wherein the 5- or 6-membered N-heterocycle may optionally be replaced by a group R 5 or C to group R 6 In such cases, the group Z is H, Me, Et or an optionally substituted C 1 -C 6 Other 5- and 6-membered N-heterocycles include pyrrole, pyridine, pyrimidine and pyrazine. When the group Y is an optionally substituted 5- or 6-membered N-heterocycle, embodiments include one R 5 group and / or one R 6 group is present and the group R 5 or R 6 is methyl, C 1 -C 3 Alkyl, C 1 -C 3 -Hydroxylalkyl, -CH(OH)Me 2 , -C(OH)Me 2 or -CH 2 In one embodiment, R 5 and R 6 The group is methyl, C 1 -C 3 Alkyl, C 1 -C 3 Hydroxyl alkyl, -CH(OH)Me 2 , -C(OH)Me 2 and -CH 2 CH(OH)Me. For example, Y is N(Me)COR 6 When R 6 can be CH(OH)Me as shown below. [ka]

[0039] As described herein and above, the group R 7 can be an optionally substituted 4-, 5- or 6-membered ring containing one heteroatom selected from O and N. For the avoidance of doubt, "containing one heteroatom" means that one of the atoms of the ring is a heteroatom selected from O or N. In certain embodiments, the 4-, 5- or 6-membered ring containing one heteroatom selected from O and N is saturated. In certain embodiments, the 4-, 5- or 6-membered ring containing one heteroatom selected from O and N is selected from azetidine, oxetane, tetrahydrofuran, pyrrolidine, tetrahydropyran and piperidine. As described herein and above, the substituent R 8 and R 9 may be joined together to form a 4-, 5-, or 6-membered ring containing one further heteroatom, which is optionally substituted. When one further heteroatom is present, the heteroatom is not directly bonded to the N, i.e., the heteroatoms in the ring are not adjacent or are not bonded to a CH 2 are not separated by groups. In certain embodiments, the resulting ring is saturated, for example the resulting ring can be a morpholine or piperazine ring.

[0040] As will be appreciated by those skilled in the art, the compounds of formula (I) and in particular R 4The substituted cyclohexyl groups, such as Y and Z, can exist in various stereochemical forms. It is understood that the claims encompass all stereochemical forms of the compounds of formula (I), although the compounds with the highest activity as IRAK4 inhibitors are preferred. It is recognized that the compounds of formula (I) can be produced, isolated and / or provided with or without one or more of the other possible stereoisomeric forms of the compounds of formula (I) present in any ratio. The production of stereoenriched or stereopure compounds can be carried out by standard techniques of organic chemistry well known in the art, such as by synthesis from stereoenriched or stereopure starting materials, by the use of suitable stereoenriched or stereopure catalysts during synthesis, and / or by resolution of racemic or partially enriched mixtures of stereoisomers, such as by chiral chromatography. For example, the compounds of the present disclosure can be provided as mixtures in which >90%, >95% or >99% of the compounds are present as single enantiomers or diastereomers.

[0041] As described herein and above, certain components of the compounds of formula (I) are optionally substituted. As used herein, the term optionally substituted means that the components of the compounds may be substituted or unsubstituted with one or more of the specified optional substituents. The optional substituents are the groups Z, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 When one or more of the optional substituents R are present, 0, 1, 2 or 3 substituents are present on each substituted group, for example, 0 or 1 substituent is present. When two hydroxyl substituents are present, it is understood that the two hydroxyl groups are not attached to the same carbon atom. When the optional substituent is F, 1, 2 or 3 F substituents can be present, and further, when two or three F substituents are present, they are generally attached directly to the same carbon atom. The group R 1 C 1 -C 3In some embodiments substituted with alkyl groups, one substituent, for example, a methyl group, may be present. These optional substituents may be used to adjust the physicochemical properties of the molecule, such as solubility, adjust metabolism, or further optimize the interaction with IRAK4 kinase, for example, against other kinases, thus resulting in more potent and selective IRAK4 kinase inhibitors. 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 The optional substituents of are OH, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C(O)Me, amino, NHMe and NMe 2 In certain embodiments selected from the group consisting of, there are zero or one independently selected substituents per group (i.e., zero or one OH, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C(O)Me, amino, NHMe and NMe 2 The substituents independently selected from Z, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 or R 9 (Z, R may be present in each of the groups. 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 In certain embodiments where the optional substituents of Z, R are independently selected from F or Cl, there may be 0, 1, 2 or 3 independently selected substituents per group (i.e., 0, 1, 2 or 3 independently selected substituents of F or Cl are present in Z, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R9 In one embodiment, the groups Z, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is unsubstituted in each occurrence.

[0042] As noted above, in a first embodiment, the present disclosure provides a compound of formula (I): [ka] [During the ceremony, R 1 i) H, Me, Et, Pr, i-Pr, cyclopropyl, CH 2 CN, CH 2 F and oxetane or ii) in each case optionally Me, F, Cl, CN, OMe and C 1 -C 3 C substituted with one or more substituents selected from alkyl 1 -C 6 Alkyl group, C 3 -C 6 selected from a cycloalkyl group or a 5-membered N-heterocycle; R 2 is selected from H, F, Cl, D and Me; R 3 and R 4 each independently represents H, Me, Et, F, Cl, optionally substituted C 1 -C 3 Alkyl and C 1 -C 3 haloalkyl; Y is N(Me)COMe, N(R 5 )COMe, N(Me)COR 6 , N(Me)COCH(OH)Me, N(Me)COCH(OR 5 )R 6 , N(R 5 )COR 6 , CONMe 2 ,CONR 5 R 6, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole, 2-pyrrolidinone, 2-imidazolidinone, imidazole or pyrazole, or a 6-membered N-heterocycle such as 1-pyridone or pyridazine, in which the 5- or 6-membered N-heterocycle can optionally be replaced by a group R 5 or C to group R 6 and Z is H, Me, Et or an optionally substituted C 1 -C 6 is alkyl; or Y and Z together form an optionally substituted 4-, 5-, or 6-membered ring; X is OR 7 and N.R. 8 R 9 Selected from; R 5 is H, Me, optionally substituted C 1 -C 6 Alkyl and optionally substituted C 3 -C 6 cycloalkyl; R 6 is Me, optionally substituted C 1 -C 6 Alkyl and optionally substituted C 3 -C 6 cycloalkyl; R 7 is Me, Et, i-propyl, n-propyl, cyclopropyl, cyclobutyl, optionally substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, -CH 2 (C 3 -C 6 cycloalkyl) or a 4-, 5- or 6-membered ring containing one heteroatom selected from O and N; R 8 and R 9 are independently H, Me and optionally substituted C 1 -C 6alkyl, or together optionally substituted C 3 -C 6 forming an optionally substituted 4-, 5- or 6-membered ring containing cycloalkyl or one further heteroatom selected from O and N; Here, Z, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 The optional substituents, when present, are OH, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C(O)Me, amino, NHMe, NMe 2 , F or Cl. or a pharma- ceutically acceptable salt thereof.

[0043] In certain embodiments, the compound of formula (I) comprises a group R 1 but [ka] is a compound of formula (Ia) selected from:

[0044] For clarity, the symbol used here is " * " indicates the atom from which the group is attached via a single bond to the remainder of the molecule, in this case the nitrogen atom of the pyridone.

[0045] In certain embodiments, the compound of formula (I) comprises a group R 1 is selected from methyl, fluoromethyl and cyanomethyl.

[0046] In certain embodiments, the compound of formula (I) comprises a group R 1 is cyclopropyl. [ka]

[0047] In certain embodiments, the compounds of Formula (I), (Ia), (Ib), (Ic) may further comprise a group R 2 is H. [ka]

[0048] In certain embodiments, the compound of Formula (I), (Ia), (Ib), (Ic) or (Id) is 7 is a compound of formula (Ie), [ka]

[0049] In certain embodiments, the compound of Formula (Ie) is R 7 is Me. [ka]

[0050] In certain embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) comprises a group R 3 is H.

[0051] In certain embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig) is R 4 is methyl.

[0052] In certain embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig) is R 4 is H.

[0053] In certain embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) is a compound wherein Y is N(Me)COMe, N(R 5 )COMe, N(Me)COR 6 , N(Me)COCH(OH)Me, N(Me)COCH(OR 5 )R 6 , N(R 5 )COR 6 , CONMe 2 ,CONR 5 R 6 , 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole, 2-pyrrolidinone, 2-imidazolidinone, imidazole or pyrazole, or a 6-membered N-heterocycle such as 1-pyridone or pyridazine, and Z is H, Me, Et or an optionally substituted C 1 -C 6 The compound of formula (Ij) is

[0054] In certain embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) is a compound wherein Y is N(Me)COMe, N(R 5 )COMe, N(Me)COR 6 , N(Me)COCH(OH)Me, N(Me)COCH(OR 5 )R 6 , N(R 5 )COR 6 , CONMe 2 ,CONR 5 R 6 , 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole, 2-pyrrolidinone, 2-imidazolidinone, 5-membered N-heterocycles such as imidazole or pyrazole or 6-membered N-heterocycles such as 1-pyridone or pyridazine, and Z is H.

[0055] In certain embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) is a compound wherein Y is N(Me)COMe, N(Me)COCH(OH)Me, CONMe 2 or optionally N is replaced by a group R 5 or C to group R 6 and Z is H.

[0056] In certain embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) is a compound wherein Y optionally replaces N with a group R 5 or C to group R 6 has been replaced with [ka] and Z is H.

[0057] In certain embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) is a compound of Formula (In), wherein Y and Z together form an optionally substituted 4-, 5- or 6-membered ring.

[0058] In certain embodiments, the compound of formula (In) is an oxazolidinone, wherein Y and Z together with the carbon atom to which they are attached form an oxazolidinone, e.g., N-methyloxazolidinone, [ka] where the carbon atom to which Y and Z are attached is designated by the symbol α.

[0059] In certain embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) is [ka] is a compound of formula (Io),

[0060] In certain embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) is [ka] and Z is H.

[0061] In certain embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih) or (Ii) is [ka] and Z is H.

[0062] In certain embodiments, the compound of Formula (I) is selected from: 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide; 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide; 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2S,4R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide; 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1S,2R,4S)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide; rel-6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2S,4S)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; N-(1-(fluoromethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxamide; N-(1-(cyanomethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxamide; N-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1S,4r)-4-((S)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxamide; N-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-(oxetan-3-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(2-oxo-1-(1H-pyrazol-4-yl)-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-(1-methyl-1H-1,2,3-triazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-(2-methyl-2H-1,2,3-triazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(2-oxopyrrolidin-1-yl)cyclohexyl)-2H-indazole-5-carboxamide; 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(3-methyl-2-oxoimidazolidin-1-yl)cyclohexyl)-2H-indazole-5-carboxamide; 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((5s,8s)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide; 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((5r,8r)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide; 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(2-oxopyridin-1(2H)-yl)cyclohexyl)-2H-indazole-5-carboxamide; 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-(4-(pyridazin-3-yl)cyclohexyl)-2H-indazole-5-carboxamide; 2-((1r,4r)-4-(1,3,4-oxadiazol-2-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; 2-((1r,4r)-4-(1H-1,2,4-triazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; 2-((1r,4r)-4-(1H-1,2,3-triazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; 2-((1r,4r)-4-(2-(1-hydroxyethyl)-1H-imidazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide and 2-((1r,4r)-4-(4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; or a pharma- ceutically acceptable salt thereof.

[0063] The IRAK4 inhibitors of the present disclosure can be prepared from readily available starting materials, which can be obtained from commercial suppliers such as Merck KGaA, or by methods within the general knowledge of those skilled in the art. The following reaction schemes describe various methods for the synthesis of IRAK4 inhibitors. Although typical or preferred reaction conditions are shown for the synthesis, those skilled in the art can envision modifications of these conditions to obtain analogs not described herein. The following schemes are therefore representative synthetic methods for the compounds of the present disclosure, and should not be construed as limiting the scope of the present disclosure in any way. Furthermore, the order of reactions can be modified to change the overall synthesis to allow for diversity at various positions of the molecule, at various stages of the synthesis.

[0064] Those skilled in the art will recognize that the compounds in the schemes below may, in some cases, be obtained as mixtures of regioisomers and stereoisomers, which may be separated at various stages of the synthesis using techniques such as silica / C18 chromatography, HPLC, SFC, crystallization, etc., well known to those skilled in the art.

[0065] General synthetic approach to compounds of formula (I): Scheme 1: A group R a General synthesis of building block I-2, which is a parallel structure of 4 , Y and Z are as defined for compounds of formula (I) or suitably protected precursors thereof. [ka]

[0066] Scheme 1 describes the regioselective synthesis of N-2 indazole building blocks I-2. From the commercially available starting material I-1, amine R a -NH 2 Treatment with 1,2-dichlorophenyl ether at elevated temperature in an appropriate solvent (eg, i-PrOH) followed by addition of tri-n-butylphosphine results in the formation of I-2.

[0067] When the target molecule contains a functional group that is sensitive or incompatible with the condensation reaction conditions, reagent R a -NH 2 may comprise a suitably protected precursor of a component of, for example, group Y, of the final target compound that can be unmasked at a later stage of the synthesis. For example, if the group Y of the final product comprises an amine or amide, the reaction shown in Scheme 1 may be carried out using a reagent R a -NH 2 and the protecting group can be cleaved after the indazole core of I-2 is constructed. The amine can then be appropriately alkylated or converted to an amide. Similarly, when the group Y of the target molecule contains an alcohol functionality, the precursor R a -NH 2 The corresponding functional group of may be protected with a suitable alcohol protecting group that can withstand the reaction conditions of the reaction shown in Scheme 1 and be cleaved at a later stage in the synthesis of the target compound. Protecting groups are well known in the art (see, for example, Greene's Protective Groups in Organic Synthesis, Ed PGM Wuts, Wiley, NY 2014, 5 th (See Edition). Alternatively, use Reagent R a -NH 2 may contain precursors of amine / amide / alcohol functionalities in the form of suitable protected carbonyl functionalities, which can be deprotected at a later stage of the synthesis by synthetic methods known to those skilled in the art and converted to the desired amine / amide / alcohol functionalities in the target compound.

[0068] General synthesis of compounds of formula (I): Scheme 2: General synthesis of compounds of formula (I), Method 1: [ka]

[0069] The preparation of compounds of formula (I) is shown in Scheme 2. A suitable starting material for this route is the indazole I-2 (wherein R 4, Y and Z are as defined in relation to the compound of formula (I) or suitably protected precursors thereof. Bromide I-2 can be obtained as described in Scheme 1, first by the reaction of Pd-catalyst (e.g. Pd(dppf)Cl) under CO atmosphere (at high pressure) in the presence of alcohol as solvent. 2 ) to give the ester II-2 (if MeOH is used as the solvent, Me-ester II-2 is formed). Subsequent cleavage of the ester with, for example, lithium hydroxide or potassium hydroxide in a suitable solvent (e.g., water) gives the carboxylic acid II-3. The reaction of this acid II-3 with the amine R b -NH 2 (R 1 Amide formation from the reaction of (is defined herein) can be carried out with a variety of amide coupling agents (e.g., HATU, T3P) to give the desired compounds of formula (I).

[0070] The conversion of bromide I-2 to compounds of formula (I) can also be accomplished by a one-pot aminocarbonylation protocol. 2 ) and a suitable ligand (e.g., 1,3-bis(diphenylphosphino)propane or di(adamantan-1-yl)butylphosphane) in a solvent (e.g., MeCN) with a base (e.g., TEA) and an amine R b -NH 2 Coupling under CO atmosphere (at high pressure) gives the compound of formula (I) in one step.

[0071] The series of reactions shown in Scheme 2 are a When starting from compound I-2 containing a protecting group, R a R in 4 , Y and / or Z are each optionally substituted with a suitable protected precursor of R as defined for the functional groups of the compound of formula (I). 4 , Y and Z (illustrated under Scheme 1) can be carried out at various stages in the synthetic sequence shown in Scheme 2, depending on the nature of the transformation and the compatibility of the functional groups present in the intermediate sequence with the reaction conditions (the order of steps can be determined by one skilled in the art).

[0072] Scheme 3: R c = Y and Y and R 1 General synthesis of compounds of formula (I), method 2: [ka]

[0073] Scheme 3 shows the synthesis of compound III-1 (R 1 is as defined above for compounds of formula (I) and L is a leaving group suitable for nucleophilic substitution reactions such as mesylate / tosylate) with R c An example of a method for converting a compound of formula (I) to a compound of formula (I) by nucleophilic substitution reaction with R c is, for example, an azide or a triazole. The starting material III-1 can be obtained by the method shown in Scheme 2. The method shown in Scheme 3 leads to compounds of formula (I) directly or precursors that can be converted to compounds of formula (I) by functional group interconversion (the skilled artisan can determine the necessary steps).

[0074] In certain embodiments of the disclosure, there are provided methods for the synthesis of compounds of formula (I) or pharma- ceutically acceptable salts thereof, and intermediates in the synthesis of compounds of formula (I), such as the methods and intermediates described herein and above.

[0075] In some embodiments, a pharmaceutical composition is provided that comprises the compound of formula (I) or its pharmaceutically acceptable salt together with pharmaceutically acceptable excipients.In such embodiments, the compound of formula (I) is preferably used in single enantiomer form.Minor impurities of other stereoisomeric forms, for example up to 1% by mass, may be present if desired.The pharmaceutical composition may be used for treating conditions that may benefit from IRAK4 kinase inhibition, as described herein and above in detail.

[0076] In certain embodiments, there is provided a compound of formula (I) for use in the manufacture of a medicament, optionally wherein the medicament is for use in the treatment or prophylaxis of a condition in which IRAK4 kinase inhibition may be beneficial, as detailed herein and above.

[0077] The compounds of formula (I) and their pharma- ceutically acceptable salts may be prepared, used or provided in amorphous, crystalline or semi-crystalline form, and certain compounds of formula (I) or their pharma- ceutically acceptable salts may be formed in more than one crystalline and / or polymorphic form, including hydrated (e.g., hemihydrate, monohydrate, dihydrate, trihydrate or other stoichiometric hydrate) and / or solvated forms. It is understood that the present disclosure encompasses any and all such solid forms of the compounds of formula (I) and their pharma- ceutically acceptable salts.

[0078] In a further embodiment of the present disclosure, there is provided a compound of formula (I) obtainable by the method described in the Examples section below.

[0079] The present disclosure is intended to encompass all isotopes of atoms occurring in the present compounds. It is understood that isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of formula (I) may be prepared by conventional techniques generally known to those skilled in the art or by methods analogous to those described in the accompanying Examples, substituting the appropriate isotopically labeled reagent for the unlabeled reagent previously used.

[0080] Suitable pharmaceutically acceptable salts of the compound of formula (I) can be, for example, acid addition salts.Suitable pharmaceutically acceptable salts of the compound of formula (I) can be, for example, acid addition salts of the compound of formula (I), for example, acid addition salts with inorganic or organic acids.The compounds of the present disclosure can be provided as free base compounds, i.e., in a non-salt state.

[0081] Further suitable pharma- ceutically acceptable salts of compounds of formula (I) may be, for example, salts formed in the human or animal body following administration of a compound of formula (I) to said human or animal body.

[0082] The compound of formula (I) or a pharma- ceutically acceptable salt thereof may be prepared in co-crystalline solid form. It will be understood that a pharma- ceutically acceptable co-crystal of the compound of formula (I) or a pharma- ceutically acceptable salt thereof forms an aspect of the present disclosure.

[0083] For use in medicine, it may be preferable to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof, free from the presence of significant amounts of other stereoisomeric forms.

[0084] The compound of formula (I) or a pharma- ceutically acceptable salt thereof is usually administered by the oral route, but it can also be administered parenterally, intravenously, intramuscularly, subcutaneously or other injection methods, by the buccal, rectal, vaginal, transdermal and / or nasal route and / or by inhalation in the form of a pharmaceutical preparation comprising the active ingredient or a pharma- ceutically acceptable salt or solvate thereof or a solvate of such a salt in a pharma- ceutical acceptable dosage form.Depending on the disorder and the patient to be treated and the route of administration, the composition can be administered in various doses, for example an oral dose of 1 mg to 1,000 mg or 1 mg to 2,000 mg.

[0085] Pharmaceutical formulations of the compounds of formula (I) above may be prepared, for example, for parenteral, subcutaneous, intramuscular or intravenous administration.

[0086] The pharmaceutical formulations of the compounds of formula (I) above may conveniently be administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., (1985).

[0087] Pharmaceutical preparations suitable for oral administration may contain one or more physiologically compatible carriers and / or additives and may be in solid or liquid form. Tablets and capsules may be prepared with binders; fillers; lubricants; and surfactants. Liquid compositions may contain conventional additives such as suspending agents; emulsifiers; and preservatives. Liquid compositions may be, for example, encapsulated in gelatin to provide a unit dosage form. Solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules. An example of an oral composition of the present disclosure includes the compound of formula (I) and at least one pharma-ceutically acceptable additive, which is encapsulated in a two-piece hard shell capsule or a soft elastic gelatin (SEG) capsule.

[0088] A further embodiment provides a compound of formula (I) as defined above or a pharma- ceutically acceptable salt thereof for use as a medicament in a warm-blooded animal, such as a human.In such an embodiment, the medicament may be for use in the treatment of a condition in which IRAK4 inhibition is beneficial, such as the treatment of cancer, inflammatory disease or autoinflammatory / autoimmune disease.

[0089] In some embodiments, the use of the compound is cancer treatment, the cancer can be a hematological malignancy selected from Waldenstrom's macroglobulinemia (WM), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), primary central nervous system lymphoma (PCNSL), splenic marginal zone lymphoma (SMZL), small lymphocytic lymphoma (SLL), leukemia (chronic lymphocytic leukemia (CLL)) and monoclonal gammopathy of undetermined significance (MGUS-IgM+). In such embodiments, the use can be a single agent or a combination with at least one other agent administered separately, sequentially or simultaneously. In such embodiments, the second agent can be selected from the group including BCR inhibitors, such as BTK inhibitors, such as ibrutinib, acalabrutinib, zanubrutinib or tirabrutinib, PI3Kδ inhibitors, SYK inhibitors or immunotherapy.

[0090] In some embodiments of the compound for use in the treatment of cancer, it may be used in the treatment of melanoma, and optionally, where the use may be in combination with at least one other agent administered separately, sequentially or simultaneously.In such embodiments, the second agent may be a BTK inhibitor, such as ibrutinib, acalabrutinib, zanubrutinib or tirabrutinib.

[0091] Further embodiments provide the use of the compound of formula (I) as defined above or its pharmacologic acceptable salt in the manufacture of a medicament for use in a warm-blooded animal, such as a human, in the treatment of conditions that IRAK4 inhibition is beneficial.In such embodiments, the medicament can be for the treatment of cancer, such as hematological malignancies selected from Waldenstrom's macroglobulinemia (WM), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), primary central nervous system lymphoma (PCNSL), splenic marginal zone lymphoma (SMZL), small lymphocytic lymphoma (SLL), leukemia (chronic lymphocytic leukemia (CLL)) and monoclonal gammopathy of undetermined significance (MGUS-IgM+).In such embodiments, the medicament can be used as a single agent or in combination with at least one other drug, which is administered separately, sequentially or simultaneously. In such embodiments, the second agent or medicament may be selected from the group comprising a BCR inhibitor, a BTK inhibitor such as ibrutinib, acalabrutinib, zanubrutinib or tirabrutinib, a PI3Kδ inhibitor, a SYK inhibitor or an immunotherapy.

[0092] In some embodiments, the medicament for use in the treatment of cancer can be used for the treatment of melanoma, and optionally, wherein the use can be in combination with at least one other drug administered separately, sequentially or simultaneously.In such embodiments, the second drug can be a BTK inhibitor such as ibrutinib, acalabrutinib, zanubrutinib or tirabrutinib.

[0093] In further embodiments, a method of treatment is provided, comprising administering an effective amount of the compound of formula (I) defined above or a pharmacologic acceptable salt thereof to a patient in need thereof.In such embodiments, the method of treatment can be for conditions that IRAK4 inhibition is beneficial.In such embodiments, the method of treatment can be for cancer, such as hematological malignancies selected from Waldenstrom's macroglobulinemia (WM), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), primary central nervous system lymphoma (PCNSL), splenic marginal zone lymphoma (SMZL), small lymphocytic lymphoma (SLL), leukemia (chronic lymphocytic leukemia (CLL)) and monoclonal gammopathy of undetermined significance (MGUS-IgM+).In such embodiments, the method of treatment can include administration of the compound of formula (I) alone or in combination with at least one other drug or medicament, administered separately, sequentially or simultaneously. In such embodiments, the second agent or medicament may be selected from the group comprising a BCR inhibitor, a BTK inhibitor such as ibrutinib, acalabrutinib, zanubrutinib or tirabrutinib, a PI3Kδ inhibitor, a SYK inhibitor or an immunotherapy.

[0094] In some embodiments, the treatment method can be for melanoma treatment.In such embodiments, the method can include separate, sequential or simultaneous administration of additional agent or medicament.In such embodiments, the second agent or medicament can be BTK inhibitor such as ibrutinib, acalabrutinib, zanubrutinib or tirabrutinib.

[0095] In this disclosure, unless otherwise specified, the term "effective amount" refers to an amount of a compound or composition that significantly and positively modifies the symptoms and / or condition to be treated (e.g., provides a positive clinical response). The effective amount of an active ingredient to be used in a pharmaceutical composition will vary depending on the particular condition to be treated, the severity of the condition, the duration of treatment, the nature of concurrent treatments, the particular active ingredient used, the particular pharma- ceutically acceptable excipients / carriers utilized, and similar factors within the knowledge and experience of the treating physician. An effective amount is generally in the range of 0.1 mg to 1,000 mg.

[0096] A further embodiment provides a compound of formula (I) as defined above, or a pharma- ceutically acceptable salt thereof, for use in providing an inhibitory effect on IRAK4 kinase.

[0097] A further embodiment provides the use of a compound of formula (I) as defined above, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in providing an inhibitory effect on IRAK4 kinase.

[0098] According to a further embodiment, there is also provided a method for providing an inhibitory effect on IRAK4 kinase comprising administering to a patient in need thereof an effective amount of a compound of formula (I) as defined above, or a pharma- ceutically acceptable salt thereof.

[0099] According to a further embodiment, there is provided a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined above for use in providing a selective inhibitory effect on IRAK4 kinase.In such a case, a selective inhibitory effect indicates that the concentration of compound of formula (I) required for 50% inhibition of IRAK4 kinase activity in vitro is 10-fold, 100-fold or 1000-fold or more lower than the concentration required for 50% inhibition of other kinases, for example other kinases that, if inhibited, result in toxic side effects.

[0100] A further embodiment provides the use of a compound of formula (I) as defined above, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for use in providing a selective inhibitory effect on IRAK4 kinase.

[0101] According to a further embodiment, there is also provided a method for providing a selective inhibitory effect against IRAK4 kinase comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0102] Described herein are compounds that can inhibit IRAK4 kinase.In biochemical and cell-based assays, the compounds of the present disclosure are shown to be potent IRAK4 kinase inhibitors, and therefore can be useful in treating disorders mediated by IRAK4 kinase activity, particularly respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), inflammatory diseases, and autoinflammatory / autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjogren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis, and psoriasis.

[0103] In certain embodiments, there is provided the use of a compound of formula (I) for the treatment of a respiratory disease, optionally wherein the respiratory disease is asthma and chronic obstructive pulmonary disease (COPD).

[0104] In certain embodiments, there is provided the use of a compound of Formula (I) for the treatment of inflammatory diseases or autoinflammatory / autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjogren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis and psoriasis.

[0105] In certain embodiments, a method of treatment is provided comprising administering an effective amount of a compound of Formula (I) to a patient in need thereof, wherein the patient has a respiratory disease, optionally wherein the respiratory disease is asthma and chronic obstructive pulmonary disease (COPD).

[0106] In certain embodiments, a method of treatment is provided comprising administering an effective amount of a compound of Formula (I) to a patient in need thereof, wherein the patient has an inflammatory disease or an autoinflammatory / autoimmune disease, such as systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjogren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis and psoriasis.

[0107] In a further aspect of the present disclosure, there is provided the use of a compound of formula (I) as defined above or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of disorders mediated by IRAK4 kinase activity, in particular respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), inflammatory diseases and autoinflammatory / autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjogren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis and psoriasis.

[0108] In a further embodiment of the present disclosure, a kit is provided, comprising a pharmaceutical preparation comprising the compound of formula (I) and instructions for use of said pharmaceutical preparation in treating a condition or disease.In such an embodiment, the condition or disease can be cancer, inflammatory disease or autoinflammatory / autoimmune disease.When the instructions are for treating cancer, the cancer can be melanoma or hematological malignancies selected from Waldenstrom's macroglobulinemia (WM), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), primary central nervous system lymphoma (PCNSL), splenic marginal zone lymphoma (SMZL), small lymphocytic lymphoma (SLL), leukemia (chronic lymphocytic leukemia (CLL)) and monoclonal gammopathy of undetermined significance (MGUS-IgM+). When the kit is for use in an inflammatory disease or an autoinflammatory / autoimmune disease, the disease or condition may be selected from systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjogren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis and psoriasis.

[0109] It will be appreciated that the following examples are provided so that the nature of the present invention may be fully understood, and that they are not intended to limit the scope of the present disclosure in any manner. EXAMPLES

[0110] The following abbreviations are used: [Table 1] [Table 2]

[0111] Abbreviations used in the analytical data, unless defined above, are in accordance with common usage in the art (J Med Chem Standard Abbreviations and Acronyms, 2002). http: / / pubsapp.acs.org / paragonplus / submission / jmcmar / jmcmar_abbreviations.pdf? reference).

[0112] The compound names below were created using PerkinElmer ChemDraw Professional, Version 20.0.2.51. When the absolute stereochemistry is uncertain, the relative stereochemistry is specified as much as possible.

[0113] The compounds of the present disclosure can be prepared by methods well known to those skilled in the art, for example, directly using the routes outlined in Schemes 1-3 above, or by adapting these schemes as necessary to incorporate additional functional groups. Although specific routes and reagents are illustrated in the examples below, it is recognized that alternative starting materials and reagents may be used to produce a variety of derivatives and / or reaction conditions. Thus, compounds within the scope of the claims can be readily prepared by routine adjustment or modification of chemistry well known in the art.

[0114] Compounds were analyzed or purified by standard techniques. Unless otherwise noted, reactions are generally carried out under an inert atmosphere (e.g., nitrogen or argon).

[0115] [Production of intermediates] Int 1: 5-bromo-4-methoxy-2-nitrobenzaldehyde 5-Bromo-4-fluoro-2-nitrobenzaldehyde [ka] A solution of fuming nitric acid (12.0 mL, 0.3 mol) in concentrated sulfuric acid (25 mL) was added dropwise to a solution of 3-bromo-4-fluorobenzaldehyde (19.3 g, 95.1 mmol) in concentrated sulfuric acid (75 mL) at 0° C. The resulting yellow solution was slowly warmed to rt and stirred for 4 days. The reaction mixture was then poured onto crushed ice and the resulting precipitate was collected by filtration to give 5-bromo-4-fluoro-2-nitrobenzaldehyde (22.6 g, 96%) as a yellow solid. m / z (ESI-), [MH] - = 245 / 247

[0116] 5-Bromo-4-methoxy-2-nitrobenzaldehyde (Int 1) [ka] A solution of sodium methoxide (10.9 g, 60.6 mmol) in MeOH (46 mL) was added to a solution of 5-bromo-4-fluoro-2-nitrobenzaldehyde (10.0 g, 40.3 mmol) in MeOH (150 mL) at rt. After stirring for 16 h, the reaction was quenched with water (300 mL) and the solid formed was filtered off and washed with water (100 mL) to give 5-bromo-4-methoxy-2-nitrobenzaldehyde (6.6 g, 63%) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.03 (s, 1H), 8.15 (s, 1H), 7.78 (s, 1H), 4.04 (s, 3H)

[0117] Int 2: tert-butyl ((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)carbamate [ka] A solution of tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (10.5 g, 49.0 mmol) in i-PrOH (200 mL) was added at rt with N 2 5-Bromo-4-methoxy-2-nitrobenzaldehyde (Int 1) (12.7 g, 49.0 mmol) was added under atmospheric pressure. The resulting mixture was stirred at 80 °C for 1 h, followed by the addition of tri-n-butylphosphine (29.7 g, 147.0 mmol). The reaction mixture was stirred at 80 °C for 13 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with 9-50% EtOAc in PE) to give tert-butyl ((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)carbamate (14.2 g, 68%) as a colorless solid. MS ESI, m / z = 424 / 426 [M+H] +

[0118] Int 3: Methyl 2-((1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylate tert-Butyl ((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate [ka] To a solution of tert-butyl ((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)carbamate (Int 2) (4.2 g, 9.9 mmol) in DMF (50 mL) was added NaH (60 wt.%) (792 mg, 19.8 mmol) at 0° C. The resulting mixture was stirred at 25° C. for 30 min, followed by the addition of iodomethane (1.24 mL, 19.8 mmol). The reaction mixture was stirred at rt for 13 h and then quenched with water (150 mL). The precipitate was filtered, washed with water (150 mL) and dried under reduced pressure to give tert-butyl ((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate (4.36 g, 100%) as a colorless solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.28 (s, 1H), 7.96 (s, 1H), 7.11 (s, 1H), 4.42 (ddt, 1H), 3.87 - 4.06 (m, 1H), 3.86 (s, 3H), 2.71 (s, 3H), 2.09 - 2.23 (m, MS ESI, m / z = 438 / 440 (1:1) [M+H] +

[0119] Methyl 2-((1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylate (Int 3) [ka] tert-Butyl ((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate (4.3 g, 9.8 mmol), Pd(dppf)Cl 2A suspension of (714 mg, 1.0 mmol) and TEA (13.6 mL, 97.6 mmol) in MeOH (125 mL) was stirred at 100 °C under CO atmosphere at 15 atm for 15 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with 30-50% EtOAc in PE) to give methyl 2-((1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylate (3.8 g, 93%) as a yellow solid. MS ESI, m / z = 418 [M+H] +

[0120] Int 4: Methyl 6-methoxy-2-((1r,4r)-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxylate [ka] A solution of methyl 2-((1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylate (Int 3) (2.5 g, 6.0 mmol) in DCM (50 mL) was added with 4N HCl in dioxane (15 ml, 59.9 mmol) at 25 °C under reduced pressure. 2 The resulting mixture was stirred at 25° C. for 18 h and then concentrated under reduced pressure to give the HCl salt of methyl 6-methoxy-2-((1r,4r)-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxylate (2.1 g, 100%), which was used without further purification. 1 H NMR (400 MHz, DMSO-d 6) δ 8.77 (br. s, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 7.01 (s, 1H), 4.36 - 4.56 (m, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.53 (s, 3H), 2.95 - 3.14 (m, 1H), 2.11 - 2.26 (m, 4H), 1.92 (br. q, 2H), 1.60 (br. q, 2H). MS ESI, m / z = 318 [M+H] +

[0121] Int 5: 2-((1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid [ka] To a solution of methyl 2-((1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylate (Int 3) (2.9 g, 6.9 mmol) in MeOH (50 mL) / water (25 mL) was added NaOH (556 mg, 13.9 mmol) at rt. The resulting solution was stirred at 30° C. for 12 h. The reaction mixture was cooled to rt and acidified to pH ∼6 with 4N HCl. The precipitate was filtered, washed with water (200 mL) and dried under reduced pressure to give 2-((1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (2.7 g, 95%) as a pale yellow solid. MS ESI, m / z = 404 [M+H] +

[0122] Int 6: 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid Methyl 2-((1R,4r)-4-((R)-2-acetoxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylate [ka] A solution of methyl 6-methoxy-2-((1r,4r)-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxylate HCl salt (Int 4) (800 mg, 2.3 mmol) and TEA (945 μL, 6.8 mmol) in DCM (30 mL) was added at 0 °C under N 2 (R)-1-chloro-1-oxopropan-2-yl acetate (511 mg, 3.4 mmol) was added under atmospheric conditions. The resulting solution was stirred at 25 °C for 15 h and then concentrated under reduced pressure. The residue was purified by C18-flash chromatography (10 to 100% MeCN in water (0.1% NH 4 The mixture was purified by elution with N-(OH) solution to give methyl 2-((1R,4r)-4-((R)-2-acetoxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylate (910 mg, 93%) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6 )(4:5 mixture of rotamers) δ 8.46 / 8.43 (s, 1H)(rotamers), 8.09 / 8.07 (s, 1H)(rotamers), 7.06 / 7.04 (s, 1H)(rotamers), 5.45 / 5.28 (q, 1H)(rotamers), 4.39 - 4.55 (m, 1H), 4.28 - 4.39 / 3.33 - 3.41 (m, 1H)(rotamers), 3.82 (s, 3H), 3.78 (s, 3H), 2.90 / 2.75 (s, 3H)(rotamers), 2.15 - 2.25 (m, 2H), 1.72 - 2.14 (m, 8H), 1.56 - 1.69 (m, 1H), 1.29 - 1.36 (m, 3H). MS ESI, m / z = 432 [M+H] +

[0123] 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (Int 6) [ka] A solution of methyl 2-((1R,4r)-4-((R)-2-acetoxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylate (900 mg, 2.1 mmol) in MeOH (10 mL) was added at 25 °C under reduced pressure. 2 A solution of LiOH monohydrate (525 mg, 12.5 mmol) in water (10 mL) was added under atmospheric pressure. The resulting solution was stirred at 25° C. for 16 h. The pH of the reaction mixture was adjusted to pH 7 with 1N HCl. The mixture was purified by C18-flash chromatography (eluted with 5-100% MeCN in water (0.1% FA)) to give 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (750 mg, 96%) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6 )(4:5 mixture of rotamers) δ 8.43 / 8.40 (s, 1H)(rotamers), 8.25 (s, 1H), 8.04 / 8.03 (s, 1H)(rotamers), 7.01 / 7.00 (s, 1H)(rotamers), 4.38 - 4.58 (m, 2H), 4.32 - 4.41 / 3.93 - 4.02 (m, 1H)(rotamers), 3.81 (s, 3H), 2.90 / 2.76 (s, 3H)(rotamers), 1.94 - 2.24 (m, 4H), 1.71 - 1.94 (m, 3H), 1.59 - 1.71 (m, 1H), 1.17 - 1.26 (m, 3H). MS ESI, m / z = 376 [M+H] +

[0124] Int 7: 2-((1r,4r)-4-aminocyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide Methyl 2-((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylate [ka] tert-Butyl ((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)carbamate (Int 2) (1.5 g, 3.5 mmol), Pd(dppf)Cl in MeOH (30 mL). 2 -CH 2 Cl 2 A mixture of (577 mg, 0.7 mmol) and DIPEA (3.1 mL, 17.7 mmol) was stirred in a sealed vessel under CO atmosphere at 15 atm and then heated at 110° C. for 12 h. Three parallel reactions of the same scale were carried out. The combined reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with 50% EtOAc in PE) to give methyl 2-((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylate (4.4 g, quantitative yield) as a grey solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.44 (s, 1H), 8.08 (s, 1H), 7.06 (s, 1H), 6.86 (d, 1H), 4.30 - 4.50 (m, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.28 - 3.44 (m, MS ESI, m / z = 404 [M+H] +

[0125] 2-((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid [ka] To a solution of methyl 2-((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylate (1.5 g, 3.7 mmol) in water (5 mL) and MeOH (10 mL) was added NaOH (0.3 g, 7.4 mmol). The resulting mixture was stirred at 25° C. for 4 h, after which the pH of the mixture was adjusted to pH 5 with 0.1 N HCl to give a precipitate. The precipitate was collected by filtration, washed with water (10 mL), and dried under reduced pressure to give 2-((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (1.4 g, 97%) as a pale yellow solid, which was used without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.41 (br. s, 1H), 8.42 (s, 1H), 8.06 (s, 1H), 7.03 (s, 1H), 6.86 (d, 1H), 4.29 - 4.52 (m, 1H), 3.81 (s, 3H), 2.03 - 2.17 (m, 2H), 1.86 - 2.03 (m, 4H), 1.39 (s, 9H), 1.32 - 1.49 (m, 2H). MS ESI, m / z = 390 [M+H] +

[0126] tert-Butyl ((1r,4r)-4-(6-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl)carbamate [ka] To a solution of 2-((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (600 mg, 1.5 mmol), HATU (879 mg, 2.3 mmol) and DIPEA (807 μL, 4.6 mmol) in DMF (10 mL) was added 3-amino-1-methylpyridin-2(1H)-one (383 mg, 3.1 mmol). The reaction mixture was stirred at 25 °C for 5 h. The mixture was purified by C18-flash chromatography (0-100% MeCN in water (0.1% NH 4 The crude product was purified by elution with 2-(2,4-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl (eluted with 1,2-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl)carbamate (640 mg, 84%) as a light yellow solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.04 (s, 1H), 8.55 (s, 2H), 8.44 (dd, 1H), 7.42 (dd, 1H), 7.22 (s, 1H), 6.87 (d, 1H), 6.30 (t, 1H), 4.35 - 4.50 (m, 1H), MS ESI, m / z = 496 [M+H] +

[0127] 2-((1r,4r)-4-aminocyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (Int 7) [ka] To a solution of tert-butyl ((1r,4r)-4-(6-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl)carbamate (620 mg, 1.3 mmol) in DCM (7 mL) was added 2N HCl in dioxane (6.3 mL, 12.5 mmol) and the resulting solution was stirred at 25° C. for 4 h. The mixture was concentrated under reduced pressure to give the HCl salt of 2-((1r,4r)-4-aminocyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (565 mg, quantitative yield) as a colorless solid. 1 H NMR (300 MHz, DMSO-d 6 )(HCl salt) δ 11.03 (s, 1H), 8.58 (s, 1H), 8.56 (s, 1H), 8.43 (dd, 1H), 8.36 (br d, 3H), 7.43 (dd, 1H), 7.20 (s, 1H), 6.30 (t, 1H), 4.42 - 4.57 (m, 1H), 4.06 (s, 3H), 3.55 (s, 3H), 3.02 - 3.22 (m, 1H), 2.08 - 2.29 (m, 4H), 1.90 - 2.08 (m, 2H), 1.52 - 1.73 (m, 2H). MS ESI, m / z = 396 [M+H] +

[0128] Int 8: (1s,4s)-4-(6-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl methanesulfonate (1s,4s)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexan-1-ol [ka] (1s,4s)-4-Aminocyclohexan-1-ol (6.0 g, 52.1 mmol) was added to a solution of 5-bromo-4-methoxy-2-nitrobenzaldehyde (Int 1) (13.8 g, 53.1 mmol) in i-PrOH (500 mL) 2 The mixture was stirred at 80° C. for 15 hours. The reaction mixture was then cooled to room temperature, and tributylphosphane (31.6 g, 156.3 mmol) was added to the mixture. The mixture was stirred at 80° C. for 6 hours, and then concentrated under reduced pressure. The crude was purified by silica chromatography (eluted with 70% EtOAc in PE) to give (1s,4s)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexan-1-ol (12 g, 71%) as a colorless solid. MS ESI, m / z = 325 / 327 [M+H] +

[0129] Methyl 2-((1s,4s)-4-hydroxycyclohexyl)-6-methoxy-2H-indazole-5-carboxylate [ka] (1s,4s)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexan-1-ol (10 g, 30.8 mmol), TEA (21.4 mL, 153.8 mmol) and Pd(dppf)Cl 2 -CH 2 Cl 2 A solution of (5.0 g, 6.2 mmol) in MeOH (200 mL) was stirred at 110° C. under CO atmosphere at 15 atm for 15 h. The mixture was cooled to rt and concentrated under reduced pressure. The crude was purified by silica chromatography (eluting with 1% MeOH in DCM) to give methyl 2-((1s,4s)-4-hydroxycyclohexyl)-6-methoxy-2H-indazole-5-carboxylate (8.0 g, 85%) as a brown oil. MS ESI, m / z = 305 [M+H] +

[0130] 2-((1s,4s)-4-Hydroxycyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid [ka] 2M NaOH aqueous solution (50 ml, 100.0 mmol) was added to a solution of methyl 2-((1s,4s)-4-hydroxycyclohexyl)-6-methoxy-2H-indazole-5-carboxylate (8.0 g, 26.1 mmol) in MeOH (100 mL). The resulting mixture was stirred at rt for 15 h. The reaction mixture was then diluted with water (700 mL) and washed with EtOAc (2×600 mL). The aqueous phase was collected and the pH was adjusted to pH 4 with 2M HCl aqueous solution. The aqueous phase was extracted with EtOAc (1×600 mL) and DCM (2×500 mL). The organic layers were combined and washed with Na 2 SO 4 and concentrated under reduced pressure to give 2-((1s,4s)-4-hydroxycyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (7.0 g, 92%) as an orange solid which was used without further purification. MS ESI, m / z = 291 [M+H] +

[0131] 2-((1s,4s)-4-Hydroxycyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide [ka] A solution of 2-((1s,4s)-4-hydroxycyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (7.0 g, 23.9 mmol) and HATU (10.9 g, 28.7 mmol) in DMF (100 mL) was added at rt with N 2DIPEA (12.5 mL, 71.8 mmol) was added under atmosphere. The resulting solution was stirred for 10 min followed by the addition of 3-amino-1-methylpyridin-2(1H)-one hydrochloride (4.4 g, 27.5 mmol). The reaction mixture was stirred at rt for 15 h and then filtered. The solid was washed with water (50 mL) to give 2-((1s,4s)-4-hydroxycyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (7.5 g, 79%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.04 (s, 1H), 8.57 (s, 1H), 8.55 (s, 1H), 8.45 (dd, 1H), 7.41 (dd, 1H), 7.21 (s, 1H), 6.30 (t, 1H), 4.51 (d, 1H), 4.44 (tt, 1H), 4.07 (s, 3H), 3.84 - 3.93 (m, 1H), 3.55 (s, 3H), 2.29 (qd, 2H), 1.82 - 1.94 (m, 2H), 1.72 - 1.82 (m, 2H), 1.57 - 1.70 (m, 2H). MS ESI, m / z = 397 [M+H] +

[0132] (1s,4s)-4-(6-Methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl methanesulfonate (Int 8) [ka] MsCl (2.5 mL, 31.5 mmol) was added to a solution of 2-((1s,4s)-4-hydroxycyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (5.0 g, 12.6 mmol) and TEA (10.6 mL, 75.7 mmol) in DCM (300 mL) at 0 °C under reduced pressure. 2The mixture was added dropwise under atmospheric pressure. The resulting solution was stirred at rt for 15 h. The reaction mixture was then quenched with MeOH (10 mL), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with 2% MeOH in DCM) to give (1s,4s)-4-(6-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl methanesulfonate (4.10 g, 69%) as a pink solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.04 (s, 1H), 8.59 (s, 1H), 8.57 (s, 1H), 8.45 (dd, 1H), 7.42 (dd, 1H), 7.25 (s, 1H), 6.30 (t, 1H), 4.94 - 5.04 (m, 1H), 4.60 (tt, 1H), 4.07 (s, 3H), 3.56 (s, 3H), 3.23 (s, 3H), 1.96 - 2.29 (m, 6H), 1.82 - 1.96 (m, 2H). MS ESI, m / z = 475 [M+H] +

[0133] [Example] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (Example 1) Methyl 6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxylate [ka] To a solution of methyl 6-methoxy-2-((1r,4r)-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxylate HCl salt (Int 4) (410 mg, 1.2 mmol) and TEA (485 μL, 3.5 mmol) in DCM (8 mL) was added acetic anhydride (219 μL, 2.3 mmol). The resulting mixture was stirred at 25 °C for 2 h, then diluted with DCM (25 mL) and washed with saturated NaHCO 3 The organic layer was washed successively with aqueous solution (20 mL) and brine (25 mL). 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure afforded methyl 6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxylate (415 mg, 100%) as a brown oil which was used in the next step without further purification. 1 H NMR (300 MHz, DMSO-d 6 )(3:2 rotamer mixture) δ 8.46 / 8.44 (s, 1H)(rotamer), 8.09 / 8.08 (s, 1H)(rotamer), 7.05 / 7.04 (s, 1H)(rotamer), 4.34 - 4.56 / 3.68 - 3.90 (m, 2H)(rotamer), 3.81 (s, 3H), 3.78 (s, 3H), 2.85 / 2.72 (s, 3H)(rotamer), 1.90 - 2.19 (m, 7H), 1.57 - 1.88 (m, 4H). MS ESI, m / z = 360 [M+H] +

[0134] 6-Methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxylic acid [ka] A solution of methyl 6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxylate (Int 5) (400 mg, 1.1 mmol) in MeOH / water (9 mL, 2:1) was diluted with N 2NaOH (89 mg, 2.23 mmol) was added under atmospheric pressure. The resulting solution was stirred at 25° C. for 2 h, then acidified to pH 6 with 2N HCl and concentrated under reduced pressure. The residue was purified by C18-flash chromatography (eluted with 0-80% MeCN in water (0.1% FA)) to give 6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxylic acid (384 mg, 100%) as a colorless solid. 1 H NMR (300 MHz, DMSO-d 6 )(3:2 rotamer mixture) δ 12.44 (br. s, 1H), 8.44 / 8.42 (s, 1H)(rotamer), 8.08 / 8.06 (s, 1H)(rotamer), 7.02 / 7.01 (s, 1H)(rotamer), 4.34 - 4.54 / 3.70 - 3.81 (m, 2H)(rotamer), 3.82 (s, 3H), 2.85 / 2.72 (s, 3H)(rotamer), 2.12 - 2.24 (m, 2H), 1.89 - 2.12 (m, 5H), 1.68 - 1.89 (m, 3H), 1.57 - 1.68 (m, 1H). MS ESI, m / z = 346 [M+H] +

[0135] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide, Example 1 [ka] A solution of 6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxylic acid (100 mg, 0.29 mmol), DIPEA (152 μL, 0.87 mmol) and 3-amino-1-methylpyridin-2(1H)-one (53.9 mg, 0.43 mmol) in DCM (3 mL) was added at 25 °C under reduced pressure. 2 Atmosphere, T3P (登録商標)(50 wt.% in EtOAc) (553 mg, 0.87 mmol) was added. The resulting solution was stirred at 25 °C for 2 h and then concentrated under reduced pressure. The residue was purified by C18-flash chromatography (eluted with 0-80% MeCN in water (0.1% FA)) and further purified by preparative HPLC (YMC-Actus Triart C18 ExRS 5 μm 30 × 150 mm; elution gradient 12-45% MeCN in water (10 mM (NH 4 ) 2 CO 3 +0.1%NH 4 OH) solution for 7 min; 60 mL / min) to afford 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (93 mg, 71%), Example 1, as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )(3:2 rotamer mixture) δ 11.04 (s, 1H), 8.53 - 8.60 (m, 2H), 8.45 (dd, 1H), 7.43 (dd, 1H), 7.22 / 7.20 (s, 1H)(rotamer), 6.31 (t, 1H), 4.45 - 4.55 (m, 1H), 4.36 - 4.45 / 3.72 - 3.85 (m, 1H)(rotamer), 4.07 (s, 3H), 3.56 (s, 3H), 2.86 / 2.72 (s, 3H)(rotamer), 2.15 - 2.25 (m, 2H), 1.94 - 2.15 (m, 5H), 1.70 - 1.93 (m, 3H), 1.58 - 1.70 (m, 1H). MS ESI, m / z = 452 [M+H] +

[0136] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 1 (Example 2) and Isomer 2 (Example 3) rac-(7R,8R)-N-benzyl-7-methyl-1,4-dioxaspiro[4.5]decane-8-amine [ka] A solution of 7-methyl-1,4-dioxaspiro[4.5]decan-8-one (3.0 g, 17.6 mmol) and phenylmethanamine (2.8 g, 26.4 mmol) in toluene (50 mL) was 2 4-Methylbenzenesulfonic acid monohydrate (335 mg, 1.8 mmol) was added under atmospheric pressure. The resulting solution was stirred at 120° C. for 15 h. The reaction mixture was cooled to rt and concentrated under reduced pressure to give the crude imine intermediate. A solution of the imine in MeOH (60 mL) was added at −60° C. with NaBH 4 (0.6 g, 15.8 mmol) was added to a 200-mL flask over a 5 min period. 2 The mixture was added portionwise under atmospheric pressure. The resulting mixture was stirred at -60°C for 1 h, then slowly warmed to rt and stirred for 3 h. Five batches of crude product solution were prepared in parallel as above, combined and subsequently purified. The reaction mixture was concentrated under reduced pressure, dissolved in EtOAc (500 mL) and washed with brine (300 mL x 3). The organic layer was extracted with Na 2 SO 4 The residue was purified by C18-flash chromatography (0-100% MeCN in water (0.05% NH 4 HCO 3 ) solution) to give rac-(7R,8R)-N-benzyl-7-methyl-1,4-dioxaspiro[4.5]decan-8-amine (8.1 g, 35%) as an orange oil. MS ESI, m / z = 262 [M+H] +

[0137] rac-(7R,8R)-7-Methyl-1,4-dioxaspiro[4.5]decane-8-amine [ka] A solution of rac-(7R,8R)-N-benzyl-7-methyl-1,4-dioxaspiro[4.5]decane-8-amine (8.1 g, 31.0 mmol) in MeOH (100 mL) was 2 Under atmosphere, Pd(OH) 2 To the mixture was added 1,2-dichloro-1,4-dimethyl-2,5-dioxaspiro[4.5]decane-8-amine (20 wt.%) (872 mg, 1.2 mmol). The resulting suspension was stirred at rt under 2 atm of hydrogen for 15 h. The reaction mixture was filtered through Celite and the Celite cake was washed with MeOH (150 mL). The combined eOH solutions were concentrated under reduced pressure to give crude rac-(7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decane-8-amine (5.0 g) as a brown oil, which was used without further purification.

[0138] 5-Bromo-6-methoxy-2-((7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole [ka] A solution of 5-bromo-4-methoxy-2-nitrobenzaldehyde (Int 1) (10.6 g, 40.9 mmol) in i-PrOH (200 mL) was added at rt under N 2 Crude rac-(7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decane-8-amine (7.0 g) was added under atmospheric pressure. The resulting mixture was stirred at 80° C. for 2 h and then cooled to rt, followed by the addition of tri-n-butylphosphine (41.4 g, 204.4 mmol). The reaction mixture was stirred at 80° C. for 24 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with 0-10% MeOH in DCM) and further purified by C18-flash chromatography (eluted with 0-100% MeCN in water (0.05% NH 4 The material was purified by chiral preparative SFC (Chiralpak) to give rac-5-bromo-6-methoxy-2-((7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole as a yellow solid. (登録商標) IG, 5μm 50×250mm;CO 2(35 °C, 100 bar) in 50% MeOH (0.1% 2N NH 3 —MeOH) to give 5-bromo-6-methoxy-2-((7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole (3.0 g, 19%, 100% ee) as a grey solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.25 (d, 1H), 7.96 (s, 1H), 7.12 (s, 1H), 4.13 (td, 1H), 3.87 - 3.99 (m, 4H), 3.87 (s, 3H), 2.26 - 2.43 (m, 1H), 2.19 (td, MS ESI, m / z = 381 / 383 [M+H] +

[0139] (3R,4R)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-methylcyclohexan-1-one [ka] A solution of 5-bromo-6-methoxy-2-((7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole (185 mg, 0.5 mmol) in THF (5 mL) was added at rt with N 2 4N HCl aqueous solution (5 mL, 20.0 mmol) was added under atmosphere. The reaction mixture was stirred at rt for 12 h. The reaction mixture was diluted with NH 4 The mixture was neutralized to pH 7 with aqueous OH and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with 0-50% EtOAc in PE) to give (3R,4R)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-methylcyclohexan-1-one (160 mg, 98%) as a yellow oil. MS ESI, m / z = 337 / 339 [M+H] +

[0140] (3R,4R)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-N,3-dimethylcyclohexan-1-amine [ka] To a solution of (3R,4R)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-methylcyclohexan-1-one (180 mg, 0.5 mmol) and methanamine (33 wt.% in MeOH) (754 mg, 8.0 mmol) in DCE (6 mL) was added sodium triacetoxyborohydride (339 mg, 1.6 mmol). The resulting mixture was stirred at rt for 2 h, then quenched with water (1 mL) and concentrated under reduced pressure. The residue was purified by C18-flash chromatography (0-100% MeCN in water (2% NH 4 The resulting mixture was purified by elution with 5-bromo-6-methoxy-2H-indazol-2-yl (OH) solution to give (3R,4R)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-N,3-dimethylcyclohexan-1-amine (150 mg, 80%) as a colorless solid. MS ESI, m / z = 337 / 339 (1:1) [M+H] +

[0141] N-((3R,4R)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-methylcyclohexyl)-N-methylacetamide [ka] To a solution of (3R,4R)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-N,3-dimethylcyclohexan-1-amine (140 mg, 0.4 mmol) and TEA (222 μL, 1.6 mmol) in DCM (5 mL) was added acetic anhydride (81 mg, 0.8 mmol). The resulting mixture was stirred at rt for 1 h. The reaction mixture was then concentrated under reduced pressure and purified by C18-flash chromatography (eluted with 0-100% MeCN in water (0.1% FA)) to give N-((3R,4R)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-methylcyclohexyl)-N-methylacetamide (125 mg, 80%) as a yellow solid. MS ESI, m / z = 394 / 396 (1:1) [M+H] +

[0142] Methyl 6-methoxy-2-((1R,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxylate [ka] N-((3R,4R)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-methylcyclohexyl)-N-methylacetamide (120 mg, 0.3 mmol), Pd(dppf)Cl in MeOH (10 mL) 2 A mixture of (45 mg, 0.06 mmol) and DIPEA (266 μL, 1.5 mmol) was stirred in a sealed vessel under a CO atmosphere at 15 atm and then heated at 110 °C for 15 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18-flash chromatography (0-100% MeCN in water (0.05% NH 4 Purification by elution with hexanes (1R,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxylate (105 mg, 92%) as a waxy yellow solid. MS ESI, m / z = 374 [M+H] +

[0143] 6-Methoxy-2-((1R,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxylic acid [ka] A solution of methyl 6-methoxy-2-((1R,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxylate (102 mg, 0.3 mmol) in MeOH (3 mL) was added at rt with 2 A solution of LiOH (20 mg, 0.8 mmol) in water (10 mL) was added under atmospheric pressure. The resulting solution was stirred at rt for 2 h and then adjusted to pH 6 with 2N HCl. The reaction mixture was directly purified by C18-flash chromatography (eluted with 5-100% MeCN in water (0.05% FA)) to give 6-methoxy-2-((1R,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxylic acid (98 mg, 100%) as a colorless solid. MS ESI, m / z = 360 [M+H] +

[0144] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 1, Example 2 and Isomer 2, Example 3 [ka] A solution of 6-methoxy-2-((1R,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxylic acid (88 mg, 0.2 mmol), DIPEA (171 μL, 1.0 mmol) and 3-amino-1-methylpyridin-2(1H)-one hydrochloride (79 mg, 0.5 mmol) in DCM (5 mL) was added at 25 °C under reduced pressure. 2 Atmosphere, T3P (登録商標)(50 wt.% in EtOAc) (312 mg, 0.5 mmol) was added. The resulting solution was stirred at rt for 2 h and then concentrated under reduced pressure. The residue was purified by C18-flash chromatography (eluting with 0-100% MeCN in water (0.05% FA)) and then by chiral preparative HPLC (Chiralpak (登録商標) IF, 5 μm 20 mm × 250 mm; 50% MTBE (0.5% 2M NH) in EtOH for 26 min 3 -MeOH solution) isocratic; 20.0 mL / min) to give 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - isomer 1 (40 mg, 35%, 100% ee) and 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - isomer 2 (14 mg, 12%, 99.6% ee), both as colorless solids. Isomer 1 (Example 2): 1 H NMR (400 MHz, DMSO-d 6 )(3:2 rotamer mixture) δ 11.04 (s, 1H), 8.68 (s, 1H), 8.59 (s, 1H), 8.45 (dd, 1H), 7.43 (dd, 1H), 7.25 (s, 1H), 6.31 (t, 1H), 4.52 - 4.70 / 3.91 - 4.05 (m, 1H)(rotamer), 4.30 - 4.48 (m, 1H), 4.08 (s, 3H), 3.56 (s, 3H), 2.85 / 2.70 (br. s, 4H)(rotamer), 0.89 - 2.38 (m, 12H). MS ESI, m / z = 466 [M+H] + Isomer 2 (Example 3): 1 H NMR (400 MHz, DMSO-d 6)(3:2 mixture of rotamers) δ 11.04 (s, 1H), 8.57 - 8.60 (m, 1H), 8.57 / 8.55 (s, 1H)(rotamers), 8.45 (dd, 1H), 7.43 (dd, 1H), 7.24 / 7.21 (s, 1H)(rotamers), 6.31 (t, 1H), 4.45 - 4.55 (m, 1H), 4.45 - 4.55 / 3.81 - 3.92 (m, 1H)(rotamers), 4.09 - 4.18 (m, 1H), 4.07 (s, 3H), 3.56 (s, 3H), 2.86 / 2.72 (s, 3H)(rotamers), 1.94 - 2.28 (m, 6H), 1.56 - 1.90 (m, 4H), 0.53 - 0.63 (m, 3H). MS ESI, m / z = 466 [M+H] +

[0145] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2S,4R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (Example 4) 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1S,2R,4S)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (Example 5) rel-6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2S,4S)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 1 (Example 6) and Isomer 2 (Example 7) rac-(7R,8S)-N-benzyl-7-methyl-1,4-dioxaspiro[4.5]decane-8-amine [ka] A solution of N-benzyl-7-methyl-1,4-dioxaspiro[4.5]decan-8-imine (3.2 kg, 12.3 mol) in MeOH (15 L) cooled to below -60 °C was added to the 4 (466.8g, 12.3mol) was dissolved in N 2 The mixture was added under atmosphere in 5 batches over 30 min. The resulting mixture was warmed from -60°C to -30°C over 1 h, then from -30°C to 10°C over 0.5 h. The mixture was diluted with saturated NH 4 The mixture was quenched with aqueous Cl (5 L) and extracted with DCM (5 L x 3). The combined organic layers were washed with water (6 L) and brine (6 L) and then diluted with Na 2 SO 4 The residue was purified by C18-flash chromatography (40-70% MeCN in water (0.05% NH 4 HCO 3 ) solution) to give the trans-isomer (1.3 kg, 40%) and the desired rac-(7R,8S)-N-benzyl-7-methyl-1,4-dioxaspiro[4.5]decan-8-amine. 1 H NMR (300 MHz, CDCl 3 ) δ 7.19 - 7.38 (m, 5H), 3.87 - 4 (m, 4H), 3.84 (d, 1H), 3.65 (d, 1H), 2.70 (q, 1H), 1.93 - 2.07 (m, 1H), 1.79 - 1.93 (m, 2H), 1.71 (dd, 1H), 1.43 - 1.62 (m, 3H), 0.96 (d, 3H). MS ESI, m / z = 262 [M+H] +

[0146] rac-(7R,8S)-7-Methyl-1,4-dioxaspiro[4.5]decane-8-amine [ka] A suspension of palladium on carbon (10 wt.%) (3.0 g, 2.8 mmol) and rac-(7R,8S)-N-benzyl-7-methyl-1,4-dioxaspiro[4.5]decan-8-amine (20.0 g, 76.5 mmol) in MeOH (200 mL) was heated at rt with H 2 The mixture was stirred at 2 atm for 15 h under atmospheric pressure, and then the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give rac-(7R,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-amine (11.0 g, 84%) as a dark oil, which was used without further purification. 1 H NMR (300 MHz, DMSO-d 6 ) δ 3.77 - 3.87 (m, 4H), 2.79 (q, 1H), 1.65 - 1.78 (m, 2H), 1.48 - 1.6 (m, 3H), 1.06 - 1.47 (m, 4H), 0.83 (d, 3H). MS ESI, m / z = 172 [M+H] +

[0147] rac-5-bromo-6-methoxy-2-((7R,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole [ka] To a solution of 5-bromo-4-methoxy-2-nitrobenzaldehyde (Int 1) (16.6 g, 65.2 mmol) in i-PrOH (102 mL), rac-(7R,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-amine (10.2 g, 59.6 mmol) was added in N 2The mixture was stirred at 80° C. for 3 h and then cooled to rt, followed by the addition of tri-n-butylphosphine (46.8 g, 231.3 mmol). The reaction mixture was stirred at 80° C. for 11 h, then cooled and stirred at 0° C. for 1 h. The resulting suspension was filtered through filter paper and the collected solid was suspended in i-PrOH (60 mL) / n-heptane (36 mL) and stirred at 60° C. for 1 day. After cooling to rt, the desired product was obtained by filtration to give rac-5-bromo-6-methoxy-2-((7R,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole (16.3 g, 72%) as a grey solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.25 (s, 1H), 7.97 (s, 1H), 7.15 (s, 1H), 4.66 (q, 1H), 3.83 - 3.98 (m, 7H), 2.24 - 2.40 (m, 2H), 2.00 - 2.16 (m, 3H), 1.57 - 1.70 (m, 2H), 0.55 (d, 3H). MS ESI, m / z = 381 / 383 [M+H] +

[0148] rac-(3R,4S)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-methylcyclohexan-1-one [ka] To a solution of rac-5-bromo-6-methoxy-2-((7R,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole (16.3 g, 42.6 mmol) in THF / water (300 mL 1:1) was added 12N aqueous HCl (60 mL, 720.0 mmol). The reaction mixture was stirred at rt for 2 h, after which the pH of the mixture was adjusted to pH 6 with 2N aqueous NaOH. The THF was removed under reduced pressure to give an aqueous suspension. The suspension was filtered and the collected precipitate was washed with PE (100 mL) and dried under reduced pressure to give rac-(3R,4S)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-methylcyclohexan-1-one (13.70 g, 95%) as a pale yellow solid, which was used without further purification. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.35 (d, 1H), 8.01 (s, 1H), 7.15 (s, 1H), 5.02 (dt, 1H), 3.87 (s, 3H), 2.61 - 2.8 (m, 2H), 2.24 - 2.61 (m, 5H), 0.60 (d, 3H). MS ESI, m / z = 337 / 339 [M+H] +

[0149] rac-(3R,4S)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-N,3-dimethylcyclohexan-1-amine [ka] To a solution of rac-(3R,4S)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-methylcyclohexan-1-one (780 mg, 2.3 mmol) and methanamine (33 wt.% in MeOH) (2.2 g, 23.1 mmol) in DCE (10 mL) was added sodium triacetoxyborohydride (1.5 g, 6.9 mmol). The resulting mixture was stirred at 25° C. for 1 h, quenched with water (20 mL), and extracted with DCM (50 mL×2). The combined organic layers were washed with Na 2 SO 4Drying at 40° C., filtration, and concentration under reduced pressure afforded rac-(3R,4S)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-N,3-dimethylcyclohexan-1-amine (800 mg, 98%) as a yellow solid, which was used without further purification. MS ESI, m / z = 352 / 354 [M+H] +

[0150] rac-N-((3R,4S)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-methylcyclohexyl)-N-methylacetamide [ka] To a solution of rac-(3R,4S)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-N,3-dimethylcyclohexan-1-amine (780 mg, 2.2 mmol) and TEA (1.2 mL, 8.9 mmol) in DCM (10 mL) was added acetic anhydride (452 ​​mg, 4.4 mmol). The resulting mixture was stirred at rt for 1 h. The reaction mixture was then concentrated under reduced pressure and purified by C18-flash chromatography (eluted with 0-100% MeCN in water (0.1% FA)) to give rac-N-((3R,4S)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-methylcyclohexyl)-N-methylacetamide (720 mg, 82%) as a solid. 1 H NMR (300 MHz, DMSO-d 6 )(4:5 stereoisomer mixture) δ 8.29 / 8.28 (s, 1H)(stereoisomer), 8.00 (s, 1H), 7.11 (s, 1H), 4.61 - 4.69 (m, 1H), 4.46 - 4.61 / 3.85 - 3.92 (m, 1H)(stereoisomer), 3.89 (s, 3H), 2.97 / 2.84 (s, 3H)(stereoisomer), 1.93 - 2.24 (m, 7H), 1.22 - 1.55 (m, 2H), 0.52 - 0.6 (m, 3H). MS ESI, m / z = 394 / 396 [M+H] +

[0151] rac-Methyl 6-methoxy-2-((1S,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxylate [ka] rac-N-((3R,4S)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-methylcyclohexyl)-N-methylacetamide (720 mg, 1.8 mmol), Pd(dppf)Cl in MeOH (10 mL) 2 A mixture of (267 mg, 0.4 mmol) and DIPEA (1.6 mL, 9.1 mmol) was stirred in a sealed vessel under a CO atmosphere at 15 atm, then heated at 110 °C for 15 h, after which it was concentrated under reduced pressure. The residue was purified by C18-flash chromatography (0–100% MeCN in water (0.05% NH 4 Purification by elution with (1S,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxylate (640 mg, 94%) as a waxy yellow solid. 1 H NMR (300 MHz, DMSO-d 6 )(4:5 stereoisomer mixture) δ 8.46 / 8.45 (s, 1H)(stereoisomer), 8.10 (s, 1H), 7.05 (s, 1H), 4.62 - 4.73 (m, 1H), 4.47 - 4.62 (m, 1H), 4.47 - 4.62 / 3.81 - 3.92 (m, 1H)(stereoisomer), 3.84 (s, 3H), 3.78 (s, 3H), 2.97 / 2.84 (s, 3H)(stereoisomer),1.90 - 2.37 (m, 7H), 1.22 - 1.58 (m, 2H), 0.53 - 0.63 (m, 3H). MS ESI, m / z = 374 [M+H] +

[0152] rac-6-Methoxy-2-((1S,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxylic acid [ka] A solution of rac-methyl 6-methoxy-2-((1S,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxylate (620 mg, 1.7 mmol) in MeOH (3 mL) was added at rt with 2 A solution of LiOH (119 mg, 5.0 mmol) in water (3 mL) was added under atmosphere. The resulting solution was stirred at rt for 2 h. The pH of the reaction mixture was then adjusted to pH 6 with 2N HCl. The mixture was directly purified by C18-flash chromatography (eluted with 5-100% MeCN in water (0.05% FA)) to give rac-6-methoxy-2-((1S,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxylic acid (590 mg, 99%) as a colorless solid. 1 H NMR (300 MHz, DMSO-d 6 )(2:3 stereoisomer mixture) δ 8.43 / 8.42 (s, 1H)(stereoisomer), 8.07 (s, 1H), 7.03 (s, 1H), 4.62 - 4.71 (m, 1H), 4.47 - 4.62 / 3.79 - 3.93 (m, 1H)(stereoisomer), 3.84 (s, 3H), 2.97 / 2.84 (s, 3H)(stereoisomer), 2.43 - 2.65 (m, 1H), 1.92 - 2.38 (m, 7H), 1.22 - 1.60 (m, 2H), 0.51 - 0.65 (m, 3H). MS ESI, m / z = 360 [M+H] +

[0153] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2S,4R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide, Example 4 [ka] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1S,2R,4S)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide, Example 5 [ka] rel-6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2S,4S)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 1, Example 6 and Isomer 2, Example 7 [ka] A solution of rac-6-methoxy-2-((1S,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxylic acid (550 mg, 1.5 mmol), HATU (698 mg, 1.8 mmol) and DIPEA (1.3 mL, 7.7 mmol) in DMF (7 mL) was added to a reaction mixture containing 100 mL of 1000 mM tris(2,4-dichlorophenyl)-1,2-dimethylphenylacetamide (DMF) and 1000 mM tris(2,4-dichlorophenyl)acetamide (DMF). The mixture was cooled to 25° C. and cooled to 37° C. for 1 hour. 2 3-Amino-1-methylpyridin-2(1H)-one hydrochloride (614 mg, 3.8 mmol) was added under atmospheric conditions. The reaction mixture was stirred at rt for 2 h and then concentrated under reduced pressure. The residue was purified by C18-flash chromatography (0-100% MeCN in water (0.05% NH 4 The mixture was purified by elution with 2-(2,4-dihydro-1,2-tetrahydropyridin-3-yl)-2-((1R,2S,4R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (130 mg) and rac-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2S,4S)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (450 mg).

[0154] rac-6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2S,4R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide Preparative Chiral HPLC (Chiralpak (登録商標) Separation by IA, 5 μm 21.2 mm × 150 mm; isocratic with 50% MTBE in EtOH for 30 min; 20.0 mL / min) afforded 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2S,4R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (31 mg, 4%, 100% ee) and 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1S,2R,4S)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (30 mg, 4%, 99.8% ee), both as colorless solids.

[0155] rac-6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2S,4S)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide Preparative Chiral HPLC (Chiralpak (登録商標) IH, 5 μm 20 mm × 250 mm; 80% MTBE (0.5% 2M NH) in EtOH for 14 min 3-MeOH solution) isocratic; 20.0 mL / min) to give rel-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2S,4S)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - isomer 1 (177 mg, 25%, 100% ee) and rel-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2S,4S)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - isomer 2 (169 mg, 24%, 100% ee), both as colorless solids.

[0156] (1R,2S,4R)-isomer, Example 4: 1 H NMR (400 MHz, DMSO-d 6 )(2:3 mixture of rotamers) δ 11.04 (s, 1H), 8.59 / 8.57 (s, 1H)(rotamers), 8.54 / 8.51 (s, 1H)(rotamers), 8.45 (dd, 1H), 7.43 (dd, 1H), 7.20 - 7.25 (m, 1H), 6.31 (t, 1H), 4.58 - 4.73 (m, 1H), 4.58 - 4.73 / 3.84 - 3.98 (m, 1H)(rotamers), 4.07 (s, 3H), 3.56 (s, 3H), 2.84 / 2.72 (s, 3H)(rotamers), 2.62 - 2.70 (m, 1H), 2.31 - 2.45 (m, 1H), 1.93 - 2.19 (m, 5H), 1.63 - 1.93 (m, 2H), 1.55 - 1.63 / 1.40 - 1.51 (m, 1H)(rotamer), 0.67 / 0.63 (d, 3H)(rotamer). MS ESI, m / z = 466 [M+H] +

[0157] (1S,2R,4S)-isomer, Example 5: 1 H NMR (400 MHz, DMSO-d 6)(2:3 heterosexual mixture) δ 11.04 (s, 1H), 8.59 / 8.57 (s, 1H)(isosexual body), 8.54 / 8.50 (s, 1H)(isosexual body), 8.45 (dd, 1H), 7.43 (dd, 1H), 7.20 - 7.25 (m, 1H), 6.31 (t, 1H), 4.60 - 4.72 (m, 1H), 4.60 - 4.72 / 3.84 - 3.98 (m, 1H) (reverse body), 4.07 (s, 3H), 3.56 (s, 3H), 2.84 / 2.72 (s, 3H)(cycloisomer), 2.62 - 2.70 (m, 1H), 2.31 - 2.45 (m, 1H), 1.97 - 2.16 (m, 5H), 1.63 - 1.91 (m, 2H), 1.55 - 1.63 / 1.42 - 1.50 (m, 1H)(cycloisomer), 0.67 / 0.63 (d, 3H)(cycloisomer). MS ESI, m / z = 466 [M+H] +

[0158] (1R, 2S, 4S)-heterosexual body 1, Example 6: 1 H NMR (400 MHz, DMSO-d 6 )(5:4 heterosexual mixture) δ 11.03 (s, 1H), 8.60 (s, 1H), 8.58 / 8.56 (s, 1H)(reverse body), 8.45 (dd, 1H), 7.43 (dd, 1H), 7.22 (s, 1H), 6.31 (t, 1H), 4.66 - 4.75 (m, 1H), 4.50 - 4.61 / 3.82 - 3.92 (m, 1H) (reverse body), 4.09 (s, 3H), 3.56 (s, 3H), 2.98 / 2.85 (s, 3H) (return to the opposite sex), 2.40 - 2.69 (m, 1H), 1.95 - 2.39 (m, 7H), 1.49 - 1.57 / 1.33 - 1.41 (m, 1H)(cycloisomer), 1.41 - 1.49 / 1.26 - 1.33 (m, 1H)(cycloisomer), 0.53 - 0.66 (m, 3H). MS ESI, m / z = 466 [M+H] +

[0159] (1R,2S,4S)-Isomer 2, Example 7: 1 H NMR (400 MHz, DMSO-d 6 )(5:4 mixture of rotamers) δ 11.03 (s, 1H), 8.60 (s, 1H), 8.58 / 8.56 (s, 1H)(rotamers), 8.45 (dd, 1H), 7.43 (dd, 1H), 7.22 (s, 1H), 6.31 (t, 1H), 4.66 - 4.75 (m, 1H), 4.49 - 4.61 / 3.81 - 3.94 (m, 1H)(rotamers), 4.09 (s, 3H), 3.56 (s, 3H), 2.98 / 2.85 (s, 3H)(rotamers), 2.40 - 2.67 (m, 1H), 1.96 - 2.39 (m, MS ESI, m / z = 466 [M+H] +

[0160] 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (Example 8) tert-Butyl ((1r,4r)-4-(6-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate [ka] A solution of 2-((1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (Int 5) (120 mg, 0.3 mmol), 3-amino-1-methylpyridin-2(1H)-one (44 mg, 0.4 mmol) and DIPEA (156 μL, 0.9 mmol) in DMF (5 mL) was heated at 25 °C with N 2 HATU (170 mg, 0.5 mmol) was added under atmospheric pressure. The reaction mixture was stirred at 25° C. for 15 h. The mixture was directly purified by C18-flash chromatography (eluted with 0-100% MeCN in water (0.1% FA)) to give tert-butyl ((1r,4r)-4-(6-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate (110 mg, 73%) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.04 (s, 1H), 8.54 - 8.60 (m, 2H), 8.45 (dd, 1H), 7.43 (dd, 1H), 7.22 (s, 1H), 6.31 (t, 1H), 4.39 - 4.55 (m, 1H), 4.06 (s, 3H), 3.75 - 4.04 (m, 1H), 3.56 (s, 3H), 2.72 (s, 3H), 2.11 - 2.24 (m, 2H), 1.90 - 2.06 (m, 2H), 1.65 - 1.90 (m, 4H), 1.42 (s, 9H). MS ESI, m / z = 510 [M+H] +

[0161] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxamide [ka] tert-Butyl ((1r,4r)-4-(6-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate (100 mg, 0.2 mmol) was dissolved in 2N HCl in dioxane (8.0 mL, 16.0 mmol) at 25 °C and cooled to 37 °C with N 2 The resulting mixture was stirred at 25° C. for 2 h and then concentrated under reduced pressure to give 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxamide (95 mg, 100%) as the HCl salt, which was used without further purification. 1 H NMR (400 MHz, DMSO-d 6 )(HCl salt) δ 11.03 (s, 1H), 8.97 - 9.11 (m, 2H), 8.57 (s, 2H), 8.44 (dd, 1H), 7.43 (dd, 1H), 7.21 (s, 1H), 6.31 (t, 1H), 4.46 - 4.58 (m, 1H), 4.06 (s, 3H), 3.56 (s, 3H), 3.00 - 3.16 (m, 1H), 2.56 (t, 3H), 2.16 - 2.29 (m, 4H), 1.89 - 2.05 (m, 2H), 1.54 - 1.69 (m, 2H). MS ESI, m / z = 410 [M+H] +

[0162] (R)-1-(((1r,4R)-4-(6-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)amino)-1-oxopropan-2-yl acetate [ka] A solution of 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxamide (90 mg, 0.2 mmol) and the HCl salt of TEA (113 μL, 0.8 mmol) in DCM (8 mL) was added to a 25° C. 2 (R)-1-chloro-1-oxopropan-2-yl acetate (46 mg, 0.3 mmol) was added under atmospheric pressure. The resulting solution was stirred at 25° C. for 2 h and then washed with saturated NH 4 The organic layer was poured into a Cl solution (10 mL) and extracted with DCM (25 mL x 2). 2 SO 4 Drying at 40° C., filtering and concentrating under reduced pressure gave (R)-1-(((1r,4R)-4-(6-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)amino)-1-oxopropan-2-yl acetate (100 mg, 95%) as a yellow solid which was used without further purification. 1 H NMR (400 MHz, DMSO-d 6 )(5:4 rotamer mixture) δ 11.04 (s, 1H), 8.53 - 8.61 (m, 2H), 8.45 (dd, 1H), 7.43 (dd, 1H), 7.22 / 7.20 (s, 1H)(rotamer), 6.31 (t, 1H), 5.46 / 5.28 (q, 1H)(rotamer), 4.40 - 4.58 (m, 1H), 4.29 - 4.40 (m, 1H), 4.06 (s, 3H), 3.56 (s, 3H), 2.91 / 2.75 (s, 3H)(rotamer), 1.58 - 2.28 (m, 11H), 1.33 / 1.31 (d, 3H)(rotamer). MS ESI, m / z = 524 [M+H] +

[0163] 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide, Example 8 [ka] A solution of (R)-1-(((1r,4R)-4-(6-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)amino)-1-oxopropan-2-yl acetate (90 mg, 0.2 mmol) in THF / water (8 mL, 1:1) was added at 25 °C under reduced pressure. 2 LiOH (21 mg, 0.9 mmol) was added under atmospheric pressure. The resulting solution was stirred at 25° C. for 2 h and then saturated NH 4 The organic layer was poured into a Cl solution (10 mL) and extracted with DCM (25 mL x 3). 2 SO 4 The residue was purified by preparative HPLC (Xbridge (登録商標) BEH OBD C18 5 μm 30 × 150 mm; elution gradient 18–38% MeCN in water (10 mM NH 4 HCO 3 +0.1%NH 4 60 mL / min) of the 4-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (52 mg, 63%), Example 8, as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d 6)(5:4 rotamer mixture) δ 11.05 (s, 1H), 8.54 - 8.61 (m, 2H), 8.45 (dd, 1H), 7.43 (dd, 1H), 7.22 / 7.20 (s, 1H)(rotamer), 6.31 (t, 1H), 4.86 - 5.02 / 4.66 - 4.86 (m, 1H)(rotamer), 4.33 - 4.58 / 3.93 - 4.03 (m, 3H)(rotamer), 4.07 (s, 3H), 3.56 (s, 3H), 2.90 / 2.76 (s, 3H)(rotamer), 2.14 - 2.26 (m, 2H), 1.58 - 2.14 (m, 6H), 1.21 / 1.18 (d, 3H) (rotamer). MS ESI, m / z = 482 [M+H] +

[0164] N-(1-(fluoromethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxamide (Example 9) 1-(Fluoromethyl)-3-nitropyridin-2(1H)-one [ka] 3-Nitropyridin-2(1H)-one (300 mg, 2.1 mmol) and K 2 CO 3 A suspension of (888 mg, 6.4 mmol) in DMF (8 mL) was added at 25 °C and N 2 Fluoroiodomethane (856 mg, 5.4 mmol) was added under atmospheric pressure. The resulting mixture was heated at 80° C. for 2 h, then quenched with water (20 mL) and extracted with DCM / i-PrOH (3 / 1) (25 mL×3). The organic layer was extracted with Na 2 SO 4 The residue was purified by preparative HPLC (Waters SunFire). (登録商標)Purification (C18 OBD, 5 μm 30 × 150 mm; elution gradient 4 to 20% MeCN in water (0.1% TFA) over 7 min; 60 mL / min) afforded 1-(fluoromethyl)-3-nitropyridin-2(1H)-one (130 mg, 35%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.51 (dd, 1H), 8.32 (dd, 1H), 6.53 (dd, 1H), 6.05 (d, 2H). MS ESI, m / z = 173 [M+H] +

[0165] 3-Amino-1-(fluoromethyl)pyridin-2(1H)-one [ka] A suspension of 1-(fluoromethyl)-3-nitropyridin-2(1H)-one (120 mg, 0.7 mmol) and zinc (228 mg, 3.5 mmol) in THF / MeOH (1:2, 6 mL) was added at 25 °C under reduced pressure. 2 Under atmospheric conditions, NH 4 A solution of Cl (186 mg, 3.5 mmol) in water (2 mL) was added. The resulting suspension was heated at 60° C. for 2 h. The reaction mixture was filtered through silica gel and the silica gel cake was washed with MeOH (20 mL). The combined filtrate was concentrated under reduced pressure. The residue was dissolved in 30% NH 4 The mixture was basified with aqueous OH, diluted with water (10 mL) and extracted with EtOAc (25 mL×3). 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (eluted with 50% EtOAc in PE) to give 3-amino-1-(fluoromethyl)pyridin-2(1H)-one (70 mg, 71%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.02 (dd, 1H), 6.45 (dd, 1H), 6.10 (t, 1H), 5.95 (d, 2H), 5.26 (s, 2H). MS ESI, m / z = 143 [M+H] +

[0166] N-(1-(fluoromethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxamide, Example 9 [ka] A solution of 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (Int 6) (40 mg, 0.1 mmol), HATU (49 mg, 0.1 mmol) and DIPEA (74 µL, 0.4 mmol) in DMF (3 mL) was heated at 25 °C with N 2 The mixture was stirred under atmospheric pressure for 1 h, followed by the addition of 3-amino-1-(fluoromethyl)pyridin-2(1H)-one (53 mg, 0.4 mmol). The resulting solution was stirred at 60 °C for 12 h. The reaction mixture was directly purified by preparative HPLC (YMC-Actus Triart C18 ExRS 5 μm 30 × 150 mm; elution gradient 24-36% MeCN in water (10 mM NH 4 HCO 3 +0.1%NH 4 The N-(1-(fluoromethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxamide (23 mg, 43%), Example 9, was purified twice for 10 min at 60 mL / min to afford N-(1-(fluoromethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxamide (23 mg, 43%), Example 9, as a colorless solid. 1 H NMR (400 MHz, DMSO-d 6)(5:6 rotamer mixture) δ 11.05 (s, 1H), 8.56 - 8.63 (m, 2H), 8.51 (dd, 1H), 7.57 (dd, 1H), 7.24 / 7.21 (s, 1H)(rotamer), 6.41 (t, 1H), 6.07 (d, 2H), 4.93 / 4.75 (d, 1H)(rotamer), 4.33 - 4.59 / 3.93 - 4.04 (m, 3H)(rotamer), 4.08 (s, 3H), 2.91 (s, 2H), 2.76 (s, 1H), 2.91 / 2.76 (s, 3H)(rotamer), 2.15 - 2.27 (m, 2H), 1.6 - 2.15 (m, 6H), 1.22 / 1.18 (d, 3H)(rotamer). MS ESI, m / z = 500 [M+H] +

[0167] N-(1-(cyanomethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxamide (Example 10) [ka] A solution of 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (Int 6) (40 mg, 0.1 mmol), HATU (49 mg, 0.1 mmol) and DIPEA (74 µL, 0.4 mmol) in DMF (3 mL) was heated at 25 °C for 3 h under N 2 The mixture was stirred under atmospheric pressure for 1 h, followed by the addition of 2-(3-amino-2-oxopyridin-1(2H)-yl)acetonitrile (40 mg, 0.3 mmol). The reaction mixture was stirred at 60° C. for 2 h. The mixture was directly analyzed by preparative HPLC (Xbridge (登録商標) BEH OBD C18 5 μm 30 × 150 mm; elution gradient 21–36% MeCN in water (10 mM NH 4 HCO 3 +0.1%NH 4OH) solution for 8 min; 60 mL / min) to afford N-(1-(cyanomethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxamide (29 mg, 55%), Example 10, as a colorless solid. 1 H NMR (400 MHz, DMSO-d 6 )(5:6 rotamer mixture) δ 11.03 (s, 1H), 8.55 - 8.64 (m, 2H), 8.51 (dd, 1H), 7.51 (dd, 1H), 7.24 / 7.22 (s, 1H)(rotamer), 6.45 (t, 1H), 5.16 (s, 2H), 4.93 / 4.75 (d, 1H)(rotamer), 4.34 - 4.57 / 3.93 - 4.03 (m, 3H)(rotamer), 4.09 (s, 3H), 2.91 / 2.76 (s, 3H)(rotamer), 2.15 - 2.26 (m, 2H), 1.62 - 2.15 (m, 6H), 1.22 / 1.18 (d, 3H) (rotamer). MS ESI, m / z = 507 [M+H] +

[0168] N-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1S,4r)-4-((S)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxamide (Example 11) tert-Butyl ((1r,4r)-4-(5-((1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate [ka] A solution of 2-((1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (Int 5) (300 mg, 0.7 mmol), HATU (339 mg, 0.9 mmol) and DIPEA (519 μL, 3.0 mmol) in DMF (5 mL) was added to a flask at 25 °C under reduced pressure with N 2 3-Amino-1-cyclopropylpyridin-2(1H)-one hydrochloride (167 mg, 0.9 mmol) was added under atmospheric conditions. The reaction mixture was stirred at 25° C. for 15 h. The mixture was directly purified by C18-flash chromatography (0-100% MeCN in water (0.05% NH 4 The mixture was purified by elution with 5-(5-((1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate (300 mg, 75%) as a colorless solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.05 (s, 1H), 8.53 - 8.59 (m, 2H), 8.42 (dd, 1H), 7.29 (dd, 1H), 7.22 (s, 1H), 6.27 (t, 1H), 4.37 - 4.54 (m, 1H), 4.07 (s, 3H), 3.76 - 4.03 (m, 1H), 3.39 - 3.49 (m, 1H), 2.71 (s, 3H), 2.09 - 2.26 (m, 2H), 1.87 - 2.08 (m, 2H), 1.59 - 1.86 (m, 4H), 1.41 (s, 9H), 0.97 - 1.09 (m, 2H), 0.81 - 0.93 (m, 2H). MS ESI, m / z = 536 [M+H] +

[0169] N-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)-6-methoxy-2-((1r,4r)-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxamide [ka] A solution of tert-butyl ((1r,4r)-4-(5-((1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate (295 mg, 0.6 mmol) in DCM (1 mL) was added with 4N HCl in dioxane (688 μL, 2.8 mmol) at 25 °C under reduced pressure. 2 The resulting mixture was stirred at 25° C. for 17 h and then concentrated under reduced pressure to give the HCl salt of N-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)-6-methoxy-2-((1r,4r)-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxamide (260 mg, 100%) as a colorless solid, which was used without further purification. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.04 (s, 1H), 8.57 (s, 2H), 8.42 (dd, 1H), 7.29 (dd, 1H), 7.21 (s, 1H), 6.27 (t, 1H), 4.43 - 4.58 (m, 1H), 4.07 (s, 3H), 3.39 - 3.48 (m, 1H), 2.97 - 3.13 (m, 1H), 2.54 (t, 3H), 2.13 - 2.31 (m, 4H), 1.86 - 2.06 (m, 2H), 1.52 - 1.71 (m, 2H), 0.97 - 1.10 (m, 2H), 0.85 - 0.93 (m, 2H). MS ESI, m / z = 436 [M+H] +

[0170] (S)-1-(((1r,4S)-4-(5-((1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)amino)-1-oxopropan-2-yl acetate [ka] To a solution of N-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)-6-methoxy-2-((1r,4r)-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxamide HCl salt (255 mg, 0.5 mmol) and TEA (226 μL, 1.6 mmol) in DCM (20 mL) at 0° C., N 2 (S)-1-chloro-1-oxopropan-2-yl acetate (114 mg, 0.8 mmol) was added under atmospheric pressure. The resulting mixture was stirred at 25° C. for 30 min, then quenched with water (25 mL) and extracted with DCM (15 mL). The organic layer was washed with Na 2 SO 4 The residue was purified by C18-flash chromatography (0-100% MeCN in water (0.05% NH 4 The crude product was purified by elution with 3-chloro-2-phenylindole (OH) solution) to give (S)-1-(((1r,4S)-4-(5-((1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)amino)-1-oxopropan-2-yl acetate (295 mg, 99%) as a colorless solid. 1 H NMR (300 MHz, DMSO-d 6 )(2:3 mixture of rotamers) δ 11.05 (s, 1H), 8.50 - 8.59 (m, 2H), 8.42 (dd, 1H), 7.29 (dd, 1H), 7.22 / 7.20 (s, 1H)(rotamers), 6.27 (t, 1H), 5.45 / 5.27 (q, 1H)(rotamers), 4.40 - 4.56 (m, 1H), 4.26 - 4.39 / 3.71 - 3.86 (m, 1H)(rotamers), 4.07 (s, 3H), 3.39 - 3.49 (m, 1H), 2.90 / 2.74 (s, 3H)(rotamers), 1.69 - 2.28 (m, 10H), 1.54 - 1.68 (m, 1H), 1.31 (t, 3H), 0.98 - 1.11 (m, 2H), 0.84 - 0.94 (m, 2H). MS ESI, m / z = 550 [M+H]+

[0171] N-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1S,4r)-4-((S)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxamide, Example 11 [ka] A solution of (S)-1-(((1r,4S)-4-(5-((1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)amino)-1-oxopropan-2-yl acetate (290 mg, 0.5 mmol) in MeOH (10 mL) was added at 25 °C under reduced pressure. 2 A solution of LiOH (38 mg, 1.6 mmol) in water (10 mL) was added under atmospheric pressure. The resulting solution was stirred at 25 °C for 15 h. The reaction mixture was directly purified by C18-flash chromatography (20-50% MeCN in water (0.05% NH 4 The extract was purified by elution with N-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1S,4r)-4-((S)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxamide (250 mg, 93%, 99.8% ee), Example 11, as a colorless solid. 1 H NMR (400 MHz, DMSO-d 6)(2:3 rotamer mixture) δ 11.05 (s, 1H), 8.53 - 8.61 (m, 2H), 8.42 (dd, 1H), 7.29 (dd, 1H), 7.22 / 7.19 (s, 1H)(rotamer), 6.27 (t, 1H), 4.91 / 4.75 (br.s, 1H)(rotamer), 4.32 - 4.56 / 3.91 - 4.03 (m, 3H)(rotamer), 4.07 (s, 3H), 3.40 - 3.48 (m, 1H), 2.90 / 2.75 (s, 3H)(rotamer), 1.71 - 2.27 (m, 7H), 1.60 - 1.70 (m, 1H), 1.21 / 1.17 (d, 3H)(rotamer), 0.99 - 1.08 (m, 2H), 0.86 - 0.92 (m, 2H). MS ESI, m / z = 508 [M+H] +

[0172] N-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxamide (Example 12) [ka] A solution of 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (Int 6) (200 mg, 0.5 mmol), 3-amino-1-cyclopropylpyridin-2(1H)-one (120 mg, 0.8 mmol) and DIPEA (372 μL, 2.1 mmol) in DMF (2 mL) was diluted with N 2 Under atmospheric conditions, HATU (243 mg, 0.6 mmol) was added. The reaction mixture was stirred at 20° C. for 17 h. The reaction mixture was directly purified by C18-flash chromatography (eluted with 0-100% MeCN in water (0.05% FA)) and further by preparative HPLC (YMC-Actus Triart C18 5 μm 30 × 150 mm; elution gradient 15-40% MeCN in water (10 mM (NH 4 )2 CO 3 +0.1%NH 4 OH) solution for 10 min; 60 mL / min) to afford N-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxamide (32 mg, 12%), Example 12, as a colorless solid. 1 H NMR (400 MHz, DMSO-d 6 )(4:5 rotamer mixture) δ 11.05 (s, 1H), 8.54 - 8.61 (m, 2H), 8.43 (dd, 1H), 7.29 (dd, 1H), 7.23 / 7.20 (s, 1H)(rotamer), 6.28 (t, 1H), 4.91 / 4.73 (d, 1H)(rotamer), 4.37 - 4.56 (m, 2H), 4.34 - 4.45 / 3.93 - 4.04 (m, 1H)(rotamer), 4.08 (s, 3H), 3.45 (tt, 1H), 2.91 / 2.77 (s, 3H)(rotamer), 2.15 - 2.28 (m, 2H), 1.96 - 2.15 (m, 2H), 1.72 - 1.96 (m, 3H), 1.68 (s, 1H), 1.16 - 1.26 (m, 3H), 1 - 1.09 (m, 2H), 0.87 - 0.95 (m, 2H). MS ESI, m / z = 508 [M+H] +

[0173] 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-(oxetan-3-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (Example 13) [ka] A solution of 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (Int 6) (50 mg, 0.1 mmol), HATU (61 mg, 0.2 mmol) and DIPEA (93 µL, 0.5 mmol) in DMF (2 mL) was added to a reaction mixture of 100 mL of 1000 mM NaCl and 1000 mM MgCl. The mixture was cooled to 37°C and cooled to 37°C. 2 Under atmospheric conditions, 3-amino-1-(oxetan-3-yl)pyridin-2(1H)-one (27 mg, 0.2 mmol) was added. The reaction mixture was stirred at 25 °C for 16 h. The mixture was directly analyzed by preparative HPLC (Waters XSelect CSH Fluoro-Phenyl OBD, 5 μm 30 × 150 mm; elution gradient 26-36% MeCN in water (0.1% FA) for 8 min at 60 mL / min; followed by Xbridge (登録商標) BEH OBD C18 5 μm 30 × 150 mm; elution gradient 17–37% MeCN in water (10 mM NH 4 HCO 3 +0.1%NH 4 OH) solution for 8 min; 60 mL / min) to afford 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-(oxetan-3-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (33 mg, 47%), Example 13, as a colorless solid. 1 H NMR (400 MHz, DMSO-d 6)(5:6 rotamer mixture) δ 10.98 (s, 1H), 8.53 - 8.63 (m, 2H), 8.49 (dd, 1H), 7.57 (dd, 1H), 7.22 / 7.19 (s, 1H)(rotamer), 6.45 (t, 1H), 5.66 (p, 1H), 4.92 (t, 2H), 4.80 (t, 2H), 4.33 - 4.57 / 3.93 - 4.02 (m, 3H)(rotamer), 4.05 (s, 3H), 2.91 / 2.76 (s, 3H)(rotamer), 2.14 - 2.28 (m, 2H), 1.61 - 2.14 (m, 6H), 1.21 / 1.18 (d, 3H)(rotamer). MS ESI, m / z = 524 [M+H] +

[0174] 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(2-oxo-1-(1H-pyrazol-4-yl)-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (Example 14) 3-Amino-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridin-2(1H)-one [ka] 3-Aminopyridin-2(1H)-one (100 mg, 0.9 mmol), N,N'-dimethylethylenediamine (160 mg, 1.8 mmol), Cs 2 CO 3 (592 mg, 1.8 mmol) and copper(I) iodide (35 mg, 0.2 mmol) in 1,4-dioxane (10 mL) at 25 °C and 2Under atmospheric pressure, 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (252 mg, 0.9 mmol) was added. The resulting mixture was heated at 105° C. for 15 h. Eleven reactions of the same scale were run in parallel. The combined reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by C18 flash chromatography (0 to 100% MeCN in water (0.05% NH 4 The resulting mixture was purified by elution with 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridin-2(1H)-one (2.1 g, 69%) as a dark oil. MS ESI, m / z = 307 [M+H] +

[0175] 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(2-oxo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide [ka] A solution of 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (Int 6) (199 mg, 0.5 mmol), HATU (242 mg, 0.6 mmol) and DIPEA (370 μL, 2.1 mmol) in DMF (10 mL) was added to the reaction mixture at 25 °C under reduced pressure. 2 Under atmospheric conditions, 3-amino-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyridin-2(1H)-one (195 mg, 0.6 mmol) was added. The reaction mixture was stirred at 25 °C for 16 h. The mixture was purified by C18-flash chromatography (5-100% MeCN in water (0.05% NH 4OH solution) to give 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(2-oxo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (193 mg, 55%) as a grey solid. 1 H NMR (300 MHz, DMSO-d 6 )(5:6 rotamer mixture) δ 11.10 (s, 1H), 8.56 - 8.64 (m, 2H), 8.55 (s, 1H), 8.51 (dd, 1H), 8.02 (s, 1H), 7.62 (dd, 1H), 7.23 / 7.20 (s, 1H)(rotamer), 6.47 (t, 1H), 5.48 (s, 2H), 4.92 / 4.74 (d, 1H)(rotamer), 4.31 - 4.59 / 3.92 - 4.03 (m, 3H)(rotamer), 4.07 (s, 3H), 3.61 (t, 2H), 2.91 / 2.77 (s, 3H)(rotamer), 1.59 - 2.30 (m, 8H), 1.14 - 1.27 (m, 3H), 0.87 (t, 2H), -0.02 (s, 9H). MS ESI, m / z = 664 [M+H] +

[0176] 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(2-oxo-1-(1H-pyrazol-4-yl)-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide, Example 14 [ka] A solution of 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(2-oxo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (190 mg, 0.3 mmol) in DCM (20 mL) was added with 4N HCl in dioxane (358 μL, 1.43 mmol) at 25 °C and cooled to 37 °C. 2 The mixture was stirred at 25° C. for 16 h and then concentrated under reduced pressure. The residue was analyzed by preparative HPLC (Xbridge (登録商標) BEH OBD C18 5 μm 30 × 150 mm; elution gradient 18–38% MeCN in water (10 mM NH 4 HCO 3 +0.1%NH 4 Purification twice with 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(2-oxo-1-(1H-pyrazol-4-yl)-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (26 mg, 17%), Example 14, as a colorless solid. 1 H NMR (400 MHz, DMSO-d 6)(5:6 rotamer mixture) δ 13.15 (br. s, 1H), 11.10 (s, 1H), 8.54 - 8.64 (m, 2H), 8.50 (dd, 1H), 8.32 (s, 1H), 7.94 (s, 1H), 7.59 (dd, 1H), 7.22 / 7.20 (s, 1H)(rotamer), 6.44 (t, 1H), 4.92 / 4.72 (d, 1H)(rotamer), 4.33 - 4.57 / 3.93 - 4.03 (m, 3H)(rotamer), 4.06 (s, 3H), 2.91 / 2.76 (s, 3H) (rotamer), 2.15 - 2.27 (m, 2H), 1.62 - 2.15 (m, 6H), 1.22 / 1.18 (d, 3H)(rotamer). MS ESI, m / z = 534 [M+H] +

[0177] 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (Example 15) [ka] A solution of 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (Int 6) (150 mg, 0.4 mmol), HATU (213 mg, 0.6 mmol) and DIPEA (209 µL, 1.2 mmol) in DMF (6 mL) was added to the reaction mixture at 25 °C under reduced pressure. 2 Under atmospheric conditions, 3-amino-1-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one (114 mg, 0.6 mmol) was added. The reaction mixture was stirred at 25° C. for 16 h. The mixture was directly purified by C18-flash chromatography (0-100% MeCN in water (0.1% NH 4 (OH) solution), followed by preparative HPLC (Xbridge (登録商標)BEH OBD C18 5 μm 30 × 150 mm; elution gradient 21–41% MeCN in water (10 mM NH 4 HCO 3 +0.1%NH 4 OH) solution for 8 min; 60 mL / min) to afford 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (64 mg, 30%), Example 15, as a colorless solid. 1 H NMR (400 MHz, DMSO-d 6 )(5:6 rotamer mixture) δ 11.09 (s, 1H), 8.55 - 8.62 (m, 2H), 8.50 (dd, 1H), 8.33 (s, 1H), 7.87 (s, 1H), 7.58 (dd, 1H), 7.22 / 7.20 (s, 1H)(rotamer), 6.45 (t, 1H), 4.91 / 4.73 (d, 1H)(rotamer), 4.34 - 4.57 / 3.94 - 4.04 (m, 3H)(rotamer), 4.07 (s, 3H), 3.91 (s, 3H), 2.91 / 2.77 (s, 3H) (rotamer), 2.15 - 2.28 (m, 2H), 1.62 - 2.15 (m, 6H), 1.22 / 1.19 (d, 1H)(rotamer). MS ESI, m / z = 548 [M+H] +

[0178] 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-(1-methyl-1H-1,2,3-triazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (Example 16) [ka] 3-Amino-1-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-2(1H)-one [ka] 3-Aminopyridin-2(1H)-one (100 mg, 0.9 mmol), 4-bromo-1-methyl-1H-1,2,3-triazole (221 mg, 1.4 mmol), Cs 2 CO 3 (592 mg, 1.8 mmol) and copper(I) iodide (35 mg, 0.2 mmol) in 1,4-dioxane (10 mL) at 25 °C and 2 N,N'-Dimethylethylenediamine (160 mg, 1.8 mmol) was added under atmospheric pressure. The resulting mixture was heated at 105 °C for 16 h. Six reactions of the same scale were run in parallel. The combined reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by C18 flash chromatography (0-30% MeCN in water (0.05% NH 4 OH solution), then twice with 0–30% MeCN in water (0.1% HCl), followed by preparative HPLC (YMC-Actus Triart C18 5 μm 30 × 150 mm; elution gradient 5–20% MeCN in water (10 mM NH 4 HCO 3 +0.1%NH 4 OH) solution for 8 min; 60 mL / min), followed by C18 flash chromatography (0–30% MeCN in water (0.05% NH 4 The mixture was purified by elution with hexanes (eluted with 3H-CHCl3) to give 3-amino-1-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-2(1H)-one (53 mg, 5%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.64 (s, 1H), 7.62 (d, 1H), 6.50 (d, 1H), 6.27 (t, 1H), 5.34 (s, 2H), 4.13 (s, 3H). MS ESI, m / z = 192 [M+H] +

[0179] 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-(1-methyl-1H-1,2,3-triazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide, Example 16 [ka] A solution of 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (Int 6) (48 mg, 0.1 mmol), 3-amino-1-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-2(1H)-one (36 mg, 0.2 mmol) and DIPEA (89 μL, 0.6 mmol) in DMF (3 mL) was cooled to 25° C. with N 2 Under atmospheric conditions, HATU (58 mg, 0.2 mmol) was added. The reaction mixture was heated at 50° C. for 16 h. The mixture was directly purified by C18-flash chromatography (0–100% MeCN in water (0.05% NH 4 OH) solution), and then preparative HPLC (YMC-Actus Triart C18 5 μm 30 × 150 mm; elution gradient 25–45% MeCN in water (10 mM NH 4 HCO 3 +0.1%NH 4 OH) solution for 10 min; 60 mL / min) to afford 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-(1-methyl-1H-1,2,3-triazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (40 mg, 61%), Example 16, as a colorless solid. 1 H NMR (400 MHz, DMSO-d 6)(5:6 rotamer mixture) δ 11.10 (s, 1H), 8.74 (s, 1H), 8.57 - 8.65 (m, 2H), 8.56 (dd, 1H), 8.07 (dd, 1H), 7.24 / 7.22 (s, 1H)(rotamer), 6.57 (t, J = 7.3 Hz, 1H), 4.92 / 4.73 (d, 1H)(rotamer), 4.33 - 4.58 / 3.93 - 4.04 (m, 3H)(rotamer), 4.17 (s, 3H), 4.09 (s, 3H), 2.91 / 2.77 (s, 3H)(rotamer), 2.15 - 2.28 (m, 2H), 1.61 - 2.15 (m, 6H), 1.22 / 1.19 (d, 3H)(rotamer). MS ESI, m / z = 549 [M+H] +

[0180] 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-(2-methyl-2H-1,2,3-triazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (Example 17) 3-Amino-1-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2(1H)-one [ka] 3-Aminopyridin-2(1H)-one (100 mg, 0.9 mmol), 4-bromo-1-methyl-1H-1,2,3-triazole (221 mg, 1.4 mmol), Cs 2 CO 3 (592 mg, 1.8 mmol) and copper(I) iodide (35 mg, 0.2 mmol) in 1,4-dioxane (10 mL) at 25 °C and 2N,N'-Dimethylethylenediamine (160 mg, 1.8 mmol) was added under atmospheric pressure. The resulting mixture was heated at 105 °C for 16 h. Six reactions of the same scale were run in parallel. The combined reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified by C18 flash chromatography (5-30% MeCN in water (0.05% NH 4 OH) solution), and then preparative HPLC (Xbridge (登録商標) BEH OBD C18 5 μm 30 × 150 mm; elution gradient 5–25% MeCN in water (10 mM NH 4 HCO 3 +0.1%NH 4 The resulting solution was purified by filtration (8 min; 60 mL / min) with 5% COOH to afford 3-amino-1-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2(1H)-one (150 mg, 14%) as a dark solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (s, 1H), 7.28 (dd, 1H), 6.48 (dd, 1H), 6.23 (t, 1H), 5.37 (s, 2H), 4.19 (s, 3H). MS ESI, m / z = 192 [M+H] +

[0181] 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-(2-methyl-2H-1,2,3-triazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide, Example 17 [ka] A solution of 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (Int 6) (60 mg, 0.2 mmol), 3-amino-1-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2(1H)-one (40 mg, 0.2 mmol) and DIPEA (112 μL, 0.6 mmol) in DMF (2 mL) was heated at 25 °C for 30 min at 40 °C for 1 h. 2 HATU (91 mg, 0.24 mmol) was added under atmospheric conditions. The reaction mixture was stirred at 50° C. for 15 hours. The mixture was directly analyzed by preparative HPLC (Xbridge (登録商標) BEH OBD C18 5 μm 30 × 150 mm; elution gradient 25–42% MeCN in water (10 mM NH 4 HCO 3 +0.1%NH 4 OH) solution for 8 min; 60 mL / min) to afford 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-(2-methyl-2H-1,2,3-triazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (34 mg, 39%), Example 17, as a colorless solid. 1 H NMR (400 MHz, DMSO-d 6 )(5:6 rotamer mixture) δ 11.09 (s, 1H), 8.56 - 8.65 (m, 2H), 8.54 (dd, 1H), 8.28 (s, 1H), 7.73 (dd, 1H), 7.23 / 7.21 (s, 1H)(rotamer), 6.53 (t, 1H), 4.94 / 4.75 (d, 1H)(rotamer), 4.33 - 4.58 / 3.93 - 4.03 (m, 3H)(rotamer), 4.23 (s, 3H), 4.07 (s, 3H), 2.91 / 2.76 (s, 3H)(rotamer), 2.14 - 2.28 (m, 2H), 1.62 - 2.14 (m, 6H), 1.22 / 1.18 (d, 3H) (rotamer). MS ESI, m / z = 549 [M+H] +

[0182] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(2-oxopyrrolidin-1-yl)cyclohexyl)-2H-indazole-5-carboxamide (Example 18) 2-((1r,4r)-4-(4-chlorobutanamido)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide [ka] To a solution of 2-((1r,4r)-4-aminocyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide HCl salt (Int 7) (150 mg, 0.3 mmol) and TEA (165 μL, 1.1 mmol) in DCM (1 mL) was added 4-chlorobutanoyl chloride (98 mg, 0.7 mmol). The resulting mixture was stirred at 25 °C for 1 h. The mixture was directly purified by C18-flash chromatography (0-100% MeCN in water (0.1% NH 4 The extract was purified by elution with 2-((1r,4r)-4-(4-chlorobutanamido)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (90 mg, 53%) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6) δ 11.03 (br. s, 1H), 8.54 - 8.62 (m, 2H), 8.47 (br. s, 1H), 8.44 (dd, 1H), 7.44 (dd, 1H), 7.19 - 7.24 (m, 1H), 6.30 (t, 1H), 4.43 - 4.54 (m, 1H), 4.06 (s, 3H), 3.58 - 3.66 (m, 3H), 3.55 (s, 3H), 2.06 - 2.29 (m, 5H), 1.85 - 2.06 (m, 5H), 1.58 - 1.72 (m, 1H), 1.36 - 1.51 (m, 1H). MS ESI, m / z = 500 / 502 (2:1) [M+H] +

[0183] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(2-oxopyrrolidin-1-yl)cyclohexyl)-2H-indazole-5-carboxamide, Example 18 [ka] To a solution of potassium tert-butoxide (9 mg, 0.1 mmol) in THF (4 mL) was added 2-((1r,4r)-4-(4-chlorobutanamido)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (20 mg, 0.04 mmol). The resulting mixture was heated at 50° C. for 10 h under reduced pressure. 2 The mixture was stirred under atmospheric pressure. Two reactions of the same scale were carried out in parallel. The combined reaction mixture was directly purified by C18 flash chromatography (0-100% MeCN in water (0.1% NH 4 OH) solution), and then preparative HPLC (YMC-Actus Triart C18 5 μm 30 × 150 mm; elution gradient 30–40% MeCN in water (10 mM NH 4 HCO 3 +0.1%NH 4OH) solution for 8 min; 60 mL / min) to afford 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(2-oxopyrrolidin-1-yl)cyclohexyl)-2H-indazole-5-carboxamide (15 mg, 41%), Example 18, as a colorless solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.04 (s, 1H), 8.58 (s, 1H), 8.57 (s, 1H), 8.45 (dd, 1H), 7.43 (dd, 1H), 7.22 (s, 1H), 6.31 (t, 1H), 4.43 - 4.54 (m, 1H), MS ESI, m / z = 464 [M+H] +

[0184] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(3-methyl-2-oxoimidazolidin-1-yl)cyclohexyl)-2H-indazole-5-carboxamide (Example 19) tert-Butyl (2-(((1r,4r)-4-(6-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl)amino)ethyl)(methyl)carbamate [ka] tert-Butyl methyl(2-oxoethyl)carbamate (20 mg, 0.1 mmol) was added to a solution of 2-((1r,4r)-4-aminocyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide HCl salt (Int 7) (79 wt.%) (50 mg, 0.1 mmol) in DCE (4 mL), followed by sodium triacetoxyborohydride (52 mg, 0.2 mmol). The resulting mixture was stirred at 25 °C for 6 h. The reaction mixture was directly purified by C18 flash chromatography (0-100% MeCN in water (0.1% NH 4 OH) to give tert-butyl (2-(((1r,4r)-4-(6-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl)amino)ethyl)(methyl)carbamate (100 mg, 52%) as a brown solid. MS ESI, m / z = 553 [M+H] +

[0185] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-((2-(methylamino)ethyl)amino)cyclohexyl)-2H-indazole-5-carboxamide [ka] To a solution of tert-butyl (2-(((1r,4r)-4-(6-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl)amino)ethyl)(methyl)carbamate (95 mg, 0.2 mmol) in DCM (15 mL) was added 2N HCl in dioxane (860 μL, 1.7 mmol) and the resulting solution was stirred at 25° C. for 4 h. The mixture was concentrated under reduced pressure to give the HCl salt of 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-((2-(methylamino)ethyl)amino)cyclohexyl)-2H-indazole-5-carboxamide (78 mg, 100%) as a brown solid. MS ESI, m / z = 453 [M+H] +

[0186] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(3-methyl-2-oxoimidazolidin-1-yl)cyclohexyl)-2H-indazole-5-carboxamide, Example 19 [ka] A solution of 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-((2-(methylamino)ethyl)amino)cyclohexyl)-2H-indazole-5-carboxamide hydrochloride (30 mg, 0.1 mmol) and DIPEA (46 μL, 0.3 mmol) in DCE (5 mL) was 2 CDI (13 mg, 0.1 mmol) was added under atmospheric pressure. The resulting solution was stirred at 60 °C for 5 h. Two reactions of the same scale were carried out in parallel. The combined reaction mixture was directly purified by preparative HPLC (YMC-Actus Triart C18 ExRS 5 μm 30 × 150 mm; elution gradient 21–43% MeCN in water (10 mM NH 4 HCO 3 +0.1%NH 4OH) solution for 8 min; 60 mL / min) to afford 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(3-methyl-2-oxoimidazolidin-1-yl)cyclohexyl)-2H-indazole-5-carboxamide (10 mg, 17%), Example 19, as a light yellow solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.04 (s, 1H), 8.54 - 8.60 (m, 2H), 8.45 (dd, 1H), 7.43 (dd, 1H), 7.22 (s, 1H), 6.31 (t, 1H), 4.40 - 4.54 (m, 1H), 4.06 (s, 3H), 3.59 - 3.74 (m, 1H), 3.56 (s, 3H), 3.16 - 3.29 (m, 4H), 2.65 (s, 3H), 2.12 - 2.31 (m, 2H), 1.92 - 2.12 (m, 2H), 1.64 - 1.83 (m, 4H). MS ESI, m / z = 479 [M+H] +

[0187] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((5s,8s)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide (Example 20) (4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)methanol [ka] To a solution of (4-aminocyclohexyl)methanol (4.2 g, 25.4 mmol) in i-PrOH (40 mL) at rt, 5-bromo-4-methoxy-2-nitrobenzaldehyde (Int 1) (6.6 g, 25.4 mmol) and TEA (10.6 mL, 76.1 mmol) were added in N 2The resulting mixture was stirred at 90 °C for 30 min, then cooled to rt, followed by the addition of tri-n-butylphosphine (15.4 g, 76.1 mmol). The reaction mixture was stirred at 90 °C for 10 h. The mixture was cooled to rt and directly purified by C-18 flash chromatography (0-100% MeCN in water (1% NH 4 The residue was purified by elution with 1,2-dichlorophenyl ether (OH) solution to give a black liquid which was used in the next step without further purification. MS ESI, m / z = 339 / 341 [M+H] +

[0188] (4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)methylcarbamate [ka] To a solution of crude (4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)methanol (7.9 g) in DCM (1000 mL) was added 2,2,2-trichloroacetyl isocyanate (5.3 g, 32.0 mmol) at 0° C. The resulting solution was warmed to rt and stirred for 2 h. Then, MeOH (20 mL) and K 2 CO 3 (320 mg, 2.3 mmol) was added. The resulting mixture was stirred at rt for 3 h and then concentrated under reduced pressure. The residue was directly purified by C-18 flash chromatography (0-100% MeCN in water (1% NH 4 The mixture was purified by elution with 5-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)methylcarbamate (6.6 g, 85%) as a dark oil. MS ESI, m / z = 382 / 384 [M+H] +

[0189] (5s,8s)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-oxa-1-azaspiro[4.5]decan-2-one [ka] (5r,8r)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-oxa-1-azaspiro[4.5]decan-2-one [ka] Magnesium oxide (3.1 g, 77.0 mmol), phenyl-λ 3 A suspension of 15.1 g (46.9 mmol) of 1-iodanediyl diacetate and crude (4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)methyl carbamate (6.4 g) in DCM (80 mL) was heated at 20 °C with N 2 Under atmospheric conditions, [Rh 2 (OAc) 4 ] (1.5 g, 3.4 mmol) was added. The resulting mixture was stirred at 40° C. for 15 h. The reaction mixture was then filtered through filter paper. The filtrate was diluted with DCM (200 mL), washed with brine (100 mL), and added with Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and then concentrated under reduced pressure. The residue was purified by C-18 flash chromatography (0-100% MeCN in water (1% NH 4 OH) solution), and then preparative SFC (GreenSep TM Basic, 5μm 30mm×150mm;CO 2 (35 °C, 100 bar) in 25% MeOH (0.5% 2M NH 3 -MeOH) isocratic at 80 mL / min to give (5s,8s)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-oxa-1-azaspiro[4.5]decan-2-one (60 mg, 1%) and (5r,8r)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-oxa-1-azaspiro[4.5]decan-2-one (150 mg, 2%), both as yellow solids. (5s,8s)-isomer: 1 H NMR (300 MHz, DMSO-d 6) δ 8.41 (s, 1H), 8.30 (s, 1H), 8.03 (s, 1H), 7.07 (s, 1H), 4.35 - 4.52 (m, 1H), 4.04 (s, 2H), 3.87 (s, 3H), 1.65 - 2.23 (m, 8H). MS ESI, m / z = 380 / 382 (1:1) [M+H] + (5r,8r)-isomer: 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.30 (s, 1H), 7.99 (s, 1H), 7.85 (s, 1H), 7.12 (s, 1H), 4.37 - 4.51 (m, 1H), 4.22 (s, 2H), 3.86 (s, 3H), 1.65 - 2.15 (m, 8H). MS ESI, m / z = 380 / 382 (1:1) [M+H] +

[0190] (5s,8s)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-1-methyl-3-oxa-1-azaspiro[4.5]decan-2-one [ka] A suspension of (5s,8s)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-oxa-1-azaspiro[4.5]decan-2-one (60 mg, 0.2 mmol) and NaH (60 wt.%) (10 mg, 0.2 mmol) in DMF (6 mL) was added to the flask at 25 °C under reduced pressure. 2 Iodomethane (67 mg, 0.5 mmol) was added under atmospheric pressure. The reaction mixture was stirred at 25° C. for 15 h, then saturated NH 4 Quenching with aqueous Cl (5 mL) and direct purification by C18-flash chromatography (eluting with 0–100% MeCN in water (0.1% FA)) afforded (5s,8s)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-1-methyl-3-oxa-1-azaspiro[4.5]decan-2-one (45 mg, 72%) as a red solid. 1H NMR (300 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.98 (s, 1H), 7.15 (s, 1H), 4.58 - 4.67 (m, 1H), 4.21 (s, 2H), 3.87 (s, 3H), 2.58 (s, 3H), 2.35 - 2.48 (m, 2H), 1.87 - 2.12 (m, 4H), 1.40 - 1.58 (m, 2H). MS ESI, m / z = 394 / 396 (1:1) [M+H] +

[0191] Methyl 6-methoxy-2-((5s,8s)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxylate [ka] (5s,8s)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-1-methyl-3-oxa-1-azaspiro[4.5]decan-2-one (45 mg, 0.1 mmol), Pd(dppf)Cl in MeOH (10 mL). 2 A mixture of (17 mg, 0.02 mmol) and TEA (250 μL, 1.8 mmol) was stirred in a sealed vessel under CO atmosphere at 10 atm and then heated at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18-flash chromatography (0-100% MeCN in water (1% NH 4 The mixture was purified by elution with (5s,8s)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxylate (40 mg, 94%) as a colorless solid. 1 H NMR (300 MHz, DMSO-d 6) δ 8.60 (s, 1H), 8.09 (s, 1H), 7.09 (s, 1H), 4.58 - 4.69 (m, 1H), 4.22 (s, 2H), 3.83 (s, 3H), 3.79 (s, 3H), 2.58 (s, 3H), 1.91 - 2.08 (m, 8H). MS ESI, m / z = 374 [M+H] +

[0192] 6-Methoxy-2-((5s,8s)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxylic acid [ka] To a solution of methyl 6-methoxy-2-((5s,8s)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxylate (38 mg, 0.1 mmol) in MeOH (1 mL) was added a solution of LiOH (7 mg, 0.3 mmol) in water (1 mL) at 25 °C. The resulting solution was stirred at 25 °C for 10 h. The pH of the reaction mixture was adjusted to pH 6 with 2N HCl. The reaction mixture was directly purified by C18-flash chromatography (eluted with 0-100% MeCN in water (0.1% FA)) to give 6-methoxy-2-((5s,8s)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxylic acid (35 mg, 96%) as a yellow solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.53 (s, 1H), 7.96 (s, 1H), 7.02 (s, 1H), 4.58 - 4.68 (m, 1H), 4.22 (s, 2H), 3.81 (s, 3H), 2.57 (s, 3H), 1.87 - 2.16 (m, 8H). MS ESI, m / z = 360 [M+H] +

[0193] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((5s,8s)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide, Example 20 [ka] A solution of 6-methoxy-2-((5s,8s)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxylic acid (33 mg, 0.1 mmol), DIPEA (17 μL, 0.1 mmol) and T3P (50 wt.% in EtOAc) (62 mg, 0.1 mmol) in DCM (0.5 mL) was added at 25 °C under reduced pressure with N 2 Under atmospheric conditions, (62 mg, 0.1 mmol) 3-amino-1-methylpyridin-2(1H)-one (24 mg, 0.2 mmol) was added. The resulting solution was stirred at 50° C. for 10 hours. The reaction mixture was concentrated under reduced pressure and then purified by preparative HPLC (Waters Xbridge (登録商標) Shield RP18 OBD, 5 μm 30 × 150 mm; elution gradient 20–35% MeCN in water (10 mM NH 4 HCO 3 +0.1%NH 4 OH) solution for 8 min, then 35% for 2 min; 60 mL / min) to afford 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((5s,8s)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide (15 mg, 35%), Example 20, as a colorless solid. 1 H NMR (300 MHz, DMSO-d 6) δ 11.05 (s, 1H), 8.72 (s, 1H), 8.59 (s, 1H), 8.45 (dd, 1H), 7.44 (dd, 1H), 7.26 (s, 1H), 6.31 (t, 1H), 4.64 - 4.73 (m, 1H), 4.23 (s, 2H), 4.08 (s, 3H), 3.56 (s, 3H), 2.59 (s, 3H), 1.90 - 2.17 (m, 4H), 1.43 - 1.61 (m, 2H). MS ESI, m / z = 466 [M+H] +

[0194] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((5r,8r)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide (Example 21) [ka] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((5r,8r)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide was reacted with (5r,8r)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-oxa This was prepared from sa-1-azaspiro[4.5]decan-2-one in a manner similar to the synthesis of 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((5s,8s)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide (Example 20) described above. Crude 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((5r,8r)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide was purified by preparative HPLC (YMC-Actus Triart C18 5 μm 30 × 150 mm; elution gradient 20–50% MeCN in water (10 mM NH 4 HCO3 +0.1%NH 4 OH) solution for 8 min; 60 mL / min), followed by preparative SFC (DAICEL DCpak® P4VP, 5 μm 30 mm × 250 mm; CO 2 (35 °C, 100 bar) in 50% IPA (0.5% 2M NH 3 -MeOH) isocratic; 60 mL / min) to afford 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((5r,8r)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide (10 mg, 14% over four steps), Example 21, as a colorless solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.04 (s, 1H), 8.58 (s, 2H), 8.45 (dd, 1H), 7.43 (dd, 1H), 7.23 (s, 1H), 6.31 (t, 1H), 4.45 - 4.61 (m, 1H), 4.27 (s, 2H), MS ESI, m / z = 466 [M+H] +

[0195] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(2-oxopyridin-1(2H)-yl)cyclohexyl)-2H-indazole-5-carboxamide (Example 22) tert-Butyl ((1r,4r)-4-(2-oxopyridin-1(2H)-yl)cyclohexyl)carbamate [ka] (1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate (1.0 g, 2.7 mmol) and Cs 2CO 3 To a solution of (2.7 g, 8.1 mmol) in THF (30 mL) was added pyridin-2(1H)-one (0.5 g, 5.4 mmol). The reaction mixture was stirred at 90 °C for 24 h, then quenched with water (300 mL) and extracted with EtOAc (300 mL × 2). The organic layer was concentrated under reduced pressure. The residue was purified by C18-flash chromatography (0-70% MeCN in water (0.1% NH 4 The mixture was purified by elution with (2-chloro-3,4-dichlorophenyl)hexane (eluted with ... 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.70 (dd, 1H), 7.34 (ddd, 1H), 6.77 (d, 1H), 6.34 (dd, 1H), 6.21 (td,), 4.60 (tt, 1H), 3.23 - 3.41 (m, 1H), 1.80 - 1.95 (m, 2H), 1.56 - 1.78 (m, 4H), 1.37 (s, 11H). MS ESI, m / z = 293 [M+H] +

[0196] 1-((1r,4r)-4-aminocyclohexyl)pyridin-2(1H)-one [ka] To a solution of tert-butyl ((1r,4r)-4-(2-oxopyridin-1(2H)-yl)cyclohexyl)carbamate (200 mg, 0.7 mmol) in DCM (5 mL) was added 4N HCl in dioxane (1.7 mL, 6.8 mmol). The resulting mixture was stirred at 25° C. for 5 h. The reaction mixture was concentrated under reduced pressure to give the HCl salt of 1-((1r,4r)-4-aminocyclohexyl)pyridin-2(1H)-one (156 mg, 100%) as a pale yellow solid, which was used without further purification. 1 H NMR (300 MHz, DMSO-d 6) δ 7.68 (dd, 1H), 7.36 (ddd, 1H), 6.36 (dd, 1H), 6.24 (td, 1H), 5.88 (br. s, 2H), 4.64 (p, 8 1H), 2.92 - 3.14 (m, 1H), 1.99 - 2.13 (m, 2H), 1.66 - 1.87 (m, 4H), 1.39 - 1.63 (m, 2H). MS ESI, m / z = 193 [M+H] +

[0197] 1-((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)pyridin-2(1H)-one [ka] A solution of 1-((1r,4r)-4-aminocyclohexyl)pyridin-2(1H)-one (145 mg, 0.6 mmol) and TEA (192 mg, 1.9 mmol) in i-PrOH (5 mL) was treated with 5-bromo-4-methoxy-2-nitrobenzaldehyde HCl salt (Int 1) (165 mg, 0.6 mmol) at 25 °C under N 2 The resulting mixture was stirred at 80° C. for 1 h, then cooled to rt, followed by the addition of tri-n-butylphosphine (385 mg, 1.9 mmol). The reaction mixture was stirred at 80° C. for 13 h, then concentrated under reduced pressure. The residue was purified by C18-flash chromatography (0-100% MeCN in water (0.1% NH 4 The mixture was purified by elution with 5-(2,4-dichlorophenyl)-2,4-dihydro-1,2,3,4-tetrahydrofuran (PE) (elution with 5-methyl-2,4-dihydro-1,2,3,4-tetrahydrofuran (PE) solution) to give a mixture of the desired product and tri-n-butylphosphine. The mixture was then washed with PE (25 mL) to give 1-((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)pyridin-2(1H)-one (170 mg, 67%) as a pale yellow solid. 1 H NMR (300 MHz, DMSO-d 6) δ 8.35 (s, 1H), 7.98 (s, 1H), 7.77 (dd, 1H), 7.39 (ddd, 1H), 7.12 (s, 1H), 6.40 (dd, 1H), 6.28 (td, 1H), 4.79 - 4.93 (m, 1H), 4.48 - 4.62 (m, 1H), 3.87 (s, 3H), 2.19 - 2.32 (m, 2H), 1.82 - 2.19 (m, 6H). MS ESI, m / z = 402 / 404 [M+H] +

[0198] Methyl 6-methoxy-2-((1r,4r)-4-(2-oxopyridin-1(2H)-yl)cyclohexyl)-2H-indazole-5-carboxylate [ka] 1-((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)pyridin-2(1H)-one (150 mg, 0.4 mmol), TEA (520 μL, 3.7 mmol) and Pd(dppf)Cl in MeOH (10 mL). 2 -CH 2 Cl 2 A mixture of (46 mg, 0.06 mmol) was stirred in a sealed vessel under a CO atmosphere at 15 atm and then heated at 110 °C for 15 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18-flash chromatography (0-100% MeCN in water (0.1% NH 4 The mixture was purified by elution with 2-(2-oxopyridin-1(2H)-yl)cyclohexyl)-2H-indazole-5-carboxylate (120 mg, 84%) as a colorless solid. 1 H NMR (400 MHz, DMSO-d 6) δ 8.52 (d, 1H), 8.09 (s, 1H), 7.77 (dd, 1H), 7.39 (ddd, 1H), 7.06 (s, 1H), 6.41 (dd, 1H), 6.28 (td, 1H), 4.82 - 4.92 (m, 1H), 4.52 - 4.61 (m, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 2.22 - 2.31 (m, 2H), 2.05 - 2.18 (m, 2H), 1.84 - 2.05 (m, 4H). MS ESI, m / z = 382 [M+H] +

[0199] 6-Methoxy-2-((1r,4r)-4-(2-oxopyridin-1(2H)-yl)cyclohexyl)-2H-indazole-5-carboxylic acid [ka] To a solution of methyl 6-methoxy-2-((1r,4r)-4-(2-oxopyridin-1(2H)-yl)cyclohexyl)-2H-indazole-5-carboxylate (115 mg, 0.3 mmol) in MeOH / water (2:1, 7.5 mL) was added LiOH (22 mg, 0.9 mmol). The resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was acidified to pH 6 with 2N HCl and then directly purified by C18-flash chromatography (eluted with 0-70% MeCN in water (0.1% FA)) to give 6-methoxy-2-((1r,4r)-4-(2-oxopyridin-1(2H)-yl)cyclohexyl)-2H-indazole-5-carboxylic acid (109 mg, 98%) as a colorless solid. 1 H NMR (300 MHz, DMSO-d 6) δ 8.49 (s, 1H), 8.06 (s, 1H), 7.78 (dd, 1H), 7.39 (ddd, 1H), 7.03 (s, 1H), 6.41 (dd, 1H), 6.28 (td, 1H), 4.80 - 4.94 (m, 1H), 4.50 - 4.62 (m, 1H), 3.82 (s, 3H), 2.20 - 2.33 (m, 2H), 1.82 - 2.20 (m, 6H). MS ESI, m / z = 368 [M+H] +

[0200] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(2-oxopyridin-1(2H)-yl)cyclohexyl)-2H-indazole-5-carboxamide, Example 22 [ka] To a solution of 6-methoxy-2-((1r,4r)-4-(2-oxopyridin-1(2H)-yl)cyclohexyl)-2H-indazole-5-carboxylic acid (100 mg, 0.3 mmol) and DIPEA (190 μL, 1.1 mmol) in DMF (3 mL), HATU (135 mg, 0.4 mmol) was added at 25 °C under N 2 The resulting mixture was stirred at 25° C. for 5 min, followed by the addition of 3-amino-1-methylpyridin-2(1H)-one hydrochloride (87 mg, 0.5 mmol). The reaction mixture was stirred at 25° C. for 12 h. The mixture was directly purified by C18-flash chromatography (eluted with 0-70% MeCN in water (0.1% HCl) and further by preparative HPLC (Waters Xbridge (登録商標) BEH OBD C18 5 μm 30 × 150 mm; elution gradient 15–45% MeCN in water (10 mM NH 4 HCO 3 +0.1%NH 4 OH) solution for 8 min, then 45% MeCN in water (10 mM NH 4 HCO 3 +0.1%NH 4Purification by isocratic elution with N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(2-oxopyridin-1(2H)-yl)cyclohexyl)-2H-indazole-5-carboxamide (93 mg, 72%), Example 22, as a colorless solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.05 (s, 1H), 8.64 (d, 1H), 8.58 (s, 1H), 8.45 (dd, 1H), 7.78 (dd, 1H), 7.36 - 7.47 (m, 2H), 7.23 (s, 1H), 6.41 (dd, 1H), 6.26 - 6.34 (m, 2H), 4.83 - 4.93 (m, 1H), 4.55 - 4.65 (m, 1H), 4.07 (s, 3H), 3.56 (s, 3H), 2.23 - 2.35 (m, 2H), 2.14 (qd, 2H), 1.86 - 2.07 (m, 4H). MS ESI, m / z = 474 [M+H] +

[0201] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-(4-(pyridazin-3-yl)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 1 (Example 23) and Isomer 2 (Example 24) tert-Butyl (4-(pyridazin-3-yl)cyclohex-3-en-1-yl)carbamate [ka] tert-Butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)carbamate (2.0 g, 6.2 mmol), 3-chloropyridazine (921 mg, 8.0 mmol), Pd(dppf)Cl 2 -CH 2 Cl 2 (1.0 g, 1.2 mmol) and K 2 CO3 A suspension of (2.6 g, 18.6 mmol) in 1,4-dioxane (30 mL) was heated at 80° C. for 3 h. The reaction mixture was extracted with EtOAc (50 mL×2), and the organic layer was diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a brown oil. The residue was purified by silica gel chromatography (eluted with 100% EtOAc) to give tert-butyl (4-(pyridazin-3-yl)cyclohex-3-en-1-yl)carbamate (1.7 g, 97%) as a yellow oil. 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.07 (dd, 1H), 7.86 (dd, 1H), 7.61 (dd, 1H), 6.89 (d, 1H), 6.63 - 6.73 (m, 1H), 3.50 - 3.66 (m, 1H), 2.73 - 2.88 (m, 1H), 2.42 - 2.64 (m, 2H), 2.07 - 2.24 (m, 1H), 1.89 - 2.03 (m, 1H), 1.50 - 1.66 (m, 1H), 1.40 (s, 9H). MS ESI, m / z = 276 [M+H] +

[0202] tert-Butyl (4-(pyridazin-3-yl)cyclohexyl)carbamate [ka] A suspension of 10 wt.% palladium on carbon (0.6 g, 0.6 mmol) and tert-butyl (4-(pyridazin-3-yl)cyclohex-3-en-1-yl)carbamate (1.6 g, 5.6 mmol) in EtOAc (30 mL) was heated at 25 °C under 1 atm of H 2 The reaction mixture was stirred at room temperature for 2 hours under reduced pressure. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure to give tert-butyl (4-(pyridazin-3-yl)cyclohexyl)carbamate (1.6 g, 100%) as a brown oil, which was used without further purification. 1 H NMR (300 MHz, DMSO-d 6)(stereoisomer mixture) δ 9.02 - 9.12 (m, 1H), 7.57 - 7.74 (m, 2H), 6.95 / 6.80 (d, 1H)(stereoisomer), 3.61 - 3.78 / 3.23 - 3.38 (m, 1H)(stereoisomer), 2.72 - 3.01 (m, 1H)(stereoisomer), 1.82 - 1.97 (m, 2H), 1.52 - 1.77 (m, 4H), 1.22 - 1.47 (m, 11H). MS ESI, m / z = 278 [M+H] +

[0203] 4-(pyridazin-3-yl)cyclohexan-1-amine [ka] A mixture of tert-butyl (4-(pyridazin-3-yl)cyclohexyl)carbamate (500 mg, 1.8 mmol) and 2N HCl in dioxane (9.0 mL, 18.0 mmol) in MeOH (25 mL) was stirred for 3 h at 25° C. The reaction mixture was then concentrated under reduced pressure to give the HCl salt of 4-(pyridazin-3-yl)cyclohexan-1-amine (600 mg, quantitative yield, 64 wt.%) as a brown oil, which was used without further purification. 1 H NMR (300 MHz, DMSO-d 6 )(stereoisomer mixture) δ 9.31 - 9.54 (m, 1H), 8.18 - 8.35 (m, 2H), 3.39 - 3.46 / 3.18 - 3.32 (m, 1H)(stereoisomer), 2.98 - 3.14 (m, 1H), 2.08 - 2.34 (m, 2H), 1.86 - 2.08 (m, 2H), 1.64 - 1.86 (m, 3H), 1.45 - 1.64 (m, 1H). MS ESI, m / z = 178 [M+H] +

[0204] 5-Bromo-6-methoxy-2-(4-(pyridazin-3-yl)cyclohexyl)-2H-indazole [ka] To a solution of 5-bromo-4-methoxy-2-nitrobenzaldehyde (Int 1) (498 mg, 1.9 mmol) and TEA (1.2 mL, 8.7 mmol) in i-PrOH (20 mL), 4-(pyridazin-3-yl)cyclohexan-1-amine HCl salt (64 wt.%) (580 mg, 1.7 mmol) was added in N 2 Atmosphere was added. The resulting mixture was stirred at 80° C. for 3 h, then cooled to rt, followed by the addition of tri-n-butylphosphine (1.7 mL, 7.0 mmol). The reaction mixture was stirred at 80° C. for 11 h, then concentrated under reduced pressure. The residue was purified by C18-flash chromatography (eluted with 0-100% MeCN in water (0.1% FA)) to give 5-bromo-6-methoxy-2-(4-(pyridazin-3-yl)cyclohexyl)-2H-indazole (1.1 g, quantitative yield, 60 wt.%) as a brown oil, which was used without further purification. 1 H NMR (400MHz, DMSO-d 6 )(stereoisomer mixture) δ 9.10 / 9.08 (dd, 1H)(stereoisomer), 8.35 / 8.54 (s, 1H)(stereoisomer), 7.98 / 7.95 (s, 1H)(stereoisomer), 7.64 - 7.67 / 7.60 - 7.63 (m, 2H)(stereoisomer), 7.14 / 7.13 (s, 1H)(stereoisomer), 4.63 - 4.72 / 4.51 - 4.63 (m, 1H)(stereoisomer), 3.87 / 3.85 (s, 3H)(stereoisomer), 3.16 - 3.26 / 2.99 - 3.11 (m, 1H)(stereoisomer), 2.31 - 2.45 (m, MS ESI, m / z = 387 / 389 (1:1) [M+H] +

[0205] Methyl 6-methoxy-2-(4-(pyridazin-3-yl)cyclohexyl)-2H-indazole-5-carboxylate [ka] 5-Bromo-6-methoxy-2-(4-(pyridazin-3-yl)cyclohexyl)-2H-indazole (60 wt.%) (1.1 g, 1.7 mmol), TEA (2.7 g, 27.0 mmol) and Pd(dppf)Cl 2 -CH 2 Cl 2 A mixture of (441 mg, 0.5 mmol) was stirred in a sealed vessel under a CO atmosphere at 15 atm and then heated at 110° C. for 15 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by C18-flash chromatography (eluted with 0–100% MeCN in water (0.05% FA)) to give methyl 6-methoxy-2-(4-(pyridazin-3-yl)cyclohexyl)-2H-indazole-5-carboxylate (315 mg, 49%) as a brown solid. 1 H NMR (300 MHz, DMSO-d 6 )(stereoisomer mixture) δ 9.06 - 9.13 (m, 1H), 8.5 - 8.55 (m, 1H), 8.09 - 8.16 (m, 1H), 7.61 - 7.68 (m, 2H), 7.08 (s, 1H), 4.66 - 4.75 / 4.52 - 4.66 (m, 1H)(stereoisomer), 3.76 - 3.85 (m, 6H), 3.28 - 3.13 / 2.97 - 3.13 (m, 1H)(stereoisomer), 1.81 - 2.33 (m, 8H). MS ESI, m / z = 367 [M+H] +

[0206] 6-Methoxy-2-(4-(pyridazin-3-yl)cyclohexyl)-2H-indazole-5-carboxylic acid [ka] To a solution of methyl 6-methoxy-2-(4-(pyridazin-3-yl)cyclohexyl)-2H-indazole-5-carboxylate (295 mg, 0.8 mmol) in THF / water (1:1, 30 mL) was added LiOH (193 mg, 8.1 mmol). The resulting mixture was stirred at 25° C. for 3 h. The reaction mixture was then acidified to pH 6 with 2N HCl and extracted with EtOAc (50 mL×2). The organic layer was washed with Na 2 SO 4 The residue was purified by C18-flash chromatography (eluted with 0-100% MeCN in water (0.1% FA)) to give 6-methoxy-2-(4-(pyridazin-3-yl)cyclohexyl)-2H-indazole-5-carboxylic acid (150 mg, 53%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )(1:1 stereoisomer mixture) δ 9.11 / 9.08 (dd, 1H)(stereoisomer), 8.43 / 8.42 (s, 1H)(stereoisomer), 8.38 (br. s, 1H), 7.92 / 7.90 (s, 1H)(stereoisomer), 7.58 - 7.70 (m, 2H), 6.99 (s, 1H), 4.63 - 4.73 / 4.51 - 4.62 (m, 1H)(stereoisomer), 3.80 / 3.78 (s, 3H)(stereoisomer), 3.17 - 3.26 / 3.01 - 3.11 (m, 1H)(stereoisomer), 2.35 - 2.46 (m, 1H), 2.22 - 2.32 (m, 1H), 2.00 - 2.20 (m, 4H), 1.82 - 1.97 (m, 2H). MS ESI, m / z = 353 [M+H] +

[0207] 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-(4-(pyridazin-3-yl)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 1, Example 23 and Isomer 2, Example 24 [ka] To a solution of 6-methoxy-2-(4-(pyridazin-3-yl)cyclohexyl)-2H-indazole-5-carboxylic acid (130 mg, 0.4 mmol), DIPEA (322 μL, 1.8 mmol) and 3-amino-1-methylpyridin-2(1H)-one hydrochloride (59 mg, 0.4 mmol) in DMF (10 mL) was added HATU (421 mg, 1.1 mmol) at 25 °C under N 2 The mixture was stirred at 25° C. for 15 h. The mixture was directly purified by C18-flash chromatography (eluted with 0-100% MeCN in water (0.1% FA)) and further purified by chiral preparative HPLC (Chiralpak (登録商標) IF, 5 μm 20 mm × 250 mm; 50% MTBE (0.5% 2M NH) in MeOH for 26 min 3 -MeOH solution) isocratic; 20.0 mL / min) to give 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-(4-(pyridazin-3-yl)cyclohexyl)-2H-indazole-5-carboxamide - isomer 1 (10.6 mg, 6%) and 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-(4-(pyridazin-3-yl)cyclohexyl)-2H-indazole-5-carboxamide - isomer 2 (15.1 mg, 9%) both as colorless solids. Isomer 1, Example 23: 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.04 (s, 1H), 9.09 (dd, 1H), 8.65 (s, 1H), 8.58 (s, 1H), 8.45 (dd, 1H), 7.70 - 7.58 (m, 2H), 7.43 (dd, 1H), 7.25 (s, 1H), 6.31 (d, 1H), 4.70 - 4.80 (m, 1H), 4.06 (s, 3H), 3.56 (s, 3H), 3.18 - 3.28 (m, 1H), 2.35 - 2.47 (m, 2H), 2.23 - 2.03 (m, 4H), 1.88 - 2.00 (m, 2H). MS ESI, m / z = 459 [M+H] + Isomer 2, Example 24:1 H NMR (400 MHz, DMSO-d 6 ) δ 11.05 (s, 1H), 9.11 (dd, 1H), 8.63 (s, 1H), 8.59 (s, 1H), 8.46 (dd, 1H), 7.63 - 7.73 (m, 2H), 7.44 (dd, 1H), 7.24 (s, 1H), 6.31 (t, 1H), 4.58 - 4.68 (m, 1H), 4.08 (s, 3H), 3.56 (s, 3H), 3.02 - 3.12 (m, 1H), 2.26 - 2.35 (m, 2H), 2.06 - 2.21 (m, 4H), 1.84 - 1.98 (m, 2H). MS ESI, m / z = 459 [M+H] +

[0208] 2-((1r,4r)-4-(1,3,4-oxadiazol-2-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (Example 25) Benzyl ((1r,4r)-4-(hydrazinecarbonyl)cyclohexyl)carbamate [ka] To a solution of (1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexane-1-carboxylic acid (3.0 g, 10.8 mmol) in THF (100 mL) was added CDI (2.2 g, 13.5 mmol) in one portion. The resulting solution was stirred at 25 °C for 15 h. Then, hydrazine monohydrate (2.2 g, 43.3 mmol) was added to the above solution. The resulting mixture was stirred at 25 °C for 1 h. The precipitate was collected by filtration, washed with EtOAc / PE (1:2, 150 mL), and then dried under reduced pressure to give benzyl ((1r,4r)-4-(hydrazinecarbonyl)cyclohexyl)carbamate (2.3 g, 73%) as a colorless solid, which was used without further purification. 1 H NMR (300 MHz, DMSO-d 6) δ 8.91 (s, 1H), 7.26 - 7.44 (m, 5H), 7.16 - 7.24 (m, 1H), 5.00 (s, 2H), 3.11 - 3.31 (m, 1H), 1.89 - 2.04 (m, 1H), 1.67 - 1.89 (m, 4H), 1.38 - 1.67 (m, 2H), 1.00 - 1.38 (m, 2H). MS ESI, m / z = 292 [M+H] +

[0209] Benzyl ((1r,4r)-4-(1,3,4-oxadiazol-2-yl)cyclohexyl)carbamate [ka] To a mixture of benzyl ((1r,4r)-4-(hydrazinecarbonyl)cyclohexyl)carbamate (2.1 g, 7.2 mmol) and trimethoxymethane (19.1 g, 180.2 mmol) was added 4-methylbenzenesulfonic acid (248 mg, 1.4 mmol). The resulting mixture was stirred at 90 °C for 2 h. The reaction mixture was directly purified by C18 flash chromatography (eluted with 5-80% MeCN in water (0.05% FA)) to give benzyl ((1r,4r)-4-(1,3,4-oxadiazol-2-yl)cyclohexyl)carbamate (1.5 g, 70%) as a colorless solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.13 (s, 1H), 7.26 - 7.43 (m, 6H), 5.02 (s, 2H), 3.25 - 3.80 (m, 1H), 2.90 (tt, 1H), 2.00 - 2.15 (m, 2H), 1.80 - 2.00 (m, 2H), 1.45 - 1.63 (m, 2H), 1.20 - 1.45 (m, 2H). MS ESI, m / z = 302 [M+H] +

[0210] (1r,4r)-4-(1,3,4-oxadiazol-2-yl)cyclohexan-1-amine [ka] A suspension of 10 wt.% palladium on carbon (470 mg, 0.4 mmol) and benzyl ((1r,4r)-4-(1,3,4-oxadiazol-2-yl)cyclohexyl)carbamate (1.3 g, 4.4 mmol) in MeOH (60 mL) was stirred at 50° C. under 1 atm of hydrogen for 2 h. The reaction mixture was then filtered through Celite. The filtrate was concentrated under reduced pressure to give (1r,4r)-4-(1,3,4-oxadiazol-2-yl)cyclohexan-1-amine (680 mg, 92%) as a colorless solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.10 (s, 1H), 2.80 - 2.95 (m, 1H), 2.51 - 2.61 (m, 1H), 1.06 - 2.18 (m, 8H)). MS ESI, m / z = 168 [M+H] +

[0211] 2-((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)-1,3,4-oxadiazole [ka] To a solution of (1r,4r)-4-(1,3,4-oxadiazol-2-yl)cyclohexan-1-amine (640 mg, 3.8 mmol) in i-PrOH (100 mL), 5-bromo-4-methoxy-2-nitrobenzaldehyde (Int 1) (1.1 g, 4.2 mmol) was added in N 2 The resulting mixture was stirred at 80° C. for 3 h, then cooled to rt, followed by the addition of tri-n-butylphosphine (3.8 mL, 15.3 mmol). The reaction mixture was stirred at 80° C. for 11 h, then concentrated under reduced pressure. The residue was purified by C18 flash chromatography (0-100% MeCN in water (0.1% NH 4The residue was eluted with 5-methyl-2-oxopropyl alcohol (OH) solution) and further purified by crystallization from PE (50 mL) to give 2-((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)-1,3,4-oxadiazole (640 mg, 44%) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.18 (s, 1H), 8.30 (d, 1H), 7.98 (s, 1H), 7.11 (s, 1H), 4.55 (tt, 1H), 3.86 (s, 3H), 3.08 - 3.17 (m, 1H), 2.17 - 2.28 (m, 4H), 2.07 (qd, 2H), 1.77 (qd, 2H). MS ESI, m / z = 377 / 379 (1:1) [M+H] +

[0212] Methyl 2-((1r,4r)-4-(1,3,4-oxadiazol-2-yl)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylate [ka] 2-((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)-1,3,4-oxadiazole (300 mg, 0.8 mmol), Pd(dppf)Cl in MeOH (10 mL) 2 -CH 2 Cl 2 A mixture of (130 mg, 0.2 mmol) and DIPEA (694 μL, 4.0 mmol) was stirred in a sealed vessel under a CO atmosphere at 15 atm and then heated at 110 °C for 12 h. The reaction mixture was purified directly by C18 flash chromatography (0–100% MeCN in water (0.1% NH 4 The mixture was purified by elution with hexanes (eluted with 1,3,4-oxadiazol-2-yl)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylate (240 mg, 85%) as a light yellow solid. 1 H NMR (300 MHz, DMSO-d6 ) δ 9.18 (s, 1H), 8.47 (s, 1H), 8.11 (s, 1H), 7.07 (s, 1H), 4.50 - 4.64 (m, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.07 - 3.21 (m, MS ESI, m / z = 357 [M+H] +

[0213] 2-((1r,4r)-4-(1,3,4-oxadiazol-2-yl)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid [ka] To a solution of methyl 2-((1r,4r)-4-(1,3,4-oxadiazol-2-yl)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylate (235 mg, 0.7 mmol) in MeOH / water (2:1, 7.5 mL) was added LiOH (40 mg, 1.7 mmol). The resulting solution was stirred at 25 °C for 5 h. The pH of the reaction mixture was then adjusted to pH 3-4 with 0.1 N HCl. The resulting precipitate was collected by filtration and dried under reduced pressure to afford 2-((1r,4r)-4-(1,3,4-oxadiazol-2-yl)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (155 mg, 69%) as a pale yellow solid, which was used without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.24 (br. s, 1H), 9.17 (s, 1H), 8.44 (s, 1H), 8.08 (s, 1H), 7.03 (s, 1H), 4.56 (tt, 1H), 3.82 (s, 3H), 3.06 - 3.16 (m, MS ESI, m / z = 343 [M+H]+

[0214] 2-((1r,4r)-4-(1,3,4-oxadiazol-2-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide, Example 25 [ka] To a solution of 2-((1r,4r)-4-(1,3,4-oxadiazol-2-yl)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (135 mg, 0.4 mmol), HATU (225 mg, 0.6 mmol) and DIPEA (207 μL, 1.2 mmol) in DMF (5 mL) was added 3-amino-1-methylpyridin-2(1H)-one hydrochloride (127 mg, 0.8 mmol). The reaction mixture was stirred at 25° C. for 1 hour at 4° C. for 2 hours at 4° C. for 1 hour. 2 The mixture was stirred under atmospheric pressure for 10 hours. (登録商標) BEH OBD C18 5 μm 30 × 150 mm; elution gradient 19–39% MeCN in water (10 mM NH 4 HCO 3 +0.1%NH 4 OH) solution for 8 min; 60 mL / min) to afford 2-((1r,4r)-4-(1,3,4-oxadiazol-2-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (105 mg, 59%), Example 25, as a colorless solid. 1 H NMR (400 MHz, DMSO-d 6) δ 11.05 (s, 1H), 9.18 (s, 1H), 8.59 (s, 2H), 8.45 (dd, 1H), 7.43 (dd, 1H), 7.23 (s, 1H), 6.31 (t, 1H), 4.55 - 4.66 (m, 1H), MS ESI, m / z = 449 [M+H] +

[0215] 2-((1r,4r)-4-(1H-1,2,4-triazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (Example 26) [ka] A solution of (1s,4s)-4-(6-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl methanesulfonate (Int 8) (400 mg, 0.8 mmol) and 4H-1,2,4-triazole (1.2 g, 16.9 mmol) in toluene (5 mL) was added to the reaction mixture, and the resulting mixture was cooled to 5° C. 2 CO 3 (824 mg, 2.5 mmol) was added. The resulting mixture was stirred at 90 °C for 15 h and then concentrated under reduced pressure. The residue was directly purified by C18-flash chromatography (0-100% MeCN in water (0.1% NH 4 OH) solution), and then preparative HPLC (Xbridge (登録商標) BEH OBD C18 5 μm 30 × 150 mm; elution gradient 15–35% MeCN in water (10 mM NH 4 HCO 3 +0.1%NH 4 OH) solution for 8 min, then 35% MeCN in water (10 mM NH 4 HCO 3 +0.1%NH4 Purification by isocratic elution with N-(1H-1,2,4-triazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (34 mg, 9%), Example 26, as a colorless solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.05 (s, 1H), 8.56 - 8.63 (m, 3H), 8.45 (dd, 1H), 8.00 (s, 1H), 7.43 (dd, 1H), 7.23 (s, 1H), 6.31 (t, 1H), 4.57 - 4.72 (m, MS ESI, m / z = 448 [M+H] +

[0216] 2-((1r,4r)-4-(1H-1,2,3-triazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (Example 27) [ka] (1s,4s)-4-(6-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl methanesulfonate (Int 8) (74 wt.%) (500 mg, 0.8 mmol) and Cs 2 CO 3A suspension of 1H-1,2,3-triazole (1.0 g, 14.8 mmol) in DMF (5 mL) was added to the reaction mixture and stirred at 90 °C for 2 h. The reaction mixture was directly purified by C18-flash chromatography (eluted with 0-100% MeCN in water (0.1% FA)) and further by preparative HPLC (Xbridge (登録商標) BEH OBD C18 5 μm 30 × 150 mm; elution gradient 20–35% MeCN in water (10 mM NH 4 HCO 3 +0.1%NH 4 OH) solution for 8 min; 60 mL / min) to afford 2-((1r,4r)-4-(1H-1,2,3-triazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (20 mg, 44%), Example 27, as a colorless solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.05 (s, 1H), 8.62 (s, 1H), 8.59 (s, 1H), 8.45 (dd, 1H), 8.24 (d, 1H), 7.76 (d, 1H), 7.44 (dd, 1H), 7.24 (s, 1H), 6.31 (t, MS ESI, m / z = 448 [M+H] +

[0217] 2-((1r,4r)-4-(2-(1-hydroxyethyl)-1H-imidazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 28) and Isomer 2 (Example 29) 2-((1r,4r)-4-(2-acetyl-1H-imidazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide [ka] A solution of (1s,4s)-4-(6-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl methanesulfonate (Int 8) (500 mg, 1.1 mmol) and 1-(1H-imidazol-2-yl)ethan-1-one (2.3 g, 21.1 mmol) in xylene (10 mL) was added to the reaction mixture, and the resulting mixture was cooled to 30° C. 2 CO 3 (1.0 g, 3.2 mmol) was dissolved in N 2 The mixture was stirred at 120° C. for 4 hours. The reaction mixture was then concentrated under reduced pressure. The residue was purified by C18-flash chromatography (0-100% MeCN in water (0.1% NH 4 The extract was purified by elution with 2-((1r,4r)-4-(2-acetyl-1H-imidazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (60 mg, 12%) as a brown solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.05 (s, 1H), 8.64 (d, 1H), 8.58 (s, 1H), 8.45 (dd, 1H), 7.78 (d, 1H), 7.43 (dd, 1H), 7.23 (s, 1H), 7.18 (d, 1H), 6.31 (t, 1H), 5.11 - 5.32 (m, 1H), 4.51 - 4.70 (m, 1H), 4.07 (s, 3H), 3.56 (s, 3H), 2.58 (s, 3H), 2.21 - 2.39 (m, 2H), 1.90 - 2.21 (m, 6H). MS ESI, m / z = 489 [M+H] +

[0218] 2-((1r,4r)-4-(2-(1-hydroxyethyl)-1H-imidazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide - Isomer 1, Example 28 and Isomer 2, Example 29 [ka] A solution of 2-((1r,4r)-4-(2-acetyl-1H-imidazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (55 mg, 0.1 mmol) in MeOH (5 mL) was 2 NaBH 4 (9 mg, 0.2 mmol) was added. The resulting mixture was stirred at rt for 1 h and then concentrated under reduced pressure. The residue was purified by C18-flash chromatography (0-100% MeCN in water (0.1% NH 4 The product was purified by preparative chiral HPLC (YMC CHIRAL ART Cellulose-SC 5 μm 20 mm × 250 mm; 20% hexane / DCM (1 / 1) (eluted with 0.5% 2M NH 3 -MeOH) in IPA (isocratic; 20 mL / min) to give 2-((1r,4r)-4-(2-(1-hydroxyethyl)-1H-imidazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide - isomer 1 (15 mg, 27%; 100% ee) and 2-((1r,4r)-4-(2-(1-hydroxyethyl)-1H-imidazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide - Isomer 2 (14 mg, 25%; 98.3% ee) was obtained as both colourless solids.

[0219] Isomer 1, Example 28: 1 H NMR (400 MHz, DMSO-d6 ) δ 11.04 (s, 1H), 8.61 (s, 1H), 8.59 (s, 1H), 8.45 (dd, 1H), 7.43 (dd, 1H), 7.28 (d, 1H), 7.22 (s, 1H), 6.81 (d, 1H), 6.31 (t, 1H), 5.31 (d, 1H), 4.89 (p, 1H), 4.48 - 4.66 (m, 2H), 4.08 (s, 3H), 3.56 (s, 3H), 2.21 - 2.32 (m, 2H), 1.90 - 2.21 (m, 6H), 1.50 (d, 3H). MS ESI, m / z = 491 [M+H] +

[0220] Isomer 2, Example 29: 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.04 (s, 1H), 8.62 (s, 1H), 8.59 (s, 1H), 8.45 (dd, 1H), 7.43 (dd, 1H), 7.28 (d, 1H), 7.22 (s, 1H), 6.81 (d, 1H), 6.31 (t, 1H), 5.31 (d, 1H), 4.89 (p, 1H), 4.47 - 4.67 (m, 2H), 4.08 (s, 3H), 3.56 (s, 3H), 2.20 - 2.32 (m, 2H), 1.92 - 2.20 (m, 6H), 1.50 (d, 3H). MS ESI, m / z = 491 [M+H] +

[0221] 2-((1r,4r)-4-(4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (Example 30) 2-((1r,4r)-4-azidocyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide [ka] A solution of (1s,4s)-4-(6-methoxy-5-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)-2H-indazol-2-yl)cyclohexyl methanesulfonate (Int 8) (70 wt.%) (500 mg, 0.7 mmol) in DMF (0.5 mL) was added to the reaction mixture. 2 Sodium azide (121 mg, 1.9 mmol) was added under atmospheric pressure. The resulting mixture was stirred at 90° C. for 5 h, then diluted with water (150 mL) and extracted with DCM (250 mL). The organic layer was concentrated under reduced pressure. The residue was purified by C18-flash chromatography (30-80% MeCN in water (0.1% NH 4 The extract was purified by elution with 2-((1r,4r)-4-azidocyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (250 mg, 80%) as a colorless solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.04 (s, 1H), 8.57 (s, 1H), 8.55 (br. s, 1H), 8.44 (dd, 1H), 7.43 (dd, 1H), 7.21 (s, 1H), 6.31 (t, 1H), 4.45 - 4.61 (m, 1H), 4.06 (s, 3H), 3.52 - 3.68 (m, 1H), 3.56 (s, 3H), 1.93 - 2.25 (m, 6H), 1.47 - 1.67 (m, 2H). MS ESI, m / z = 422 [M+H] +

[0222] 2-((1r,4r)-4-(4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide, Example 30 [ka] A solution of 2-((1r,4r)-4-azidocyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (250 mg, 0.6 mmol) in DMF (5 mL) was 2 2-Methylbut-3-yn-2-ol (1.5 g, 17.8 mmol) was added under atmospheric pressure. The resulting mixture was stirred at 100 °C for 15 h. The reaction mixture was directly purified by C18-flash chromatography (0-100% MeCN in water (0.1% NH 4 This was eluted with 2-((1r,4r)-4-(4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide (145 mg, 48%), Example 30, as a colorless solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.05 (s, 1H), 8.61 (s, 1H), 8.59 (s, 1H), 8.45 (dd, 1H), 7.98 (s, 1H), 7.44 (dd, 1H), 7.23 (s, 1H), 6.31 (t, 1H), 5.11 (s, MS ESI, m / z = 506 [M+H] +

[0223] Potency of IRAK4 inhibitor compounds in the IRAK4 enzyme assay The inhibitory activity of compounds against IRAK4 was determined in an enzymatic assay with a mass spectrometry readout. Ten-point half-log compound concentration response curves with a top concentration of 1 μM or 10 μM were generated using an Echo 655 (Labcyte Inc) from 10 mM stock solutions of compounds dissolved in DMSO and added to a 384-well assay plate (Greiner #781280). To the assay plate, 10 μL of human recombinant IRAK4 protein (Life Technologies #PV4002) diluted to a final concentration of 0.2 nM in assay buffer (50 mM Tris-HCl pH 7.4, 10 mM MgCl, 5 mM glutathione, 0.01% BSA, 3 mM ATP) was added. The enzyme was incubated with the compound for 15 min at room temperature, after which the peptide substrate (KKARFSRFAGSSPSQSSMVAR, Innovagen custom synthesis, 10 mM in DMSO) was added to each well at a final concentration of 10 μM using an Echo 655 (Labcyte Inc). After 2 h at room temperature, the reaction was stopped with 65 μL of 0.4% formic acid (Merck #33015). Non-phosphorylated and phosphorylated peptides were measured by LC-MS / MS on a Waters TQ-S mass spectrometer. Peaks were integrated and phosphorylated to non-phosphorylated peptide ratios were calculated using TargetLynx software. Curves were fitted and compound potency was determined with Genedata Screener 19 (Genedata AG). IC 50 Values ​​are the geometric means of at least two experiments.

[0224] IRAK4 phosphorylation cell assay IRAK4 activation by TLR or IL-1R ligands leads to IRAK4 autophosphorylation, which can be prevented by IRAK4 kinase inhibitors. The effect of IRAK4 inhibitor compounds on IRAK4 autophosphorylation was evaluated in IL-1β stimulated Karpas-299 cells as an indicator of cell differentiation potential. Karpas-299 cells were cultured in RPMI 1640 (Gibco 61870-010) containing 10% FBS (Gibco #10270). Cells were cultured at 2×10 4Cells / well were seeded onto poly-D-lysine coated 384-well plates (Corning #356663) loaded with various concentrations of compounds (10-point half-log dose response with a final top concentration of 30 μM) using an Echo 655 (Labcyte Inc). Cells were centrifuged (250g, 4 min), incubated at 37°C for 1 h, then stimulated with 22.7ng / mL recombinant IL-1β (R&D Systems, #201-LB-025) for 10 min at 37°C, followed by fixation with 4% paraformaldehyde for 20 min and permeabilization with ice-cold 70% MeOH in PBS for 30 min. Cells were washed twice with phosphate buffered saline (PBS) on a BlueWasher (BlueCatBio) and then blocked with 10% FBS in PBS for 20 min. The blocking solution was removed with a BlueWasher and cells were stained with anti-pIRAK4 (Thr345 / Ser346) (CST, #11927, 1:400) in blocking buffer containing 0.05% Tween-20 for 1 h, then washed twice with PBS containing 0.05% Tween-20 on the BlueWasher, followed by staining with Alexa 647-conjugated secondary anti-rabbit IgG antibody (CST, #4414, 1:2,000) and Hoechst 33342 (Sigma, 1:2,000) in blocking buffer containing 0.05% Tween-20 for 30 min. Finally, cells were washed twice with PBS containing 0.05% Tween-20 and imaged with a 10x air objective on an ImageXpress Micro (Molecular Devices) using appropriate filters. Images were analyzed with a Columbus (PerkinElmer) and the fluorescence intensity per cell from the secondary antibodies was quantified. Quantitative data was analyzed with Genedata Screener 19 (Genedata AG). The results from this assay are presented in the table and show the ability of compounds of the present disclosure to inhibit IRAK4 in cells. IC 50 Values ​​are the geometric means of at least two experiments. [Table 3]

[0225] Potency of IRAK4 inhibitor compounds in the cKit enzyme assay The effect of IRAK4 inhibitor compounds on the activity of human cKit kinase was evaluated using the human recombinant enzyme and the LANCE assay of Eurofins CEREP, catalog item 3070, SOP no 1C768. (登録商標) The detection method was quantified by measuring the phosphorylation of the substrate Ulight-TK peptide: test compounds, reference compounds or water (control) were incubated in 40 mM Hepes / Tris (pH 7.4), 0.8 mM EGTA / Tris, 8 mM MgCl 2 , mixed with enzyme (0.38 ng) in a buffer containing 1.6 mM DTT and 0.008% Tween 20. The reaction is then started by the addition of 100 nM of the substrate Ulight-TK peptide and 50 μM ATP, and the mixture is incubated for 30 min at room temperature. For a control basal measurement, the enzyme is omitted from the reaction mixture. After incubation, the reaction is stopped by the addition of 13 mM EDTA. After 5 min, an anti-phospho-PT66 antibody labeled with a europium chelate is added. After a further 60 min, the fluorescence transmission is measured at lex=337 nm, lem=620 nm and lem=665 nm using a microplate reader (Envision, Perkin Elmer). The enzyme activity is determined by dividing the signal measured at 665 nm by that at 620 nm (ratio). The results are expressed as percent inhibition of the control enzyme activity. The standard reference inhibitor compound was staurosporine, which was tested at several concentrations in each experiment to obtain inhibition curves and their IC 50 Calculate the value.

[0226] Data shown are geometric means of at least n=2 or * indicates from one experiment. As can be seen from comparing the data in Tables 1 and 2, compounds of the present disclosure selectively inhibit IRAK4 over cKit. Further screening not shown here shows that compounds of the present disclosure are selective for IRAK4 over a broad range of kinases. Kinase selectivity can be an important determinant of clinical utility because off-target toxicity can be reduced or eliminated. [Table 4]

[0227] Plasma protein binding can have important implications for the pharmacokinetic behavior of drugs. This is especially true for highly bound drugs, where the unbound fraction (fu) drug in plasma is an important parameter in the interpretation of in vivo experiments. Traditionally, there are several different techniques used to measure the degree of drug binding to plasma proteins, with equilibrium dialysis being perhaps the most common.

[0228] This method describes our current automated equilibrium dialysis assay in human plasma using the RED (Rapid Equilibrium Dialysis) device and Hamilton sample handling system as described in Wernevik J et al. (2020) “A Fully Integrated Assay Panel for Early Drug Metabolism and Pharmacokinetics Profiling” Assay. Drug. Dev. Technol 18:157-179; DOI 10.1089 / adt.2020.970.

[0229] Assays are generally run over a 3 day period including the time to result. Pooled compounds are diluted to 5 μM in plasma and equilibrium dialyzed through a semipermeable membrane with a molecular weight cutoff of 8 kDa with phosphate buffer (pH 7.4) added to the inner chamber of the RED device and phosphate buffer (pH 7.4) added to the surrounding chamber. Sampling is performed at both 0 and 18 hours using the 5 μM solution to also establish compound stability and recovery (mass balance) in plasma with the RED device. Low recovery indicates binding to the dialysis equipment or solubility problems.

[0230] After 18 h dialysis, plasma and buffer samples are prepared for analysis by liquid chromatography and mass spectrometry (LC / MSMS). Samples are quantified using a seven-point calibration curve ranging from 1.4 nM to 7 µM in plasma. All samples with calibration curves contain an internal standard (IS) to allow normalization for variations in injection volume into the UPLC-MS / MS instrument.

[0231] Three quality controls (QCs) are used in each run. Warfarin with low fu (average fu approx. 1%) is used as a control for each pool. Propranolol (approx. 30%) and metoprolol (approx. 90%) are randomly included in each run. Controls are monitored in the 'Manhattan tool' (Winiwarter et al. (2015) "Time dependent analysis of assay comparability: a novel approach to understand intra- and inter-site variability over time" J. Comput. Aided Mol. Des. 29:795-807; DOI 10.1007 / s10822-015-9836-5), which defines the acceptance criterion for QCs as 2.58 x standard deviation.

[0232] As can be seen in the data in Table 3, the concentrations of compounds of the present disclosure are unbound in plasma indicating that free compounds are available to bind and inhibit IRAK4 in vivo. [Table 5]

Claims

1. Formula (I) 【Chemistry 1】 [During the ceremony, R １ i) H, Me, Et, Pr, i-Pr, cyclopropyl, CH ２ C.N., C.H. ２ F and oxetane or ii) in each case optionally Me, F, Cl, CN, OMe and C １ -C ３ C substituted with one or more substituents selected from alkyl １ -C ６ Alkyl group, C ３ -C ６ selected from a cycloalkyl group or a 5-membered N-heterocycle; R ２ is selected from H, F, Cl, D and Me; R ３ and R ４ each independently represents H, Me, Et, F, Cl, optionally substituted C １ -C ３ Alkyl and C １ -C ３ haloalkyl; Y is N(Me)COMe, N(R ５ )COMe, N(Me)COR ６ , N(Me)COCH(OH)Me, N(Me)COCH(OR ５ )R ６ , N(R ５ )COR ６ , CONMe ２ , C.O.R. ５ R ６ , 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole, 2-pyrrolidinone, 2-imidazolidinone, imidazole or pyrazole, or a 6-membered N-heterocycle such as 1-pyridone or pyridazine, wherein the 5- or 6-membered N-heterocycle optionally replaces N with a group R ５ or C as a group R ６ and Z is H, Me, Et or an optionally substituted C １ -C ６ is alkyl; or Y and Z together form an optionally substituted 4-, 5-, or 6-membered ring; X is OR ７ and N.R. ８ R ９ Selected from: R ５ is H, Me, optionally substituted C １ -C ６ Alkyl and optionally substituted C ３ -C ６ cycloalkyl; R ６ is Me, optionally substituted C １ -C ６ Alkyl and optionally substituted C ３ -C ６ cycloalkyl; R ７ is Me, Et, i-propyl, n-propyl, cyclopropyl, cyclobutyl, optionally substituted C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, —CH ２ (C ３ -C ６ cycloalkyl) or a 4-, 5-, or 6-membered ring containing one heteroatom selected from O and N; R ８ and R ９ are independently H, Me, and optionally substituted C １ -C ６ alkyl, or together optionally substituted C ３ -C ６ forming an optionally substituted 4-, 5-, or 6-membered ring containing cycloalkyl or one further heteroatom selected from O and N; Here, Z and R ３ , R ４ , R ５ , R ６ , R ７ , R ８ and R ９ The optional substituents, when present, are OH, C １ -C ３ Alkyl, C １ -C ３ Alkoxy, C(O)Me, amino, NHMe, NMe ２ , F, or Cl. or a pharmaceutically acceptable salt thereof, which is the following compound N-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1S,4r)-4-((S)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxamide: 【Chemistry 2】 and pharmaceutically acceptable salts thereof, A compound or a pharmaceutically acceptable salt thereof.

2. group R １ but 【Transformation 3】 2. The compound of claim 1, selected from: or a pharmaceutically acceptable salt thereof.

3. group R １ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is selected from methyl, fluoromethyl, cyanomethyl and cyclopropyl.

4. group R ２ is H and the group R ３ is H and / or a group R ４ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein

5. The group Y is N(Me)COMe, N(R ５ )COMe, N(Me)COR ６ , N(Me)COCH(OH)Me, N(Me)COCH(OR ５ )R ６ , N(R ５ )COR ６ , CONMe ２ , C.O.R. ５ R ６ , 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole, 2-pyrrolidinone, 2-imidazolidinone, 5-membered N-heterocycles such as imidazole or pyrazole, or 6-membered N-heterocycles such as 1-pyridone or pyridazine, and Z is H, Me, Et or optionally substituted C １ -C ６ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl.

6. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein the group Y is selected from N(Me)COMe, N(R 5 )COMe, N(Me)COR 6 , N(Me)COCH(OH)Me, N(Me)COCH(OR 5 )R 6 , N(R 5 )COR 6 , CONMe 2 , CONR 5 R 6 , 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole, 2-pyrrolidinone, 2-imidazolidinone, imidazole or pyrazole, a 5-membered N-heterocycle, or a 6-membered N-heterocycle, such as 1-pyridone or pyridazine, and Z is H, Me, Et or optionally substituted C 1 -C 6 alkyl.

7. The group Y optionally converts N into a group R ５ or C as a group R ６ is replaced by 【Chemistry 4】 and Z is H, or a pharmaceutically acceptable salt thereof.

8. The group Y is optionally substituted at N with a group R 5 or at C with a group R 6 . 【Transformation 5】 and Z is H, or a pharmaceutically acceptable salt thereof.

9. Group Y is 【Transformation 6】 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

10. Group Y is 【Transformation 7】 5. The compound of claim 4, selected from: or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 selected from the following: 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide; 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide; 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2S,4R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide; 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1S,2R,4S)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide; rel-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,2S,4S)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; N-(1-(fluoromethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxamide; N-(1-(cyanomethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxamide; N-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-(oxetan-3-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(2-oxo-1-(1H-pyrazol-4-yl)-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-(1-methyl-1H-1,2,3-triazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(1-(2-methyl-2H-1,2,3-triazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(2-oxopyrrolidin-1-yl)cyclohexyl)-2H-indazole-5-carboxamide; 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(3-methyl-2-oxoimidazolidin-1-yl)cyclohexyl)-2H-indazole-5-carboxamide; 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((5s,8s)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide; 6-Methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((5r,8r)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide; 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-((1r,4r)-4-(2-oxopyridin-1(2H)-yl)cyclohexyl)-2H-indazole-5-carboxamide; 6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-(4-(pyridazin-3-yl)cyclohexyl)-2H-indazole-5-carboxamide; 2-((1r,4r)-4-(1,3,4-oxadiazol-2-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; 2-((1r,4r)-4-(1H-1,2,4-triazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; 2-((1r,4r)-4-(1H-1,2,3-triazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; 2-((1r,4r)-4-(2-(1-hydroxyethyl)-1H-imidazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide and 2-((1r,4r)-4-(4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)cyclohexyl)-6-methoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2H-indazole-5-carboxamide; or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

13. 13. A pharmaceutical composition according to claim 12 for use as a medicament.

14. 10. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament.

15. The pharmaceutical composition of claim 13 for treating inflammatory diseases or autoinflammatory / autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjogren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis and psoriasis.

16. The pharmaceutical composition of claim 13 for treating a hematological malignancy selected from melanoma or Waldenstrom's macroglobulinemia (WM), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), primary central nervous system lymphoma (PCNSL), splenic marginal zone lymphoma (SMZL), small lymphocytic lymphoma (SLL), leukemia (chronic lymphocytic leukemia (CLL)), and monoclonal gammopathy of undetermined significance (MGUS-IgM+).

17. The use of claim 14 for treating inflammatory diseases or autoinflammatory / autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjogren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis and psoriasis.

18. The use of claim 14 for treating a hematological malignancy selected from melanoma or Waldenstrom's macroglobulinemia (WM), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), primary central nervous system lymphoma (PCNSL), splenic marginal zone lymphoma (SMZL), small lymphocytic lymphoma (SLL), leukemia (chronic lymphocytic leukemia (CLL)), and monoclonal gammopathy of undetermined significance (MGUS-IgM+).

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