N-(imidazo[1,2-B]pyridazin-3-yl)-1-cyclohexyl-2H-indazole-5-carboxamide and N-(pyrazolo[1,5-A]pyrimidin-3-yl)-1-cyclohexyl-2H-indazole-5-carboxamide derivatives as IRAK4 inhibitors for the treatment of asthma

Abstract

The present application relates to compounds of formula (A), wherein R1 is selected from formula (II) and formula (III) and R2 is selected from formula (IV), formula (V), and formula (VI), as IRAK4 inhibitors for use in the treatment of, for example, asthma and chronic obstructive pulmonary disease (COPD), cancer, inflammatory diseases, and autoinflammatory / autoimmune diseases such as, for example, systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjogren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis, and psoriasis. Preferred compounds of the present invention are, for example, N-(imidazo[1,2-b]pyridazin-3-yl)-1-cyclohexyl-2H-indazole-5-carboxamide, N-(pyrazolo[1,5-a]pyrimidin-3-yl)-1-cyclohexyl-2H-indazole-5-carboxamide, N-(imidazo[1,2-b]pyridazin-3-yl)-1-azaspiro[4.5]decan-8-yl-2H-indazole-5-carboxamide, and N-(pyrazolo[1,5-a]pyrimidin-3-yl)-1-azaspiro[4.5]decan-8-yl-2H-indazole-5-carboxamide derivatives. An exemplary compound of the present invention is, for example, N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide (Example 1): Formula (VII). [Formula 1] TIFF2023552838000310.tif122161

Description

[Technical Field]

[0001] This disclosure relates to chemical compounds and pharmaceutically acceptable salts thereof that inhibit IRAK4 and thus have potential utility in medicine. This 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, Sjögren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis, and psoriasis. This disclosure also relates to processes and intermediate compounds related to the preparation of the above IRAK4 inhibitors, as well as 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 ligands derived from microorganisms, such as lipopolysaccharide (LPS) or microbial RNA or DNA, while IL-1 family receptors can be activated by endogenous ligands produced by TLR-activated cells (IL-1β and IL-18) or upon tissue injury (IL-1α and IL-33). Activation of TLRs or IL-1 receptors by these ligands recruits the adaptor protein myeloid differentiation primary response 88 (MyD88) to the receptor and forms a multimeric protein complex with members of the IRAK family (IRAK1, IRAK2, and IRAK4) called the "myddosome." The myosinosome functions as a signaling platform that induces the nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, resulting in the activation of the transcription factors NF-κB, activator protein 1 (AP1), c-AMP response element-binding protein (CREB), and interferon regulatory factor 5 (IRF5), driving the transcription of proinflammatory cytokines and chemokines. Mice lacking IRAK4 are viable but lack proinflammatory cytokine responses to IL-1β, IL-18, and LPS. Humans with loss-of-function mutations in IRAK4 exhibit an immunodeficient phenotype, and these immune cells exhibit abrogated cytokine responses to TLR agonists and IL-1 receptor ligands.

[0003] IRAK4 is characterized by an N-terminal death domain that mediates interaction with MyD88 and a centrally located kinase domain. Mydosome formation promotes IRAK4 autophosphorylation, which regulates mydosome 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 inducing inflammatory responses, IRAK4 is a target for drugs that exert anti-inflammatory effects.

[0005] Asthma and COPD (chronic obstructive pulmonary disease) are chronic lung diseases that constitute a significant unmet medical need worldwide. Asthma and COPD are characterized by chronic airway inflammation accompanied by abnormal cytokine release, dysregulated immune cell activation, and airway remodeling. In asthma, airway insults, such as allergic, viral, and bacterial insults, activate TLR receptors via pathogen-associated molecular patterns (PAMPs), IL-1R, and ST2 receptors via the release of alarmins, including IL-33 and IL-1α, as well as IL-1β, which is released upon inflammasome activation. TLR and IL-1 family receptors are present in multiple cell types within the airways, including macrophages, dendritic cells, mast cells, monocytes, and epithelial cells. They respond to these ligands by releasing proinflammatory cytokines (TNF-α, IL-6, IL-8, GM-CSF, and IL-5), leading to airway inflammation, recruitment of inflammatory cells such as neutrophils and eosinophils, airway hyperresponsiveness, and mucus production. Inhibition of IRAK4 has the potential to suppress these inflammatory pathways in the airways. Gene expression analysis of lung samples from asthma and COPD patients revealed upregulated expression of genes related to the IL-1R and TLR2 / 4 inflammatory pathways in a subset of severely ill patients. To our knowledge, IRAK4 inhibitors have not yet been clinically investigated for the treatment of respiratory diseases. However, preclinical data from several research groups indicate that disrupting the IRAK4-regulated pathway attenuates airway inflammation in animal models of both asthma and COPD. For example, mice lacking MyD88, a central component of the myosin, are protected from allergen- or IL-33-induced airway inflammation, as are mice treated with a small molecule mimetic that blocks the interaction between IRAK2 and IRAK4. Blockade of IL-1β with a monoclonal antibody has also been shown to suppress allergen- and bacteria-induced airway inflammation in a steroid-resistant mouse model of asthma. Furthermore, treating mice with the IL-1R antagonist anakinra at the time of allergen challenge ameliorates asthma-like symptoms in a mouse model of allergic asthma.Chronic exposure to cigarette smoke is a major contributor to the development of COPD. IL-1 signaling plays a central role in mediating neutrophilic airway inflammation in cigarette smoke-exposed mice. Blocking IL-1 signaling with antibodies against IL-1α, IL-1β, or IL-1R ameliorates neutrophilic inflammation in the lung and reduces bacterial- or viral-induced disease exacerbations in cigarette smoke-exposed mice. Collectively, IRAK4 inhibition has the potential to provide broad anti-inflammatory effects in inflammatory respiratory diseases by simultaneously blocking several disease-related signaling pathways.

[0006] As a central regulator of the myosin, IRAK4 is also a promising therapeutic target in other inflammatory diseases driven by IL-1R, TLR, or ST2-mediated mechanisms. As previously disclosed, IRAK4 plays a role in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus (SLE) (see, for example, U.S. Patent No. 5,929,297 and U.S. Patent No. 5,929,297). In SLE, immune complexes composed of autoantibodies and autoantigens can drive TLR-dependent pathological signaling. It has been reported that in the pathogenesis of SLE, inhibition of IRAK4 blocks the release of type I interferon and proinflammatory cytokines mediated by activation of TLR7 and TLR9 in plasmacytoid dendritic cells. Mice expressing a kinase-dead mutant of IRAK4 or treated with an IRAK4 kinase inhibitor are resistant to experimentally induced arthritis and lupus (see, for example, U.S. Patent No. 5,929,297). The use of anakinra (an IL-1 receptor antagonist), approved 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, which have been suggested to be involved in the pathogenesis of Sjögren's syndrome. MyD88 knockout mice also show reduced disease symptoms in an experimental mouse model of Sjögren's syndrome. Systemic sclerosis is a severe autoimmune disease involving microangiopathy and fibrosis, and IL-1R, TLR4, TLR8, and ST2 signaling may drive pathogenic mechanisms. Therefore, inhibiting IRAK4 as a treatment for systemic sclerosis simultaneously blocks multiple disease-related pathways. In myositis, elevated levels of IL-1α and IL-1β may contribute to inflammation in muscle tissue. 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 is supported by improved clinical outcomes in myositis patients treated with anakinra in a smaller mechanistic clinical trial.As a central regulator of the IL-1R pathway, IRAK4 is also a promising target for the treatment of gout. Monosodium urate crystals, which characteristically form in gout patients, can trigger inflammasome activation and IL-1β release. The use of both the anti-IL-1β monoclonal antibody canakinumab and anakinra has demonstrated clinical efficacy in treating gouty inflammation. 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 has been demonstrated in a mouse model in which oral administration of an IRAK4 inhibitor suppressed lesion formation. MyD88 knockout mice are also protected against the development of endometriosis in the same mouse model. IL-33 / ST2 signaling is an important mechanism in atopic dermatitis and is involved in the control of skin inflammation, epithelial barrier integrity, and eosinophil recruitment. IL-33 can trigger eczema and dermatitis in mice in a MyD88-dependent manner. As a regulator of ST2 signaling and a central component of the myosin, inhibition of IRAK4 has the potential to block 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 the pathogenesis of psoriasis. IRAK4 kinase activity has also been shown to be required for T17 differentiation and the control of T17-mediated disease in vivo.

[0007] Many IRAK4 kinase inhibitors are known and have been developed primarily for use in oncology or inflammatory diseases (see, e.g., U.S. Patent Nos. 6,229,999; 6,229,999; 6,229,999; 6,229,999; and 6,229,999). Of the known IRAK4 kinase inhibitors, PF-06650833 recently completed a Phase 2 clinical trial for the treatment of rheumatoid arthritis (see clinicaltrials.gov entry for NCT02996500).

[0008] Taken together, IRAK4 inhibitors have potential for the treatment of many diseases and conditions, even though to date no such inhibitors have been approved for clinical use. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2017207386 Brochure [Patent Document 2] International Publication No. 2015150995 Brochure [Patent Document 3] International Publication No. 2017009806 Brochure [Patent Document 4] International Publication No. 2016174183 Brochure [Patent Document 5] International Publication No. 2018234342 Brochure Summary of the Invention [Problem to be solved by the invention]

[0010] The objective herein is 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 activation of IRAK4-mediated pathways, such as, for example, asthma, COPD, and chronic autoimmune / autoinflammatory diseases. [Means for solving the problem]

[0011] In a first aspect, the present disclosure provides a compound of formula (A), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 1 teeth, [ka] Selected from; R 2 teeth, [ka] Selected from; R 3 and R 4 are each independently selected from H, Me, Et, optionally substituted C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl; Y is N(Me)COMe, N(R 5 )COMe, N(Me)COR 6 , N(R 5 )COR 6 , CONMe2, or 1,2,3-triazole, and Z is H, Me, Et, and optionally substituted C1-C6 alkyl; or Y and Z join to form an optionally substituted 4-, 5-, or 6-membered ring; X is OR 7 and NR 8 R 9 Selected from; R 5 is selected from H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl; R 6 is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 5- or 6-membered saturated N-heterocycle; R 7is Me, Et, i-propyl, n-propyl, cyclopropyl, cyclobutyl, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl group, or a 4-, 5-, or 6-membered ring containing a heteroatom selected from O and N; R 8 and R 9 are independently selected from H, Me, and optionally substituted C1-C6 alkyl, or together form an optionally substituted 4-, 5-, or 6-membered ring containing an optionally substituted C3-C6 cycloalkyl, or an additional heteroatom selected from O and N; Z, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 The optional substituents, when present, are independently selected from OH, C1-C3 alkyl, C1-C3 alkoxy, C(O)Me, amino, NHMe, NMe2, F, or Cl.

[0012] In a second aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 1 teeth, [ka] Selected from; R 2 teeth, [ka] Selected from; R 3 and R 4 are each independently selected from H, Me, Et, optionally substituted C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl; Y is N(Me)COMe, N(R 5 )COMe, N(Me)COR 6 , N(R 5 )COR 6 , CONMe2, or 1,2,3-triazole, and Z is H, Me, Et, and optionally substituted C1-C6 alkyl; or Y and Z join to form an optionally substituted 4-, 5-, or 6-membered ring; X is OR 7 and NR 8 R 9 Selected from; R 5 is selected from H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl; R 6 is selected from optionally substituted C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl; R 7 is Me, Et, i-propyl, n-propyl, cyclopropyl, cyclobutyl, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl group, or a 4-, 5-, or 6-membered ring containing a heteroatom selected from O and N; R 8 and R 9 are independently selected from H, Me, and optionally substituted C1-C6 alkyl, or together form an optionally substituted 4-, 5-, or 6-membered ring containing an optionally substituted C3-C6 cycloalkyl, or an additional heteroatom selected from O and N; Z, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 The optional substituents, when present, are independently selected from OH, C1-C3 alkyl, C1-C3 alkoxy, C(O)Me, amino, NHMe, NMe2, F, or Cl.

[0013] References herein below to compounds of formula (I) should be construed as including references to compounds of formula (A) and as referring to compounds of formula (I).

[0014] This specification also describes pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0015] This specification also describes a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0016] This specification also describes compounds of formula (I), or pharmaceutically acceptable salts thereof, for use in the treatment of respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD).

[0017] The present specification also describes a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory diseases.

[0018] The present specification also describes a compound of formula (I) or a pharmaceutically 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.

[0019] The present specification also describes compounds of formula (I), or pharmaceutically acceptable salts thereof, for use in the treatment of cancer, e.g., for use in combination with a BTK inhibitor.

[0020] This specification also describes a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer. In such use, the compound of Formula (I) can be used as a monotherapy or in combination with an additional therapeutic agent, for example, to treat a hematological malignancy. The hematological malignancy 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, this use may be for treating hematological malignancies with MyD88 mutations, B-cell receptor (BCR) mutations, or both MYD88 mutations and BCR mutations. When the compound is used in combination with an additional therapeutic agent, the second agent may be selected from the group including BTK inhibitors (examples include ibrutinib, acalabrutinib, zanubrutinib, or tirabrutinib), PI3Kd inhibitors, and BCR inhibitors such as SYK inhibitors, or immunotherapy.

[0021] The present specification also describes the use of a compound of formula (I) for the manufacture of a medicament, for example, wherein 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 inflammatory diseases.

[0022] The present specification also describes a method of treatment comprising administering 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; an autoinflammatory / autoimmune disease, such as systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjogren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis, and psoriasis; or an inflammatory disease.

[0023] This specification also relates to processes for preparing compounds of formula (I).

[0024] Further aspects of the present specification will become apparent to those skilled in the art from reading the specification.

[0025] This specification makes reference to the following drawings: [Brief explanation of the drawings]

[0026] [Figure 1] In vivo dose response of Example 89 in an acute mouse model of LPS-induced pulmonary inflammation. The compound of Example 89 was orally administered (1 mg / mL) to mice 1 hour before inhalation LPS challenge. Four hours after challenge, the animals were terminated, and the levels of IL-6 and TNF-α released in bronchoalveolar lavage fluid were measured. Example 89 dose-dependently reduced the levels of IL-6 and TNF-α. Individual data points represent individual animals, and bars represent the mean values ​​for each group. Statistical differences between groups were calculated using one-way ANOVA tests comparing the treated and vehicle groups. **p<0.01, ***p<0.001. The ability of the IRAK4 inhibitors herein to reduce inflammatory cytokines and TNF-α in vivo is thus established. DETAILED DESCRIPTION OF THE INVENTION

[0027] As described above, compounds of formula (I), or pharmaceutically acceptable salts thereof, have been found to be potent inhibitors of IRAK4 kinase. Furthermore, preferred compounds of formula (I) exhibit excellent selectivity over other kinases, thus providing a profile that avoids off-target effects and toxicity. This desirable combination of IRAK4 inhibitory activity and a lack of adverse off-target effects indicates that the compounds herein are suitable for use in medicine.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. For example, the 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 the 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.

[0029] In order that this specification may be more readily understood, certain terms are specifically defined below. Further definitions are set forth throughout the detailed description, where appropriate.

[0030] Units, prefixes, and symbols are denoted in their International System of Units (SI) accepted form. Numerical ranges are inclusive of the numbers delimiting the range.

[0031] The term "pharmaceutical composition" refers to a formulation that is in a form that allows the biological activity of the active ingredient and does not contain any additional ingredients that are unacceptably toxic to the subject to which the composition is administered. Such compositions may be sterile. The pharmaceutical compositions herein include a compound of Formula (A), e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0032] The terms "treating," or "treatment," or "treat," or "alleviating," or "alleviating," and the like, refer to both (1) therapeutic measures that cure, slow, reduce, and / or halt the progression of a diagnosed condition or disease, and (2) prophylactic or preventative measures that prevent and / or slow the onset of the targeted condition or disease. Thus, those in need of treatment include those already with the disease; those with or prone to developing the disease; and those in whom the disease is to be prevented. In certain aspects, a subject's respiratory disease has been successfully "treated" by the methods of the present disclosure when the patient, for example, exhibits complete, partial, or temporary relief from the symptoms of the respiratory disease.

[0033] The term "subject" refers to any animal (e.g., mammal) that will be the recipient of a particular treatment, including, but not limited to, humans, non-human primates, rodents, etc. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to human subjects.

[0034] As used herein and above, the symbol * is used to indicate the point of attachment of one component of a compound of formula (I) to another component of the compound. This is illustrated by example when a compound of formula (I) is bonded to a bond designated R 1 motif, the compound will be a compound of structure A. Similarly, if a compound of formula (I) has the following R 2 If the compound has the motif, it will be a compound of structure B. [ka]

[0035] As used herein, the term "alkyl" refers to both straight- and branched-chain saturated hydrocarbon groups having the specified number of carbon atoms. As used herein, the term deuteroalkyl refers to an alkyl group in which one or more, optionally all, of the hydrogens have been replaced with deuterium atoms. The term cycloalkyl refers to a saturated cyclic hydrocarbon.

[0036] In this specification, C x ~C y The prefix C used in terms such as alkyl, where x and y are integers x ~C y indicates the numerical range of carbon atoms present in the group. For example, C1-C4 alkyl includes methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, and t-butyl, and C1-C3 alkyl includes methyl, ethyl, n-propyl, and i-propyl. C1-C4 alkoxy includes methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, and t-butoxy. Examples of C1-C3 alkoxy groups include methoxy, ethoxy, n-propoxy, and i-propoxy.

[0037] Unless otherwise specified, the atom or bond of a group may be at any suitable atom of that group; for example, propyl includes prop-1-yl and prop-2-yl.

[0038] As used herein, the term cycloalkyl refers to a cyclic saturated hydrocarbon radical having the specified number of carbon atoms. Thus, C3-C6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0039] As used herein, the term alkoxy refers to a group containing an oxygen atom linked 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. Thus, C1-C3 alkoxy includes methoxy, ethoxy, O n Pr and O i Refers to the Pr group.

[0040] As explained herein and above, the group R 2 is the group R 4 In such cases, the group R 4 may be attached to any available ring carbon, but R4 is preferably bonded to a carbon atom adjacent to the carbon atom bonded to the indazole ring as shown below. [ka]

[0041] As used herein and above, the term acetyl refers to a group of formula -C(O)Me. References herein to N-acylated groups are used to refer to amides with small alkyl side chains, i.e., optionally substituted C1-C6 alkyl side chains, or optionally substituted C3-C6 cycloalkyl, in each case the optional substituents being selected from OH, C1-C3 alkoxy, C(O)Me, amino, NHMe, NMe2, F, or Cl, with the preferred N-acylated group being the N-acetyl group, i.e., the group -NRC(O)Me.

[0042] As explained herein and above, compounds of formula (I) may contain a group R which may be a cyclohexyl ring substituted with two groups Y and Z which are linked to form a 4-, 5-, or 6-membered ring. 2In this case, the 4-, 5-, or 6-membered ring is a saturated hydrocarbon ring system, optionally with one or two ring carbons replaced with a heteroatom selected from O and N. In this case, two ring carbons are replaced with heteroatoms, and the heteroatoms are not directly bonded, i.e., the heteroatoms replace non-adjacent ring carbons, and they are not separated in the ring by a CH group, but can be linked, for example, by a carbonyl group, to provide, for example, a carbonate or carbamate motif. The hydrocarbon ring can incorporate a carbonyl group, as when Y and Z are linked to form a cyclic amide. In a preferred case, 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 can be linked to form an azetidine substituted at the nitrogen position with an acyl group. Additionally, the 4-, 5-, or 6-membered ring may be substituted with a group selected from OH, C1-C3 alkyl, C1-C3 alkoxy, C(O)Me, amino, NHMe, NMe2, 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., compared to other kinases, thereby delivering a more potent and selective IRAK4 kinase inhibitor.

[0043] As described herein, compounds of formula (A) include N(R 5 )COMe, N(Me)COR 6 , and N(R 5 )COR 6 In such cases, the group R 6 may be an optionally substituted 5- or 6-membered saturated N-heterocycle, such as pyrrolidine or piperidine, linked to the carbonyl group of Y through the nitrogen atom of the heterocycle to provide a urea moiety. For example, Y may be a group N(Me)COR 6 where R 6 is 3-hydroxypyrrolidine. [ka]

[0044] As explained herein and above, the group R 7 may be an optionally substituted 4-, 5-, or 6-membered ring containing a heteroatom selected from O and N. For the avoidance of doubt, "containing a heteroatom" means that one of the atoms of the ring is a heteroatom selected from O or N. In such cases, saturated 4-, 5-, or 6-membered rings containing a heteroatom selected from O and N are preferred. Examples of preferred 4-, 5-, or 6-membered rings containing a heteroatom selected from O and N are azetidine, oxetane, tetrahydrofuran, pyrrolidine, tetrahydropyran, and piperidine. As explained herein and above, the substituent R 8 and R 9 can be linked to form an optionally substituted 4-, 5-, or 6-membered ring containing an additional heteroatom selected from O and N. When an additional heteroatom is present, the heteroatom is not directly bonded to N, i.e., the heteroatoms in the ring are non-adjacent and are not separated by a CH group. In such cases, it is preferred that the resulting ring is saturated; for example, the resulting ring may be a morpholine or piperazine ring.

[0045] As will be apparent to those skilled in the art, compounds of formula (I), and in particular the group R 2can exist in various stereochemical forms. While compounds with the highest activity as inhibitors of IRAK4 are preferred, it will be understood that the claims encompass all stereochemical forms of compounds of formula (I). It will be recognized that compounds of formula (I) can be prepared, isolated, and / or provided with or without the presence of one or more of the other possible stereoisomers of compounds of formula (I), in any relative proportions. Preparation of stereoenriched or stereoisomerically pure compounds can be carried out by standard techniques of organic chemistry well known in the art, for example, by synthesis from stereoenriched or stereoisomerically pure starting materials, by using appropriate stereoenriched or stereoisomerically pure catalysts during synthesis, and / or by resolving racemic or partially stereoisomerically enriched mixtures of stereoisomers, for example, by chiral chromatography.

[0046] For example, in the following case, the substituent R 2 is a 1,3-substituted cyclohexanol group. In this system, the relative stereochemistry of the alcohol and indazole groups on the ring can be cis or trans, and each of the cis and trans isomers will then exist in two enantiomers reflecting the (R) or (S) configuration of the chiral centers (i.e., the carbons attached to the hydroxyl and indazole groups). In the specific cases described herein, compounds are referred to as isomers 1 and 2 of compounds having the relative stereochemical arrangement; therefore, for a compound designated as rel-(1S,3R), the two possible isomers are the (1S,3R) isomer and the (1R,3S) isomer, which have the same relative stereochemistry but are enantiomers of each other. Thus, reference to a compound below having cis relative stereochemistry refers to the two possible compounds with this relative stereochemistry. Structures herein of known relative stereochemistry and of undetermined absolute stereochemistry are depicted as single enantiomers with the modifier "or enantiomer." [ka]

[0047] As explained herein and above, the characteristic components of the compounds of formula (I) are optionally substituted. As used herein, the term optionally substituted means that the structural elements of the compound may or may not be substituted with one or more of the specified optional substituents. The optional substituents may be 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 are present, it is generally preferred that there be zero, one, or two substituents per substituted group, e.g., zero or one substituent. It will be understood that when two hydroxyl substituents are present, the two hydroxyl groups are not attached to the same carbon atom. When an optional substituent is F, preferably one, two, or three F substituents are present, and further, when two or three substituents are present, they are directly attached to the same carbon atom. These optional substituents may be used to adjust the physicochemical properties of the molecule, such as solubility, to adjust metabolism, or to further optimize interaction with IRAK4 kinase, e.g., compared to other kinases, thereby delivering a more potent and selective IRAK4 kinase inhibitor.

[0048] As noted above, in a first embodiment, the present disclosure provides a compound of formula (A), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 1 teeth, [ka] Selected from; R 2 teeth, [ka] Selected from; R 3 and R 4 are each independently selected from H, Me, Et, optionally substituted C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl; Y is N(Me)COMe, N(R 5 )COMe, N(Me)COR 6 , N(R 5 )COR 6 , CONMe2, or 1,2,3-triazole, and Z is H, Me, Et, and optionally substituted C1-C6 alkyl; or Y and Z join to form an optionally substituted 4-, 5-, or 6-membered ring; X is OR 7 and NR 8 R 9 Selected from; R 5 is selected from H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl; R 6 is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, and optionally substituted 5- or 6-membered saturated N-heterocycle; R 7 is Me, Et, i-propyl, n-propyl, cyclopropyl, cyclobutyl, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl group, or a 4-, 5-, or 6-membered ring containing a heteroatom selected from O and N; R 8 and R 9 are independently selected from H, Me, and optionally substituted C1-C6 alkyl, or together form an optionally substituted 4-, 5-, or 6-membered ring containing an optionally substituted C3-C6 cycloalkyl, or an additional heteroatom selected from O and N; Z, R 3 , R4 , R 5 , R 6 , R 7 , R 8 , and R 9 The optional substituents, when present, are independently selected from OH, C1-C3 alkyl, C1-C3 alkoxy, C(O)Me, amino, NHMe, NMe2, F, or Cl.

[0049] In embodiments, the compound of Formula (A) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 1 teeth, [ka] Selected from; R 2 teeth, [ka] Selected from; R 3 and R 4 are each independently selected from H, Me, Et, optionally substituted C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl; Y is N(Me)COMe, N(R 5 )COMe, N(Me)COR 6 , N(R 5 )COR 6 , CONMe2, or 1,2,3-triazole, and Z is H, Me, Et, and optionally substituted C1-C6 alkyl; or Y and Z join to form an optionally substituted 4-, 5-, or 6-membered ring; X is OR 7 and NR 8 R 9 Selected from; R 5is selected from H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl; R 6 is selected from optionally substituted C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl; R 7 is Me, Et, i-propyl, n-propyl, cyclopropyl, cyclobutyl, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl group, or a 4-, 5-, or 6-membered ring containing a heteroatom selected from O and N; R 8 and R 9 are independently selected from H, Me, and optionally substituted C1-C6 alkyl, or together form an optionally substituted 4-, 5-, or 6-membered ring containing an optionally substituted C3-C6 cycloalkyl, or an additional heteroatom selected from O and N; Z, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 The optional substituents, when present, are independently selected from OH, C1-C3 alkyl, C1-C3 alkoxy, C(O)Me, amino, NHMe, NMe2, F, or Cl.

[0050] In an embodiment, the compound of formula (I) or formula (A) is a compound of formula (Ia), wherein the group R 2 teeth, [ka] and The groups Y and Z are joined to form a 4-, 5-, or 6-membered ring which is an optionally substituted 3-hydroxycyclobutyl, N-acylated azetidine, pyrrolidin-2-one, 1-alkylpyrrolidin-2-one, 3-alkyloxazolidin-2-one, 1-alkylpiperidin-2-one, or 3-alkyl-1,3-oxazinan-2-one ring.

[0051] In an embodiment, the compound of formula (I) or formula (A) is a compound of formula (Ib), wherein the group R 2 teeth, [ka] and The groups Y and Z are joined to form a 4-, 5-, or 6-membered ring selected from 3-hydroxycyclobutyl, N-acetylazetidine, 1-methylpyrrolidin-2-one, 3-methyloxazolidin-2-one, 1-methylpiperidin-2-one, and 3-methyl-1,3-oxazinan-2-one.

[0052] In an embodiment, the compound of formula (I) or formula (A) is a compound of formula (Ic), wherein the group R 2 teeth, [ka] and groups Y and Z are linked to form [ka] forming a 4-, 5-, or 6-membered ring selected from where * indicates the attachment site for the cyclohexyl group and R 10 is Me or a C1-C6 alkyl group optionally substituted with OH, C1-C3 alkoxy, C(O)Me, NH2, NHMe, NMe2, F, or Cl.

[0053] In an embodiment, the compound of formula (A) is a compound of formula (Ac), wherein the group R 2 teeth, [ka] and groups Y and Z are linked to form [ka] forming a 4-, 5-, or 6-membered ring, where * indicates the attachment site for the cyclohexyl group and R10 is Me or a C1-C6 alkyl group optionally substituted with OH, C1-C3 alkoxy, C(O)Me, NH2, NHMe, NMe2, F, or Cl.

[0054] In an embodiment, the compound of formula (I) or formula (A) is a compound of formula (Id), wherein the group R 2 teeth, [ka] and Y is N(Me)COMe, N(R 5 )COMe, N(Me)COR 6 , N(R 5 )COR 6 and CONMe2, and Z is H.

[0055] In an embodiment, the compound of formula (I) or formula (A) is a compound of formula (Ie), wherein the group R 2 teeth, [ka] and optionally, wherein R 4 is H.

[0056] In an embodiment, the compound of formula (I) or formula (A) is a compound of formula (If), wherein the group R 2 teeth, [ka] and optionally, R 3 and R 4 is methyl.

[0057] In an embodiment, the compound of formula (If) is a compound of formula (Ig), wherein the group R 2 teeth, [ka] is selected from.

[0058] In an embodiment, the compound of formula (If) is a compound of formula (Ih), wherein the group R 2 teeth, [ka] is selected from.

[0059] In an embodiment, the compound of formula (If) is a compound of formula (Ah), wherein the group R 2 teeth, [ka] is selected from.

[0060] In embodiments, a compound of Formula (I), e.g., a compound of any of Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), is a compound of Formula (Ii), wherein R 1 teeth, [ka] is.

[0061] In embodiments, the compound of formula (I), e.g., a compound of either formula (Ac) or (Ah), is a compound of formula (Ai), wherein R 1 teeth, [ka] is.

[0062] In embodiments, the compound of formula (I), e.g., a compound of either formula (Ac) or (Ah), is a compound of formula (Aj), wherein R 1 teeth, [ka] is.

[0063] In embodiments, a compound of Formula (I), e.g., a compound of any of Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), is a compound of Formula (Ij), wherein R 1 teeth, [ka] is.

[0064] In embodiments, a compound of Formula (I), e.g., a compound of any of Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), or (Ij), is a compound of Formula (Ik), wherein X is OR 7 and optionally, wherein R 7 is OMe.

[0065] In embodiments, a compound of formula (I), such as a compound of either formula (Ac) or (Ah), is a compound of formula (Ak) wherein X is OR 7 and optionally, wherein R 7 In embodiments, a compound of formula (I), such as a compound of any of formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), or (Ij), is a compound of formula (II) wherein X is NR 8 R 9 is.

[0066] In embodiments, the compound of formula (I), e.g., a compound of either formula (Ac) or (Ah), is a compound of formula (A), wherein X is NR 8 R 9 is.

[0067] In embodiments, the compound of formula (A) is N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide; N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((5s,8s)-1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide; 2-((1s,4s)-4-(dimethylcarbamoyl)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; 2-((1r,4r)-4-(dimethylcarbamoyl)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; 2-(2-hydroxy-2-methylspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; 2-((1s,4s)-4-hydroxycyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; 2-((1r,4r)-4-hydroxycyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; rel-2-((1S,3R)-3-hydroxycyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; 6-Methoxy-2-(1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; rel-2-((1S,3R)-3-hydroxycyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; 6-Cyclopropoxy-2-(2-hydroxy-2-methylspiro[3.5]nonan-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; 6-Cyclopropoxy-2-((1R,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 6-Cyclopropoxy-2-((1S,3R)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; rel-6-cyclopropoxy-2-((1S,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; 2-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide; N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide; 6-Methoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 6-Methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1r,4r)-4-(cyclopropanecarboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1s,4s)-4-(cyclopropanecarboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; rel-2-((6R,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; rel-2-((6S,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; 6-Cyclopropoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 6-Cyclopropoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1S,2S,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1R,2R,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; rel-2-((1S,2S,4S)-4-hydroxy-2-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; rel-2-((1S,2S,4R)-4-hydroxy-2-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; rel-6-cyclopropoxy-2-((1S,2S,4R)-4-hydroxy-2-methylcyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; rel-6-cyclopropoxy-2-((1S,2S,4S)-4-hydroxy-2-methylcyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; 6-Cyclopropoxy-2-(2-hydroxyspiro[3.5]nonan-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; 2-(4-hydroxy-4-methylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; rel-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; rel-2-((1S,3S)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; rel-6-cyclopropoxy-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; 6-Cyclopropoxy-2-((1s,4s)-4-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 6-Cyclopropoxy-2-((1r,4r)-4-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1S,4r)-4-((S)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 6-Methoxy-2-((1R,2R,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; 6-Methoxy-2-((1S,2S,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; rel-2-((6S,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; rel-2-((6R,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((5s,8s)-2-methyl-3-oxo-2-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide; N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-2-methyl-3-oxo-2-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide; rel-2-((7R,8R)-2,7-dimethyl-3-oxo-2-azaspiro[4.5]decan-8-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide or rel-2-((7S,8S)-2,7-dimethyl-3-oxo-2-azaspiro[4.5]decan-8-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide isomer 1, 2, 3 or 4; N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-(1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide Isomer 1 or Isomer 2; rel-2-((1R,3R,4S)-4-hydroxy-3-methylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; rel-2-((1S,3R,4S)-4-hydroxy-3-methylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; rel-2-((1S,3S,4S)-4-hydroxy-3-methylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; rel-2-((1R,3S,4S)-4-hydroxy-3-methylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; 6-Cyclopropoxy-2-((1r,4r)-4-hydroxycyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-2H-indazole-5-carboxamide; 6-Cyclopropoxy-2-((1s,4s)-4-hydroxycyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-2H-indazole-5-carboxamide; 6-Methoxy-2-((5r,8r)-2-methyl-3-oxo-2-azaspiro[4.5]decan-8-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 6-Methoxy-2-((5s,8s)-2-methyl-3-oxo-2-azaspiro[4.5]decan-8-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1R,2R,4S)-4-hydroxy-2-methylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; 2-((1R,2R,4R)-4-hydroxy-2-methylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; 2-((1S,2S,4R)-4-hydroxy-2-methylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; 2-((1S,2S,4S)-4-hydroxy-2-methylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; 2-((1R,2R,4S)-4-hydroxy-2,4-dimethylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; 2-((1R,2R,4R)-4-hydroxy-2,4-dimethylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; 2-((1S,4r)-4-((S)-2-hydroxy-N-methylpropanamido)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; 6-Methoxy-2-((1r,4r)-4-(N-methylcyclopropanecarboxamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((1r,3R)-3-hydroxy-N-methylcyclobutane-1-carboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((1s,3S)-3-hydroxy-N-methylcyclobutane-1-carboxamide)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1r,4r)-4-(2-hydroxy-N,2-dimethylpropanamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-((1r,3r)-3-methoxycyclobutoxy)-2H-indazole-5-carboxamide; 2-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-((1s,3s)-3-methoxycyclobutoxy)-2H-indazole-5-carboxamide; 2-((1r,4r)-4-(1H-1,2,3-triazol-1-yl)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; 2-((1r,4r)-4-(2H-1,2,3-triazol-2-yl)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; rel-2-((1S,2S,3R)-3-hydroxy-2-methylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; rel-2-((1S,2R,3S)-3-hydroxy-2-methylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; rel-2-((1S,2R,3R)-3-hydroxy-2-methylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; 2-((1S,4r)-4-((S)-3-hydroxy-N-methylbutanamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-3-hydroxy-N-methylbutanamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; rel-2-((1R,4r)-4-((1R,3R)-3-hydroxy-N-methylcyclopentane-1-carboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; rel-2-((1R,4r)-4-((1R,3S)-3-hydroxy-N-methylcyclopentane-1-carboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; 2-((1S,4r)-4-((S)-3-hydroxy-N-methylpyrrolidine-1-carboxamide)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-3-hydroxy-N-methylpyrrolidine-1-carboxamido)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; 6-Methoxy-2-(1-methyl-2-oxo-4-oxa-1-azaspiro[5.5]undecan-9-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; rel-2-((5R,7R,8R)-1,7-dimethyl-2-oxo-1-azaspiro[4.5]decan-8-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; and rel-2-((5S,7R,8R)-1,7-dimethyl-2-oxo-1-azaspiro[4.5]decan-8-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-Isomer 1 or Isomer 2; or a pharmaceutically acceptable salt thereof.

[0068] The IRAK4 inhibitors of the present invention can be prepared from readily available starting materials, available from commercial suppliers such as Merck KGaA, or by methods within the common knowledge of those skilled in the art. The following reaction schemes illustrate various methods for synthesizing IRAK4 inhibitors. Typical or preferred reaction conditions may be provided for the synthesis, but those skilled in the art may be able to suggest modifications of these conditions to obtain analogs not described herein. Therefore, the schemes shown below are representative methods for synthesizing the compounds of the present invention, and are not intended to constrain the scope of the present invention in any way. Furthermore, the order of reactions may be modified to change the overall synthesis to introduce changes at various positions in the molecule at various stages of the synthesis.

[0069] The knowledgeable reader will recognize that the compounds depicted 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.

[0070] General synthesis of scaffolds / building blocks Scheme 1: Synthesis of scaffold I-6 using Hal = halide. [ka] The scaffold I-6 shown in Scheme 1 can be prepared from commercially available 2,4-difluorobenzaldehyde (I-1). I-1 can be nitrated using standard nitration conditions, for example, using a mixture of concentrated sulfuric acid and concentrated nitric acid, or using a mixture of concentrated sulfuric acid and potassium nitrate as described in WO 2017 / 009798, to give the nitro compound I-2. Treatment of I-2 with cyclopropanol in the presence of a base (e.g., DIPEA) and a suitable solvent (e.g., DMF) at elevated temperature forms the isopropyl ether I-3. The indazole I-4 can be obtained from I-3 by reaction with hydrazine in a suitable solvent at elevated temperature (e.g., 80 °C). The aromatic amine I-5 can then be obtained by reduction of the nitro compound I-4, for example, by treatment with Fe and ammonium chloride in an ethanol / water mixture (alternatively, using Pd on carbon (or Pd(OH) on carbon) in MeOH under an H atmosphere). Amines I-5 can be converted to the corresponding bromides I-6 (Hal = Br), for example, by treatment with tert-butyl nitrite and copper(I) bromide in a suitable solvent (e.g., acetonitrile). Protecting the indazole NH of I-4, for example, with a PMB protecting group, followed by reduction of the nitro group and subsequent deprotection after introduction of the bromide, increases the yield of these transformations. Amines I-5 can be converted to the corresponding iodides I-6 (Hal = I), for example, by treatment with sodium nitrite and potassium iodide in water / acetic acid.

[0071] Scheme 2: R as defined in the claims 1 , and R 7 = General synthesis of building blocks II-4 using -Me or -cyclopropyl. [ka] Halide II-1 (Hal = Br or I) can be used as a starting material for synthesizing building block II-4, as shown in Scheme 2. Halide II-1 can be commercially available or can be obtained using the process described in Scheme 1 above. Treatment of II-1 with a Pd catalyst (e.g., Pd(dppf)Cl) in the presence of an alcohol as a solvent under an atmosphere of CO (optionally generated in situ using COware® and SilaCOgen®) provides ester II-2 (shown herein as the methyl ester when MeOH is used as the solvent). Subsequent cleavage of the ester with, for example, lithium hydroxide or potassium hydroxide in a suitable solvent (e.g., water) provides carboxylic acid II-3. Amine R 1 Amide formation of this acid II-3 with NH can be carried out using a variety of amide coupling reagents (e.g., HATU) in the presence of a base (e.g., DIPEA) and DMF and / or THF as solvent to afford the desired building blocks II-4.

[0072] The conversion of halide II-1 to amide II-4 can also be carried out in a one-step procedure using an aminocarbonylation reaction. II-1 (Hal = Br or I) is reacted with a base (e.g., TEA) and an amine R under an atmosphere of CO (optionally generated in situ). 1 Stirring with a Pd source (e.g., Pd(OAc)2) and a suitable ligand (e.g., 1,3-bis(diphenylphosphino)propane) in a solvent (e.g., CH3CN) in the presence of -NH2 provides amide II-4 in one step.

[0073] Scheme 3: Hal = halide (Br, I); R = R 2 (as defined in the claims) or R as defined below 2 Protected precursor of;R 7 General synthesis of building block III-2 using -Me or -cyclopropyl etc. [ka] Indazole III-2, as shown in Scheme 3, can be prepared by the addition of a base (e.g., K2CO3, Cs2CO3, NaHCO3, NaOH, KOH, Na) in a suitable solvent (e.g., DMF, THF, dioxane, xylene, MeCN) at elevated temperature. t OBu, K t OBu, KOEt, KHMDS, DIPEA, pyridine, TEA), and alkylating reagents RY, such as R 2 Alternatively, alkylation can be achieved by reacting compound III-1 with R 2 This can also be carried out by a Michael reaction with an α,β-unsaturated carbonyl precursor of formula R 2 contains a functional group that requires protection by a suitable protecting group for this synthetic step, a suitable R 2 Furthermore, the alkylation reaction shown in Scheme 3 can be carried out by using R 2 can be converted in R 2 This can be carried out using a suitable precursor of, for example, R 2 If R contains an amine or amide functionality, the amine can be protected in the alkylating agent with a suitable protecting group (e.g., Boc) that is cleaved after the alkylation reaction. The amine can then be alkylated or converted to an amide. 2If the alkylating agent contains an alcohol functional group, this functional group can be protected with a suitable alcohol protecting group that withstands the reaction conditions of the alkylation reaction and is 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, 5th Edition). Alternatively, the alkylating agent may contain a precursor to the amine / amide / alcohol functional group in the form of a suitable protected carbonyl functional group, which can be deprotected and converted to the desired amine / amide / alcohol functional group of the target compound at a later stage in the synthesis by synthetic methods known to those skilled in the art.

[0074] Depending on the reaction conditions used in the alkylation reaction, a mixture of N1 and N2 regioisomers can be obtained. For example, the N1 isomer can be separated from the N2 isomer by column chromatography either immediately after the alkylation reaction or at a later stage in the synthesis of the target compound.

[0075] Scheme 4: R=R 2 (as defined in the claims), or a suitable protected precursor thereof as described in Scheme 3; R 7 General synthesis of building blocks IV-2 and IV-7 using -Me or -cyclopropyl etc. [ka] Scheme 4 describes the regioselective synthesis of N-2 indazole isomers IV-2 and IV-7. For the synthesis of IV-2, commercially available starting material IV-1 is treated with an amine R—NH in a suitable solvent (e.g., iPrOH) at elevated temperature, followed by the addition of tri-n-butylphosphine, leading to the formation of IV-2. Starting material IV-3 for the synthesis of IV-7 is commercially available (IV-3, R 7 = Me, CAS 586412-86-4), or Scheme 1 (R 7= for cyclopropyl). Treatment of benzaldehyde IV-3 with an amine R—NH in a suitable solvent (e.g., EtOH) to form the corresponding imine, followed by stirring the crude imine IV-4 with sodium azide in a suitable solvent (e.g., DMF) affords the bicyclic intermediate IV-5. Reduction of the nitro group of IV-5 (e.g., with Pd(OH) on carbon under an H atmosphere) affords the aromatic amine IV-6. Subsequent treatment of IV-6 with, for example, sodium nitrite and potassium iodide in acetic acid affords the corresponding iodo compound IV-7.

[0076] General synthesis of compounds of formula (I): Scheme 5: General synthesis of compounds of formula (I), method 1: [ka] Compounds of formula (I) can be prepared from compounds II-4 (R 7 = -Me, -cyclopropyl, etc.: R 1 (As defined in the claims.) The reaction sequence for preparing compound II-4 is shown in Scheme 2.

[0077] Indazole II-4 can be prepared by the reaction of a base (e.g., KOH, KHMDS, CsCO) with a suitable alkylating reagent RY (as defined in Scheme 3 above, Y=mesylate, tosylate, halide, R=R) in a base-compatible solvent. 2 or R 2 R Y (R = R 2 (a suitable precursor of) is used in the alkylation reaction, the process illustrated in Scheme 3 involves alkylating R to R of the target compound. 2 This can be implemented after converting it into

[0078] Depending on the reaction conditions used in the alkylation reaction, a mixture of N1 and N2 regioisomers can be obtained. The N1 isomer can be separated from the N2 isomer by, for example, column chromatography to give the compound of formula (I).

[0079] Scheme 6: General synthesis of compounds of formula (I), method 2: [ka] Another method for preparing compounds of formula (I) is shown in Scheme 6. A suitable starting material for this route is indazole III-2 (Hal = halide (Br, I); R = R as defined in the claims). 2 or a suitable precursor thereof as described in Scheme 3; R 7 = Me, -cyclopropyl, etc.). Halide III-2 can be obtained as described in Schemes 3 and 4, and can be first treated with a Pd catalyst (e.g., Pd(dppf)Cl2) in the presence of an alcohol as a solvent under a CO atmosphere (high pressure) to give ester VI-1 (when MeOH is used as the solvent, Me-ester VI-1 is formed). Subsequent cleavage of the ester with, for example, lithium hydroxide or potassium hydroxide in a suitable solvent (e.g., water) gives carboxylic acid VI-2. Amine R 1 ~NH2(R 1 Amide formation of this acid VI-2 with VI-(VI-2) (as defined in the claims) can be carried out with a variety of amide coupling reagents (e.g., HATU, T3P) to give the desired compounds of formula (I).

[0080] The reaction sequence shown in Scheme 6 is used to prepare compound III-2 (R = R 2 If you start with a protected precursor of R, then R 2 The transformation into (described in Scheme 3) can be carried out at various stages of the synthetic sequence shown in Scheme 6, depending on the nature of the transformation and the compatibility of the reaction conditions with the functional groups present in the sequence intermediates (the skilled person is able to determine the order of steps).

[0081] Halide III-2 (R=R 2 ) to compounds of formula (I) can also be carried out in a one-pot aminocarbonylation protocol. 2 ) under CO atmosphere (high pressure) with a base (e.g., TEA) and a coupling amine R 1 By stirring a Pd source (e.g., Pd(OAc)) and a suitable ligand (e.g., 1,3-bis(diphenylphosphino)propane or di(adamantan-1-yl)butylphosphane) in a solvent (e.g., CHCN) in the presence of -NH, compounds of formula (I) are obtained in one step.

[0082] The aminocarbonylation reaction was carried out to give compound III-2 (R = R 2 When carried out with a suitable protected precursor of R, the aminocarbonylation reaction shown in Scheme 6 is followed by conversion of R to R 2 (described in Scheme 3) can be carried out to give compounds of formula (I).

[0083] Scheme 7: General synthesis of compounds of formula (I), method 3: [ka] Scheme 7 shows the addition of substituent R 7

[0046] Figure 1 illustrates a method for obtaining compounds of formula (I) by varying the methoxy ether. Starting with compound VII-1, the methoxy ether can be cleaved, for example, with BBr in DCM, to give phenol VII-2. Subsequently, the alkylating reagent R in either an alkylation reaction or a Mitsunobu coupling can be used. 7 -Y, e.g., mesylate, tosylate, or halide, or an alcohol R 7 Reaction of VII-2 with -OH provides compounds of formula (I).

[0084] In embodiments herein, there are provided methods of synthesizing a compound of formula (I), or a pharmaceutically acceptable salt thereof, and intermediates in the synthesis of a compound of formula (I), such as the methods and intermediates described herein and above.

[0085] In embodiments, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient. In such embodiments, the compound of formula (i) is preferably used as a single enantiomer. Minor impurities, e.g., up to 1% by weight of other stereoisomers, may optionally be present. The pharmaceutical composition may be used to treat conditions in which inhibition of IRAK4 kinase may be useful, as described herein and in more detail above.

[0086] In embodiments, there is provided a compound of formula (I) for use in the manufacture of a medicament, optionally the medicament for use in the treatment or prevention of a condition in which inhibition of IRAK4 kinase may be useful as described in more detail herein and above.

[0087] The compounds of formula (I) and their pharmaceutically acceptable salts may be prepared, used, or supplied in amorphous, crystalline, or semi-crystalline form, and any compound of formula (I) or pharmaceutically acceptable salt thereof may be capable of being formed into more than one crystalline and / or polymorphic form, including hydrated forms (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, or other stoichiometric hydrates) and / or solvated forms. It should be understood that the present specification encompasses compounds of formula (I) and their pharmaceutically acceptable salts in any and all such solid forms.

[0088] In a further embodiment herein there is provided a compound of formula (I) obtainable by the methods described in the Examples section below.

[0089] The present specification is intended to include all isotopes of atoms present in the compounds of the present invention. It will be 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 14C. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the accompanying Examples, substituting an appropriate isotopically labeled reagent for the previously utilized unlabeled reagent.

[0090] Suitable pharmaceutically acceptable salts of the compounds of formula (I) may be, for example, acid addition salts. Suitable pharmaceutically acceptable salts of the compounds of formula (I) may be, for example, acid addition salts of the compounds of formula (I), for example, acid addition salts with inorganic or organic acids. The compounds herein may be provided as free base compounds, i.e., in a non-salted state.

[0091] Further suitable pharmaceutically acceptable salts of compounds of formula (I) may be, for example, salts which are formed in the human or animal body after administration of a compound of formula (I) to said body.

[0092] The compound of formula (I) or a pharmaceutically acceptable salt thereof may be prepared as a co-crystalline solid form. It should be understood that pharmaceutically acceptable co-crystals of the compound of formula (I) or a pharmaceutically acceptable salt thereof form an aspect of the present specification.

[0093] For use in a pharmaceutical context, it may be preferable to provide the compounds of formula (I) or pharmaceutically acceptable salts thereof in the absence of significant amounts of other stereoisomeric forms.

[0094] The compound of formula (I) or its pharmaceutically acceptable salt is usually administered in any possible pharmaceutically acceptable dosage form in the form of a pharmaceutical preparation containing the active ingredient or its pharmaceutically acceptable salt or solvate, or a solvate of such a salt, via the oral route, parenterally, intravenously, intramuscularly, subcutaneously, or by other injection methods, buccal, rectal, vaginal, transdermal and / or intranasal routes and / or by inhalation. Depending on the disease and patient to be treated and the route of administration, the composition can be administered in various dosage amounts, for example, in an oral dosage amount of 1 mg to 1,000 mg or 100 mg to 2,000 mg.

[0095] Pharmaceutical formulations of the compounds of formula (I) above may be prepared, for example, for parenteral, subcutaneous, intramuscular, or intravenous administration.

[0096] The pharmaceutical formulations of the compounds of formula (I) described 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).

[0097] Pharmaceutical formulations suitable for oral administration may contain one or more physiologically compatible carriers and / or excipients and may be in solid or liquid form. Tablets and capsules can be prepared using binders, fillers, lubricants, and surfactants. Liquid compositions may contain conventional additives such as suspending agents, emulsifiers, and preservatives. Liquid compositions can be encapsulated, for example, 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. Exemplary oral compositions herein include a compound of Formula (I) and at least one pharmaceutically acceptable excipient filled into a two-piece hard shell capsule or a soft elastic gelatin (SEG) capsule.

[0098] According to a further embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein above for use as a medicament in a warm-blooded animal such as man.

[0099] According to a further embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein above for use in the production of an antiproliferative effect in a warm-blooded animal such as man.

[0100] According to a further embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein above for use in a warm-blooded animal such as man as an anti-invasive agent in the prevention and / or treatment of solid tumour disease.

[0101] According to a further embodiment, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein above for the production of an antiproliferative effect in a warm-blooded animal such as man.

[0102] According to a further embodiment, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein above in the manufacture of a medicament for use in a warm-blooded animal such as man as an anti-invasive agent in the prevention and / or treatment of solid tumour disease.

[0103] It will be appreciated that in embodiments where the compounds of formula (I) are for use in the treatment of conditions characterised by hyperproliferative or solid tumour disease and related therapies, and for use in the manufacture of medicaments for the treatment of such diseases, in a preferred embodiment the disease is melanoma, and further combination with a Bruton's tyrosine kinase inhibitor is preferred.

[0104] As used herein, unless otherwise specified, the phrase "effective amount" refers to an amount of a compound or composition sufficient to significantly and positively alter the symptoms and / or condition being treated (e.g., result in a favorable clinical response). The effective amount of active ingredient used in a pharmaceutical composition will vary depending on the particular condition being treated, the severity of the condition, the duration of treatment, the nature of any concurrent therapy, the particular active ingredient being used, the particular pharmaceutically acceptable excipients / carriers used, and similar factors within the knowledge and expertise of the attending physician. An effective amount may generally be in the range of 0.1 mg to 1,000 mg.

[0105] According to a further embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein above for use in providing an inhibitory effect on IRAK4 kinase.

[0106] According to a further embodiment, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein above, in the manufacture of a medicament for use in providing an inhibitory effect on IRAK4 kinase.

[0107] According to a further embodiment, there is also provided a method of 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 herein above, or a pharmaceutically acceptable salt thereof.

[0108] According to a further embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein above, for use in providing selective inhibition of IRAK4 kinase, wherein selective inhibition refers to the concentration of compound of formula (I) required to effect 50% inhibition of IRAK4 kinase activity in vitro being 10-fold, 100-fold, or 1000-fold or more lower than that required to effect 50% inhibition of another kinase, for example, another kinase that, when inhibited, causes toxic side effects.

[0109] According to a further embodiment, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein above, in the manufacture of a medicament for use in providing a selective inhibitory effect on IRAK4 kinase.

[0110] According to further embodiments, there is also provided a method for providing selective inhibitory effect on IRAK4 kinase, comprising administering to a patient in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0111] Described herein are compounds capable of inhibiting IRAK4 kinase. Biochemical and cell-based assays have shown that the compounds herein are potent IRAK4 kinase inhibitors, and therefore may 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, Sjögren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis, and psoriasis.

[0112] In an embodiment, there is provided the use of a compound of formula (I) for treating a respiratory disorder, optionally wherein the respiratory disorder is asthma and chronic obstructive pulmonary disease (COPD).

[0113] In an embodiment, there is provided the use of a compound of formula (I) 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.

[0114] In embodiments, there is provided a method of treatment comprising administering an effective amount of a compound of Formula (I) to a patient in need thereof, wherein the patient has a respiratory disorder, and optionally the respiratory disorder is asthma and chronic obstructive pulmonary disease (COPD).

[0115] In embodiments, there is provided a method of treatment 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.

[0116] According to a further aspect of the present specification, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein above, 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, Sjögren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis, and psoriasis.

[0117] It will be appreciated that the following examples are provided so that the nature of the present invention may be fully understood, and it will also be appreciated that the following examples are not intended to limit the scope of the present invention in any way. Furthermore, the present application also includes the following: Item 1) A compound of formula (A), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 1 teeth, [ka] Selected from; R 2 teeth, [ka] Selected from; R 3 and R 4 is H, Me, Et, optionally substituted C 1 ~C 6 Alkyl and optionally substituted C 3 ~C 6 are each independently selected from cycloalkyl; Y is N(Me)COMe, N(R 5 )COMe, N(Me)COR 6 , N(R 5 )COR 6 , CONMe 2 or 1,2,3-triazole, and Z is H, Me, Et, and optionally substituted C 1 ~C 6 alkyl, or Y and Z join to form an optionally substituted 4-, 5-, or 6-membered ring; X is OR 7 and NR 8 R 9 Selected from; R 5 is H, optionally substituted C 1 ~C 6 Alkyl and optionally substituted C 3 ~C 6 cycloalkyl; R 6 is an optionally substituted C 1 ~C 6 Alkyl, optionally substituted C 3 ~C 6 cycloalkyl, and optionally substituted 5- or 6-membered saturated N-heterocycle; R 7 is Me, Et, i-propyl, n-propyl, cyclopropyl, cyclobutyl, optionally substituted C 1 ~C 6 Alkyl, C 3 ~C 6 a cycloalkyl group or a 4-, 5-, or 6-membered ring containing a heteroatom selected from O and N; R 8 and R 9 is H, Me, and optionally substituted C 1 ~C 6 alkyl, or both optionally substituted C 3 ~C 6 forming an optionally substituted 4-, 5-, or 6-membered ring containing a cycloalkyl or an additional heteroatom selected from O and N, 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 pharmaceutically acceptable salt thereof. Section 2) The compound according to item 1, wherein Y and Z are joined to form a 4-, 5-, or 6-membered ring selected from optionally substituted 3-hydroxycyclobutyl, N-acylated azetidine, pyrrolidin-2-one, 1-alkylpyrrolidin-2-one, 3-alkyloxazolidin-2-one, 1-alkylpiperidin-2-one, or 3-alkyl-1,3-oxazinan-2-one. Section 3) Item 1. The compound according to item 1, wherein Y and Z are linked to form a 4-, 5-, or 6-membered ring selected from 3-hydroxycyclobutyl, N-acylazetidine, 1-methylpyrrolidin-2-one, 3-methyloxazolidin-2-one, 1-methylpiperidin-2-one, and 3-methyl-1,3-oxazinan-2-one. Section 4) When Y and Z join to form a 4-, 5-, or 6-membered ring, said ring is

change

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[0118] The following abbreviations are used:

[0119] [Table 1]

[0120] [Table 2]

[0121] Abbreviations used in analytical data, if not defined above, are consistent with common usage in the art (see J Med Chem Standard Abbreviations and Acronyms http: / / pubsapp.acs.org / paragonplus / submission / jmcmar / jmcmar_abbreviations.pdf?).

[0122] The compound names provided below were generated using PerkinElmer ChemDraw Professional, Version 20.0.2.51. Whenever uncertainty exists regarding absolute stereochemistry, relative stereochemistry is specified, whenever possible.

[0123] Preparation of intermediates Intermediate Int I-1: Synthesis of 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 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.

[0124] 5-Bromo-4-methoxy-2-nitrobenzaldehyde (Int I-1) [ka] Sodium methoxide (10.9 g, 60.6 mmol) in MeOH (46 mL) was added to 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(300MHz,DMSO-d6)δ 10.03(s,1H),8.15(s,1H),7.78(s,1H),4.04(s,3H).

[0125] Intermediate Int I-2: Synthesis of 6-cyclopropoxy-5-nitro-1H-indazole 2,4-Difluoro-5-nitrobenzaldehyde [ka] To a solution of 2,4-difluorobenzaldehyde (50.0 g, 351.9 mmol) in sulfuric acid (180 mL) was slowly added a mixture of nitric acid (15 M) (30.5 mL, 457.4 mmol) and sulfuric acid (900 mL) over 1 h under a N atmosphere at 0 °C. After the reaction mixture was stirred at rt for an additional 3 h, the mixture was poured into ice / water and extracted with EtOAc (400 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give 2,4-difluoro-5-nitrobenzaldehyde (50.0 g, 76%) as a yellow oil.

[0126] 4-Cyclopropoxy-2-fluoro-5-nitrobenzaldehyde [ka] 2,4-Difluoro-5-nitrobenzaldehyde (20.0 g, 106.9 mmol), cyclopropanol (6.2 g, 106.9 mmol), and DIPEA (37.3 mL, 213.8 mmol) in DMF (25 mL) were stirred at 100° C. for 2 h. The reaction mixture was cooled to rt, poured into ice / water (750 mL), and extracted with EtOAc (350 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with PE / EtOAc (6:1)) to give crude 4-cyclopropoxy-2-fluoro-5-nitrobenzaldehyde (12.0 g) as a yellow solid. MS ESI, m / z=226 [M+H] + .

[0127] 6-Cyclopropoxy-5-nitro-1H-indazole (Int I-2) [ka] 4-Cyclopropoxy-2-fluoro-5-nitrobenzaldehyde (37.0 g, 164.3 mmol) was slowly added to hydrazine hydrate (80% in water) (32.9 g, 525.8 mmol) in EtOH (100 mL). The resulting mixture was stirred at rt for 15 min, followed by stirring at 80° C. for 2 h. The reaction mixture was cooled to rt and concentrated under reduced pressure to give 6-cyclopropoxy-5-nitro-1H-indazole (34.0 g, 94%) as a red solid. MS ESI, m / z=220 [M+H] + .

[0128] Intermediate Int I-3: Synthesis of 6-cyclopropoxy-5-iodo-1H-indazole 6-Cyclopropoxy-1H-indazol-5-amine [ka] To a suspension of 6-cyclopropoxy-5-nitro-1H-indazole (Int I-2) (35.0 g, 159.7 mmol) and NH₄Cl (42.7 g, 798.4 mmol) in EtOH (100 mL) / water (100 mL) was added iron (44.6 g, 798.4 mmol). The resulting mixture was stirred at 80 °C for 2 h, cooled to rt, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with PE / EtOAc (2:1)) to give 6-cyclopropoxy-1H-indazol-5-amine (15.3 g, 51%) as a red solid. MS ESI, m / z = 190 [M+H] + .

[0129] 6-Cyclopropoxy-5-iodo-1H-indazole (Int I-3) [ka] To a solution of 6-cyclopropoxy-1H-indazol-5-amine (5.0 g, 26.4 mmol) in acetic acid (100 mL) was slowly added a solution of sodium nitrite (2.7 g, 39.6 mmol) in water (10 mL) at 0 °C. The resulting mixture was stirred at rt for 1 h. Subsequently, a solution of potassium iodide (8.8 g, 52.9 mmol) in water (10 mL) was added dropwise, and the mixture was stirred at 60 °C for 4 h. The reaction mixture was cooled to rt, poured into water (400 mL), and extracted with EtOAc (500 mL). The organic layer was dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with PE / EtOAc (2:1)) to give 6-cyclopropoxy-5-iodo-1H-indazole (4.0 g, 50%) as a red solid. 1 H NMR(300MHz,DMSO-d6)δ 12.95(s,1H),8.16(s,1H),7.89(s,1H),7.28(s,1H),3.94-4.02(m,1H),0.61-0.95(m,4H).MS ESI,m / z=301[M+H] + .

[0130] Intermediate Int I-4: Synthesis of 5-bromo-6-cyclopropoxy-1H-indazole 6-Cyclopropoxy-1-(4-methoxybenzyl)-5-nitro-1H-indazole [ka] NaH (60 wt%) (2.6 g, 63.9 mmol) was slowly added to 1-(chloromethyl)-4-methoxybenzene (7.5 g, 47.9 mmol) and 6-cyclopropoxy-5-nitro-1H-indazole (Int I-2) (7.0 g, 31.9 mmol) in DMF (20 mL). The resulting mixture was stirred at rt for 2 h. The mixture was poured into water (750 mL) and extracted with EtOAc (1 × 400 mL). The organic layer was dried over NaSO, filtered, and concentrated to give the crude product, which was purified by silica gel chromatography (eluting with PE / EtOAc (2 / 1)) to give 6-cyclopropoxy-1-(4-methoxybenzyl)-5-nitro-1H-indazole (6.0 g, 55%) as a red solid. MS ESI, m / z = 340 [M+H] + 。

[0131] 6-Cyclopropoxy-1-(4-methoxybenzyl)-1H-indazol-5-amine [ka] Iron (4.9 g, 88.4 mmol) was added to NH4Cl (4.7 g, 88.4 mmol) and 6-cyclopropoxy-1-(4-methoxybenzyl)-5-nitro-1H-indazole (6.0 g, 17.7 mmol) in EtOH (20 mL) and water (20.00 mL). The resulting mixture was stirred at 80 °C for 2 h, cooled to rt, and then filtered and concentrated. The crude product was purified by silica gel chromatography (eluting with PE / EtOAc 2 / 1) to give 6-cyclopropoxy-1-(4-methoxybenzyl)-1H-indazol-5-amine (4.8 g, 88%) as a red gum. MS ESI, m / z = 310 [M+H] + .

[0132] 5-Bromo-6-cyclopropoxy-1-(4-methoxybenzyl)-1H-indazole [ka] Copper bromide (464 mg, 3.2 mmol) was added to tert-butyl nitrite (333 mg, 3.2 mmol) and 6-cyclopropoxy-1-(4-methoxybenzyl)-1H-indazol-5-amine (500 mg, 1.6 mmol) in MeCN (5 mL) over 20 min under a N atmosphere at 16 °C. The resulting mixture was stirred at 50 °C for 0.5 h. The mixture was cooled to rt and then poured into water (400 mL) and extracted with EtOAc (2 × 400 mL). The organic phase was dried over Na SO , filtered, and concentrated. The crude product was purified by silica gel chromatography (eluting with EtOAc / PE (1:3)) to give 5-bromo-6-cyclopropoxy-1-(4-methoxybenzyl)-1H-indazole (68 mg, 11%) as a pale yellow solid. MS ESI, m / z = 373 / 375 [M+H] + .

[0133] 5-Bromo-6-cyclopropoxy-1H-indazole (Int I-4) [ka] TFA (3.0 mL, 39.0 mmol) was added to 5-bromo-6-cyclopropoxy-1-(4-methoxybenzyl)-1H-indazole (400 mg, 1.1 mmol) in DCE (1 mL). The resulting mixture was stirred at 100 °C for 12 h, cooled to rt, and then concentrated. The crude product was purified by flash C18 chromatography (eluting with 0–100% MeCN (5% NH4OH) in water) to give 5-bromo-6-cyclopropoxy-1H-indazole (156 mg, 58%) as a gray solid. 1H NMR(300MHz,DMSO-d6)δ 13.00(s,1H),7.99(s,1H),7.94(s,1H),7.36(s,1H),4.00(tt,1H),0.83-0.92(m,2H),0.70-0.80(m,2H).MS ESI,m / z=253 / 255[M+H] + .

[0134] Intermediate Int I-5: Synthesis of pyrazolo[1,5-a]pyrimidin-3-amine [ka] Aqueous NH3 (25%) (34.9 mL, 403.0 mmol) was added to a solution of the TFA salt of pyrazolo[1,5-a]pyrimidin-3-amine (20.0 g, 80.6 mmol) in EtOH (300 mL). The resulting mixture was stirred at rt for 2 h, and then the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 50-90% EtOAc in PE) to give pyrazolo[1,5-a]pyrimidin-3-amine (9.9 g, 92%) as an orange solid. MS ESI, m / z = 135 [M+H] + .

[0135] Intermediate Int II-1: Synthesis of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-1H-indazole-5-carboxamide [ka] Pd(OAc) (89 mg, 0.4 mmol) was added to TEA (3.7 mL, 26.4 mmol), dppp (165 mg, 0.4 mmol), 5-bromo-6-methoxy-1H-indazole (2.0 g, 8.8 mmol), and imidazo[1,2-b]pyridazin-3-amine (1.3 g, 9.7 mmol) in degassed MeCN (30 mL). The resulting mixture was stirred at 4 bar and 100 °C under a CO atmosphere for 23 h. After the mixture was cooled to rt, the formed precipitate was collected by filtration, washed with MeCN (2 mL), and dried in vacuo to give N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-1H-indazole-5-carboxamide (2.4 g, 87%) as a gray solid, which was used without further purification. 1 H NMR(500MHz,DMSO-d6)δ 12.86(s,1H),10.79(s,1H),8.50-8.65(m,2H),8.15(s,1H),8.01-8.12(m,2H),7.23(s,1H),7.18(dd,1H),4.18(s,3H).m / z(ESI+)[M+H] + =309.

[0136] Intermediate Int II-2: Synthesis of 6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-indazole-5-carboxamide Methyl 6-methoxy-1H-indazole-5-carboxylate [ka] A solution of Pd(dppf)Cl2 (9.7 g, 13.2 mmol), DIPEA (77 mL, 440.4 mmol), and 5-bromo-6-methoxy-1H-indazole (20.0 g, 88 mmol) in MeOH (500 mL) was stirred under a CO atmosphere at 15 atm and 110 °C for 12 h. After cooling the mixture to rt, the reaction mixture was filtered through silica gel and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (eluting with 0-30% EtOAc in PE) to give methyl 6-methoxy-1H-indazole-5-carboxylate (8.0 g, 44%) as a brown solid. m / z (ESI+), [M+H] + =207.

[0137] 6-Methoxy-1H-indazole-5-carboxylic acid [ka] LiOH (732 mg, 30.5 mmol) in water (5 mL) was added to methyl 6-methoxy-1H-indazole-5-carboxylate (2.1 g, 10.2 mmol) in MeOH (5 mL) under a N atmosphere at rt. The reaction mixture was stirred at rt for 3 h and then acidified with aqueous HCl (0.1 M). The precipitate that formed was collected by filtration, washed with MeOH, and dried in vacuo to give 6-methoxy-1H-indazole-5-carboxylic acid (1.6 g, 80%) as a gray solid, which was used without further purification. m / z (ESI+), [M+H] + =193.

[0138] 6-Methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-indazole-5-carboxamide (Int II-2) [ka] Pyrazolo[1,5-a]pyrimidin-3-amine (Int I-5) (7.3 g, 54.0 mmol) was added to HATU (20.6 g, 54.0 mmol), DIPEA (36 mL, 208.0 mmol), and 6-methoxy-1H-indazole-5-carboxylic acid (8.0 g, 42.0 mmol) in THF (20 mL) under a N atmosphere at rt. The resulting solution was stirred for 2 h. The reaction mixture was poured into water (20 mL), and the solid formed was collected by filtration, washed with water (100 mL), and dried in vacuo to give 6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-indazole-5-carboxamide (10.0 g) as a yellow solid, which was used without further purification. 1 H NMR(300MHz,DMSO-d6)δ 13.13(s,1H),10.32(s,1H),9.01-9.12(m,1H),8.74(s,1H),8.53-8.56(m,1H),8.48 (s,1H),8.16(s,1H),7.18(s,1H),7.00-7.11(m,1H),4.10(s,3H).m / z(ESI+),[M+H] + =309.

[0139] Intermediate Int II-3: Synthesis of 6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-indazole-5-carboxamide Methyl 6-cyclopropoxy-1H-indazole-5-carboxylate [ka] A suspension of 5-bromo-6-cyclopropoxy-1H-indazole (Int I-4) (5.5 g, 21.7 mmol), DIPEA (2.1 g, 16.6 mmol), and Pd(dppf)Cl (15.9 g, 21.7 mmol) in MeOH (30 mL) was stirred under a CO atmosphere at 15 atm and 110 °C for 12 h. The mixture was cooled to rt, concentrated, and purified by silica gel chromatography (eluting with 0-50% EtOAc in PE) to give methyl 6-cyclopropoxy-1H-indazole-5-carboxylate (4.4 g, 87%) as a yellow solid. MS ESI, m / z = 233 [M+H] + .

[0140] 6-Cyclopropoxy-1H-indazole-5-carboxylic acid [ka] To a solution of methyl 6-cyclopropoxy-1H-indazole-5-carboxylate (4.4 g, 19.0 mmol) in MeOH (5 mL) was added a solution of LiOH (1.4 g, 56.8 mmol) in water (5 mL) at rt. The resulting solution was stirred at 30 °C for 12 h. The reaction mixture was cooled to rt, diluted with water (25 mL), and washed with EtOAc (10 mL × 3). The aqueous layer was acidified to pH 4-5 with 0.1 N HCl, and the formed precipitate was collected by filtration to give 6-cyclopropoxy-1H-indazole-5-carboxylic acid (2.7 g, 65%). MS ESI, m / z = 219 [M+H] + .

[0141] 6-Cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-indazole-5-carboxamide (Int II-3) [ka] To a solution of 6-cyclopropoxy-1H-indazole-5-carboxylic acid (5.5 g, 25.2 mmol), HATU (14.4 g, 37.8 mmol), and DIPEA (22.0 mL, 126.0 mmol) in DMF (6 mL) and THF (54 mL) at rt, pyrazolo[1,5-a]pyrimidin-3-amine (Int I-5) (5.1 g, 37.8 mmol) was added. The resulting solution was stirred at rt for 12 h. The reaction mixture was poured into water (1 L), and the formed precipitate was collected by filtration. The solid was suspended in MeOH (150 mL), followed by the addition of K2CO3 (15 g), and the resulting mixture was stirred at rt for 2 h. The suspension was then poured into water (1 L) and filtered to give 6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-indazole-5-carboxamide (6.9 g, 81%) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ 13.14(s,1H),10.26(s,1H),8.97-9.17(m,1H),8.76(s,1H),8.42-8.64(m,2H),8.18(s,1H) ,7.48(s,1H),6.95-7.10(m,1H),4.17-4.39(m,1H),1.06-0.90(m,2H),0.90-1.20(m,2H).MS ESI,m / z=335[M+H] + .

[0142] Intermediate Int III-1: Synthesis of 1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl 4-methylbenzenesulfonate 8-Hydroxy-1azaspiro[4.5]decan-2-one [ka] To 1-azaspiro[4.5]decane-2,8-dione (4.5 g, 26.9 mmol) in MeOH (100 mL) at 0 °C was added NaBH (2.0 g, 53.8 mmol) in one portion, and the resulting solution was stirred at rt. After 14 h, the reaction mixture was quenched with EtOAc (50 mL), the solvent was removed under reduced pressure, and the resulting residue was purified using silica gel chromatography (eluting with EtOAc) to give 8-hydroxy-1-azaspiro[4.5]decan-2-one (2.5 g, 55%) as a colorless oil. m / z (ESI+), [M+H] + =170.

[0143] 2-Oxo-1-azaspiro[4.5]decan-8-yl 4-methylbenzenesulfonate [ka] TsCl (6.8 g, 35.8 mmol) was slowly added to a solution of 8-hydroxy-1-azaspiro[4.5]decan-2-one (2.8 g, 16.3 mmol), DMAP (199 mg, 1.6 mmol), and TEA (9.1 mL, 65.0 mmol) in DCM (15 mL) under a N atmosphere at rt. The resulting mixture was stirred at rt for 3 h. The reaction mixture was quenched with water (100 mL), extracted with DCM (15 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 30–60% EtOAc in PE) to give 2-oxo-1-azaspiro[4.5]decan-8-yl 4-methylbenzenesulfonate (2.00 g, 38%) as a colorless solid. 1 H NMR(300MHz,DMSO-d6)δ 7.79(d,2H),7.47(d,2H),4.39-4.59(m,1H),2.42(s,3H),2.07-2.19(m,2H),1.48-1.83(m,8H),1.35-1.48(m,2H).m / z(ESI+),[M+H] + =324.

[0144] 1-Methyl-2-oxo-1-azaspiro[4.5]decan-8-yl 4-methylbenzenesulfonate (Int III-1) [ka] To a solution of 2-oxo-1-azaspiro[4.5]decan-8-yl 4-methylbenzenesulfonate (1.9 g, 5.9 mmol) in DMF (8 mL) was added NaH (60 wt%) (352 mg, 8.8 mmol) under a N atmosphere at 0 °C. The resulting suspension was stirred at 0 °C for 30 min, followed by the addition of iodomethane (1.5 mL, 23.5 mmol). The reaction mixture was stirred at rt for an additional 6 h and then quenched with water (10 mL). The mixture was directly purified by C18 flash chromatography (eluting with 0–60% MeCN in water (0.5% NH4OH)) to afford 1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl 4-methylbenzenesulfonate (1.8 g, 91%) as a colorless solid. 1 H NMR (400MHz, DMSO-d6) (3:1 mixture of isomers) δ 7.78-7.86(m,2H),7.48(d,2H),4.61-4.70 / 4.43-4.53(m,1H)(isomer),2.59 / 2.55(s,3H)(isomer),2.42( s,3H),2.13-2.23(m,2H),1.54-1.89(m,8H),1.15-1.26 / 1.26-1.37(m,2H)(isomer).m / z(ESI+),[M+H] + =338.

[0145] Intermediate Int III-2: Synthesis of tert-butyl 7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate [ka] To tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate (2.0 g, 8.3 mmol) and TEA (2.3 mL, 16.6 mmol) in DCM (15 mL) under a N atmosphere at 0 °C, MsCl (839 μL, 10.8 mmol) was added, and the resulting solution was stirred at rt. After 15 h, the reaction mixture was poured into water (150 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were dried over NaSO, filtered, and the solvent was removed under reduced pressure to give crude tert-butyl 7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate (2.70 g) as an orange solid. 1 H NMR(300MHz,DMSO-d6)δ 4.57-4.70(m,1H),3.53(s,2H),3.50(s,2H),3.16(s,3H),1.71-1.90(m,4H),1.51-1.66(m,4H),1.38(s,9H).m / z(ESI+),[M-tBu+H] + =264.

[0146] Intermediate Int III-3: Synthesis of 2-hydroxy-2-methylspiro[3.5]nonan-7-yl 4-methylbenzenesulfonate 2-Methyl-8,11-dioxadispiro[3.2.4 7 .2 4 ]Tridecan-2-ol [ka] A solution of methylmagnesium bromide in THF (3N, 10.0 mL, 30.0 mmol) was added to 8,11-dioxadispiro[3.2.4] in THF (50 mL) under N2 atmosphere at -78 °C. 7 .2 4]tridecan-2-one (2.0 g, 10.2 mmol) was slowly added. The resulting mixture was stirred at -65 °C for 1 h, followed by -40 °C for 2 h. At -40 °C, the reaction mixture was quenched with saturated aqueous NH4Cl (50 mL), warmed to rt, and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified using silica gel chromatography (eluting with 30-40% EtOAc in PE) to give 2-methyl-8,11-dioxadispiro[3.2.4 7 .2 4 ]Tridecan-2-ol (2.1 g, 97%) was obtained as a colorless oil.

[0147] 2-Hydroxy-2-methylspiro[3.5]nonan-7-one [ka] Aqueous HCl (2N, 20 mL, 40 mmol) was added to 2-methyl-8,11-dioxadispiro[3.2.4] in THF (20 mL) under N2 atmosphere at rt. 7 .2 4 ]tridecan-2-ol (2.1 g, 9.9 mmol) was slowly added and stirring was continued for 2 h. The mixture was neutralized to pH 7 with aqueous NaOH (2 m) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over Na2SO4, and concentrated under reduced pressure to give crude 2-hydroxy-2-methylspiro[3.5]nonan-7-one (1.7 g) as a colorless oil. m / z (ESI+), [M+H] + =169.

[0148] 2-Methylspiro[3.5]nonane-2,7-diol [ka] NaBH (37.8 mg, 1.0 mmol) was slowly added to crude 2-hydroxy-2-methylspiro[3.5]nonan-7-one (84 mg) in MeOH (3 mL) under a N atmosphere at rt, and the resulting mixture was stirred for 30 min. The solvent was then removed under reduced pressure, and the resulting residue was purified using silica gel chromatography (eluting with 50-70% EtOAc in PE) to afford 2-methylspiro[3.5]nonane-2,7-diol (78 mg, 92%) as a colorless solid.

[0149] 2-Hydroxy-2-methylspiro[3.5]nonan-7-yl 4-methylbenzenesulfonate (Int III-3) [ka] TsCl (4.0 g, 21.0 mmol) was slowly added to 2-methylspiro[3.5]nonane-2,7-diol (1.2 g, 7.1 mmol), DMAP (172 mg, 1.4 mmol), and TEA (4.9 mL, 35.2 mmol) in DCM (50 mL) under a N atmosphere at rt, and the resulting mixture was stirred at 50 °C. After 16 h, the reaction mixture was cooled to rt, quenched with water (50 mL), and extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, and concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography (eluting with 10–50% EtOAc in PE) to afford 2-hydroxy-2-methylspiro[3.5]nonan-7-yl 4-methylbenzenesulfonate (1.7 g, 74%) as a pale yellow oil. 1 H NMR(300MHz,DMSO-d6)δ 7.77(d,2H),7.46(d,2H),4.38-4.51(m,1H),2.41(s,3H),1.21-1.81(m,12H),1.18(s,3H).

[0150] Intermediate Int III-4: Synthesis of tert-butyl 6-methyl-7-oxo-2-azaspiro[3.5]nonane-2-carboxylate [ka] 1M LiHMDS in THF (157.0 mL, 157.0 mmol) was added to THF (100 mL) at −78° C. over 30 minutes under a N atmosphere, followed by the dropwise addition of a solution of tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (18.8 g, 78.6 mmol) in THF (300 mL). The resulting mixture was stirred at −78° C. for 1 hour. Iodomethane (22.3 g, 157.1 mmol) was then added dropwise. The reaction mixture was stirred at −78° C. for an additional 30 minutes, followed by stirring at rt for 15 hours. The mixture was quenched with ice water (150 mL) and extracted with EtOAc (500 mL × 3). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 16-20% EtOAc in PE) to give tert-butyl 6-methyl-7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (9.5 g, 48%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 3.83(br.s,2H),3.53(br.s,2H),2.40-2.49(m,2H),2.06-2.22(m,3H),1.72-1.83(m,1H),1.47-1.57(m,1H),1.39(s,9H),0.88(d,3H).MS ESI,m / z=239[M-tBu+CH3CN+2H] + .

[0151] Intermediates Int III-5 and Int III-6: Synthesis of rac-tert-butyl (6R,7S)-6-methyl-7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate and rac-tert-butyl (6S,7S)-6-methyl-7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate rac-tert-butyl (6R,7S)-7-hydroxy-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate and rac-tert-butyl (6S,7S)-7-hydroxy-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate [ka] To a solution of tert-butyl 6-methyl-7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (Int III-4) (19.5 g, 77.0 mmol) in MeOH (300 mL) at 0 °C under a N atmosphere was added NaBH (5.8 g, 153.9 mmol) in small portions over 40 min. The resulting mixture was allowed to warm to rt over 5 h. The reaction was quenched with brine (300 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were dried over NaSO, filtered, and evaporated under reduced pressure. The residue was purified twice by silica gel chromatography ((1.): eluting with 25-30% EtOAc in PE; (2.): eluting with 25% EtOAc in PE) to give rac-tert-butyl (6R,7S)-7-hydroxy-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate (13.6 g, 69%) and rac-tert-butyl (6S,7S)-7-hydroxy-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate (1.8 g, 9%) as colorless solids. (6R,7S)-isomer: MS ESI, m / z = 200 [M-tBu+2H] + ;(6S,7S)-isomer:MS ESI, m / z=200[M-tBu+2H] + .

[0152] rac-tert-butyl (6R,7S)-6-methyl-7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate (Int III-5) [ka] MsCl (7.7 mL, 98.7 mmol) was added dropwise over 15 min at rt to a solution of rac-tert-butyl (6R,7S)-7-hydroxy-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate (4.2 g, 16.5 mmol) and TEA (22.9 mL, 165 mmol) in DCM (20 mL). The resulting mixture was stirred at rt for 12 h. The mixture was washed with water (25 mL × 2). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 50–100% EtOAc in PE) to give rac-tert-butyl (6R,7S)-6-methyl-7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate (3.5 g, 64%) as a yellow oil. 1 H NMR(300MHz,DMSO-d6)δ 4.64-4.68(m,1H),3.41-3.61(m,4H),3.16(s,3H),1.94-2.02(m,1H),1.52-1.82(m,5H),1.38(s,10H),0.88-0.97(m,3H).

[0153] rac-tert-butyl (6S,7S)-6-methyl-7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate (Int III-6) [ka] MsCl (0.55 mL, 7.1 mmol) was added dropwise to a solution of rac-tert-butyl (6S,7S)-7-hydroxy-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate (1.8 g, 7.1 mmol) and TEA (983 μL, 7.1 mmol) in DCM (8 mL) under a N atmosphere at 0 °C. The resulting solution was stirred at rt for 3 h. The reaction mixture was quenched with water (10 mL) and extracted with DCM (15 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 0–60% EtOAc in PE) to give rac-tert-butyl (6S,7S)-6-methyl-7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate (1.4 g, 60%) as a yellow solid. MS ESI, m / z = 667 [2M+H] + .

[0154] Intermediate Int III-7: Synthesis of rac-(1R,3R)-3-hydroxycyclohexyl 4-methylbenzenesulfonate [ka] TsCl (8.2 g, 42.0 mmol) was added to TEA (12.0 mL, 86.1 mmol), DMAP (526 mg, 4.3 mmol), and rac-(1R,3R)-cyclohexane-1,3-diol (5 mg, 43.0 mmol) in DCM (300 mL) at 0 °C, and the resulting mixture was stirred at rt. After 2 h, the reaction mixture was quenched with water (200 mL) and extracted with DCM (2 × 300 mL). The combined organic layers were washed with brine (1 × 200 mL), dried over NaSO, and concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography (eluting with 0–40% EtOAc in DCM) to afford rac-(1R,3R)-3-hydroxycyclohexyl 4-methylbenzenesulfonate (5.0 g, 43%) as a pale yellow oil. 1H NMR(300MHz,DMSO-d6)δ 7.77(d,2H),7.47(d,2H),4.68-4.80(m,1H),4.59(br.s,1H),3.70-3.81(m,1H),2.42(s,3H),1.20-1.73(m,8H).

[0155] Intermediate Int III-8: Synthesis of (1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate [ka] TsCl (33.2 g, 174.2 mmol) was added to a solution of tert-butyl ((1s,4s)-4-hydroxycyclohexyl)carbamate (15.0 g, 69.7 mmol), DMAP (851 mg, 7.0 mmol), and TEA (29.1 mL, 209.0 mmol) in DCM (300 mL) over 5 min under a N atmosphere at rt. The resulting mixture was stirred at 50 °C for 20 h. The reaction mixture was cooled to rt, diluted with DCM (500 mL), washed with brine (150 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 10–50% EtOAc in PE) to give (1s,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate (15.5 g, 60%) as a colorless solid. 1 H NMR(300MHz,DMSO-d6)δ 7.70-7.85(m,2H),7.41-7.54(m,2H),6.80(d,1H),4.58(s,1H),3.14-3.34(m,1H),2.42(s,3H),1.61-1.79(m,2H),1.32-1.60(m,15H).

[0156] Intermediate Int III-9: Synthesis of 4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate [ka] TsCl (21.3 g, 111.5 mmol) was added dropwise to a solution of tert-butyl (4-hydroxycyclohexyl)carbamate (cis / trans ratio 1:5) (20.0 g, 92.9 mmol) and TEA (25.9 mL, 185.8 mmol) in DCM (400 mL) over 5 min under a N atmosphere at rt. The resulting mixture was stirred at rt for 20 h. The reaction mixture was diluted with DCM (400 mL), washed with water (150 mL × 2), and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 10–25% EtOAc in PE) to give 4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate (cis / trans ratio 1:5) (26.0 g, 76%) as a colorless solid. 1 H NMR (300MHz, DMSO-d6) (1:5 mixture of cis / trans isomers) δ 7.75-7.85(m,2H),7.47(d,2H),6.81 / 6.71(d,1H)(isomer),4.54-4.62 / 4.27-4.42(m,1H)(isomer),3.10-3.28 (m,1H),2.42(s,3H),1.62-1.83(m,4H),1.39-1.58(m,2H),1.30-1.38(m,9H)(isomer),1.09-1.27(m,2H).MS ESI,m / z=270[M-Boc+2H] + .

[0157] Intermediate Int III-10: Synthesis of 4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl 4-methylbenzenesulfonate [ka] Iodomethane (3.8 g, 27.1 mmol) was dissolved in NaH (60 wt%) (812 mg, 20.3 mmol) and 4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate (cis / trans ratio 1:5) (Int The resulting mixture was stirred at 60 °C for 4 h. The mixture was cooled to rt, and the reaction was quenched with water (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with brine (100 mL × 4), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a pale yellow solid. The solid was purified by silica gel chromatography (eluting with 10–25% EtOAc in PE) to give 4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl 4-methylbenzenesulfonate (cis / trans ratio 1:5) (2.5 g, 48%) as a colorless solid. 1 H NMR(300MHz,DMSO-d6)δ 7.80(d,2H),7.48(d,2H),4.32-4.45(m,1H),3.57-3.89(m,1H),2.60(s ,3H),2.43(s,3H),1.67-1.91(m,2H),1.42-1.67(m,6H),1.38(s,9H).MS ESI,m / z=284[M-Boc+2H] + .

[0158] Intermediates Int III-11 and Int III-12: Synthesis of rac-(7R,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-ol and rac-(7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-ol [ka] To a solution of 7-methyl-1,4-dioxaspiro[4.5]decan-8-one (50.0 g, 293.8 mmol) in MeOH (500 mL) was added NaBH (22.3 g, 587.5 mmol) in small portions over 20 min at 0 °C under a N atmosphere. The resulting mixture was stirred at rt for 1 h and then concentrated under reduced pressure. The residue was directly purified by silica gel chromatography (eluting with 16% EtOAc in PE) to give rac-(7R,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-ol (3.18 g, 6%) and rac-(7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-ol (19.00 g, 38%). rac-(7R,8S) isomer: 1 H NMR(300MHz,DMSO-d6)δ 4.27(d,1H),3.75-3.9(m,4H),3.51-3.6(m,1H),1.44-1.78(m,5H),1.25-1.44(m,2H),0.86(d,3H).rac-(7S,8S) isomer: 1 H NMR(300MHz,DMSO-d6)δ 4.45(d,1H),3.75-3.89(m,4H),2.89-3.05(m,1H),1.27-1.77(m,6H),1.19(t,1H),0.90(d,3H).

[0159] Intermediate Int III-13: Synthesis of rac-(7R,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate [ka] MsCl (1.4 mL, 17.4 mmol) was added dropwise to a solution of rac-(7R,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-ol (Int III-11) (2.5 g, 14.5 mmol) and TEA (6.1 mL, 43.6 mmol) in DCM (50 mL) under a N atmosphere at 0 °C over 30 min. The resulting mixture was stirred at rt for 2 h. The reaction mixture was quenched with brine (100 mL) and extracted with DCM (100 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 0-20% EtOAc in PE) to give rac-(7R,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (2.1 g, 58%) as a brown solid. 1 H NMR(300MHz,DMSO-d6)δ 4.71(br.s,1H),3.80-3.92(m,4H),3.17(s,3H),2.02-2.13(m,1H),1.85-2.02(m,1H),1.32-1.83(m,5H),0.94(d,3H).

[0160] Intermediate Int IV-1: Synthesis of (1s,4s)-4-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)cyclohexan-1-ol (1r,4r)-4-Hydroxycyclohexyl 4-methylbenzenesulfonate [ka] To a solution of TsCl (8.2 g, 43.0 mmol), TEA (8.7 g, 86.1 mmol), and DMAP (591 mg, 4.8 mmol) in DCM (100 mL) was added (1R,4R)-cyclohexane-1,4-diol (5.0 g, 43.0 mmol). The resulting mixture was stirred at rt for 14 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluting with 20–50% EtOAc in PE) to give (1R,4R)-4-hydroxycyclohexyl 4-methylbenzenesulfonate (2.1 g, 18%) as a colorless solid. 1H NMR(300MHz,DMSO-d6)δ 7.78(d,2H),7.47(d,2H),4.40-4.53(m,1H),3.39-3.54(m,1H),2.42(s,3H),1.60-1.83(m,4H),1.32-1.60(m,2H),1.13-1.32(m,2H).

[0161] (1s,4s)-4-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)cyclohexan-1-ol (Int IV-1) [ka] To a solution of 6-cyclopropoxy-5-iodo-1H-indazole (Int I-3) (300 mg, 1.0 mmol) and KOH (224 mg, 4.0 mmol) in DMF (30 mL) at rt, (1r,4r)-4-hydroxycyclohexyl 4-methylbenzenesulfonate (946 mg, 3.5 mmol) was added. The resulting mixture was stirred at 80 °C for 14 h. The mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (50 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0–100% MeCN in water (0.1% FA)) to give (1s,4s)-4-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)cyclohexan-1-ol (115 mg, 25%) as a yellow solid. MS ESI, m / z = 399 [M+H] + .

[0162] Intermediate Int IV-2: Synthesis of (1r,4r)-4-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)cyclohexan-1-ol (1s,4s)-4-Hydroxycyclohexyl 4-methylbenzenesulfonate [ka] To a solution of (1s,4s)-cyclohexane-1,4-diol (3.0 g, 25.8 mmol), TEA (5.2 g, 51.7 mmol), and DMAP (316 mg, 2.6 mmol) in DCM (50 mL) was added TsCl (5.2 g, 27.1 mmol) at 0 °C. The resulting mixture was stirred at rt for 1 h. The reaction mixture was diluted with DCM (50 mL) and washed sequentially with 0.1 N HCl (50 mL) and water (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 0–60% EtOAc in PE) to give (1s,4s)-4-hydroxycyclohexyl 4-methylbenzenesulfonate (2.2 g, 32%) as a colorless liquid. 1 H NMR(300MHz,DMSO-d6)δ 7.78(d,2H),7.47(d,2H),4.47-4.55(m,1H),3.43-3.53(m,1H),2.42(s,3H),1.60-1.78(m,2H),1.35-1.60(m,6H).

[0163] (1r,4r)-4-(6-Cyclopropoxy-5-iodo-2H-indazol-2-yl)cyclohexan-1-ol (Int IV-2) [ka] To a solution of (1s,4s)-4-hydroxycyclohexyl 4-methylbenzenesulfonate (1.3 g, 4.7 mmol) and 6-cyclopropoxy-5-iodo-1H-indazole (Int I-3) (350 mg, 1.2 mmol) in DMF (20 mL) was added KOH (196 mg, 3.5 mmol). The resulting mixture was stirred at 70 °C for 13 h. The reaction mixture was cooled to rt, diluted with EtOAc (50 mL), and washed with water (50 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0–100% MeCN in water (0.1% FA)) to give (1r,4r)-4-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)cyclohexan-1-ol (110 mg, 24%) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ 8.23(s,1H),8.16(s,1H),7.30(s,1H),4.66(br.s,1H),4.32-4.47(m,1H),3.87-3.99(m,1H),3 .43-3.59(m,1H),1.82-2.12(m,6H),1.35-1.47(m,2H),0.82-0.91(m,2H),0.66-0.75(m,2H).MS ESI,m / z=399[M+H] + .

[0164] Intermediate Int IV-3: Synthesis of rac-5-bromo-6-methoxy-2-((7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole [ka] To a solution of 5-bromo-6-methoxy-1H-indazole (1.5 g, 6.6 mmol) and KOH (1.5 g, 26.4 mmol) in DMF (40 mL) was added rac-(7R,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (Int III-13) (2.0 g, 8.0 mmol) at rt. The resulting mixture was stirred at 80 °C overnight. The reaction mixture was diluted with EtOAc (300 mL) and washed with brine (150 mL × 4). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0-80% MeCN in water (0.1% FA)) to give rac-5-bromo-6-methoxy-2-((7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole (600 mg, 22%) as a brown solid. MS ESI, m / z = 381 / 383 [M+H] + .

[0165] Intermediates Int IV-4 and Int IV-5: Synthesis of 5-bromo-6-methoxy-2-((7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole and 5-bromo-6-methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole [ka] rac-5-Bromo-6-methoxy-2-((7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole (Int IV-3) (7.3 g, 19.2 mmol) was purified by preparative SFC (Chiralpak® IG, 5 μm 50 × 250 mm; CO (35 °C, 100 bar)) with 50% MeOH (0.1% 2N Separation by isocratic elution with NH3-MeOH (200 mL / min) afforded 5-bromo-6-methoxy-2-((7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole (3.1 g, 43%, 100% ee) and 5-bromo-6-methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole (3.0 g, 41%, 100% ee), both as gray solids. 1 1 H NMR and MS were identical. 1 H NMR(300MHz,DMSO-d6)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,1H),1.75-1.99(m,3H),1.68(td,1H),1.46(t,1H),0.52(d,3H).MS ESI,m / z=381 / 383[M+H] + .

[0166] Intermediates Int IV-6 and Int IV-7: Synthesis of (5s,8s)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2-methyl-2-azaspiro[4.5]decan-3-one and (5r,8r)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2-methyl-2-azaspiro[4.5]decan-3-one 2-Methyl-3-oxo-2-azaspiro[4.5]decan-8-yl methanesulfonate [ka] MsCl (2.0 g, 17.6 mmol) was added dropwise to a solution of 8-hydroxy-2-methyl-2-azaspiro[4.5]decan-3-one (1.9 g, 10.4 mmol) and DIPEA (4.7 g, 36.3 mmol) in DCM (25 mL) at 0 °C. The resulting mixture was warmed to rt and stirred for 48 h. The reaction mixture was quenched with ice-cold half-saturated aqueous NaHCO (30 mL) and extracted with DCM (50 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with DCM) to give 2-methyl-3-oxo-2-azaspiro[4.5]decan-8-yl methanesulfonate (3.1 g, 96%) as an orange oil.

[0167] (5s,8s)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2-methyl-2-azaspiro[4.5]decan-3-one (Int IV-6) and (5r,8r)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2-methyl-2-azaspiro[4.5]decan-3-one (Int IV-7) [ka] To a solution of 5-bromo-6-methoxy-1H-indazole (775 mg, 3.4 mmol) and KOH (434 mg, 7.0 mmol) in THF (15 mL) was added 2-methyl-3-oxo-2-azaspiro[4.5]decan-8-yl methanesulfonate (1.3 g, 5.0 mmol) at 75 °C. The resulting mixture was stirred at 75 °C overnight. The reaction was cooled to rt, quenched with water, extracted with DCM (40 mL × 4), dried, and concentrated under reduced pressure. The residue was loaded onto a 10 g Isolute® SCX2 exchange cartridge. The cartridge was washed with DCM / MeOH (1:1) (150 mL) to remove the unwanted 1H-indazole isomer, followed by elution with 100 mL of 2N NH3-MeOH solution / DCM (1:1) to give the crude product after evaporation of the solvent. The brown residue was further purified by silica gel chromatography (eluting with EtOAc, followed by 0-2% 2N NH3-MeOH in DCM) to give 8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2-methyl-2-azaspiro[4.5]decan-3-one. This material was further separated by chiral preparative SFC (Lux® Cellulose-3, 5 μm 30 mm × 250 mm; isocratic with 20% EtOH (20 mM diethylamine) in CO (40 °C, 130 bar); 120 mL / min) to give (5s,8s)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2-methyl-2-azaspiro[4.5]decan-3-one (153 mg, 3%, 100% ee) as the first eluting isomer and (5r,8r)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2-methyl-2-azaspiro[4.5]decan-3-one (153 mg, 3%, 99.2% ee) as the second eluting isomer. (5s,8s) isomer: 1H NMR(500MHz,CDCl3)δ 7.83(s,1H),7.80(s,1H),7.03(s,1H),4.26-4.36(m,1H),3.91(s,3H),3.34(s,2H),2.85(s,3 H),2.28(s,2H),2.12-2.20(m,2H),2.01-2.12(m,2H),1.87-1.96(m,2H),1.57-1.68(m,2H).MS ESI,m / z=392 / 394[M+H] + .(5r,8r) Heterosexual: 1 H NMR(500MHz,CDCl3)δ 7.85(s,1H),7.82(s,1H),7.03(s,1H),4.29-4.41(m,1H),3.92(s,3H),3.18(s,2H),2.85(s,3 H),2.41(s,2H),2.18-2.26(m,2H),1.96-2.09(m,2H),1.85-1.95(m,2H),1.57-1.69(m,2H).MS ESI,m / z=392 / 394[M+H] + .

[0168] IntermediateInt IV-8:tert-ブチル((1r,4r)-4-(5-ブロモ-6-メトキシ-2H-インダゾール-2-イル)シクロヘキシル)カルバメートの synthesis

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[0169] Intermediates Int V-1 and Int V-2: Synthesis of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1S,2S)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxamide and N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1R,2R)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxamide rac-(3R,4R)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-methylcyclohexan-1-one [ka] rac-5-Bromo-6-methoxy-2-((7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole (Int IV-3) (400 mg, 1.1 mmol) was added to a 1.2 N HCl solution in THF (5 mL) / water (5 mL) under a N atmosphere at rt. The resulting mixture was stirred at rt overnight. The reaction mixture was purified by C18 flash chromatography (eluting with 0-60% MeCN in water (0.05% TFA)) to give rac-(3R,4R)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-methylcyclohexan-1-one (330 mg, 93%) as a yellow solid. MS ESI, m / z=337 / 339 [M+H] + .

[0170] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1S,2S)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxamide (Int V-1) and N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1R,2R)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxamide (Int V-2) [ka] A suspension of rac-(3R,4R)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-methylcyclohexan-1-one (330 mg, 1.0 mmol), imidazo[1,2-b]pyridazin-3-amine (201 mg, 1.5 mmol), Pd(OAc)2 (22 mg, 0.1 mmol), dppp (81 mg, 0.2 mmol), and TEA (409 μL, 2.9 mmol) in MeCN (15 mL) was stirred under a CO atmosphere at 15 atm and 90°C for 15 h. The mixture was cooled to rt, concentrated, and purified by C18 flash chromatography (eluting with 0-80% MeCN in water (0.1% NH4OH)) to give rac-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1R,2R)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxamide as a yellow solid. This material was purified by preparative chiral SFC (Chiralpak® AS-H, 5 μm 20 mm × 250 mm; 45% i-PrOH (2 mM) in CO2 (40 °C, 70 bar)). Separation by isocratic elution with NH3-MeOH (40 mL / min) afforded N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1S,2S)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxamide (220 mg, 34%, 71.2% ee) as the first eluting isomer and N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1R,2R)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxamide (200 mg, 31%, 83.3% ee) as the second eluting isomer, both as yellow solids. 1 1 H NMR and MS were identical. 1H NMR(400MHz,DMSO-d6)δ 11.05(s,1H),8.67(s,1H),8.65(dd,1H),8.60(s,1H),8.16(dd,1H),8.06(s,1H),7.30(s,1H),7.23(dd,1H) ),4.61-4.76(m,1H),4.13(s,3H),2.64-2.79(m,1H),2.52-2.60(m,1H),2.23-2.49(m,5H),0.65(d,3H).MS ESI,m / z=419[M+H] + .

[0171] Intermediate Int V-3: Synthesis of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxamide 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 IV-8) (990 mg, 2.3 mmol) in DMF (10 mL) was added NaH (60 wt%) (1.1 g, 28.0 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 30 min, followed by the addition of iodomethane (662 mg, 4.7 mmol). The reaction mixture was stirred at rt for 15 h, then quenched with water (10 mL) and directly purified by C18 flash chromatography (eluting with 0-100% MeCN in water (0.05% NH4OH)) to afford tert-butyl ((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate (600 mg, 59%) as a black solid, which was used without further purification. MS ESI, m / z = 438 / 440 [M+H] + .

[0172] tert-Butyl ((1r,4r)-4-(5-(imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate [ka] A suspension of tert-butyl ((1r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate (380 mg, 0.9 mmol), imidazo[1,2-b]pyridazin-3-amine (134 mg, 1.0 mmol), Pd(OAc) (44 mg, 0.2 mmol), dppp (165 mg, 0.4 mmol), and TEA (604 μL, 4.3 mmol) in MeCN (20 mL) was stirred under a CO atmosphere at 15 atm and 100° C. for 15 h. The mixture was then cooled to rt and concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0 to 100% acetronitrile in water (0.05% NH4OH)) to give tert-butyl ((1r,4r)-4-(5-(imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate (430 mg, 95%) as a red solid. 1 H NMR(300MHz,DMSO-d6)δ 11.04(s,1H),8.63(d,1H),8.60(s,1H),8.56(s,1H),8.14(dd,1H),8.05(s,1H),7.26(s,1H),7.21(dd,1H),4.34-4.61(m, MS ESI,m / z=520[M+H] + .

[0173] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxamide (Int V-3) [ka] tert-Butyl ((1r,4r)-4-(5-(imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate (430 mg, 0.8 mmol) was added to 2 N HCl in dioxane (12 mL, 24.0 mmol) under a N atmosphere at rt. The resulting mixture was stirred at rt for 2 h and then concentrated under reduced pressure to give the crude HCl salt of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxamide (300 mg), which was used directly without further purification. 1 H NMR(300MHz,DMSO-d6)δ 11.26(s,1H),8.97(dd,1H),8.63(s,1H),8.60(s,1H),8.43(dd,1H),8.37(s,1H),7.67(dd,1H),7.28(s,1H),4.48-4.6 4(m,1H),4.13(s,3H),3.01-3.22(m,1H),2.54-2.59(m,3H),2.12-2.29(m,4H),1.85-2.12(m,2H),1.47-1.73(m,2H).MS ESI,m / z=420[M+H] + .

[0174] Intermediate Int V-4: Synthesis of 6-methoxy-2-((1r,4r)-4-(methylamino)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide 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 IV-8) (4.2 g, 9.9 mmol) in DMF (50 mL) was added NaH (60 wt%) (792 mg, 19.8 mmol) under a N atmosphere at 0 °C. The resulting suspension was stirred at rt for 30 min, followed by the addition of iodomethane (1.2 mL, 19.8 mmol). After stirring for 13 h, the reaction was 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 (4.4 g, 100%) as a colorless solid. MS ESI, m / z = 438 / 440 [M+H] + .

[0175] Methyl 2-((1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylate [ka] A suspension of 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 (714 mg, 1.0 mmol), and TEA (13.6 mL, 97.6 mmol) in MeOH (125 mL) was stirred under a CO atmosphere at 15 atm and 100 °C for 15 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting 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] + .

[0176] 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 (2.9 g, 6.9 mmol) in MeOH (50 mL) / water (25 mL) at rt was added NaOH (556 mg, 13.9 mmol). The resulting solution was stirred at 30° C. for 12 h. The reaction mixture was cooled to rt and acidified with 4 N HCl to pH ∼6. The precipitate was filtered, washed with water (200 mL), and dried under vacuum 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] + .

[0177] tert-Butyl ((1r,4r)-4-(6-methoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate [ka] To a solution of 2-((1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (2.6 g, 6.4 mmol) and DIPEA (3.4 mL, 19.3 mmol) in DMF (50 mL) under a N atmosphere at rt was added HATU (2.9 g, 7.7 mmol). The resulting mixture was stirred at rt for 15 min, followed by the addition of the HCl salt of pyrazolo[1,5-a]pyrimidin-3-amine (1.4 g, 8.4 mmol). The reaction mixture was stirred at rt for 13 h. The mixture was diluted with water (100 mL) and filtered to give a crude solid. The solid was washed with water (100 mL) and subsequently purified by silica gel chromatography (eluting with 0-5% MeOH in DCM) to give tert-butyl ((1r,4r)-4-(6-methoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate (3.3 g, 99%) as a yellow solid. MS ESI, m / z = 520 [M+H] + .

[0178] 6-Methoxy-2-((1r,4r)-4-(methylamino)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Int V-4) [ka] To a solution of tert-butyl ((1r,4r)-4-(6-methoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate (3.3 g, 6.4 mmol) in DCM (40 mL) under a N atmosphere at rt was added 4 N HCl in dioxane (15.9 mL, 63.5 mmol), and the resulting solution was stirred at rt for 12 h. The mixture was concentrated under reduced pressure to give the HCl salt of 6-methoxy-2-((1r,4r)-4-(methylamino)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (2.9 g) as a pale yellow solid, which was used directly without further purification. MS ESI, m / z = 420 [M+H] + .

[0179] Intermediate Int V-5: Synthesis of 2-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-6-hydroxy-N-(imidazo[1,2-b]pyridazin-3-yl)-2H-indazole-5-carboxamide [ka] BBr3 (8.0 mL, 8.3 mmol) was added dropwise to 2-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (Example 21, see below) (380 mg, 0.8 mmol) in DCM (15 mL) over 5 min under a N2 atmosphere at 0 °C, and the resulting mixture was stirred at 40 °C. After 6 h, the reaction mixture was cooled to rt, quenched with saturated aqueous NaHCO3 (10 mL), and diluted with brine (50 mL). The mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified using C18 flash chromatography (eluting with 0% to 25% MeCN in water) followed by silica gel chromatography (eluting with 9% to 10% MeOH in DCM) to afford 2-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-6-hydroxy-N-(imidazo[1,2-b]pyridazin-3-yl)-2H-indazole-5-carboxamide (170 mg, 46%) as a light brown solid. 1 H NMR (300MHz, DMSO-d6) (1:1 mixture of rotamers) δ 11.69(s,1H),11.62(s,1H),8.62(s,1H),8.60(dd,1H),8.57(s,1H),8.15(dd,1H),8.10(s,1H),7.21(dd,1H),7.00(s,1H),4.33-4.53(m,1 H),3.92(s,1H),3.80(s,1H),3.63(s,1H),3.52(s,1H),1.83-2.12(m,6H),1.76 / 1.78(s,3H)(rotamer),1.61-1.74(m,2H).m / z(ESI+),[M+H] + =460.

[0180] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide (Example 1) 8-Amino-1azaspiro[4.5]decan-2-one [ka] 1-Azaspiro[4.5]decane-2,8-dione (1.0 g, 6.0 mmol) was mixed with 4N NH in MeOH (46.0 mL, 0.18 mol) and stirred at rt. After 1 h, the resulting solution was added to a suspension of NaBH (256 mg, 6.8 mmol) in THF (20 mL) at −50° C. and allowed to warm to rt. The reaction was quenched with water (10 mL), and the organic solvents were removed under reduced pressure. Subsequently, 4 M aqueous NaOH (40 mL) and sodium chloride (10 g) were added. The resulting suspension was extracted with DCM (4 mL × 70), the combined organic phases were dried over MgSO, and the solvent was removed under reduced pressure to give crude 8-amino-1-azaspiro[4.5]decan-2-one (0.9 g), which was used without further purification.

[0181] (5r,8r)-8-(5-Bromo-6-methoxy-2H-indazol-2-yl)-1-azaspiro[4.5]decan-2-one [ka] To crude 8-amino-1-azaspiro[4.5]decan-2-one (600 mg) in i-PrOH (25 mL) was added 5-bromo-4-methoxy-2-nitrobenzaldehyde (Int I-1) (1.1 g, 2.2 mmol), and the resulting mixture was stirred at 80 °C. After 4 h, tri-n-butylphosphine (1.6 mL, 6.5 mmol) was added, and the mixture was stirred at 80 °C overnight. The reaction mixture was then cooled to rt and filtered. The collected solid was washed with heptane (3 × 10 mL), washed with 250 mL of DCM / MeOH (1:1), and purified using ion exchange chromatography eluting with DCM / 4N NH3-MeOH solution (1 / 1). The isolated solid was subsequently recrystallized using i-PrOH to remove undesired (5s,8s)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-1-azaspiro[4.5]decan-2-one. The filtrate was further purified by silica gel chromatography (eluting with 50–100% EtOAc in heptane, then EtOAc, followed by 0–3% NH3-MeOH in DCM) to give (5r,8r)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-1-azaspiro[4.5]decan-2-one (320 mg, 39%). m / z (ESI+), [M+H] + =378 / 380.

[0182] (5r,8r)-8-(5-Bromo-6-methoxy-2H-indazol-2-yl)-1-methyl-1-azaspiro[4.5]decan-2-one [ka] To a stirred solution of (5r,8r)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-1-azaspiro[4.5]decan-2-one (310 mg, 0.7 mmol) in DMF (5 mL) / THF (5 mL) was added NaH (60 wt%) (93 mg, 2.1 mmol) at 0 °C. After 20 min, methyl iodide (130 μL, 2.1 mmol) was added slowly at 0 °C. The resulting mixture was allowed to warm to rt and stirred overnight. The reaction mixture was then quenched with ice water (250 mL) and extracted with DCM (4 × 25 mL). The combined organic phase was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (eluting with DCM (300 mL), EtOAc (2 L), followed by 2% NH3-MeOH in DCM (150 mL)) to afford (5r,8r)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-1-methyl-1-azaspiro[4.5]decan-2-one (225 mg, 78%) as a beige solid. m / z (ESI+), [M+H] + =392 / 394.

[0183] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide (Example 1) [ka] Methyldiphenylsilane carboxylic acid (193 mg, 0.8 mmol) and KF (46 mg, 0.8 mmol) were added to Chamber A of a dried, N-flushed COware gas reactor. (5r,8r)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-1-methyl-1-azaspiro[4.5]decan-2-one (116 mg, 0.3 mmol), imidazo[1,2-b]pyridazin-3-amine (121 mg, 0.9 mmol), dppp (41 mg, 0.1 mmol), Pd(OAc) (27 mg, 0.1 mmol), and TEA (223 μL, 1.6 mmol) in degassed anhydrous MeCN (2 mL) were added to Chamber B. DMSO (350 μL) was then added to Chamber A, and Chamber B was stirred at 85 °C overnight. The reaction mixture was cooled to rt. The reaction in Chamber B was quenched with saturated NaHCO3, the solvent was removed under reduced pressure, and the resulting residue was purified using ion exchange chromatography, washing with DCM / MeOH (1 / 1; 200 mL) and eluting with 4N NH3 in MeOH (200 mL). The resulting dark brown solid was further purified using silica gel chromatography (eluting with EtOAc (2 L) followed by 0–3% NH3-MeOH in DCM) to give an orange-yellow solid. The orange-yellow solid was triturated with EtOAc (20 mL) to give a light yellow solid, which was slurried in i-PrOH (3 mL) overnight. The slurry solution was filtered and the collected precipitate was washed with i-PrOH (4 × 500 μL) and pentane (3 × 1 mL) to give N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide (93 mg, 74%) as a pale yellow solid. 1H NMR(500MHz,DMSO-d6)δ 11.05(s,1H),8.65(dd,1H),8.64(d,1H),8.59(s,1H),8.16(dd,1H),8.05(s,1H),7.29(s,1H),7.23(dd,1H),4.49-4.61( m,1H),4.12(s,3H),2.68(s,3H),2.28(t,2H),2.07-2.18(m,4H),1.94-2.03(m,4H),1.53-1.59(m,2H).m / z(ESI+),[M+H] + =474.

[0184] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((5s,8s)-1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide (Example 2) [ka] To 1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl 4-methylbenzenesulfonate (Int III-1) (1.4 g, 4.2 mmol), DMF (15 mL), N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-1H-indazole-5-carboxamide (Int II-1) (1.3 g, 4.2 mmol), and KOH (466 mg, 8.3 mmol) were added. The resulting solution was stirred at 100 °C. After 12 h, the reaction mixture was cooled to rt and directly purified using C18 flash chromatography (eluting with 0% to 100% MeCN in water (0.05% FA)) followed by chiral HPLC (CHIRAL ART Cellulose-SB, 2 x 25 mm, 5 μm; mobile phase A: MTBE (2 mm NH in MeOH), mobile phase B: i-PrOH; gradient: isocratic 50% B in 21.5 min; flow rate: 20 mL / min) to afford N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((5s,8s)-1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide (28.0 mg, 1%) as a yellow solid. 1H NMR(300MHz,CD3OD)δ 8.75(d,1H),8.62(s,1H),8.59(d,1H),8.15(s,1H),8.04(dd,1H),7.21-7.28(m,2H),4.71-4.79(m,1H),4.23 (s,3H),2.68(s,3H),2.59-2.69(m,2H),2.44(t,2H),2.07-2.33(m,6H),1.45-1.55(m,2H).m / z(ESI+),[M+H] + =474.

[0185] 2-((1s,4s)-4-(dimethylcarbamoyl)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (Example 3) (1r,4r)-4-Hydroxy-N,N-dimethylcyclohexane-1-carboxamide [ka] HATU (9.5 g, 25.0 mmol) was added to (1r,4r)-4-hydroxycyclohexane-1-carboxylic acid (3.0 g, 20.8 mmol), dimethylamine hydrochloride (5.1 g, 62.5 mmol), and DIPEA (14.5 mL, 83.0 mmol) in DCM (30 mL) over 3 h under a N atmosphere at rt. After stirring the resulting mixture for 3 h, the reaction mixture was poured into water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried over NaSO, filtered, and the solvent was removed under reduced pressure. The crude product was subjected to silica gel chromatography (eluting with 0% to 50% EtOAc in PE) to give crude (1r,4r)-4-hydroxy-N,N-dimethylcyclohexane-1-carboxamide (2.1 g), which was used without further purification. m / z (ESI+), [M+H] + =172.

[0186] (1r,4r)-4-(Dimethylcarbamoyl)cyclohexyl 4-methylbenzenesulfonate [ka] TsCl (8.4 g, 44.1 mmol) was added dropwise to a solution of TEA (7.3 mL, 52.4 mmol), DMAP (214 mg, 1.8 mmol), and crude (1r,4r)-4-hydroxy-N,N-dimethylcyclohexane-1-carboxamide (2 g) in DCM (20 mL) under a N atmosphere at 0 °C, and the resulting solution was stirred at rt. After 11 h, the reaction mixture was poured into water (20 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were dried over NaSO, filtered, and the solvent removed under reduced pressure. The resulting residue was subjected to silica gel chromatography (eluting with 10% to 20% EtOAc in PE) to give crude (1r,4r)-4-(dimethylcarbamoyl)cyclohexyl 4-methylbenzenesulfonate (2.1 g), which was used without further purification. m / z (ESI+), [M+H] + =326.

[0187] 2-((1s,4s)-4-(dimethylcarbamoyl)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (Example 3) [ka] KOH (218 mg, 3.9 mmol) was added to N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-1H-indazole-5-carboxamide (Int II-1) (300 mg, 1.0 mmol) and crude (1r,4r)-4-(dimethylcarbamoyl)cyclohexyl 4-methylbenzenesulfonate (950 mg) in DMF (6 mL) under a N atmosphere at rt, and the resulting solution was stirred at 100 °C. After 12 h, the reaction mixture was cooled to rt and directly subjected to C18 flash chromatography (eluting with 10% to 60% MeCN in water (0.5% FA)), followed by preparative HPLC (XSelect CSH Prep C18 OBD column, 5 μm, 19 mm × 150 mm; mobile phase A: water (0.1% FA); mobile phase B: MeCN; gradient: 15% to 27% B in 7 min, followed by 27% B in 2 min, flow rate: 60 mL / min) to give 2-((1s,4s)-4-(dimethylcarbamoyl)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (40 mg, 9%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 11.05(s,1H),8.64(t,2H),8.59(s,1H),8.15(dd,1H),8.05(s,1H),7.29(s,1H),7.22(dd,1H),4.56-4.65(m,1H), 4.12(s,3H),3.03(s,3H),2.85-2.97(m,1H),2.80(s,3H),1.94-2.04(m,3H),1.59-1.81(m,6H).m / z(ESI+),[M+H] + =462.

[0188] 2-((1r,4r)-4-(dimethylcarbamoyl)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (Example 4) (1s,4s)-4-Hydroxy-N,N-dimethylcyclohexanecarboxamide [ka] HATU (9.5 g, 24.9 mmol) was added to a solution of DIPEA (14.5 mL, 83.2 mmol), dimethylamine × HCl (5.1 g, 62.4 mmol), and (1s,4s)-4-hydroxycyclohexanecarboxylic acid (3.0 g, 20.8 mmol) in DCM (30 mL) under a N atmosphere at rt. The resulting mixture was stirred at rt for 3 h. The reaction mixture was poured into water (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (eluting with 0% to 80% EtOAc in PE) to give crude (1s,4s)-4-hydroxy-N,N-dimethylcyclohexanecarboxamide (3.5 g) as a yellow oil.

[0189] (1s,4s)-4-(Dimethylcarbamoyl)cyclohexyl 4-methylbenzenesulfonate [ka] TEA (7.3 mL, 52.6 mmol) was added to DMAP (214 mg, 1.8 mmol), (1s,4s)-4-hydroxy-N,N-dimethylcyclohexanecarboxamide (3.0 g, 17.0 mmol), and TsCl (6.7 g, 35 mmol) in DCM (30 mL) at rt under a N atmosphere over 3 h. The resulting mixture was stirred at rt for 3 h. The reaction mixture was poured into water (20 mL) and extracted with DCM (3 × 25 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel chromatography (eluting with 0% to 20% EtOAc in PE) to give (1s,4s)-4-(dimethylcarbamoyl)cyclohexyl 4-methylbenzenesulfonate (2.1 g, 37%) as a yellow oil. m / z (ESI+) [M+H] + =326.

[0190] 2-((1r,4r)-4-(dimethylcarbamoyl)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (Example 4) [ka] KOH (80 mg, 1.4 mmol) was added to a solution of (1s,4s)-4-(dimethylcarbamoyl)cyclohexyl 4-methylbenzenesulfonate (348 mg, 1.1 mmol) and N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-1H-indazole-5-carboxamide (Int II-1) (110 mg, 0.4 mmol) in DMF (10 mL) under a N atmosphere at rt. The resulting solution was stirred at 100 °C for 12 h, and after cooling to rt, the mixture was poured into water (10 mL). The aqueous phase was extracted with EtOAc (3 × 20 mL), and the combined organic layers were dried over NaSO, filtered, and concentrated to give a yellow oil. The crude product was purified by silica gel chromatography (eluting with 0% to 30% EtOAc in PE) followed by preparative HPLC (Xselect CSH Fluoro phenyl OBD column, 5 μm silica, 30 × 150 mm, mobile phase A: water (0.1% FA), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 20% B to 30% B in 7 min) to give 2-((1r,4r)-4-(dimethylcarbamoyl)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (10 mg, 17%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 11.05(s,1H),8.61-8.67(m,1H),8.59(s,2H),8.14-8.18(m,1H),8.05(s,1H),7.18-7.27(m,2H),4.48-4.54(m,1H),4.13(s,3H),3.0 7(s,3H),2.83(s,3H),2.70-2.80(m,1H),2.16-2.20(m,2H),1.99-2.05(m,2H),1.84-1.88(m,2H),1.58-1.65(m,2H).m / z(ESI+)[M+H] + =462.

[0191] 2-(2-Hydroxy-2-methylspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide - Isomer 1 (Example 5) and Isomer 2 (Example 6) [ka] CsCO (793 mg, 2.4 mmol) was added to N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-1H-indazole-5-carboxamide (Int II-1) (300 mg, 1.0 mmol) and 2-hydroxy-2-methylspiro[3.5]nonan-7-yl 4-methylbenzenesulfonate (Int III-3) (631 mg, 2.0 mmol) in DMF (15 mL), and the resulting mixture was stirred at 85 °C under a N atmosphere. After 5 h, the reaction mixture was cooled to rt and purified by C18 flash chromatography (eluting with 0% to 100% MeCN in water (0.5% FA)), followed by two rounds of preparative HPLC purification ((1st preparative HPLC: XBridge Prep OBD C18, 30 × 150 mm 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH4OH); mobile phase B: MeCN; gradient: 28% B to 48% B in 7 min; flow rate: 60 mL / min), (2nd preparative HPLC: Chiralpak ID-2, 2 × 25 cm, 5 μm; mobile phase A: MTBE (0.1% 2N NH3-MeOH; mobile phase B: MeOH; gradient: isocratic 50% B in 14 min; flow rate: 16 mL / min) to give 2-(2-hydroxy-2-methylspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-isomer 1 (25 mg, 6%, 100% ee) and 2-(2-hydroxy-2-methylspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-isomer 2 (23 mg, 5%, 99.5% ee), both as yellow solids. 1 1 H NMR and MS were identical. 1H NMR(300MHz,DMSO-d6)δ 11.04(s,1H),8.63(dd,1H),8.58(s,1H),8.57(s,1H),8.15(dd,1H),8.05(s,1H),7.28(s,1H),7.21(dd,1H),4. 75(s,1H),4.33-4.52(m,1H),4.12(s,3H),1.71-2.05(m,10H),1.43-1.61(m,2H),1.26(s,3H).m / z(ESI+),[M+H] + =461.

[0192] 2-((1s,4s)-4-Hydroxycyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (Example 7) and 2-((1r,4r)-4-hydroxycyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (Example 8) (1s,4s)-4-Hydroxycyclohexylmethanesulfonate [ka] MsCl (1.9 mL, 23.7 mmol) was added to a solution of (1s,4s)-cyclohexane-1,4-diol (2.5 g, 21.5 mmol) and TEA (6.0 mL, 43.0 mmol) in DCM (200 mL) at 0 °C. The resulting mixture was stirred at rt for 12 h. The mixture was poured into water (20 mL), the aqueous layer was extracted with DCM (1 × 20 mL), and the organic layer was dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel chromatography (eluting with PE:EtOAc 50% to 100%) to give crude (1s,4s)-4-hydroxycyclohexylmethanesulfonate (2.9 g) as a colorless solid.

[0193] 2-((1s,4s)-4-Hydroxycyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (Example 7) and 2-((1r,4r)-4-hydroxycyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (Example 8) [ka] CsCO (1.8 g, 5.7 mmol) was added to a solution of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-1H-indazole-5-carboxamide (Int II-1) (350 mg, 1.1 mmol) and crude (1s,4s)-4-hydroxycyclohexyl methanesulfonate (1.3 g) in DMF (20 mL). The resulting mixture was stirred at 100 °C for 15 h. The mixture was cooled to rt, concentrated, and purified by C18 flash chromatography (eluting with 0 to 100% MeCN in water (0.1% FA)) to give a mixture of trans and cis isomers of 2-(4-hydroxycyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide as a pale yellow solid. This material was separated by preparative SFC (CHIRALPAK IH, 2.0 × 25 cm, 5 μm; mobile phase A: CO, mobile phase B: EtOH (8 mmol / L NH-MeOH); flow rate: 40 mL / min; gradient: 40% B) to give first eluting 2-((1s,4s)-4-hydroxycyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (4 mg, 1%) and second eluting 2-((1r,4r)-4-hydroxycyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (12 mg, 3%), both as pale yellow solids. (1s,4s)-isomer: 1H NMR(300MHz,DMSO-d6)δ 11.06(s,1H),8.49-8.70(m,3H),8.13-8.20(m,1H),8.06(s,1H),7.17-7.31(m,2H),4.39-4.62 (m,2H),4.13(s,3H),3.85-3.92(m,1H),2.21-2.38(m,2H),1.56-1.98(m,6H).m / z(ESI+)[M+H] + =407.(1r,4r)-isomer: 1 H NMR(300MHz,DMSO-d6)δ 11.05(s,1H),8.61-8.67(m,1H),8.55-8.60(m,2H),8.12-8.19(m,1H),8.06(s,1H),7.18-7.29(m,2H),4.70-4.78 (m,1H),4.41-4.53(m,1H),4.13(s,3H),3.72-3.47(m,1H),1.88-2.18(m,6H),1.39-1.49(m,2H).m / z(ESI+)[M+H] + =407.

[0194] rel-2-((1S,3R)-3-hydroxycyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide - Isomer 1 (Example 9) and Isomer 2 (Example 10) [ka] To rac-(1R,3R)-3-hydroxycyclohexyl 4-methylbenzenesulfonate (Int III-7) (351 mg, 1.3 mmol) and CsCO (423 mg, 1.3 mmol) in DMF (10 mL) under N atmosphere was added N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-1H-indazole-5-carboxamide (Int II-1) (400 mg, 1.3 mmol), and the resulting mixture was stirred at 90 °C. After 5 h, the reaction mixture was cooled to rt and purified by C18 flash chromatography (eluting with 0% to 100% MeCN in water (0.05% FA)), followed by preparative HPLC (XBridge Prep OBD C18, 30 × 150 mm 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH4OH); mobile phase B: MeCN; gradient: 16% B to 36% B in 7 min; flow rate: 60 mL / min), and chiral preparative HPLC (CHIRAL ART Cellulose-SB, 4.6 × 100 mm, 3 μm; mobile phase A: (MTBE + 0.5% 2NNH in MeOH), mobile phase B: i-PrOH; gradient: isocratic 30% B in 25 min; flow rate: 18 mL / min) was directly subjected to HPLC analysis using 100% methylparaben-2-ol ((1S,3R)-3-hydroxycyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methylparaben-2-one. Toxo-2H-indazole-5-carboxamide-isomer 1 (16 mg, 3%, 99% ee) and rel-2-((1S,3R)-3-hydroxycyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-isomer 2 (17 mg, 3%, 98.7% ee) were obtained, both as yellow solids. Isomer 1: 1H NMR(400MHz,DMSO-d6)δ 11.04(s,1H),8.64(dd,1H),8.59(d,1H),8.58(s,1H),8.15(dd,1H),8. 05(s,1H),7.26(s,1H),7.22(dd,1H),4.86(d,1H),4.46-4.57(m,1H),4 .12(s,3H),3.56-3.67(m,1H),2.27-2.37(m,1H),2.01-2.09(m,1H),1. 67-1.95(m,4H),1.39-1.48(m,1H),1.12-1.26(m,1H).m / z(ESI+),[M+H] + =407.Isomer 2: 1 H NMR(400MHz,DMSO-d6)δ 11.04(s,1H),8.64(dd,1H),8.59(d,1H),8.58(s,1H),8.15(dd,1H),8. 05(s,1H),7.26(s,1H),7.22(dd,1H),4.86(d,1H),4.46-4.57(m,1H),4 .12(s,3H),3.55-3.67(m,1H),2.25-2.37(m,1H),2.02-2.12(m,1H),1. 65-1.95(m,4H),1.32-1.53(m,1H),1.12-1.26(m,1H).m / z(ESI+),[M+H] + =407.

[0195] 6-Methoxy-2-(1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 11) and Isomer 2 (Example 12) [ka] To a solution of 6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-indazole-5-carboxamide (Int II-2) (450 mg, 1.5 mmol) and 1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl 4-methylbenzenesulfonate (Int III-1) (985 mg, 2.9 mmol) in DMF (8 mL) was added CsCO (1.4 g, 4.4 mmol) under a N atmosphere at rt. The reaction mixture was stirred at 90 °C for 12 h. The mixture was cooled to rt and purified directly by C18 flash chromatography (eluting with 0% to 40% MeCN in water (0.5% FA)) and further by preparative HPLC (Waters Xbridge® Shield RP18 OBD, 5 μm 30 × 150 mm; elution gradient of 22 to 32% MeCN in water (0.1% FA) over 9 min; 60 mL / min) to give 6-methoxy-2-(1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide as a yellow solid. The solid was purified by chiral preparative HPLC (YMC Chiral ART Cellulose-SB 5 μm 20 mm × 250 mm; isocratic in 50% hexane / DCM (75 / 25, 0.5% 2M NH3-MeOH) in MeOH for 9 min; 20 mL / min) to give 6-methoxy-2-(1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 1 (55 mg, 8%, 100% ee) and 6-methoxy-2-(1-methyl-2-oxo-1-azaspiro[4.5]decan-8-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 2 (32 mg, 5%, 99.8% ee). Isomer 1: 1H NMR (400MHz, DMSO-d6) (3:7 mixture of rotamers) δ 10.32(s,1H),9.08(dd,1H),8.73(br.s,1H),8.54(dd,1H),8.46 / 8.45(s,1H)(rotamer),8.16(s,1H),7.44(s,1H),7.06(d d,1H),4.70-4.80(m,1H),4.15(s,3H),2.72(s,3H),2.29(t,2H),1.92-2.21(m,8H),1.51-1.61(m,2H).m / z(ESI+),[M+H] + =474.Isomer 2: 1 H NMR (400MHz, DMSO-d6) (1:7 mixture of rotamers) δ 10.35(s,1H),9.08(dd,1H),8.73(s,1H),8.59(s,1H),8.54(dd,1H),8.49 / 8.48(s,1H)(rotamer),7.25(s,1H),7.05(dd,1H),4.48 -4.60(m,1H),4.06(s,3H),2.68(s,3H),2.28(t,2H),2.08-2.18(m,4H),1.93-2.04(m,4H),1.52-1.60(m,2H).m / z(ESI+),[M+H] + =474.

[0196] rel-2-((1S,3R)-3-hydroxycyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 13) and Isomer 2 (Example 14) [ka] 6-Methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-indazole-5-carboxamide (Int II-2) (400 mg, 1.3 mmol) was added to a slurry of CsCO (1.3 g, 3.9 mmol) and rac-(1R,3R)-3-hydroxycyclohexyl 4-methylbenzenesulfonate (Int III-7) (702 mg, 2.6 mmol) in DMF (15 mL) under a N atmosphere at rt. The resulting mixture was stirred at 90 °C for 12 h. The reaction mixture was cooled to rt, concentrated, and directly purified first by C18 flash chromatography (eluting with 0–100% MeCN in water (0.05% NH4OH)) and then by preparative HPLC (XBridge Prep OBD C18, 30 × 150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH4OH) mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 21% B to 30% B in 7 min) to afford the desired regioisomer of rac-2-((1S,3R)-3-hydroxycyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide as a yellow solid. This material was purified by chiral preparative HPLC (CHIRAL ART Cellulose-SB column, 2 × 25 cm, 5 μm; mobile phase A: MTBE (0.5% 2N NH3-MeOH), mobile phase B: i-PrOH; flow rate: 20 mL / min; 50% B isocratic in 14 min) to give rel-2-((1S,3R)-3-hydroxycyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 1 (26 mg, 5%, 99% ee) and rel-2-((1S,3R)-3-hydroxycyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 2 (26 mg, 5%, 99% ee), both as yellow solids. Isomer 1: 1H NMR(400MHz,DMSO-d6)δ 10.35(s,1H),9.05-9.12(m,1H),8.73(s,1H),8.51-8.57(m,2H),8.47(s ,1H),7.22(s,1H),7.00-7.10(m,1H),4.82-4.86(m,1H),4.45-4.55(m,1H) ),4.06(s,3H),3.55-3.67(m,1H),2.25-2.34(m,1H),2.00-2.11(m,1H), 1.68-1.95(m,4H),1.40-1.51(m,1H),1.13-1.26(m,1H).m / z(ES+),[M+H] + =407.Isomer 2: 1 H NMR(400MHz,DMSO-d6)δ 10.35(s,1H),9.05-9.10(m,1H),8.73(s,1H),8.51-8.56(m,2H),8.47(s ,1H),7.22(s,1H),7.01-7.10(m,1H),4.45-4.55(m,1H),4.06(s,3H),3.5 6-3.67(m,1H),2.28-2.32(m,1H),2.00-2.10(m,1H),1.87-1.92(m,1H), 1.67-1.87(m,3H),1.36-1.50(m,1H),1.12-1.26(m,1H).m / z(ES+),[M+H] + =407.

[0197] 6-Cyclopropoxy-2-(2-hydroxy-2-methylspiro[3.5]nonan-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 15) and Isomer 2 (Example 16) [ka] To a solution of 6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-indazole-5-carboxamide (Int II-3) (330 mg, 1.0 mmol) and 2-hydroxy-2-methylspiro[3.5]nonan-7-yl 4-methylbenzenesulfonate (Int III-3) (480 mg, 1.5 mmol) in DMF (15 mL) was added CsCO (643 mg, 2.0 mmol) at rt. The reaction mixture was stirred at 85 °C under a N atmosphere for 5 h. The mixture was cooled to rt and purified directly by C18 flash chromatography (eluting with 0-100% MeCN in water (0.5% FA)) and further by preparative HPLC (Waters XBridge BEH C18 OBD, 5 μm, 30 × 150 mm; elution gradient of 35-55% MeCN in water (10 mM NH4HCO3 + 0.1% NH4OH) over 7 min; 60 mL / min) to give 6-cyclopropoxy-2-(2-hydroxy-2-methylspiro[3.5]nonan-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide as a yellow solid. This material was purified by preparative chiral HPLC (Chiralpak® IE 5 μm 20 mm × 250 mm; 50% hexane / DCM (75 / 25, 10 mM HCl) in MeOH). Separation by isocratic distillation with NH3-MeOH (20 mL / min) afforded 6-cyclopropoxy-2-(2-hydroxy-2-methylspiro[3.5]nonan-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 1 (37 mg, 9%, 100% ee) and 6-cyclopropoxy-2-(2-hydroxy-2-methylspiro[3.5]nonan-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 2 (38 mg, 9%, 95.8% ee), both as yellow solids. 1 1 H NMR and MS were identical. 1H NMR(300MHz,DMSO-d6)δ 10.31(s,1H),9.07(dd,1H),8.75(s,1H),8.46-8.63(m,3H),7.53(s,1H),7.05(dd,1H),4.76(s,1H),4.34-4.49(m, 1H),4.15-4.26(m,1H),1.67-2.08(m,10H),1.37-1.67(m,2H),1.27(s,3H),1.03-1.12(m,2H).0.92-1.03(m,2H).MS ESI,m / z=487[M+H] + .

[0198] 6-Cyclopropoxy-2-((1R,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 17) and 6-cyclopropoxy-2-((1S,3R)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 18) rel-6-Cyclopropoxy-2-((1S,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 19) and Isomer 2 (Example 20) 3-Hydroxycyclohexyl 4-methylbenzenesulfonate [ka] TsCl (17.2 g, 90.4 mmol) was slowly added to a solution of cyclohexane-1,3-diol (10.0 g, 86.1 mmol), DMAP (1.1 g, 8.6 mmol), and TEA (36.0 mL, 258.3 mmol) in DCM (100 mL) over 5 min under a N atmosphere at 0 °C. The resulting mixture was stirred at rt for 15 h. The mixture was quenched with brine (100 mL), extracted with DCM (100 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 25–30% EtOAc in PE) to give 3-hydroxycyclohexyl 4-methylbenzenesulfonate (8.0 g, 34%) as a yellow oil. MS ESI, m / z = 271 [M+H] + .

[0199] rac-6-Cyclopropoxy-2-((1S,3R)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide and rac-6-Cyclopropoxy-2-((1S,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide [ka] To a solution of 6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-indazole-5-carboxamide (Int II-3) (500 mg, 1.5 mmol) and 3-hydroxycyclohexyl 4-methylbenzenesulfonate (1.2 g, 4.5 mmol) in DMF (20 mL) at rt, CsCO (1.5 g, 4.5 mmol) was added. The reaction mixture was stirred at 100 °C for 5 h. The reaction mixture was cooled to rt and purified by C18 flash chromatography (eluting with 0-100% MeCN in water (0.5% FA)) followed by preparative HPLC (Waters XBridge BEH OBD C18, 5 μm 30 mm × 150 mm; 24-34% MeCN in water (10 mM FA)). Direct purification by elution with NH4HCO3 + 0.1% NH4OH (elution gradient: 60 mL / min; elution gradient: 60 mL / min) afforded rac-6-cyclopropoxy-2-((1S,3R)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (31 mg, 5%) and rac-6-cyclopropoxy-2-((1S,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (110 mg, 17%), both as yellow solids.

[0200] 6-Cyclopropoxy-2-((1R,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 17) and 6-cyclopropoxy-2-((1S,3R)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 18) [ka] rac-6-Cyclopropoxy-2-((1S,3R)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (31 mg, 0.1 mmol) was purified by preparative chiral HPLC (Chiralpak® ID 5 μm 30 × 250 mm; 80% hexane / DCM (75 / 25, 10 mM MgCl) in EtOH for 30 min). NH3-MeOH) isocratic (45 mL / min) to give 6-cyclopropoxy-2-((1R,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (6 mg, 20%, 99.9% ee) and 6-cyclopropoxy-2-((1S,3R)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (10 mg, 33%, 99.5% ee), both as yellow solids. (1R,3S)-isomer: 1 H NMR(300MHz,DMSO-d6)δ 10.31(s,1H),9.07(dd,1H),8.75(s,1H),8.57(s,1H),8.55(dd,1H),8.53 (s,1H),7.51(s,1H),7.05(dd,1H),4.85(d,1H),4.45-4.62(m,1H),4.18- 4.28(m,1H),3.53-3.69(m,1H),2.24-2.29(m,1H),1.98-2.12(m,1H),1.6 9-1.96(m,4H),1.31-1.53(m,1H),1.10-1.31(m,1H),0.93-1.10(m,4H).MS ESI, m / z=433 [M+H] + .(1S,3R)-isomer: 1H NMR(300MHz,DMSO-d6)δ 10.31(s,1H),9.07(dd,1H),8.75(s,1H),8.49-8.58(m,3H),7.51(s,1H),7.05(dd,1H),4.85(d,1H),4.43-4.60(m,1H),4.16-4.28(m,1H) ),3.54-3.68(m,1H),2.24-2.38(m,1H),1.98-2.14(m,1H),1.64-1.98(m,4H),1.30-1.54(m,1H),1.12-1.30(m,1H),0.89-1.12(m,4H).MS ESI,m / z=433[M+H] + .

[0201] rel-6-Cyclopropoxy-2-((1S,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 19) and Isomer 2 (Example 20) [ka] rac-6-Cyclopropoxy-2-((1S,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (110 mg, 0.3 mmol) was purified by preparative chiral HPLC (YMC Chiral ART Cellulose-SB 5 μm 20 mm × 250 mm; 90% hexane / DCM (75 / 25, 10 mM MgCl) in EtOH within 17 min). Separation by isocratic elution with NH3-MeOH (20 mL / min) gave rel-6-cyclopropoxy-2-((1S,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 (37 mg, 34%, 100% ee) and rel-6-cyclopropoxy-2-((1S,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (22 mg, 20%, 98% ee)-Isomer 2, both as yellow solids. Isomer 1: 1H NMR(300MHz,DMSO-d6)δ 10.31(s,1H),9.07(dd,1H),8.75(s,1H),8.59(s,1H),8.55(dd,1H),8.52(s,1H),7.51(s,1H),7.05(dd,1H),4.74-4.88(m,1H),4.71(d,1 H),4.17-4.27(m,1H),4.10-4.17(m,1H),2.00-2.16(m,3H),1.75-2.00(m,2H),1.53-1.75(m,2H),1.42-1.53(m,1H),0.94-1.12(m,4H).MS ESI,m / z=433[M+H] + Isomer 2: 1 H NMR(300MHz,DMSO-d6)δ 10.31(s,1H),9.07(dd,1H),8.75(s,1H),8.59(s,1H),8.55(dd,1H),8.52(s,1H),7.52(s,1H),7.05(dd,1H),4.70-4.88(m,1H),4.1 6-4.26(m,1H),4.08-4.16(m,1H),1.99-2.17(m,3H),1.76-1.99(m,2H),1.56-1.76(m,2H),1.38-1.56(m,1H),0.93-1.12(m,4H).MS ESI,m / z=433[M+H] + .

[0202] 2-(2-Acetyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (Example 21) tert-Butyl 7-(5-(imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2-yl)-2-azaspiro[3.5]nonane-2-carboxylate [ka] To crude tert-butyl 7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate (Int III-2) (1.5 g, 4.5 mmol) and N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-1H-indazole-5-carboxamide (Int II-1) (700 mg, 2.3 mmol) in DMF (20 mL) was added KOH (255 mg, 4.5 mmol) over 2 min at rt, and the resulting mixture was stirred at 100 °C overnight. Subsequently, the reaction mixture was cooled to rt, poured into water (150 mL), and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over NaSO, filtered, and the solvent was removed under reduced pressure to give a yellow solid. The residue was purified using C18 flash chromatography (eluting with 0 to 80% MeCN in water (0.05% FA)) to provide crude tert-butyl 7-(5-(imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2-yl)-2-azaspiro[3.5]nonane-2-carboxylate (280 mg), which was used without further purification.

[0203] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-(2-azaspiro[3.5]nonan-7-yl)-2H-indazole-5-carboxamide [ka] To crude tert-butyl 7-(5-(imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2-yl)-2-azaspiro[3.5]nonane-2-carboxylate (280 mg) in DCM (4 mL) was added TFA (1.0 mL, 13.0 mmol), and the resulting mixture was stirred at rt. After 2 h, the solvent was removed under reduced pressure, and the resulting residue was purified using C18 flash chromatography (eluting with 0–80% MeCN in water (5% NH4OH)) to afford N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-(2-azaspiro[3.5]nonan-7-yl)-2H-indazole-5-carboxamide (60 mg, 26%) as a yellow solid. m / z (ESI+), [M+H] + =432.

[0204] 2-(2-Acetyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (Example 21) [ka] To N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-(2-azaspiro[3.5]nonan-7-yl)-2H-indazole-5-carboxamide (350 mg, 0.8 mmol) and TEA (452 ​​μL, 3.2 mmol) in DCM (1 mL) was added acetic anhydride (0.2 mL, 1.6 mmol) under a N atmosphere at rt. The resulting solution was stirred for 1 h, after which the solvent was removed under reduced pressure to give a yellow solid. The residue was purified using C18 flash chromatography (eluting with 60% to 70% MeCN in water (0.1% FA)) to afford 2-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (400 mg, 99%) as a yellow solid. 1H NMR (300MHz, CD3OD) (1:1 mixture of rotamers) δ 8.69(s,1H),8.55-8.58(m,1H),8.45(s,1H),8.12(s,1H),8.01(d,1H),7.22(dd,1H),7.18(s,1H),4.52-4.55(m,1H),4.21(s,3H),4. 06(s,1H),3.93(s,1H),3.83(s,1H),3.69(s,1H),1.95-2.28(m,6H),1.89 / 1.91(s,3H)(rotamer),1.74-1.87(m,2H).m / z(ESI+),[M+H] + =474.

[0205] N-(Imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (Example 22) (1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate [ka] TsCl (5.3 g, 27.8 mmol) was added to tert-butyl ((1r,4r)-4-hydroxycyclohexyl)carbamate (5.0 g, 23.2 mmol) and TEA (6.5 mL, 46.6 mmol) in DCM (30 mL) under a N atmosphere at rt over 5 min. After 2 h, the reaction mixture was poured into water (50 mL) and extracted with DCM (2 × 75 mL). The combined organic layers were dried over NaSO, filtered, and the solvent removed under reduced pressure. The resulting red oil was dissolved in DCM (50 mL) and filtered through a silica pad. The silica pad was washed with DCM (500 mL), and the solvent removed under reduced pressure to give crude (1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate (4.5 g), which was used without further purification.

[0206] (1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl 4-methylbenzenesulfonate [ka] To crude (1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate (4.5 g) and NaH (60 wt%) (731 mg, 18.3 mmol) in DMF (10 mL) was added iodomethane (6.9 g, 48.6 mmol) dropwise at rt, and the resulting mixture was stirred at 60° C. After 2 h, the reaction mixture was cooled to rt, quenched with water (20 mL), and extracted with EtOAc (3×25 mL). The combined organic layers were dried over NaSO, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified using C18 flash chromatography (eluting with 30% to 60% MeCN in water (0.05% FA)) to provide crude (1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl 4-methylbenzenesulfonate (2.4 g), which was used without further purification.

[0207] tert-Butyl ((1s,4s)-4-(5-(imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate [ka] To crude (1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl 4-methylbenzenesulfonate (2.4 g) and KOH (182 mg, 3.2 mmol) in DMF (10 mL) was added N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-1H-indazole-5-carboxamide (Int II-1) (500 mg, 1.6 mmol), and the resulting solution was stirred at 100 °C. After 12 h, the reaction mixture was cooled to rt and directly purified using C18 flash chromatography (eluting with 20% to 100% MeCN in water (0.05% FA)) to give crude tert-butyl ((1s,4s)-4-(5-(imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate (0.6 g). m / z (ESI+), [M+H] + =520.

[0208] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1s,4s)-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxamide [ka] To crude tert-butyl ((1s,4s)-4-(5-(imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate (0.6 g) in 1,4-dioxane (6 mL) was added aqueous HCl (12 N, 1 mL, 12.0 mmol), and the resulting mixture was stirred at rt. After 2 h, the solvent was removed under reduced pressure to give the crude HCl salt of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1s,4s)-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxamide (0.5 g), which was used without further purification. m / z (ESI+), [M+H] + =420.

[0209] N-(Imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (Example 22) [ka] To the crude HCl salt of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1s,4s)-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxamide (0.5 g) at rt was added acetic anhydride (0.2 mL, 1.7 mmol) and TEA (0.6 mL, 4.4 mmol) in DCM (1 mL), and the resulting mixture was stirred at rt. After 5 min, additional acetic anhydride (0.2 mL, 1.7 mmol) was added, and stirring was continued for 1 h. Subsequently, the reaction mixture was quenched with water (5 mL), and the solvent was removed under reduced pressure. The resulting residue was purified using preparative HPLC (YMC-Actus Triart C18, 30 × 250, 5 μm; mobile phase A: water (0.05% NH4OH); mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 27% B to 47% B in 7 min) to afford N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (21.5 mg, 4%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) (1:2 mixture of rotamers) δ 11.06(s,1H),8.74(s,1H),8.64(dd,1H),8.60(s,1H),8.15(dd,1H),8.05(s ,1H),7.30(s,1H),7.22(dd,1H),4.40-4.49(m,1H),4.13(s,3H),3.75-3.86( m,1H),2.68(s,2H),2.55(s,1H),1.99-2.15(m,3H),2.07(s,1H),1.96(s,2H) ),1.63-1.88(m,3H),1.52-1.63(m,1H),1.38-1.47(m,1H).m / z(ESI+),[M+H] + =462.

[0210] N-(Imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (Example 23) [ka] The crude HCl salt (390 mg) of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxamide (Int V-3) was added to TEA (477 μL, 3.4 mmol) in DCM (5 mL) at rt. The resulting mixture was stirred for 5 min before the addition of acetic anhydride (121 μL, 1.3 mmol). Stirring was continued for 1 h before the reaction was quenched with water (5 mL) and concentrated to give the crude product as a yellow oil. The crude product was purified by preparative HPLC (YMC-Actus Triart C18, 30 × 250, 5 μm; mobile phase A: water (0.05% NH4OH), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 27% B to 47% B in 7 min) to give N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (62 mg, 16%) as a yellow solid. 1H NMR (400MHz, MeOD-d4) (2:3 mixture of rotamers) δ 8.69-8.73(m,1H),8.55-8.61(m,1H),8.45-8.49(m,1H),8.13(m,1H),7.99-8.06(m,1H),7.21-7.26(m,1H),7.20(s,1H),4.45-4.62 / 3. 87-3.97(m,2H)(rotamer),4.22 / 4.21(s,3H)(rotamer),2.99 / 2.88(s,3H)(rotamer),2.30-2.40(m,2H),2.06-2.25(m,5H),1.81-2.01(m,4H).

[0211] 6-Methoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 24) and 6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 25) tert-Butyl 4-(6-methoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl(methyl)carbamate [ka] CsCO (3.2 g, 9.7 mmol) was added to a solution of 4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl 4-methylbenzenesulfonate (cis / trans ratio 1:5) (Int III-10) (2.5 g, 6.5 mmol) and 6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-indazole-5-carboxamide (Int II-2) (1.0 g, 3.2 mmol) in DMF (40 mL) under a N atmosphere. The resulting mixture was stirred at 90 °C for 4 h, cooled to rt, and directly purified first by flash C18 flash chromatography (eluting with 0–70% MeCN in water) followed by preparative HPLC (XBridge Prep OBD C18 column, 30 × 150 mm 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH4OH), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 40% B to 60% B in 7 min) to afford tert-butyl 4-(6-methoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl(methylcarbamate) (270 mg, 16%, cis / trans ratio 5:1) as a yellow solid. m / z (ES+), [M+H] + =520.

[0212] 6-Methoxy-2-(4-(methylamino)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide [ka] TFA (2 mL, 3.0 mmol) was added to tert-butyl 4-(6-methoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl(methylcarbamate) (150 mg, 0.3 mmol; cis / trans ratio 5:1) in DCM (4 mL). The resulting mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure, and the residue was dissolved in EtOAc and saturated. The organic layer was washed with brine (3 × 50 mL), dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give the TFA salt of 6-methoxy-2-(4-(methylamino)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (120 mg, 99%; cis / trans ratio 5:1). m / z (ES+), [M+H] + =420.

[0213] 6-Methoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 24) and 6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 25) [ka] Acetic anhydride (58 mg, 0.6 mmol) was added to a solution of TEA (120 μL, 1.1 mmol) and the TFA salt of 6-methoxy-2-(4-(methylamino)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (120 mg, 0.3 mmol) (cis / trans ratio 5:1) in DCM (3 mL). The resulting mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure, and the residue was purified first by C18 flash chromatography (eluting with 0–70% MeCN in water) and then by preparative HPLC (XBridge Prep OBD C18 column, 30 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH4OH), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 16% B to 36% B in 7 min) to give 6-methoxy-2-(4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (cis / trans ratio 5:1) as an orange solid. The two isomers were separated by chiral preparative HPLC (CHIRAL ART Cellulose-SB column, 2 × 25 cm, 5 μm; elution gradient 50% MTBE in EtOH (0.5% 2N NH3-MeOH; flow rate: 20 mL / min; over 13 min) to give the first eluting isomer, 6-methoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (90 mg, 68%, 100% ee), and the second eluting isomer, 6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (20 mg, 15%, 100% ee), both as yellow solids. (1s,4s)-isomer: 1H NMR (300MHz, DMSO-d6) (1:1 mixture of rotamers) δ 10.37(s,1H),9.05-9.12(m,1H),8.75(s,1H),8.70(s,1H),8.53-8.57 (m,1H),8.49(s,1H),7.27(s,1H),7.00-7.11(m,1H),4.70(s,1H),4.3 9-4.54 / 3.74-3.88(m,1H)(rotamer),4.08(s,3H),2.54-2.72(m,5H),1. 92-2.20(m,5H),1.52-1.90(m,3H),1.38-1.50(m,1H).m / z(ES+),[M+H] += 462.(1r,4r)-isomer: 1 H NMR (300MHz, DMSO-d6) (1:1 mixture of rotamers) δ 10.36(s,1H),9.01-9.11(m,1H),8.74(s,1H),8.52-8.63(m,2H),8.46-8.49(m,1H),7.19-7.24(m,1H),6.99-7.09(m,1H),4.36 -4.59 / 3.70-3.90(m,3H)(rotamer),4.07(s,3H),2.90(s,2H),2.70(s,1H),2.31-1.93(m,7H),1.59-1.92(m,4H).m / z(ES+),[M+H] + =462.

[0214] 2-((1r,4r)-4-(cyclopropanecarboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 26) and 2-((1s,4s)-4-(cyclopropanecarboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 27) tert-Butyl (4-(6-methoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl)carbamate [ka] To a suspension of 6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-indazole-5-carboxamide (Int II-2) (500 mg, 1.6 mmol) and 4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate (cis / trans ratio 1:5) (Int III-9) (1.5 g, 4.1 mmol) in DMF (15 mL) under a N atmosphere, CsCO (1.6 g, 4.9 mmol) was added over 2 min at rt. The reaction mixture was stirred at 90 °C for 3 h. The mixture was cooled to rt and directly purified by C18 flash chromatography (eluting with 0-80% MeCN in water (1% NH4OH)) to give tert-butyl (4-(6-methoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl)carbamate (cis / trans ratio 7:1) (280 mg, 34%) as a yellow solid. MS ESI, m / z = 506 [M+H] + .

[0215] 2-(4-aminocyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide [ka] To a solution of tert-butyl (4-(6-methoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl)carbamate (cis / trans ratio 7:1) (280 mg, 0.6 mmol) in DCM (20 mL) at rt under a N atmosphere was added 4 N HCl in dioxane (1.4 mL, 5.6 mmol) dropwise over 2 min. After stirring the reaction mixture for 2 h, it was concentrated under reduced pressure to give the crude HCl salt of 2-(4-aminocyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (cis / trans ratio 7:1)) (270 mg, ca. 90% wt.), which was used without further purification. MS ESI, m / z = 406 [M+H] + .

[0216] 2-((1r,4r)-4-(cyclopropanecarboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 26) and 2-((1s,4s)-4-(cyclopropanecarboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 27) [ka] To a solution of the crude HCl salt of 2-(4-aminocyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (cis / trans ratio 7:1) (90 wt%) (270 mg) and TEA (250 μL, 1.8 mmol) in DCM (4 mL) under a N atmosphere at rt over 2 min, 4-bromobutanoyl chloride (227 mg, 1.2 mmol) was added slowly, and the resulting mixture was stirred for 2 h. The mixture was directly purified by C18 flash chromatography (eluting with 0% to 90% MeCN in water (0.5% FA)) and further by preparative HPLC (Waters Xbridge® Shield RP18 OBD, 5 μm 30 × 150 mm; elution gradient of 26 to 34% MeCN in water (0.05% NH4OH) in 8 min; 60 mL / min) to give 2-((1r,4r)-4-(cyclopropanecarboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (8 mg, 3%), which was then purified by preparative HPLC (Waters Xbridge® BEH OBD C18, 5 μm 30 × 150 mm; elution gradient of 35 to 50% MeCN in water (10 mM NH4HCO3 and 0.1% NH4OH) in 7 min). Purification again with an elution gradient of 1,000 mL / min (NHOH; 60 mL / min) afforded 2-((1s,4s)-4-(cyclopropanecarboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (52 mg, 20%), both as yellow solids. (1r,4r)-isomer: 1 H NMR(300MHz,DMSO-d6)δ 10.34(s,1H),9.07(dd,1H),8.73(s,1H),8.51-8.59(m,2H),8.47(s,1H),8.04(d,1H),7.22(s,1H),7.05(dd,1H),4.42-4 .56(m,1H),4.06(s,3H),3.60-3.74(m,1H),2.10-2.23(m,2H),1.89-2.06(m,4H),1.33-1.61(m,3H),0.58-0.74(m,4H).MS ESI,m / z=474[M+H] +.(1s,4s)-isomer: 1 H NMR(300MHz,DMSO-d6)δ 10.35(s,1H),9.07(dd,1H),8.73(s,1H),8.59(s,1H),8.54(dd,1H),8.50(s,1H),8.07(d,1H),7.22(s,1H),7.05(dd,1H),4.4 6-4.60(m,1H),4.07(s,3H),3.87-4.00(m,1H),2.25-2.39(m,2H),1.89-2.10(m,2H),1.58-1.87(m,5H),0.56-0.76(m,4H).MS ESI,m / z=474[M+H] + .

[0217] rel-2-((6R,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 28) and Isomer 2 (Example 29) rel-2-((6S,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 30) and Isomer 2 (Example 31) rac-tert-butyl (6R,7R)-7-(6-cyclopropoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate [ka] To a solution of 6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-indazole-5-carboxamide (Int II-3) (500 mg, 1.5 mmol) and rac-tert-butyl (6R,7S)-6-methyl-7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate (Int III-5) (748 mg, 2.2 mmol) in DMF (10 mL) was added CsCO (1.5 g, 4.5 mmol) at rt. The reaction mixture was stirred at 100 °C for 12 h. The mixture was cooled to rt and directly purified by C18 flash chromatography (eluting with 80-100% MeCN in water (0.1% NH4OH)) to give crude rac-tert-butyl (6R,7R)-7-(6-cyclopropoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate (400 mg). MS ESI, m / z = 572 [M+H] + .

[0218] rac-6-Cyclopropoxy-2-((6R,7R)-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide [ka] To a solution of crude rac-tert-butyl (6R,7R)-7-(6-cyclopropoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate (400 mg) in DCM (8 mL) was added TFA (2.0 mL, 26.0 mmol) dropwise, and the resulting solution was stirred at rt for 4 h. The mixture was concentrated under reduced pressure to give the crude TFA salt of rac-6-cyclopropoxy-2-((6R,7R)-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (350 mg) as a yellow oil, which was used without further purification. MS ESI, m / z = 472 [M+H] + .

[0219] rel-2-((6R,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 28) and Isomer 2 (Example 29) [ka] To a solution of the crude TFA salt of rac-6-cyclopropoxy-2-((6R,7R)-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (350 mg) and TEA (250 μL, 1.8 mmol) in DCM (5 mL) was added acetyl chloride (110 mg, 1.4 mmol) under a N atmosphere at 0° C. The resulting mixture was stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters SunFire® C18 OBD, 5 μm 30 × 150 mm; elution gradient of 35 to 45% MeCN (0.1% FA) in water over 7 min; 60 mL / min) followed by preparative chiral HPLC (Chiralpak® IA 5 μm 20 mm × 250 mm; elution gradient of 25% MTBE (2 mM) in EtOH over 27 min). Purification by isocratic elution with NH3-MeOH (15 mL / min) afforded rel-2-((6R,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 1 (15 mg, 5%, 100% ee) and rel-2-((6R,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 2 (15 mg, 5%, 99.7% ee), both as yellow solids. 1 1 H NMR and MS were identical. 1H NMR (400 MHz, DMSO-d6) (1:1 mixture of rotamers) δ 10.30 (s, 1H), 9.07 (d, 1H), 8.75 (s, 1H), 8.56 (s, 1H), 8.55 (d, 1H), 8.53 (s, 1H), 7.54 / 7.52 (s, 1H) (rotamers), 7.05 (dd, 1H), 4.16-4.24 (m, 1H), 4.05-4.16 (m, 1H), 3.97 / 3.80 (s, 2H) (rotamers) ),3.68 / 3.53(s,2H)(rotameric),2.06-2.17(m,1H),1.88-2.06(m,4H),1.80 / 1.77(s,3H)(rotameric body),1.60-1.72(m,1H),1.42(t,1H),1.03-1.11(m,2H),0.93-1.03(m,2H),0.59(br.d,3H).MS ESI,m / z=514[M+H] + .

[0220] rac-tert-butyl (6S,7R)-7-(6-cyclopropoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate [ka] To a solution of 6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-indazole-5-carboxamide (Int II-3) (600 mg, 1.8 mmol) and rac-tert-butyl (6S,7S)-6-methyl-7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate (Int III-6) (1.1 g, 3.2 mmol) in DMF (6 mL) at rt was added CsCO (1.8 g, 5.4 mmol) under a N atmosphere. The reaction mixture was stirred at 95 °C for 12 h. The mixture was cooled to rt and directly purified by C18 flash chromatography (eluting with 0% to 100% MeOH in water (0.05% FA)) to give crude rac-tert-butyl (6S,7R)-7-(6-cyclopropoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate (900 mg) containing approximately 30% of the N1 isomer as a yellow solid. MS ESI, m / z = 572 [M+H] + .

[0221] rac-6-Cyclopropoxy-2-((6S,7R)-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide [ka] To a solution of crude rac-tert-butyl (6S,7R)-7-(6-cyclopropoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate (900 mg) (containing 30% of the N1 isomer) in DCM (5 mL) was added TFA (243 mL, 31.5 mmol) dropwise under a N2 atmosphere and the resulting solution was stirred at rt for 12 h. The mixture was concentrated under reduced pressure to give the crude TFA salt of rac-6-cyclopropoxy-2-((6S,7R)-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (710 mg) as a yellow solid, containing some N1 isomer. MS ESI, m / z = 472 [M+H] + .

[0222] rel-2-((6S,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 30) and Isomer 2 (Example 31) [ka] To a solution of the crude TFA salt of rac-6-cyclopropoxy-2-((6S,7R)-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (700 mg) and TEA (833 μL, 6.0 mmol) in DCM (5 mL) was added acetyl chloride (188 mg, 2.4 mmol) under a N atmosphere at rt. The resulting mixture was stirred at rt for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0–100% MeCN in water (0.05% TFA)) to give rac-2-((6S,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (100 mg), which was further purified by preparative HPLC (Waters XBridge BEH OBD C18, 5 μm, 30 × 150 mm; elution gradient of 30–50% MeCN in water (10 mM NH4HCO3 + 0.1% NH4OH) in 7 min; 60 mL / min) followed by preparative chiral HPLC (YMC CHIRAL ART Cellulose-SB 5 μm). 20 mm x 250 mm; 50% hexane / DCM (75 / 25, 10 mM) in EtOH Separation by isocratic distillation with NH3-MeOH (20 mL / min) afforded rel-2-((6S,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 1 (30 mg, 4%, 99.5% ee) and rel-2-((6S,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 2 (30 mg, 4%, 100% ee) as yellow solids. 1 1 H NMR and MS were identical. 1H NMR(400MHz,DMSO-d6)δ 10.31(s,1H),9.07(dd,1H),8.75(s,1H),8.50-8.59(m,3H),7.53(d,1H),7.05(dd,1H),4.68(br.s,1H),4.24(br.s,1H),3.82-3.93(m,2H) ),3.56-3.67(m,2H),2.30-2.42(m,1H),1.90-2.30(m,4H),1.69-1.83(m,5H),1.03-1.12(m,2H),0.92-1.03(m,2H),0.52-0.67(m,3H).MS ESI,m / z=514[M+H] + .

[0223] 6-Cyclopropoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 32) and 6-cyclopropoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 33) tert-Butyl (4-(6-cyclopropoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate [ka] To a solution of 4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl 4-methylbenzenesulfonate (cis / trans ratio 1:5) (Int III-10) (2.3 g, 6.0 mmol) and 6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-indazole-5-carboxamide (Int II-3) (1.0 g, 3.0 mmol) in DMF (30 mL) was added CsCO (2.9 g, 9.0 mmol). The reaction mixture was stirred at 90 °C for 4 h. The mixture was cooled to rt and purified directly by C18 flash chromatography (eluting with 0-80% MeCN in water (0.1% NH4OH)) and further by preparative HPLC (Waters XBridge BEH OBD C18 5 μm, 30 × 150 mm; elution gradient of 47-67% MeCN in water (10 mM NH4HCO3 and 0.1% NH4OH) in 7 min; 60 mL / min) to give tert-butyl (4-(6-cyclopropoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate (cis / trans ratio 5:1) (180 mg, 11%) as an orange solid. MS ESI, m / z = 546 [M+H] + .

[0224] 6-Cyclopropoxy-2-(4-(methylamino)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide [ka] To a solution of tert-butyl (4-(6-cyclopropoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate (cis / trans ratio 5:1) (150 mg, 0.3 mmol) in DCM (6 mL) was added TFA (3.0 mL, 38.9 mmol) dropwise, and the resulting solution was stirred at rt for 1 h. The mixture was concentrated under reduced pressure to give the crude TFA salt of 6-cyclopropoxy-2-(4-(methylamino)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (cis / trans ratio 5:1) (130 mg, 94 wt%). The crude product was used without further purification. MS ESI, m / z=446 [M+H] + .

[0225] 6-Cyclopropoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 32) and 6-cyclopropoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 33) [ka] To a solution of the crude TFA salt of 6-cyclopropoxy-2-(4-(methylamino)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (cis / trans ratio 5:1) (120 mg, 94 wt%) and TEA (150 μL, 1.1 mmol) in DCM (5 mL) was added acetic anhydride (55 mg, 0.5 mmol) at rt. The resulting mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by C18 flash chromatography (eluting with 0–80% MeCN in water (0.1% FA)) to give 6-cyclopropoxy-2-(4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide as an orange solid. The solid was purified by preparative chiral HPLC (Chiralpak® ID-2, 5 μm 20 × 250 mm; 70% hexane / DCM (3 / 1, 0.5% 2N in MeOH) Isocratic separation with NH3-MeOH (flow rate: 20 mL / min) gave 6-cyclopropoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (90 mg, 63%, 99.9% ee) and 6-cyclopropoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (20 mg, 14%, 99.0% ee). (1s,4s)-isomer: 1H NMR (300MHz, DMSO-d6) (mixture of rotamers) δ 10.34(s,1H),9.08(dd,1H),8.76(s,1H),8.73(s,1H),8.50-8.65(m,2H),7.55(s,1H),7.06(dd,1H),4.63-4.78(m,1H),4.38-4.54 / 3.72-3.90(m,1H)(rotamer),4.17-4.30(m,1H),2.54-2.77(m,2H),2.55 / 2.69(s,3H)(rotamer),1.91-2.22(m,2H),1.97 / 2.08(s,3H)(rotamer),1.38-1.89(m,4H),1.04-1.13(m,2H),0.94-1.04(m,2H).MS ESI,m / z=488[M+H] + (1r,4r)-isomer: 1 H NMR (300MHz, DMSO-d6) (mixture of rotamers) δ 10.34(s,1H),9.08(dd,1H),8.76(s,1H),8.49-8.67(m,3H),7.44-7.57(m,1H),7.06(dd,1H),4.46-4.61(m,1H),4.36-4.46 / 3.71-3.87(m,1H)(rotamer),4.17-4.30(m,1H),2.74 / 2.87(s,3H)(rotamer),2.16-2.33(m,2H),2.01 / 2.10(s,3H)(rotamer),1.93-2.16(m,2H),1.65-1.93(m,4H),1.02-1.13(m,2H),0.92-1.02(m,2H).MS ESI,m / z=488[M+H] + .

[0226] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1S,2S,4R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 1 (Example 34) and Isomer 2 (Example 35) N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1R,2R,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 1 (Example 36) and Isomer 2 (Example 37) N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1S,2S)-2-methyl-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxamide [ka] To a solution of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1S,2S)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxamide (Int V-1) (100 mg, 0.2 mmol) and 1 M methylamine-MeOH solution (1.2 mL, 1.2 mmol) in DCM (5 mL) was added sodium triacetoxyborohydride (101 mg, 0.5 mmol). The resulting mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0-40% MeCN in water (0.1% FA)) to give N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1S,2S)-2-methyl-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxamide (90 mg, 87%) as a yellow solid. MS ESI, m / z = 434 [M+H] + .

[0227] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1S,2S,4R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 1 (Example 34) and Isomer 2 (Example 35) [ka] To a solution of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1S,2S)-2-methyl-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxamide (80 mg, 0.2 mmol) and TEA (103 μL, 0.7 mmol) in DCM (2 mL) was added acetic anhydride (38 mg, 0.4 mmol). The resulting mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure and purified by C18 flash chromatography (eluting with 0-60% MeCN in water) and further by preparative HPLC (Waters XSelect CSH C18 OBD, 5 μm 30 × 150 mm; elution gradient of 50-65% MeCN in water (0.1% FA) over 10 min; 60 mL / min) to give N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1S,2S)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (45 mg) as a yellow solid. The solid was purified by preparative chiral HPLC (Chiralpak® IF, 5 μm 20 × 250 mm; elution gradient of 50% MTBE in MeOH (0.5% 2N) over 28 min). Separation by isocratic elution with NH3-MeOH (flow rate: 15 mL / min) gave N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1S,2S,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide-isomer 1 (11 mg, 12%, 99.9% ee) and N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1S,2S,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide-isomer 2 (20 mg, 22%, 99.9% ee), both as yellow solids. Isomer 1: 1H NMR (300MHz, DMSO-d6) (1.2:1 mixture of rotamers) δ 11.05(s,1H),8.64(dd,1H),8.60(d,1H),8.58(s,1H),8.15(dd,1H),8.05(s,1H),7.27(d,1H),7.22(dd,1H),4.42-4.59 / 3.78- 3.96(m,1H)(rotamer),4.06-4.22(m,4H),2.86 / 2.73(s,3H)(rotamer),1.92-2.39(m,6H),1.41-1.90(m,4H),0.52-0.66(m,3H).MS ESI,m / z=476[M+H] + Isomer 2: 1 H NMR (300MHz, DMSO-d6) (3:2 mixture of rotamers) δ 11.05(s,1H),8.71(s,1H),8.64(dd,1H),8.59(s,1H),8.15(dd,1H),8.05(s,1H),7.29(s,1H),7.22(dd,1H),4.51-4.76 / 3.90-4.08(m,1H) (rotamer),4.31-4.48(m,1H),4.13(s,3H),2.59-2.99(m,4H),2.24-2.40(m,1H),1.74-2.24(m,6H),1.26-1.74(m,2H),0.92-1.20(m,3H).MS ESI, m / z=476 [M+H] + .

[0228] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1R,2R)-2-methyl-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxamide [ka] To a solution of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1R,2R)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxamide (Int V-2) (120 mg, 0.3 mmol) and 2 M methylamine-MeOH solution (717 μL, 1.4 mmol) in DCM (2 mL) was added sodium triacetoxyborohydride (122 mg, 0.6 mmol). The resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0-20% MeCN in water (0.1% FA)) to give N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1R,2R)-2-methyl-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxamide (100 mg, 80%) as a yellow solid. MS ESI, m / z = 434 [M+H] + .

[0229] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1R,2R,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 1 (Example 36) and Isomer 2 (Example 37) [ka] To a solution of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1R,2R)-2-methyl-4-(methylamino)cyclohexyl)-2H-indazole-5-carboxamide (90 mg, 0.2 mmol) and TEA (116 μL, 0.8 mmol) in DCM (2 mL) was added acetic anhydride (42 mg, 0.4 mmol). The resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and purified by C18 flash chromatography (eluting with 0-50% MeCN in water) and further purified by preparative HPLC (Waters Xbridge® BEH C18 OBD, 5 μm 19 × 250 mm; elution gradient of 50-60% MeCN in water (10 mM NH4HCO3 and 0.1% NH4OH) over 10 min; 25 mL / min) to give N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1R,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (62 mg) as a yellow solid. The solid was purified by preparative chiral HPLC (Chiralpak® IF, 5 μm 20 × 250 mm; elution gradient of 50% MTBE in MeOH (0.5% 2N) over 18 min). Separation by isocratic elution with NH3-MeOH (flow rate: 15 mL / min) gave N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1R,2R,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide-isomer 1 (25 mg, 25%, 100% ee) and N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1R,2R,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide-isomer 2 (20 mg, 20%, 99.8% ee), both as yellow solids. Isomer 1: 1H NMR (300MHz, DMSO-d6) (1.6:1 mixture of rotamers) δ 11.05(s,1H),8.71(s,1H),8.63(d,1H),8.59(s,1H),8.15(d,1H),8.05(s,1H),7.29(s,1H),7.22(dd,1H),4.51-4.74 / 3.89-4.0 8(m,1H)(rotamer),4.31-4.48(m,1H),4.13(s,3H),2.60-2.94(m,4H),1.76-2.42(m,7H),1.25-1.73(m,2H),0.91-1.20(m,3H).MS ESI,m / z=476[M+H] + Isomer 2: 1 H NMR (300MHz, DMSO-d6) (1.2:1 mixture of rotamers) δ 11.05(s,1H),8.53-8.73(m,3H),8.15(dd,1H),8.05(s,1H),7.16-7.35(m,2H),4.44-4.57 / 3.81-3.95(m,1H)(times 4.03-4.27(m,4H),2.86 / 2.72(s,3H)(rotamer),1.93-2.40(m,6H),1.42-1.93(m,4H),0.41-0.73(m,3H).MS ESI,m / z=476[M+H] + .

[0230] rel-2-((1S,2S,4S)-4-hydroxy-2-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 38) and Isomer 2 (Example 39) rel-2-((1S,2S,4R)-4-hydroxy-2-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 40) and Isomer 2 (Example 41) rac-6-Methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2-indazole-5-carboxamide [ka] To a solution of 6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-1H-indazole-5-carboxamide (Int II-2) (1.1 g, 3.6 mmol) and rac-(7R,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (Int III-13) (1.8 g, 7.1 mmol) in DMF (10 mL) was added CsCO (3.5 g, 10.7 mmol) under a N atmosphere. The reaction mixture was stirred at 90 °C for 12 h. The mixture was cooled to rt, poured into water (50 mL), and extracted with EtOAc (25 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Xbridge® Shield RP18 OBD, 5 μm 30 × 150 mm; elution gradient of 30 to 40% MeCN (0.1% FA) in water over 9 min; 60 mL / min) to give rac-6-methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2-indazole-5-carboxamide (700 mg, 42%). m / z (ESI+), [M+H] + =463.

[0231] rac-6-Methoxy-2-((1S,2S)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide [ka] To a solution of rac-6-methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (300 mg, 0.7 mmol) in 1,4-dioxane (2 mL) was added 3 N aqueous HCl (2.7 mL, 8.0 mmol) under a N atmosphere at rt. The resulting mixture was stirred at rt for 2 h. The reaction mixture was basified with concentrated aqueous NH4OH and directly purified by C18 flash chromatography (eluting with 20-50% MeCN in water (1% FA)) to give rac-6-methoxy-2-((1S,2S)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (200 mg, 74%) as a yellow solid. m / z (ESI+), [M+H] + =419.

[0232] rel-2-((1S,2S,4S)-4-hydroxy-2-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 38) and Isomer 2 (Example 39) [ka] rel-2-((1S,2S,4R)-4-hydroxy-2-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 40) and Isomer 2 (Example 41) [ka] To a solution of rac-6-methoxy-2-((1S,2S)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (200 mg, 0.5 mmol) in MeOH (5 mL) was added NaBH (36 mg, 1.0 mmol) under a N atmosphere. The resulting mixture was stirred at rt for 1 h. The reaction mixture was quenched with water (10 mL) and directly purified by C18 flash chromatography (eluting with 0–50% MeCN in water (0.5% FA)) to give rac-2-((1S,2S)-4-hydroxy-2-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide. This mixture was purified by preparative chiral HPLC (Chiralpak® ID-2, 5 μm 20 × 250 mm; MTBE (0.1% 2N Separation by isocratic NH3-MeOH / MeOH 60 / 40 (flow rate: 16 mL / min) gave rel-2-((1S,2S,4R)-4-hydroxy-2-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 1 (7 mg, 4%, 100% ee) as the first eluting isomer, and rel-2-((1S,2S,4S)-4-hydroxy-2-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 1 (56 mg, 28%, 99.9% ee) as the second eluting isomer.The following two compounds, which eluted as the third and fourth isomers but were less pure, were purified by a second chiral preparative HPLC (Chiralpak® IE, 5 μm 20 × 250 mm; MTBE (2 mM Purification with NH3-MeOH / MeOH 50 / 50 isocratic (flow rate: 20 mL / min) gave rel-2-((1S,2S,4S)-4-hydroxy-2-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide isomer 2 (36 mg, 18%, 99.9% ee) and rel-2-((1S,2S,4R)-4-hydroxy-2-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide isomer 2 (6 mg, 3%, 99.6% ee) as yellow solids. rel-(1S,2S,4R)-isomer 1: 1 H NMR (400 MHz, DMSO-d6) δ 10.35(s,1H),9.07(dd,1H),8.74(s,1H),8.54(dd,1H),8.51(s,1H),8.47( s,1H),7.23(s,1H),7.05(dd,1H),4.55(d,1H),4.01-4.12(m,4H),3.96(br. s,1H),2.52-2.59(m,1H),2.31-2.47(m,1H),1.78-1.89(m,2H),1.67-1.77( m,1H),1.55-1.65(m,1H),1.28-1.40(m,1H),0.54(d,3H).m / z(ESI+),[M+H] + =421. rel-(1S,2S,4S)-isomer 1: 11H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.07 (dd, 1H), 8.73 (s, 1H), 8.54 (dd, 1H), 8.52 (s, 1H), 8.46 (s, 1H), 7.22 (s, 1H), 7.05 (dd, 1H), 4.71 (d, 1H), 4.01 - 4.11 (m, 4H), 3.55 - 3.67 (m, 1H), 2.11 - 2.24 (m, 1H), 1.88 - 2.10 (m, 4H), 1.29 - 1.45 (m, 1H), 1.16 (q, 1H), 0.57 (d, 3H). m / z (ESI+), [M+H] + = 421. rel-(1S,2S,4S)-isomer 2: 1 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.07 (dd, 1H), 8.73 (s, 1H), 8.54 (dd, 1H), 8.52 (s, 1H), 8.46 (s, 1H), 7.22 (s, 1H), 7.05 (dd, 1H), 4.71 (d, 1H), 4.00 - 4.14 (m, 4H), �.56 - 3.६7 (m, 1H), 2.11 - 2.26 (m, 1H), 1.89 - 2.11 (m, 4H), 1.30 - 1.45 (m, 1H), 1.16 (q, 1H), 0.57 (d, 3H). m / z (ESI+), [M+H] + = 421. rel-(1S,2S,4R)-isomer 2: 1 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.07 (dd, 1H), 8.74 (s, 1H), 8.54 (dd, 1H), 8.51 (s, 1H), 8.47 (s, 1H), 7.23 (s, 1H), 7.05 (dd, 1H), 4.55 (d, 1H), 4.03 - 4.12 (m, 4H), 3.92 - 3.99 (m, 1H), 2.52 - 2.59 (m, 1H), 2.34 - 2.47 (m, 1H), 1.78 - 1.89 (m, 2H), 1.68 - 1.77 (m, 1H), 1.55 - 1.67 (m, 1H), 1.25 - 1.40 (m, 1H), 0.54 (d, 3H). m / z (ESI+), [M+H] + = 421.

[0233] rel-6-Cyclopropoxy-2-((1S,2S,4R)-4-hydroxy-2-methylcyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 42) and Isomer 2 (Example 43) rel-6-Cyclopropoxy-2-((1S,2S,4S)-4-hydroxy-2-methylcyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 44) and Isomer 2 (Example 45) rac-6-Cyclopropoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide [ka] To a solution of 6-cyclopropoxy-N-((pyrazolo[1,5-a]pyrimidin-3-yl)-1H-indazole-5-carboxamide (Int II-3) (1.4 g, 4.2 mmol) and rac-(7R,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl methanesulfonate (Int III-13) (1.1 g, 8.4 mmol) in DMF (30 mL) was added CsCO (2.9 g, 9.0 mmol). The reaction mixture was stirred at 95 °C for 3 h and cooled at rt, then diluted with EtOAc (500 mL) and washed with brine (100 mL × 3). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative SFC (DAICEL DCpak® P4VP, 5 μm Purification by HPLC (30 mm x 250 mm; isocratic with 30% DCM / MeOH (50 / 50, 0.1% 2M NH-MEOH) in CO (35 °C, 70 bar; 60 mL / min) gave rac-6-cyclopropoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (440 mg, 22%) as an orange solid. MS ESI, m / z = 489 [M+H]+ .

[0234] rac-6-Cyclopropoxy-2-((1S,2S)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide [ka] To a solution of rac-6-cyclopropoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (400 mg, 0.8 mmol) in THF (5 mL) and water (5 mL) was added concentrated aqueous HCl (2.0 mL, 24.0 mmol). The resulting mixture was stirred at rt for 3 h. The reaction mixture was purified directly by C18 flash chromatography (eluting with 0-60% MeCN in water (0.1% FA)) and further by preparative SFC (YMC Chiral ART Amylose-C Neo 5 μm 30 mm × 250 mm; isocratic with 60% MeOH / MeCN (50 / 50, 0.1% 2M NH3-MeOH) in CO2 (35 °C, 78 bar); 60 mL / min) to give rac-6-cyclopropoxy-2-((1S,2S)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (196 mg, 54%) as an orange solid. MS ESI, m / z = 445 [M+H] + .

[0235] rel-6-Cyclopropoxy-2-((1S,2S,4R)-4-hydroxy-2-methylcyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 42) and Isomer 2 (Example 43) [ka] rel-6-Cyclopropoxy-2-((1S,2S,4S)-4-hydroxy-2-methylcyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 44) and Isomer 2 (Example 45) [ka] To a solution of rac-6-cyclopropoxy-2-((1S,2S)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (180 mg, 0.4 mmol) in MeOH (5 mL) was added NaBH (31 mg, 0.8 mmol) under a N atmosphere. The resulting mixture was stirred at rt for 2 h. The reaction mixture was quenched with water (1 mL) and subsequently concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0-50% MeCN in water) to give rac-6-cyclopropoxy-2-((1S,2S)-4-hydroxy-2-methylcyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide as an orange solid. The solid was separated by preparative chiral HPLC (Chiralpak® IA 5 μm 20 mm × 250 mm; 80% MTBE in MeOH (0.1% 2N NH3-MeOH) isocratic; 17 mL / min) to give rel-6-cyclopropoxy-2-((1S,2S,4R)-4-hydroxy-2-methylcyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 1 (8 mg, 4%, 98.9% ee) as the first eluting isomer and rel-6-cyclopropoxy-2-((1S,2S,4R)-4-hydroxy-2-methylcyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 2 (7 mg, 4%, 98.4% ee) as the second eluting isomer. ee), the third eluting isomer rel-6-cyclopropoxy-2-((1S,2S,4S)-4-hydroxy-2-methylcyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 1 (40 mg, 22%, 99.6% ee), and the fourth eluting isomer rel-6-cyclopropoxy-2-((1S,2S,4S)-4-hydroxy-2-methylcyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 2 (30 mg, 17%, 99.5% ee), all as yellow solids. rel-(1S,2S,4R)-isomeric 1: 1 H NMR(300MHz,DMSO-d6)δ 10.31(s,1H),9.07(dd,1H),8.75(s,1H),8.48-8.61(m,3H),7.53(s,1H),7.05(dd,1H),4.55(d,1H),4.16-4.27(m,1H),4.10(td,1 H),3.96(br.s,1H),2.24-2.47(m,2H),1.77-1.90(m,2H),1.50-1.77(m,2H),1.28-1.42(m,1H),0.93-1.15(m,4H),0.55(d,3H).MS ESI,m / z=447[M+H] + . rel-(1S,2S,4R)-isomorph 2: 1 H NMR(300MHz,DMSO-d6)δ 10.31(s,1H),9.07(d,1H),8.75(s,1H),8.48-8.64(m,3H),7.53(s,1H),7.05(dd,1H),4.55(d,1H),4.22(br.s,1H),4.01-4.15(m, 1H),3.96(br.s,1H),2.22-2.46(m,2H),1.77-1.92(m,2H),1.50-1.77(m,2H),1.27-1.45(m,1H),0.92-1.15(m,4H),0.55(d,3H).MS ESI,m / z=447[M+H] + . rel-(1S,2S,4S)-isomeric 1: 1 H NMR(300MHz,DMSO-d6)δ 10.30(s,1H),9.06(dd,1H),8.75(s,1H),8.48-8.65(m,3H),7.51(s,1H),7.04(dd,1H),4.71(d,1H),4.15-4.25(m,1H),4.02- 4.15(m,1H),3.54-3.69(m,1H),),1.87-2.30(m,5H),1.29-1.50(m,1H),1.11-1.29(m,1H),0.92-1.11(m,4H),0.58(d,3H).MS ESI,m / z=447[M+H] + . rel-(1S,2S,4S)-isomorph 2: 1H NMR(300MHz,DMSO-d6)δ 10.30(s,1H),9.02-9.11(m,1H),8.75(s,1H),8.48-8.65(m,3H),7.51(s,1H),7.10-7.00(m,1H),4.71(d,1H),4.15-4.25(m,1H), 4.02-4.15(m,1H),3.54-3.69(m,1H),1.87-2.30(m,5H),1.27-1.50(m,1H),1.11-1.27(m,1H),0.92-1.11(m,4H),0.58(d,3H).MS ESI,m / z=447[M+H] + .

[0236] 6-Cyclopropoxy-2-(2-hydroxyspiro[3.5]nonan-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 46) and Isomer 2 (Example 47) 8,11-Dioxadispiro[3.2.4 7 .2 4 ]Tridecan-2-ol [ka] 8,11-Dioxadispiro[3.2.4] in MeOH (50 mL) 7 .2 4 To a solution of 8,11-dioxadispiro[3.2.4]tridecan-2-one (3.0 g, 15.3 mmol) was added NaBH4 (867 mg, 22.9 mmol) under a N2 atmosphere at 0 °C. The resulting mixture was stirred at rt for 2 h. The reaction solution was purified by silica gel chromatography (eluting with 0-50% EtOAc in PE) to give 8,11-dioxadispiro[3.2.4]tridecan-2-one (3.0 g, 15.3 mmol). 7 .2 4 ]tridecan-2-ol (3.0 g, 99%) was obtained as a colorless solid. 1 H NMR(400MHz,DMSO-d6)δ 4.80-4.90(m,1H),3.98-4.11(m,1H),3.83(s,4H),2.02-2.15(m,2H),1.40-1.55(m,10H).

[0237] 8,11-Dioxadispiro[3.2.4 7 .2 4 ]Tridecan-2-yl 4-nitrobenzoate [ka] 4-Nitrobenzoyl chloride (3.7 g, 19.7 mmol) was dissolved in TEA (5.3 mL, 37.8 mmol) and 8,11-dioxadispiro[3.2.4] in DCM (50 mL) at 0 °C. 7 .2 4 To a solution of 8,11-dioxadispiro[3.2.4]tridecan-2-ol (3.0 g, 15.1 mmol) was added. The resulting solution was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (eluting with 20-50% EtOAc in PE) to give crude 8,11-dioxadispiro[3.2.4]tridecan-2-ol (3.0 g, 15.1 mmol). ... 7 .2 4 ] to give tridecan-2-yl 4-nitrobenzoate (6.0 g, 75 wt%). MS ESI, m / z = 348 [M+H] + .

[0238] 7-Oxospiro[3.5]nonan-2-yl 4-nitrobenzoate [ka] Crude 8,11-dioxadispiro[3.2.4 7 .2 4 To a solution of 7-oxospiro[3.5]nonan-2-yl 4-nitrobenzoate (75 wt%) (6.0 g), 2 N HCl (40.0 mL, 80.0 mmol) was added, and the reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc (200 mL), washed with water (100 mL), dried over NaSO, filtered, and then concentrated under reduced pressure to give 7-oxospiro[3.5]nonan-2-yl 4-nitrobenzoate (3.5 g, 50%). 1H NMR(300MHz,DMSO-d6)δ 8.36(d,2H),8.22(d,2H),5.15-5.36(m,1H),2.52-2.61(m,2H),2.17-2.43(m,4H),2.04-2.17(m,2H),1.82-2.00(m,4H).

[0239] 7-Hydroxyspiro[3.5]nonan-2-yl 4-nitrobenzoate [ka] To a solution of 7-oxospiro[3.5]nonan-2-yl 4-nitrobenzoate (3.4 g, 11.2 mmol) in MeOH (60 mL) under a N atmosphere at rt was added NaBH (848 mg, 22.4 mmol). The resulting solution was stirred for 2 h. The reaction mixture was diluted with EtOAc (250 mL) and washed with water (75 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure to give 7-hydroxyspiro[3.5]nonan-2-yl 4-nitrobenzoate (2.0 g, 58%) as a colorless solid. 1 H NMR(300MHz,DMSO-d6)δ 8.34(d,1H),8.18(d,1H),5.18(p,1H),4.42(d,1H),3.34-3.50(m,2H), 2.19-2.46(m,2H),1.89(td,2H),1.50-1.78(m,4H),1.06-1.50(m,4H).

[0240] 7-(Tosyloxy)spiro[3.5]nonan-2-yl 4-nitrobenzoate [ka] TsCl (2.8 g, 14.7 mmol) was slowly added to a solution of 7-hydroxyspiro[3.5]nonan-2-yl 4-nitrobenzoate (1.8 g, 5.9 mmol), DMAP (72 mg, 0.6 mmol), and TEA (2.5 mL, 17.7 mmol) in DCM (50 mL). The resulting mixture was stirred at rt for 2 h, then diluted with DCM (100 mL) and washed with 0.1 N HCl (75 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 0–30% EtOAc in PE) to give 7-(tosyloxy)spiro[3.5]nonan-2-yl 4-nitrobenzoate (1.20 g, 44%) as a colorless solid. 1 H NMR(400MHz,DMSO-d6)δ 8.34(d,2H),8.14(d,2H),7.80(d,2H),7.47(d,2H),5.16(p,1H),4.41-4.59(m,1H),2. 43(s,3H),2.24-2.42(m,2H),1.83-1.95(m,2H),1.60-1.71(m,4H),1.38-1.60(m,4H).

[0241] 6-Cyclopropoxy-2-(2-hydroxyspiro[3.5]nonan-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 46), Isomer 2 (Example 47) [ka] To a solution of 7-(tosyloxy)spiro[3.5]nonan-2-yl 4-nitrobenzoate (1.2 g, 2.6 mmol) and 6-cyclopropoxy-N-((pyrazolo[1,5-a]pyrimidin-3-yl)-1H-indazole-5-carboxamide (Int II-3) (350 mg, 1.1 mmol) in DMF (20 mL) at rt was added CsCO (1.0 g, 3.1 mmol). The reaction mixture was stirred at 90 °C for 12 h. After that, the reaction mixture was cooled to rt, followed by the addition of CsCO (314 mg, 1.0 mmol) and MeOH (20 mL). The resulting mixture was stirred for an additional 3 h. The reaction mixture was directly purified by C flash chromatography (eluting with 0–100% MeCN in water (0.1% FA)) to give 6-cyclopropoxy-N-((pyrazolo[1,5-a]pyrimidin-3-yl)-1H-indazole-5-carboxamide). 6-Cyclopropoxy-2-(2-hydroxyspiro[3.5]nonan-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide was obtained as a yellow solid, which contained some N1 regiomer. 6-Cyclopropoxy-2-(2-hydroxyspiro[3.5]nonan-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (70 mg) was purified by preparative HPLC (Waters Further purification was performed by XBridge BEH OBD C18 5 μm, 30 × 150 mm; elution gradient of 30–40% MeCN in water (10 mM NH4HCO3 and 0.1% NHNH4OHOH) over 7 min; 60 mL / min), followed by chiral preparative HPLC (Chiralpak® IF, 20 × 250 mm, 5 μm; MTBE / MeOH (0.1% 2N Separation by HCl / MeOH (80 / 20 isocratic; flow rate: 14 mL / min) gave 6-cyclopropoxy-2-(2-hydroxyspiro[3.5]nonan-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide isomer 1 (12 mg, 9%, 100% ee) and 6-cyclopropoxy-2-(2-hydroxyspiro[3.5]nonan-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide isomer 2 (9 mg, 7%, 99% ee) as yellow solids.was obtained for both products. 1 1 H NMR and MS were identical. 1 H NMR(300MHz,DMSO-d6)δ 10.32(s,1H),9.08(dd,1H),8.76(s,1H),8.50-8.60(m,3H),7.53(s,1H),7.06(dd,1H),4.92(d,1H),4.33-4.52(m,1H),4.18-4 MS ESI,m / z=473[M+H] + .

[0242] 2-(4-Hydroxy-4-methylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide - Isomer 1 (Example 48) and Isomer 2 (Example 49) 5-Bromo-6-methoxy-2-(1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole [ka] To a solution of 5-bromo-4-methoxy-2-nitrobenzaldehyde (Int I-1) (3.3 g, 12.7 mmol) in i-PrOH (30 mL) was added 1,4-dioxaspiro[4.5]decan-8-amine (2.0 g, 12.7 mmol) at rt under a N atmosphere. The resulting mixture was stirred at 80 °C for 1 h and then cooled to rt, followed by the addition of tri-n-butylphosphine (12.9 g, 63.6 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 (eluting with 10-100% EtOAc in PE) to give crude 5-bromo-6-methoxy-2-(1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole as a yellow solid (8.2 g, 41% wt), which was used in the next step without further purification. MS ESI, m / z = 367 / 369 [M+H]+ .

[0243] 4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexan-1-one [ka] To a solution of crude 5-bromo-6-methoxy-2-(1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole (41 wt%) (8.2 g) in THF (50 mL) at rt was added 4N HCl in water (22.9 mL, 91.6 mmol), and the resulting solution was stirred at rt under a N atmosphere for 12 h. The mixture was neutralized with 2N NaOH and extracted with EtOAc (150 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was crystallized from PE / EtOAc (3 / 1, 100 mL) to give 4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexan-1-one (3.0 g, 100%) as a pale yellow solid. MS ESI, m / z = 323 / 325 [M+H] + .

[0244] 4-(5-Bromo-6-methoxy-2H-indazol-2-yl)-1-methylcyclohexan-1-ol [ka] To a solution of 4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexan-1-one (700 mg, 2.2 mmol) in THF (120 mL) at -20 °C under a N atmosphere, 3N methylmagnesium bromide in THF (4.3 mL, 13.0 mmol) was slowly added. The resulting mixture was stirred at -20 °C for 2 h. The reaction was quenched with saturated aqueous NH4Cl (5 mL) and then concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0-100% MeCN in water (0.05% FA)) to give 4-(5-bromo-6-methoxy-2H-indazol-2-yl)-1-methylcyclohexan-1-ol (730 mg, 99%) as a brown solid. MS ESI, m / z = 339 / 341 [M+H]+ .

[0245] Methyl 2-(4-hydroxy-4-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylate [ka] A mixture of 4-(5-bromo-6-methoxy-2H-indazol-2-yl)-1-methylcyclohexan-1-ol (730 mg, 2.2 mmol), Pd(dppf)Cl (157 mg, 0.2 mmol), and DIPEA (2.3 mL, 12.9 mmol) in MeOH (25 mL) was stirred under a CO atmosphere at 15 atm and 110 °C for 24 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0–100% MeCN in water (0.05% NH4OH)) to give methyl 2-(4-hydroxy-4-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylate (635 mg, 93%) as a brown oil. MS ESI, m / z = 319 [M+H] + .

[0246] 2-(4-hydroxy-4-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid [ka] To a suspension of methyl 2-(4-hydroxy-4-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylate (635 mg, 2.0 mmol) in MeOH (20 mL) under a N atmosphere was added a solution of LiOH (155 mg, 6.5 mmol) in water (20 mL). The resulting mixture was stirred at rt for 17 h. The reaction mixture was neutralized with 1N HCl and subsequently purified directly by C18 flash chromatography (eluting with 0–100% MeCN in water (0.05% FA)) to afford 2-(4-hydroxy-4-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (600 mg, 99%) as a brown gum. MS ESI, m / z = 305 [M+H] + .

[0247] 2-(4-Hydroxy-4-methylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide - Isomer 1 (Example 48) and Isomer 2 (Example 49) [ka] To a solution of 2-(4-hydroxy-4-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (100 mg, 0.3 mmol) and HATU (150 mg, 0.4 mmol) in DMF (20 mL) under a N atmosphere at rt, DIPEA (230 μL, 1.3 mmol) was added, followed by imidazo[1,2-b]pyridazin-3-amine (53 mg, 0.4 mmol). The reaction mixture was stirred at rt for 19 h. The crude material was purified by C18 flash chromatography (eluting with 0-100% MeCN in water (0.05% NH4OH)) followed by chiral preparative HPLC (Chiralpak® ID 5 μm 20 mm × 250 mm; 20% MTBE (0.1% 2N NH4OH) in DCM / MeOH (1:1)). 3-MeOH) for 12 min isocratic; 20.0 mL / min) to give 2-(4-hydroxy-4-methylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-isomer 1 (11 mg, 8%, 100% ee) and 2-(4-hydroxy-4-methylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-isomer 2 (7 mg, 5%, 99.9% ee), both as yellow solids. Isomer 1: 1 H NMR(400MHz,DMSO-d6)δ 11.05(s,1H),8.61-8.67(m,1H),8.58(s,2H),8.14(dd,1H),8.05(s,1H),7.25(s,1H),7.21(dd,1H),4.34-4.48(m,1H) ),4.27(s,1H),4.12(s,3H),2.18-2.35(m,2H),1.82-1.94(m,2H),1.62-1.76(m,2H),1.44-1.6(m,2H),1.17(s,3H).MS ESI,m / z=421[M+H] + Isomer 2: 1 H NMR(400MHz,DMSO-d6)δ 11.04(s,1H),8.60-8.68(m,2H),8.57(s,1H),8.14(d,1H),8.05(s,1H),7.27(s,1H),7.21(d dd,1H),4.44-4.56(m,2H),4.11(s,3H),1.98-2.12(m,4H),1.53-1.73(m,4H),1.23(s,3H).MS ESI,m / z=421[M+H] + .

[0248] rel-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 50) and Isomer 2 (Example 51) rac-2-((1S,3S)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 52) and Isomer 2 (Example 53) 3-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexan-1-one [ka] To a solution of 5-bromo-6-methoxy-1H-indazole (5.0 g, 22.0 mmol) and cyclohex-2-en-1-one (16.9 g, 176.2 mmol) in 1,4-dioxane (1 L) was added K2CO3 (9.13 g, 66.06 mmol) at rt. The reaction mixture was stirred at 80 °C for 12 h. The mixture was cooled to rt, quenched with water (1 L), and extracted with EtOAc (500 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to a yellow oil. The oil was purified by silica gel chromatography (eluting with 0–60% EtOAc in PE) to give 3-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexan-1-one (1.6 g, 22%) as a colorless solid. m / z (ESI+), [M+H] + =323 / 324.

[0249] 3-(5-bromo-6-methoxy-2H-indazol-2-yl)-1-methylcyclohexan-1-ol [ka] To a solution of 3-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexan-1-one (2.0 g, 6.2 mmol) in THF (30 mL) at −40° C. under a N atmosphere, 1 M methylmagnesium bromide in THF (24.8 mL, 24.8 mmol) was added dropwise over 10 min. The resulting mixture was stirred at −40° C. for 12 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0–60% MeCN in water (0.5% FA)) to afford 3-(5-bromo-6-methoxy-2H-indazol-2-yl)-1-methylcyclohexan-1-ol (2.0 g, 95%) as a yellow solid. m / z(ESI+), [M+H] + =339 / 341.

[0250] rac-Methyl 2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylate and rac-methyl 2-((1S,3S)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylate [ka] A suspension of 3-(5-bromo-6-methoxy-2H-indazol-2-yl)-1-methylcyclohexan-1-ol (2.0 g, 5.9 mmol), DIPEA (5.1 mL, 29.5 mmol), and Pd(dppf)Cl (648 mg, 0.9 mmol) in MeOH (30 mL) was stirred for 12 h under a CO atmosphere at 15 atm and 110° C. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 30-60% EtOAc in PE) and further purified by preparative HPLC (Waters XSelect CSH C18 OBD, 5 μm 30 × 150 mm; elution gradient of 20-45% MeCN (0.1% FA) in water over 10 min; 60 mL / min) to give rac-methyl 2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylate (550 mg, 29%) and rac-methyl 2-((1S,3S)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylate (800 mg, 43%), both as yellow solids. m / z (ESI+), [M+H] + =319.

[0251] rac-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid [ka] To a solution of rac-methyl 2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylate (500 mg, 1.6 mmol) in MeOH (2 mL) at rt was added a solution of LiOH (113 mg, 4.7 mmol) in water (2 mL). The resulting solution was stirred at rt for 12 h. The reaction mixture was acidified to pH 4-5 with 0.1 N HCl and subsequently purified by C18 flash chromatography (eluting with 40-60% MeCN in water (0.05% FA)) to give rac-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (400 mg, 84%) as a colorless solid. m / z (ESI+), [M+H]+ = 305.

[0252] rel-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 50) and Isomer 2 (Example 51) [ka] To a solution of rac-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (200 mg, 0.7 mmol), HATU (300 mg, 0.8 mmol), and DIPEA (574 μL, 3.3 mmol) in DMF (3 mL) was added pyrazolo[1,5-a]pyrimidin-3-amine (Int I-5) (141 mg, 1.1 mmol). The resulting solution was stirred at rt for 6 h. The reaction mixture was quenched with water (5 mL) and then purified by C18 flash chromatography (eluting with 10–60% MeCN in water (0.05% FA)) followed by preparative chiral HPLC (Chiralpak IA, 2 × 25 cm, 5 μm; mobile phase A: Hex / DCM (2:1, 0.5% 2N Direct purification by HCl (NH3-MeOH), mobile phase B: MeOH; flow rate: 20 mL / min; gradient: 50% B in 12 min) gave rel-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide isomer 1 (44 mg, 16%, 100% ee) and rel-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide isomer 2 (42 mg, 15%, 98.4% ee). 1 1 H NMR and MS were identical. 1 H NMR(400MHz,DMSO-d6)δ 10.34(s,1H),9.07(dd,1H),8.73(s,1H),8.52-8.58(m,2H),8.47(s,1H),7.21(s,1H),7.05(dd,1H),4.68(s,1H),4.51-4.61( m,1H),4.06(s,3H),1.93-2.12(m,3H),1.72-1.87(m,2H),1.58-1.67(m,1H),1.38-1.55(m,2H),1.24(s,3H).m / z(ESI+),[M+H] + =421.

[0253] rac-2-((1S,3S)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid [ka] To a solution of rac-methyl 2-((1S,3S)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylate (800 mg, 2.5 mmol) in MeOH (6 mL) under a N atmosphere at rt was added a solution of LiOH (181 mg, 7.5 mmol) in water (6 mL). The resulting solution was stirred at rt for 12 h. The reaction mixture was acidified to pH 4-5 with 0.1 N HCl and subsequently purified by C18 flash chromatography (eluting with 30-60% MeCN in water (0.05% FA)) to give rac-2-((1S,3S)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (600 mg, 78%) as a colorless solid. MS ESI, m / z = 305 [M+H] + .

[0254] rac-2-((1S,3S)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 52) and Isomer 2 (Example 53) [ka] A solution of rac-2-((1S,3S)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (200 mg, 0.7 mmol), HATU (300 mg, 0.8 mmol), and DIPEA (574 μL, 3.3 mmol) in THF (15 mL) was stirred under a N atmosphere for 1 h, followed by the addition of pyrazolo[1,5-a]pyrimidin-3-amine (Int I-5) (132 mg, 1.0 mmol). The resulting solution was stirred at rt for 4 h. The reaction was quenched with water (5 mL) and the precipitate that formed was collected by filtration to give rac-2-((1S,3S)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide as a yellow solid. The solid was purified by preparative chiral HPLC (Chiralpak® ID-2, 5 μm 20 mm × 250 mm; 50% MTBE in MeOH (0.5% 2N NH3-MeOH (isocratic; 17 mL / min) for 25 min to give rel-2-((1S,3S)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 1 (40 mg, 19%, 99.8% ee) and rel-2-((1S,3S)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 2 (48 mg, 23%, 99.8% ee), both as yellow solids. Isomer 1: 1 H NMR(300MHz,DMSO-d6)δ 10.35(s,1H),9.07(dd,1H),8.73(s,1H),8.51-8.59(m,2H),8.46(d,1H),7.20(s,1H),7.05(dd,1H),4.64-4.83(m,1H) MS ESI,m / z=421[M+H] + Isomer 2: 1H NMR(400MHz,DMSO-d6)δ 10.34(s,1H),9.07(dd,1H),8.73(s,1H),8.52-8.57(m,2H),8.46(d,1H),7.20(s,1H),7.05(dd,1H),4.68-4.79(m,1H),4.41(s,1H),4 MS ESI,m / z=421[M+H] + .

[0255] rel-6-Cyclopropoxy-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 54) and Isomer 2 (Example 55) 3-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)cyclohexan-1-one [ka] To a solution of 6-cyclopropoxy-5-iodo-1H-indazole (Int I-3) (3.0 g, 10.0 mmol) and cyclohex-2-en-1-one (7.7 g, 80.0 mmol) in 1,4-dioxane (500 mL) at rt, K2CO3 (4.1 g, 30.0 mmol) was added. The reaction mixture was stirred at 80 °C for 12 h. The mixture was cooled to rt, quenched with water (100 mL), and extracted with EtOAc (300 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 0–50% EtOAc in PE) to give 3-(5-iodo-6-methoxy-2H-indazol-2-yl)cyclohexan-1-one (980 mg, 25%) as a colorless solid. MS ESI, m / z = 397 [M+H] + .

[0256] 3-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)-1-methylcyclohexan-1-ol [ka] To a solution of 3-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)cyclohexan-1-one (800 mg, 2.0 mmol) in THF (10 mL) at rt under a N atmosphere was added 1 M methylmagnesium bromide in THF (8.1 mL, 8.1 mmol) dropwise. The resulting mixture was stirred at −40° C. for 5 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 30–60% MeCN in water (0.05% FA)) to afford crude 3-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)-1-methylcyclohexan-1-ol (720 mg) as a colorless solid, which was used directly without further purification. MS ESI, m / z = 413 [M+H] + .

[0257] rac-Methyl 6-cyclopropoxy-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-2H-indazole-5-carboxylate [ka] A suspension of crude 3-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)-1-methylcyclohexan-1-ol (720 mg), DIPEA (1.5 mL, 8.7 mmol), and Pd(dppf)Cl (128 mg, 0.2 mmol) in MeOH (100 mL) was stirred for 12 h under a CO atmosphere at 15 atm and 110° C. The mixture was cooled to rt and filtered. The filtrate was purified directly by C18 flash chromatography (eluting with 0-60% MeCN in PE) and further purified by preparative HPLC (Waters Xbridge® Shield RP18 OBD, 5 μm 30 × 150 mm; elution gradient of 30-40% MeCN (0.1% FA) in water over 7 min; 60 mL / min) to give rac-methyl 6-cyclopropoxy-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-2H-indazole-5-carboxylate (240 mg, 40%). MS ESI, m / z = 345 [M+H] + .

[0258] rac-6-Cyclopropoxy-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-2H-indazole-5-carboxylic acid [ka] To a solution of rac-methyl 6-cyclopropoxy-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-2H-indazole-5-carboxylate (180 mg, 0.5 mmol) in MeOH (2 mL) was added a solution of LiOH (38 mg, 1.6 mmol) in water (2 mL). The resulting mixture was stirred at rt for 12 h. The mixture was acidified to pH 4-5 with 0.1 N HCl. The mixture was directly purified by C18 flash chromatography (eluting with 0-60% MeCN in water (0.5% FA)) to give rac-6-cyclopropoxy-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-2H-indazole-5-carboxylic acid (160 mg, 93%) as a colorless solid. MS ESI, m / z = 331 [M+H] + .

[0259] rel-6-Cyclopropoxy-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 54) and Isomer 2 (Example 55) [ka] To a solution of rac-6-cyclopropoxy-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-2H-indazole-5-carboxylic acid (100 mg, 0.3 mmol), HATU (115 mg, 0.3 mmol), and DIPEA (53 μL, 0.3 mmol) in THF (10 mL) under a N atmosphere was added pyrazolo[1,5-a]pyrimidin-3-amine (Int I-5) (41 mg, 0.3 mmol). The resulting solution was stirred at rt for 2 h. The reaction was quenched with water (1 mL). The mixture was purified by preparative chiral HPLC (Chiralpak® IA 5 μm 20 mm × 250 mm; 50% MTBE in MeOH (0.5% 2N Direct purification by isocratic elution with NH3-MeOH (50 mL / min) afforded rel-6-cyclopropoxy-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 1 (42 mg, 42%, 100% ee) and rel-6-cyclopropoxy-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 2 (46 mg, 46%, 100% ee), both as yellow solids. 1 1 H NMR and MS were identical. 1H NMR(400MHz,DMSO-d6)δ 10.31(s,1H),9.07(dd,1H),8.75(s,1H),8.58(s,1H),8.55(dd,1H),5.53(s,1H),7.51(s,1H),7.05(dd,1H),4.50-4.64(m,1H),4.19-4. 25(m,1H),1.94-2.11(m,3H),1.72-1.86(m,2H),1.63(br.d,1H),1.37-1.56(m,2H),1.25(s,3H),1.01-1.11(m,2H),0.93-1.03(m,2H).MS ESI,m / z=447[M+H] + .

[0260] 6-Cyclopropoxy-2-((1s,4s)-4-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 56) Methyl 6-cyclopropoxy-2-((1s,4s)-4-hydroxycyclohexyl)-2H-indazole-5-carboxylate [ka] A suspension of (1s,4s)-4-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)cyclohexan-1-ol (Int IV-1) (110 mg, 0.3 mmol), TEA (115 μL, 0.8 mmol), and Pd(dppf)Cl-CHCl (226 mg, 0.3 mmol) in MeOH (20 mL) was stirred under a CO atmosphere at 15 atm and 100 °C for 14 h. The mixture was cooled to rt, concentrated, and purified by C18 flash chromatography (eluting with 0–100% MeOH in water (0.1% FA)) to give methyl 6-cyclopropoxy-2-((1s,4s)-4-hydroxycyclohexyl)-2H-indazole-5-carboxylate (67 mg, 73%) as a yellow solid. MS ESI, m / z = 331 [M+H] + .

[0261] 6-Cyclopropoxy-2-((1s,4s)-4-hydroxycyclohexyl)-2H-indazole-5-carboxylic acid [ka] To a solution of NaOH (35 mg, 0.9 mmol) in MeOH (1 mL) and water (0.5 mL) was added methyl 6-cyclopropoxy-2-((1s,4s)-4-hydroxycyclohexyl)-2H-indazole-5-carboxylate (57 mg, 0.2 mmol). The resulting solution was stirred at rt for 4 h. The reaction mixture was acidified to pH ∼6 with 0.1 N HCl and then concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0-100% MeCN in water (0.1% FA)) to give crude 6-cyclopropoxy-2-((1s,4s)-4-hydroxycyclohexyl)-2H-indazole-5-carboxylic acid (64 mg, 86 wt%) as a colorless solid. MS ESI, m / z = 317 [M+H] + .

[0262] 6-Cyclopropoxy-2-((1s,4s)-4-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 56) [ka] To a solution of crude 6-cyclopropoxy-2-((1s,4s)-4-hydroxycyclohexyl)-2H-indazole-5-carboxylic acid (86 wt%) (54 mg), DIPEA (119 μL, 0.7 mmol), HOBt (5 mg, 0.03 mmol), and HATU (97 mg, 0.3 mmol) in DMF (5 mL) was added pyrazolo[1,5-a]pyrimidin-3-amine (Int I-5) (46 mg, 0.34 mmol). The resulting mixture was stirred at rt for 4 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (25 mL). The organic layer was concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0–100% MeCN in water (0.1% FA)) and further by preparative HPLC (Waters XBridge BEH C18 OBD 5 μm, 30 × 150 mm; elution gradient of 27–34% MeCN in water (10 mM NH4HCO3 + 0.1% NH4OH) over 7 min; 60 mL / min) to give 6-cyclopropoxy-2-((1s,4s)-4-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (20 mg, 27%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 10.32(s,1H),9.07(dd,1H),8.75(s,1H),8.58(s,1H),8.49-8.58(m,2H ),7.51(s,1H),7.05(dd,1H),4.52(d,1H),4.42-4.51(m,1H),4.18-4.27 (m,1H),3.85-3.94(m,1H),2.24-2.39(m,2H),1.82-1.92(m,2H),1.72- 1.82(m,2H),1.58-1.72(m,2H),1.03-1.13(m,2H),0.94-1.03(m,2H).MS ESI, m / z=433 [M+H] + .

[0263] 6-Cyclopropoxy-2-((1r,4r)-4-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 57) Methyl 6-cyclopropoxy-2-((1r,4r)-4-hydroxycyclohexyl)-2H-indazole-5-carboxylate [ka] A suspension of (1r,4r)-4-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)cyclohexan-1-ol (Int IV-2) (110 mg, 0.3 mmol), TEA (115 μL, 0.8 mmol), and Pd(dppf)Cl-CHCl (45 mg, 0.1 mmol) in MeOH (10 mL) was stirred under a CO atmosphere at 15 atm and 100 °C for 13 h. The reaction mixture was cooled to rt and directly purified by C18 flash chromatography (eluting with 0–100% MeOH in water (0.1% FA)) to give methyl 6-cyclopropoxy-2-((1r,4r)-4-hydroxycyclohexyl)-2H-indazole-5-carboxylate (80 mg, 88%) as a yellow solid. MS ESI, m / z = 331 [M+H] + .

[0264] 6-Cyclopropoxy-2-((1r,4r)-4-hydroxycyclohexyl)-2H-indazole-5-carboxylic acid [ka] To a solution of methyl 6-cyclopropoxy-2-((1r,4r)-4-hydroxycyclohexyl)-2H-indazole-5-carboxylate (70 mg, 0.2 mmol) in MeOH (1 mL) was added a solution of NaOH (34 mg, 0.9 mmol) in water (1 mL). The resulting solution was stirred at rt for 14 h. The reaction mixture was adjusted to pH 5-6 with 2 N HCl and then concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0-100% MeCN in water (0.1% FA)) to give 6-cyclopropoxy-2-(((1r,4r)-4-hydroxycyclohexyl)-2H-indazole-5-carboxylic acid (45 mg, 67%) as a yellow solid. MS ESI, m / z = 317 [M+H] + .

[0265] 6-Cyclopropoxy-2-((1r,4r)-4-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 57) [ka] To a solution of 6-cyclopropoxy-2-((1r,4r)-4-hydroxycyclohexyl)-2H-indazole-5-carboxylic acid (40 mg, 0.1 mmol), pyrazolo[1,5-a]pyrimidin-3-amine TFA salt (62 mg, 0.3 mmol), HOBt (4 mg, 0.03 mmol), and HATU (72 mg, 0.2 mmol) in DMF (5 mL) was added DIPEA (66 μL, 0.4 mmol). The resulting mixture was stirred at rt for 3 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0–100% MeCN in water (0.1% FA)) and further by preparative HPLC (Waters XBridge BEH C18 OBD 5 μm, 30 × 150 mm; elution gradient of 24–32% MeCN in water (10 mM NH4HCO3 + 0.1% NH4OH) over 7 min; 60 mL / min) to give 6-cyclopropoxy-2-((1r,4r)-4-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (12 mg, 22%) as a yellow solid. 1 H NMR(300MHz,DMSO-d6)δ 10.30(s,1H),9.07(dd,1H),8.74(s,1H),8.55(s,1H),8.54(dd,1H),8.53(s,1H),7.50(s,1H),7.04(dd,1H),4.72(d,1H),4.41- 4.55(m,1H),4.15-4.25(m,1H),3.48-3.63(m,1H),2.04-2.16(m,2H),1.89-2.04(m,4H),1.30-1.51(m,2H),0.93-1.10(m,4H).MS ESI,m / z=433[M+H]+ .

[0266] 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 58) (R)-1-(((1r,4R)-4-(6-methoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)amino)-1-oxopropan-2-yl acetate [ka] To a solution of 6-methoxy-2-((1r,4r)-4-(methylamino)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Int V-4) HCl salt (300 mg, 0.7 mmol) and TEA (200 mg, 2.0 mmol) in DCM (10 mL) under a N atmosphere at rt, (R)-1-chloro-1-oxopropan-2-yl acetate (149 mg, 1.0 mmol) was added. The resulting mixture was stirred at rt for 1 h. The reaction mixture was quenched with MeOH (2 mL) and concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0-80% MeCN in water (0.1% FA)) to give (R)-1-(((1r,4R)-4-(6-methoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)amino)-1-oxopropan-2-yl acetate (320 mg, 91%) as a yellow solid. MS ESI, m / z = 534 [M+H] + .

[0267] 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 58) [ka] To a solution of (R)-1-(((1r,4R)-4-(6-methoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)amino)-1-oxopropan-2-yl acetate (300 mg, 0.6 mmol) in MeOH (10 mL) / water (5 mL) under a N atmosphere at rt was added NaOH (68 mg, 1.7 mmol). The resulting solution was stirred at rt for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was directly purified by preparative HPLC (Waters XBridge® BEH OBD C18, 5 μm, 30 × 150 mm; elution gradient of 12 to 42% MeCN (10 mM NH4HCO3 + 0.1% NH4OH) in water over 8 min; 60 mL / min) to give 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (265 mg, 96%, 100% ee) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) (5:6 mixture of rotamers) δ 10.35 (s, 1H), 9.08 (dd, 1H), 8.73 (s, 1H), 8.53-8.59 (m, 2H), 8.48 / 8.47 (s, 1H) (rotamers), 7.22 / 7.20 (s, 1H) (rotamers), 7.05 (dd, 1H), 4.93 / 4.74 (d, 1H) (rotamers), 4.34-4.58 / 3.93-4.02 (m, 3H) (rotamers), 4.06 (s, 3H), 2.91 / 2.77 (s, 3H) (rotamers), 1.62-2.27 (m, 8H), 1.22 / 1.18 (d, 3H) (rotamers). MS ESI, m / z=492 [M+H] + .

[0268] 2-((1S,4r)-4-((S)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 59) (S)-1-(((1r,4S)-4-(6-methoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)amino)-1-oxopropan-2-yl acetate [ka] To a solution of 6-methoxy-2-((1r,4r)-4-(methylamino)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Int V-4) HCl salt (130 mg, 0.3 mmol) and TEA (87 mg, 0.9 mmol) in DCM (8 mL) under a N atmosphere at rt, (S)-1-chloro-1-oxopropan-2-yl acetate (64 mg, 0.4 mmol) was added. The resulting mixture was stirred at rt for 1 h. The reaction mixture was quenched with MeOH (2 mL) and subsequently purified directly by C18 flash chromatography (eluting with 0-80% MeCN in water (0.1% FA)) to afford (S)-1-(((1r,4S)-4-(6-methoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)amino)-1-oxopropan-2-yl acetate (152 mg, 100%) as a yellow solid. MS ESI, m / z = 534 [M+H] + .

[0269] 2-((1S,4r)-4-((S)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 59) [ka] To a solution of (S)-1-(((1r,4S)-4-(6-methoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)amino)-1-oxopropan-2-yl acetate (145 mg, 0.3 mmol) in MeOH (5 mL) / water (2.5 mL) under a N atmosphere at rt was added NaOH (22 mg, 0.5 mmol). The resulting solution was stirred at rt for 12 h. The reaction mixture was diluted with water (10 mL) and the formed precipitate was collected by filtration. The solid was washed successively with acetroniltrile (2 mL) and water (5 mL), followed by drying under reduced pressure to give 2-((1S,4r)-4-((S)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (118 mg, 88%, 100% ee) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) (1:1 mixture of rotamers) δ 10.35(s,1H),9.08(dd,1H),8.73(s,1H),8.52-8.59(m,2H),8.48 / 8.47(s,1 H)(rotamer),7.22 / 7.20(s,1H)(rotamer),7.05(dd,1H),4.93 / 4.75(d,1H)(rotamer) 4.45-4.57 / 3.93-4.03(m,2H)(rotamer),4.34-4.45(m,1H),4.06(s,3H), 2.91 / 2.77(s,3H)(rotamer),1.62-2.28(m,8H),1.22 / 1.18(d,3H)(rotamer).MS ESI, m / z=492 [M+H] + .

[0270] 6-Methoxy-2-((1R,2R,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 60) and Isomer 2 (Example 61) 6-Methoxy-2-((1S,2S,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 62) and Isomer 2 (Example 63) Methyl 6-methoxy-2-((7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxylate [ka] A mixture of 5-bromo-6-methoxy-2-((7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole (Int IV-4) (380 mg, 1.0 mmol), Pd(dppf)Cl-CHCl (163 mg, 0.2 mmol), and TEA (695 μL, 5.0 mmol) in MeOH (10 mL) was stirred under a CO atmosphere at 15 atm and 110 °C for 20 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0-100% MeCN in water (0.1% NH4OH)) to give methyl 6-methoxy-2-((7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxylate (350 mg, 97%) as a colorless solid. MS ESI, m / z = 361 [M+H] + .

[0271] Methyl 6-methoxy-2-((1R,2R)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxylate [ka] To a solution of methyl 6-methoxy-2-((7R,8R)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxylate (340 mg, 0.9 mmol) in THF (5 mL) / water (5 mL) was added aqueous HCl (12 N) (2.0 mL, 24.0 mmol). The resulting mixture was stirred at rt for 2 h. The mixture was neutralized with saturated aqueous NaHCO3, diluted with EtOAc (200 mL), and washed with water (100 mL × 2). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was directly purified by C18 flash chromatography (eluting with 0-100% MeCN in water (0.1% FA)) to give methyl 6-methoxy-2-((1R,2R)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxylate (290 mg, 97%) as a colorless solid. MS ESI, m / z = 317 [M+H] + .

[0272] 6-Methoxy-2-((1R,2R)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxylic acid [ka] To a suspension of methyl 6-methoxy-2-((1R,2R)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxylate (285 mg, 0.9 mmol) in MeOH (5 mL) / water (2.5 mL) was added NaOH (144 mg, 3.6 mmol). The resulting mixture was stirred at rt for 2 h. The mixture was acidified to pH 5 with 2 N HCl and subsequently purified by C18 flash chromatography (eluting with 0-100% MeCN in water (0.1% FA)) to afford 6-methoxy-2-((1R,2R)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxylic acid (270 mg, 99%) as a colorless gum. MS ESI, m / z = 303 [M+H] + .

[0273] 6-Methoxy-2-((1R,2R)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide [ka] To a solution of 6-methoxy-2-((1R,2R)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxylic acid (265 mg, 0.9 mmol) and HATU (367 mg, 1.0 mmol) in DMF (5 mL) under a N atmosphere was added DIPEA (612 μL, 3.5 mmol). The resulting solution was stirred at rt for 15 min, followed by the addition of pyrazolo[1,5-a]pyrimidin-3-amine (Int I-5) (176 mg, 1.3 mmol). The reaction mixture was stirred at rt for 2 h and then directly purified by C18 flash chromatography (eluting with 0-100% MeCN in water (0.1% NH4OH)) to give 6-methoxy-2-((1R,2R)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (230 mg, 63%) as a yellow solid. MS ESI, m / z = 419 [M+H] + .

[0274] 6-Methoxy-2-((1R,2R)-2-methyl-4-(methylamino)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide [ka] To a solution of 6-methoxy-2-((1R,2R)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (105 mg, 0.3 mmol) and methanamine (31 wt% in MeOH) (126 mg, 1.3 mmol) in DCE (5 mL) was added sodium triacetoxyborohydride (106 mg, 0.5 mmol). The resulting mixture was stirred at rt for 3 h. The mixture was concentrated under reduced pressure and subsequently purified by C18 flash chromatography (eluting with 0-100% MeCN in water (0.1% NH4OH)) to give 6-methoxy-2-((1R,2R)-2-methyl-4-(methylamino)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (100 mg, 92%) as a yellow solid. MS ESI, m / z = 434 [M+H] + .

[0275] 6-Methoxy-2-((1R,2R,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 60) and Isomer 2 (Example 61) [ka] To a solution of 6-methoxy-2-((1R,2R)-2-methyl-4-(methylamino)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (95 mg, 0.2 mmol) and TEA (122 μL, 0.9 mmol) in DCM (2 mL) was added acetic anhydride (45 mg, 0.4 mmol). The resulting mixture was stirred at rt for 2 h. The mixture was concentrated under reduced pressure and purified by C18 flash chromatography (eluting with 0–100% MeCN in water (0.1% NH4OH)) to give 6-methoxy-2-((1R,2R)-2-methyl-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide. This material was purified by chiral preparative HPLC (Chiralpak® IH 5 μm 20 mm × 250 mm; 50% MTBE in MeOH (0.1% 2N NH3-MeOH) for 7.5 min isocratic; 20.0 mL / min) to give 6-methoxy-2-((1R,2R,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide isomer 1 (20 mg, 19%, 99.9% ee) and 6-methoxy-2-((1R,2R,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide isomer 2 (68 mg, 65%, 100% ee), both as yellow solids. Isomer 1: 1H NMR (400 MHz, DMSO-d6) (2:3 mixture of rotamers) δ 10.36 (s, 1H), 9.08 (dd, 1H), 8.73 (s, 1H), 8.56 / 8.53 (s, 1H) (rotamers), 8.54 (dd, 1H), 8.47 / 8.46 (s, 1H) (rotamers), 7.24 / 7.21 (s, 1H) (rotamers), 7.05 (dd, 1H), 4.45-4.59 / 3.8-3.93 (m, 1H) (rotamers), 4.08-4.18 (m, 1H), 4.06 (s, 3H), 2.86 / 2.73 (s, 3H) (rotamers), 1.97-2.38 (m, 6H), 1.43-1.89 (m, 4H), 0.53-0.65 (m, 3H). MS ESI, m / z=476 [M+H] + Isomer 2: 1 H NMR (400MHz, DMSO-d6) (1:1 mixture of rotamers) δ 10.36(s,1H),9.08(dd,1H),8.74(s,1H),8.66(s,1H),8.54(dd,1H),8.48(s,1H),7.25(s,1H),7.05(dd,1H),4.6 3 / 4.02(br.s,1H)(rotamer),4.38(s,1H),4.06(s,3H),2.65-2.93(m,3H),1.26-2.39(m,10H),0.94-1.21(m,3H).MS ESI,m / z=476[M+H] + .

[0276] Methyl 6-methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxylate [ka] A mixture of 5-bromo-6-methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole (Int IV-5) (1.0 g, 2.6 mmol), Pd(dppf)Cl (384 mg, 0.5 mmol), and DIPEA (2.3 mL, 13.1 mmol) in MeOH (60 mL) was stirred under a CO atmosphere at 15 atm and 110 °C for 15 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0-100% MeCN in water (0.05% NH4OH)) to give methyl 6-methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxylate (860 mg, 91%) as a yellow solid. MS ESI, m / z = 361 [M+H] + .

[0277] 6-Methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxylic acid [ka] To a suspension of methyl 6-methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxylate (850 mg, 2.4 mmol) in MeOH (6 mL) under a N atmosphere was added a solution of LiOH (169 mg, 7.1 mmol) in water (6 mL). The resulting mixture was stirred at rt for 2 h. The reaction mixture was acidified to pH 6 with 0.1 N HCl followed by direct purification by C18 flash chromatography (eluting with 0-100% MeCN in water (0.05% FA)) to give crude 6-methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxylic acid (720 mg) containing 32% 6-methoxy-2-((1S,2S)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxylic acid as a yellow solid. MS ESI, m / z = 347 [M+H] +.

[0278] 6-Methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide [ka] To a solution of crude 6-methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxylic acid (710 mg) and DIPEA (1.4 mL, 8.2 mmol) in DMF (10 mL) under a N atmosphere at rt was added HATU (935 mg, 2.5 mmol), followed by pyrazolo[1,5-a]pyrimidin-3-amine (412 mg, 3.1 mmol). The reaction was stirred at rt for 2 h. The crude material was directly purified by C18 flash chromatography (eluting with 0-100% MeCN in water (0.05% NH4OH)) to give 6-methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (640 mg, 68%) as a yellow solid. MS ESI, m / z = 463 [M+H] + .

[0279] 6-Methoxy-2-((1S,2S)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide [ka] To a suspension of 6-methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (630 mg, 1.4 mmol) in THF (8 mL) was added 2.4 N HCl (10.0 mL, 24.0 mmol). The resulting mixture was stirred at rt for 12 h. The reaction mixture was neutralized with saturated aqueous NaHCO3 and then directly purified by C18 flash chromatography (eluting with 0-100% MeCN in water (0.1% FA)) to give 6-methoxy-2-((1S,2S)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (570 mg, 100%) as a colorless solid. MS ESI, m / z = 419 [M+H] + .

[0280] 6-Methoxy-2-((1S,2S)-2-methyl-4-(methylamino)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide [ka] To a solution of 6-methoxy-2-((1S,2S)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (200 mg, 0.5 mmol) and methanamine (30 wt% in MeOH) (495 mg, 4.8 mmol) in DCE (6 mL) was added sodium triacetoxyborohydride (203 mg, 1.0 mmol). The resulting mixture was stirred at rt for 3 h. The mixture was concentrated under reduced pressure and subsequently purified by C18 flash chromatography (eluting with 0-100% MeCN in water (0.05% NH4OH)) to give 6-methoxy-2-((1S,2S)-2-methyl-4-(methylamino)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (170 mg, 82%) as a yellow solid. MS ESI, m / z = 434 [M+H]+ .

[0281] 6-Methoxy-2-((1S,2S,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 62) and Isomer 2 (Example 63) [ka] To a solution of 6-methoxy-2-((1S,2S)-2-methyl-4-(methylamino)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (160 mg, 0.4 mmol) and TEA (257 μL, 1.9 mmol) in DCM (5 mL) was added acetic anhydride (94 mg, 0.9 mmol). The resulting mixture was stirred at rt for 1 h. The mixture was concentrated under reduced pressure and purified by C18 flash chromatography (eluting with 0-100% MeCN in water (0.1% FA)) to give 6-methoxy-2-((1S,2S)-2-methyl-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide as a yellow solid. The solid was purified by chiral preparative HPLC (Chiralpak® IH 5 μm 20 mm × 250 mm; 80% MTBE in MeOH (0.1% 2N NH3-MeOH) for 14 min (isocratic; 20.0 mL / min) to give 6-methoxy-2-((1S,2S,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 1 (17 mg, 10%, 99.4% ee) and 6-methoxy-2-((1S,2S,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 2 (59 mg, 34%, 99.9% ee), both as yellow solids. Isomer 1: 1H NMR (400 MHz, DMSO-d6) (3:4 mixture of rotamers) δ 10.36 (s, 1H), 9.08 (dd, 1H), 8.74 (s, 1H), 8.56 / 8.53 (s, 1H) (rotamers), 8.54 (dd, 1H), 8.47 / 8.46 (s, 1H) (rotamers), 7.24 / 7.21 (s, 1H) (rotamers), 7.05 (dd, 1H), 4.45-4.56 / 3.82-3.93 (m, 1H) (rotamers), 4.08-4.18 (m, 1H), 4.06 (s, 3H), 2.86 / 2.73 (s, 3H) (rotamers), 1.94-2.39 (m, 6H), 1.44-1.87 (m, 4H), 0.54-0.65 (m, 3H). MS ESI, m / z=476 [M+H] + Isomer 2: 1 H NMR (400MHz, DMSO-d6) (2:3 mixture of rotamers) δ 10.36(s,1H),9.08(dd,1H),8.74(s,1H),8.66(s,1H),8.54(dd,1H),8.48(s,1H),7.25(s,1H),7.05(dd,1H),4.6 3 / 4.02(br.s,1H)(rotamer),4.38(s,1H),4.06(s,3H),2.61-2.93(m,3H),1.25-2.43(m,10H),0.95-1.17(m,3H).MS ESI,m / z=476[M+H] + .

[0282] rel-2-((6S,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide Isomer 1 (Example 64) and Isomer 2 (Example 65) tert-Butyl 7-hydroxy-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate [ka] NaBH4 (388 mg, 10.3 mmol) was added in portions to a solution of tert-butyl 6-methyl-7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (Int III-4) (1.3 g, 5.1 mmol) in MeOH (20 mL) under a N2 atmosphere at 0 °C over 5 min. The resulting mixture was stirred at rt for 1 h. The reaction was quenched with water (5 mL) and directly concentrated. The residue was purified by silica gel chromatography (eluting with 30% to 40% EtOAc in PE) to afford tert-butyl 7-hydroxy-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate (1.2 g, 92%) (cis / trans 1:2) as a yellow oil.

[0283] tert-Butyl 6-methyl-7-(methylsulfonyloxy)-2-azaspiro[3.5]nonane-2-carboxylate [ka] MsCl (1.6 g, 14.1 mmol) was added dropwise over 5 min to a solution of TEA (2.6 mL, 18.8 mmol) and tert-butyl 7-hydroxy-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate (1.2 g, 4.7 mmol) (cis / trans 1:2) in DCM (25 mL) under a N atmosphere at 0 °C. The resulting mixture was stirred at rt for 12 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (100 mL × 3). The combined organic layers were dried over NaSO, filtered, and the solvent was evaporated to give crude tert-butyl 6-methyl-7-(methylsulfonyloxy)-2-azaspiro[3.5]nonane-2-carboxylate (1.5 g) (predominantly trans isomer) as a yellow oil. The product was used in the next step without further purification.

[0284] rac-tert-butyl (6S,7R)-7-(5-bromo-6-methoxy-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate [ka] KOH (1.2 g, 22.0 mmol) was added slowly to a solution of crude tert-butyl 6-methyl-7-(methylsulfonyloxy)-2-azaspiro[3.5]nonane-2-carboxylate (1.5 g) (predominantly trans isomer) and 5-bromo-6-methoxy-1H-indazole (1.0 g, 4.4 mmol) in DMF (20 mL) at rt. The reaction mixture was stirred at 100 °C overnight. The mixture was cooled to rt, quenched with water (5 mL), and the aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dried over Na SO , filtered, and the solvent was evaporated. The crude material was purified by silica gel chromatography (eluting with 20%-30% EtOAc in PE) to give crude rac-(6S,7R)-tert-butyl 7-(5-bromo-6-methoxy-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate (400 mg) as a yellow solid. m / z (ESI+) [M-tBu] + =408 / 410.

[0285] rac-5-bromo-6-methoxy-2-((6S,7R)-6-methyl-2-azaspiro[3.5]nonan-7-yl)-2H-indazole [ka] TFA (4 mL) was added dropwise to a solution of crude rac-(6S,7R)-tert-butyl 7-(5-bromo-6-methoxy-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate (400 mg) in DCM (20 mL) under a N atmosphere at 0 °C. The resulting mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure to give the crude TFA salt of rac-5-bromo-6-methoxy-2-((6S,7R)-6-methyl-2-azaspiro[3.5]nonan-7-yl)-2H-indazole (500 mg), which was used without further purification. MS ESI, m / z = 364 / 366 [M+H] + .

[0286] rac-1-((6S,7R)-7-(5-bromo-6-methoxy-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonan-2-yl)ethanone [ka] Acetyl chloride (223 μL, 3.1 mmol) was added dropwise to a solution of the crude TFA salt of rac-5-bromo-6-methoxy-2-((6S,7R)-6-methyl-2-azaspiro[3.5]nonan-7-yl)-2H-indazole (500 mg) and TEA (1.5 mL, 10.5 mmol) in DCM (10 mL) under a N atmosphere at 0 °C. The resulting mixture was stirred at rt for 2 h. The reaction was quenched with water (5 mL), and the aqueous layer was extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over NaSO, filtered, and concentrated. The residue was purified by C18 flash chromatography (eluting with 50-100% MeCN in water (0.05% HCOOH)) to give rac-1-((6S,7R)-7-(5-bromo-6-methoxy-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonan-2-yl)ethanone (190 mg, 45%) as a yellow solid. m / z (ESI+) [M+H] + =406, 408.

[0287] rel-2-((6S,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide Isomer 1 (Example 64) and Isomer 2 (Example 65) [ka] Pd(OAc)2 (9 mg, 0.04 mmol) was dissolved in MeCN (10 mL) with dppp (41 mg, 0.1 mmol), TEA (123 μL, 0.9 mmol), imidazo[1,2-b]pyridazin-3-amine (174 mg, 1.3 mmol), and rac-1-((6S,7R)-7-(5-bromo-6-methoxy-2H-indazol-2-yl)-6-methyl-2-azaspipri. To a solution of 2,4-dichloro[3.5]nonan-2-yl)ethan-1-one (180 mg, 0.4 mmol) was added. The resulting mixture was stirred at 90 °C under 15 atm CO atmosphere overnight. The crude product was cooled to rt and directly purified by C18 flash chromatography (eluting with 50%-55% MeCN (0.1% HCOOH) in water). The resulting material was subsequently purified by preparative HPLC (XBridge Prep OBD C18 column, 30 × 150 mm 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH4OH), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 20% B to 47% B in 7 min) to give rac-2-((6S,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide as a yellow solid. The solid was separated by chiral preparative SFC (CelluCoat column, 250 × 30 mm, 5 μm, mobile phase: 30% MeOH in CO2 at 120 bar and 40 °C, and flow rate: 100 mL / min) to give rel-2-((6S,7R)-2 rel-2-((6S,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-isomer 1 (37 mg, 21%, 100% ee) and rel-2-((6S,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-isomer 2 (34 mg, 19%, 100% ee). Both isomers were recovered as gums. The elution fractions obtained for both products were 1 1 H NMR and MS were identical. 1H NMR (500MHz, DMSO-d6) (3:4 mixture of rotamers) δ 11.05(s,1H),8.64(dd,1H),8.55-8.61(m,2H),8.15(dd,1H),8.05(s,1 H),7.30 / 7.29(s,1H)(rotamer),7.22(dd,1H),4.65-4.74(m,1H),4.13(s ,3H),3.83-3.93(m,2H),3.55-3.65(m,2H),1.93-2.41(m,5H),1.77(br .s,3H),1.67-1.76(m,2H),0.57 / 0.56(d,3H)(rotamer).m / z(ESI+)[M+H] + =488.

[0288] rel-2-((6R,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide Isomer 1 (Example 66) and Isomer 2 (Example 67) rac-tert-butyl (6R,7R)-7-(5-bromo-6-methoxy-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate [ka] KOH (1.4, 25.0 mmol) was added to a solution of rac-tert-butyl (6R,7S)-6-methyl-7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate (Int III-5) (3.0 g, 9.0 mmol) and 5-bromo-6-methoxy-1H-indazole (1.9 g, 8.2 mmol) in THF (50 mL) under a N atmosphere at 0 °C. The resulting mixture was stirred at 80 °C for 12 h. The reaction mixture was cooled to rt, diluted with water (100 mL), and extracted with EtOAc (2 × 75 mL). The combined organic layers were dried over NaSO, filtered, and concentrated to give a yellow oil. The oil was purified by C18 flash chromatography (eluting with 50% to 90% MeCN in water (0.05% FA)) to give rac-tert-butyl (6R,7R)-7-(5-bromo-6-methoxy-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate (0.5 g, 13%) as a yellow solid. m / z (ESI+) [M+H] + =464 / 466.

[0289] rac-tert-butyl (6R,7R)-7-(5-(imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate [ka] A solution of imidazo[1,2-b]pyridazin-3-amine (255 mg, 1.9 mmol), dppp (82 mg, 0.2 mmol), Pd(OAc) (44 mg, 0.2 mmol), TEA (588 mg, 5.8 mmol), and rac-tert-butyl (6R,7R)-7-(5-bromo-6-methoxy-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate (450 mg, 1.0 mmol) in MeCN (8 mL) was stirred under a CO atmosphere at 15 atm and 90° C. for 12 h, then cooled to rt. The solvent was removed under reduced pressure, and the residue was purified by C18 flash chromatography (eluting with 40% to 90% MeCN in water (0.05% FA)) to give crude rac-tert-butyl (6R,7R)-7-(5-(imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate (450 mg) as a yellow oil. m / z (ESI+) [M+H] + =546.

[0290] rac-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((6R,7R)-6-methyl-2-azaspiro[3.5]nonan-7-yl)-2H-indazole-5-carboxamide [ka] To crude rac-tert-butyl (6R,7R)-7-(5-(imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylate (450 mg) was added TFA (2 mL, 26.0 mmol) in DCM (4 mL). The resulting mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure to give the crude TFA salt of rac-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((6R,7R)-6-methyl-2-azaspiro[3.5]nonan-7-yl)-2H-indazole-5-carboxamide (350 mg) as a yellow oil. The product was used without further purification. m / z(ESI+)[M+H] + =446.

[0291] rel-2-((6R,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide Isomer 1 (Example 66) and Isomer 2 (Example 67) [ka] The crude TFA salt of rac-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((6R,7R)-6-methyl-2-azaspiro[3.5]nonan-7-yl)-2H-indazole-5-carboxamide (350 mg) was added to TEA (195 mg, 1.9 mmol) in DCM (8 mL) at rt. The mixture was stirred at rt for 5 min, followed by the addition of acetic anhydride (99 mg, 1.0 mmol). The reaction mixture was stirred at rt for 1 h. The mixture was quenched with water (5 mL) and purified by C18 flash chromatography (eluting with 20 to 100% MeCN in water (0.05% FA)) to give rac-2-((6R,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide as a yellow solid. The isomers were separated by chiral preparative HPLC (CHIRALPAK IF, 2 × 25 cm, 5 μm; mobile phase A: MTBE (2 mM NH3-MeOH), mobile phase B: MeOH; flow rate: 17 mL / min; isocratic 50% B in 18 min) to give rel-2-((6R,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-isomer 1 (95 mg, 30%, 100% ee) and isomer 2, which were separated by preparative HPLC (XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% A second purification with HCl (NH4OH), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 20% B to 40% B in 7 min) gave rel-2-((6R,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-isomer 2 (66 mg, 21%, 99% ee). Both isomers were recovered as yellow solids. Isomer 1: 1H NMR (400 MHz, DMSO-d6) (1:1 mixture of rotamers) δ 11.04 (s, 1H), 8.64 (dd, 1H), 8.59 (s, 1H), 8.580 / 8.577 (s, 1H) (rotamers), 8.15 (dd, 1H), 8.05 (s, 1H), 7.29 (d, 1H), 7.22 (dd, 1H), 4.12 (s, 3H), 4.06-4.17 (m, 1H), 3.93-4.01 / 3.65-3.73 (m, 2H) H)(rotamer),3.80 / 3.53(s,2H)(rotamer),2.06-2.19(m,1H),1.90-2.05(m,4H),1.80 / 1.77(s,3 H)(rotamer),1.60-1.73(m,1H),1.38-1.49(m,1H),0.60 / 0.58(d,3H)(rotamer).m / z(ESI+)[M+H] + =488.Isomer 2: 1 H NMR (400MHz, DMSO-d6) (1:1 mixture of rotamers) δ 11.04(s,1H),8.63(d,1H),8.55-8.61(m,2H),8.15(d,1H),8.05(s,1H),7.28(d,1H) ,7.22(dd,1H),4.12(s,3H),4.05-4.17(m,1H),3.92-4.00 / 3.65-3.72(m,2H)(rotamer) ,3.79 / 3.52(s,2H)(rotamer),2.05-2.20(m,1H),1.89-2.05(m,4H),1.79 / 1.76(s,3H) (rotamer),1.61-1.72(m,1H),1.42(t,1H),0.59 / 0.57(s,3H)(rotamer).m / z(ESI+)[M+H] + =488.

[0292] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((5s,8s)-2-methyl-3-oxo-2-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide (Example 68) [ka] Methyldiphenylsilane carboxylic acid (95 mg, 0.4 mmol) and KF (23 mg, 0.4 mmol) were added to Chamber A of a dried, N-flushed COware gas reactor. (5s,8s)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2-methyl-2-azaspiro[4.5]decan-3-one (Int IV-6) (35 mg, 0.3 mmol), dppp (14 mg, 0.03 mmol), Pd(OAc) (7 mg, 0.03 mmol), imidazo[1,2-b]pyridazin-3-amine (80 mg, 0.6 mmol), and DIPEA (138 μL, 0.8 mmol) in degassed anhydrous MeCN (1 mL) were added to Chamber B. DMSO (350 μL) was then added to Chamber A, and Chamber B was stirred at 85° C. overnight. The reaction mixture was cooled to rt. The reaction in Chamber B was quenched with saturated aqueous NaHCO3, concentrated under reduced pressure, dissolved in DCM (30 mL), and loaded onto a 5 g Isolute® SCX2 exchange cartridge. The cartridge was washed with DCM / MeOH (1:1; 100 mL), followed by elution with DCM / 4N NH3-MeOH solution (1:1; 100 mL) and then 2N NH3-MeOH solution (100 mL) to give a dark yellow solid. The solid was purified by silica gel chromatography (eluting with 0-2.5% 2N NH3-MeOH solution in DCM) to give a yellow solid. The solid was suspended and stirred in MeCN (2 mL) at rt for 48 h. The suspension was then filtered and washed with ice-cold MeCN (500 μL × 2) to give N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((5s,8s)-2-methyl-3-oxo-2-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide (36 mg, 58%) as a pale yellow solid. 1H NMR(500MHz,CDCl3)δ 11.25(s,1H),8.83(d,1H),8.35-8.44(m,2H),8.10(d,1H),7.99(d,1H),7.19(s,1H),7.02(dd,1H),4.36-4.46(m,1H), 4.19(s,3H),3.38(s,2H),2.89(s,3H),2.33(s,2H),2.20-2.28(m,2H),2.06-2.17(m,2H),1.97(d,2H),1.68(td,2H).MS ESI,m / z=474[M+H] + .

[0293] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-2-methyl-3-oxo-2-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide (Example 69) [ka] Methyldiphenylsilane carboxylic acid (88 mg, 0.4 mmol) and KF (21 mg, 0.4 mmol) were added to Chamber A of a dried, N-flushed COware gas reactor. (5r,8r)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2-methyl-2-azaspiro[4.5]decan-3-one (Int IV-7) (49 mg, 0.1 mmol), imidazo[1,2-b]pyridazin-3-amine (27 mg, 0.2 mmol), dppp (13 mg, 0.03 mmol), Pd(OAc) (7 mg, 0.03 mmol), and DIPEA (127 μL, 0.7 mmol) in degassed anhydrous MeCN (1 mL) were added to Chamber B. DMSO (200 μL) was then added to Chamber A, and Chamber B was stirred at 85°C overnight. The reaction mixture was cooled to rt. The reaction in Chamber B was quenched with saturated aqueous NaHCO3, concentrated under reduced pressure, dissolved in DCM (30 mL), and loaded onto a 5 g Isolute® SCX2 exchange cartridge. The loaded SCX2 cartridge was washed with DCM / MeOH (1:1; 100 mL), followed by elution with DCM / 4N NH3-MeOH solution (1:1; 100 mL) and then 2N NH3-MeOH solution (100 mL) to give a dark yellow solid. The solid was purified by silica gel chromatography (eluting with 0-2.5% 2N NH3-MeOH solution in DCM) to give a yellow solid, which was suspended and stirred in MeCN (3 mL) at rt for 48 h. The suspension was filtered and washed with ice-cold MeCN (500 μL × 2) to give a solid. The solid was dissolved in 15 mL of boiling MeCN and slowly concentrated to 5 mL under reduced pressure at 45° C. to give a suspension, which was kept at rt overnight. The suspension was filtered, and the residue was washed with ice-cold MeCN (500 μL × 2) to give N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-2-methyl-3-oxo-2-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide (46 mg, 90%) as a pale yellow solid. 1H NMR(500MHz,CDCl3)δ 11.28(s,1H),8.8-8.84(m,1H),8.47(dd,1H),8.40(s,1H),8.16(d,1H),8.10(d,1H),7.18(s,1H),7.12(dd,1H),4.40(tt,1H) MS ESI,m / z=474[M+H] + .

[0294] rel-2-((5R,7R,8R)-2,7-dimethyl-3-oxo-2-azaspiro[4.5]decan-8-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide, or rel-2-((5R,7S,8S)-2,7-dimethyl-3-oxo-2-azaspiro[4.5]decan-8-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide - Isomer 1 (Example 70), Isomer 2 (Example 71), Isomer 3 (Example 72), and Isomer 4 (Example 73) tert-Butyl 7-methyl-8-oxo-2-azaspiro[4.5]decane-2-carboxylate [ka] To a solution of tert-butyl 8-oxo-2-azaspiro[4.5]decane-2-carboxylate (15.0 g, 59.2 mmol) in THF (150 mL) was added 1 M LiHMDS in THF (118.5 mL, 118.5 mmol) dropwise over 20 min at −78 °C under a N atmosphere. The resulting mixture was stirred at −78 °C for 2 h. Subsequently, iodomethane (7.4 mL, 118.5 mmol) was slowly added. The reaction mixture was allowed to warm to rt and stirred for 15 h. The reaction was then quenched with saturated aqueous NH4Cl (300 mL) and extracted with EtOAc (250 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 5-20% EtOAc in PE) to give tert-butyl 7-methyl-8-oxo-2-azaspiro[4.5]decane-2-carboxylate (6.6 g, 42%) as a yellow semi-solid. MS ESI, m / z = 212 [M-tBu] + .

[0295] Mixture of rac-tert-butyl (5R,7R,8S)-7,8-dihydroxy-2-azaspiro[4.5]decane-2-carboxylate and rac-tert-butyl (5R,7S,8R)-7,8-dihydroxy-2-azaspiro[4.5]decane-2-carboxylate [ka] To a solution of tert-butyl 7-methyl-8-oxo-2-azaspiro[4.5]decane-2-carboxylate (5.0 g, 18.7 mmol) in THF (70 mL) was added 2 M tri-sec-butyllithium borohydride in THF (18.7 mL, 37.4 mmol) over 1 minute under a N atmosphere at 0° C. The resulting mixture was stirred at 0° C. for 3 hours. The reaction mixture was quenched with acetone (20 mL) and subsequently concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 25% to 50% EtOAc in PE) to give a mixture of rac-tert-butyl (5R,7R,8S)-7,8-dihydroxy-2-azaspiro[4.5]decane-2-carboxylate and rac-tert-butyl (5R,7S,8R)-7,8-dihydroxy-2-azaspiro[4.5]decane-2-carboxylate (4.8 g, 95%) as a pale yellow oil. MS ESI, m / z = 214 [M-tBu] + .

[0296] Mixture of rac-tert-butyl (5R,7R,8R)-8-(1,3-dioxoisoindolin-2-yl)-7-methyl-2-azaspiro[4.5]decane-2-carboxylate and rac-tert-butyl (5R,7S,8S)-8-(1,3-dioxoisoindolin-2-yl)-7-methyl-2-azaspiro[4.5]decane-2-carboxylate [ka] To a solution of a mixture of rac-tert-butyl (5R,7R,8S)-7,8-dihydroxy-2-azaspiro[4.5]decane-2-carboxylate and rac-tert-butyl (5R,7S,8R)-7,8-dihydroxy-2-azaspiro[4.5]decane-2-carboxylate (3.4 g, 12.6 mmol), triphenylphosphine (6.6 g, 25.2 mmol), and isoindoline-1,3-dione (2.8 g, 18.9 mmol) in THF (60 mL) was added DIAD (4.9 mL, 25.2 mmol) under a N atmosphere at 0 °C. The resulting mixture was stirred at 45 °C for 15 h. The mixture was cooled to rt, poured into brine (200 mL), and extracted with EtOAc (250 mL). The organic layer was dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with DCM) and further by C18 flash chromatography (eluting with 0-100% MeCN in water (0.05% NH4OH)) to give a mixture of rac-tert-butyl (5R,7R,8R)-8-(1,3-dioxoisoindolin-2-yl)-7-methyl-2-azaspiro[4.5]decane-2-carboxylate and rac-tert-butyl (5R,7S,8S)-8-(1,3-dioxoisoindolin-2-yl)-7-methyl-2-azaspiro[4.5]decane-2-carboxylate (1.9 g, 37%) as a pale yellow solid. MS ESI, m / z = 384 [M-tBu + CH3CN] + .

[0297] Mixture of rac-tert-butyl (5R,7R,8R)-8-amino-7-methyl-2-azaspiro[4.5]decane-2-carboxylate and rac-tert-butyl (5R,7S,8S)-8-amino-7-methyl-2-azaspiro[4.5]decane-2-carboxylate [ka] To a solution of a mixture of rac-tert-butyl (5R,7R,8R)-8-(1,3-dioxoisoindolin-2-yl)-7-methyl-2-azaspiro[4.5]decane-2-carboxylate and rac-tert-butyl (5R,7S,8S)-8-(1,3-dioxoisoindolin-2-yl)-7-methyl-2-azaspiro[4.5]decane-2-carboxylate (1.9 g, 4.6 mmol) in EtOH (30 mL) was added hydrazine hydrate (80% in water) (2.9 g, 46.4 mmol). The resulting mixture was stirred at 50 °C for 3 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with DCM) and further by C18 flash chromatography (eluting with 0–100% MeCN in water (0.1% FA)) to give the formate salt of the title compound. The formate salt was dissolved in water (50 mL) and basified to pH 9 with saturated aqueous NaHCO3, followed by extraction with EtOAc (100 mL × 2) and chloroform (100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a mixture of rac-tert-butyl (5R,7R,8R)-8-amino-7-methyl-2-azaspiro[4.5]decane-2-carboxylate and rac-tert-butyl (5R,7S,8S)-8-amino-7-methyl-2-azaspiro[4.5]decane-2-carboxylate (380 mg, 31%) as a pale yellow oil. MS ESI, m / z = 269 [M+H] + .

[0298] Mixture of rac-tert-butyl (5R,7R,8R)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-7-methyl-2-azaspiro[4.5]decane-2-carboxylate and rac-tert-butyl (5R,7S,8S)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-7-methyl-2-azaspiro[4.5]decane-2-carboxylate [ka] To a solution of a mixture of rac-tert-butyl (5R,7R,8R)-8-amino-7-methyl-2-azaspiro[4.5]decane-2-carboxylate and rac-tert-butyl (5R,7S,8S)-8-amino-7-methyl-2-azaspiro[4.5]decane-2-carboxylate (360 mg, 1.3 mmol) in i-PrOH (15 mL) was added 5-bromo-4-methoxy-2-nitrobenzaldehyde (Int I-1) (384 mg, 1.5 mmol). The resulting mixture was stirred at 50 °C for 2 h, then cooled to 30 °C, followed by the addition of tri-n-butylphosphine (814 mg, 4.0 mmol). The reaction mixture was stirred overnight at 80 °C under a N atmosphere. The mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0–100% MeCN in water (0.05% FA)) to give a mixture of rac-tert-butyl (5R,7R,8R)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-7-methyl-2-azaspiro[4.5]decane-2-carboxylate and rac-tert-butyl (5R,7S,8S)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-7-methyl-2-azaspiro[4.5]decane-2-carboxylate (440 mg, 69%) as a pale yellow solid. MS ESI, m / z = 478 / 480 [M+H] + .

[0299] Mixture of rac-(5R,7R,8R)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-7-methyl-2-azaspiro[4.5]decane and rac-(5R,7S,8S)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-7-methyl-2-azaspiro[4.5]decane [ka] To a solution of a mixture of rac-tert-butyl (5R,7R,8R)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-7-methyl-2-azaspiro[4.5]decane-2-carboxylate and rac-tert-butyl (5R,7S,8S)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-7-methyl-2-azaspiro[4.5]decane-2-carboxylate (410 mg, 0.9 mmol) in dioxane (4 mL) was added 4 N HCl in dioxane (2.0 mL, 8.0 mmol), and the resulting solution was stirred at rt for 20 h. The reaction mixture was concentrated under reduced pressure to give a crude mixture of rac-(5R,7R,8R)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-7-methyl-2-azaspiro[4.5]decane and rac-(5R,7S,8S)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-7-methyl-2-azaspiro[4.5]decane HCl salts (354 mg), which was used directly without further purification. MS ESI, m / z = 378 / 380 [M+H] + .

[0300] Mixture of rac-(5R,7R,8R)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2,7-dimethyl-2-azaspiro[4.5]decane and rac-(5R,7S,8S)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2,7-dimethyl-2-azaspiro[4.5]decane [ka] To a crude mixture of rac-(5R,7R,8R)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-7-methyl-2-azaspiro[4.5]decane and rac-(5R,7S,8S)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-7-methyl-2-azaspiro[4.5]decane HCl salts (354 mg, 0.9 mmol), acetic acid (51 mg, 0.9 mmol), and aqueous formaldehyde (40 wt%) (674 mg, 8.3 mmol) in MeOH (10 mL) was added sodium triacetoxyborohydride (362 mg, 1.7 mmol) under a N atmosphere at rt. The reaction mixture was stirred at rt for 3 h. The mixture was directly purified by C18 flash chromatography (eluting with 0–100% MeOH in water (2% NH4OH)) to give a mixture of rac-(5R,7R,8R)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2,7-dimethyl-2-azaspiro[4.5]decane and rac-(5R,7S,8S)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2,7-dimethyl-2-azaspiro[4.5]decane (335 mg, 100%) as a pale yellow solid. MS ESI, m / z = 392 / 394 [M+H] + .

[0301] Mixture of rac-(5R,7R,8R)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2,7-dimethyl-2-azaspiro[4.5]decan-3-one and rac-(5R,7S,8S)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2,7-dimethyl-2-azaspiro[4.5]decan-3-one [ka] To a solution of a mixture of rac-(5R,7R,8R)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2,7-dimethyl-2-azaspiro[4.5]decane and rac-(5R,7S,8S)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2,7-dimethyl-2-azaspiro[4.5]decane (310 mg, 0.8 mmol) in THF (25 mL) was added iodine solution (1.5 g, 5.9 mmol). The resulting solution was stirred at rt for 2 h, followed by the addition of sodium bicarbonate (664 mg, 7.9 mmol) in water (10 mL). The reaction mixture was then stirred at rt for an additional 2 h. The reaction was quenched with saturated aqueous NaSO until the color became pale yellow, followed by extraction with DCM (200 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters XSelect CSH Fluoro-Phenyl OBD, 5 μm Purification by column chromatography (30 × 150 mm; elution gradient of 32–42% MeCN (0.1% FA) in water over 12 min; 60 mL / min) afforded a mixture of rac-(5R,7R,8R)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2,7-dimethyl-2-azaspiro[4.5]decan-3-one containing 40% 8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2,7-dimethyl-2-azaspiro[4.5]decan-1-one (120 mg) and rac-(5R,7S,8S)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2,7-dimethyl-2-azaspiro[4.5]decan-3-one as a pale yellow solid, which was used without further separation.

[0302] rel-2-((5R,7R,8R)-2,7-dimethyl-3-oxo-2-azaspiro[4.5]decan-8-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide, or rel-2-((5R,7S,8S)-2,7-dimethyl-3-oxo-2-azaspiro[4.5]decan-8-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide - Isomer 1 (Example 70), Isomer 2 (Example 71), Isomer 3 (Example 72), and Isomer 4 (Example 73) [ka] A mixture of rac-(5R,7R,8R)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2,7-dimethyl-2-azaspiro[4.5]decan-3-one and rac-(5R,7S,8S)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2,7-dimethyl-2-azaspiro[4.5]decan-3-one containing 40% 8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2,7-dimethyl-2-azaspiro[4.5]decan-1-one in MeCN (15 mL) A suspension of the mixture of (indazol-2-yl)-2,7-dimethyl-2-azaspiro[4.5]decan-3-one (115 mg), imidazo[1,2-b]pyridazin-3-amine (80 mg, 0.6 mmol), Pd(OAc) (14 mg, 0.06 mmol), dppp (41 mg, 0.1 mmol), and DIPEA (183 mg, 1.4 mmol) was stirred under a CO atmosphere at 15 atm and 100° C. for 15 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0–100% acetonitrile in water (0.05% FA)) to give rel-2-((5R,7R,8R)-2,7-dimethyl-3-oxo-2-azaspiro[4.5]decan-8-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide, containing 40% 2-(2,7-dimethyl-1-oxo-2-azaspiro[4.5]decan-8-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide. A mixture of 2-((5R,7S,8S)-2,7-dimethyl-3-oxo-2-azaspiro[4.5]decan-8-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide and 2-((5R,7S,8S)-2,7-dimethyl-3-oxo-2-azaspiro[4.5]decan-8-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide isomers 1 to 4 was obtained.The desired product was separated from by-products and separated by three consecutive chiral preparative HPLC runs (first run: Chiralpak® IA 5 μm 20 mm × 250 mm; 50% MTBE in EtOH (0.1% 2N NH3-MeOH) isocratic; 20.0 mL / min; second and third runs: Chiralpak® ID 5 μm 20 mm × 250 mm; 50% MTBE in MeOH (0.1% 2N NH3-MeOH) isocratic for 16 min; 20.0 mL / min) to give the following four isomers: Isomer 1 (7 mg, 5%), Isomer 2 (7 mg, 5%), Isomer 3 (5 mg, 3%), and Isomer 4 (5 mg, 3%) as pale yellow solids. Isomers 1 and 2 are enantiomers of each other, and LCMS / MS data obtained for both isomers were analyzed. 1 The H NMR are identical; isomer 3 and isomer 4 are enantiomers of each other, and the LCMS / MS obtained for both isomers are 1 H NMR is identical. Isomer 1 / Isomer 2: 1 H NMR(400MHz,DMSO-d6)δ 11.05(s,1H),8.64(dd,1H),8.62(d,1H),8.58(s,1H),8.15(dd,1H),8.05(s,1H),7.31(s,1H),7.22(dd,1H),4.06-4.17(m,4H),3.14(s MS ESI,m / z=488[M+H] + Isomer 3 / Isomer 4: 1H NMR(400MHz,DMSO-d6)δ 11.05(s,1H),8.64(dd,1H),8.62(d,1H),8.58(s,1H),8.15(dd,1H),8.05(s,1H),7.28(s,1H),7.22(dd,1H),4.07-4.17(m,4H),3 .38(s,2H),2.76(s,3H),2.06-2.28(m,4H),1.86-1.96(m,1H),1.76-1.86(m,2H),1.51-1.63(m,1H),1.33(t,1H),0.57(d,3H).MS ESI,m / z=488[M+H] + .

[0303] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-(1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 74) and Isomer 2 (Example 75) (4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)methanol [ka] To a solution of (4-aminocyclohexyl)methanol (2.0 g, 15.5 mmol) in i-PrOH (20 mL) at rt under a N atmosphere, 5-bromo-4-methoxy-2-nitrobenzaldehyde (Int I-1) (4.0 g, 15.5 mmol) was added. The resulting mixture was stirred at 80 °C for 1 h and then cooled to rt, followed by the addition of tri-n-butylphosphine (15.7 g, 77.4 mmol). The reaction mixture was stirred at 80 °C for 15 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 20–50% EtOAc in PE) to give a yellow oil. The oil was subsequently crystallized from EtOAc (2 mL) / PE (12 mL) to give (4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)methanol (900 mg, 17%) as a colorless solid. The filtrate from the crystallization was concentrated under reduced pressure to give (4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)methanol (5.0 g, 47% by weight) as a solid, which was used in the next step without further purification. MS ESI, m / z=339 / 341 [M+H] + .

[0304] (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 (47 wt%) (4.9 g) in DCM (20 mL) at 0 °C, 2,2,2-trichloroacetyl isocyanate (1.5 g, 8.2 mmol) was added. The resulting solution was allowed to warm to rt and stirred for 2 h. Subsequently, MeOH and K2CO3 (94 mg, 0.7 mmol) were added. The resulting mixture was stirred at rt for 15 h. The reaction was quenched with water (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was crystallized from EtOAc / pentane (3 / 1) (20 mL) to give (4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)methylcarbamate (2.5 g, 96%) as a colorless solid. MS ESI, m / z=382 / 384 [M+H] + .

[0305] 8-(5-Bromo-6-methoxy-2H-indazol-2-yl)-3-oxa-1-azaspiro[4.5]decan-2-one [ka] Magnesium oxide (728 mg, 18.1 mmol), [acetyloxy(phenyl)-λ 3To a solution of [4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl]methylcarbamate (1.5 g, 3.9 mmol) was added rhodium(II) acetate (347 mg, 0.8 mmol) over 3 min under a N atmosphere. The resulting solution was stirred at 40 °C for 15 h. The mixture was cooled to rt, poured into water (100 mL), and extracted with DCM (200 mL × 2). The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0-100% MeCN in water (0.1% FA)) and further by preparative HPLC (Waters XSelect CSH C18 OBD, 5 μm 30 × 150 mm; elution gradient of 34-35% MeCN in water (0.05% TFA) over 8 min; 60 mL / min) to give 8-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-oxa-1-azaspiro[4.5]decan-2-one (340 mg, 23%) as a pale yellow solid. MS ESI, m / z = 380 / 382 [M+H] + .

[0306] 8-(5-Bromo-6-methoxy-2H-indazol-2-yl)-1-methyl-3-oxa-1-azaspiro[4.5]decan-2-one [ka] Iodomethane (134 mg, 1.0 mmol) was added dropwise to a suspension of NaH (60 wt%) (19 mg, 0.5 mmol) and 8-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-oxa-1-azaspiro[4.5]decan-2-one (120 mg, 0.3 mmol) in DMF (6 mL) under a N atmosphere at rt. The resulting mixture was stirred at rt for 15 h. The reaction was quenched with saturated aqueous NH4Cl (5 mL) and directly purified by C18 flash chromatography (eluting with 0–100% MeCN in water (0.1% FA)) to afford 8-(5-bromo-6-methoxy-2H-indazol-2-yl)-1-methyl-3-oxa-1-azaspiro[4.5]decan-2-one (70 mg, 56%) as a red solid. MS ESI, m / z = 380 / 382 [M+H] + .

[0307] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-(1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 74) and Isomer 2 (Example 75) [ka] A suspension of 8-(5-bromo-6-methoxy-2H-indazol-2-yl)-1-methyl-3-oxa-1-azaspiro[4.5]decan-2-one (124 mg, 0.3 mmol), imidazo[1,2-b]pyridazin-3-amine (121 mg, 0.9 mmol), Pd(OAc) (14 mg, 0.06 mmol), dppp (41 mg, 0.1 mmol), and TEA (438 μL, 3.2 mmol) in MeCN (10 mL) was stirred under a CO atmosphere at 15 atm and 100° C. for 15 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0-90% MeCN in water (0.1% FA)) and further by preparative HPLC (Waters Xbridge® BEH OBD C18, 5 μm 30 × 150 mm; elution gradient of 30-60% MeOH in water (10 mM NH4HCO3 + 0.1% NH4OH) over 8 min; 60 mL / min) to give N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-(1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide as a yellow solid. The solid was purified by chiral preparative HPLC (Chiralpak® IF, 5 μm 20 mm × 250 mm; 50% MTBE (0.5% 2M) in EtOH). NH3-MeOH) for 26 min (isocratic; 13.0 mL / min) to give rel-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide isomer 1 (7m g, 4%, 100% ee) and rel-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-1-methyl-2-oxo-3-oxa-1-azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide-isomer 2 (1 mg, 1%, 98.9% ee), both as yellow solids. Isomer 1: 1H NMR(400MHz,DMSO-d6)δ 11.05(s,1H),8.74(s,1H),8.63(dd,1H),8.59(s,1H),8.15(dd,1H),8.05(s,1H),7.30(s,1H),7.22(dd,1H),4 .65-4.73(m,1H),4.23(s,2H),4.13(s,3H),2.60(s,3H),2.51-2.58(m,2H),1.93-2.15(m,4H),1.53(d,2H).MS ESI,m / z=476[M+H] + Isomer 2: 1 H NMR(400MHz,DMSO-d6)δ 11.04(s,1H),8.62-8.66(m,1H),8.61(s,1H),8.59(s,1H),8.15(dd,1H),8.05(s,1H),7.25-7.29(m,1H),7.22(dd, 1H),4.48-4.61(m,1H),4.27(s,2H),4.12(s,3H),2.72(s,3H),2.18(s,2H),1.95-2.09(m,4H),1.66-1.76(m,2H).MS ESI,m / z=476[M+H] + .

[0308] rel-2-((1R,3R,4S)-4-hydroxy-3-methylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide - Isomer 1 (Example 76), Isomer 2 (Example 77) rel-2-((1S,3R,4S)-4-hydroxy-3-methylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide - Isomer 1 (Example 78) and Isomer 2 (Example 79) rac-(3R,4S)-4-Hydroxy-3-methylcyclohexan-1-one [ka] Aqueous HCl (12N) (10.0 mL, 120.0 mmol) was added to THF (10 mL) and water (10 mL), followed by the addition of rac-(7R,8S)-7-methyl-1,4-dioxaspiro[4.5]decan-8-ol (Int III-11) (3.1 g, 18.0 mmol). The resulting mixture was stirred at rt for 12 h. The pH of the reaction mixture was adjusted to pH 5-6 with 30 wt% aqueous NH4OH, and the mixture was then concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with 0-50% EtOAc in PE) to give rac-(3R,4S)-4-hydroxy-3-methylcyclohexan-1-one (2.1 g, 91%) as a yellow oil. MS ESI, m / z = 170 [M + CH3CN + H] + .

[0309] Mixture of rac-(1S,2R,4R)-4-(benzylamino)-2-methylcyclohexan-1-ol and rac-(1S,2R,4S)-4-(benzylamino)-2-methylcyclohexan-1-ol [ka] To a solution of rac-(3R,4S)-4-hydroxy-3-methylcyclohexan-1-one (2.0 g, 15.6 mmol) in DCE (40 mL) under a N atmosphere at rt was added phenylmethanamine (2.0 g, 18.7 mmol). The resulting solution was stirred for 1 h, followed by the addition of sodium triacetoxyborohydride (9.9 g, 46.8 mmol). The mixture was stirred at rt for an additional 3 h. The reaction was quenched with water (15 mL) and concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluting with 0–80% MeCN in water (0.1% NH4OH)) to give a mixture of rac-(1S,2R,4R)-4-(benzylamino)-2-methylcyclohexan-1-ol and rac-(1S,2R,4S)-4-(benzylamino)-2-methylcyclohexan-1-ol (2.10 g, 61%) as a brown solid.

[0310] Mixture of rac-(1S,2R,4R)-4-amino-2-methylcyclohexan-1-ol and rac-(1S,2R,4S)-4-amino-2-methylcyclohexan-1-ol [ka] To a solution of a mixture of rac-(1S,2R,4R)-4-(benzylamino)-2-methylcyclohexan-1-ol and rac-(1S,2R,4S)-4-(benzylamino)-2-methylcyclohexan-1-ol (2.0 g, 9.1 mmol) in MeOH (30 mL) was added Pd(OH)2 on carbon (20 wt%) (640 mg, 0.9 mmol) under a N2 atmosphere. The resulting suspension was stirred at rt under 2 atm of hydrogen for 12 h. The reaction mixture was filtered through silica gel, and the silica gel cake was washe...

Claims

1. Formula (Id) 【Chemical 1】 [During the ceremony, R １ teeth, 【Chemistry 2】 and R ２ teeth, 【Chemistry 3】 and R ４ is H, Me, Et, optionally substituted C １ ~C ６ alkyl, or optionally substituted C ３ ~C ６ is cycloalkyl; Y is N(Me)COMe, N(R ５ )COMe, N(Me)COR ６ , N(R ５ ) COR ６ , or CONMe ２ and Z is H; X is OR ７ or NR ８ R ９ and R ５ is H, optionally substituted C １ ~C ６ alkyl, or optionally substituted C ３ ~C ６ is cycloalkyl; R ６ is an optionally substituted C １ ~C ６ Alkyl, optionally substituted C ３ ~C ６ cycloalkyl, or an optionally substituted 5- or 6-membered saturated N-heterocycle; R ７ is Me, Et, i-propyl, n-propyl, cyclopropyl, cyclobutyl, optionally substituted C １ ~C ６ Alkyl, C ３ ~C ６ a cycloalkyl group or a 4-, 5-, or 6-membered ring containing a heteroatom selected from O and N; R ８ and R ９ is H, Me, and optionally substituted C １ ~C ６ alkyl, or both are optionally substituted C ３ ~C ６ forming an optionally substituted 4-, 5-, or 6-membered ring containing a cycloalkyl or an additional heteroatom selected from O and N; 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, and Cl. or a pharmaceutically acceptable salt thereof.

2. R １ but, 【Chemistry 4】 2. The compound of claim 1, wherein:

3. R １ but, 【Chemistry 5】 2. The compound of claim 1, wherein:

4. X is OR ７ where optionally R ７ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is Me.

5. R ５ But H, C １ ~C ６ Alkyl, or C ３ ~C ６ The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

6. R ２ but, 【Chemistry 6】 where optionally R ４ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein is H.

7. N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide; N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide; 6-methoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1r,4r)-4-(cyclopropanecarboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1s,4s)-4-(cyclopropanecarboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 6-cyclopropoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 6-cyclopropoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1S,2S,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide; N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1R,2R,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1S,4r)-4-((S)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 6-methoxy-2-((1R,2R,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 6-methoxy-2-((1S,2S,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1S,4r)-4-((S)-2-hydroxy-N-methylpropanamido)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; 6-methoxy-2-((1r,4r)-4-(N-methylcyclopropanecarboxamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((1r,3R)-3-hydroxy-N-methylcyclobutane-1-carboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((1s,3S)-3-hydroxy-N-methylcyclobutane-1-carboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1r,4r)-4-(2-hydroxy-N,2-dimethylpropanamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1S,4r)-4-((S)-3-hydroxy-N-methylbutanamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-3-hydroxy-N-methylbutanamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; rel-2-((1R,4r)-4-((1R,3R)-3-hydroxy-N-methylcyclopentane-1-carboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; rel-2-((1R,4r)-4-((1R,3S)-3-hydroxy-N-methylcyclopentane-1-carboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1S,4r)-4-((S)-3-hydroxy-N-methylpyrrolidine-1-carboxamido)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; and 2-((1R,4r)-4-((R)-3-hydroxy-N-methylpyrrolidine-1-carboxamido)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; and pharmaceutically acceptable salts thereof 2. A compound of formula (Id) according to claim 1 selected from: or a pharmaceutically acceptable salt thereof.

8. N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide 【Chemistry 7】 2. The compound of formula (Id) according to claim 1, which is: or a pharmaceutically acceptable salt thereof.

9. N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1R,2R,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide 【Chemistry 8】 2. The compound of formula (Id) according to claim 1, which is: or a pharmaceutically acceptable salt thereof.

10. 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide 【Chemistry 9】 2. The compound of formula (Id) according to claim 1, which is: or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound of formula (Id) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

12. A medicament comprising a compound of formula (Id) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

13. 13. The pharmaceutical composition according to claim 12, for the treatment of a disease selected from 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.

14. 13. The medicament of claim 12 for the treatment of 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+).

15. 13. The medicament according to claim 12 for the treatment of asthma, chronic obstructive pulmonary disease, systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjogren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis, or psoriasis.

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