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 methods of treating, for example, 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. Preferred compounds of the present application are, for example: N-(imidazo[l,2-b]pyridazin-3-yl)-l-cyclohexyl-2H-indazole-5-carboxamide, N-(pyrazolo[l,5-a]pyrimidin-3-yl)-l-cyclohexyl-2H-indazole-5-carboxamide, N-(imidazo[l,2-b]pyridazin-3-yl)-l-azaspiro[4.5]dec-8-yl-2H-indazole-5-carboxamide and N-(pyrazolo[l,5-a]pyrimidin-3-yl)-l-azaspiro[4.5]dec-8-yl-2H-indazole-5-carboxamide derivatives. An exemplary compound of the present application is, for example: N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-l-methyl-2-oxo-l-azaspiro[4.5]dec-8-yl)-2H-indazole-5-carboxamide (Example 1): formula (VII).

Description

[0001] The present specification relates to chemical compounds and pharmaceutically acceptable salts thereof that inhibit IRAK4 and thus have potential use in medicine. The present specification also relates to the use of these IRAK4 inhibitors in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), inflammatory diseases and autoinflammatory / autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjogren’s syndrome (SS), systemic sclerosis, gout, endometriosis, atopic dermatitis, and psoriasis. The present specification also relates to processes and intermediate compounds involved in making the IRAK4 inhibitors, and to pharmaceutical compositions containing the inhibitors.

[0002] Interleukin-1 receptor (IL-1R) associated kinase 4 (IRAK4) is a key regulator of immune signaling. IRAK4 is expressed by a variety of cell types and mediates signaling from Toll-like receptors (TLRs) and receptors of the interleukin-1 (IL-1) family, including IL-1R, IL-18R, and IL-33 receptor ST2. TLRs recognize and respond to ligands derived from microorganisms, such as lipopolysaccharide (LPS) or microbial RNA or DNA, while receptors of the IL-1 family can be activated by endogenous ligands produced by activated cells of TLR (IL-1β and IL-18) or by tissue injury (IL-1α and IL-33). Upon activation of TLR or IL-1 receptors by their ligands, the adaptor protein myeloid differentiation primary response 88 (MyD88) is recruited to the receptor and, together with proteins of the IRAK family (IRAK1, IRAK2, and IRAK4), forms a multimeric protein complex known as the “Myddosome”. The Myddosome serves as a signaling platform to induce the nuclear factor KB (NF-κΒ) and mitogen-activated protein kinase (MAPK) signaling pathways for the activation of the transcription factors NF-κΒ, activating protein 1 (AP1), c-AMP response element binding protein (CREB), and interferon regulatory factor 5 (IRF5), driving the transcription of inflammatory cytokines and chemokines. Mice lacking IRAK4 are viable but lack inflammatory cytokine responses to IL-1β, IL-18, and LPS. Humans presenting loss-of-function mutations in IRAK4 exhibit an immunocompromised phenotype, and their immune cells show 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 central kinase domain. Myddosome formation promotes IRAK4 autophosphorylation, which regulates Myddosome stability and downstream signaling. Cytokine induction by TLRs and IL-1Rs requires kinase activity of IRAK4, as shown by studies in knock-in mice expressing kinase-dead IRAK4 and studies using small molecule IRAK4 kinase inhibitors.

[0004] In view of its key role in eliminating inflammatory responses, IRAK4 constitutes a target for drugs exerting anti-inflammatory effects.

[0005] Asthma and COPD (chronic obstructive pulmonary disease) are chronic lung diseases that constitute an unmet medical need worldwide. Asthma and COPD are characterized by chronic airway inflammation involving abnormal cytokine release, dysregulated immune cell activation, and airway remodeling. In asthma, stimuli to the airway, such as allergic, viral, and bacterial stimuli, activate TLR receptors via pathogen-associated molecular patterns (PAMPs), and IL-1R and ST2 receptors via release of alarmins, including IL-33 and IL-1a, and IL-1b released upon inflammasome activation. Receptors of the TLR and IL-1 family are present in multiple cell types in the airway, including macrophages, dendritic cells, mast cells, monocytes, and epithelial cells, and respond to their ligands by releasing inflammatory cytokines (TNF-a, IL-6, IL-8, GM-CSF, IL-5) leading to airway inflammation, recruitment of inflammatory cells such as neutrophils and eosinophils, airway hyperresponsiveness, and mucus production. IRAK4 inhibition has the potential to inhibit these inflammatory pathways in the airway. Gene expression analysis of lung samples from patients with asthma and COPD has revealed upregulation of gene expression associated with IL-1R and TLR2 / 4 inflammatory pathways in subsets of several patients. To our knowledge, while IRAK4 inhibitors have not been explored in the clinic for the treatment of respiratory diseases, preclinical data from several groups indicate that interfering with pathways modulated by IRAK4 attenuates airway inflammation in animal models of both asthma and COPD. For example, mice lacking MyD88, a central component of myddosomes, are protected from airway inflammation induced by allergen or IL-33, as are mice treated with small molecule mimetics that block the interaction between IRAK2 and IRAK4. Blocking IL-1b with monoclonal antibodies has also been found to inhibit airway inflammation induced by allergen and bacteria in a steroid-resistant mouse model of asthma. Furthermore, treatment of mice with the IL-1R antagonist anakinra at the time of allergen challenge improves asthma-like symptoms in a mouse model of allergic asthma. Chronic exposure to cigarette smoke is a major factor in the development of COPD. In mice exposed to cigarette smoke, IL-1 signaling is important in mediating neutrophilic airway inflammation, and blocking IL-1 signaling with antibodies against IL-1a, IL-1b, or IL-1R can improve neutrophilic inflammation in the lung and reduce bacterial or viral-induced exacerbations in mice exposed to cigarette smoke. Taken together, IRAK4 inhibition has the potential to provide broad anti-inflammatory effects in inflammatory respiratory diseases by simultaneously blocking several disease-relevant signaling pathways.

[0006] As an important regulator of Myddosome, 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 disorders such as rheumatoid arthritis and systemic lupus erythematosus (SLE) (see, e.g., WO 2017207386 and WO 2015150995). In SLE, immune complexes composed of autoantibodies and self-antigens can drive TLR-dependent pathogenic signaling. In SLE pathology, IRAK4 inhibition was reported to block type I interferon and proinflammatory cytokine release mediated by TLR7 and TLR9 activation in plasmacytoid dendritic cells. Mice expressing kinase-dead mutants of IRAK4 or treated with IRAK4 kinase inhibitor compounds were resistant to experimentally induced arthritis and lupus (see, e.g., WO 2017207386). The approved use of anakinra, an IL-1 receptor antagonist, for the treatment of rheumatoid arthritis also supports a role for pathogenic IL-1R signaling in this disease. In Sjogren’s syndrome, TLRs are upregulated in PBMCs (peripheral blood mononuclear cells), and salivary gland and TLR activation can stimulate the release of interferons and other inflammatory cytokines, suggesting its involvement in the pathology of Sjogren’s syndrome. MyD88 knockout mice also exhibited reduced disease performance in an experimental mouse model of Sjogren’s syndrome. Systemic sclerosis is a severe autoimmune disorder in which IL-1R, TLR0, TLR8, and ST2 signaling can drive pathogenic mechanisms, including microvascular damage and fibrosis. Inhibition of IRAK4 as a treatment for systemic sclerosis would thus block multiple disease-associated pathways simultaneously. In myositis, high levels of IL-1 αand IL-1 β can promote muscle cell inflammation. Myolitic patients are also characterized by a high type I interferon gene signature, which can be partially driven by TLR7 / 9 activation, and the relevance of IL-1 R signaling is supported by improved clinical outcomes in myolitic patients treated with anakinra in small mechanistic clinical trials. As an important regulator of the IL-1 R pathway, IRAK4 is also a promising target in the treatment of gout. Uric acid monosodium crystals, which form particularly in gout patients, can trigger inflammasome activation and release of IL-1 β. Both the use of canakinumab, an anti-IL-1 β monoclonal antibody, or anakinra have demonstrated clinical efficacy in the treatment of gout flares. High levels of IL-1 β and IL-33 have also been found in patients with endometriosis. The importance of IRAK4 in the disease process of endometriosis was shown in a mouse model of oral administration of an IRAK4 inhibitor inhibiting lesion formation. MyD88 knockout mice were also protected from developing endometriosis in the same mouse model. IL-33 / ST2 signaling is a key mechanism in atopic dermatitis, which involves the regulation 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 an important component of the myddosome, IRAK4 has the potential to inhibit pathogenic IL-33 / ST2 signaling in atopic dermatitis. Both TLR7 and IL-1 R-mediated mechanisms have been implicated in psoriasis. Imiquimod, a TLR / 8 agonist, can induce psoriasis-like disease in mice in a MyD88-dependent manner. IL-1 β is upregulated in psoriatic lesions and it has been shown that the IL-1 β / IL-1 R axis promotes skin inflammation and regulates IL-17 production in psoriasis pathology, a key cytokine released from TH17 cells. IRAK4 kinase activity has been further shown to be required in vivo to regulate TH17 differentiation and TH17-mediated disease.

[0007] A variety of IRAK4 kinase inhibitors are known and have been developed in principle for oncology or inflammatory diseases (see e.g. WO 2015150995, WO 2017207386, WO 2017009806, WO 2016174183, WO 2018234342). Among the known IRAK4 kinase inhibitors, PF-06650833 has recently completed a phase II clinical trial for the treatment of rheumatoid arthritis (see entry NCT02996500 at clinicaltrials.gov).

[0008] Taken together, IRAK4 inhibitors have potential for treating a variety of diseases and conditions, although to date no such inhibitors have been approved for clinical use. It is an object of the present specification to provide new IRAK4 inhibitors having physicochemical and selectivity profiles that render them suitable for clinical use, e.g., for treating inflammatory diseases associated with activation of IRAK4-mediated pathways such as asthma, COPD, and chronic autoimmune / autoinflammatory diseases.

[0009] In a first aspect, the present specification provides a compound of Formula (A), or a pharmaceutically acceptable salt thereof,

[0010]

[0011] wherein:

[0012] R 1 is selected from

[0013]

[0014] R 2 is selected from

[0015]

[0016] R 3 and 0 0 are each independently selected from H, Me, Et, optionally substituted C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl;

[0017] Y is N(Me)COMe, N(R 5 )COMe, N(Me)COR 6 , N(R 5 )COR 6 , CONMe2, or a 5-membered N-heterocycle such as 1,2,3-triazole, and Z is H, Me, Et, and optionally substituted C1-C6 alkyl; or

[0018] Y and Z, in combination, form an optionally substituted 4-, 5-, or 6-membered ring;

[0019] X is selected from OR 7 and NR 8 R 9 ;

[0020] R 5 is selected from H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl;

[0021] R 6selected from the group consisting of optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, and optionally substituted 5- or 6-membered saturated N-heterocycle:

[0022] R 7 is Me, Et, i-propyl, n-propyl, cyclopropyl, cyclobutyl, optionally substituted C1-C6alkyl, C3-C6cycloalkyl, or a 4-, 5-, or 6-membered ring containing a heteroatom selected from O and N;

[0023] R 8 and R 9 are each independently selected from H, Me, and optionally substituted C1-C6alkyl, or together form an optionally substituted C3-C6cycloalkyl or an optionally substituted 4-, 5-, or 6-membered ring containing an additional heteroatom selected from O and N;

[0024] wherein when present, the optional substituents of Z, R 3 , 0 0 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from OH, C1-C3alkyl, C1-C3alkoxy, C(O)Me, amino, NHMe, NMe2, F, or Cl.

[0025] In a second aspect, the present specification provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0026]

[0027] wherein:

[0028] R 1 is selected from

[0029]

[0030] R 2 is selected from

[0031]

[0032] R 3 and 0 0 are each independently selected from H, Me, Et, optionally substituted C1-C6alkyl, and optionally substituted C3-C6cycloalkyl;

[0033] Y is N(Me)COMe, N(R 5 )COMe, N(Me)COR 6 , N(R 5 )COR 6CONH2, CONHMe, CONMe2, or a 5-membered N-heterocycle such as 1,2,3-triazole, and Z is H, Me, Et, and optionally substituted C1-C6alkyl; or

[0034] Y and Z, in combination, form an optionally substituted 4-, 5-, or 6-membered ring;

[0035] X is selected from OR 7 and NR 8 R 9 ;

[0036] R 5 is selected from H, optionally substituted C1-C6alkyl, and optionally substituted C3-C6cycloalkyl;

[0037] R 6 is selected from optionally substituted C1-C6alkyl, and optionally substituted C3-C6cycloalkyl;

[0038] R 7 is Me, Et, isopropyl, n-propyl, cyclopropyl, cyclobutyl, optionally substituted C1-C6alkyl, C3-C6cycloalkyl, or a 4-, 5-, or 6-membered ring containing a heteroatom selected from O and N;

[0039] R 8 and R 9 are independently selected from H, Me, and optionally substituted C1-C6alkyl, or together form an optionally substituted C3-C6cycloalkyl or an optionally substituted 4-, 5-, or 6-membered ring containing an additional heteroatom selected from O and N;

[0040] wherein when present, the optional substituents of Z, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from OH, C1-C3alkyl, C1-C3alkoxy, C(O)Me, amino, NHMe, NMe2, F, or Cl.

[0041] The following references herein to compounds of Formula (I) are to be read as including references to compounds of Formula (A) as well as references to compounds of Formula (I).

[0042] The specification also describes a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0043] The specification also describes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0044] This specification also describes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD).

[0045] This specification also describes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory diseases.

[0046] This 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.

[0047] This specification also describes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, for example for use in combination with a BTK inhibitor.

[0048] 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 another therapeutic agent, for example for the treatment of a haematological malignancy. The haematological malignancy to be treated can be selected from the group consisting of 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), leukaemia (chronic lymphocytic leukaemia (CLL)) and monoclonal gammopathy of undetermined significance (MGUS-IgM+). Furthermore, the use can be for the treatment of a haematological malignancy having a MYD88 mutation, a B-cell receptor (BCR) mutation or both MYD88 and BCR mutations. When the compound is used in combination with another therapeutic agent, the second agent can be selected from the group consisting of a BCR inhibitor such as a BTK inhibitor (examples include ibrutinib, acalabrutinib, zanubrutinib or tirabrutinib), a PI3K delta inhibitor and a SYK inhibitor or an immunotherapy.

[0049] The specification also describes the use of a compound of Formula (I) for the manufacture of a medicament, for example where the medicament is for the treatment of a respiratory disease such as asthma and chronic obstructive pulmonary disease (COPD), or for the treatment of a cancer or for the treatment of an autoinflammatory / autoimmune disease such as systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjogren’s syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis and psoriasis, or for the treatment of an inflammatory disease.

[0050] The specification also describes a method of treatment comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), wherein the patient in need thereof has a respiratory disease such as asthma and chronic obstructive pulmonary disease (COPD), a 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.

[0051] The specification also relates to a process for the manufacture of a compound of Formula (I).

[0052] Further aspects of the specification will be apparent to those skilled in the art upon reading this specification.

[0053] The specification makes reference to the following figures.

[0054] Figure 1 In vivo dose response of Example 89 in an acute mouse model of LPS-induced lung inflammation. Mice were dosed orally with Example 89 compound 1 h prior to inhaled LPS challenge (1 mg / mL). Four hours after challenge, animals were sacrificed and levels of released IL-6 and TNF-a in bronchoalveolar lavage fluid were measured. Example 89 reduced levels of IL-6 and TNF-a in a dose-dependent manner. Individual data points represent individual animals and bars represent mean values for each group. Statistical differences between groups were calculated by one-way ANOVA test comparing treatment groups to vehicle group. ** p < 0.01, *** p < 0.001. The ability of IRAK4 inhibitors according to the specification to reduce inflammatory cytokines and TNF-a in vivo is thus established.

[0055] As described above, it has been found that compounds of Formula (I) or pharmaceutically acceptable salts thereof are potent inhibitors of IRAK4 kinase. Furthermore, preferred compounds of Formula (I) exhibit excellent selectivity over other kinases, providing a profile that avoids off-target effects and toxicity. This desirable combination of IRAK4 inhibitory activity and lack of deleterious off-target effects indicates the suitability of the compounds of the specification for use in medicine.

[0056] Unless defined otherwise, 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 belongs. 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 one of skill with a general dictionary of many of the terms used in this disclosure.

[0057] To enable a clearer understanding of the present specification, certain terms are defined below. Furthermore, definitions are set forth throughout the detailed description for purposes of clarity.

[0058] Units, prefixes, and symbols are denoted in their Systeme International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range.

[0059] The term "pharmaceutical composition" refers to a preparation which is in a form suitable for administration into a subject and which is not biologically unacceptable. Such compositions can be sterile. A pharmaceutical composition according to the present specification will comprise a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0060] The terms "treating" or "treatment" or "to treat" or "alleviating" or "alleviate" refer to both (1) therapeutic measures that cure, slow down, lessen symptoms of, and / or halt the progression of a diagnosed pathologic condition or disorder and (2) prophylactic or preventative measures that prevent and / or slow the development of a pathologic condition or disorder targeted for treatment. Thus, those in need of treatment include those already with the disorder; those prone to have or suffer from the disorder; and those in whom the disorder is to be prevented. In certain aspects, a subject's respiratory disease is successfully "treated" according to the methods of the disclosure if the patient shows, e.g., relief of symptoms of the respiratory disease, total, partial, or transient.

[0061] The term "subject" refers to any animal (e.g., a mammal), including, but not limited to, humans, non-human primates, rodents, and the like, that is the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein with respect to human subjects.

[0062] As used herein and above, the symbol ★ is used to indicate the point of attachment of a component of a compound of Formula (I) to other components of the compound. To illustrate this by example, when a compound of Formula (I) has the following R 1 motif, the compound will be a compound of Structure A. Similarly, when a compound of Formula (I) has the following R 2 motif, the compound will be a compound of Structure B.

[0063]

[0064] As used herein, the term "alkyl" refers to straight and branched chain saturated hydrocarbon groups having the indicated number of carbon atoms. As used herein, the term deuterium alkyl refers to an alkyl group in which one or more, optionally all, hydrogens are replaced by deuterium atoms. The term cycloalkyl refers to a saturated cyclic hydrocarbon.

[0065] In this specification, the prefix C x -C y such as C x -C yAlkyl and like designations in which x and y are integers indicate a range of the number of carbon atoms present in the group. For example, C1-C4 alkyl includes methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, and t-butyl, while an example of C1-C3 alkyl includes methyl, ethyl, n-propyl, and i-propyl. C1-C4 alkoxy includes methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy, and t-butoxy. Examples of C1-C3 alkoxy include methoxy, ethoxy, n-propoxy, and i-propoxy.

[0066] Unless explicitly otherwise stated, the bonded atom of a group can be any suitable atom of the group; for example, propyl includes prop-1-yl and prop-2-yl.

[0067] As used herein, the term cycloalkyl refers to saturated cyclic hydrocarbon groups having the indicated number of carbon atoms. Thus, C3-C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. b Cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0068] As used herein, the term alkoxy refers to groups having an oxygen atom attached to an alkyl chain, where alkyl chain is a straight chain and branched chain saturated hydrocarbon group having the indicated number of carbon atoms as defined above. Thus, C1-C3 alkoxy refers to methoxy, ethoxy, O n Pr and O i Pr groups.

[0069] As described herein and above, the group R 2 may be substituted with the group R 4 In such cases, the group R 4 may be attached to any available ring carbon, although R 4 is preferably attached to the carbon atom adjacent to the carbon atom attached to the indazole ring shown below.

[0070]

[0071] As described herein and above, the term acetyl refers to a group of formula -C(O)Me. Reference to N-acylated groups herein is used to refer to amides having a small alkyl side chain (i.e., an optionally substituted C1-C6 alkyl side chain or an 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 N-acetyl, i.e., the group -NRC(O)Me.

[0072] As described herein and above, the compound of formula (I) includes the group R 2which can be a cyclohexyl ring substituted with two groups Y and Z combined to form a 4-, 5- or 6-membered ring. In such cases, the 4-, 5- or 6-membered ring is a saturated hydrocarbon ring system, optionally wherein one or two ring carbons are replaced by a heteroatom selected from O and N. In cases where two ring carbons are replaced by heteroatoms, the heteroatoms are not directly bound, i.e. the heteroatoms replace non-adjacent ring carbons, or they are not separated in the ring by a CH2group, but can for example be connected by a carbonyl group to provide for example a carbonate or carbamate motif. The hydrocarbon ring can incorporate a carbonyl group, as in the case where Y and Z combine to form a cyclic amide. In preferred examples, 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, groups Y and Z can combine to form an azetidine substituted at nitrogen by an acyl group. Furthermore, the 4-, 5- or 6-membered ring can be substituted by a group selected from OH, C1-C3alkyl, C1-C3alkoxy, C(O)Me, amino, NHMe, NMe2, F or Cl. These optional substituents can be advantageous to modulate the physicochemical properties of the molecule, such as solubility, or for example to further optimize the interaction with IRAK4 kinase over other kinases, thereby providing more potent and selective IRAK4 kinase inhibitors.

[0073] As described herein, the compound of formula (A) comprises a group Y which can be selected from 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, for example a pyrrolidine or piperidine connected to the carbonyl group of Y via the nitrogen atom of the heterocycle to provide a urea moiety. For example, Y can be the group N(Me)COR 6 , wherein R 6 is a 3-hydroxypyrrolidine as shown below.

[0074]

[0075] As described 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, a saturated 4-, 5- or 6-membered ring containing a heteroatom selected from O and N is 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 described herein and above, the substituents R 8 and R9 may be combined to form an optionally substituted 4-, 5-, or 6-membered ring containing another heteroatom selected from O and N. In cases where another heteroatom is present, the heteroatoms are not directly bound to N, i.e., the heteroatoms in the ring are not adjacent, or they are not separated by a CH2group. In such cases, it is preferred that the resulting ring is saturated, e.g., the resulting ring can be a morpholine or piperazine ring.

[0076] As will be apparent to the reader skilled in the art, the compounds of formula (I) and in particular the group R 2 may exist in various stereochemical forms. It is to be understood that the claims encompass all stereochemical forms of the compounds of formula (I), although the compounds having the highest activity as IRAK4 inhibitors are preferred. It will be recognized that the compounds of formula (I) can be prepared, isolated, and / or provided in the presence or absence of one or more other possible stereochemical forms of the compounds of formula (I) in any relevant proportion. The preparation of stereochemically enriched or stereochemically pure compounds can be performed by standard techniques of organic chemistry well known in the art, for example by synthesis from stereochemically enriched or stereochemically pure starting materials, use of appropriate stereochemically enriched or stereochemically pure catalysts during synthesis, and / or by resolution of racemic or partially enriched stereo isomeric mixtures (e.g. via chiral chromatography).

[0077] As an example, in the case where the substituent R 2 is a 1,3-substituted cyclohexanol group. In this system, the relative (rel) stereochemistry of the alcohol and indazole groups on the ring can be cis or trans, and each of the cis or trans isomers will in turn exist in the form of two enantiomers reflecting the (R) or (S) configuration of the chiral center (i.e., the carbon attached to the hydroxyl and indazole groups). In certain cases described herein, the compounds will be referred to as isomers 1 and 2 of the compound having the relative (rel) stereochemical arrangement, so in the case of a compound referred to as rel-(1S,3R) it is to be understood that 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 a reference to the following compound having cis relative stereochemistry refers to the two possible compounds having this relative stereochemistry. Structures with known relative stereochemistry and undetermined absolute stereochemistry are depicted herein as single enantiomers “or enantiomer” with a defined symbol.

[0078]

[0079] As described herein and above, certain components of compounds having formula (I) are optionally substituted. As stated herein, the term "optionally substituted" means that structural elements of the compound may or may not be substituted by one or more specified optional substituents. In which groups Z, R... 3 R 4 R 5 R 6 R 7 R 8 and R 9 When one or more of the substituents are present, it is generally preferred that each substituent group has zero, one, or two substituents, for example, zero or one substituent. When two hydroxyl substituents are present, it should be understood that the two hydroxyl groups do not attach to the same carbon atom. When the optional substituent is F, it is preferred to have one, two, or three F substituents, and furthermore, when two or three substituents are present, they are directly bonded to the same carbon atom. These optional substituents can be used to modulate the physicochemical properties of the molecule, such as solubility, regulate metabolism, or, for example, further optimize the interaction with IRAK4 kinase relative to other kinases, thereby providing a more effective and selective IRAK4 kinase inhibitor.

[0080] As described above, in the first embodiment, this specification provides a compound having formula (A) or a pharmaceutically acceptable salt thereof.

[0081]

[0082] in:

[0083] R 1 Selected from

[0084]

[0085] R 2 Selected from

[0086]

[0087] R 3 and R 4 Each is independently selected from H, Me, Et, optionally substituted C1-C6 alkyl and optionally substituted C3-C6 cycloalkyl;

[0088] Y is N(Me)COMe, N(R) 5 )COMe、N(Me)COR 6 、N(R 5 )COR 6 CONMe2 or a 5-membered N-heterocyclic compound such as 1,2,3-triazole, and Z is H, Me, Et, or optionally substituted C1-C6 alkyl; or

[0089] Y and Z combine to form an optionally substituted 4-, 5-, or 6-membered ring;

[0090] X is selected from OR 7 and NR 8 R 9 ;

[0091] R 5 is selected from H, optionally substituted C1-C6alkyl, and optionally substituted C3-C6cycloalkyl;

[0092] R 6 is selected from optionally substituted C1-C6alkyl, optionally substituted C3-C6cycloalkyl, and optionally substituted 5- or 6-membered saturated N-heterocycle;

[0093] R 7 is Me, Et, i-propyl, n-propyl, cyclopropyl, cyclobutyl, optionally substituted C1-C6alkyl, C3-C6cycloalkyl, or a 4-, 5-, or 6-membered ring containing a heteroatom selected from O and N;

[0094] R 8 and R 9 are independently selected from H, Me, and optionally substituted C1-C6alkyl, or together form an optionally substituted C3-C6cycloalkyl or an optionally substituted 4-, 5-, or 6-membered ring containing an additional heteroatom selected from O and N;

[0095] wherein when present, Z, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from OH, C1-C3alkyl, C1-C3alkoxy, C(O)Me, amino, NHMe, NMe2, F, or Cl.

[0096] In embodiments, the compound of Formula (A) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0097]

[0098] wherein:

[0099] R 1 is selected from

[0100]

[0101] R 2 is selected from

[0102]

[0103] R 3 and R 4 are each independently selected from H, Me, Et, optionally substituted C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl;

[0104] Y is N(Me)COMe, N(R 5 )COMe, N(Me)COR 6 , N(R 5 )COR 6 , CONMe2, or a 5-membered N-heterocycle such as 1,2,3-triazole, and Z is H, Me, Et, and optionally substituted C1-C6 alkyl; or

[0105] Y and Z, in combination, form an optionally substituted 4-, 5-, or 6-membered ring;

[0106] X is selected from OR 7 and NR 8 R 9 ;

[0107] R 5 is selected from H, optionally substituted C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl;

[0108] R 6 is selected from optionally substituted C1-C6 alkyl, and optionally substituted C3-C6 cycloalkyl;

[0109] R 7 is Me, Et, isopropyl, n-propyl, cyclopropyl, cyclobutyl, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, or a 4-, 5-, or 6-membered ring containing a heteroatom selected from O and N;

[0110] R 8 and R 9 are independently selected from H, Me, and optionally substituted C1-C6 alkyl, or together form an optionally substituted C3-C6 cycloalkyl or an optionally substituted 4-, 5-, or 6-membered ring containing an additional heteroatom selected from O and N;

[0111] wherein when present, the optional substituents of Z, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from OH, C1-C3 alkyl, C1-C3 alkoxy, C(O)Me, amino, NHMe, NMe2, F, or Cl.

[0112] In embodiments, the compound of Formula (I) or Formula (A) is a compound of Formula (la) wherein the group R 2 is and the groups Y and Z combine to form a 4-, 5-, or 6-membered ring that is an optionally substituted 3-hydroxycyclobutyl, N-acylated azetidine, pyrrolidine-2-one, 1-alkylpyrrolidine-2-one, 3-alkyloxazolidine-2-one, 1-alkylpiperidine-2-one, or 3-alkyl-l,3-oxazinane-2-one ring.

[0113] In embodiments, the compound of Formula (I) or Formula (A) is a compound of Formula (lb) wherein the group R 2 is and the groups Y and Z combine to form a 4-, 5-, or 6-membered ring selected from 3-hydroxycyclobutyl, N-acetylazetidine, 1-methylpyrrolidine-2-one, 3-methyloxazolidine-2-one, 1-methylpiperidine-2-one, and 3-methyl-l,3-oxazinane-2-one.

[0114] In embodiments, the compound of Formula (I) or Formula (A) is a compound of Formula (lc) wherein the group R 2 is and the groups Y and Z combine to form a 4-, 5-, or 6-membered ring selected from

[0115]

[0116] wherein ★ represents the site of attachment to the cyclohexyl group, and R 10 is Me or C1-C6 alkyl optionally substituted with OH, C1-C3 alkoxy, C(O)Me, NH2, NHMe, NMe2, F, or Cl.

[0117] In embodiments, the compound of Formula (A) is a compound of Formula (Ac) wherein the group R 2 is and the groups Y and Z combine to form a 4-, 5-, or 6-membered ring that is wherein ★ represents the site of attachment to the cyclohexyl group, and R 10 is Me or C1-C6 alkyl optionally substituted with OH, C1-C3 alkoxy, C(O)Me, NH2, NHMe, NMe2, F, or Cl.

[0118] In embodiments, the compound of Formula (I) or Formula (A) is a compound of Formula (Id) wherein the group R 2 is Y is selected from N(Me)COMe, N(R 5 )COMe, N(Me)COR 6, N(R 5 )COR 6 and CONMe2and Z is H.

[0119] In embodiments, the compound of Formula (I) or Formula (A) is a compound of Formula (Ie), wherein the group R 2 is optionally wherein R 4 is H.

[0120] In embodiments, the compound of Formula (I) or Formula (A) is a compound of Formula (If), wherein the group R 2 is optionally wherein R 3 and R 0 are methyl.

[0121] In embodiments, the compound of Formula (If) is a compound of Formula (Ig), wherein the group R 2 is selected from

[0122]

[0123] In embodiments, the compound of Formula (If) is a compound of Formula (Ih), wherein the group R 2 is selected from

[0124]

[0125] In embodiments, the compound of Formula (If) is a compound of Formula (Ah), wherein the group R 2 is selected from

[0126]

[0127] In embodiments, the compound of Formula (I), for example the compound of any one of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), is a compound of Formula (Ii), wherein R 1 is

[0128] In embodiments, the compound of Formula (I), for example the compound of any one of Formula (Ac) or (Ah), is a compound of Formula (Ai), wherein R 1 is

[0129] In embodiments, the compound of Formula (I), for example the compound of any one of Formula (Ac) or (Ah), is a compound of Formula (Aj), wherein R ′ is

[0130] In embodiments, the compound of Formula (I), e.g., a compound of any one of Formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih), is a compound of Formula (Ij), wherein R 1 is

[0131] In embodiments, the compound of Formula (I), e.g., a compound of any one of Formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), or (Ij), is a compound of Formula (Ik), wherein X is OR 7 , optionally wherein R 7 is OMe.

[0132] In embodiments, the compound of Formula (I), e.g., a compound of any one of Formulae (Ac) or (Ah), is a compound of Formula (Ak), wherein X is OR 7 , optionally wherein R 7 is OMe. In embodiments, the compound of Formula (I), e.g., a compound of any one of Formulae (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), or (Ij), is a compound of Formula (II), wherein X is NR 8 R 9 .

[0133] In embodiments, the compound of Formula (I), e.g., a compound of any one of Formulae (Ac) or (Ah), is a compound of Formula (A), wherein X is NR 8 R 9 .

[0134] In embodiments, the compound of Formula (A) is selected from:

[0135] N-(Imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-l-methyl-2-oxo-l- azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide;

[0136] N-(Imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((5s,8s)-l-methyl-2-oxo-l- azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide;

[0137] 2-((ls,4s)-4-(Dimethylcarbamoyl)cyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide;

[0138] 2-((1r,4r)-4-(dimethylcarbamoyl)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide;

[0139] 2-(2-hydroxy-2-methylspiro[3.5]non-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy- 2H-indazole-5-carboxamide - Isomer 1 or Isomer 2;

[0140] 2-((1s,4s)-4-hydroxycyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H- indazole-5-carboxamide;

[0141] 2-((1r,4r)-4-hydroxycyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H- indazole-5-carboxamide;

[0142] 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;

[0143] 6-methoxy-2-(1-methyl-2-oxo-1-azaspiro[4.5]dec-8-yl)-N-(pyrazolo[1,5-a]pyrimidin-3- yl)-2H-indazole-5-carboxamide - Isomer 1 or Isomer 2;

[0144] 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;

[0145] 6-cyclopropoxy-2-(2-hydroxy-2-methylspiro[3.5]non-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3- yl)-2H-indazole-5-carboxamide - Isomer 1 or Isomer 2;

[0146] 6-cyclopropoxy-2-((1R,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H- indazole-5-carboxamide;

[0147] 6-cyclopropoxy-2-((1S,3R)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H- indazole-5-carboxamide;

[0148] rel-6-cyclopropoxy-2-((1 S,3 S)-3-hydroxycyclohexyl)-N-(pyrazolo[1,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - isomer 1 or isomer 2;

[0149] 2-(2-acetyl-2-azaspiro[3.5]non-7-yl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy- 2H-indazole-5-carboxamide;

[0150] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1 s,4s)-4-(N-methylacetamido)cyclohexyl)- 2H-indazole-5-carboxamide;

[0151] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1 r,4r)-4-(N-methylacetamido)cyclohexyl)- 2H-indazole-5-carboxamide;

[0152] 6-methoxy-2-((1 s,4s)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3- yl)-2H-indazole-5-carboxamide;

[0153] 6-methoxy-2-((1 r,4r)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3- yl)-2H-indazole-5-carboxamide;

[0154] 2-((1 r,4r)-4-(cyclopropanecarboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin- 3-yl)-2H-indazole-5-carboxamide;

[0155] 2-((1 s,4s)-4-(cyclopropanecarboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin- 3-yl)-2H-indazole-5-carboxamide;

[0156] rel-2-((6R,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]non-7-yl)-6-cyclopropoxy-N-(pyrazolo[1,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - isomer 1 or isomer 2;

[0157] rel-2-((6S,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]non-7-yl)-6-cyclopropoxy-N-(pyrazolo[1,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - isomer 1 or isomer 2;

[0158] 6-cyclopropoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide;

[0159] 6-cyclopropoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide;

[0160] 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;

[0161] 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;

[0162] 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;

[0163] 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;

[0164] 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;

[0165] 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;

[0166] 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;

[0167] 2-(4-hydroxy-4-methylcyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5- carboxamide - Isomer 1 or Isomer 2;

[0168] rel-2-((lS,3R)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)- 2H-indazole-5-carboxamide - Isomer 1 or Isomer 2;

[0169] rel-2-((lS,3S)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)- 2H-indazole-5-carboxamide - Isomer 1 or Isomer 2;

[0170] rel-6-cyclopropyloxy-2-((lS,3R)-3-hydroxy-3-methylcyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3- yl)-2H-indazole-5-carboxamide - Isomer 1 or Isomer 2;

[0171] 6-cyclopropyloxy-2-((ls,4s)-4-hydroxycyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H- indazole-5-carboxamide;

[0172] 6-cyclopropyloxy-2-((lr,4r)-4-hydroxycyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H- indazole-5-carboxamide;

[0173] 2-((lR,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N- (pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide;

[0174] 2-((lS,4r)-4-((S)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N- (pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide;

[0175] 6-methoxy-2-((lR,2R,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 or Isomer 2;

[0176] 6-methoxy-2-((lS,2S,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 or Isomer 2;

[0177] rel-2-((6S,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[l,2- b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide - Isomer 1 or Isomer 2:

[0178] rel-2-((6R,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[l,2- b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide - Isomer 1 or Isomer 2;

[0179] N-(imidazo[l,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;

[0180] N-(imidazo[l,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;

[0181] rel-2-((7R,8R)-2,7-dimethyl-3-oxo-2-azaspiro[4.5]decan-8-yl)-N-(imidazo[l,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[l,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide - Isomer 1, 2, 3 or 4;

[0182] N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-(l-methyl-2-oxo-3-oxa-l- azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide - Isomer 1 or Isomer 2;

[0183] rel-2-((lR,3R,4S)-4-hydroxy-3-methylcyclohexyl)-N-(imidazo[l,2-b]pyridazin-3- yl)-6-methoxy-2H-indazole-5-carboxamide - Isomer 1 or Isomer 2;

[0184] rel-2-((lS,3R,4S)-4-hydroxy-3-methylcyclohexyl)-N-(imidazo[l,2-b]pyridazin-3- yl)-6-methoxy-2H-indazole-5-carboxamide - Isomer 1 or Isomer 2;

[0185] rel-2-((1S,3S,4S)-4-hydroxy-3-methylcyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)- 6-methoxy-2H-indazole-5-carboxamide - isomer 1 or isomer 2;

[0186] rel-2-((1R,3S,4S)-4-hydroxy-3-methylcyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)- 6-methoxy-2H-indazole-5-carboxamide - isomer 1 or isomer 2;

[0187] 6-cyclopropoxy-2-((1 r,4r)-4-hydroxycyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)- 2H-indazole-5-carboxamide;

[0188] 6-cyclopropoxy-2-((1 s,4s)-4-hydroxycyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)- 2H-indazole-5-carboxamide;

[0189] 6-methoxy-2-((5r,8r)-2-methyl-3-oxo-2-azaspiro[4.5]dec-8-yl)-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide;

[0190] 6-methoxy-2-((5s,8s)-2-methyl-3-oxo-2-azaspiro[4.5]dec-8-yl)-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide;

[0191] 2-((1R,2R,4S)-4-hydroxy-2-methylcyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide;

[0192] 2-((1R,2R,4R)-4-hydroxy-2-methylcyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide;

[0193] 2-((1S,2S,4R)-4-hydroxy-2-methylcyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide;

[0194] 2-((1S,2S,4S)-4-hydroxy-2-methylcyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide;

[0195] 2-((1R,2R,4S)-4-hydroxy-2,4-dimethylcyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide;

[0196] 2-((1R,2R,4S)-4-hydroxy-2,4-dimethylcyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide;

[0197] 2-((1S,4r)-4-((S)-2-hydroxy-N-methylpropanamido)cyclohexyl)-N-(imidazo[l,2-b]pyridazin-3- yl)-6-methoxy-2H-indazole-5-carboxamide;

[0198] 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-N-(imidazo[l,2-b]pyridazin-3- yl)-6-methoxy-2H-indazole-5-carboxamide;

[0199] 6-methoxy-2-((1r,4r)-4-(N-methylcyclopropanecarboxamido)cyclohexyl)-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide;

[0200] 2-((1R,4r)-4-((1r,3R)-3-hydroxy-N-methylcyclobutane-1-carboxamido)cyclohexyl)-6-methoxy- N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide;

[0201] 2-((1R,4r)-4-((1s,3S)-3-hydroxy-N-methylcyclobutane-1-carboxamido)cyclohexyl)-6-methoxy- N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide;

[0202] 2-((1r,4r)-4-(2-hydroxy-N,2-dimethylpropanamido)cyclohexyl)-6-methoxy-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide;

[0203] 2-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6-((1r,3r)-3- methoxycyclobutoxy)-2H-indazole-5-carboxamide;

[0204] 2-((1 r,4r)-4-(1 H-1,2,3-triazol-1 -yl)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide;

[0205] 2-((1 r,4r)-4-(1 H-1,2,3-triazol-1 -yl)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide;

[0206] 2-((1 r,4r)-4-(1 H-1,2,3-triazol-1 -yl)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide

[0207] rel-2-((1 S,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;

[0208] rel-2-((1 S,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;

[0209] rel-2-((1 S,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;

[0210] 2-((1 S,4r)-4-((S)-3-hydroxy-N-methylbutanamido)cyclohexyl)-6-methoxy-N- (pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide;

[0211] 2-((1 S,4r)-4-((S)-3-hydroxy-N-methylbutanamido)cyclohexyl)-6-methoxy-N- (pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide;

[0212] rel-2-((1 R,4r)-4-((1 R,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;

[0213] 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;

[0214] 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;

[0215] 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;

[0216] 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;

[0217] rel-2-((5R, 7R, 8R)-1,7-dimethyl-2-oxo-1 -azaspiro[4.5]dec-8-yl)-N-(imidazo[1,2- b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide - Isomer 1 or Isomer 2 and

[0218] rel-2-((5S, 7R, 8R)-1,7-dimethyl-2-oxo-1 -azaspiro[4.5]dec-8-yl)-N-(imidazo[1,2- b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide - Isomer 1 or Isomer 2

[0219] or pharmaceutically acceptable salts thereof.

[0220] The IRAK4 inhibitors of the present application can be prepared from readily available starting materials, available from commercial suppliers such as Merck KGaA or obtained by methods included in the general knowledge of a person skilled in the art. The following reaction schemes describe various methods for the synthesis of IRAK4 inhibitors. Typical or preferred reaction conditions for the synthesis can be given, but a person skilled in the art will be able to propose modifications of these conditions to obtain analogs not described herein. The schemes presented below are thus representative methods for the synthesis of the compounds of the present specification and they should not be interpreted as limiting the scope of the present specification in any way. Furthermore, the reaction sequences can be modified to change the overall synthesis in order to allow variations at different positions of the molecule at different stages of the synthesis.

[0221] The knowledgeable reader will recognize that the compounds described in the following schemes can in some cases be obtained as mixtures of regioisomers and stereoisomers, which can be separated at different stages of the synthesis using techniques well known to those skilled in the art such as silica gel / C18 chromatography, HPLC, SFC, crystallization, and the like.

[0222] General synthesis of the backbones / building blocks:

[0223] Scheme 1: Synthesis of backbones I-6 with Hal = halide.

[0224]

[0225] The backbones I-6 as shown in Scheme 1 can be prepared from the commercially available 2,4-difluorobenzaldehyde (I-l). I-l can be treated with standard nitration conditions, for example using a mixture of concentrated sulfuric acid and concentrated nitric acid or a mixed nitration using concentrated sulfuric acid and potassium nitrate as described in, for example, WO 2017 / 009798, to give the nitro compound I-2. Treatment of I-2 with cyclopropanol in the presence of a base (for example, DIPEA) and a suitable solvent (for example, DMF) at elevated temperature forms the isopropyl ether I-3. The indazole I-4 can be obtained from I-3 by its reaction with hydrazine in a suitable solvent at elevated temperature (for example, 80 °C). Subsequently, the aromatic amine I-5 can 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, Pd on carbon (or Pd(OH)2on carbon) in MeOH under H2atmosphere can be used). The amine I-5 can be converted to the corresponding bromide I-6 (Hal = Br) by, for example, treatment with tert-butylnitrite and copper(I) bromide in a suitable solvent (for example, acetonitrile). Protection of the indazole NH of I-4 with, for example, a PMB protecting group prior to the nitro reduction followed by deprotection after introduction of the bromide increases the yield of these transformations. The amine I-5 can be converted to the corresponding iodide I-6 (Hal = I) by, for example, treatment with sodium nitrite and potassium iodide in water / acetic acid.

[0226] Scheme 2: General synthesis of building block II-4 with R 1 and R 7 = -Me or -cyclopropyl as defined in the claims.

[0227]

[0228] Halide II-1 (Hal = Br or I) can be used as a starting material for the synthesis of building unit II-4, as described in Scheme 2. Halide II-1 is commercially available or can be obtained using the steps described in Scheme 1 above. The synthesis is carried out in the presence of an alcohol as a solvent under a CO atmosphere (optionally in…). and With the aid of an in-situ catalyst (e.g., Pd(dppf)Cl2), II-1 is treated to produce ester II-2 (shown here as a methyl ester when MeOH is used as the solvent). The ester is then cleaved in a suitable solvent (e.g., water) with, for example, lithium hydroxide or potassium hydroxide to produce carboxylic acid II-3. The ester is then further cleaved with amine R... 1 The amide formation of this acid II-3 by -NH2 can be carried out with various amide coupling agents (e.g., HATU) in the presence of a base (e.g., DIPEA) and DMF and / or THF as a solvent to produce the desired building block II-4.

[0229] The conversion of halide II-1 to amide II-4 can also be carried out in a one-step manner using an amino carbonylation reaction. This can be achieved using a base (e.g., TEA) and an amine R... 1 In the presence of -NH2, under a CO atmosphere (optionally generated in situ), in a solvent (e.g., CH3CN), with stirring of II-1 (Hal = Br or I) with a Pd source (e.g., Pd(OAc)2) and a suitable ligand (e.g., 1,3-bis(diphenylphosphine)propane), amide II-4 is obtained in one step by stirring II-1 (Hal = Br or I).

[0230] Option 3: Use the following substances to universally synthesize and construct unit III-2: Hal = halide (Br, I); R = R 2 (as defined in the claims) or R as defined below 2 Protective precursor; R 7 =-Me or -cyclopropyl, etc.

[0231]

[0232] The indazole III-2 shown in Scheme 3 can be produced by using a base (e.g., K2CO3, Cs2CO3, NaHCO3, NaOH, KOH, Na) in a suitable solvent (e.g., DMF, THF, dioxane, xylene, MeCN). t OBu、K t OBu, KOEt, KHMDS, DIPEA, pyridine, TEA) and R 2 The alkylating agent RY (e.g., methanesulfonate, toluenesulfonate, or halide) is treated at high temperature to obtain compound III-1 (commercially available or obtained by the synthesis shown in Scheme 1 above). Alternatively, alkylation can be achieved by reacting compound III-1 with R 2The reaction proceeds via the Michael reaction of α,β-unsaturated carbonyl precursors. In R... 2 If the functional group contains a component that requires protection by a suitable protecting group for use in this synthetic step, R should be used. 2 A suitable protected precursor. Furthermore, the alkylation reaction as shown in Scheme 3 can be carried out using a suitable precursor of R2, which can later be converted to R in the synthesis toward the target compound. 2 For example, if R 2 If the amine contains an amine or amide functional group, the amine can be protected in the alkylating agent with a suitable protecting group (e.g., Boc), which is cleaved after the alkylation reaction. Subsequently, the amine can be alkylated or converted to an amide. If R 2 If an alcohol functional group is present, this functional group can be protected with a suitable alcohol protecting group that withstands the reaction conditions of the alkylation reaction and is cleaved in a subsequent stage of 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 PGMWuts, Wiley, NY 2014, 5th edition). Alternatively, the alkylating agent may contain a precursor with an 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 in a subsequent stage of synthesis using synthetic methods known to those skilled in the art.

[0233] Based on the reaction conditions used in the alkylation reaction described above, a mixture of N1 and N2-regioisomers can be obtained. The N1 isomer can be separated from the N2 isomer immediately after the alkylation reaction described above or in a subsequent stage during the synthesis of the target compound by, for example, column chromatography.

[0234] Option 4: Use the following substances to universally synthesize building blocks IV-2 and IV-7: R = R 2 (Precursors as defined in the claims or as suitably protected as described in Scheme 3; R7 = -Me, -cyclopropyl, etc.)

[0235]

[0236] Scheme 4 describes the regioselective synthesis of the N-2 indazole isomers IV-2 and IV-7. A commercially available starting material IV-1 for the synthesis of IV-2 is treated with an amine R-NH2 at high temperature in a suitable solvent (e.g., iPrOH), followed by the addition of tri-n-butylphosphine to form IV-2. The starting material IV-3 for the synthesis of IV-7 is a commercially available (IV-3, R-NH2) 7= Me, CAS 586412-86-4), or can be obtained as shown in the synthetic sequence outlined in Scheme 1 (for R 7 = cyclopropyl). Treatment of benzaldehyde IV-3 with an amine R-NH2in a suitable solvent (e.g., EtOH) to form the corresponding imine, followed by stirring of the crude imine IV-4 with sodium azide in a suitable solvent (e.g., DMF) yields the bicyclic intermediate IV-5. Reduction of the nitro group of IV-5 (under H2atmosphere with e.g., Pd(OH)2on carbon) yields the aromatic amine IV-6. Subsequent treatment of IV-6 with e.g., sodium nitrite and potassium iodide in acetic acid yields the corresponding iodo compound IV-7.

[0237] General synthesis of compounds of Formula (I):

[0238] Scheme 5: General synthesis of compounds of Formula (I), Method 1:

[0239]

[0240] Compounds of Formula (I) can be prepared from compound II-4 as shown in Scheme 5 (R 7 = -Me, -cyclopropyl, and the like; R 1 is as defined in the claims). The reaction sequence to prepare compound II-4 is shown in Scheme 2.

[0241] Indazoles II-4 can be alkylated by treatment with a base (e.g., KOH, KHMDS, Cs2CO3) and a suitable alkylating reagent R-Y (Y = mesylate, tosylate, halide, R = R 2 or R 2 as defined above in Scheme 3) in a base-compatible solvent. In the case where R-Y (where R = R 2 is used in the alkylation reaction, the steps described in Scheme 3 can be carried out after alkylation to convert R to R 2 of the target compound.

[0242] Depending on the reaction conditions used in the alkylation reactions described above, mixtures of N1 and N2-regioisomers can be obtained. The N1 isomer can be separated from the N2 isomer by e.g., column chromatography to obtain compounds of Formula (I).

[0243] Scheme 6: General synthesis of compounds of Formula (I), Method 2:

[0244]

[0245] Another method for preparing compounds of Formula (I) is shown in Scheme 6. Suitable starting materials for this approach are indazoles III-2 (Hal = halide (Br, I); R = R 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 first be treated with a Pd catalyst (e.g., Pd(dppf)Cl2) in the presence of an alcohol as solvent under a CO atmosphere (at high pressure) to yield ester VI-1 (Me-ester VI-1 is formed if MeOH is used as solvent). Subsequent cleavage of the ester in a suitable solvent (e.g., water) by, for example, lithium hydroxide or potassium hydroxide yields carboxylic acid VI-2. Amide formation of this acid VI-2 with an amine R 1 -NH2(R 1 as defined in the claims) can be performed with various amide coupling reagents (e.g., HATU, T3P) to yield the desired compound of Formula (I).

[0246] If the reaction sequence shown in Scheme 6 is started with a compound III-2 (R = R 2 , a protected precursor thereof), the conversion of R to R 2 (as described in Scheme 3) can be performed at different stages of the synthetic sequence shown in Scheme 6, depending on the nature of the conversion and the compatibility of the functional groups present in the sequence of intermediates with the reaction conditions (one skilled in the art will be able to decide the order of the steps).

[0247] The conversion of halide III-2 (R = R 2 ) to a compound of Formula (I) can also be performed in a one-pot aminocarbonylation sequence. Stirring III-2 (R = R 1 -NH2in the presence of a base (e.g., TEA) and a coupling amine R 2 in a solvent (e.g., CH3CN) with a Pd source (e.g., Pd(OAc)2) and a suitable ligand (e.g., 1,3-bis(diphenylphosphino)propane or di(adamant-1-yl)butylphosphane) under a CO atmosphere (at high pressure) yields a compound of Formula (I) in one step.

[0248] If the aminocarbonylation reaction is performed with a suitable protected precursor of compound III-2 (R = R 2 , the conversion of R to R 2 (as described in Scheme 3) can be performed after the aminocarbonylation reaction shown in Scheme 6 to yield a compound of Formula (I).

[0249] Scheme 7: General synthesis of compounds of Formula (I), Method 3:

[0250]

[0251] Scheme 7 illustrates changing the substituent R later in the synthesis 7 with an alkylating agent R 7 -Y (e.g., mesylate, tosylate, or halide) or alcohol R 7 -OH to yield a compound of Formula (I).

[0252] In the Examples of the present specification, methods of synthesizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, intermediates in the synthesis of a compound of Formula (I), e.g., the methods and intermediates described herein and above, are provided.

[0253] In an embodiment, a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient is provided. In such embodiments, the compound of Formula (i) is preferably used as a single enantiomeric form. A small amount of impurities, e.g., up to 1% by mass of other stereoisomeric forms, can optionally be present. These pharmaceutical compositions can be used to treat conditions in which an IRAK4 kinase inhibitor can be beneficial, as described in more detail herein and above.

[0254] In an embodiment, a compound of Formula (I) for use in the production of a medicament, optionally wherein the medicament is for the treatment or prevention of a condition in which an IRAK4 kinase inhibitor can be beneficial, as described in more detail herein and above, is provided.

[0255] Compounds of Formula (I) and pharmaceutically acceptable salts thereof can be prepared, used or provided in amorphous form, crystalline form, or semi-crystalline form and any given compound of Formula (I) and pharmaceutically acceptable salt thereof can be capable of forming more than one crystal and / or polymorphic form, including hydrated (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, or other stoichiometric hydrate) and / or solvated forms. It is understood that the present specification encompasses any and all such solid forms of compounds of Formula (I) and pharmaceutically acceptable salts thereof.

[0256] In further embodiments of the present specification, a compound of Formula (I) is provided, obtainable by the methods described in the ‘Examples’ section below.

[0257] This specification is intended to include all isotopes of atoms occurring in the compounds of this application. Isotopes are atoms having the same atomic number but different mass numbers. By way of general example, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include 13 C and 14 C. 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 using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0258] A suitable pharmaceutically acceptable salt of a compound of Formula (I) can be, for example, an acid addition salt. A suitable pharmaceutically acceptable salt of a compound of Formula (I) can be, for example, an acid addition salt of a compound of Formula (I), for example, with an inorganic or organic acid. The compounds in this specification can be provided as free base compounds (i.e. in a non-salted state).

[0259] Another suitable pharmaceutically acceptable salt of a compound of Formula (I) can be, for example, a salt that forms upon administration of a compound of Formula (I) to the human or animal body and which then forms in the human or animal body.

[0260] A compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be prepared as a co-crystal solid form. It will be appreciated that pharmaceutically acceptable co-crystals of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, form an aspect of the present specification.

[0261] For use in a pharmaceutical context, it can be preferred to provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the absence of substantial amounts of other stereoisomeric forms.

[0262] A compound of Formula (I), or a pharmaceutically acceptable salt thereof, will generally be administered via the oral route, but administration by parenteral, intravenous, intramuscular, subcutaneous or other injectable means, buccal, rectal, vaginal, transdermal and / or nasal routes and / or via inhalation in the form of a pharmaceutical formulation containing the active ingredient or a pharmaceutically acceptable salt thereof or a solvate or such salt of a solvate, in a pharmaceutically acceptable dosage form, is also possible. Depending on the disorder and patient to be treated and the route of administration, these compositions can be administered in varying doses, for example, in oral doses from 1 mg to 1,000 mg or from 100 mg to 2,000 mg.

[0263] The pharmaceutical formulations of a compound of Formula (I) described above can be prepared, for example, for parenteral, subcutaneous, intramuscular or intravenous administration.

[0264] The pharmaceutical formulations of the compounds of Formula (I) described above can be conveniently presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy, for example as described in Remington's Pharmaceutical Sciences, 17th Ed., Mack Publishing Company, Easton, PA. (1985).

[0265] Pharmaceutical formulations adapted for oral administration can be presented as solid or liquid forms. Tablets and capsules can be prepared with the following: binders; fillers; lubricants; and surface active or dispersing agents. Liquid compositions can contain conventional additives such as suspending agents; emulsifying agents; and preservatives. Liquid compositions can be encapsulated in, for example, gelatin to provide unit dosage forms. Solid oral dosage forms include tablets, two-piece hard shell capsules, and soft elastic gelatin (SEG) capsules. Exemplary oral compositions according to the present description comprise 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.

[0266] According to another embodiment, there is provided a compound of Formula (I) as defined above or a pharmaceutically acceptable salt thereof, for use as a medicament in a warm-blooded animal such as a human.

[0267] According to another embodiment, there is provided a compound of Formula (I) as defined above or a pharmaceutically acceptable salt thereof, for use in the production of an anti-proliferative effect in a warm-blooded animal such as a human.

[0268] According to another embodiment, there is provided a compound of Formula (I) as defined above or a pharmaceutically acceptable salt thereof, for use as an anti-invasive agent for inhibiting and / or treating a solid tumor disease in a warm-blooded animal such as a human.

[0269] According to another embodiment, there is provided the use of a compound of Formula (I) as defined above or a pharmaceutically acceptable salt thereof for the production of an anti-proliferative effect in a warm-blooded animal such as a human.

[0270] According to another embodiment, there is provided the use of a compound of Formula (I) as defined above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use as an anti-invasive agent for inhibiting and / or treating a solid tumor disease in a warm-blooded animal such as a human.

[0271] In embodiments wherein the compound of Formula (I) is used to treat a disorder characterized by a hyperproliferative disease or a solid tumor disease and related methods of treatment and for the manufacture of a medicament intended to treat such diseases, it is understood that in preferred embodiments the disease is melanoma and further that the use in combination with a Bruton's tyrosine kinase inhibitor is preferred.

[0272] In the present specification, the phrase "effective amount" means, unless otherwise indicated, an amount of a compound or composition sufficient to significantly and positively alter the symptoms and / or condition to be treated (e.g., to provide a positive clinical response). An effective amount of an active ingredient in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being utilized, the particular pharmaceutical excipient(s) / carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician. An effective amount is typically in the range of 0.1 mg to 1,000 mg.

[0273] According to another embodiment, there is provided a compound of Formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in providing an inhibitory effect on IRAK4 kinase.

[0274] According to another embodiment, there is provided the use of a compound of Formula (I) as defined above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for providing an inhibitory effect on IRAK4 kinase.

[0275] According to another embodiment, there is also provided a method for providing an inhibitory effect on IRAK4 kinase comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[0276] According to another embodiment, there is provided a compound of Formula (I) as defined above or a pharmaceutically acceptable salt thereof for use in providing a selective inhibitory effect on IRAK4 kinase. In such cases, a selective inhibitory effect indicates that the concentration of the compound of Formula (I) required to achieve 50% inhibition of IRAK4 kinase activity in vitro is less than 10-fold, 100-fold or 1000-fold or less than the concentration required to achieve 50% inhibition of another kinase (e.g., another kinase whose inhibition results in toxic side effects).

[0277] According to another embodiment, there is provided the use of a compound of Formula (I) as defined above or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for providing a selective inhibitory effect on IRAK4 kinase.

[0278] According to another embodiment, there is also provided a method for providing a 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.

[0279] Described herein are compounds that can inhibit IRAK4 kinase. In biochemical and cell-based assays, the compounds of the present description show to be potent IRAK4 kinase inhibitors and are therefore useful in the treatment of disorders mediated by IRAK4 kinase activity, particularly in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), inflammatory diseases and autoinflammatory / autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjogren’s syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis, and psoriasis.

[0280] In embodiments, there is provided use of a compound of Formula (I) for the treatment of respiratory diseases, optionally wherein the respiratory disease is asthma and chronic obstructive pulmonary disease (COPD).

[0281] In embodiments, there is provided use of a compound of Formula (I) for the treatment of inflammatory diseases or autoinflammatory / autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjogren’s syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis, and psoriasis.

[0282] In embodiments, there is provided a method of treatment comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), wherein the patient has a respiratory disease, optionally wherein the respiratory disease is asthma and chronic obstructive pulmonary disease (COPD).

[0283] In embodiments, there is provided a method of treatment comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), wherein the patient has a respiratory disease, optionally wherein the respiratory disease is asthma and chronic obstructive pulmonary disease (COPD).

[0284] According to another aspect of the present description, there is provided use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament for the treatment of disorders mediated by IRAK4 kinase activity, particularly for the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), inflammatory diseases and autoinflammatory / autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjogren’s syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis, and psoriasis.

[0285] It should be appreciated that the following examples are provided to more fully demonstrate the nature of the application. It should also be appreciated that the following examples are not intended to limit the scope of the description in any way.

[0286] Examples

[0287] The following abbreviations are used:

[0288]

[0289]

[0290]

[0291] If not defined above, abbreviations used in analyzing data are consistent with common usage in the art (see J Med Chem Standard Abbreviations and Acronyms http: / / pubsapp.acs.org / paragoplus / submission / jmcmar / jmcmar_abbrevtions.pdf ?

[0292] The compound names provided below were generated using PerkinElmer ChemDraw Professional, Version 20.0.2.51. In cases where there is uncertainty regarding absolute stereochemistry, relative stereochemistry is specified where possible.

[0293] Preparation of intermediates

[0294] Synthesis of intermediate Int I-1 : 5-bromo-4-methoxy-2-nitrobenzaldehyde

[0295] 5-bromo-4-fluoro-2-nitrobenzaldehyde

[0296]

[0297] 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 d. 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-), [M-H] - 245 / 247.

[0298] 5-bromo-4-methoxy-2-nitrobenzaldehyde (Int I-1 )

[0299]

[0300] 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), the formed solid was filtered off and washed with water (100 mL) to give 5-bromo-4-methoxy-2-nitrobenzaldehyde (6.6 g, 63%) as a light yellow solid. 1 H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.15 (s, 1H), 7.78 (s, 1H), 4.04 (s, 3H).

[0301] Synthesis of intermediate Int I-2: 6-cyclopropoxy-5-nitro-lH-indazole

[0302] 2,4-difluoro-5-nitrobenzaldehyde

[0303]

[0304] 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) at 0 °C under N2atmosphere over a period of 1 h. The reaction mixture was stirred at rt for an additional 3 h, after which the mixture was poured on ice / water and extracted with EtOAc (400 mL x 3). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure to give 2,4-difluoro-5-nitrobenzaldehyde (50.0 g, 76%) as a yellow oil.

[0305] 4-cyclopropoxy-2-fluoro-5-nitrobenzaldehyde

[0306]

[0307] A mixture of 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) was stirred at 100 °C for 2 h. The reaction mixture was allowed to cool to rt, poured into ice / water (750 mL) and extracted with EtOAc (350 mL). The organic layer was dried over Na2SO4, 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] + .

[0308] 6-cyclopropoxy-5-nitro-lH-indazole (Int I-2)

[0309]

[0310] To a suspension of 6-cyclopropoxy-5-nitro-lH-indazole (Int I-2) (35.0 g, 159.7 mmol) and NH4CI (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 concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EtOAc (2:1) to give 6-cyclopropoxy-lH-indazol-5-amine (15.3 g, 51%) as a red solid. MS ESI, m / z = 190 [M+H] + .

[0311] Synthesis of intermediate Int I-3: 6-cyclopropoxy-5-iodo-lH-indazole

[0312] 6-cyclopropoxy-lH-indazol-5-amine

[0313]

[0314] To a suspension of 6-cyclopropoxy-5-nitro-lH-indazole (Int I-2) (35.0 g, 159.7 mmol) and NH4CI (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 concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EtOAc (2:1) to give 6-cyclopropoxy-lH-indazol-5-amine (15.3 g, 51%) as a red solid. MS ESI, m / z = 190 [M+H]+ .

[0315] 6-cyclopropoxy-5-iodo-lH-indazole (Int I-3)

[0316]

[0317] To a solution of 6-cyclopropoxy-lH-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. Then 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 Na2S04, 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-lH-indazole (4.0 g, 50%) as a red solid. 1 H NMR (300 MHz, 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] + .

[0318] Synthesis of intermediate Int I-4: 5-bromo-6-cyclopropoxy-lH-indazole

[0319] 6-cyclopropoxy-l-(4-methoxybenzyl)-5-nitro-lH-indazole

[0320]

[0321] 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 x 400 mL). The organic layer was dried over Na2S04, 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 as a red solid (6.0 g, 55%). MS ESI, m / z = 340 [M+H] + .

[0322] 6-cyclopropoxy-1-(4-methoxybenzyl)-1H-indazol-5-amine

[0323]

[0324] Iron (4.9 g, 88.4 mmol) was added to NH4CI (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 as a red gum (4.8 g, 88%). MS ESI, m / z = 310 [M+H] + .

[0325] 5-bromo-6-cyclopropoxy-1-(4-methoxybenzyl)-1H-indazole

[0326]

[0327] Copper bromide (464 mg, 3.2 mmol) was added to tert-butylnitrite (333 mg, 3.2 mmol) and 6-cyclopropoxy-1-(4-methoxybenzyl)-1H-indazol-5-amine (500 mg, 1.6 mmol) in MeCN (5 mL) at 16 °C under N2atmosphere over a period of 20 min. The resulting mixture was stirred at 50 °C for 0.5 h. The mixture was cooled to rt, then poured into water (400 mL) and extracted with EtOAc (2 x 400 mL). The organic phase was dried over Na2SO4, 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 light yellow solid. MS ESI, m / z = 373 / 375 [M+H] + .

[0328] 5-bromo-6-cyclopropoxy-1H-indazole (Int I-4)

[0329]

[0330] 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 flash chromatography eluting with 0% to 100% MeCN in water (5% NH4OH) to give 5-bromo-6-cyclopropoxy-1H-indazole (156 mg, 58%) as a grey solid. 1 H NMR (300 MHz, 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] + .

[0331] Synthesis of intermediate Int I-5: pyrazolo[1,5-a]pyrimidin-3-amine

[0332]

[0333] NH3aq (25%) (34.9 mL, 403.0 mmol) was added to a solution of pyrazolo[l,5- a]pyrimidine-3-amine (20.0 g, 80.6 mmol) as its TFA salt in EtOH (300 mL). The resulting mixture was stirred at rt for 2 h, after which 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[l,5-a]pyrimidine-3-amine as an orange solid (9.9 g, 92%). MS ESI, m / z = 135 [M+H] + .

[0334] Synthesis of intermediate Int II-1 : N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy- lH-indazole-5-carboxamide

[0335]

[0336] Pd(OAc)2(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-lH-indazole (2.0 g, 8.8 mmol) and imidazo[l,2-b]pyridazin-3-amine (1.3 g, 9.7 mmol) in degassed MeCN (30 mL). The resulting mixture was stirred at 100 °C under a CO atmosphere at 4 bar for 23 h. After cooling the mixture to rt, the formed precipitate was collected by filtration, washed with MeCN (2 mL) and dried under vacuum to give N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-lH-indazole-5-carboxamide as a grey solid (2.4 g, 87%) which was used without further purification. 1 H NMR (500 MHz, 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.

[0337] Synthesis of intermediate Int II-2: 6-methoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)- lH-indazole-5-carboxamide

[0338] 6-methoxy-lH-indazole-5-carboxylic acid methyl ester

[0339]

[0340] A solution of Pd(dppf)Cl2(9.7 g, 13.2 mmol), DIPEA (77 mL, 440.4 mmol) and 5-bromo-6-methoxy-lH-indazole (20.0 g, 88 mmol) in MeOH (500 mL) was stirred under a CO atmosphere at 15 atm and at 110 °C for 12 h. After cooling the mixture to rt, the reaction mixture was filtered through silica and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography eluting with 0% to 30% EtOAc in PE to give 6-methoxy-lH-indazole-5-carboxylic acid methyl ester (8.0 g, 44%) as a brown solid. m / z (ESI+), [M+H] 207. + = 207.

[0341] 6-methoxy-lH-indazole-5-carboxylic acid

[0342]

[0343] LiOH (732 mg, 30.5 mmol) in water (5 mL) was added to 6-methoxy-lH-indazole-5- carboxylic acid methyl ester (2.1 g, 10.2 mmol) in MeOH (5 mL) at rt under a N2atmosphere. The reaction mixture was stirred at rt for 3 h and then acidified with aqueous HC1 (0.1 M). The precipitate formed was collected by filtration, washed with MeOH and dried under vacuum to give 6-methoxy-lH-indazole-5-carboxylic acid (1.6 g, 80%) as a grey solid which was used without further purification. m / z (ESI+), [M+H] 193. + = 193.

[0344] 6-methoxy-lH-indazole-5-carboxylic acid methyl ester (2.1 g, 10.2 mmol) in MeOH (5 mL) at rt under a N2atmosphere. The reaction mixture was stirred at rt for 3 h and then acidified with aqueous HC1 (0.1 M). The precipitate formed was collected by filtration, washed with MeOH and dried under vacuum to give 6-methoxy-lH-indazole-5-carboxylic acid (1.6 g, 80%) as a grey solid which was used without further purification. m / z (ESI+), [M+H] 193.

[0345]

[0346] Pyrazolo[l,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-lH-indazole-5-carboxylic acid (8.0 g, 42.0 mmol) in THF (20 mL) at rt under N2atmosphere. The resulting solution was stirred for 2 h. The reaction mixture was poured into water (20 mL) and the formed solid was collected by filtration, washed with water (100 mL) and dried under vacuum to give 6-methoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-lH-indazole-5- carboxamide as a yellow solid (10.0 g) which was used without further purification. 1 H NMR (300 MHz, 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.

[0347] Synthesis of intermediate Int II-3: 6-cyclopropoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-lH-indazole-5-carboxamide

[0348] 6-cyclopropoxy-lH-indazole-5-carboxylic acid methyl ester

[0349]

[0350] A suspension of 5-bromo-6-cyclopropoxy-lH-indazole (Int I-4) (5.5 g, 21.7 mmol), DIPEA (2.1 g, 16.6 mmol) and Pd(dppf)Cl2(15.9 g, 21.7 mmol) in MeOH (30 mL) was stirred under CO atmosphere at 15 atm and at 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 6-cyclopropoxy-lH-indazole-5-carboxylic acid methyl ester as a yellow solid (4.4 g, 87%). MS ESI, m / z = 233 [M+H] + .

[0351] 6-cyclopropoxy-lH-indazole-5-carboxylic acid

[0352]

[0353] To a solution of 6-cyclopropoxy-lH-indazole-5-carboxylic acid methyl ester (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 x 3). The aqueous layer was acidified with 0.1 N HC1 to pH 4-5, and the formed precipitate was collected by filtration to give 6-cyclopropoxy-lH-indazole-5-carboxylic acid (2.7 g, 65%). MS ESI, m / z = 219 [M+H] + .

[0354] 6-cyclopropoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-lH-indazole-5-carboxamide (Int-II-3)

[0355]

[0356] To a solution of 6-cyclopropoxy-lH-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) was added pyrazolo[l,5-a]pyrimidin-3-amine (Int I-5) (5.1 g, 37.8 mmol) at rt. 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. Subsequently, the suspension was poured into water (1 L) and filtered to give 6-cyclopropoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-lH-indazole-5-carboxamide (6.9 g, 81%) as a yellow solid. 1 H NMR (300 MHz, 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] + .

[0357] Synthesis of Intermediate Int III-1 : 1 -Methyl-2-oxo- 1 -azaspiro [4.5] decan-8-yl 4- methylbenzenesulfonate

[0358] 8-Hydroxy- 1 -azaspiro [4.5] decan-2-one

[0359]

[0360] To 1 -azaspiro [4.5] decan-2,8-dione (4.5 g, 26.9 mmol) in MeOH (100 mL) was added NaBH4(2.0 g, 53.8 mmol) in one portion at 0 °C and the resulting solution was stirred at rt. After 14 h, the reaction mixture was quenched with EtOAc (50 mL), the solvent was removed in vacuo 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.

[0361] 2-Oxo- 1 -azaspiro [4.5] decan-8-yl 4-methylbenzenesulfonate

[0362]

[0363] 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) was slowly added TsCl (6.8 g, 35.8 mmol) at rt under N2atmosphere. The resulting mixture was stirred at rt for 3 h. The reaction mixture was quenched with water (100 mL), extracted with DCM (15 mL x 3), dried over Na2S04, 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 (300 MHz, DMSO-d6) d 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.

[0364] 1 -Methyl-2-oxo- 1 -azaspiro[4.5]dec-8-yl 4-toluenesulfonate (Int III- 1)

[0365]

[0366] To a solution of 2-oxo- 1 -azaspiro[4.5]dec-8-yl 4-toluenesulfonate (1.9 g, 5.9 mmol) in DMF (8 mL) was added NaH (60 wt.%) (352 mg, 8.8 mmol) at 0 °C under N2atmosphere. 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 purified directly by C18 flash chromatography eluting with 0-60% MeCN (0.5% NH4OH) in water to give 1 -methyl-2-oxo- 1 -azaspiro[4.5]dec-8-yl 4-toluenesulfonate (1.8 g, 91%) as a colorless solid. 1 H NMR (400 MHz, 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) (isomers), 2.59 / 2.55 (s, 3H) (isomers), 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) (isomers). m / z (ESI+), [M+H] + = 338.

[0367] Synthesis of intermediate Int III-2: tert-butyl 7-((methylsulfonyl)oxy)-2- azaspiro[3.5]nonane-2-carboxylate

[0368]

[0369] 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) was added MsCI (839 μL, 10.8 mmol) at 0 °C under N2atmosphere 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 x 100 mL). The combined organic layers were dried over Na2S04, filtered and the solvent was removed in vacuo 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 (300 MHz, 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.

[0370] Synthesis of intermediate Int III-3: 2-hydroxy-2-methylspiro[3.5]nonan-7-yl 4- methylbenzenesulfonate

[0371] 2-methyl-8, 11-dioxaspiro[3.2.4 7 .2 4 ]tridecan-2-ol

[0372]

[0373] A solution of methylmagnesium bromide in THF (3N, 10.0 mL, 30.0 mmol) was slowly added to 8, 11-dioxaspiro[3.2.4 7 .2 4 ]tridecan-2-one (2.0 g, 10.2 mmol) in THF (50 mL) at -78 °C under N2atmosphere. The resulting mixture was stirred at -65 °C for 1 h and at -40 °C for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution (50 mL) at -40 °C, allowed to warm to rt and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The resulting residue was purified using silica gel chromatography eluting with 30% to 40% EtOAc in PE to give 2-methyl-8, 11-dioxaspiro[3.2.4 7 .2 4 ]tridecan-2-ol (2.1 g, 97%) as a colorless oil.

[0374] 2-hydroxy-2-methylspiro[3.5]nonan-7-one

[0375]

[0376] Aqueous HC1 solution (2N, 20 mL, 40 mmol) was slowly added to 2-methyl-8, 11-dioxaspiro[3.2.4 7 .2 4]tridecan-2-ol (2.1 g, 9.9 mmol) and stirring was continued for 2 h. The mixture was neutralized with aqueous NaOH (2 M) to pH 7 and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over Na2S04and concentrated in vacuo 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.

[0377] 2-methylspiro[3.5]nonane-2,7-diol

[0378]

[0379] NaBH4(37.8 mg, 1.0 mmol) was added slowly to crude 2-hydroxy-2-methylspiro[3.5]nonan-7-one (84 mg) in MeOH (3 mL) at rt under N2atmosphere and the resulting mixture was stirred for 30 min. The solvent was then removed in vacuo and the resulting residue was purified using silica gel chromatography eluting with 50% to 70% EtOAc in PE to give 2-methylspiro[3.5]nonane-2,7-diol (78 mg, 92%) as a colorless solid.

[0380] 2-hydroxy-2-methylspiro[3.5]nonan-7-yl 4-methylbenzenesulfonate (Int-III-3)

[0381]

[0382] TsCl (4.0 g, 21.0 mmol) was added slowly 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) at rt under N2atmosphere and the resulting mixture was stirred at 50 °C. After 16 h, the reaction mixture was allowed to cool to rt, quenched with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2S04and concentrated in vacuo. The resulting residue was purified using silica gel chromatography eluting with 10% to 50% EtOAc in PE to give 2-hydroxy-2-methylspiro[3.5]nonan-7-yl 4-methylbenzenesulfonate (1.7 g, 74%) as a pale yellow oil. 1H NMR (300 MHz, DMSO-d6) d 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).

[0383] Synthesis of intermediate Int III-4: tert-butyl 6-methyl-7-oxo-2- azaspiro[3.5]nonane-2-carboxylate

[0384]

[0385] LiHMDS (1 M in THF, 157.0 mL, 157.0 mmol) was added to THF (100 mL) at -78 °C, followed by 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) over a period of 30 min under N2atmosphere. The resulting mixture was stirred at -78 °C for 1 h. Subsequently, iodomethane (22.3 g, 157.1 mmol) was added dropwise. The reaction mixture was stirred at -78 °C for another 30 min, then at rt for 15 h. The mixture was quenched with ice water (150 mL) and extracted with EtOAc (500 mL x 3). The organic layer was dried over Na2SO4, 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 light yellow solid. 1 H NMR (400 MHz, DMSO-d6) d 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] + .

[0386] Intermediate Int III-5 and Int III-6: rac-(6R,7S)-tert-butyl 6-methyl-7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate and rac-(6S,7S)-tert-butyl 6-methyl-7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylate

[0387] rac-(6R,7S)-7-hydroxy-6-methyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester and rac-(6S,7S)-7-hydroxy-6-methyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

[0388]

[0389] 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) was added NaBH4(5.8 g, 153.9 mmol) portionwise at 0 °C under N2atmosphere over a period of 40 min. The resulting mixture was warmed to rt for 5 h. The reaction was quenched with brine (300 mL) and extracted with EtOAc (500 mL x 3). The combined organic layers were dried over Na2SO4, 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-(6R,7S)-7-hydroxy-6-methyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (13.6 g, 69%) and rac-(6S,7S)-7-hydroxy-6-methyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (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] + .

[0390] rac-(6R,7S)-6-methyl-7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (Int III-5)

[0391]

[0392] MsCl (7.7 mL, 98.7 mmol) was added dropwise to a solution of rac-(6R,7S)-7-hydroxy-6-methyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (4.2 g, 16.5 mmol) and TEA (22.9 mL, 165 mmol) in DCM (20 mL) at rt over 15 min. The resulting mixture was stirred at rt for 12 h. The mixture was washed with water (25 mL x 2). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 50% to 100% EtOAc in PE to give rac-(6R,7S)-6-methyl-7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (3.5 g, 64%) as a yellow oil. 1 H NMR (300 MHz, 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).

[0393] rac-(6S,7S)-6-methyl-7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (Int III-6)

[0394]

[0395] MsCl (0.55 mL, 7.1 mmol) was added dropwise to a solution of rac-(6S,7S)-7-hydroxy-6-methyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.8 g, 7.1 mmol) and TEA (983 μL, 7.1 mmol) in DCM (8 mL) at 0 °C under N2atmosphere. 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 x 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% - 60% EtOAc in PE to give rac-(6S,7S)-6-methyl-7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.4 g, 60%) as a yellow solid. MS ESI, m / z = 667 [2M+H] + .

[0396] Intermediate Int III-7: rac-(1R,3R)-3-hydroxycyclohexyl 4-methylbenzenesulfonate

[0397]

[0398] 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-(lR,3R)-cyclohexane-l,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 x 300 mL). The combined organic layers were washed with brine (1 x 200 mL), dried over Na2S04and concentrated in vacuo. The resulting residue was purified using silica gel chromatography eluting with 0% to 40% EtOAc in DCM to give rac-(lR,3R)-3-hydroxycyclohexyl 4-methylbenzenesulfonate (5.0 g, 43%) as a pale yellow oil. 1 H NMR (300 MHz, 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).

[0399] Synthesis of intermediate Int III-8: (ls,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate

[0400]

[0401] TsCl (33.2 g, 174.2 mmol) was added to a solution of tert-butyl ((ls,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) at rt under N2atmosphere over a period of 5 min. The resulting mixture was stirred at 50 °C for 20 h. The reaction mixture was allowed to cool to rt, diluted with DCM (500 mL), washed with brine (150 mL), dried over Na2S04and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10% to 50% EtOAc in PE to give (ls,4s)-4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate (15.5 g, 60%) as a colourless solid.

[0402] 1H NMR (300 MHz, 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).

[0403] Synthesis of intermediate Int III-9: 4-((tert-butoxycarbonyl)amino)cyclohexyl 4- toluenesulfonate

[0404]

[0405] 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) at rt under N2atmosphere over a period of 5 min. The resulting mixture was stirred at rt for 20 h. The reaction mixture was diluted with DCM (400 mL), washed with water (150 mL x 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-toluenesulfonate (cis / trans ratio 1 :5) as a colorless solid (26.0 g, 76%). 1 H NMR (300 MHz, DMSO-d6) (1 :5 cis / trans isomer mixture) δ 7.75-7.85 (m, 2H), 7.47 (d, 2H), 6.81 / 6.71 (d, 1H) (isomers), 4.54-4.62 / 4.27-4.42 (m, 1H) (isomers), 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) (isomers), 1.09-1.27 (m, 2H). MS ESI, m / z = 270 [M-Boc+2H] + .

[0406] Synthesis of intermediate Int III-10: 4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl 4- toluenesulfonate

[0407]

[0408] Iodomethane (3.8 g, 27.1 mmol) was added dropwise to a suspension of NaH (60 wt.%) (812 mg, 20.3 mmol) and 4-((tert-butoxycarbonyl)amino)cyclohexyl 4- toluenesulfonate (cis / trans 1 :5) (Int III-9) (5.0 g, 13.5 mmol) in DMF (50 mL) at rt. The resulting mixture was stirred at 60 °C for 4 h. The mixture was allowed to cool to rt, the reaction was quenched with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with brine (100 mL x 4), dried over Na2S04, filtered and concentrated under reduced pressure to give a light 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- toluenesulfonate (cis / trans 1 :5) (2.5 g, 48%) as a colorless solid. 1 H NMR (300 MHz, 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] + .

[0409] Intermediate Int III-11 and Int III-12: rac-(7R,8S)-7-methyl-1,4-dioxaspiro[4.5]decane-8-ol and rac-(7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decane-8-ol

[0410]

[0411] To a solution of 7-methyl-1,4-dioxaspiro[4.5]decane-8-one (50.0 g, 293.8 mmol) in MeOH (500 mL) was added NaBH4(22.3 g, 587.5 mmol) portionwise over a 20 min period at 0 °C under N2atmosphere. The resulting mixture was stirred at rt for 1 h and then concentrated under reduced pressure. The residue was purified directly by silica gel chromatography eluting with 16% EtOAc in PE to give rac-(7R,8S)-7-methyl-1,4-dioxaspiro[4.5]decane-8-ol (3.18 g, 6%) and rac-(7S,8S)-7-methyl-1,4-dioxaspiro[4.5]decane-8-ol (19.00 g, 38%). rac-(7R,8S)-isomer:1 H NMR (300 MHz, DMSO-d6) δ 4.27 (d, 1 H), 3.75-3.9 (m, 4 H), 3.51-3.6 (m, 1 H), 1.44-1.78 (m, 5 H), 1.25-1.44 (m, 2 H), 0.86 (d, 3 H). Racemic-(7S,8S)-isomer: 1 H NMR (300 MHz, DMSO-d6) δ 4.45 (d, 1 H), 3.75-3.89 (m, 4 H), 2.89-3.05 (m, 1 H), 1.27-1.77 (m, 6 H), 1.19 (t, 1 H), 0.90 (d, 3 H).

[0412] Synthesis of intermediate Int III-13: racemic-(7R,8S)-7-methyl-1,4-dioxaspiro[4.5]dec-8-yl methanesulfonate

[0413]

[0414] MsCI (1.4 mL, 17.4 mmol) was added dropwise to a solution of racemic-(7R,8S)-7-methyl-1,4-dioxaspiro[4.5]dec-8-ol (Int III-11) (2.5 g, 14.5 mmol) and TEA (6.1 mL, 43.6 mmol) in DCM (50 mL) at 0 °C under N2atmosphere over a period of 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 x 3). The combined organic layers were dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-20% EtOAc in PE to give racemic-(7R,8S)-7-methyl-1,4-dioxaspiro[4.5]dec-8-yl methanesulfonate (2.1 g, 58%) as a brown oil. 1 H NMR (300 MHz, DMSO-d6) δ 4.71 (br. s, 1 H), 3.80-3.92 (m, 4 H), 3.17 (s, 3 H), 2.02-2.13 (m, 1 H), 1.85-2.02 (m, 1 H), 1.32-1.83 (m, 5 H), 0.94 (d, 3 H).

[0415] Intermediate Int IV-1: (1s,4s)-4-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)cyclohexan-1-ol

[0416] (1r,4r)-4-hydroxycyclohexyl 4-methylbenzenesulfonate

[0417]

[0418] 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-toluenesulfonate as a colorless solid (2.1 g, 18%). 1 H NMR (300 MHz, 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).

[0419] (1s,4s)-4-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)cyclohexan-1-ol (Int IV-1)

[0420]

[0421] 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) was added (1r,4r)-4-hydroxycyclohexyl 4-toluenesulfonate (946 mg, 3.5 mmol) at rt. 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 Na2SO4, 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] + .

[0422] Synthesis of intermediate Int IV-2: (1r,4r)-4-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)cyclohexan-1-ol

[0423] (1s,4s)-4-hydroxycyclohexyl 4-methylbenzenesulfonate

[0424]

[0425] 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 with 0.1 N HC1 (50 mL) and water (50 mL) successively. The organic layer was dried over Na2S04, 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 solid. 1 H NMR (300 MHz, 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).

[0426] (1r,4r)-4-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)cyclohexan-1-ol (Int IV-2)

[0427]

[0428] 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 Na2S04, 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. 1H NMR (300 MHz, 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] + .

[0429] Synthesis of Intermediate Int IV-3: rac-5-bromo-6-methoxy-2-((7R,8R)-7-methyl- 1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole

[0430]

[0431] To a solution of 5-bromo-6-methoxy-lH-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-l,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 x 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 (0.1% FA) in water to give rac-5-bromo-6-methoxy-2-((7R,8R)-7-methyl-l,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole (600 mg, 22%) as a brown solid. MS ESI, m / z = 381 / 383 [M+H] + .

[0432] Synthesis of Intermediate Int IV-3: rac-5-bromo-6-methoxy-2-((7R,8R)-7-methyl- 1,4-dioxaspiro[4.5]decan-8-yl)-2H-indazole

[0433]

[0434] Rac-5-bromo-6-methoxy-2-((7R,8R)-7-methyl-l,4-dioxaspiro[4.5]dec-8-yl)- 2H-indazole (Int IV-3) (7.3 g, 19.2 mmol) was separated by the following: preparative SFC IG, 5 pm 50 x 250 mm; isocratic with 50% MeOH (0.1% 2N NH3-MeOH) in CO2(35 °C, 100 bar); 200 mL / min) to give 5-bromo-6-methoxy-2-((7R,8R)-7-methyl-l,4- dioxaspiro[4.5]dec-8-yl)-2H-indazole (3.1 g, 43%, 100% ee) and 5-bromo-6- methoxy-2-((7S,8S)-7-methyl-l,4-dioxaspiro[4.5]dec-8-yl)-2H-indazole (3.0 g, 41%, 100% ee) both as grey solids. The ee obtained for both products 1 H NMR and MS were identical. 1 H NMR (300 MHz, 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),

[0435] 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] + .

[0436] Synthesis of intermediates Int IV-6 and Int IV-7: (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

[0437] 2-methyl-3-oxo-2-azaspiro[4.5]dec-8-yl methanesulfonate

[0438]

[0439] 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 NaHCO3solution (30 mL) and extracted with DCM (50 mL x 2). The combined organic layers were dried over Na2SO4, 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]dec-8-yl methanesulfonate (3.1 g, 96%) as an orange oil.

[0440] (5s,8s)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2-methyl-2-azaspiro[4.5]decane-3- one (Int IV-6) and (5r,8r)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2-methyl-2- azaspiro[4.5]decane-3-one (Int IV-7)

[0441]

[0442] To a solution of 5-bromo-6-methoxy-lH-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]dec-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 x 4), dried and concentrated under reduced pressure. The residue was loaded onto a 10 g SCX2 cartridge. The cartridge was washed with DCM / MeOH (1 : 1) (150 mL) to remove the unwanted lH-indazole isomer and then eluted with 100 mL 2N NH3-MeOH solution in DCM (1 : 1) after evaporation of the solvent to give the crude product. The brown residue was further purified by silica gel chromatography eluting with EtOAc and then with 0-2% 2N NH3-MeOH solution in DCM to give 8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2-methyl-2-azaspiro[4.5]decane-3- one. This material was further isolated by chiral preparative SFC (Chiralpak® IC column, 30 x 250 mm, 5 pm, 40% MeOH in CO2, 40 mL / min, 40 bar, 40 °C, 220 nm) to give (5s,8s)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2-methyl-2-azaspiro[4.5]decane-3- one (Int IV-6) and (5r,8r)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2-methyl-2-azaspiro[4.5]decane-3-one (Int IV-7). ​Cellulose-3, 5 μm 30 mm x 250 mm; isocratic with 20% EtOH (20 mM diethylamine) in CO2(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. 1 H NMR (500 MHz, CDC13) 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, 3H), 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)-isomer: 1 H NMR (500 MHz, CDC13) 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, 3H), 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] + .

[0443] Intermediate Int IV-8: tert-Butyl ((1 r, 4r)-4-(5-bromo-6-methoxy-2H-indazol-2- yl)cyclohexyl)carbamate

[0444]

[0445] To a solution of tert-butyl ((lr,4r)-4-aminocyclohexyl)carbamate (10.5 g, 49.0 mmol) in i-PrOH (200 mL) was added 5-bromo-4-methoxy-2-nitrobenzaldehyde (Int I-l) (12.7 g, 49.0 mmol) at rt under N2atmosphere. The resulting mixture was stirred at 80 °C for 1 h, followed by the addition of tri-n-butylphosphine (29.7 g, 147.0 mmol). The reaction mixture was stirred at 80 °C for 13 h. The mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 9% - 50% EtOAc in PE to give tert-butyl ((lr,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)carbamate (14.2 g, 68%) as a colorless solid. MS ESI, m / z = 424 / 426 [M+H] + .

[0446] Synthesis of intermediates Int V-l and Int V-2: N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lS,2S)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxamide and N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lR,2R)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxamide

[0447] rac-(3R,4R)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-methylcyclohexan-l-one

[0448]

[0449] rac-5-bromo-6-methoxy-2-((7R,8R)-7-methyl-l,4-dioxaspiro[4.5]dec-8-yl)-2H-indazole (Int IV-3) (400 mg, 1.1 mmol) was added to a 1.2 N HC1 solution in THF (5 mL) / water (5 mL) at rt under N2atmosphere. The resulting mixture was stirred at rt overnight. The reaction mixture was purified by C18 flash chromatography eluting with 0% - 60% MeCN (0.05% TFA) in water to give rac-(3R,4R)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-methylcyclohexan-l-one (330 mg, 93%) as a yellow solid. MS ESI, m / z = 337 / 339 [M+H] + .

[0450] N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lS,2S)-2-methyl-4- oxocyclohexyl)-2H-indazole-5-carboxamide (Int V-l) and N-(imidazo[l,2- b]pyridazin-3-yl)-6-methoxy-2-((lR,2R)-2-methyl-4-oxocyclohexyl)-2H- indazole-5-carboxamide (Int V-2)

[0451]

[0452] A suspension of rac-(3R,4R)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-3- methylcyclohexan-l-one (330 mg, 1.0 mmol), imidazo[l,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 at 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[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lR,2R)-2-methyl-4- oxocyclohexyl)-2H-indazole-5-carboxamide as a yellow solid. This material was separated by preparative chiral SFC (Chiralpak® AS-H, 5 μm 20 mm x 250 mm; isocratic with 45% i-PrOH (2 mM NH3-MeOH) in C02(40 °C, 70 bar); 40 mL / min) to give N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lS,2S)-2-methyl-4- oxocyclohexyl)-2H-indazole-5-carboxamide (220 mg, 34%, 71.2% ee) as the first eluting isomer and N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lR,2R)-2-methyl-4- oxocyclohexyl)-2H-indazole-5-carboxamide (200 mg, 31%, 83.3% ee) as the second eluting isomer. AS-H, 5 μm 20 mm x 250 mm; isocratic with 45% i-PrOH (2 mM NH3-MeOH) in C02(40 °C, 70 bar); 40 mL / min), to give N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lS,2S)-2-methyl-4- oxocyclohexyl)-2H-indazole-5-carboxamide (220 mg, 34%, 71.2% ee) as the first eluting isomer and N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lR,2R)-2-methyl-4- oxocyclohexyl)-2H-indazole-5-carboxamide (200 mg, 31%, 83.3% ee) as the second eluting isomer. The ee's obtained for both products were identical. 1 H NMR and MS were identical. 1H NMR (400 MHz, 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] + .

[0453] Intermediate Int V-3: N-(Imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lr,4r)-4- (methylamino)cyclohexyl)-2H-indazole-5-carboxamide

[0454] ((lr,4r)-4-(5-Bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)carbamic acid tert-butyl ester

[0455]

[0456] To a solution of tert-butyl ((lr,4r)-4-(5-bromo-6-methoxy-2H-indazol-2- yl)cyclohexyl)(methyl)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 purified directly by C18 flash chromatography eluting with 0-100% MeCN in water (0.05% NH4OH) to give tert-butyl ((lr,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] + .

[0457] ((lr,4r)-4-(5-(Imidazo[l,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2- yl)cyclohexyl)(methyl)carbamic acid tert-butyl ester

[0458]

[0459] A suspension of tert-butyl ((lr,4r)-4-(5-bromo-6-methoxy-2H-indazol-2- yl)cyclohexyl)(methyl)carbamate (380 mg, 0.9 mmol), imidazo[l,2-b]pyridazin-3-amine (134 mg, 1.0 mmol), Pd(OAc)2(44 mg, 0.2 mmol), dppp (165 mg, 0.4 mmol) and TEA (604 μί, 4.3 mmol) in MeCN (20 mL) was stirred under a CO atmosphere at 15 atm and at 100 °C for 15 h. Then, 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% NH4OH) to give tert-butyl ((lr,4r)-4-(5-(imidazo[l,2-b]pyridazin-3- ylcarbamoyl)-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate (430 mg, 95%) as a red solid. 1 H NMR (300 MHz, 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, 1H), 4.11 (s, 3H), 3.79-4.04 (m, 1H), 2.73 (s, 3H), 2.12-2.33 (m, 2H), 1.92-2.12 (m, 2H), 1.62-1.92 (m, 4H), 1.42 (s, 9H). MS ESI, m / z = 520 [M+H] + .

[0460] N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lr,4r)-4-(methylamino)cyclohexyl)- 2H-indazole-5-carboxamide (Int V-3)

[0461]

[0462] ((1 r,4r)-4-(5-(imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2- yl)cyclohexyl)(methyl)carbamic acid tert-butyl ester (430 mg, 0.8 mmol) was added to 2N HCI in dioxane (12 mL, 24.0 mmol) at rt under N2atmosphere. The resulting mixture was stirred at rt for 2 h and then concentrated under reduced pressure to give crude HCI salt of N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1 r,4r)-4-(methylamino)cyclohexyl)-2H-indazole-5- carboxamide (300 mg) which was used as such without further purification. 1 H NMR (300 MHz, DMSO-d6) δ 11.26 (s, 1 H), 8.97 (dd, 1 H), 8.63 (s, 1 H), 8.60 (s, 1 H), 8.43 (dd, 1 H), 8.37 (s, 1 H), 7.67 (dd, 1 H), 7.28 (s, 1 H), 4.48 - 4.64 (m, 1 H), 4.13 (s, 3H), 3.01 - 3.22 (m, 1 H), 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] + .

[0463] Synthesis of intermediate Int V-4: 6-methoxy-2-((1 r,4r)-4-(methylamino)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide

[0464] ((1 r,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)carbamic acid tert-butyl ester

[0465]

[0466] To a solution of tert-butyl ((lr,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) at 0 °C under N2atmosphere. 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 vacuum to yield tert-butyl ((lr,4r)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate as a colorless solid (4.4 g, 100%). MS ESI, m / z = 438 / 440 [M+H] + .

[0467] 2-((lr,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)-6-methoxy-2H- indazole-5-carboxylic acid

[0468]

[0469] A suspension of tert-butyl ((lr,4r)-4-(5-bromo-6-methoxy-2H-indazol-2- yl)cyclohexyl)(methyl)carbamate (4.3 g, 9.8 mmol), Pd(dppf)Cl2(714 mg, 1.0 mmol) and TEA (13.6 mL, 97.6 mmol) in MeOH (125 mL) was stirred under CO atmosphere at 15 atm and at 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 yield methyl 2-((lr,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)-6-methoxy-2H-indazole-5-carboxylate as a yellow solid (3.8 g, 93%). MS ESI, m / z = 418 [M+H] + .

[0470] 2-((lr,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)-6-methoxy-2H- indazole-5-carboxylic acid

[0471]

[0472] To a solution of methyl 2-((lr,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) was added NaOH (556 mg, 13.9 mmol) at rt. The resulting solution was stirred at 30 °C for 12 h. The reaction mixture was cooled to rt and acidified with 4 N HC1 to pH ~ 6. The precipitate was filtered, washed with water (200 mL) and dried under vacuum to give 2-((lr,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)-6-methoxy-2H-indazole-5- carboxylic acid as a light yellow solid (2.7 g, 95%). MS ESI, m / z = 404 [M+H] + .

[0473] ((lr,4r)-4-(6-methoxy-5-(pyrazolo[l,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)carbamic acid tert-butyl ester

[0474]

[0475] To a solution of 2-((lr,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) was added HATU (2.9 g, 7.7 mmol) at rt under N2atmosphere. The resulting mixture was stirred at rt for 15 min followed by the addition of pyrazolo[l,5-a]pyrimidin-3-amine HC1 salt (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 obtain a crude solid. The solid was washed with water (100 mL) and then purified by silica gel chromatography eluting with 0-5% MeOH in DCM to give ((lr,4r)-4-(6-methoxy-5-(pyrazolo[l,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2- yl)cyclohexyl)(methyl)carbamic acid tert-butyl ester (3.3 g, 99%) as a yellow solid. MS ESI, m / z = 520 [M+H] + .

[0476] 6-methoxy-2-((lr,4r)-4-(methylamino)cyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H- indazole-5-carboxamide (Int V-4)

[0477]

[0478] To a solution of tert-butyl ((lr,4r)-4-(6-methoxy-5-(pyrazolo[l,5- a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)carbamate (3.3 g, 6.4 mmol) in DCM (40 mL) at rt under N2atmosphere was added 4N HC1 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 HC1 salt of 6-methoxy-2-((lr,4r)-4-(methylamino)cyclohexyl)-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide as a light yellow solid (2.9 g) which was used without further purification. MS ESI, m / z = 420 [M+H] + .

[0479] Synthesis of intermediate Int V-5: 2-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-6-hydroxy-N-(imidazo[l,2-b]pyridazin-3-yl)-2H-indazole-5-carboxamide

[0480]

[0481] To a solution of 2-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (Example 21, see below) (380 mg, 0.8 mmol) in DCM (15 mL) at 0 °C under N2atmosphere was added BBr3(8.0 mL, 8.3 mmol) dropwise over a period of 5 min and the resulting mixture was stirred at 40 °C. After 6 h, the reaction mixture was allowed to cool to rt, quenched with saturated aqueous NaHC03solution (10 mL) and diluted with brine (50 mL). The mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified using C18flash chromatography eluting with 0% to 25% MeCN in water followed by silica gel chromatography eluting with 9% to 10% MeOH in DCM to give 2-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-6-hydroxy-N-(imidazo[l,2-b]pyridazin-3-yl)-2H-indazole-5-carboxamide as a light brown solid (170 mg, 46%). 1H NMR (300 MHz, 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, 1H), 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) (rotamers), 1.61-1.74 (m, 2H). m / z (ESI+), [M+H] + = 460.

[0482] Example

[0483] N-(Imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-l-methyl-2-oxo-l- azaspiro[4.5]decan-8-yl)-2H-indazole-5-carboxamide (Example 1)

[0484] 8-Amino-l-azaspiro[4.5]decan-2-one

[0485]

[0486] l-Azaspiro[4.5]decan-2,8-dione (1.0 g, 6.0 mmol) was mixed with 4 N NH3in MeOH (46.0 mL, 0.18 mol) and stirred at rt. After 1 h, the resulting solution was added to NaBH4(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 in vacuo. Then, 4 M aqueous NaOH (40 mL) and sodium chloride (10 g) were added. The resulting suspension was extracted with DCM (4 x 70 mL), the combined organic phases were dried over MgS04and the solvent was removed in vacuo to give crude 8-amino-l-azaspiro[4.5]decan-2-one (0.9 g) which was used without further purification.

[0487] (5r,8r)-8-(5-Bromo-6-methoxy-2H-indazol-2-yl)-l-azaspiro[4.5]decan-2-one

[0488]

[0489] To crude 8-amino-1 -azaspiro[4.5]decane-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 allowed to cool to rt and filtered. The collected solid was washed with heptane (3 x 10 mL) and purified using ion exchange chromatography, eluting with 250 mL DCM / MeOH (1 :1) and DCM / 4N NH3-MeOH solution (1 / 1). The isolated solid was then recrystallised using i-PrOH to remove unwanted (5s,8s)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-1 -azaspiro[4.5]decane-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 -methyl-1 -azaspiro[4.5]decane-2-one (320 mg, 39%). m / z (ESI+), [M+H] = 378 / 380. + = 378 / 380.

[0490] (5r,8r)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-1 -methyl-1 -azaspiro[4.5]decane-2-one

[0491]

[0492] 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, iodomethane (130 μL, 2.1 mmol) was added slowly at 0 °C. The resulting mixture was warmed to rt and stirred overnight. The reaction mixture was then quenched with ice water (250 mL) and extracted with DCM (4 x 25 mL). The combined organic phases were concentrated in vacuo and the resulting residue was purified using silica gel chromatography eluting with DCM (300 mL), EtOAc (2 L), then 2% NH3-MeOH in DCM (150 mL) to give (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. + = 392 / 394.

[0493] 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 )

[0494]

[0495] Methyldiphenylsilane carboxylic acid (193 mg, 0.8 mmol) and KF (46 mg, 0.8 mmol) were added to chamber A of a dry and N2-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]pyridazine-3-amine (121 mg, 0.9 mmol), dppp (41 mg, 0.1 mmol), Pd(OAc)2(27 mg, 0.1 mmol) and TEA (223 μL, 1.6 mmol) were added to chamber B. Then, DMSO (350 μL) was added to chamber A and chamber B was stirred at 85 °C overnight. The reaction mixture was allowed to cool to rt. The reaction in chamber B was quenched with saturated NaHCO3, the solvent was removed in vacuo and the resulting residue was purified using ion exchange chromatography, washed with DCM / MeOH (1 / 1; 200 mL) and eluted with 4 N NH3 in MeOH (200 mL). The resulting dark brown solid was further purified using silica gel chromatography, eluting with EtOAc (2 L) and then 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 bright 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 x 500 μL) and pentane (3 x 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 as a light yellow solid (93 mg, 74%). 1 H NMR (500 MHz, 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.

[0496] N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((5s,8s)-l-methyl-2-oxo-l- azaspiro[4.5]dec-8-yl)-2H-indazole-5-carboxamide (Example 2)

[0497]

[0498] To l-methyl-2-oxo-l-azaspiro[4.5]dec-8-yl 4-toluenesulfonate (Int III-l) (1.4 g, 4.2 mmol) was added DMF (15 mL), N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-lH- indazole-5-carboxamide (Int II-l) (1.3 g, 4.2 mmol) and KOH (466 mg, 8.3 mmol). The resulting solution was stirred at 100 °C. After 12 h, the reaction mixture was cooled to rt and purified directly 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 NH3 in MeOH); mobile phase B: i-PrOH; gradient: isocratic 50% B for 21.5 min; flow rate: 20 mL / min) to give N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((5s,8s)-l-methyl-2-oxo-l- azaspiro[4.5]dec-8-yl)-2H-indazole-5-carboxamide (28.0 mg, 1%) as a yellow solid. 1 H NMR (300 MHz, 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.

[0499] 2-((l s,4s)-4-(dimethylcarbamoyl)cyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide (Example 3)

[0500] (lr,4r)-4-hydroxy-N,N-dimethylcyclohexane-l-carboxamide

[0501]

[0502] 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) at rt under N2atmosphere over a period of 3 h. After stirring the resulting mixture for 3 h, the reaction mixture was poured into water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were dried over Na2S04, filtered and the solvent was removed in vacuo. 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] 206.2. + = 172.

[0503] (1r,4r)-4-(Dimethylcarbamoyl)cyclohexyl 4-methylbenzenesulfonate

[0504]

[0505] TsCl (8.4 g, 44.1 mmol) was added dropwise to 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) at 0 °C under N2atmosphere and the resulting solution was stirred at rt. After 11 h, the reaction mixture was poured into water (20 mL), extracted with DCM (3 x 10 mL), the combined organic layers were dried over Na2S04, filtered and the solvent was removed in vacuo. 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] 326.2. + = 326.

[0506] 2-((1s,4s)-4-(Dimethylcarbamoyl)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide (Example 3)

[0507]

[0508] KOH (218 mg, 3.9 mmol) was added to N-(imidazo[l,2-b]pyridazin-3-yl)-6- methoxy-lH-indazole-5-carboxamide (Int II-1) (300 mg, 1.0 mmol) and crude (lr,4r)-4- (dimethylcarbamoyl)cyclohexyl 4-methylbenzenesulfonate (950 mg) in DMF (6 mL) at rt under N2atmosphere and the resulting solution was stirred at 100 °C. After 12 h, the reaction mixture was allowed to cool to rt and was directly subjected to C18flash chromatography eluting with 10% to 60% MeCN (0.5% FA) in water, followed by preparative HPLC (XSelect CSH Prep C18 OBD column, 5 pm, 19 mm x 150 mm; mobile phase A: water (0.1% FA); mobile phase B: MeCN; gradient: 15% to 27% B over 7 min, then 27% B for 2 min, flow rate: 60 mL / min) to give 2-((ls,4s)-4-(dimethylcarbamoyl)cyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide (40 mg, 9%) as a yellow solid. 1 H NMR (400 MHz, 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.

[0509] 2-((lr,4r)-4-(dimethylcarbamoyl)cyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide (Example 4)

[0510] (ls,4s)-4-hydroxy-N,N-dimethylcyclohexanecarboxamide

[0511]

[0512] HATU (9.5 g, 24.9 mmol) was added to a solution of DIPEA (14.5 mL, 83.2 mmol), dimethylamine x HCI (5.1 g, 62.4 mmol) and (1s,4s)-4-hydroxycyclohexanecarboxylic acid (3.0 g, 20.8 mmol) in DCM (30 mL) at rt under N2atmosphere. The resulting mixture was stirred at rt for 3 h. The reaction mixture was poured into water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over Na2S04, 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 as a yellow oil (3.5 g).

[0513] (1s,4s)-4-(dimethylcarbamoyl)cyclohexyl 4-methylbenzenesulfonate

[0514]

[0515] 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 N2atmosphere over a 3 h period. The resulting mixture was stirred at rt for 3 h. The reaction mixture was poured into water (20 mL) and extracted with DCM (3 x 25 mL). The combined organic layers were dried over Na2S04, 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 as a yellow oil (2.1 g, 37%). m / z (ESI+) [M+H] + = 326.

[0516] 2-((1r,4r)-4-(dimethylcarbamoyl)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide (Example 4)

[0517]

[0518] KOH (80 mg, 1.4 mmol) was added to a solution of (1s,4s)-4-(dimethylcarbamoyl)cyclohexyl 4- toluenesulfonate (348 mg, 1.1 mmol) and N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-lH- indazole-5-carboxamide (Int II-1) (110 mg, 0.4 mmol) in DMF (10 mL) at rt under N2atmosphere. The resulting solution was stirred at 100 °C for 12 h and cooled to rt, after which the mixture was poured into water (10 mL). The aqueous phase was extracted with EtOAc (3 x 20 mL), the combined organic layers were dried over Na2SO4, 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 purification by preparative HPLC (Xselect CSH FluoroPhenyl OBD column, 5 pm silica, 30 x 150 mm, mobile phase A: water (0.1% FA), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 20% B to 30% B over 7 min) to give 2-((1r,4r)-4-(dimethylcarbamoyl)cyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide as a yellow solid (10 mg, 17%). 1 H NMR (400 MHz, 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), 3.07 (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.

[0519] 2-(2-Hydroxy-2-methylspiro[3.5]nonan-7-yl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy- 2H-indazole-5-carboxamide - Isomer 1 (Example 5) and Isomer 2 (Example 6)

[0520]

[0521] Cs2CO3(793 mg, 2.4 mmol) was added to N-(imidazo[l,2-b]pyridazin-3-yl)-6- methoxy-lH-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 N2atmosphere. After 5 h, the reaction mixture was allowed to cool to rt and directly subjected to C18 flash chromatography eluting with 0% to 100% MeCN (0.5% FA) in water, followed by two-step preparative HPLC purification ((1st preparative HPLC: XBridge Prep OBD C18, 30 x 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 x 25 cm, 5 μm; mobile phase A: MTBE (0.1% 2N NH3-MeOH); mobile phase B: MeOH; gradient: 50% B isocratic in 14 min; flow rate: 16 mL / min.)) to give 2-(2-hydroxy-2-methylspiro[3.5]nonan-7-yl)-N-(imidazo[l,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[l,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5- carboxamide - Isomer 2 (23 mg, 5%, 99.5% ee) as yellow solids. The obtained data for both products are 1 H NMR and MS are identical. 1 H NMR (300 MHz, 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.

[0522] 2-((ls,4s)-4-hydroxycyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy- 2H-indazole-5-carboxamide (Example 7) and 2-((lr,4r)-4-hydroxycyclohexyl)-N- (imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (Example 8)

[0523] (1s,4s)-4-hydroxycyclohexyl methanesulfonate

[0524]

[0525] MsCI (1.9 mL, 23.7 mmol) was added to a solution of (ls,4s)-cyclohexane-l,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 x 20 mL), and the organic layer was dried over Na2S04, filtered and concentrated. The crude (ls,4s)-4-hydroxycyclohexyl methanesulfonate (2.9 g) was purified by silica gel chromatography (with PE:EtOAc 50% to 100%) to give a colorless solid.

[0526] 2-((ls,4s)-4-hydroxycyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy- 2H-indazole-5-carboxamide (Example 7) and 2-((lr,4r)-4-hydroxycyclohexyl)-N- (imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (Example 8)

[0527]

[0528] Cs2CO3(1.8 g, 5.7 mmol) was added to a solution of N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-lH-indazole-5-carboxamide (Int II-l) (350 mg, 1.1 mmol) and crude (ls,4s)-4-hydroxycyclohexylmethane sulfonate (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 the trans and cis isomers of 2-(4-hydroxycyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5- carboxamide as a light yellow solid. This material was separated by preparative SFC (CHIRALPAK IH, 2.0 x 25 cm, 5 μm; mobile phase A: CO2, mobile phase B: EtOH (8 mmol / L NH3-MeOH); flow rate: 40 mL / min; gradient: 40% B) to give the first elute 2-((ls,4s)-4-hydroxycyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (4 mg, 1%) and the second elute 2-(lr,4r)-4-hydroxycyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (12 mg, 3%) both as light yellow solids. (ls,4s)-isomer: 1 H NMR (300 MHz, 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. (lr,4r)-isomer: 1 H NMR (300 MHz, 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.

[0529] 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)

[0530]

[0531] To rac-(1R,3R)-3-hydroxycyclohexyl 4-tosylate (Int III-7) (351 mg, 1.3 mmol) and Cs2CO3(423 mg, 1.3 mmol) in DMF (10 mL) was added N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-1H-indazole-5-carboxamide (Int II-1) (400 mg, 1.3 mmol) under N2atmosphere and the resulting mixture was stirred at 90 °C. After 5 h, the reaction mixture was allowed to cool to rt and directly subjected to C18 flash chromatography (eluting with 0% to 100% MeCN in water (0.05% FA), followed by preparative HPLC (XBridge Prep OBD C18, 30 x 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 x 100 mm, 3 μm; mobile phase A: (MTBE + 0.5% 2N NH3 in MeOH), mobile phase B: i-PrOH; gradient: 30% B isocratic in 25 min; flow rate: 18 mL / min) to give rel-2-((1S,3R)-3-hydroxycyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-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) as yellow solids. Isomer 1: 1H NMR (400 MHz, 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 (400 MHz, 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.

[0532] 6-Methoxy-2-(l-methyl-2-oxo-l-azaspiro[4.5]dec-8-yl)-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 11) and Isomer 2 (Example 12)

[0533]

[0534] To a solution of 6-methoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-lH-indazole-5- carboxamide (Int II-2) (450 mg, 1.5 mmol) and l-methyl-2-oxo-l-azaspiro[4.5]dec-8-yl 4- toluenesulfonate (Int III-l) (985 mg, 2.9 mmol) in DMF (8 mL) was added Cs2CO3(1.4 g, 4.4 mmol) at rt under N2atmosphere. The reaction mixture was stirred at 90 °C for 12 h. The mixture was cooled to rt and purified directly by C18 flash chromatography (eluted with 0-40% MeCN (0.5% FA) in water) and further purified by preparative HPLC (Waters Shield RP18 OBD, 5 pm 30 x 150 mm; elution gradient was 22-32% MeCN (0.1% FA) in water over 9 min; 60 mL / min) to give 6-methoxy-2-(l-methyl-2-oxo-l-azaspiro[4.5]dec-8-yl)-N- (pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide as a yellow solid. The solid was isolated by chiral preparative HPLC (YMC Chiral ART Cellulose-SB 5 pm 20 mm x 250 mm; 50% hexanes / DCM (75 / 25, 0.5% 2M NH3-MeOH) in MeOH isocratic over 9 min; 20 mL / min) to give 6-methoxy-2-(l-methyl-2-oxo-l-azaspiro[4.5]dec-8-yl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)- 2H-indazole-5-carboxamide - Isomer 1 (55 mg, 8%, 100% ee) and 6-methoxy-2-(l-methyl-2-oxo-l- azaspiro[4.5]dec-8-yl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 2 (32 mg, 5%, 99.8% ee). Isomer 1: 1 H NMR (400 MHz, 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) (rotamers), 8.16 (s, 1H), 7.44 (s, 1H), 7.06 (dd, 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 (400 MHz, DMSO-d6) (1 :7 mixture of rotamers) δ 10.35 (s, 1 H), 9.08 (dd, 1 H), 8.73 (s, 1 H), 8.59 (s, 1 H), 8.54 (dd, 1 H), 8.49 / 8.48 (s, 1 H) (rotamers), 7.25 (s, 1 H), 7.05 (dd, 1 H), 4.48-4.60 (m, 1 H), 4.06 (s, 3 H), 2.68 (s, 3 H), 2.28 (t, 2 H), 2.08-2.18 (m, 4 H), 1.93-2.04 (m, 4 H), 1.52-1.60 (m, 2 H). m / z (ESI+), [M+H] + = 474.

[0535] rel-2-((1 S,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)

[0536]

[0537] To a slurry of 6-methoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-lH-indazole-5- carboxamide (Int II-2) (400 mg, 1.3 mmol) and rac-(lR,3R)-3-hydroxycyclohexyl 4- toluenesulfonate (Int III-7) (702 mg, 2.6 mmol) in DMF (15 mL) was added Cs2CO3(1.3 g, 3.9 mmol) at rt under N2atmosphere. The resulting mixture was stirred at 90 °C for 12 h. The reaction mixture was allowed to cool to rt, concentrated and purified directly by C18 flash chromatography (eluting with 0 to 100% MeCN in water (0.05% NH4OH), then by preparative HPLC (XBridge Prep OBD C18, 30 x 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 over 7 min) to give the desired regioisomer rac-2-((lS,3R)-3-hydroxycyclohexyl)-6-methoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide as a yellow solid. This material was separated by chiral preparative HPLC (CHIRAL ART Cellulose-SB column, 2 x 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 over 14 min) to give rel-2-((lS,3R)-3-hydroxycyclohexyl)-6-methoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 1 (26 mg, 5%, 99% ee) and rel-2-((lS,3R)-3-hydroxycyclohexyl)-6-methoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 2 (26 mg, 5%, 99% ee) as yellow solids. Isomer 1: 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, IH), 9.05-9.12 (m, IH), 8.73 (s, IH), 8.51-8.57 (m, 2H), 8.47 (s, IH), 7.22 (s, IH), 7.00-7.10 (m, IH), 4.82-4.86 (m, IH), 4.45-4.55 (m, IH), 4.06 (s, 3H), 3.55-3.67 (m, IH), 2.25-2.34 (m, IH), 2.00-2.11 (m, IH), 1.68-1.95 (m, 4H), 1.40-1.51 (m, IH), 1.13-1.26 (m, IH). m / z (ES+), [M+H] 507.2. + H NMR (400 MHz, DMSO-d6) δ 10.35 (s, IH), 9.05-9.12 (m, IH), 8.73 (s, IH), 8.51-8.57 (m, 2H), 8.47 (s, IH), 7.22 (s, IH), 7.00-7.10 (m, IH), 4.82-4.86 (m, IH), 4.45-4.55 (m, IH), 4.06 (s, 3H), 3.55-3.67 (m, IH), 2.25-2.34 (m, IH), 2.00-2.11 (m, IH), 1.68-1.95 (m, 4H), 1.40-1.51 (m, IH), 1.13-1.26 (m, IH). m / z (ES+), [M+H] 507.2. + = 407.

[0538] 6-Cyclopropoxy-2-(2-hydroxy-2-methylspiro[3.5]non-7-yl)-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 15) and Isomer 2 (Example 16)

[0539]

[0540] To 6-cyclopropoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-lH-indazole-5-carboxamide (Int II-3) (330 mg, 1.0 mmol) in DMF (3 mL) was added 2-hydroxy-2-methylspiro[3.5]nonane (Example 1) (0.25 g, 1.5 mmol) and K2CO3(0.69 g, 5.0 mmol) at rt. The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 0-100% EtOAc in hexanes) to give the title compound (Example 15 and 16) as a mixture of isomers. Isomer 1: 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, IH), 9.05-9.10 (m, IH), 8.73 (s, IH), 8.51-8.56 (m, 2H), 8.47 (s, IH), 7.22 (s, IH), 7.01-7.10 (m, IH), 4.45-4.55 (m, IH), 4.06 (s, 3H), 3.56-3.67 (m, IH), 2.28-2.32 (m, IH), 2.00-2.10 (m, IH), 1.87-1.92 (m, IH), 1.67-1.87 (m, 3H), 1.36-1.50 (m, IH), 1.12-1.26 (m, IH). m / z (ES+), [M+H] 507.2. Isomer 2: 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, IH), 9.05-9.12 (m, IH), 8.73 (s, IH), 8.51-8.57 (m, 2H), 8.47 (s, IH), 7.22 (s, IH), 7.00-7.10 (m, IH), 4.82-4.86 (m, IH), 4.45-4.55 (m, IH), 4.06 (s, 3H), 3.55-3.67 (m, IH), 2.25-2.34 (m, IH), 2.00-2.11 (m, IH), 1.68-1.95 (m, 4H), 1.40-1.51 (m, IH), 1.13-1.26 (m, IH). m / z (ES+), [M+H] 507.2. ol) 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 CS2CO3 (643 mg, 2.0 mmol). The reaction mixture was stirred at 85 °C under N2atmosphere 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 purified by preparative HPLC (Waters XBridge BEH C18 OBD, 5 pm, 30 x 150 mm; elution gradient 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[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide as a yellow solid. This material was isolated by preparative chiral HPLC (ChiralPak® AD-H 5 pm 20 mm x 250 mm; isocratic with 50% hexanes / DCM (75 / 25, 10 mM NH3-MeOH) in MeOH; 20 mL / min) to give 6-cyclopropoxy-2-(2-hydroxy-2-methylspiro[3.5]nonan-7-yl)-N-(pyrazolo[l,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[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 2 (38 mg, 9%, 95.8% ee) as yellow solids. The ee's were obtained for both products by chiral HPLC. IE 5 pm 20 mm x 250 mm; isocratic with 50% hexanes / DCM (75 / 25, 10 mM NH3-MeOH) in MeOH; 20 mL / min) to give 6-cyclopropoxy-2-(2-hydroxy-2-methylspiro[3.5]nonan-7-yl)-N-(pyrazolo[l,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[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 2 (38 mg, 9%, 95.8% ee) as yellow solids. The ee's were obtained for both products by chiral HPLC. 1 H NMR and MS were identical. 1 H NMR and MS were identical. + .

[0541] 6-cyclopropoxy-2-((lR,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3- yl)-2H-indazole-5-carboxamide (Example 17) and 6-cyclopropoxy-2-((lS,3R)-3- hydroxycyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 18)

[0542] rel-6-cyclopropoxy-2-((lS,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3- yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 19) and Isomer 2 (Example 20)

[0543] 3-hydroxycyclohexyl 4-methylbenzenesulfonate

[0544]

[0545] TsCl (17.2 g, 90.4 mmol) was added slowly 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) at 0 °C under N2atmosphere over a period of 5 min. The resulting mixture was stirred at rt for 15 h. The reaction mixture was quenched with brine (100 mL), extracted with DCM (100 mL x 2), dried over Na2S04, 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 as a yellow oil (8.0 g, 34%). MS ESI, m / z = 271 [M+H] + .

[0546] rac-6-cyclopropoxy-2-((lS,3R)-3-hydroxycyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3- yl)-2H-indazole-5-carboxamide and rac-6-cyclopropoxy-2-((lS,3S)-3- hydroxycyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide

[0547]

[0548] To a solution of 6-cyclopropoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-lH-indazole-5- carboxamide (Int II-3) (500 mg, 1.5 mmol) and 3-hydroxycyclohexyl 4- toluenesulfonate (1.2 g, 4.5 mmol) in DMF (20 mL) was added Cs2CO3(1.5 g, 4.5 mmol) at rt. The reaction mixture was stirred at 100 °C for 5 h. The reaction mixture was cooled to rt and purified directly 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 x 150 mm; elution gradient 24-34% MeCN in water (10 mM NH4HCO3 + 0.1% NH4OH); 60 mL / min) to give rac-6-cyclopropoxy-2-((lS,3R)-3-hydroxycyclohexyl)-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (31 mg, 5%) and rac-6-cyclopropoxy-2- ((lS,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5- carboxamide (110 mg, 17%) as yellow solids.

[0549] 6-cyclopropoxy-2-((lR,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)- 2H-indazole-5-carboxamide (Example 17) and 6-cyclopropoxy-2-((lS,3R)-3- hydroxycyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 18)

[0550]

[0551] rac-6-cyclopropoxy-2-((lS,3R)-3-hydroxycyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3- yl)-2H-indazole-5-carboxamide (31 mg, 0.1 mmol) was isolated by preparative chiral HPLC (ChiralPak AD-H, 5 μm, 4.6 x 250 mm, 1 mL / min, 20% i-PrOH in hexanes) ID, 5 μm 30 x 250 mm; isocratic with 80% hexanes / DCM (75 / 25, 10 mM NH3-MeOH) in EtOH over 30 min; 45 mL / min) to give 6-cyclopropyloxy-2-((lR,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (6 mg, 20%, 99.9% ee) and 6-cyclopropyloxy-2-((lS,3R)-3-hydroxycyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5- carboxamide (10 mg, 33%, 99.5% ee) as yellow solids. (lR,3S)-isomer: 1 H NMR (300 MHz, DMSO-d6) δ 10.31 (s, IH), 9.07 (dd, IH), 8.75 (s, IH), 8.57 (s, IH), 8.55 (dd, IH), 8.53 (s, IH), 7.51 (s, IH), 7.05 (dd, IH), 4.85 (d, IH), 4.45-4.62 (m, IH), 4.18-4.28 (m, IH), 3.53-3.69 (m, IH), 2.24-2.29 (m, IH), 1.98-2.12 (m, IH), 1.69-1.96 (m, 4H), 1.31-1.53 (m, IH), 1.10-1.31 (m, IH), 0.93-1.10 (m, 4H). MS ESI, m / z = 433 [M+H] + (lS,3R)-isomer: 1 H NMR (300 MHz, DMSO-d6) δ 10.31 (s, IH), 9.07 (dd, IH), 8.75 (s, IH), 8.57 (s, IH), 8.55 (dd, IH), 8.53 (s, IH), 7.51 (s, IH), 7.05 (dd, IH), 4.85 (d, IH), 4.45-4.62 (m, IH), 4.18-4.28 (m, IH), 3.53-3.69 (m, IH), 2.24-2.29 (m, IH), 1.98-2.12 (m, IH), 1.69-1.96 (m, 4H), 1.31-1.53 (m, IH), 1.10-1.31 (m, IH), 0.93-1.10 (m, 4H). MS ESI, m / z = 433 [M+H] + .

[0552] rel-6-cyclopropyloxy-2-((lS,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)- 2H-indazole-5-carboxamide - isomer 1 (Example 19) and isomer 2 (Example 20)

[0553]

[0554] rac-6-cyclopropoxy-2-((lS,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (110 mg, 0.3 mmol) was separated by preparative chiral HPLC (YMC Chiral ART Cellulose-SB 5 μm 20 mm x 250 mm; 90% hexanes / DCM (75 / 25, 10 mM NH3-MeOH) in EtOH isocratic over 17 min; 20 mL / min) to give rel-6-cyclopropoxy-2-((lS,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 1 (37 mg, 34%, 100% ee) and rel-6-cyclopropoxy-2-((lS,3S)-3-hydroxycyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3- yl)-2H-indazole-5-carboxamide-isomer 2 (22 mg, 20%, 98% ee) as yellow solids. Isomer 1: 1 H NMR (300 MHz, 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, 1H), 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: 1H NMR (300 MHz, 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), 4.16-4.26 (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] + .

[0555] 2-(2-Acetyl-2-azaspiro[3.5]non-7-yl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy- 2H-indazole-5-carboxamide (Example 21)

[0556] 7-(5-(Imidazo[l,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2-yl)-2- azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

[0557] To crude 7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (Int III-2) (1.5 g, 4.5 mmol) and N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-lH- indazole-5-carboxamide (Int II-1) (700 mg, 2.3 mmol) in DMF (20 mL) was added KOH (255 mg, 4.5 mmol) at rt over a 2 min period and the resulting mixture was stirred at 100 °C overnight. The reaction mixture was then allowed to cool to rt, poured into water (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent removed in vacuo to give a yellow solid. The residue was purified using C18 flash chromatography eluting with 0% to 80% MeCN (0.05% FA) in water to yield crude 7-(5-(imidazo[l,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2-yl)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (280 mg) which was used without further purification.

[0558] N-(Imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-(2-azaspiro[3.5]nonan-7-yl)-2H- indazole-5-carboxamide

[0559]

[0560] To crude 7-(5-(imidazo[l,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2-yl)- 2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (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 in vacuo and the resulting residue was purified using C18 flash chromatography eluting with 0% to 80% MeCN (5% NH4OH in water) to afford N-(imidazo[l,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] 432.3. + = 432.

[0561] 2-(2-Acetyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy- 2H-indazole-5-carboxamide (Example 21)

[0562]

[0563] To N-(imidazo[l,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) at rt under N2atmosphere. The resulting solution was stirred for 1 h before the solvent was removed in vacuo to afford a yellow solid. The residue was purified using C18 flash chromatography eluting with 60% to 70% MeCN (0.1% FA in water) to afford 2-(2-acetyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide (400 mg, 99%) as a yellow solid. 1H NMR (300 MHz, CD3OD) (1 : 1 mixture of rotamers) δ 8.69 (s, 1 H), 8.55-8.58 (m, 1 H), 8.45 (s, 1 H), 8.12 (s, 1 H), 8.01 (d, 1 H), 7.22 (dd, 1 H), 7.18 (s, 1 H), 4.52-4.55 (m, 1 H), 4.21 (s, 3H), 4.06 (s, 1 H), 3.93 (s, 1 H), 3.83 (s, 1 H), 3.69 (s, 1 H), 1.95-2.28 (m, 6H), 1.89 / 1.91 (s, 3H) (rotamers), 1.74-1.87 (m, 2H). m / z (ESI+), [M+H] + = 474.

[0564] N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((ls,4s)-4-(N-methylacetamido)cyclohexyl)- 2H-indazole-5-carboxamide (Example 22)

[0565] (1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl 4-methylbenzenesulfonate

[0566]

[0567] 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) at rt under N2atmosphere over a 5 min period. After 2 h, the reaction mixture was poured into water (50 mL) and extracted with DCM (2 x 75 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The resulting red oil was dissolved in DCM (50 mL) and filtered through a pad of silica gel. The silica gel pad was washed with DCM (500 mL) and the solvent was removed in vacuo to give crude (1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate (4.5 g) which was used without further purification.

[0568] (1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl 4-methylbenzenesulfonate

[0569]

[0570] To crude (1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl 4- toluenesulfonate (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 allowed to cool to rt, quenched with water (20 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The resulting residue was purified using C18 flash chromatography (eluting with 30% to 60% MeCN (0.05% FA) in water) to give crude (1r,4r)-4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl 4- toluenesulfonate (2.4 g) which was used without further purification.

[0571] ((1s,4s)-4-(5-(imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2- yl)cyclohexyl)(methyl)carbamic acid tert-butyl ester

[0572]

[0573] To crude (1r,4r)-4-(tert-butoxycarbonyl)(methyl)amino)cyclohexyl 4- toluenesulfonate (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 allowed to cool to rt and purified directly using C18 flash chromatography (eluting with 20% to 100% MeCN (0.05% FA) in water) to give crude ((1s,4s)-4-(5-(imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2-yl)cyclohexyl)(methyl)carbamic acid tert-butyl ester (0.6 g). m / z (ESI+), [M+H] = 520. +

[0574] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1s,4s)-4-(methylamino)cyclohexyl)- 2H-indazole-5-carboxamide

[0575]

[0576] ​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 HC1 (12 N, 1 mL, 12.0 mmol) and the resulting mixture was stirred at rt. After 2 h, the solvent was removed in vacuo to give crude HC1 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. + = 420.

[0577] N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-2H- indazole-5-carboxamide (Example 22)

[0578]

[0579] To crude HC1 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) was added acetic anhydride (0.2 mL, 1.7 mmol) and TEA (0.6 mL, 4.4 mmol) in DCM (1 mL) at rt 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. Then, the reaction mixture was quenched with water (5 mL) and the solvent was removed in vacuo. The resulting residue was purified using preparative HPLC (YMC-Actus Triart C18, 30 x 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 over 7 min) to give N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide as a yellow solid (21.5 mg, 4%). 1H NMR (400 MHz, DMSO-d6) (1 :2 mixture of rotamers) δ 11.06 (s, 1 H), 8.74 (s, 1 H), 8.64 (dd, 1 H), 8.60 (s, 1 H), 8.15 (dd, 1 H), 8.05 (s, 1 H), 7.30 (s, 1 H), 7.22 (dd, 1 H), 4.40-4.49 (m, 1 H), 4.13 (s, 3H), 3.75-3.86 (m, 1 H), 2.68 (s, 2H), 2.55 (s, 1 H), 1.99-2.15 (m, 3H), 2.07 (s, 1 H), 1.96 (s, 2H), 1.63-1.88 (m, 3H), 1.52-1.63 (m, 1 H), 1.38-1.47 (m, 1 H). m / z (ESI+), [M+H] + = 462.

[0580] N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lr,4r)-4-(N-methylacetamido)cyclohexyl)- 2H-indazole-5-carboxamide (Example 23)

[0581]

[0582] To a solution of N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lr,4r)-4- (methylamino)cyclohexyl)-2H-indazole-5-carboxamide (Int V-3) (390 mg) in DCM (5 mL) was added TEA (477 μί, 3.4 mmol) at rt. After stirring the resulting mixture for 5 min, acetic anhydride (121 μί, 1.3 mmol) was added. Stirring was continued for 1 h, after which 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 x 250, 5 μιη; mobile phase A: water (0.05% NH4OH), mobile phase B: MeCN; flow rate: 60 mL / min; gradient: 27% B to 47% B over 7 min) to give N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lr,4r)-4-(N- methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (62 mg, 16%) as a yellow solid. 1H NMR (400 MHz, MeOD-d4) (2:3 rotameric mixture) 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) (rotamers), 4.22 / 4.21 (s, 3H) (rotamers), 2.99 / 2.88 (s, 3H) (rotamers), 2.30-2.40 (m, 2H), 2.06-2.25 (m, 5H), 1.81-2.01 (m, 4H).

[0583] 6-methoxy-2-((ls,4s)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin- 3-yl)-2H-indazole-5-carboxamide (Example 24) and 6-methoxy-2-((lr,4r)-4-(N- methylacetamido)cyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5- carboxamide (Example 25)

[0584] 4-(6-methoxy-5-(pyrazolo[l,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl (methyl)carbamate

[0585]

[0586] Cs2CO3(3.2 g, 9.7 mmol) was added to a solution of 4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl 4-tosylate (cis / trans ratio 1 :5) (Int III-10) (2.5 g, 6.5 mmol) and 6-methoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-lH-indazole-5- carboxamide (Int II-2) (1.0 g, 3.2 mmol) in DMF (40 mL) under N2atmosphere. The resulting mixture was stirred at 90 °C for 4 h, allowed to cool to rt and purified directly by flash C18 flash chromatography (eluted with 0% to 70% MeCN in water) followed by preparative HPLC (XBridge Prep OBD C18 column, 30 x 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 give tert-butyl 4-(6-methoxy-5-(pyrazolo[l,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl(methyl)carbamate as a yellow solid (270 mg, 16%, cis / trans ratio 5: 1). m / z (ES+), [M+H] = 520. + = 420.

[0587] 6-methoxy-2-(4-(methylamino)cyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5- carboxamide

[0588]

[0589] TFA (2 mL, 3.0 mmol) was added to tert-butyl 4-(6-methoxy-5-(pyrazolo[l,5-a]pyrimidin-3- ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl(methyl)carbamate (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, the residue was dissolved in EtOAc and basified with saturated aqueous NaHCO3solution. The organic layer was washed with brine (3 x 50 mL), dried over Na2SO4, filtered and the solvent evaporated under reduced pressure to give the TFA salt of 6-methoxy-2-(4-(methylamino)cyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5- carboxamide (120 mg, 99%; cis / trans ratio 5: 1). m / z (ES+), [M+H] = 420. + = 420.

[0590] 6-methoxy-2-((ls,4s)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 24) and 6-methoxy-2- ((lr,4r)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H- indazole-5-carboxamide (Example 25)

[0591]

[0592] 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[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (120 mg, 0.3 mmol) (5: 1 ratio of cis / trans) 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% to 70% MeCN in water) and then by preparative HPLC (XBridge Prep OBD C18 column, 30 x 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 over 7 min) to give 6-methoxy-2-(4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (5: 1 ratio of cis / trans) as an orange solid. The two isomers were separated by chiral preparative HPLC (CHIRAL ART Cellulose-SB column, 2 x 25 cm, 5 μm; elution gradient 50% MTBE (0.5% 2N NH3-MeOH) in EtOH; flow rate: 20 mL / min; over 13 min) to give 6-methoxy-2-((ls,4s)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (90 mg, 68%, 100% ee) as the first eluting isomer and 6-methoxy-2-((lr,4r)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (20 mg, 15%, 100% ee) as the second eluting isomer. (ls,4s)-isomer: 1H NMR (300 MHz, DMSO-d6) (1 :1 mixture of rotamers) δ 10.37 (s, 1 H), 9.05-9.12 (m, 1 H), 8.75 (s, 1 H), 8.70 (s, 1 H), 8.53-8.57 (m, 1 H), 8.49 (s, 1 H), 7.27 (s, 1 H), 7.00-7.11 (m, 1 H), 4.70 (s, 1 H), 4.39-4.54 / 3.74-3.88 (m, 1 H) (rotamers), 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, 1 H). m / z (ES+), [M+H] 562.3. + = 462. (1r,4r)-isomer: 1 H NMR (300 MHz, DMSO-d6) (1 :1 mixture of rotamers) δ 10.36 (s, 1 H), 9.01-9.11 (m, 1 H), 8.74 (s, 1 H), 8.52-8.63 (m, 2H), 8.46-8.49 (m, 1 H), 7.19-7.24 (m, 1 H), 6.99-7.09 (m, 1 H), 4.36-4.59 / 3.70-3.90 (m, 3H) (rotamers), 4.07 (s, 3H), 2.90 (s, 2H), 2.70 (s, 1 H), 2.31-1.93 (m, 7H), 1.59-1.92 (m, 4H). m / z (ES+), [M+H] 562.3. + = 462.

[0593] 2-((1r,4r)-4-(cyclopropanecarboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 26) and 2-((1 s,4s)-4- (cyclopropanecarboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3- yl)-2H-indazole-5-carboxamide (Example 27)

[0594] (4-(6-methoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H-indazol-2- yl)cyclohexyl)carbamic acid tert-butyl ester

[0595]

[0596] To a suspension of 6-methoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-lH-indazole-5- carboxamide (Int II-2) (500 mg, 1.6 mmol) and 4-((tert-butoxycarbonyl)amino)cyclohexyl 4- toluenesulfonate (cis / trans ratio 1 :5) (Int III-9) (1.5 g, 4.1 mmol) in DMF (15 mL) was added Cs2CO3(1.6 g, 4.9 mmol) at rt under N2atmosphere over a period of 2 min. The reaction mixture was stirred at 90 °C for 3 h. The mixture was cooled to rt and purified directly by C18 flash chromatography eluting with 0-80% MeCN in water (1% NH4OH) to give tert-butyl (4-(6-methoxy-5-(pyrazolo[l,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] + .

[0597] 2-(4-Aminocyclohexyl)-6-methoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5- carboxamide

[0598]

[0599] To a solution of tert-butyl (4-(6-methoxy-5-(pyrazolo[l,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) was added 4N HC1 in dioxane (1.4 mL, 5.6 mmol) dropwise at rt under N2atmosphere over a period of 2 min. The reaction mixture was stirred for 2 h after which it was concentrated under reduced pressure to give 2-(4- aminocyclohexyl)-6-methoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (cis / trans ratio 7: 1) (270 mg, ~90 wt.%) as a crude HC1 salt which was used without further purification. MS ESI, m / z = 406 [M+H] + .

[0600] 2-((lr,4r)-4-(Cyclopropanecarboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[l,5-a]pyrimidin- 3-yl)-2H-indazole-5-carboxamide (Example 26) and 2-((ls,4s)-4-(cyclopropanecarboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5- carboxamide (Example 27)

[0601]

[0602] To a solution of crude HC1 salt of 2-(4-aminocyclohexyl)-6-methoxy-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (cis / trans ratio 7: 1) (90 wt.%) (270 mg) and TEA (250 μί, 1.8 mmol) in DCM (4 mL) was added 4-bromobutyryl chloride (227 mg, 1.2 mmol) slowly over a 2 min period at rt under N2atmosphere and the resulting mixture was stirred for 2 h. The mixture was purified directly by C18 flash chromatography eluting with 0-90% MeCN in water (0.5% FA) and further purified by preparative HPLC (Waters Shield RP18 OBD, 5 μιη 30 x 150 mm; elution gradient was 26-34% MeCN in water (0.05% NH4OH) over 8 min; 60 mL / min) to give 2-((lr,4r)-4-(cyclopropanecarboxamido)cyclohexyl)-6-methoxy-N- (pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (8 mg, 3%) after which this material was again isolated by preparative HPLC (Waters BEH OBD C18, 5 μιη 30 x 150 mm; elution gradient was 35-50% MeCN in water (10 mM NH4HCO3 and 0.1% NH4OH) over 7 min; 60 mL / min) to give 2-((ls,4s)-4-(cyclopropanecarboxamido)cyclohexyl)-6-methoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (52 mg, 20%) both as yellow solids. (lr,4r)-isomer: 1 H NMR (300 MHz, 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: 1H NMR (300 MHz, DMSO-d6) δ 10.35 (s, 1 H), 9.07 (dd, 1 H), 8.73 (s, 1 H), 8.59 (s, 1 H), 8.54 (dd, 1 H), 8.50 (s, 1 H), 8.07 (d, 1 H), 7.22 (s, 1 H), 7.05 (dd, 1 H), 4.46-4.60 (m, 1 H), 4.07 (s, 3 H), 3.87-4.00 (m, 1 H), 2.25-2.39 (m, 2 H), 1.89-2.10 (m, 2 H), 1.58-1.87 (m, 5 H), 0.56-0.76 (m, 4 H). MS ESI, m / z = 474 [M+H] + .

[0603] 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)

[0604] 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 )

[0605] rac-(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-carboxylic acid tert-butyl ester

[0606]

[0607] To a solution of 6-cyclopropoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-lH-indazole-5- carboxamide (Int II-3) (500 mg, 1.5 mmol) and rac-(6R,7S)-6-methyl-7-((methylsulfonyl)oxy)- 2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (Int III-5) (748 mg, 2.2 mmol) in DMF (10 mL) was added Cs2CO3(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 purified directly by C18 flash chromatography eluting with 80-100% MeCN in water (0.1% NH4OH) to give crude rac-(6R,7R)-7-(6-cyclopropoxy-5-(pyrazolo[l,5-a]pyrimidin-3-ylcarbamoyl)-2H- indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (400 mg). MS ESI, m / z = 572 [M+H] + .

[0608] rac-6-cyclopropoxy-2-((6R,7R)-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide

[0609]

[0610] To a solution of crude rac-(6R,7R)-7-(6-cyclopropoxy-5-(pyrazolo[l,5-a]pyrimidin-3- ylcarbamoyl)-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (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 crude rac-6-cyclopropoxy-2-((6R,7R)-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide as a TFA salt (350 mg) as a yellow oil which was used without further purification. MS ESI, m / z = 472 [M+H] + .

[0611] rel-2-((6R,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-6-cyclopropoxy-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 28) and Isomer 2 (Example 29)

[0612]

[0613] A crude TFA salt (350 mg) of racemic 6-cyclopropoxy-2-((6R,7R)-6-methyl-2-azaspiro[3.5]nonane-7-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide was added to a solution of TEA (250 μL, 1.8 mmol) in DCM (5 mL) at 0 °C under N2 atmosphere, along with acetyl chloride (110 mg, 1.4 mmol). The resulting mixture was stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was analyzed by preparative HPLC (Waters). C18OBD, 5μm 30×150mm; elution gradient of 35%-45% MeCN (0.1% FA) in water over 7 min; 60 mL / min) was purified and then subjected to preparative chiral HPLC ( IA 5μm 20mm×250mm; reacts with 25% MTBE (2mM) in EtOH within 27min. Purified at NH3-MeOH (15 mL / min) to give rel-2-((6R,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonane-7-yl)-6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 1 (15 mg, 5%, 100% e) and rel-2-((6R,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonane-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 H NMR and MS are the same. 1HNMR (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) (rotamers), 2.06-2.17 (m, 1H), 1.88-2.06 (m, 4H), 1.80 / 1.77 (s, 3H) (rotamers), 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] + .

[0614] rac-(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-carboxylic acid

[0615]

[0616] To a solution of 6-cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-1 H-indazole-5- carboxamide (Int II-3) (600 mg, 1.8 mmol) and rac-(6S,7S)-6-methyl-7-((methylsulfonyl)oxy)- 2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (Int III-6) (1.1 g, 3.2 mmol) in DMF (6 mL) was added Cs2CO3(1.8 g, 5.4 mmol) at rt under N2atmosphere. The reaction mixture was stirred at 95 °C for 12 h. The mixture was cooled to rt and purified directly by C18 flash chromatography eluting with 0% - 100% MeOH in water (0.05% FA) to give crude rac-(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-carboxylic acid tert-butyl ester (900 mg) as a yellow solid containing approximately 30% N1 -isomer. MS ESI, m / z = 572 [M+H] + .

[0617] rac-6-cyclopropoxy-2-((6S,7R)-6-methyl-2-azaspiro[3.5]non-7-yl)-N-(pyrazolo[1,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide

[0618]

[0619] To a solution of crude rac-(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-carboxylic acid tert-butyl ester (900 mg) (containing 30% N1 -isomer) in DCM (5 mL) under N2atmosphere was added TFA (243 mL, 31.5 mmol) dropwise and the resulting solution was stirred at rt for 12 h. The mixture was concentrated under reduced pressure to give crude TFA salt of rac-6-cyclopropoxy-2-((6S,7R)-6-methyl-2-azaspiro[3.5]non-7-yl)-N-(pyrazolo[1,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide as a yellow solid (710 mg) containing some N1 -isomer. MS ESI, m / z = 472 [M+H] + .

[0620] rel-2-((6S,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]non-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)

[0621]

[0622] To a solution of crude TFA salt of rac-6-cyclopropoxy-2-((6S,7R)-6-methyl-2- azaspiro[3.5]non-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) at rt under N2atmosphere. 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]non-7-yl)-6- cyclopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (100 mg) which was purified by preparative HPLC (Waters XBridge BEH OBD C18, 5 μm 30 x 150 mm; elution gradient 30-50% MeCN in water (10 mM NH4HCO3 + 0.1% NH4OH) over 7 min; 60 mL / min) and then separated by preparative chiral HPLC (YMC Chiral ART Cellulose-SB 5 μm 20 mm x 250 mm; isocratic with 50% hexanes / DCM (75 / 25, 10 mM NH3-MeOH) in EtOH; 20 mL / min) to give rel-2-((6S,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]non-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]non-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. The ee of both products was obtained by chiral HPLC. 1 H NMR and MS were the same. 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1 H), 9.07 (dd, 1 H), 8.75 (s, 1 H), 8.50-8.59 (m, 3H), 7.53 (d, 1 H), 7.05 (dd, 1 H), 4.68 (br. s, 1 H), 4.24 (br. s, 1 H), 3.82-3.93 (m, 2H), 3.56-3.67 (m, 2H), 2.30-2.42 (m, 1 H), 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] + .

[0623] 6-cyclopropoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5- b]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 32) and 6-cyclopropoxy-2-((1 r,4r)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-b]pyrimidin-3-yl)-2H- indazole-5-carboxamide (Example 33)

[0624] (4-(6-cyclopropoxy-5-(pyrazolo[1,5-b]pyrimidin-3-ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)carbamic acid tert-butyl ester

[0625]

[0626] To a solution of 4-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl 4- toluenesulfonate (cis / trans ratio 1 :5) (Int III-10) (2.3 g, 6.0 mmol) and 6-cyclopropoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-lH-indazole-5- carboxamide (Int II-3) (1.0 g, 3.0 mmol) in DMF (30 mL) was added Cs2CO3(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 purified by preparative HPLC (Waters XBridge BEH OBD C18 5μm 30 x 150 mm; elution gradient 47-67% MeCN in water (10 mM NH4HCO3 and 0.1% NH4OH) over 7 min; 60 mL / min) to give tert-butyl (4-(6-cyclopropoxy-5-(pyrazolo[l,5-a]pyrimidin-3-ylcarbamoyl)-2H- indazol-2-yl)cyclohexyl)(methyl)carbamate (cis / trans ratio 5: 1) as an orange solid (180 mg, 11%). MS ESI, m / z = 546 [M+H] + .

[0627] 6-cyclopropoxy-2-(4-(methylamino)cyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)- 2H-indazole-5-carboxamide

[0628]

[0629] To a solution of tert-butyl (4-(6-cyclopropoxy-5-(pyrazolo[l,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 6-cyclopropoxy-2-(4-(methylamino)cyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (cis / trans ratio 5: 1) (130 mg, 94 wt.%) as a crude TFA salt. The crude product was used without further purification. MS ESI, m / z = 446 [M+H] + .

[0630] 6-cyclopropoxy-2-((1 s,4s)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 32) and 6-cyclopropoxy-2- ((1 r,4r)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H- indazole-5-carboxamide (Example 33)

[0631]

[0632] 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 isolated by preparative chiral HPLC (ChiralPak AD-H, 30 x 250 mm, 5 μm, 90:10 hexane:EtOH, 40 mL / min, 230 nm) to give 6-cyclopropoxy-2-((1 s,4s)-4-(N-methylacetamido)cyclohexyl)-N- (pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 32) and 6- cyclopropoxy-2-((1 r,4r)-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin- 3-yl)-2H-indazole-5-carboxamide (Example 33) as orange solids. ID-2, 5 μm 20 x 250 mm; isocratic with 70% hexanes / DCM (3 / 1, 0.5% 2N NH3-MeOH solution) in MeOH; flow rate: 20 mL / min) to give 6-cyclopropyloxy-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-cyclopropyloxy-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 (300 MHz, 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) (rotamers), 4.17-4.30 (m, 1H), 2.54-2.77 (m, 2H), 2.55 / 2.69 (s, 3H) (rotamers), 1.91-2.22 (m, 2H), 1.97 / 2.08 (s, 3H) (rotamers), 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 (300 MHz, 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) (rotamers), 4.17-4.30 (m, 1H), 2.54-2.77 (m, 2H), 2.55 / 2.69 (s, 3H) (rotamers), 1.91-2.22 (m, 2H), 1.97 / 2.08 (s, 3H) (rotamers), 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] + .

[0633] N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lR,2R,4R*)-2-methyl-4-(N- methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 1 (Example 36) and Isomer 2 (Example 37)

[0634] N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lR,2R,4R*)-2-methyl-4-(N- methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 1 (Example 36) and Isomer 2 (Example 37)

[0635] N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lS,2S)-2-methyl-4-oxocyclohexyl)- 2H-indazole-5-carboxamide

[0636]

[0637] To a solution of N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lS,2S)-2-methyl-4- oxocyclohexyl)-2H-indazole-5-carboxamide (Int V-l) (100 mg, 0.2 mmol) and 1 M methylamine in MeOH (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 (0.1% FA) in water to afford N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lS,2S)-2-methyl-4- (methylamino)cyclohexyl)-2H-indazole-5-carboxamide (90 mg, 87%) as a yellow solid. MS ESI, m / z = 434 [M+H] + .

[0638] N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lS,2S,4R*)-2-methyl-4-(N- methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 1 (Example 34) and Isomer 2 (Example 35)

[0639]

[0640] To a solution of N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lS,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 purified by preparative HPLC (Waters XSelect CSH C18 OBD, 5 μm 30 x 150 mm; elution gradient 50-65% MeCN in water (0.1% FA) over 10 min; 60 mL / min) to give N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lS,2S)-2-methyl-4-(N- methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (45 mg) as a yellow solid. The solid was isolated by preparative chiral HPLC (Chiralpak® AD-H, 5 μm 20 x 250 mm; isocratic with 50% MTBE in MeOH (0.5% 2N NH3-MeOH solution) over 28 min; flow rate: 15 mL / min) to give N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lS,2S,4R*)-2-methyl-4-(N- methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 1 (11 mg, 12%, 99.9% ee) and N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lS,2S,4R*)-2-methyl-4-(N- methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 2 (20 mg, 22%, 99.9% ee) as yellow solids. IF, 5 μm 20 x 250 mm; isocratic with 50% MTBE in MeOH (0.5% 2N NH3-MeOH solution) over 28 min; flow rate: 15 mL / min) to give N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lS,2S,4R*)-2-methyl-4-(N- methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 1 (11 mg, 12%, 99.9% ee) and N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lS,2S,4R*)-2-methyl-4-(N- methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 2 (20 mg, 22%, 99.9% ee) as yellow solids. Isomer 1: 1 H NMR (300 MHz, 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) (rotamers), 4.06-4.22 (m, 4H), 2.86 / 2.73 (s, 3H) (rotamers), 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 (300 MHz, 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) (rotamers), 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] + .

[0641] N-(Imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lR,2R)-2-methyl-4- (methylamino)cyclohexyl)-2H-indazole-5-carboxamide

[0642]

[0643] To a solution of N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lR,2R)-2- methyl-4-oxocyclohexyl)-2H-indazole-5-carboxamide (Int V-2) (120 mg, 0.3 mmol) and 2M 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 (0.1% FA) in water to give N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lR,2R)-2-methyl-4- (methylamino)cyclohexyl)-2H-indazole-5-carboxamide (100 mg, 80%) as a yellow solid. MS ESI, m / z = 434 [M+H] + .

[0644] N-(Imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lR,2R,4R*)-2-methyl-4-(N- methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 1 (Example 36) and Isomer 2 (Example 37)

[0645]

[0646] To a solution of N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lR,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 BEH C18 OBD, 5 μm 19 x 250 mm; elution gradient 50-60% MeCN in water (10 mM NH4HCO3 and 0.1% NH4OH) over 10 min; 25 mL / min) to give N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lR,2R)-2-methyl-4-(N- methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide (62 mg) as a yellow solid. The solid was isolated by preparative chiral HPLC (ChiralPak® AD-H, 5 μm 20 x 250 mm; 50% MTBE in MeOH (0.5% 2N NH3-MeOH solution) isocratic over 18 min; flow rate: 15 mL / min) to give N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lR,2R,4R*)-2-methyl-4-(N- methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 1 (25 mg, 25%, 100% ee) and N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lR,2R,4R*)-2-methyl-4-(N- methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 2 (20 mg, 20%, 99.8% ee) as yellow solids. IF, 5 μm 20 x 250 mm; 50% MTBE in MeOH (0.5% 2N NH3-MeOH solution) isocratic over 18 min; flow rate: 15 mL / min), to give N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lR,2R,4R*)-2-methyl-4-(N- methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 1 (25 mg, 25%, 100% ee) and N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((lR,2R,4R*)-2-methyl-4-(N- methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide - Isomer 2 (20 mg, 20%, 99.8% ee) as yellow solids. Isomer 1: 1H NMR (300 MHz, 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 / 3.89-4.08 (m, 1H) (rotamers), 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 (300 MHz, 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) (rotamers), 4.03-4.27 (m, 4H), 2.86 / 2.72 (s, 3H) (rotamers), 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] + .

[0647] 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)

[0648] 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)

[0649] rac-6-methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]dec-8-yl)-N-(pyrazolo[1,5- a]pyrimidin-3-yl)-2-indazole-5-carboxamide

[0650]

[0651] To a solution of 6-methoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-lH-indazole-5- carboxamide (Int II-2) (1.1 g, 3.6 mmol) and rac-(7R,8S)-7-methyl-l,4-dioxaspiro[4.5]dec-8- ylmethanesulfonate (Int III-13) (1.8 g, 7.1 mmol) in DMF (10 mL) was added Cs2CO3(3.5 g, 10.7 mmol) under N2atmosphere. 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 x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire™ Prep C18 OBD, 5 pm 30 x 150 mm; elution gradient was 30-40% MeCN (0.1% FA) in water over 9 min; 60 mL / min) to give rac-6-methoxy-2-((7S,8S)-7-methyl-l,4-dioxaspiro[4.5]dec-8-yl)-N- (pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (700 mg, 42%). m / z (ESI+), [M+H] 463.3. Shield RP18 OBD, 5 pm 30 x 150 mm; elution gradient was 30-40% MeCN (0.1% FA) in water over 9 min; 60 mL / min) to give rac-6-methoxy-2-((7S,8S)-7-methyl-l,4-dioxaspiro[4.5]dec-8-yl)-N- (pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (700 mg, 42%). m / z (ESI+), [M+H] + = 463.

[0652] rac-6-methoxy-2-((lS,2S)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3- yl)-2H-indazole-5-carboxamide

[0653]

[0654] To a solution of rac-6-methoxy-2-((7S,8S)-7-methyl-l,4-dioxaspiro[4.5]dec-8-yl)-N- (pyrazolo[l,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 HC1 (2.7 mL, 8.0 mmol) at rt under N2atmosphere. The resulting mixture was stirred at rt for 2 h. The reaction mixture was acidified with concentrated aqueous NH4OH solution and purified directly by C18 flash chromatography (eluted with 20-50% MeCN (1% FA) in water) to give rac-6-methoxy-2-((lS,2S)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3- yl)-2H-indazole-5-carboxamide (200 mg, 74%) as a yellow solid. m / z (ESI+), [M+H] + = 419.

[0655] 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)

[0656]

[0657] 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)

[0658]

[0659] 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 NaBH4(36 mg, 1.0 mmol) under N2atmosphere. The resulting mixture was stirred at rt for 1 h. The reaction mixture was quenched with water (10 mL) and purified directly by C18 flash chromatography (eluting with 0-50% MeCN (0.5% FA) in water) to give rac-2-((1S,2S)-4-hydroxy-2-methylcyclohexyl)-6-methoxy-N-(pyrazolo[1,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide as a yellow solid. This mixture was separated by preparative chiral HPLC (ChiralPak® ID-2, 5 μm 20 x 250 mm; with MTBE (0.1% 2N NH3-MeOH) / MeOH, 60 / 40 isocratic; flow rate: 16 mL / min) to give 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 with lower purity, were purified by a second chiral preparative HPLC (ChiralPak® ID-2, 5 μm 20 x 250 mm; with MTBE (0.1% 2N NH3-MeOH) / MeOH, 60 / 40 isocratic; flow rate: 16 mL / min) to give 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 (5 mg, 3%, 99.9% 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 2 (5 mg, 3%, 99.9% ee) as the second eluting isomer. ID-2, 5 μm 20 x 250 mm; with MTBE (0.1% 2N NH3-MeOH) / MeOH, 60 / 40 isocratic; flow rate: 16 mL / min) to give 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 with lower purity, were purified by a second chiral preparative HPLC (ChiralPak® ID-2, 5 μm 20 x 250 mm; with MTBE (0.1% 2N NH3-MeOH) / MeOH, 60 / 40 isocratic; flow rate: 16 mL / min) to give 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 (5 mg, 3%, 99.9% 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 2 (5 mg, 3%, 99.9% ee) as the second eluting isomer. IE, 5 μιη 20 x 250 mm; with MTBE (2 mM NH3-MeOH solution) / MeOH, 50 / 50 isocratic; flow rate: 20 mL / min) to give 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.

[0660] 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.

[0661] rel-(1S,2S,4S)-isomer 1: 1 H 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.

[0662] rel-(1S,2S,4S)-isomer 2: 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), 3.56 - 3.67 (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.

[0663] rel-(1S,2S,4R)-isomer 2: 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), 4.03 - 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.

[0664] 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)

[0665] 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)

[0666] rac-6-cyclopropoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]dec-8-yl)-N-(pyrazolo[1,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide

[0667]

[0668] To a solution of 6-cyclopropoxy-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-lH-indazole-5- carboxamide (Int II-3) (1.4 g, 4.2 mmol) and rac-(7R,8S)-7-methyl-l,4-dioxaspiro[4.5]dec-8- ylmethanesulfonate (Int III-13) (1.1 g, 8.4 mmol) in DMF (30 mL) was added Cs2CO3(2.9 g, 9.0 mmol). The reaction mixture was stirred at 95 °C for 3 h, and after cooling to rt was diluted with EtOAc (500 mL) and washed with brine (100 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative SFC (DAICEL Chiralpak IC, 5 pm, 30 mm x 250 mm; isocratic with 30% DCM / MeOH (50 / 50, 0.1% 2M NH3-MEOH) in CO2(35 °C, 70 bar); 60 mL / min) to give rac-6-cyclopropoxy-2-((7S,8S)-7-methyl-l,4-dioxaspiro[4.5]dec-8-yl)-N- (pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (440 mg, 22%) as an orange solid. MS ESI, m / z = 489 [M+H] P4VP, 5 pm 30 mm x 250 mm; isocratic with 30% DCM / MeOH (50 / 50, 0.1% 2M NH3-MEOH) in CO2(35 °C, 70 bar); 60 mL / min) to give rac-6-cyclopropoxy-2-((7S,8S)-7-methyl-l,4-dioxaspiro[4.5]dec-8-yl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (440 mg, 22%) as an orange solid. MS ESI, m / z = 489 [M+H] + .

[0669] rac-6-cyclopropoxy-2-((lS,2S)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3- yl)-2H-indazole-5-carboxamide

[0670]

[0671] To a solution of rac-6-cyclopropoxy-2-((7S,8S)-7-methyl-l,4-dioxaspiro[4.5]dec-8-yl)-N- (pyrazolo[l,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 HC1 (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 (0.1% FA) in water) and by preparative SFC (YMC Chiral ART Amylose-C Ne o5 μm 30 mm x 250 mm; isocratic with 60% MeOH / MeCN (50 / 50, 0.1% 2M NH3-MeOH) in CO2(35 °C, 78 bar); 60 mL / min) further purification to give rac-6-cyclopropoxy-2-((1S,2S)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[1,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide as an orange solid (196 mg, 54%). MS ESI, m / z = 445 [M+H] + .

[0672] 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)

[0673]

[0674] 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)

[0675]

[0676] 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 NaBH4(31 mg, 0.8 mmol) under N2atmosphere. The resulting mixture was stirred at rt for 2 h. The reaction mixture was quenched with water (1 mL) and then concentrated under reduced pressure. The residue was purified by C18 flash chromatography (eluted 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 isolated by preparative chiral HPLC (ChiralPak AD-H, 30 x 250 mm, 5 μm, 90% i-PrOH / hexane, 40 mL / min) to give rac-6-cyclopropoxy-2-((1S,2S)-4-hydroxy-2-methylcyclohexyl)-N-(pyrazolo[1,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - isomer 1 (Example 46) and isomer 2 (Example 47) as orange solids. IA 5 μm 20 mm x 250 mm; isocratic with 80% MTBE in MeOH (0.1% 2N NH3-MeOH); 17 mL / min) to give rel-6-cyclopropyloxy-2-((lS,2S,4R)-4-hydroxy-2- methylcyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide- Isomer 1 (8 mg, 4%, 98.9% ee) as the first eluting isomer, rel-6-cyclopropyloxy-2- ((lS,2S,4R)-4-hydroxy-2-methylcyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H- indazole-5-carboxamide-Isomer 2 (7 mg, 4%, 98.4% ee) as the second eluting isomer, rel-6-cyclopropyloxy-2-((lS,2S,4S)-4-hydroxy-2-methylcyclohexyl)-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-Isomer 1 (40 mg, 22%, 99.6% ee) as the third eluting isomer and rel-6-cyclopropyloxy-2-((lS,2S,4S)-4-hydroxy-2- methylcyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide- Isomer 2 (30 mg, 17%, 99.5% ee) as the fourth eluting isomer.

[0677] rel-(lS,2S,4R)-Isomer 1: 1 H NMR (300 MHz, DMSO-d6) δ 10.31 (s, IH), 9.07 (dd, IH), 8.75 (s, IH), 8.48-8.61 (m, 3H), 7.53 (s, IH), 7.05 (dd, IH), 4.55 (d, IH), 4.16-4.27 (m, IH), 4.10 (td, IH), 3.96 (br. s, IH), 2.24-2.47 (m, 2H), 1.77-1.90 (m, 2H), 1.50-1.77 (m, 2H), 1.28-1.42 (m, IH), 0.93-1.15 (m, 4H), 0.55 (d, 3H). MS ESI, m / z = 447 [M+H] + .

[0678] rel-(lS,2S,4R)-Isomer 2: 1H NMR (300 MHz, 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] + .

[0679] rel-(1S,2S,4S)-isomer 1: 1 H NMR (300 MHz, 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] + .

[0680] rel-(1S,2S,4S)-isomer 2: 1 H NMR (300 MHz, 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] + .

[0681] 6-cyclopropoxy-2-(2-hydroxyspiro[3.5]non-7-yl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)- 2H-indazole-5-carboxamide - Isomer 1 (Example 46) and Isomer 2 (Example 47)

[0682] 8, 11-dioxaspiro[3.2.4 7 .2 4 ]tridecan-2-ol

[0683]

[0684] To a solution of 8, 11-dioxaspiro[3.2.4 7 .2 4 ]tridecan-2-one (3.0 g, 15.3 mmol) in MeOH (50 mL) at 0 °C under N2atmosphere was added NaBH4(867 mg, 22.9 mmol). 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-dioxaspiro[3.2.4 7 .2 4 ]tridecan-2-ol (3.0 g, 99%) as a colorless solid.1H NMR (400 MHz, 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).

[0685] 8, 11-dioxaspiro[3.2.4 7 .2 4 ]tridecan-2-yl 4-nitrobenzoate

[0686]

[0687] To a solution of 8, 11-dioxaspiro[3.2.4 7 .2 4 ]tridecan-2-ol (3.0 g, 15.1 mmol) in DCM (50 mL) at 0 °C was added 4-nitrobenzoyl chloride (3.7 g, 19.7 mmol). 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-dioxaspiro[3.2.4 7 .2 4Tridecan-2-yl 4-nitrobenzoate (6.0 g, 75 wt.%). MS ESI, m / z = 348 [M+H] + .

[0688] 7-Oxospiro[3.5]nonan-2-yl 4-nitrobenzoate

[0689]

[0690] To a solution of crude 8,11-dioxodispiro[3.2.4 7 .2 4 ]tridecan-2-yl 4-nitrobenzoate (75 Wt.%) (6.0 g) in THF (40 mL) was added 2N HC1 (40.0 mL, 80.0 mmol) 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 Na2S04, filtered and then concentrated under reduced pressure to give 7-oxospiro[3.5]nonan-2-yl 4-nitrobenzoate (3.5 g, 50%). 1 H NMR (300 MHz, 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).

[0691] 7-Hydroxyspiro[3.5]nonan-2-yl 4-nitrobenzoate

[0692]

[0693] To a solution of 7-oxospiro[3.5]nonan-2-yl 4-nitrobenzoate (3.4 g, 11.2 mmol) in MeOH (60 mL) was added NaBH4(848 mg, 22.4 mmol) at rt under N2atmosphere. 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 Na2S04, 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. 1H NMR (300 MHz, DMSO-d6) δ 8.34 (d, 1 H), 8.18 (d, 1 H), 5.18 (p, 1 H), 4.42 (d, 1 H), 3.34 - 3.50 (m, 2 H), 2.19 - 2.46 (m, 2 H), 1.89 (td, 2 H), 1.50 - 1.78 (m, 4 H), 1.06 - 1.50 (m, 4 H).

[0694] 7-(Methoxycarbonyl)spiro[3.5]nonan-2-yl 4-nitrobenzoate

[0695]

[0696] 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) was slowly added TsCl (2.8 g, 14.7 mmol). The resulting mixture was stirred at rt for 2 h, then diluted with DCM (100 mL) and washed with 0.1 N HC1 (75 mL). The organic layer was dried over Na2S04, 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 as a colorless solid (1.20 g, 44%). 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (d, 2 H), 8.14 (d, 2 H), 7.80 (d, 2 H), 7.47 (d, 2 H), 5.16 (p, 1 H), 4.41 - 4.59 (m, 1 H), 2.43 (s, 3 H), 2.24 - 2.42 (m, 2 H), 1.83 - 1.95 (m, 2 H), 1.60 - 1.71 (m, 4 H), 1.38 - 1.60 (m, 4 H).

[0697] 6-Cyclopropoxy-2-(2-hydroxyspiro[3.5]nonan-7-yl)-N-(pyrazolo[l,5-a]pyrimidin-3- yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 46), Isomer 2 (Example 47)

[0698]

[0699] 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[l,5-a]pyrimidin-3-yl)-lH-indazole-5- carboxamide (Int II-3) (350 mg, 1.1 mmol) in DMF (20 mL) was added Cs2CO3(1.0 g, 3.1 mmol) at rt. The reaction mixture was stirred at 90 °C for 12 h. After this time, the reaction mixture was cooled to rt followed by the addition of Cs2CO3(314 mg, 1.0 mmol) and MeOH (20 mL). The resulting mixture was stirred for an additional 3 h. The reaction mixture was purified directly by C18 flash chromatography eluting with 0-100% MeCN in water (0.1% FA) to give 6-cyclopropoxy-2-(2-hydroxyspiro[3.5]nonan-7-yl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide as a yellow solid containing some Nl-regioisomer. 6-Cyclopropoxy-2-(2-hydroxyspiro[3.5]nonan-7-yl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (70 mg) was further purified by preparative HPLC (Waters XBridge BEH OBD C18 5 μm 30 x 150 mm; elution gradient 30-40% MeCN in water (10 mM NH4HCO3 and 0.1% NH4OH) over 7 min; 60 mL / min) and then by chiral preparative HPLC (Chiralpak® AD-H, 20 x 250 mm, 5 μm; with MTBE / MeOH (0.1% 2N NH3-MeOH), 80 / 20 isocratic; flow rate: 14 mL / min) to give 6-cyclopropoxy-2-(2-hydroxyspiro[3.5]nonan-7-yl)-N-(pyrazolo[l,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[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 2 (9 mg, 7%, 99% ee) as yellow solids. The ee's were obtained for both products by chiral HPLC. IF, 20 x 250 mm, 5 μm; with MTBE / MeOH (0.1% 2N NH3-MeOH), 80 / 20 isocratic; flow rate: 14 mL / min), to give 6-cyclopropoxy-2-(2-hydroxyspiro[3.5]nonan-7-yl)-N-(pyrazolo[l,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[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide-isomer 2 (9 mg, 7%, 99% ee) as yellow solids. The ee's were obtained for both products by chiral HPLC. 1 H NMR and MS were the same. 1H NMR (300 MHz, DMSO-d6) δ 10.32 (s, 1 H), 9.08 (dd, 1 H), 8.76 (s, 1 H), 8.50-8.60 (m, 3 H), 7.53 (s, 1 H), 7.06 (dd, 1 H), 4.92 (d, 1 H), 4.33-4.52 (m, 1 H), 4.18-4.27 (m, 1 H), 4.06-4.18 (m, 1 H), 2.24-2.39 (m, 1 H), 1.82-2.15 (m, 5 H), 1.42-1.82 (m, 6 H), 1.02-1.10 (m, 2 H), 0.93-1.02 (m, 2 H). MS ESI, m / z = 473 [M+H] + .

[0700] 2-(4-hydroxy-4-methylcyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy- 2H-indazole-5-carboxamide - Isomer 1 (Example 48) and Isomer 2 (Example 49)

[0701] 5-bromo-6-methoxy-2-(l,4-dioxaspiro[4.5]dec-8-yl)-2H-indazole

[0702]

[0703] To a solution of 5-bromo-4-methoxy-2-nitrobenzaldehyde (Int I-l) (3.3 g, 12.7 mmol) in i-PrOH (30 mL) was added 1,4-dioxaspiro[4.5]dec-8-amine (2.0 g, 12.7 mmol) at rt under N2atmosphere. The resulting mixture was stirred at 80 °C for 1 h, then cooled to rt and then tri-n-butylphosphine (12.9 g, 63.6 mmol) was added. 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-(l,4-dioxaspiro[4.5]dec-8-yl)-2H-indazole (8.2 g, 41 wt.%) as a yellow solid which was used in the next step without further purification. MS ESI, m / z = 367 / 369 [M+H] + .

[0704] 4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexan-l-one

[0705]

[0706] To a solution of crude 5-bromo-6-methoxy-2-(l,4-dioxaspiro[4.5]dec-8-yl)-2H- indazole (41 wt.%) (8.2 g) in THF (50 mL) was added 4N HC1 in water (22.9 mL, 91.6 mmol) at rt and the resulting solution was stirred at rt under N2atmosphere for 12 h. The mixture was neutralized with 2N NaOH and extracted with EtOAc (150 mL x 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-l-one as a light yellow solid (3.0 g, 100%). MS ESI, m / z = 323 / 325 [M+H] + .

[0707] 4-(5-Bromo-6-methoxy-2H-indazol-2-yl)-l-methylcyclohexan-l-ol

[0708]

[0709] To a solution of 4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexan-l-one (700 mg, 2.2 mmol) in THF (120 mL) was slowly added 3N methylmagnesium bromide in THF (4.3 mL, 13.0 mmol) at -20 °C under N2atmosphere. The resulting mixture was stirred at -20 °C for 2 h. The reaction was quenched with saturated aqueous NH4C1 solution (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)-l-methylcyclohexan-l-ol as a brown solid (730 mg, 99%). MS ESI, m / z = 339 / 341 [M+H] + .

[0710] 2-(4-Hydroxy-4-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid methyl ester

[0711]

[0712] A mixture of 4-(5-bromo-6-methoxy-2H-indazol-2-yl)-1 -methylcyclohexan-1 -ol (730 mg, 2.2 mmol), Pd(dppf)Cl2(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 at 1 10 °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] + .

[0713] 2-(4-Hydroxy-4-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid

[0714]

[0715] 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 N2atmosphere 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 1 N HCI and then directly purified by C18 flash chromatography eluting with 0-100% MeCN in water (0.05% FA) to give 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] + .

[0716] 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)

[0717]

[0718] 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) was added DIPEA (230 μL, 1.3 mmol) followed by imidazo[l,2-b]pyridazin-3-amine (53 mg, 0.4 mmol) at rt under N2atmosphere. The reaction mixture was stirred at rt for 19 h. The crude product was purified directly by C18 flash chromatography eluting with 0% - 100% MeCN in water (0.05% NH4OH) and by chiral preparative HPLC (Chiralpak® AD, 5 μm 20 mm x 250 mm; isocratic with 20% MTBE in DCM / MeOH (1 : 1) with 0.1% 2N NH3-MeOH over 12 min; 20.0 mL / min) to give 2-(4-hydroxy-4-methylcyclohexyl)-N-(imidazo[l,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[l,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide - Isomer 2 (7 mg, 5%, 99.9% ee) as yellow solids. Isomer 1: H NMR (400 MHz, 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] 1 H NMR (400 MHz, 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 (400 MHz, 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] + .

[0719] 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)

[0720] 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)

[0721] 3-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexan-1-one

[0722]

[0723] 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 K2C03(9.13 g, 66.06 mmol) at rt. The reaction mixture was stirred at 80 °C for 12 h. The mixture was allowed to cool to rt, quenched with water (1 L) and extracted with EtOAc (500 mL x 3). The combined organic layers were dried over Na2S04, 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. +

[0724] 3-(5-bromo-6-methoxy-2H-indazol-2-yl)-1-methylcyclohexan-1-ol

[0725]

[0726] ​To a solution of 3-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexan-l-one (2.0 g, 6.2 mmol) in THF (30 mL) was added 1 M methylmagnesium bromide in THF (24.8 mL, 24.8 mmol) dropwise over a 10 min period at -40 °C under N2atmosphere. 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 x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by C18 flash chromatography eluting with 0-60% MeCN (0.5% FA) in water to give 3-(5-bromo-6-methoxy-2H-indazol-2-yl)-l-methylcyclohexan-l-ol (2.0 g, 95%) as a yellow solid. m / z (ESI+), [M+H] = 339 / 341. + = 319.

[0727] rac-2-((lS,3R)-3-Hydroxy-3-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid methyl ester and rac-2-((lS,3S)-3-Hydroxy-3-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid methyl ester

[0728]

[0729] A suspension of 3-(5-bromo-6-methoxy-2H-indazol-2-yl)-l-methylcyclohexan-l-ol (2.0 g, 5.9 mmol), DIPEA (5.1 mL, 29.5 mmol) and Pd(dppf)Cl2(648 mg, 0.9 mmol) in MeOH (30 mL) was stirred under CO atmosphere at 15 atm and at 110 °C for 12 h. The reaction mixture was allowed to cool to rt and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 30-60% EtOAc in PE and by preparative HPLC (Waters XSelect CSH C18 OBD, 5 pm 30 x 150 mm; elution gradient was 20-45% MeCN (0.1% FA) in water over 10 min; 60 mL / min) to give rac-2-((lS,3R)-3-Hydroxy-3-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid methyl ester (550 mg, 29%) and rac-2-((lS,3S)-3-Hydroxy-3-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid methyl ester (800 mg, 43%) as yellow solids. m / z (ESI+), [M+H] = 319. + = 319.

[0730] rac-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-2H-indazole-5- carboxylic acid

[0731]

[0732] 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 with 0.1 N HC1 to pH 4-5, and then purified by C18 flash chromatography eluting with 40-60% MeCN (0.05% FA) in water 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] 351.2. + = 305.

[0733] 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)

[0734]

[0735] To a solution of rac-2-((lS,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[l,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% to 60% MeCN in water (0.05% FA) followed by preparative chiral HPLC (Chiralpak IA, 2 x 25 cm, 5 μm; mobile phase A: Hex / DCM (2: 1, 0.5% 2N NH3-MeOH), mobile phase B: MeOH; flow rate: 20 mL / min; gradient: 50% B over 12 min) to give rel-2-((lS,3R)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide Isomer 1 (44 mg, 16%, 100% ee) and rel-2-((lS,3R)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-N-(pyrazolo[l,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide Isomer 2 (42 mg, 15%, 98.4% ee). The MS and H NMR obtained for both products are identical. 1 H NMR and MS are identical. 1 H NMR (400 MHz, 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.

[0736] rac-2-((lS,3S)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid

[0737]

[0738] A solution of racemic 2-((1S,3S)-3-hydroxy-3-methylcyclohexyl)-6-methoxy-2H-indazole-5-carboxylic acid (800 mg, 2.5 mmol) in MeOH (6 mL) was added to a solution of LiOH (181 mg, 7.5 mmol) in water (6 mL) under N2 atmosphere at rt. 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 then purified by C18 rapid chromatography (eluting with 30%-60% MeCN (0.05% FA) in water) to give racemic 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] + .

[0739] Racemic-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).

[0740]

[0741] A solution of racemic-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 for 1 h under N2 atmosphere, 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 formed was collected by filtration to give racemic-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. Solids are separated by preparative chiral HPLC. ID-2, 5 μm 20 mm x 250 mm; isocratic with 50% MTBE in MeOH (0.5% 2N NH3-MeOH solution) over 25 min; 17 mL / min) to give rel-2-((lS,3S)-3-hydroxy-3-methylcyclohexyl)-6-methoxy- N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - isomer 1 (40 mg, 19%, 99.8% ee) and rel-2-((lS,3S)-3-hydroxy-3-methylcyclohexyl)-6-methoxy- N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - isomer 2 (48 mg, 23%, 99.8% ee) as yellow solids. Isomer 1: 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, IH), 9.07 (dd, IH), 8.73 (s, IH), 8.52-8.57 (m, 2H), 8.46 (d, IH), 7.20 (s, IH), 7.05 (dd, IH), 4.68-4.79 (m, IH), 4.41 (s, IH), 4.06 (s, 3H), 2.04-2.12 (m, IH), 1.98-2.04 (m, IH), 1.92 (t, IH), 1.70-1.87 (m, 2H), 1.55-1.69 (m, 2H), 1.29-1.40 (m, IH), 1.20 (s, 3H). MS ESI, m / z = 421 [M+H] + Isomer 2: 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, IH), 9.07 (dd, IH), 8.73 (s, IH), 8.52-8.57 (m, 2H), 8.46 (d, IH), 7.20 (s, IH), 7.05 (dd, IH), 4.68-4.79 (m, IH), 4.41 (s, IH), 4.06 (s, 3H), 2.04-2.12 (m, IH), 1.98-2.04 (m, IH), 1.92 (t, IH), 1.70-1.87 (m, 2H), 1.55-1.69 (m, 2H), 1.29-1.40 (m, IH), 1.20 (s, 3H). MS ESI, m / z = 421 [M+H] + .

[0742] rel-6-cyclopropoxy-2-((lS,3R)-3-hydroxy-3-methylcyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - isomer 1 (Example 54) and isomer 2 (Example 55)

[0743] 3-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)cyclohexan-l-one

[0744]

[0745] To a solution of 6-cyclopropoxy-5-iodo-lH-indazole (Int I-3) (3.0 g, 10.0 mmol) and cyclohex-2-en-l-one (7.7 g, 80.0 mmol) in 1,4-dioxane (500 mL) was added K2CO3(4.1 g, 30.0 mmol) at rt. 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 x 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-l-one (980 mg, 25%) as a colorless solid. MS ESI, m / z = 397 [M+H] + .

[0746] 3-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)-l-methylcyclohexan-l-ol

[0747]

[0748] To a solution of 3-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)cyclohexan-l-one (800 mg, 2.0 mmol) in THF (10 mL) was added 1M methylmagnesium bromide in THF (8.1 mL, 8.1 mmol) dropwise at rt under N2atmosphere. 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 x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by C18 flash chromatography eluting with 30% - 60% MeCN (0.05% FA) in water to give crude 3-(6-cyclopropoxy-5-iodo-2H-indazol-2-yl)-l-methylcyclohexan-l-ol (720 mg) as a colorless solid which was used directly without further purification. MS ESI, m / z = 413 [M+H] + .

[0749] rac-6-cyclopropoxy-2-((lS,3R)-3-hydroxy-3-methylcyclohexyl)-2H-indazole-5- carboxylic acid methyl ester

[0750] rac-6-cyclopropoxy-2-((lS,3R)-3-hydroxy-3-methylcyclohexyl)-2H-indazole-5- carboxylic acid methyl ester

[0750]

[0751] 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)Cl2(128 mg, 0.2 mmol) in MeOH (100 mL) was stirred under a CO atmosphere at 15 atm and at 110 °C for 12 h. The mixture was allowed to cool 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 pm 30 x 150 mm; elution gradient was 30-40% MeCN in water (0.1% FA) over 7 min; 60 mL / min) to give rac-6-cyclopropoxy-2-((1S,3R)-3-hydroxy-3- methylcyclohexyl)-2H-indazole-5-carboxylic acid methyl ester (240 mg, 40%). MS ESI, m / z = 345 [M+H] Shield RP18 OBD, 5 pm 30 x 150 mm; elution gradient was 30-40% MeCN in water (0.1% FA) over 7 min; 60 mL / min) to give rac-6-cyclopropoxy-2-((1S,3R)-3-hydroxy-3- methylcyclohexyl)-2H-indazole-5-carboxylic acid methyl ester (240 mg, 40%). MS ESI, m / z = 345 [M+H] + .

[0752] rac-6-cyclopropoxy-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)-2H-indazole-5- carboxylic acid

[0753]

[0754] To a solution of rac-6-cyclopropoxy-2-((1S,3R)-3-hydroxy-3-methylcyclohexyl)- 2H-indazole-5-carboxylic acid methyl ester (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 with 0.1 N HC1 to pH 4-5. The mixture was purified directly 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 as a colorless solid (160 mg, 93%). MS ESI, m / z = 331 [M+H] + .

[0755] 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)

[0756]

[0757] Under a nitrogen atmosphere, pyrazolo[1,5-a]pyrimidine-3-amine (IntI-5) (41 mg, 0.3 mmol) was added to a solution of racemic 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 10 mL of THF. The resulting solution was stirred at rt for 2 h. The reaction was quenched with water (1 mL). The mixture was then subjected to preparative chiral HPLC. IA, 5 μm 20 mm × 250 mm; isocratic with 50% MTBE (0.5% 2N NH3-MeOH) in MeOH; 50 mL / min) direct purification to give 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 H NMR and MS are the same. 1HNMR (400MHz, DMSO-d6) δ10.31 (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] + .

[0758] 6-Cyclopropoxy-2-((1s,4s)-4-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Example 56)

[0759] methyl 6-cyclopropoxy-2-((1s,4s)-4-hydroxycyclohexyl)-2H-indazole-5-carboxylate

[0760]

[0761] A suspension of (ls,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)Cl2-CH2Cl2(226 mg, 0.3 mmol) in MeOH (20 mL) was stirred under a CO atmosphere at 15 atm and at 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-((ls,4s)-4-hydroxycyclohexyl)-2H-indazole-5- carboxylate (67 mg, 73%) as a yellow solid. MS ESI, m / z = 331 [M+H] + .

[0762] 6-cyclopropoxy-2-((ls,4s)-4-hydroxycyclohexyl)-2H-indazole-5-carboxylic acid

[0763]

[0764] 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-((ls,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 with 0.1 N HC1 to pH ~ 6 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-((ls,4s)-4-hydroxycyclohexyl)-2H-indazole-5-carboxylic acid (64 mg, 86 wt.%) as a colorless solid. MS ESI, m / z = 317 [M+H] + .

[0765] 6-cyclopropoxy-2-((ls,4s)-4-hydroxycyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)- 2H-indazole-5-carboxamide (Example 56)

[0766]

[0767] 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 purified by preparative HPLC (Waters XBridge BEH C18 OBD 5 μm 30 x 150 mm; elution gradient 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 as a yellow solid (20 mg, 27%). 1 H NMR (400 MHz, 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] + .

[0768] 6-cyclopropoxy-2-((1r,4r)-4-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)- 2H-indazole-5-carboxamide (Example 57)

[0769] 6-cyclopropoxy-2-((1r,4r)-4-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)- 2H-indazole-5-carboxamide (Example 57)

[0770]

[0771] 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)Cl2-CH2Cl2(45 mg, 0.1 mmol) in MeOH (10 mL) was stirred under CO atmosphere at 15 atm and at 100 °C for 13 h. The reaction mixture was cooled to rt and purified directly by C18 flash chromatography eluting with 0-100% MeOH in water (0.1% FA) to give 6-cyclopropoxy-2-((1r,4r)-4-hydroxycyclohexyl)-2H-indazole-5- carboxylic acid methyl ester (80 mg, 88%) as a yellow solid. MS ESI, m / z = 331 [M+H] + .

[0772] 6-cyclopropoxy-2-((1r,4r)-4-hydroxycyclohexyl)-2H-indazole-5-carboxylic acid

[0773]

[0774] To a solution of 6-cyclopropoxy-2-((1r,4r)-4-hydroxycyclohexyl)-2H-indazole-5- carboxylic acid methyl ester (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 2N 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] + .

[0775] 6-cyclopropoxy-2-((1r,4r)-4-hydroxycyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)- 2H-indazole-5-carboxamide (Example 57)

[0776]

[0777] To a solution of 6-cyclopropoxy-2-((1 r,4r)-4-hydroxycyclohexyl)-2H-indazole-5- carboxylic acid (40 mg, 0.1 mmol), TFA salt of pyrazolo[1,5-a]pyrimidine-3-amine (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 purified by preparative HPLC (Waters XBridge BEH C18 OBD 5 μm 30 x 150 mm; elution gradient 24-32% MeCN in water (10 mM NH4HCO3 + 0.1 % NH4OH) over 7 min; 60 mL / min) to give 6-cyclopropoxy-2-((1 r,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 (300 MHz, 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] + .

[0778] 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)

[0779] (R)-1-(((1 r,4R)-4-(6-methoxy-5-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2H- indazol-2-yl)cyclohexyl)(methyl)amino)-1 -oxopropan-2-yl acetate

[0780]

[0781] To a solution of HC1 salt of 6-methoxy-2-((1 r,4r)-4-(methylamino)cyclohexyl)-N- (pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Int V-4) (300 mg, 0.7 mmol) and TEA (200 mg, 2.0 mmol) in DCM (10 mL) was added (R)-1 -chloro-1 -oxopropan-2- yl acetate (149 mg, 1.0 mmol) at rt under N2 atmosphere. 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 (0.1 % FA) in water to give (R)-1 -(((1 r,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] + .

[0782] 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)

[0783]

[0784] To a solution of (R)-1 -(((1 r,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) was added NaOH (68 mg, 1.7 mmol) at rt under N2 atmosphere. The resulting solution was stirred at rt for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire C18 OBD, 10 x 150 mm, 5-95% ACN / water with 0.1 % FA over 20 min, 10 mL / min) to give (R)-1 -(((1 r,4R)-4-(6-methoxy-5-(pyrazolo[1,5-a]pyrimidin-3- ylcarbamoyl)-2H-indazol-2-yl)cyclohexyl)(methyl)amino)-1 -oxopropan-2-yl acetate (100 mg, 33%) as a white solid. MS ESI, m / z = 534 [M+H] BEH OBD C18, 5 μm 30 x 150 mm; elution gradient of 12-42% MeCN in water (10 mM NH4HCO3 + 0.1% NH4OH) over 8 min; 60 mL / min) direct purification to yield 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropanamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5- a]pyrimidin-3-yl)-2H-indazole-5-carboxamide as a yellow solid (265 mg, 96%, 100% ee). 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] + .

[0785] 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)

[0786] (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

[0787]

[0788] To a solution of the HC1 salt of 6-methoxy-2-((1 r,4r)-4-(methylamino)cyclohexyl)- N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (Int V-4) (130 mg, 0.3 mmol) and TEA (87 mg, 0.9 mmol) in DCM (8 mL) was added (S)-1 -chloro-1 -oxopropan-2- yl acetate (64 mg, 0.4 mmol) at rt under N2 atmosphere. The resulting mixture was stirred at rt for 1 h. The reaction mixture was quenched with MeOH (2 mL) and then purified by C18 flash chromatography eluting with 0-80% MeCN in water (0.1 % FA) to give (S)-1 -(((1 r,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] + .

[0789] 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)

[0790]

[0791] To a solution of (S)-1 -(((1 r,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) was added NaOH (22 mg, 0.5 mmol) at rt under N2 atmosphere. 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 with acetonitrile (2 mL) and water (5 mL) sequentially and then dried under vacuum to give 2-((1 S,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. 1H NMR (400 MHz, DMSO-d6) (1 :1 mixture of rotamers) δ 10.35 (s, 1 H), 9.08 (dd, 1 H), 8.73 (s, 1 H), 8.52-8.59 (m, 2H), 8.48 / 8.47 (s, 1 H) (rotamers), 7.22 / 7.20 (s, 1 H) (rotamers), 7.05 (dd, 1 H), 4.93 / 4.75 (d, 1 H) (rotamers), 4.45-4.57 / 3.93-4.03 (m, 2H) (rotamers), 4.34-4.45 (m, 1 H), 4.06 (s, 3H), 2.91 / 2.77 (s, 3H) (rotamers), 1.62-2.28 (m, 8H), 1.22 / 1.18 (d, 3H) (rotamers). MS ESI, m / z = 492 [M+H] + .

[0792] 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 )

[0793] 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)

[0794] 6-Methoxy-2-((7R,8R)-7-methyl-1,4-dioxaspiro[4.5]dec-8-yl)-2H-indazole-5- carboxylic acid methyl ester

[0795]

[0796] A mixture of 5-bromo-6-methoxy-2-((7R,8R)-7-methyl-l,4-dioxaspiro[4.5]dec-8-yl)- 2H-indazole (380 mg, 1.0 mmol), Pd(dppf)Cl2-CH2Cl2(163 mg, 0.2 mmol) and TEA (695 μL, 5.0 mmol) in MeOH (10 mL) was stirred under CO atmosphere at 15 atm and at 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-l,4-dioxaspiro[4.5]dec-8-yl)-2H- indazole-5-carboxylate (350 mg, 97%) as a colorless solid. MS ESI, m / z = 361 [M+H] + .

[0797] Methyl 6-methoxy-2-((lR,2R)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxylate

[0798]

[0799] To a solution of methyl 6-methoxy-2-((7R,8R)-7-methyl-l,4-dioxaspiro[4.5]dec-8-yl)- 2H-indazole-5-carboxylate (340 mg, 0.9 mmol) in THF (5 mL) / water (5 mL) was added aqueous HC1 (12 N) (2.0 mL, 24.0 mmol). The resulting mixture was stirred at rt for 2 h. The mixture was neutralized with saturated NaHC O 3 aqueous solution, diluted with EtOAc (200 mL) and washed with water (100 mL x 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-((lR,2R)-2-methyl-4- oxocyclohexyl)-2H-indazole-5-carboxylate (290 mg, 97%) as a colorless solid. MS ESI, m / z = 317 [M+H] + .

[0800] 6-methoxy-2-((lR,2R)-2-methyl-4-oxocyclohexyl)-2H-indazole-5-carboxylic acid

[0801]

[0802] To a suspension of 6-methoxy-2-((lR,2R)-2-methyl-4-oxocyclohexyl)-2H- indazole-5-carboxylic acid methyl ester (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 with 2N HC1 to pH 5, and then purified by C18 flash chromatography eluting with 0-100% MeCN in water (0.1% FA) to give 6-methoxy-2-((lR,2R)-2-methyl-4-oxocyclohexyl)-2H-indazole-5- carboxylic acid as a colorless gum (270 mg, 99%). MS ESI, m / z = 303 [M+H] + .

[0803] 6-methoxy-2-((lR,2R)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)- 2H-indazole-5-carboxamide

[0804]

[0805] To a solution of 6-methoxy-2-((lR,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) was added DIPEA (612 μί, 3.5 mmol) under N2atmosphere. The resulting solution was stirred at rt for 15 min, followed by the addition of pyrazolo[l,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 purified directly by C18 flash chromatography eluting with 0-100% MeCN in water (0.1% NH4OH) to give 6-methoxy-2-((lR,2R)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)- 2H-indazole-5-carboxamide as a yellow solid (230 mg, 63%). MS ESI, m / z = 419 [M+H] + .

[0806] 6-methoxy-2-((lR,2R)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)- 2H-indazole-5-carboxamide

[0807]

[0808] 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 methylamine (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 then 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] + .

[0809] 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 )

[0810]

[0811] 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 μί, 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 separated by chiral preparative HPLC (ChiralPak AD-H, 30 x 4.6 mm, 5 μιη, 90% i-PrOH / 10% hexane, 4 mL / min, 220 nm, 40 min) 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 - Isomer 1 (Example 60) and Isomer 2 (Example 61 ). IH, 5 μm 20 mm x 250 mm; isocratic with 50% MTBE in MeOH (0.1% 2N NH3-MeOH) over 7.5 min; 20.0 mL / min) to give both 6-methoxy-2-((lR,2R,4R*)-2-methyl-4-(N- methylacetamido)cyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5- carboxamide Isomer 1 (20 mg, 19%, 99.9% ee) and 6-methoxy-2-((lR,2R,4R*)-2- methyl-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H- indazole-5-carboxamide Isomer 2 (68 mg, 65%, 100% ee) as yellow solids. 1 H NMR (400 MHz, DMSO-d6) (2:3 rotameric mixture) δ 10.36 (s, IH), 9.08 (dd, IH), 8.73 (s, IH), 8.56 / 8.53 (s, IH) (rotamers), 8.54 (dd, IH), 8.47 / 8.46 (s, IH) (rotamers), 7.24 / 7.21 (s, IH) (rotamers), 7.05 (dd, IH), 4.45-4.59 / 3.8-3.93 (m, IH) (rotamers), 4.08-4.18 (m, IH), 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 (400 MHz, DMSO-d6) (2:3 rotameric mixture) δ 10.36 (s, IH), 9.08 (dd, IH), 8.73 (s, IH), 8.56 / 8.53 (s, IH) (rotamers), 8.54 (dd, IH), 8.47 / 8.46 (s, IH) (rotamers), 7.24 / 7.21 (s, IH) (rotamers), 7.05 (dd, IH), 4.45-4.59 / 3.8-3.93 (m, IH) (rotamers), 4.08-4.18 (m, IH), 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] + .

[0812] 6-methoxy-2-((7S,8S)-7-methyl-l,4-dioxaspiro[4.5]dec-8-yl)-2H-indazole-5-carboxylic acid methyl ester

[0813]

[0814] A mixture of 5-bromo-6-methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]dec-8-yl)- 2H-indazole (Int IV-5) (1.0 g, 2.6 mmol), Pd(dppf)Cl2(384 mg, 0.5 mmol) and DIPEA (2.3 mL, 13.1 mmol) in MeOH (60 mL) was stirred under CO atmosphere at 15 atm and at 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]dec-8-yl)-2H- indazole-5-carboxylate (860 mg, 91%) as a yellow solid. MS ESI, m / z = 361 [M+H] + .

[0815] 6-methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]dec-8-yl)-2H-indazole-5-carboxylic acid

[0816]

[0817] To a suspension of methyl 6-methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]dec-8-yl)- 2H-indazole-5-carboxylate (850 mg, 2.4 mmol) in MeOH (6 mL) was added a solution of LiOH (169 mg, 7.1 mmol) in water (6 mL) under N2atmosphere. The resulting mixture was stirred at rt for 2 h. The reaction mixture was acidified with 0.1 N HC1 to pH 6 and then directly purified 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]dec-8-yl)-2H-indazole-5- carboxylic acid containing 32% of 6-methoxy-2-((1S,2S)-2-methyl-4-oxocyclohexyl)-2H- indazole-5-carboxylic acid (720 mg) as a yellow solid. MS ESI, m / z = 347 [M+H] + .

[0818] 6-methoxy-2-((7S,8S)-7-methyl-1,4-dioxaspiro[4.5]dec-8-yl)-N-(pyrazolo[1,5-a]pyrimidin- 3-yl)-2H-indazole-5-carboxamide

[0819]

[0820] To a solution of 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) was added HATU (935 mg, 2.5 mmol) followed by pyrazolo[1,5-a]pyrimidin-3- amine (412 mg, 3.1 mmol) at rt under N2atmosphere. The reaction was stirred at rt for 2 h. The crude product was 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] + .

[0821] 6-methoxy-2-((1 S,2S)-2-methyl-4-oxocyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)- 2H-indazole-5-carboxamide

[0822]

[0823] 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 HCI (10.0 mL, 24.0 mmol). The resulting mixture was stirred at rt for 12 h. The reaction mixture was neutralized with saturated aqueous NaHC03solution and then purified directly by C18 flash chromatography eluting with 0-100% MeCN in water (0.1 % FA) to give 6-methoxy-2-((1 S,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] + .

[0824] 6-methoxy-2-((lS,2S)-2-methyl-4-(methylamino)cyclohexyl)-N- (pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide

[0825]

[0826] To a solution of 6-methoxy-2-((lS,2S)-2-methyl-4-oxocyclohexyl)-N- (pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (200 mg, 0.5 mmol) and methylamine (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 then purified by C18 flash chromatography eluting with 0-100% MeCN in water (0.05% NH4OH) to give 6-methoxy-2-((lS,2S)-2-methyl-4-(methylamino)cyclohexyl)-N- (pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide (170 mg, 82%) as a yellow solid. MS ESI, m / z = 434 [M+H] + .

[0827] 6-methoxy-2-((lS,2S,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-N- (pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 62) and Isomer 2 (Example 63)

[0828]

[0829] To a solution of 6-methoxy-2-((lS,2S)-2-methyl-4-(methylamino)cyclohexyl)-N- (pyrazolo[l,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-((lS,2S)-2-methyl-4-(N-methylacetamido)cyclohexyl)-N- (pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide as a yellow solid. The solid was isolated by chiral preparative HPLC (ChiralPak AD-H, 30 x 4.6 mm, 5 μm, 90% i-PrOH in hexanes, 1 mL / min, 40°C, 20 min) to give 6-methoxy-2-((lS,2S,4R*)-2-methyl-4-(N-methylacetamido)cyclohexyl)-N- (pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 62) and Isomer 2 (Example 63). IH, 5 μm 20 mm x 250 mm; isocratic with 80% MTBE in MeOH (0.1% 2N NH3-MeOH) over 14 min; 20.0 mL / min) to give 6-methoxy-2-((lS,2S,4R*)-2-methyl-4-(N- methylacetamido)cyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H-indazole-5- carboxamide - Isomer 1 (17 mg, 10%, 99.4% ee) and 6-methoxy-2-((lS,2S,4R*)-2- methyl-4-(N-methylacetamido)cyclohexyl)-N-(pyrazolo[l,5-a]pyrimidin-3-yl)-2H- indazole-5-carboxamide - Isomer 2 (59 mg, 34%, 99.9% ee) both as yellow solids. 1 H NMR (400 MHz, DMSO-d6) (2:3 rotameric mixture) δ 10.36 (s, IH), 9.08 (dd, IH), 8.74 (s, IH), 8.66 (s, IH), 8.54 (dd, IH), 8.48 (s, IH), 7.25 (s, IH), 7.05 (dd, IH), 4.63 / 4.02 (br. s, IH) (rotamers), 4.38 (s, IH), 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] + Isomer 2: 1 H NMR (400 MHz, DMSO-d6) (2:3 rotameric mixture) δ 10.36 (s, IH), 9.08 (dd, IH), 8.74 (s, IH), 8.66 (s, IH), 8.54 (dd, IH), 8.48 (s, IH), 7.25 (s, IH), 7.05 (dd, IH), 4.63 / 4.02 (br. s, IH) (rotamers), 4.38 (s, IH), 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] + .

[0830] rel-2-((6S,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[l,2- b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide Isomer 1 (Example 64) and Isomer 2 (Example 65)

[0831] 7-hydroxy-6-methyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

[0832]

[0833] NaBH4(388 mg, 10.3 mmol) was added portionwise to a solution of 7-hydroxy-6-methyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.2 g, 5.1 mmol) in MeOH (20 mL) at 0 °C under N2atmosphere over a period of 5 min. The resulting mixture was stirred at rt for 1 h. The reaction was quenched with water (5 mL) and concentrated directly. The residue was purified by silica gel chromatography eluting with 30% to 40% EtOAc in PE to give 7-hydroxy-6-methyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.2 g, 92%) as a yellow oil (cis / trans 1 :2).

[0834] 6-methyl-7-(methylsulfonyloxy)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

[0835]

[0836] MsCl (1.6 g, 14.1 mmol) was added dropwise to a solution of TEA (2.6 mL, 18.8 mmol) and 7-hydroxy-6-methyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.2 g, 4.7 mmol) (cis / trans 1 :2) in DCM (25 mL) at 0 °C over a period of 5 min. 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 x 3). The combined organic layers were dried over Na2SO4, filtered, and the solvent evaporated to give crude 6-methyl-7-(methylsulfonyloxy)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.5 g) as a yellow oil (mainly trans isomer). The product was used in the next step without further purification.

[0837] rac-(6S,7R)-7-(5-bromo-6-methoxy-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2- carboxylic acid tert-butyl ester

[0838]

[0839] 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) (mainly 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 x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and the solvent was evaporated. The crude product was purified by silica gel chromatography eluting with 20 to 30% EtOAc in PE to give crude rac-(6S,7R)-7-(5-bromo-6-methoxy-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2- carboxylic acid tert-butyl ester (400 mg) as a yellow solid. m / z (ESI+) [M-tBu] 408 / 410. + = 408 / 410.

[0840] rac-5-bromo-6-methoxy-2-((6S,7R)-6-methyl-2-azaspiro[3.5]nonan-7-yl)-2H- indazole

[0841]

[0842] TFA (4 mL) was added dropwise to a solution of crude rac-(6S,7R)-7-(5-bromo-6- methoxy-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (400 mg) in DCM (20 mL) at 0 °C under N2atmosphere. The resulting mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure to give 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] + .

[0843] rac-1-((6S,7R)-7-(5-bromo-6-methoxy-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonan- 2-yl)ethanone

[0844]

[0845] Acetyl chloride (223 μL, 3.1 mmol) was added dropwise to a solution of 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) at 0 °C under N2atmosphere. 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 x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, 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. + = 406, 408.

[0846] rel-2-((6S,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[l,2- b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide Isomer 1 (Example 64) and Isomer 2 (Example 65)

[0847]

[0848] Pd(OAc)2(9 mg, 0.04 mmol) was added to a solution of dppp (41 mg, 0.1 mmol), TEA (123 μL, 0.9 mmol), imidazo[l,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-azaspiro[3.5]nonan-2- yl)ethan-1-one (180 mg, 0.4 mmol) in MeCN (10 mL). The resulting mixture was stirred at 90 °C under a CO atmosphere at 15 atm overnight. The crude product was cooled to rt and purified directly by C18 flash chromatography eluting with 50% to 55% MeCN (0.1% HCOOH) in water. The obtained material was then purified by preparative HPLC (XBridge Prep OBD C18 column, 30 x 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 over 7 min) to give rac-2-((6S,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide as a yellow solid. The solid was isolated by chiral preparative SFC (CelluCOat column, 250 x 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-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[l,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[l,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide-isomer 2 (34 mg, 19%, 100% ee). Both isomers were collected as gums. The obtained 1 H NMR and MS were identical. 1H NMR (500 MHz, 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, 1H), 7.30 / 7.29 (s, 1H) (rotamers), 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) (rotamers). m / z (ESI+) [M+H] + = 488.

[0849] rel-2-((6R,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]non-7-yl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide Isomer 1 (Example 66) and Isomer 2 (Example 67)

[0850] rac-(6R,7R)-7-(5-bromo-6-methoxy-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

[0851]

[0852] KOH (1.4 g, 25.0 mmol) was added to a solution of rac-(6R,7S)-6-methyl-7-((methylsulfonyl)oxy)-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (Int III-5) (3.0 g, 9.0 mmol) and 5-bromo-6-methoxy-lH-indazole (1.9 g, 8.2 mmol) in THF (50 mL) at 0 °C under N2atmosphere. The resulting mixture was stirred at 80 °C for 12 h. The reaction mixture was cooled to rt, diluted with water (100 mL) and washed with EtOAc (2 x 75 mL). The combined organic layers were dried over Na2SO4, 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-(6R,7R)-7-(5-bromo-6-methoxy-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (0.5 g, 13%) as a yellow solid. m / z (ESI+) [M+H] + = 464 / 466.

[0853] rac-(6R,7R)-7-(5-(imidazo[l,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2-yl)-6- methyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

[0854]

[0855] A solution of imidazo[l,2-b]pyridazin-3-amine (255 mg, 1.9 mmol), dppp (82 mg, 0.2 mmol), Pd(OAc)2(44 mg, 0.2 mmol), TEA (588 mg, 5.8 mmol) and rac-(6R,7R)-7-(5-bromo-6-methoxy-2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2- carboxylic acid tert-butyl ester (450 mg, 1.0 mmol) in MeCN (8 mL) was stirred under a CO atmosphere at 15 atm and at 90 °C for 12 h and then allowed to cool 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-(6R,7R)-7-(5-(imidazo[l,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy-2H-indazol-2-yl)-6- methyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (450 mg) as a yellow oil. m / z (ESI+) [M+H] + = 546.

[0856] rac-N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((6R,7R)-6-methyl-2-azaspiro[3.5]nonan-7- yl)-2H-indazole-5-carboxamide

[0857]

[0858] To crude rac-(6R,7R)-7-(5-(imidazo[l,2-b]pyridazin-3-ylcarbamoyl)-6-methoxy- 2H-indazol-2-yl)-6-methyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (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 crude TFA salt of rac-N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((6R,7R)-6-methyl-2- azaspiro[3.5]nonan-7-yl)-2H-indazole-5-carboxamide as a yellow oil (350 mg). The product was used without further purification. m / z (ESI+) [M+H] = 446. + = 446.

[0859] rel-2-((6R,7R)-2-acetyl-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[l,2-b]pyridazin- 3-yl)-6-methoxy-2H-indazole-5-carboxamide Isomer 1 (Example 66) and Isomer 2 (Example 67)

[0860]

[0861] To a solution of rac-2-((6R,7R)-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[l,2- b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide (0.050 g, 0.11 mmol) in DCM (1 mL) was added TFA (0.1 mL, 1.3 mmol) at rt. The mixture was stirred at rt for 1 h. The mixture was concentrated and purified by C18 flash chromatography (eluting with 20% to 100% MeCN in water (0.05% FA)) to give rac-2-((6R,7R)-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[l,2-b]pyridazin-3- yl)-6-methoxy-2H-indazole-5-carboxamide TFA salt as a yellow solid. The isomers were separated by chiral preparative HPLC (CHIRALPAK IF, 2 x 25 cm, 5 μm; mobile phase A: MTBE (2 mM NH3-MeOH), mobile phase B: MeOH; flow rate: 17 mL / min; 50% B isocratic in 18 min) to give rel-2-((6R,7R)-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide-isomer 1 (35 mg, 70%, 100% ee) and isomer 2 which after a second purification by preparative HPLC (XBridge Prep OBD C18 Column, 30 x 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 40% B in 7 min) gave rel-2-((6R,7R)-6-methyl-2-azaspiro[3.5]nonan-7-yl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide-isomer 2 (30 mg, 60%, 99% ee). Both isomers were collected as yellow solids. Isomer 1: 1H NMR (400 MHz, DMSO-c / 6) (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) (rotamers), 3.80 / 3.53 (s, 2H) (rotamers), 2.06-2.19 (m, 1H), 1.90-2.05 (m, 4H), 1.80 / 1.77 (s, 3H) (rotamers), 1.60-1.73 (m, 1H), 1.38-1.49 (m, 1H), 0.60 / 0.58 (d, 3H) (rotamers). m / z (ESI+) [M+H] + = 488. Isomer 2: 1 H NMR (400 MHz, DMSO-c / 6) (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) (rotamers), 3.80 / 3.53 (s, 2H) (rotamers), 2.06-2.19 (m, 1H), 1.90-2.05 (m, 4H), 1.80 / 1.77 (s, 3H) (rotamers), 1.60-1.73 (m, 1H), 1.38-1.49 (m, 1H), 0.60 / 0.58 (d, 3H) (rotamers). m / z (ESI+) [M+H] + = 488.

[0862] N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((5s,8s)-2-methyl-3-oxo-2- azaspiro[4.5]dec-8-yl)-2H-indazole-5-carboxamide (Example 68)

[0863]

[0864] Methyldiphenylsilane carboxylic acid (95 mg, 0.4 mmol) and KF (23 mg, 0.4 mmol) were added to chamber A of a dry and N2-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)2(7 mg, 0.03 mmol), imidazo[l,2-b]pyridazin-3-amine (80 mg, 0.6 mmol) and DIPEA (138 μL, 0.8 mmol) were added to chamber B. Then, DMSO (350 μL) was added to chamber A and chamber B was stirred at 85 °C overnight. The reaction mixture was allowed to cool to rt. The reaction in chamber B was quenched with saturated aqueous NaHC03solution, concentrated under reduced pressure, dissolved in DCM (30 mL) and loaded on a 5 g SCX2exchange cartridge. The cartridge was washed with DCM / MeOH (1 : 1; 100 mL), then eluted with DCM / 4 N NH3-MeOH solution (1 : 1; 100 mL) and then with 2 N NH3-MeOH solution (100 mL) to give a dark yellow solid. The solid was purified by silica gel chromatography (eluting with 0% - 2.5% 2 N NH3-MeOH solution in DCM) to give a yellow solid. The solid was suspended in MeCN (2 mL) and stirred at rt for 48 h. The suspension was then filtered and washed with ice-cold MeCN (500 μL x 2) to give N-(imidazo[l,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 light yellow solid. SCX2exchange cartridge. The cartridge was washed with DCM / MeOH (1 : 1; 100 mL), then eluted with DCM / 4 N NH3-MeOH solution (1 : 1; 100 mL) and then with 2 N NH3-MeOH solution (100 mL) to give a dark yellow solid. The solid was purified by silica gel chromatography (eluting with 0% - 2.5% 2 N NH3-MeOH solution in DCM) to give a yellow solid. The solid was suspended in MeCN (2 mL) and stirred at rt for 48 h. The suspension was then filtered and washed with ice-cold MeCN (500 μL x 2) to give N-(imidazo[l,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 light yellow solid. 1 H NMR (500 MHz, CDC13) 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] + .

[0865] N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-2-methyl-3-oxo-2- azaspiro[4.5]dec-8-yl)-2H-indazole-5-carboxamide (Example 69)

[0866]

[0867] Methyldiphenylsilane carboxylic acid (88 mg, 0.4 mmol) and KF (21 mg, 0.4 mmol) were added to chamber A of a dry and N2-flushed COware gas reactor. (5r,8r)-8-(5-Bromo-6-methoxy-2H-indazol-2-yl)-2-methyl-2-azaspiro[4.5]decane-3- one (Int IV-7) (49 mg, 0.1 mmol), imidazo[l,2-b]pyridazin-3-amine (27 mg, 0.2 mmol), dppp (13 mg, 0.03 mmol), Pd(OAc)2(7 mg, 0.03 mmol) and DIPEA (127 μL, 0.7 mmol) were added to chamber B. Then, DMSO (200 μL) was added to chamber A and chamber B was stirred at 85 °C overnight. The reaction in chamber B was quenched with saturated aqueous NaHC03solution, concentrated under reduced pressure, dissolved in DCM (30 mL) and loaded on a 5 g SCX2exchange cartridge. The loaded SCX2cartridge was washed with DCM / MeOH (1:1:100 mL), then eluted with DCM / 4 N NH3-MeOH solution (1:1:100 mL) and then with 2 N NH3-MeOH solution (100 mL) to give a dark yellow solid. The solid was purified by silica gel chromatography eluting with 0%-2.5% 2 N NH3-MeOH solution in DCM to give a yellow solid which was suspended in MeCN (3 mL) at rt and stirred for 48 h. The suspension was filtered and washed with ice-cold MeCN (500 μL x 2) to give a solid. The solid was dissolved in 15 mL of boiling MeCN and slowly concentrated to 5 mL at 45 °C under reduced pressure 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 x 2) to give N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-2-methyl-3-oxo-2-azaspiro[4.5]dec-8-yl)-2H-indazole-5-carboxamide as a light yellow solid (46 mg, 90%). SCX2exchange cartridge. The loaded SCX2cartridge was washed with DCM / MeOH (1:1:100 mL), then eluted with DCM / 4 N NH3-MeOH solution (1:1:100 mL) and then with 2 N NH3-MeOH solution (100 mL) to give a dark yellow solid. The solid was purified by silica gel chromatography eluting with 0%-2.5% 2 N NH3-MeOH solution in DCM to give a yellow solid which was suspended in MeCN (3 mL) at rt and stirred for 48 h. The suspension was filtered and washed with ice-cold MeCN (500 μL x 2) to give a solid. The solid was dissolved in 15 mL of boiling MeCN and slowly concentrated to 5 mL at 45 °C under reduced pressure 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 x 2) to give N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-2-methyl-3-oxo-2-azaspiro[4.5]dec-8-yl)-2H-indazole-5-carboxamide as a light yellow solid (46 mg, 90%). 1H NMR (500 MHz, CDC13) δ 11.28 (s, IH), 8.8-8.84 (m, IH), 8.47 (dd, IH), 8.40 (s, IH), 8.16 (d, IH), 8.10 (d, IH), 7.18 (s, IH), 7.12 (dd, IH), 4.40 (tt, IH), 4.19 (s, 3H), 3.20 (s, 2H), 2.87 (t, 3H), 2.44 (s, 2H), 2.22-2.30 (m, 2H), 2.04-2.15 (m, 2H), 1.91-1.98 (m, 2H), 1.65 (td, 2H). MS ESI, m / z = 474 [M+H] + .

[0868] rel-2-((5R,7R,8R)-2,7-dimethyl-3-oxo-2-azaspiro[4.5]decan-8-yl)-N- (imidazo[l,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[l,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)

[0869] 7-methyl-8-oxo-2-azaspiro[4.5]decan-2-carboxylic acid tert-butyl ester

[0870]

[0871] 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 1M LiHMDS in THF (118.5 mL, 118.5 mmol) dropwise at -78 °C under N2atmosphere over a period of 20 min. The resulting mixture was stirred at -78 °C for 2 h. Subsequently, iodomethane (7.4 mL, 118.5 mmol) was added slowly. The reaction mixture was allowed to warm to rt and stirred for 15 h. The reaction was quenched with saturated aqueous NH4Cl (300 mL) and extracted with EtOAc (250 mL x 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] + .

[0872] Mixture of rac-(5R,7R,8S)-7,8-dihydroxy-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester and rac-(5R,7S,8R)-7,8-dihydroxy-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester

[0873]

[0874] 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 2M lithium tri-sec-butylborohydride in THF (18.7 mL, 37.4 mmol) at 0 °C under N2atmosphere over a period of 1 min. The resulting mixture was stirred at 0 °C for 3 h. The reaction mixture was quenched with acetone (20 mL) and then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 25-50% EtOAc in PE to give a mixture of rac-(5R,7R,8S)-7,8-dihydroxy-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester and rac-(5R,7S,8R)-7,8-dihydroxy-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (4.8 g, 95%) as a light yellow oil. MS ESI, m / z = 214 [M-tBu] + .

[0875] Mixture of rac-(5R,7R,8R)-8-(1,3-dioxoisoindolin-2-yl)-7-methyl-2- azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester and rac-(5R,7S,8S)-8-(1,3- dioxoisoindolin-2-yl)-7-methyl-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester

[0876]

[0877] To a mixture of rac-(5R,7R,8S)-7,8-dihydroxy-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester and rac-(5R,7S,8R)-7,8-dihydroxy-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (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) at 0 °C under N2atmosphere. 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 Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with DCM and further purified by C18 flash chromatography eluting with 0% - 100% MeCN (0.05% NH4OH) in water to give a mixture of rac-(5R,7R,8R)-8-(1,3-dioxoisoindolin-2-yl)-7-methyl-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester and rac-(5R,7S,8S)-8-(1,3-dioxoisoindolin-2-yl)-7-methyl-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester as a light yellow solid (1.9 g, 37%). MS ESI, m / z = 384 [M-tBu+CH3CN] + .

[0878] Mixture of rac-(5R,7R,8R)-8-amino-7-methyl-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester and rac-(5R,7S,8S)-8-amino-7-methyl-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester

[0879]

[0880] To a solution of a mixture of rac-(5R,7R,8R)-8-(1,3-dioxoisoindolin-2-yl)-7- methyl-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester and rac-(5R,7S,8S)-8-(1,3-dioxoisoindolin-2-yl)-7-methyl-2-azaspiro[4.5]decane-2- carboxylic acid tert-butyl ester (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 purified 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), basified to pH 9 with saturated aqueous NaHC03solution and then extracted with EtOAc (100 mL x 2) and chloroform (100 mL). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure to give a mixture of rac-(5R,7R,8R)-8-amino-7-methyl-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester and rac-(5R,7S,8S)-8-amino-7-methyl-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester as a light yellow oil (380 mg, 31 %). MS ESI, m / z = 269 [M+H] + .

[0881] Mixture of rac-(5R,7R,8R)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-7-methyl-2- azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester and rac-(5R,7S,8S)-8-(5-bromo-6- methoxy-2H-indazol-2-yl)-7-methyl-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester

[0882]

[0883] A mixture of racemic-(5R,7R,8R)-8-amino-7-methyl-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester and racemic-(5R,7S,8S)-8-amino-7-methyl-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (360 mg, 1.3 mmol) in i-PrOH (15 mL) was mixed with 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 then incubated at 80 °C. N2 The mixture was stirred overnight under a certain atmosphere. The mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by C18 rapid chromatography (eluting with 0%–100% MeCN (0.05% FA) in water) to give a mixture (440 mg, 69%) of racemic-(5R,7R,8R)-8-(5-bromo-6-methoxy-2H-indazole-2-yl)-7-methyl-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester and racemic-(5R,7S,8S)-8-(5-bromo-6-methoxy-2H-indazole-2-yl)-7-methyl-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester. MS ESI, m / z = 478 / 480 [M+H] + .

[0884] A mixture of racemic-(5R,7R,8R)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-7-methyl-2-azaspiro[4.5]decane and racemic-(5R,7S,8S)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-7-methyl-2-azaspiro[4.5]decane

[0885]

[0886] To a solution of a mixture of rac-(5R,7R,8R)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-7- methyl-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester and rac-(5R,7S,8S)-8-(5-bromo-6- methoxy-2H-indazol-2-yl)-7-methyl-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (410 mg, 0.9 mmol) in dioxane (4 mL) was added 4N HC1 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 HC1 salts (354 mg) which was used directly without further purification. MS ESI, m / z = 378 / 380 [M+H] + .

[0887] 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

[0888]

[0889] 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 salt (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) at rt under N2atmosphere. The reaction mixture was stirred at rt for 3 h. The mixture was purified directly 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 as a light yellow solid (335 mg, 100%). MS ESI, m / z = 392 / 394 [M+H] + .

[0890] Mixture of rac-(5R,7R,8R)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2,7-dimethyl-2- azaspiro[4.5]decane-3-one and rac-(5R,7S,8S)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)- 2,7-dimethyl-2-azaspiro[4.5]decane-3-one

[0891]

[0892] 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 Na2SO3until the color turned light yellow, and then extracted 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 30 x 150 mm; elution gradient was 32-42% MeCN (0.1% FA) in water over 12 min; 60 mL / min) 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-3-one and rac-(5R,7S,8S)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)- 2,7-dimethyl-2-azaspiro[4.5]decane-3-one containing 40% of 8-(5-bromo-6-methoxy- 2H-indazol-2-yl)-2,7-dimethyl-2-azaspiro[4.5]decane-1-one as a light yellow solid (120 mg), which was used without further isolation.

[0893] rel-2-((5R,7R,8R)-2,7-dimethyl-3-oxo-2-azaspiro[4.5]decane-8-yl)-N-(imidazo[l,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]decane-8-yl)-N-(imidazo[l,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)

[0894]

[0895] A mixture of rac-(5R,7R,8R)-8-(5-bromo-6-methoxy-2H-indazol-2-yl)-2,7- dimethyl-2-azaspiro[4.5]decane-1-one containing 40% of 8-(5-bromo-6-methoxy- 2H-indazol-2-yl)-2,7-dimethyl-2-azaspiro[4.5]decane-1-one (115 mg), imidazo[1,2- b]pyridazine-3-amine (80 mg, 0.6 mmol), Pd(OAc)2(14 mg, 0.06 mmol), dppp (41 mg, 0.1 mmol) and DIPEA (183 mg, 1.4 mmol) in MeCN (15 mL) was stirred under a CO atmosphere at 15 atm and at 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 a mixture of rel-2-((5R,7R,8R)-2,7-dimethyl-3-oxo-2-azaspiro[4.5]decane-8-yl)-N- (imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide and rel-2-((5R,7S,8S)-2,7-dimethyl-3-oxo-2-azaspiro[4.5]decane-8-yl)-N-(imidazo[1,2- b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide-isomers 1-4 containing 40% of 2-(2,7-dimethyl-1-oxo-2-azaspiro[4.5]decane-8-yl)-N-(imidazo[1,2-b]pyridazin-3- yl)-6-methoxy-2H-indazole-5-carboxamide. The desired product was separated from the by-products and isolated by three consecutive chiral preparative HPLC runs (first run: IA, 5 μm 20 mm x 250 mm; isocratic with 50% MTBE in EtOH (0.1% 2N NH3-MeOH); 20.0 mL / min; second and third runs: ID, 5 μm 20 mm x 250 mm; isocratic with 50% MTBE in MeOH (0.1% 2N NH3-MeOH) over 16 min; 20.0 mL / min) to give the following four isomers as light yellow solids: Isomer 1 (7 mg, 5%), Isomer 2 (7 mg, 5%), Isomer 3 (5 mg, 3%) and Isomer 4 (5 mg, 3%). Isomers 1 and 2 are enantiomers of each other, LCMS / 1H NMR was identical; Isomer 3 and Isomer 4 are enantiomers of each other and LCMS 1 H NMR was identical. Isomer 1 / Isomer 2: 1 H NMR (400 MHz, 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, 2H), 2.73 (s, 3H), 2.34 (s, 2H), 2.04-2.27 (m, 2H), 1.87-1.98 (m, 1H), 1.72-1.83 (m, 2H), 1.54-1.66 (m, 1H), 1.34 (t, 1H), 0.57 (d, 3H). MS ESI, m / z = 488 [M+H] + . Isomer 3 / Isomer 4: 1 H NMR (400 MHz, 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] + .

[0896] N-(Imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-(l-methyl-2-oxo-3-oxa-l- azaspiro[4.5]dec-8-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 74) and Isomer 2 (Example 75)

[0897] (4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)methanol

[0898]

[0899] To a solution of (4-aminocyclohexyl)methanol (2.0 g, 15.5 mmol) in i-PrOH (20 mL) at rt under N2atmosphere was added 5-bromo-4-methoxy-2-nitrobenzaldehyde (Int I-l) (4.0 g, 15.5 mmol). The resulting mixture was stirred at 80 °C for 1 h, 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 yield a yellow oil. The oil was then 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 wt.%) as a solid which was used in the next step without further purification. MS ESI, m / z = 339 / 341 [M+H] + .

[0900] (4-(5-bromo-6-methoxy-2H-indazol-2-yl)cyclohexyl)methylcarbamate

[0901]

[0902] 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 was added 2,2,2-trichloroacetyl isocyanate (1.5 g, 8.2 mmol). The resulting solution was warmed 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 x 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] + .

[0903] 8-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-oxa-1-azaspiro[4.5]decane-2-one

[0904]

[0905] To a solution of magnesium oxide (728 mg, 18.1 mmol), [acetyloxy(phenyl)-λ3- iodo-benzene] acetate (3.5 g, 11.0 mmol) and (4-(5-bromo-6-methoxy-2H-indazol-2- yl)cyclohexyl)methylcarbamic acid tert-butyl ester (1.5 g, 3.9 mmol) in DCM (150 mL) was added rhodium(II) acetate (347 mg, 0.8 mmol) at rt under N2atmosphere over a period of 3 min. 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 x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by C18 flash chromatography eluting with 0-100% MeCN (0.1% FA) in water and further purified by preparative HPLC (Waters XSelect CSH C18 OBD, 5 µm 30 x 150 mm; elution gradient 34-35% MeCN (0.05% TFA) in water over 8 min; 60 mL / min) to give 8-(5-bromo-6-methoxy-2H-indazol-2-yl)-3-oxa-1- azaspiro[4.5]decane-2-one as a light yellow solid (340 mg, 23%). MS ESI, m / z = 380 / 382 [M+H] + .

[0906] 8-(5-Bromo-6-methoxy-2H-indazol-2-yl)-1-methyl-3-oxa-1-azaspiro[4.5]decane-2- one

[0907]

[0908] 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]decane-2-one (120 mg, 0.3 mmol) in DMF (6 mL) at rt under N2atmosphere. The resulting mixture was stirred at rt for 15 h. The reaction was quenched with saturated aqueous NH4Cl solution (5 mL) and purified directly by C18 flash chromatography eluting with 0-100% MeCN (0.1% FA) in water to give 8-(5-bromo-6-methoxy-2H-indazol-2-yl)-1-methyl-3-oxa-1- azaspiro[4.5]decane-2-one as a red solid (70 mg, 56%). MS ESI, m / z = 380 / 382 [M+H]+ .

[0909] N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-(l-methyl-2-oxo-3-oxa-l- azaspiro[4.5]dec-8-yl)-2H-indazole-5-carboxamide - Isomer 1 (Example 74) and Isomer 2 (Example 75)

[0910]

[0911] A suspension of 8-(5-bromo-6-methoxy-2H-indazol-2-yl)-l-methyl-3-oxa-l- azaspiro[4.5]decane-2-one (124 mg, 0.3 mmol), imidazo[l,2-b]pyridazin-3-amine (121 mg, 0.9 mmol), Pd(OAc)2(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 at 100 °C for 15 h. The mixture was allowed to cool 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 purified by preparative HPLC (Waters BEH OBD C18, 5 μm 30 x 150 mm; elution gradient was 30-60% MeOH in water (10 mM NH4HCO3 + 0.1% NH4OH) over 8 min; 60 mL / min) to give N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-(l-methyl-2-oxo-3-oxa-l- azaspiro[4.5]dec-8-yl)-2H-indazole-5-carboxamide as a yellow solid. The solid was isolated by chiral preparative HPLC (Chiralpak® AD-H, 5 μm 20 mm x 250 mm; 50% MTBE in EtOH (0.5% 2M NH3-MeOH) isocratic over 26 min; 13.0 mL / min) to give rel-N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-l-methyl-2-oxo-3-oxa-l- azaspiro[4.5]dec-8-yl)-2H-indazole-5-carboxamide - Isomer 1 (7 mg, 4%, 100% ee) and rel-N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-l-methyl-2-oxo-3-oxa-l- azaspiro[4.5]dec-8-yl)-2H-indazole-5-carboxamide - Isomer 2 (1 mg, 1%, 98.9% ee). Isomer 1: IF, 5 μm 20 mm x 250 mm; 50% MTBE in EtOH (0.5% 2M NH3-MeOH) isocratic over 26 min; 13.0 mL / min) to give rel-N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-l-methyl-2-oxo-3-oxa-l- azaspiro[4.5]dec-8-yl)-2H-indazole-5-carboxamide - Isomer 1 (7 mg, 4%, 100% ee) and rel-N-(imidazo[l,2-b]pyridazin-3-yl)-6-methoxy-2-((5r,8r)-l-methyl-2-oxo-3-oxa-l- azaspiro[4.5]dec-8-yl)-2H-indazole-5-carboxamide - Isomer 2 (1 mg, 1%, 98.9% ee). Isomer 1:1 H NMR (400 MHz, 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 (400 MHz, 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] + .

[0912] rel-2-((1R,3R,4S)-4-hydroxy-3-methylcyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide - Isomer 1 (Example 76) and Isomer 2 (Example 77)

[0913] rel-2-((1S,3R,4S)-4-hydroxy-3-methylcyclohexyl)-N-(imidazo[l,2-b]pyridazin-3-yl)-6- methoxy-2H-indazole-5-carboxamide - Isomer 1 (Example 78) and Isomer 2 (Example 79)

[0914] rac-(3R,4S)-4-hydroxy-3-methylcyclohexan-l-one

[0915]

[0916] Aqueous HC1 (12 N) (10.0 mL, 120.0 mmol) was added to THF (10 mL) and water (10 mL) followed by 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 solution, then the mixture was 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 as a yellow oil (2.1 g, 91%). MS ESI, m / z = 170 [M+CH3CN+H] + .

[0917] Mixture of rac-(1S,2R,4R)-4-(benzylamino)-2-methylcyclohexan-1-ol and rac-(1S,2R,4S)-4-(benzylamino)-2-methylcyclohexan-1-ol

[0918]

[0919] To a solution of rac-(3R,4S)-4-hydroxy-3-methylcyclohexan-1-one (2.0 g, 15.6 mmol) in DCE (40 mL) was added benzylamine (2.0 g, 18.7 mmol) at rt under N2atmosphere. 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 another 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 (0.1% NH4OH) in water 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 as a brown solid (2.10 g, 61%).

[0920] Mixture of rac-(1S,2R,4R)-4-amino-2-methylcyclohexan-1-ol and rac-(1S,2R,4S)-4-amino-2-methylcyclohexan-1-ol

[0921]

[0922] To a solution of a mixture of rac-(lS,2R,4R)-4-(benzylamino)-2- methylcyclohexan-l-ol and rac-(lS,2R,4S)-4-(benzylamino)-2- methylcyclohexan-l-ol (2.0 g, 9.1 mmol) in MeOH (30 mL) under N2atmosphere was added Pd(OH)2on carbon (20 wt.%) (640 mg, 0.9 mmol). The resulting suspension was stirred under hydrogen at 2 atm at rt for 12 h. The reaction mixture was filtered through silica gel and the silica gel cake was washed with MeOH (30 mL). The combined MeOH solutions were concentrated under reduced pressure to give a crude mixture of rac-(lS,2R,4R)-4-amino-2-methylcyclohexan-l-ol and rac-(lS,2R,4S)-4-amino-2-methylcyclohexan-l-ol as a yellow oil (1.20 g, 90 wt.%) which was used in the next step without further purification.

[0923] Mixture of rac-(lS,2R,4R)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-2- methylcyclohexan-l-ol and rac-(lS,2R,4S)-4-(5-bromo-6-methoxy-2H- indazol-2-yl)-2-methylcyclohexan-l-ol

[0924]

[0925] To a solution of 5-bromo-4-methoxy-2-nitrobenzaldehyde (Int I-l) (2.2 g, 8.4 mmol) in i-PrOH (20 mL) at rt under N2atmosphere was added a crude mixture of rac-(lS,2R,4R)-4-amino-2-methylcyclohexan-l-ol and rac-(lS,2R,4S)-4-amino-2-methylcyclohexan-l-ol (90 wt.%) (1.0 g). The resulting mixture was stirred at 80 °C for 2 h, then cooled to rt followed by the addition of tri-n-butylphosphine (5.6 g, 27.9 mmol). The reaction mixture was stirred at 80 °C for 12 h. The mixture was allowed to cool to rt and concentrated under reduced pressure. The residue was purified by C18 flash chromatography eluting with 0-50% MeOH in water (0.05% FA) to give a crude mixture of rac-(lS,2R,4R)-4-(5-bromo-6-methoxy-2H-indazol-2-yl)-2- methylcyclohexan-l-ol and rac-(lS,2R,4S)-4-(5-bromo-6-methoxy-2H- indazol-2-yl)-2-methylcyclohexan-l-ol as a yellow oil (5.0 g, 45 wt.%) which was used in the next step without further purification. MS ESI, m / z = 339 / 341 [M+H] + .

[0926] a mixture of rac-2-((1R,3R,4S)-4-hydroxy-3-methylcyclohexyl)-N-(imidazo[1,2- b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide and rac-2-((1S,3R,4S)-4- hydroxy-3-methylcyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H- indazole-5-carboxamide

[0927]

[0928] A suspension of a crude mixture of rac-(1S,2R,4R)-4-(5-bromo-6-...

Claims

1. A compound having the formula (Id) or a pharmaceutically acceptable salt thereof, in: R 1 yes R 2 yes R 4 It is H, Me, Et, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl; Y is N(Me)COMe, N(R) 5 )COMe、N(Me)COR 6 、N(R 5 )COR 6 Or CONMe2; Z is H; X is OR 7 or NR 8 R 9 ; R 5 It is H, an optionally substituted C1-C6 alkyl group, or an optionally substituted C3-C6 cycloalkyl group; R 6 It is an optionally substituted C1-C6 alkyl, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted 5- or 6-membered saturated N-heterocycle; R 7 It is Me, Et, isopropyl, n-propyl, cyclopropyl, cyclobutyl, optionally substituted C1-C6 alkyl, C3-C6 cycloalkyl, or a 4-, 5-, or 6-membered ring containing heteroatoms selected from O and N; R 8 and R 9 Independently selected from H, Me and optionally substituted C1-C6 alkyl groups, or together forming optionally substituted C3-C6 cycloalkyl groups or optionally substituted 4-, 5-, or 6-membered rings containing additional heteroatoms selected from O and N; Where R exists, 4 R 5 R 6 R 7 R 8 and R 9 The optional substituents are independently selected from OH, C1-C3 alkyl, C1-C3 alkoxy, C(O)Me, amino, NHMe, NMe2, F and Cl.

2. The compound according to claim 1, wherein R 1 yes 3. The compound according to claim 1, wherein R 1 yes 4. The compound according to any one of claims 1 to 3, wherein X is OR 7 Choose any one of R 7 It's me.

5. The compound according to any one of claims 1 to 3, wherein R 5 It is H, C1-C6 alkyl or C3-C6 cycloalkyl.

6. The compound according to any one of claims 1 to 3, wherein R 2 yes Choose any one of R 4 It is H.

7. The compound of formula (Id) according to claim 1, wherein the compound is selected from: N-(imidazo[1,2-b]pyridazine-3-yl)-6-methoxy-2-((1s,4s)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide; N-(imidazo[1,2-b]pyridazine-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-(cyclopropanecarbamoyl)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1s,4s)-4-(cyclopropanecarbamoyl)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-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; 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropaneamido)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1S,4r)-4-((S)-2-hydroxy-N-methylpropaneamido)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; 2-((1S,4r)-4-((S)-2-hydroxy-N-methylpropaneamide)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropaneamido)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide; 6-Methoxy-2-((1r,4r)-4-(N-methylcyclopropanecarbamoyl)cyclohexyl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((1r,3R)-3-hydroxy-N-methylcyclobutane-1-carbamate)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carbamate; 2-((1R,4r)-4-((1s,3S)-3-hydroxy-N-methylcyclobutane-1-carbamate)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carbamate; 2-((1r,4r)-4-(2-hydroxy-N,2-dimethylpropaneamide)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1S,4r)-4-((S)-3-hydroxy-N-methylbutanediamide)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carboxamide; 2-((1R,4r)-4-((R)-3-hydroxy-N-methylbutanediamide)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-carbamoyl)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carbamoyl-isomer 1 or isomer 2; rel-2-((1R,4r)-4-((1R,3S)-3-hydroxy-N-methylcyclopentane-1-carbamoyl)cyclohexyl)-6-methoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)-2H-indazole-5-carbamoyl-isomer 1 or isomer 2; 2-((1S,4r)-4-((S)-3-hydroxy-N-methylpyrrolidine-1-carbamoyl)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carbamoyl; 2-((1R,4r)-4-((R)-3-hydroxy-N-methylpyrrolidine-1-carbamate)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carbamate, Or its pharmaceutically acceptable salt.

8. The compound of formula (Id) according to claim 1, wherein it is N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2-((1r,4r)-4-(N-methylacetamido)cyclohexyl)-2H-indazole-5-carboxamide 9. The compound of formula (Id) according to claim 1, wherein it is 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; 10. The compound of formula (Id) according to claim 1, wherein the compound is 2-((1R,4r)-4-((R)-2-hydroxy-N-methylpropaneamide)cyclohexyl)-N-(imidazo[1,2-b]pyridazin-3-yl)-6-methoxy-2H-indazole-5-carboxamide 11. A pharmaceutical composition comprising a compound having formula (Id) according to any one of claims 1 to 10 and at least one pharmaceutically acceptable excipient.

12. Use of the compound of formula (Id) according to any one of claims 1 to 10 in the preparation of a medicament for treating a disease selected from respiratory diseases, cancer, inflammatory diseases, and autoinflammatory / autoimmune diseases.

13. The use according to claim 12, wherein the respiratory disease is asthma or chronic obstructive pulmonary disease (COPD), and the inflammatory disease and autoinflammatory / autoimmune disease are systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjögren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis, or psoriasis.

14. The use according to claim 12, wherein the cancer is a hematologic malignancy selected from Waldenström macroglobulinemia (WM), non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), primary central nervous system lymphoma (PCNSL), splenic marginal zone lymphoma (SMZL), small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL), and monoclonal immunoglobulinemia of undetermined significance (MGUS-IgM+).

15. The use according to claim 12, wherein the disease is selected from asthma, chronic obstructive pulmonary disease, systemic lupus erythematosus, rheumatoid arthritis, myositis, Sjögren's syndrome, systemic sclerosis, gout, endometriosis, atopic dermatitis, and psoriasis.

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