WO2025052129A1

WO2025052129A1 - Pyridine derivatives which act as inhibitors of mptp.

Info

Publication number: WO2025052129A1
Application number: PCT/GB2024/052315
Authority: WO
Inventors: Gilles Ouvry; Stevan Djuric; John Maclean; Christopher G. THOMSON
Original assignee: Nrg Therapeutics Ltd
Current assignee: Nrg Therapeutics Ltd
Priority date: 2023-09-05
Filing date: 2024-09-05
Publication date: 2025-03-13
Anticipated expiration: 2026-03-05

Abstract

The invention relates to compounds of formula (I): and related aspects. The compounds are inhibitors of mPTP.

Description

NOVEL COMPOUNDS Field of the invention The invention relates to novel compounds which are inhibitors of the mitochondrial permeability transition pore (mPTP). The invention also inter alia relates to such compounds for use as medicaments, in particular, for the treatment or prevention of degenerative, neurodegenerative or mitochondrial diseases or other diseases or disorders in which inhibition of mPTP provides a therapeutic or prophylactic effect. Background to the invention The mitochondria permeability transition pore (mPTP) is a high conductance channel residing on the inner mitochondrial membrane that is activated under certain conditions of cellular stress, in particular excessive Ca²⁺ loading and oxidative stress. It is permeable to solutes with molecular mass <1.5 kDa, is voltage and Ca²⁺ dependent and exhibits a characteristic large conductance. Once activated, oxidative phosphorylation is uncoupled resulting in the loss of the mitochondria membrane potential and disrupted mitochondria metabolism. In addition, solutes enter the mitochondrial matrix resulting in swelling, eventual rupture of the outer membrane with consequent release of apoptotic factors as well as sequestered Ca²⁺, leading to eventual cell death via apoptosis or necrosis depending on the type and physiology of the cell. As such it has been implicated as a key pathological event in multiple degenerative and metabolic diseases. Under normal physiological conditions mitochondria play a key role in regulating cellular Ca²⁺ homeostasis. Ca²⁺ entering the cell via cell surface channels, a common mechanism of cell signalling, is rapidly sequestered by mitochondria, preventing excessive and toxic Ca²⁺ accumulation in the cell cytoplasm. In cell types such as neurons, skeletal muscle myofibers and cardiomyocytes which undergo high levels of Ca²⁺ flux, this Ca²⁺ ‘buffering’ effect of mitochondria is critical to maintain cell health. However, there is a limit to the capacity of mitochondria to sequester Ca²⁺ and if intramitochondrial Ca²⁺ levels reach a certain threshold the Ca²⁺ sensitive mPTP is activated, resulting in collapse of the mitochondria and initiation of cell death. Activation of the mPTP in degenerative diseases may occur in a variety of ways depending on the disease, for example: 1) excessive Ca²⁺ entry into cells and overload of the mitochondria with Ca²⁺ 2) dysfunctional mitochondrial Ca²⁺ efflux mechanisms, in particular decreased activity of the Ca²⁺ efflux transporter NCLX resulting in Ca²⁺ overload 3) overactivity or upregulation of the Ca²⁺ uptake mechanisms in mitochondria 4) oxidative stress 5) sensitization of the mPTP due to compromised mitochondrial function i.e. mPTP activation at lower intramitochondrial concentrations of Ca²⁺ 6) excessive transfer of Ca²⁺ from the endoplasmic reticulum into the mitochondria at contact points between the two organelles known as mitochondria- associated-membranes. While the properties and function of the mPTP can be studied in simple in vitro assays in isolated mitochondria, the molecular identity of the mPTP is not known. Multiple proteins have been proposed to comprise the pore forming complex, including the ATP synthase and the adenine nucleotide transporter (ANT) family of proteins but no single protein is widely accepted as being responsible for formation of the pore. However, the peptidyl prolyl cis-trans isomerase F (Ppif), also known as cyclophilin D, is well accepted to be a key regulator of the pore, though not forming a transmembrane channel in its own right. Genetic or pharmacological inhibition of Ppif significantly decreases the sensitivity of pore opening in response to Ca²⁺ loading and other mPTP activators. Genetic ablation or pharmacological inhibition of Ppif has therefore been utilised to evaluate involvement of the mPTP in pathological pathways in cell and animal disease models. In this way, inhibition of the mPTP has been shown to be protective in numerous models of disease, in particular those where Ca²⁺ dysregulation and oxidative stress are known to contribute to cellular degeneration. Notably, genetic knockout of Ppif was shown to be protective in various preclinical in vivo transgenic models of neurodegenerative disease including Alzheimer’s disease, Parkinson’s disease and motor neuron disease, demonstrating the therapeutic potential of mPTP inhibition. In each of these diseases, genetic mutations in particular proteins that cause inherited forms of disease (i.e. amyloid precursor protein, alpha-synuclein and superoxide dismutase 1 respectively), and are expressed in the mouse models, have been shown to cause either Ca²⁺ overload of the mitochondria or sensitization of the mPTP. Recent evidence suggests this may occur through a common mechanism in Alzheimer’s, Parkinson’s and Friedreich’s ataxia. In each case, it has been reported that in cells expressing the mutated disease associated proteins (amyloid precursor protein, PINK1 and frataxin respectively), the activity or expression of the mitochondrial Ca²⁺ efflux transporter, NCLX, is decreased, resulting in Ca²⁺ overload of the mitochondria. In the case of Parkinson’s disease, the pathological aggregated form of the protein alpha-synuclein, a common misfolded protein in sporadic and inherited cases of Parkinson’s disease, has also been shown to sensitise and activate the mPTP. Genetic ablation of Ppif has been shown to be beneficial in numerous other preclinical models of degenerative disease, therefore demonstrating the potential of mPTP inhibitors in Duchenne and congenital forms of muscular dystrophy, ischemia-reperfusion injury, bone repair, pancreatitis and inter alia other associated disorders. In addition to the demonstrated benefit of Ppif inhibition in preclinical models, mPTP function has been shown to be dysregulated in multiple other disease indications. In particular, in a number of diseases the threshold for mPTP activation in response to Ca²⁺ loading appears to be sensitised suggesting that mPTP activation may occur aberrantly under physiological conditions and drive tissue degeneration. For example, in muscle mitochondria from elderly human muscle biopsies, the threshold for mPTP activation is reduced compared to healthy control. In these diseases, this sensitization of mPTP activity underlies additional rationale for the therapeutic potential of mPTP inhibitors. mPTP inhibitors may also have therapeutic potential in other diseases where mitochondrial dysfunction, oxidative stress, inflammatory stress or Ca²⁺ dysregulation occur during disease pathogenesis. The discovery and development of inhibitors of the mPTP has largely been focussed on identification of Ppif inhibitors. Cyclosporin A (CsA), originally identified as an immunosuppressant by virtue of its inhibitory activity at calcineurin, was also found to inhibit Ppif as well as other members of the peptidyl prolyl cis-trans isomerase (Ppi) enzyme family. Several cyclosporin A derivatives e.g. Debio-25, NIM811 were subsequently developed that retained broad activity against the Ppi enzyme family without inhibiting calcineurin, however none of these progressed to market. To date, no potent brain penetrant selective Ppif inhibitors have been reported. Other more recent approaches to discover mPTP inhibitors have utilised phenotypic screens in isolated mitochondria. These have successfully identified potent small molecule mPTP inhibitors with a Ppif-independent mode of action. Yu et al., (2020, Cell, 183, 1-14) relates to the link between mPTP activation and the mechanism of TDP-43 proteinopathy such as TAR DNA-binding protein 43 (TDP-43) associated neurodegeneration. Cytoplasmic neuronal accumulation of the normally nuclear protein TDP-43 is a disease hallmark for almost all cases of ALS and 40-50% of Frontotemporal Lobar Degeneration (FTLD), with some familial cases caused by mutant forms of the protein. Both diseases are associated with a neuroinflammatory cytokine profile related to upregulation of NF-κB and type I IFN pathways, directly suggesting a role for TDP-43 in neuroinflammation. Mutant or overexpressed WT TDP-43 in neurons mis-localises to the mitochondria and induces the release of mitochondrial DNA (mtDNA) into the cytoplasm. This mtDNA then activates the immune sensor cGAS-STING triggering the induction of innate immune genes such as IL-6, TNFα, and interferonβ. Inhibition of the mPTP with cyclosporin A or via CypD knockout, prevents the TDP-43 induced release of mtDNA and subsequent induction of innate immune response genes. Furthermore, inhibition of cGAS-STING extends the survival of mutant mice expressing a mutant TDP-43. The data implicates mPTP activation in mediating the toxic effects of TDP-43 in ALS and other disease where either mutations in the TDP-43 gene causes disease or where TDP-43 proteinopathy is observed. Jang et al., (2021 American Journal of Physiology: Renal physiology, doi: 10.1152/ajprenal.00171.2021. Epub ahead of print. PMID: 34396791.) highlighted the potential therapeutic benefit of mPTP inhibition (via CypD knockout) in a mouse model a kidney fibrosis. Unilateral ureteral obstruction was used to induce kidney fibrosis in WT and CypD KO mice. Inflammation, proximal tubule atrophy and markers of fibrosis were reduced in the CypD KO mice versus WT. Measures of fibrosis included collagen deposition, α-SMA and TGFβ expression, and interstitial cell proliferation. This highlights the potential role of the mPTP in cell injury/death-mediated tissue remodelling and fibrogenesis. mPTP inhibitors may therefore be beneficial in diseases where fibrosis is a key pathological mechanism, e.g. chronic kidney disease, idiopathic pulmonary fibrosis, non-alcoholic steatohepatitis, primary biliary cholangitis and systemic sclerosis. CYP2D6 is one of the major members of the human drug metabolising cytochrome P450 enzyme system. It is involved in the hepatic metabolism of a significant proportion of clinically used drugs. Inhibition of CYP2D6 can drive drug-drug interactions with co-prescribed medications metabolised by the same enzyme, which result in increased plasma concentrations potentially to levels which may cause adverse effects. CYP2D6 is predominately expressed in the liver but also, to a lesser degree, in the central nervous system (CNS). In the CNS it is involved in the synthesis of different neurotransmitters such as dopamine. Consequently, inhibition of CYP2D6 particularly at the level of the central nervous system can potentially have detrimental effects via impairment of pathways such as the production of dopamine. In Parkinson’s disease, which is characterized by the loss of dopaminergic neurons in the Substantia Nigra, further depletion of dopamine levels through inhibition of CYP2D6 may not be tolerated. When dosed orally, the oral bioavailability and systemic exposure of a drug are largely determined by the degree of absorption from the gastrointestinal tract and the extent of first-pass metabolism in the liver. Properties such as high solubility (as measured in phosphate-buffered saline (PBS) or in the more biologically relevant Fasted State Simulated Intestinal Fluid (FaSSIF)) and high metabolic stability (as measured in vitro in either isolated liver microsomes or in human hepatocytes) are therefore predictive of improved oral bioavailability and/or systemic exposure in patients. WO2010/049768 relates to acrylamido derivatives and their use as therapeutic agents, particularly for the prevention and/or treatment of diseases associated with the activity of the mPTP (see also Plyte et al. J. Med Chem. 2014, 57, 5333-47). Chen et al. (Assay and Drug Development Technologies, 2018, 16, 445-455) relates to phenotypic screening for mPTP modulators using platelets and discloses further acrylamido derivatives. CA2884607A1 relates to acrylamido and maleimide compounds which are said to be useful in the treatment of mitochondrial diseases. WO2022/049376, WO2022/049377 and WO2023/166303 disclose cinnamide compounds which are inhibitors of the mPTP. Yannick LACROIX, “The design, synthesis and optimisation of calcium release-activated calcium (CRAC) channel inhibitors and mitochondrial permeability transition pore (mPTP) modulators, using phenotypic screening”, PhD Thesis, University of Strathclyde (released 1 November 2021) discloses cinnamide compounds which are inhibitors of the mPTP. There remains a need to find further compounds which are inhibitors of mPTP. Such compounds may also display other desirable pharmacological properties, such as low CYP2D6 inhibition, adequate solubility, low intrinsic clearance and/or low efflux by multidrug resistance protein 1 (MDR1) leading e.g. to high oral bioavailability and/or high systemic exposure and/or high brain penetration. Summary of the Invention In a first aspect the invention provides a compound of formula (I): wherein: R₁ is H or F; wherein: R2 is C1-3alkyl, -CH2OC1-3alkyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; R3 is H, C1-3alkyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; R4 is H, C1-3alkyl, -CH2OC1-3alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -CN, halo or C3- 5cycloalkyl; and R₅ is H, C_1-3alkyl, -CH₂OC_1-3alkyl, C_1-3fluoroalkyl, C_1-3alkoxy, -CN, halo or C_3-5cycloalkyl; provided that when R₅ is H then R₁ is F; B is group (Ba) or (Bb): wherein group (Ba) is:

wherein: Y is C(R_9a)(R_9b), O or N(R_9c); R_9a, R_9b and R_9c are independently H or C_1-3alkyl or R_9a and R_9b together with the carbon atom to which they are attached form a C3-6cycloalkyl group; and R6, R7 and R8 are independently H, C1-3alkyl, C2-3alkynyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; wherein group (Bb) is:

wherein: R₁₀ is H, C_1-3alkyl, C_2-3alkynyl, C_1-3fluoroalkyl, C_1-3alkoxy, -CN, halo or C_3-5cycloalkyl; D is N or C(R11) and R11, R12 and R13 are independently H, C1-3alkyl, C2-3alkynyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; or a prodrug thereof in which an available nitrogen atom in group Ba or Bb is derivatised by the moiety -CH2-OP(=O)(OH)2; or a pharmaceutically acceptable salt and/or solvate thereof. In a second aspect the invention provides a compound of formula (IA):

wherein: R2 is C1-3alkyl, -CH2OC1-3alkyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; R₃ is H, C_1-3alkyl, C_1-3fluoroalkyl, C_1-3alkoxy, -CN, halo or C_3-5cycloalkyl; R₄ is H, C_1-3alkyl, -CH₂OC_1-3alkyl, C_1-3fluoroalkyl, C_1-3alkoxy, C_1-3fluoroalkoxy, -CN, halo or C_3- ₅cycloalkyl; and R₅ is H, C_1-3alkyl, -CH₂OC_1-3alkyl, C_1-3fluoroalkyl, C_1-3alkoxy, -CN, halo or C_3-5cycloalkyl; B is group (Ba) or (Bb): wherein group (Ba) is:

wherein: Y is C(R9a)(R9b), O or N(R9c); R9a, R9b and R9c are independently H or C1-3alkyl or R9a and R9b together with the carbon atom to which they are attached form a C_3-6cycloalkyl group; and R₆ and R₈ are independently H, C_1-3alkyl, C_2-3alkynyl, C_1-3fluoroalkyl, C_1-3alkoxy, -CN, halo or C_3-5cycloalkyl; wherein group (Bb) is:

wherein: R10 is H, C1-3alkyl, C2-3alkynyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; D is N or C(R11) and R11 and R13 are independently H, C1-3alkyl, C2-3alkynyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; or a prodrug thereof in which an available nitrogen atom in group Ba or Bb is derivatised by the moiety -CH2-OP(=O)(OH)2; or a pharmaceutically acceptable salt and/or solvate thereof. In a third aspect the invention provides a compound of formula (IB):

wherein: R₂ is C_1-3alkyl, -CH₂OC_1-3alkyl, C_1-3fluoroalkyl, C_1-3alkoxy, -CN, halo or C_3-5cycloalkyl; R₃ is H, C_1-3alkyl, C_1-3fluoroalkyl, C_1-3alkoxy, -CN, halo or C_3-5cycloalkyl; R₄ is H, C_1-3alkyl, -CH₂OC_1-3alkyl, C_1-3fluoroalkyl, C_1-3alkoxy, C_1-3fluoroalkoxy -CN, halo or C_3- 5cycloalkyl; and R5 is F, Cl or -CN; B is group (Ba) or (Bb): wherein group (Ba) is:

wherein: Y is C(R_9a)(R_9b), O or N(R_9c); R_9a, R_9b and R_9c are independently H or C_1-3alkyl or R_9a and R_9b together with the carbon atom to which they are attached form a C_3-6cycloalkyl group; and R₆, R₇ and R₈ are independently H, C_1-3alkyl, C_2-3alkynyl, C_1-3fluoroalkyl, C_1-3alkoxy, -CN, halo or C_3-5cycloalkyl; wherein group (Bb) is:

wherein: R10 is H, C1-3alkyl, C2-3alkynyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; D is N or C(R11) and R11, R12 and R13 are independently H, C1-3alkyl, C2-3alkynyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; or a prodrug thereof in which an available nitrogen atom in group Ba or Bb is derivatised by the moiety -CH₂-OP(=O)(OH)₂; or a pharmaceutically acceptable salt and/or solvate thereof. In one embodiment, a compound of formula (I) is provided in the form of a pharmaceutically acceptable prodrug, salt and/or solvate. In one embodiment, a compound of formula (I) is provided in the form of a pharmaceutically acceptable salt and/or solvate. In one embodiment, a compound of formula (I) is provided in the form of a pharmaceutically acceptable salt. In one embodiment, a compound of formula (I) is provided in the form of a pharmaceutically acceptable solvate. In one embodiment, a compound of formula (I) is provided in the form of a prodrug. In one embodiment, a compound of formula (I) is provided in the form of a pharmaceutically acceptable prodrug. In one embodiment, a compound of formula (I) is provided. The invention further provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, and a pharmaceutically acceptable carrier or excipient. The invention also provides a compound of formula (I), or pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment or prophylaxis of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect. The invention also provides use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect. The invention also provides a method of preventing or treating a disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect in a subject. Suitably the disease or disorder is selected from degenerative or neurodegenerative diseases, disorders of the central nervous system, ischemia and re-perfusion injury, metabolic diseases, inflammatory or autoimmune diseases, diseases of aging and renal diseases. The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment or prophylaxis of a mitochondrial disease. The invention also provides use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the treatment or prophylaxis of a mitochondrial disease. The invention also provides a method of preventing or treating a mitochondrial disease in a subject, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof. The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment or prophylaxis of a disease or disorder associated with TDP- 43 proteinopathy such as TDP-43 associated neurodegeneration. The invention also provides use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration. The invention also provides a method of treating or preventing a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof. The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment or prophylaxis of a disease or disorder associated with fibrosis. The invention also provides use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder associated with fibrosis. The invention also provides a method of treating or preventing a disease or disorder associated with fibrosis, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof. Also provided are novel intermediate compounds of formula (II), (III), (IV), (V), (VI), (X) and (XI). Such compounds are of use in the preparation of compounds of formula (I). Detailed description of the Invention The term “alkyl” as used herein, such as in C1-3alkyl, is a straight or branched fully saturated hydrocarbon chain containing the specified number of carbon atoms. Examples of C1-3alkyl groups include methyl, ethyl, n-propyl and iso-propyl. Reference to “propyl” includes n-propyl and iso-propyl. Me means methyl. Et means ethyl. Pr means propyl. Bu means butyl. The term “alkynyl” as used herein, such as in C2-3alkynyl, is a straight or branched divalent hydrocarbon chain with a least one carbon-carbon triple bond. Examples of C_2-3alkynyl include ethynyl, 1-propynyl and 2-propynyl. The term “alkoxy” as used herein, such as in C_1-3alkoxy, refers to an alkyl group (e.g. a C_1-3alkyl group) as defined above, singularly bonded to an oxygen atom. Examples of C_1-3alkoxy groups include methoxy, ethoxy, 1-propoxy and 2-propoxy, especially methoxy. The term “cycloalkyl” as used herein, such as in C3-5cycloalkyl or C3-6cycloalkyl, is a fully saturated hydrocarbon ring containing the specified number of carbon atoms, such as 3 to 5 or 3 to 6. Examples of C_3-6cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, in particular cyclopropyl. The term “fluoroalkyl” as used herein, such as in C_1-3fluoroalkyl, is a straight or branched alkyl group containing the specified number of carbon atoms, substituted by one or more fluoro atoms, for example fluoromethyl (CH2F), di-fluoromethyl (CHF2), tri-fluoromethyl (CF3), 1-fluoroethyl (CH2FCH2) and 2- fluoroethyl (CH2CH2F). The term “fluoroalkoxy” as used herein, such as in C1-3fluoroalkoxy, is a linear or branched, saturated, monovalent C_1-3alkoxy group, as defined above, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom for example -OCF₃, -OCHF₂, -OCH₂F, - OCF₂CF₃ and -OCH₂CF₃. The term ‘halo’ or ‘halogen’ as used herein, refers to fluorine, chlorine, bromine or iodine. Particular examples of halo are bromine, fluorine and chlorine, especially fluorine. Compounds of formula (I) In one embodiment, R₁ is H. In one embodiment, R₁ is F In one embodiment, R₂ is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R₂, is methyl. In one embodiment, R₂ is -CH₂OC_1-3alkyl. In another embodiment, R₂, is -CH₂OMe. In one embodiment, R2 is C1-3fluoroalkyl. In another embodiment, R2, is CF3. In one embodiment, R2 is C1- 3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R2, is methoxy. In one embodiment, R2 is -CN. In one embodiment, R2 is halo. In another embodiment, R2 is F. In one embodiment, R2 is C3-6cycloalkyl. In one embodiment, R3 is H. In one embodiment, R3 is C1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R3 is methyl. In one embodiment, R3 is C1-3fluoroalkyl. In another embodiment, R3 is CF3. In one embodiment, R3 is C1-3alkoxy such as methoxy, ethoxy or propoxy. In another embodiment, R₃ is methoxy. In one embodiment, R₃ is -CN. In one embodiment, R₃ is halo. In another embodiment, R₃ is F. In one embodiment, R₃ is C_3-6cycloalkyl. In one embodiment, R₄ is H. In one embodiment, R₄ is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R₄ is methyl. In one embodiment, R₄ is -CH₂OC_1-3alkyl. In another embodiment, R4, is -CH2OMe. In one embodiment, R4 is C1-3fluoroalkyl. In another embodiment, R4, is CF3. In one embodiment, R4 is C1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R4, is methoxy. In one embodiment, R4 is C1-3fluoroalkoxy. In another embodiment, R4, is OCF3. In one embodiment, R4 is -CN. In one embodiment, R4 is halo. In another embodiment, R4 is F. In one embodiment, R₄ is C_3-6cycloalkyl. In one embodiment, R₅ is H. In one embodiment, R₅ is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R₅ is methyl. In one embodiment, R₅ is -CH₂OC_1-3alkyl. In another embodiment, R5, is -CH2OMe. In one embodiment, R5 is C1-3fluoroalkyl. In another embodiment, R5 is CF3. In one embodiment, R5 is C1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R5 is methoxy. In one embodiment, R5 is -CN. In one embodiment, R5 is halo. In another embodiment, R5 is F. In another embodiment, R5 is Cl. In one embodiment, R5 is C3-6cycloalkyl. In one embodiment, R5 is H, C1-3alkyl or halo. In another embodiment, R5 is H, methyl or halo. In another embodiment, R5 is methyl or halo. In another embodiment, R₅ is methyl or F. In another embodiment R₅ is methyl or Cl. In one embodiment, B is group:

In one embodiment, R₆ is H. In another embodiment, R₆ is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R₆ is methyl. In one embodiment, R₆ is C_2-3alkynyl. In one embodiment, R₆ is C_1-3fluoroalkyl. In another embodiment, R₆ is CF_3. In one embodiment, R₆ is C_1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R6 is methoxy. In one embodiment, R6 is -CN. In one embodiment, R6 is halo. In another embodiment, R6 is F. In one embodiment, R6 is C3-5cycloalkyl. In one embodiment, R7 is H. In another embodiment, R7 is C1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R7 is methyl. In one embodiment, R7 is C2-3alkynyl. In one embodiment, R7 is C1-3fluoroalkyl. In another embodiment, R7 is CF3. In one embodiment, R7 is C1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R7 is methoxy. In one embodiment, R7 is CN. In one embodiment, R7 is halo. In another embodiment, R7 is F. In one embodiment, R7 is C3-5cycloalkyl. In one embodiment, R₈ is H. In another embodiment, R₈ is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R₈ is methyl. In one embodiment, R₈ is C_2-3alkynyl. In one embodiment, R₈ is C_1-3fluoroalkyl. In another embodiment, R₈ is CF_3. In one embodiment, R₈ is C_1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R₈ is methoxy. In one embodiment, R₈ is -CN. In one embodiment, R₈ is halo. In another embodiment, R₈ is F. In one embodiment, R₈ is C_3-5cycloalkyl. In one embodiment, Y is C(R9a)(R9b). In another embodiment, Y is CH2. In one embodiment, Y is O. In one embodiment, Y is N(R9c). In another embodiment, Y is NMe. In one embodiment, R_9a is H. In one embodiment, R_9a is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R_9a is methyl. In one embodiment R_9b is H. In one embodiment, R_9b is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R9b is methyl. In one embodiment R9c is H. In one embodiment, R9c is C1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R9c is methyl. In one embodiment, R_9a and R_9b together with the carbon atom to which they are attached form a C_3- ₆cycloalkyl group. In one embodiment, B is group:

In one embodiment, R₁₀ is H. In another embodiment, R₁₀ is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R₁₀ is methyl. In one embodiment, R₁₀ is C_2-3alkynyl. In one embodiment, R₁₀ is C_1-3fluoroalkyl. In another embodiment, R₁₀ is CF_3. In one embodiment, R₁₀ is C_1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R₁₀ is methoxy. In one embodiment, R₁₀ is -CN. In one embodiment, R10 is halo. In another embodiment, R10 is F. In one embodiment, R10 is C3- 5cycloalkyl. In one embodiment, R12 is H. In another embodiment, R12 is C1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R12 is methyl. In one embodiment, R12 is C2-3alkynyl. In one embodiment, R12 is C1-3fluoroalkyl. In another embodiment, R12 is CF3. In one embodiment, R12 is C1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R₁₂ is methoxy. In one embodiment, R₁₂ is -CN. In one embodiment, R₁₂ is halo. In another embodiment, R₁₂ is F. In one embodiment, R₁₂ is C_3- ₅cycloalkyl. In one embodiment, R₁₃ is H. In another embodiment, R₁₃ is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R13 is methyl. In one embodiment, R13 is C2-3alkynyl. In one embodiment, R13 is C1-3fluoroalkyl. In another embodiment, R13 is CF3. In one embodiment, R13 is C1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R13 is methoxy. In one embodiment, R13 is -CN. In one embodiment, R13 is halo. In another embodiment, R13 is F. In one embodiment, R13 is C3- ₅cycloalkyl. In one embodiment, D is N. In one embodiment, D is C(R₁₁). In one embodiment, R11 is H. In another embodiment, R11 is C1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R11 is methyl. In one embodiment, R11 is C2-3alkynyl. In one embodiment, R11 is C1-3fluoroalkyl. In another embodiment, R11 is CF3. In one embodiment, R11 is C1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R11 is methoxy. In one embodiment, R11 is -CN. In one embodiment, R11 is halo. In another embodiment, R11 is F. In one embodiment, R11 is C3- ₅cycloalkyl. References and preferences set out with respect to the compound of formula (I), or a salt and/or solvate thereof regarding pharmaceutical compositions, compounds for use, use and method aspects apply equally to the compounds of formulae (IA) or (IB) or salts and/or solvates thereof. In an embodiment, the following compounds are disclaimed from the scope of compounds of formula (I) or a salt and/or solvate thereof: (2E)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(5-fluoro-3-methyl-1H-indazol-6-yl)prop-2-enamide; (2E)-3-(3-fluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-3-(3-chloro-5-fluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl) prop-2-enamide; (2E)-N-(5-fluoro-4-methylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2E)-3-(3,5-difluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-3-(3-chloro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2E)-N-[5-fluoro-4-(methoxymethyl)pyridin-3-yl]-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; and (2E)-N-[5-fluoro-4-(methoxymethyl)-2-methylpyridin-3-yl]-3-(3-methyl-1H-indazol-6-yl)prop-2- enamide; or a salt and/or solvate of any one thereof. In an embodiment the invention provides prodrugs of the aforesaid disclaimed compounds (or a salt and/or solvate of said prodrugs) as described herein. Compounds of formula (IA) In one embodiment, the compound of formula (I) is a compound of formula (IA):

wherein: R₂ is C_1-3alkyl, -CH₂OC_1-3alkyl, C_1-3fluoroalkyl, C_1-3alkoxy, -CN, halo or C_3-5cycloalkyl; R3 is H, C1-3alkyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; R4 is H, C1-3alkyl, -CH2OC1-3alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -CN, halo or C3- 5cycloalkyl; and R5 is H, C1-3alkyl, -CH2OC1-3alkyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; B is group (Ba) or (Bb): wherein group (Ba) is:

wherein: Y is C(R9a)(R9b), O or N(R9c); R_9a, R_9b and R_9c are independently H or C_1-3alkyl or R_9a and R_9b together with the carbon atom to which they are attached form a C_3-6cycloalkyl group; and R₆ and R₈ are independently H, C_1-3alkyl, C_2-3alkynyl, C_1-3fluoroalkyl, C_1-3alkoxy, -CN, halo or C_3-5cycloalkyl; wherein group (Bb) is: wherein: R10 is H, C1-3alkyl, C2-3alkynyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; D is N or C(R₁₁) and R₁₁ and R₁₃ are independently H, C_1-3alkyl, C_2-3alkynyl, C_1-3fluoroalkyl, C_1-3alkoxy, -CN, halo or C_3-5cycloalkyl; or a prodrug thereof in which an available nitrogen atom in group Ba or Bb is derivatised by the moiety -CH₂-OP(=O)(OH)₂. The embodiments that follow are relevant for compounds of formula (IA). In one embodiment, R2 is C1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R2, is methyl. In one embodiment, R₂ is -CH₂OC_1-3alkyl. In another embodiment, R₂, is -CH₂OMe. In one embodiment, R₂ is C_1-3fluoroalkyl. In another embodiment, R₂, is CF_3. In one embodiment, R₂ is C_1- ₃alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R₂, is methoxy. In one embodiment, R₂ is -CN. In one embodiment, R₂ is halo. In another embodiment, R₂ is F. In one embodiment, R2 is C3-6cycloalkyl. In one embodiment, R3 is H. In one embodiment, R3 is C1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R3 is methyl. In one embodiment, R3 is C1-3fluoroalkyl. In another embodiment, R3 is CF3. In one embodiment, R3 is C1-3alkoxy such as methoxy, ethoxy or propoxy. In another embodiment, R₃ is methoxy. In one embodiment, R₃ is -CN. In one embodiment, R₃ is halo. In another embodiment, R₃ is F. In one embodiment, R₃ is C_3-6cycloalkyl. In one embodiment, R₄ is H. In one embodiment, R₄ is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R4 is methyl. In one embodiment, R4 is -CH2OC1-3alkyl. In another embodiment, R4 is -CH2OMe. In one embodiment, R4 is C1-3fluoroalkyl. In another embodiment, R4 is CF3. In one embodiment, R4 is C1-3alkoxy, such as methoxy, ethoxy or propoxy. In an embodiment, one or more of the alkoxy groups may comprise one or more deuterium atoms as a substitute for one or more hydrogen atoms. Thus, in an embodiment R₄ is OCH₂D, OCHD₂ or OCD₃, such as OCD₃. In another embodiment, R₄, is methoxy. In one embodiment, R₄ is C_1-3fluoroalkoxy. In another embodiment, R₄ is OCF_3. In one embodiment, R₄ is -CN. In one embodiment, R₄ is halo. In another embodiment, R₄ is F. In one embodiment, R₄ is C_3-6cycloalkyl. In one embodiment R5 is C1-3alkyl, -CH2OC1-3alkyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3- 5cycloalkyl. In another embodiment, R5 is C1-3alkyl, -CH2OMe, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl. Thus, in one embodiment, R5 is C1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R5 is methyl. In one embodiment, R5 is -CH2OC1-3alkyl. In another embodiment, R5 is -CH2OMe. In one embodiment, R5 is C1-3fluoroalkyl. In another embodiment, R5 is CF3. In one embodiment, R5 is C1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R5 is methoxy. In one embodiment, R₅ is -CN. In one embodiment, R₅ is halo. In another embodiment, R₅ is F. In another embodiment, R₅ is Cl. In one embodiment, R₅ is C_3-6cycloalkyl. In one embodiment, R₅ is methyl, F or Cl. In one embodiment, R₅ is methyl or Cl. In another embodiment R₅ is H. In one embodiment, R2 is methyl, R3 is methyl, R4 is H and R5 is methyl, F or Cl (e.g. F or Cl). For example, R2 is methyl, R3 is methyl, R4 is H and R5 is F. Alternatively, R2 is methyl, R3 is methyl, R4 is H and R5 is Cl. In one embodiment, R₂ and R₃ are methyl, R₄ is methoxy and R₅ is H. In one such embodiment, when R₄ is methoxy, one or more of the hydrogen atoms on the methoxy group are replaced with deuterium. For example, at least two of the hydrogen atoms are replaced with deuterium, e.g. all three hydrogen atoms are replaced by deuterium. In one embodiment, R2 is C1-3alkyl and R3 is C1-3alkyl. In another embodiment, R2 is C1-3alkyl and R3 is methyl. In another embodiment, R2 is methyl and R3 is C1-3alkyl. In another embodiment, R2 is methyl and R3 is methyl. In one embodiment, R₂ is C_1-3alkyl and R₃ is H. In another embodiment, R₂ is methyl and R₃ is H. In one embodiment, R₂ is C_1-3alkyl, R₃ is C_1-3alkyl and R₄ is H. In one embodiment, R₂ is C_1-3alkyl, R₃ is methyl and R4 is H. In one embodiment, R2 is methyl, R3 is C1-3alkyl and R4 is H. In another embodiment, R2 is methyl, R3 is methyl and R4 is H. In one embodiment, R2 is C1-3alkyl, R3 is H, and R4 is H. In another embodiment, R2 is methyl, R3 is H and R₄ is H. In one embodiment, R₂ is C_1-3alkyl, R₃ is C_1-3alkyl and R₄ is C_1-3alkoxy. In another embodiment, R₂ is methyl, R₃ is C_1-3alkyl and R₄ is C_1-3alkoxy. In another embodiment, R₂ is C_1-3alkyl, R₃ is methyl and R₄ is C_1-3alkoxy. In another embodiment, R₂ is C_1-3alkyl, R₃ is C_1-3alkyl and R₄ is methoxy. In another embodiment, R2 is methyl, R3 is C1-3alkyl and R4 is methoxy. In another embodiment, R2 is C1-3alkyl, R3 is methyl and R4 is methoxy. In another embodiment, R2 is methyl, R3 is methyl and R4 is C1-3alkoxy. In another embodiment, R2 is methyl, R3 is methyl and R4 is methoxy. In one embodiment, R2 is C1-3alkyl, R3 is C1-3alkyl, R4 is H and R5 is halo. In another embodiment, R2 is methyl, R3 is C1-3alkyl, R4 is H and R5 is halo. In another embodiment, R2 is C1-3alkyl, R3 is methyl, R4 is H and R5 is halo. In another embodiment, R2 is methyl, R3 is methyl, R4 is H and R5 is halo. In another embodiment, R2 is methyl, R3 is methyl, R4 is H and R5 is F. In another embodiment, R2 is methyl, R₃ is methyl, R₄ is H and R₅ is Cl. In one embodiment, R₂ is C_1-3alkyl, R₃ is H, R₄ is H and R₅ is halo. In another embodiment, R₂ is methyl, R₃ is H, R₄ is H and R₅ is halo. In another embodiment, R₂ is methyl, R₃ is H, R₄ is H and R₅ is F. In another embodiment, R₂ is methyl, R₃ is H, R₄ is H and R₅ is Cl. In one embodiment, R2 is C1-3alkyl, R3 is C1-3alkyl, R4 is H and R5 is C1-3alkyl. In another embodiment, R2 is methyl, R3 is C1-3alkyl, R4 is H and R5 is C1-3alkyl. In another embodiment, R2 is C1-3alkyl, R3 is methyl, R4 is H and R5 is C1-3alkyl. In one embodiment, R2 is C1-3alkyl, R3 is C1-3alkyl, R4 is H and R5 is methyl. In another embodiment, R₂ is methyl, R₃ is methyl, R₄ is H and R₅ is methyl. In one embodiment, R₂ is C_1-3alkyl, R₃ is H, R₄ is H and R₅ is C_1-3alkyl. In another embodiment, R₂ is C_1-3alkyl, R₃ is H, R₄ is H and R₅ is methyl. In another embodiment, R₂ is methyl, R₃ is H, R₄ is H and R5 is C1-3alkyl. In one embodiment, R2 is methyl, R3 is H, R4 is H and R5 is methyl. In one embodiment, R2 is C1-3alkyl, R3 is C1-3alkyl, R4 is C1-3alkoxy and R5 is H. In another embodiment, R2 is methyl, R3 is C1-3alkyl, R4 is C1-3alkoxy and R5 is H. In another embodiment, R2 is C1-3alkyl, R3 is methyl, R4 is C1-3alkoxy and R5 is H. In another embodiment, R2 is C1-3alkyl, R3 is C1-3alkyl, R4 is methoxy and R₅ is H. In another embodiment, R₂ is methyl, R₃ is C_1-3alkyl, R₄ is methoxy and R₅ is H. In another embodiment, R₂ is C_1-3alkyl, R₃ is methyl, R₄ is methoxy and R₅ is H. In another embodiment, R₂ is methyl, R₃ is methyl, R₄ is methoxy and R₅ is H. In one embodiment, R3 is Me, R4 is H and R5 is Me, F or Cl. In another embodiment, R3 is Me, R4 is H and R5 is Me or Cl. In one embodiment, R2 is a C1-3haloalkyl, e.g. a C1-3fluoroalkyl (such as CF3); R3 is methyl; R4 is H and R₅ is F. In one embodiment, B is group: In one embodiment, R6 is H. In another embodiment, R6 is C1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R6 is methyl. In one embodiment, R6 is C2-3alkynyl. In one embodiment, R6 is C1-3fluoroalkyl. In another embodiment, R6 is CF3. In one embodiment, R6 is C1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R6 is methoxy. In one embodiment, R6 is -CN. In one embodiment, R6 is halo. In another embodiment, R6 is F. In one embodiment, R6 is C3-5cycloalkyl. In one embodiment, R₈ is H. In another embodiment, R₈ is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R₈ is methyl. In one embodiment, R₈ is C_2-3alkynyl. In one embodiment, R₈ is C1-3fluoroalkyl. In another embodiment, R8 is CF3. In one embodiment, R8 is C1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R8 is methoxy. In one embodiment, R8 is -CN. In one embodiment, R8 is Halo. In another embodiment, R8 is F. In one embodiment, R8 is C3-5cycloalkyl. In one embodiment, Y is C(R_9a)(R_9b). In another embodiment, Y is CH₂. In one embodiment, Y is O. In one embodiment, Y is N(R_9c). In another embodiment, Y is NMe. In one embodiment, R_9a is H. In one embodiment, R_9a is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R_9a is methyl. In one embodiment R9b is H. In one embodiment, R9b is C1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R9b is methyl. In one embodiment R_9c is H. In one embodiment, R_9c is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R_9c is methyl. In one embodiment, R_9a and R_9b together with the carbon atom to which they are attached form a C_3- 6cycloalkyl group. In one embodiment, B is group: In one embodiment, R10 is H. In another embodiment, R10 is C1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R10 is methyl. In one embodiment, R10 is C2-3alkynyl. In one embodiment, R10 is C1-3fluoroalkyl. In another embodiment, R10 is CF3. In one embodiment, R10 is C1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R10 is methoxy. In one embodiment, R10 is CN. In one embodiment, R10 is halo. In another embodiment, R10 is F. In one embodiment, R10 is C3- ₅cycloalkyl. In one embodiment, R₁₀ is H, Cl, F, Me or -CN. In another embodiment, R₁₀ is H, Cl, Me or -CN. In one embodiment, R₁₃ is H. In another embodiment, R₁₃ is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R13 is methyl. In one embodiment, R13 is C2-3alkynyl. In one embodiment, R13 is C1-3fluoroalkyl. In another embodiment, R13 is CF3. In one embodiment, R13 is C1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R13 is methoxy. In one embodiment, R13 is -CN. In one embodiment, R13 is halo. In another embodiment, R13 is F. In one embodiment, R13 is C3- ₅cycloalkyl. In one embodiment, D is N. In one embodiment, D is C(R₁₁). In one embodiment, D is C(R₁₁) and R₁₁ is F, Cl, -CN or OMe. In one embodiment, D is C(R₁₁) and R₁₁ is halo. In another embodiment, D is C(R₁₁) and R₁₁ is F. In another embodiment, D is C(R₁₁) and R₁₁ is Cl. In another embodiment, D is C(R11) and R11 is H. In one embodiment, R11 is H. In another embodiment, R11 is C1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R11 is methyl. In one embodiment, R11 is C2-3alkynyl. In one embodiment, R11 is C_1-3fluoroalkyl. In another embodiment, R₁₁ is CF_3. In one embodiment, R₁₁ is C_1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R₁₁ is methoxy. In one embodiment, R₁₁ is -CN. In one embodiment, R₁₁ is halo. In another embodiment, R₁₁ is F. In one embodiment, R₁₁ is C_3- ₅cycloalkyl. In one embodiment, R₁₁ is C_1-3alkyl, C_2-3alkynyl, C_1-3fluoroalkyl, C_1-3alkoxy, -CN, halo or C3-5cycloalkyl. In one embodiment, R10, R12 and R13 are all H. In one embodiment, R10 is halo and R12 and R13 are both H. In another embodiment, R10 is F and R12 and R13 are both H. In another embodiment, R10 is Cl and R12 and R13 are both H. In one embodiment, R10 is C1-3alkyl and R12 and R13 are both H. In one embodiment, R10 is methyl and R12 and R13 are both H. In one embodiment, R10 is -CN and R12 and R13 are both H. In one embodiment, B is selected from the group consisting of

In another embodiment, B is selected from the group consisting of

In another embodiment, B is selected from the group consisting of

(Ba1h); wherein R8’ is halo; In one embodiment, B is selected from the group consisting of

In one embodiment, B is selected from the group consisting of

wherein R10’ is C1-3alkyl; In one embodiment, B is selected from the group consisting of

wherein R_10’ is

In one embodiment, B is selected from the group consisting of

In one such embodiment, R₁₃ is hydrogen; and R₁₀ is hydrogen or halo. In one such embodiment, R₁₀ and R₁₃ are both hydrogen. Alternatively, R₁₀ is chlorine and R₁₃ is hydrogen. Alternatively, R₁₀ is hydrogen and R₁₃ is fluorine. Compounds of formula (IB) In one embodiment, the compound of formula (I) is a compound of formula (IB):

wherein: R2 is C1-3alkyl, -CH2OC1-3alkyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; R3 is H, C1-3alkyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; R₄ is H, C_1-3alkyl, -CH₂OC_1-3alkyl, C_1-3fluoroalkyl, C_1-3alkoxy, C_1-3fluoroalkoxy -CN, halo or C_3- ₅cycloalkyl; and R5 is F, Cl or -CN; B is group (Ba) or (Bb): wherein group (Ba) is:

wherein: Y is C(R9a)(R9b), O or N(R9c); R9a, R9b and R9c are independently H or C1-3alkyl or R9a and R9b together with the carbon atom to which they are attached form a C_3-6cycloalkyl group; and R₆, R₇ and R₈ are independently H, C_1-3alkyl, C_2-3alkynyl, C_1-3fluoroalkyl, C_1-3alkoxy, -CN, halo or C_3-5cycloalkyl; wherein group (Bb) is:

wherein: R10 is H, C1-3alkyl, C2-3alkynyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; D is N or C(R11) and R11, R12 and R13 are independently H, C1-3alkyl, C2-3alkynyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C_3-5cycloalkyl; or a prodrug thereof in which an available nitrogen atom in group Ba or Bb is derivatised by the moiety -CH₂-OP(=O)(OH)₂. The embodiments that follow are relevant for compounds of formula (IB). In one embodiment, R2 is C1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R2, is methyl. In one embodiment, R2 is -CH2OC1-3alkyl. In another embodiment, R2, is CH2OMe. In one embodiment, R₂ is C_1-3fluoroalkyl. In another embodiment, R₂, is CF_3. In one embodiment, R₂ is C_1- ₃alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R₂ is methoxy. In one embodiment, R₂ is -CN. In one embodiment, R₂ is halo. In another embodiment, R₂ is F. In one embodiment, R₂ is C_3-6cycloalkyl. In one embodiment, R₂ is C_1-3alkyl or -CH₂OC_1-3alkyl. In another embodiment, R₂ is Me or -(CH₂)OMe. In one embodiment, R₂ is Me, -(CH₂)OMe or -CN. In one embodiment, R3 is H. In one embodiment, R3 is C1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R3 is methyl. In one embodiment, R3 is C1-3fluoroalkyl. In another embodiment, R3 is CF3. In one embodiment, R3 is C1-3alkoxy such as methoxy, ethoxy or propoxy. In another embodiment, R3 is methoxy. In one embodiment, R3 is -CN. In one embodiment, R3 is halo. In another embodiment, R3 is F. In one embodiment, R3 is C3-6cycloalkyl. In one embodiment, R₄ is H. In one embodiment, R₄ is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R₄ is methyl. In one embodiment, R₄ is -CH₂OC_1-3alkyl. In another embodiment, R₄ is CH₂OMe. In one embodiment, R₄ is C_1-3fluoroalkyl. In another embodiment, R₄, is CF_3. In one embodiment, R₄ is C_1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R₄, is methoxy. In one embodiment, R₄ is C_1-3fluoroalkoxy. In another embodiment, R₄, is OCF_3. In one embodiment, R4 is -CN. In one embodiment, R4 is halo. In another embodiment, R4 is F. In one embodiment, R4 is C3-6cycloalkyl. In one embodiment, R5 is F. In another embodiment, R5 is Cl. In another embodiment, R5 is Cl or F. In another embodiment, R₅ is -CN. In one embodiment, R₂ is C_1-3alkyl and R₃ is H. In another embodiment, R₂ is methyl and R₃ is H. In one embodiment, R2 is -CH2OMe and R3 is H. In one embodiment, R2 is C1-3alkyl, R3 is H and R4 is H. In another embodiment, R2 is methyl, R3 is H and R4 is H. In one embodiment, R₂ is -CH₂OMe, R₃ is H and R₄ is H. In one embodiment, R₂ is C_1-3alkyl, R₃ is H, R₄ is H and R₅ is halo. In another embodiment, R₂ is methyl, R₃ is H, R₄ is H and R₅ is halo. In another embodiment, R₂ is methyl, R₃ is H, R₄ is H and R₅ is F. In another embodiment, R2 is methyl, R3 is H, R4 is H and R5 is Cl. In one embodiment, R2 is -CH2OMe, R3 is H, R4 is H and R5 is halo. In another embodiment, R2 is - CH2OMe, R3 is H, R4 is H and R5 is F. In another embodiment, R2 is -CH2OMe, R3 is H, R4 is H and R₅ is Cl. In one embodiment, R₂ is Me, R₃ is H, R₄ is H and R₅ is Cl. In another embodiment, R₂ is Me, R₃ is H, R₄ is H and R₅ is F. In another embodiment, R2 is -(CH2)OMe, R3 is H, R4 is H and R5 is F. In another embodiment, R2 is -(CH2)OMe, R3 is H, R4 is H and R5 is Cl. In another embodiment, R2 is Me, R3 is H, R4 is H and R5 is -CN. In another embodiment, R2 is -CN, R3 is H, R4 is H and R5 is Cl. In another embodiment, R₂ is Me, R₃ is H, R₄ is H and R₅ is Me. In one embodiment, B is group:

In one embodiment, R6 is H. In another embodiment, R6 is C1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R6 is methyl. In one embodiment, R6 is C2-3alkynyl. In one embodiment, R6 is C1-3fluoroalkyl. In another embodiment, R6 is CF3. In one embodiment, R6 is C1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R6 is methoxy. In one embodiment, R6 is -CN. In one embodiment, R6 is halo. In another embodiment, R6 is F. In one embodiment, R6 is C3-5cycloalkyl. In one embodiment, R₇ is H. In another embodiment, R₇ is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R₇ is methyl. In one embodiment, R₇ is C_2-3alkynyl. In one embodiment, R₇ is C_1-3fluoroalkyl. In another embodiment, R₇ is CF_3. In one embodiment, R₇ is C_1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R7 is methoxy. In one embodiment, R7 is -CN. In one embodiment, R7 is halo. In another embodiment, R7 is F. In one embodiment, R7 is C3-5cycloalkyl. In one embodiment, R8 is H. In another embodiment, R8 is C1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R8 is methyl. In one embodiment, R8 is C2-3alkynyl. In one embodiment, R8 is C1-3fluoroalkyl. In another embodiment, R8 is CF3. In one embodiment, R8 is C1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R8 is methoxy. In one embodiment, R8 is -CN. In one embodiment, R₈ is halo. In another embodiment, R₈ is F. In one embodiment, R₈ is C_3-5cycloalkyl. In one embodiment, R₆ is halo and R₈ is H. In another embodiment, R₆ is F and R₈ is H. In one embodiment, R7 is halo and R8 is H. In another embodiment, R7 is F and R8 is H In one embodiment, R6 is F and R7 and R8 are each H. In one embodiment, R7 is F and R6 and R8 are each H. In one embodiment, R8 is F and R6 and R7 are each H. In one embodiment, Y is C(R9a)(R9b). In another embodiment, Y is CH2. In one embodiment, Y is O. In one embodiment, Y is N(R_9c). In another embodiment, Y is NMe. In one embodiment, R_9a is H. In one embodiment, R_9a is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R_9a is methyl. In one embodiment R9b is H. In one embodiment, R9b is C1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R9b is methyl. In one embodiment R9c is H. In one embodiment, R9c is C1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R_9c is methyl. In one embodiment, R_9a and R_9b together with the carbon atom to which they are attached form a C_3- ₆cycloalkyl group. In one embodiment, B is group:

In one embodiment, R₁₀ is H. In another embodiment, R₁₀ is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R₁₀ is methyl. In one embodiment, R₁₀ is C_2-3alkynyl. In one embodiment, R₁₀ is C_1-3fluoroalkyl. In another embodiment, R₁₀ is CF_3. In one embodiment, R₁₀ is C_1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R10 is methoxy. In one embodiment, R10 is -CN. In one embodiment, R10 is halo. In another embodiment, R10 is F. In one embodiment, R10 is C3- 5cycloalkyl. In one embodiment, R10 is selected from H, Cl, C1-3alkyl and -CN. In another embodiment, R10 is selected from H, Cl, Me and -CN. In another embodiment, R10 is selected from H, Cl and Me. In one embodiment, R₁₂ is H. In another embodiment, R₁₂ is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R₁₂ is methyl. In one embodiment, R₁₂ is C_2-3alkynyl. In one embodiment, R₁₂ is C_1-3fluoroalkyl. In another embodiment, R₁₂ is CF_3. In one embodiment, R₁₂ is C_1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R₁₂ is methoxy. In one embodiment, R₁₂ is -CN. In one embodiment, R12 is halo. In another embodiment, R12 is F. In one embodiment, R12 is C3- 5cycloalkyl. In one embodiment, R13 is H. In another embodiment, R13 is C1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R13 is methyl. In one embodiment, R13 is C2-3alkynyl. In one embodiment, R13 is C1-3fluoroalkyl. In another embodiment, R13 is CF3. In one embodiment, R13 is C1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R₁₃ is methoxy. In one embodiment, R₁₃ is -CN. In one embodiment, R₁₃ is halo. In another embodiment, R₁₃ is F. In one embodiment, R₁₃ is C_3- ₅cycloalkyl. In one embodiment, R₁₂ and R₁₃ are both H. In one embodiment, D is N. In one embodiment, D is C(R11). In another embodiment, D is C(R11) and R11 is halo. In another embodiment, D is C(R11) and R11 is F. In another embodiment, D is C(R11) and R11 is H. In one embodiment, R₁₁ is H. In another embodiment, R₁₁ is C_1-3alkyl, such as methyl, ethyl or propyl. In another embodiment, R₁₁ is methyl. In one embodiment, R₁₁ is C_2-3alkynyl. In one embodiment, R₁₁ is C_1-3fluoroalkyl. In another embodiment, R₁₁ is CF_3. In one embodiment, R₁₁ is C_1-3alkoxy, such as methoxy, ethoxy or propoxy. In another embodiment, R11 is methoxy. In one embodiment, R11 is -CN. In one embodiment, R11 is halo. In another embodiment, R11 is F. In one embodiment, R11 is C3- 5cycloalkyl. In one embodiment, B is selected from the group consisting of

In another embodiment, B is selected from the group consisting of In another embodiment, B is selected from the group consisting of

In another embodiment, B is selected from the group consisting of

5 In one embodiment, B is selected from the group consisting of

In one embodiment, B is selected from the group consisting of

In one embodiment, B is selected from the group consisting of

In one embodiment, B is selected from the group consisting of

In one embodiment, the compound of formula (IA) is selected from the group consisting of (2Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2Z)-2-fluoro-3-(3-fluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl) prop-2-enamide; (2Z)-N-(2,5-dimethylpyridin-3-yl)-2-fluoro-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2Z)-N-(5-chloro-2-methylpyridin-3-yl)-2-fluoro-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2Z)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (Z)-3-(7-chloro-1H-indazol-6-yl)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (2Z)-2-fluoro-3-(4-fluoro-1-methyl-2-oxo-3H-1,3-benzodiazol-5-yl)-N-(5-fluoro-2,4-dimethylpyridin-3- yl)prop-2-enamide; (2Z)-3-(3-cyano-7-fluoro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2- enamide; (2Z)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-cyano-1H-indazol-6-yl)-2-fluoroprop-2-enamide; (2Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2Z)-3-(3-chloro-7-fluoro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2- enamide; (2Z)-3-(3-cyano-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2Z)-N-(2,5-dimethylpyridin-3-yl)-3-(3-cyano-1H-indazol-6-yl)-2-fluoroprop-2-enamide); (2Z)-3-(3-chloro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide; (Z)-2-fluoro-3-(7-methoxy-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(2,4,5-trimethylpyridin-3-yl)acrylamide; and (Z)-2-fluoro-3-(7-methoxy-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)acrylamide or a pharmaceutically acceptable prodrug, salt and/or solvate of any one thereof. In one embodiment, the compound of formula (IA) is selected from the group consisting of (Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)acrylamide; (Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(7-fluoro-2-oxoindolin-6-yl)acrylamide; (Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide; (Z)-3-(3-chloro-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3- yl)acrylamide; (Z)-3-(7-cyano-1H-indazol-6-yl)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-(7-methyl-1H-indazol-6-yl)acrylamide; (Z)-1-(5-chloro-6-methoxy-2,4-dimethylpyridin-3-yl)-3-fluoro-4-(7-fluoro-1H-indazol-6-yl)but-3-en-2- one; (Z)-1-(5-chloro-2,4-dimethylpyridin-3-yl)-4-(3,7-difluoro-1H-indazol-6-yl)-3-fluorobut-3-en-2-one; (Z)-1-(5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-fluoro-4-(7-fluoro-1H-indazol-6-yl)but-3-en- 2-one; (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3- yl)acrylamide; (Z)-3-(3,7-difluoro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3- yl)acrylamide; (Z)-3-(3,7-difluoro-1H-indazol-6-yl)-2-fluoro-N-(6-(methoxy-d3)-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-3-(3-(1-cyanocyclopropyl)-7-fluoro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3- yl)acrylamide; (Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-3-(2-hydroxypropan-2-yl)-1H-indazol-6- yl)acrylamide; (Z)-N-(2,5-difluoro-4-methylpyridin-3-yl)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)acrylamide; (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(2-fluoro-6-methoxy-4-methylpyridin-3-yl)acrylamide; (Z)-N-(5-cyano-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(3,7-difluoro-1H-indazol-6-yl)-2- fluoroacrylamide; (Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(7-fluoro-3-propyl-1H-indazol-6-yl)acrylamide; (Z)-N-(2-(difluoromethyl)-5-fluoro-4-methylpyridin-3-yl)-2-fluoro-3-(7-fluoro-1H-indazol-6- yl)acrylamide; (Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-3-methyl-1H-indazol-6-yl)acrylamide; (Z)-N-(5-cyano-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(3-ethynyl-7-fluoro-1H-indazol-6-yl)-2- fluoroacrylamide; (Z)-N-(5-cyano-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)acrylamide; (Z)-3-(3-chloro-7-fluoro-1H-indazol-6-yl)-N-(5-cyano-2,4-dimethylpyridin-3-yl)-2-fluoroacrylamide; (Z)-3-(7-chloro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-3-(7-cyano-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-3-(3,7-difluoro-1H-indazol-6-yl)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-3-(3-cyano-7-fluoro-1H-indazol-6-yl)-2-fluoroacrylamide; (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(5-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-3-(3,7-difluoro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(6-(methoxy-d₃)-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(4-methyl-2-(trifluoromethyl)pyridin-3-yl)acrylamide; (Z)-N-(5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(3,7-difluoro-1H-indazol-6-yl)-2- fluoroacrylamide; (Z)-N-(5-cyano-2,4-dimethylpyridin-3-yl)-3-(3,7-difluoro-1H-indazol-6-yl)-2-fluoroacrylamide; (Z)-3-(3-chloro-7-fluoro-1H-indazol-6-yl)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-3-(3-chloro-7-fluoro-1H-indazol-6-yl)-2-fluoro-N-(6-(methoxy-d₃)-2,4-dimethylpyridin-3- yl)acrylamide; (Z)-3-(3-chloro-7-fluoro-1H-indazol-6-yl)-N-(5-cyano-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-2- fluoroacrylamide; (Z)-N-(2-chloro-4-methylpyridin-3-yl)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)acrylamide; and (Z)-3-(3,7-difluoro-1H-indazol-6-yl)-N-(2-(difluoromethyl)-5-fluoro-4-methylpyridin-3-yl)-2- fluoroacrylamide; or a pharmaceutically acceptable prodrug, salt and/or solvate of any one thereof. In one embodiment, the compound of formula (IB) is selected from the group consisting of: (2E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2E)-3-(3-chloro-1H-indazol-6-yl)-N-[5-fluoro-2-(methoxymethyl)pyridin-3-yl]prop-2-enamide; (2E)-3-(3-chloro-1H-indazol-6-yl)-N-(5-fluoro-2-methylpyridin-3-yl)prop-2-enamide; (2E)-N-(5-fluoro-2-methylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(4-fluoro-1-methyl-2-oxo-3H-1,3-benzodiazol-5-yl)prop-2- enamide; and (2E)-N-[5-chloro-2-(methoxymethyl)pyridin-3-yl]-3-(7-fluoro-1H-indazol-6-yl)prop-2-enamide or a pharmaceutically acceptable prodrug, salt and/or solvate of any one thereof. In one embodiment, the compound of formula (IB) is selected from the group consisting of: (E)-N-(4-(difluoromethyl)-5-fluoro-2-methylpyridin-3-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5- yl)acrylamide; (E)-3-(3-chloro-5,7-difluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)acrylamide; (E)-1-(2-cyclopropyl-5-fluoropyridin-3-yl)-4-(7-fluoro-1H-indazol-6-yl)but-3-en-2-one; (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-ethynyl-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide; (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-chloro-5-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide; (E)-3-(3-chloro-1H-pyrazolo[3,4-b]pyridin-6-yl)-N-(5-chloro-2-cyclopropylpyridin-3-yl)acrylamide; (E)-N-(5-chloro-2-cyclopropylpyridin-3-yl)-3-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide; (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-ethynyl-5-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide; (E)-3-(7-fluoro-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)acrylamide; (E)-3-(5-fluoro-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)acrylamide; (E)-N-(5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(5-fluoro-1H-indazol-6-yl)acrylamide; (E)-N-(5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(7-fluoro-1H-indazol-6-yl)acrylamide; (E)-N-(5-fluoro-2,6-dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2,5-dimethylpyridin-3-yl)acrylamide; (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-cyano-1H-indazol-6-yl)acrylamide; (E)-3-(3-chloro-1H-indazol-6-yl)-N-(5-cyano-2-methylpyridin-3-yl)acrylamide; (E)-N-(5-cyano-2-methylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-chloro-1H-indazol-6-yl)-N-(5-chloro-2-cyanopyridin-3-yl)acrylamide; (E)-N-(5-chloro-2-cyanopyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N -(5-chloro-2-methylpyridin-3-yl)-3-(7-fluoro-3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(5-chloro-2-(methoxymethyl)pyridin-3-yl)-3-(3-cyano-1H-indazol-6-yl)acrylamide; (E)-N-(2-cyclopropylpyridin-3-yl)-3-(7-fluoro-1H-indazol-6-yl)acrylamide; (E)-3-(3-chloro-1H-indazol-6-yl)-N-(5-chloro-2-cyclopropylpyridin-3-yl)acrylamide; (E)-N-(5-chloro-2-cyclopropylpyridin-3-yl)-3-(3-fluoro-1H-indazol-6-yl)acrylamide; and (E)-3-(3-chloro-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)acrylamide; or a pharmaceutically acceptable prodrug, salt and/or solvate of any one thereof. In one embodiment, the prodrug of a compound of formula (I) is selected from the group consisting of: (Z)-(3-chloro-6-(3-((5-cyano-2,4-dimethylpyridin-3-yl)amino)-2-fluoro-3-oxoprop-1-en-1-yl)-7-fluoro- 2H-indazol-2-yl)methyl dihydrogen phosphate; (Z)-(3-chloro-6-(3-((5-cyano-2,4-dimethylpyridin-3-yl)amino)-2-fluoro-3-oxoprop-1-en-1-yl)-7-fluoro- 1H-indazol-1-yl)methyl dihydrogen phosphate; and (Z)-(7-fluoro-6-(2-fluoro-3-((6-methoxy-2,4-dimethylpyridin-3-yl)amino)-3-oxoprop-1-en-1-yl)-2H- indazol-2-yl)methyl dihydrogen phosphate; or a pharmaceutically acceptable salt and/or solvate of any one thereof. The definition of the compounds of formula (I) is intended to include all tautomers of said compounds. The compounds of the invention may be provided in the form of a pharmaceutically acceptable salt and/or solvate thereof. In particular, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable solvate. In particular, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable salt. In particular, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable prodrug. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Non-pharmaceutically acceptable salts of the compounds of formula (I) may be of use in other contexts such as during preparation of the compounds of formula (I). Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge et al. (1977). Such pharmaceutically acceptable salts include acid and base addition salts. Pharmaceutically acceptable acid additional salts may be formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Other salts e.g. oxalates or formates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention. Pharmaceutically acceptable salts may also be formed with organic bases such as basic amines e.g. with ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine or lysine. Pharmaceutically acceptable salts may also be formed with inorganic bases such as group 1 or 2 metal ions e.g. lithium, sodium, potassium, magnesium or calcium. Certain compounds of formula (I) may form acid or base addition salts with one or more equivalents of the acid or base. The present invention includes within its scope all possible stoichiometric and non- stoichiometric forms. In one embodiment the compound of formula (I) is the free base form. Alternatively, there is provided a compound of formula (I) in the form of a free acid. When the compound contains a basic group as well as the free acid it may be Zwitterionic. The compounds of formula (I) may be prepared in crystalline or non-crystalline form and, if crystalline, may optionally be solvated, e.g. as the hydrate. This invention includes within its scope stoichiometric solvates (e.g. hydrates) as well as compounds containing variable amounts of solvent (e.g. water). It is to be understood that the present invention encompasses all isomers of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exist as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or >99% by number of the atoms of that atomic number (the latter embodiment referred to as an “isotopically enriched variant form”). The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms. An unnatural variant Isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (²H or D), carbon-11 (¹¹C), carbon-13 (¹³C), carbon-14 (¹⁴C), nitrogen-13 (¹³N), nitrogen-15 (¹⁵N), oxygen-15 (¹⁵O), oxygen-17 (¹⁷O), oxygen-18 (¹⁸O), phosphorus-32 (³²P), sulphur-35 (³⁵S), chlorine-36 (³⁶Cl), chlorine-37 (³⁷Cl), fluorine-18 (¹⁸F) iodine-123 (¹²³I), iodine-125 (¹²⁵I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms. Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.³H, and carbon-14, i.e.¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e.²H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half- life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. In one embodiment, the compounds of the invention are provided in a natural isotopic form. In one embodiment, the compounds of the invention are provided in an unnatural variant isotopic form. In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (i.e.²H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention. In one embodiment, the atoms of the compounds of the invention are in an isotopic form which is not radioactive. In one embodiment, one or more atoms of the compounds of the invention are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably the unnatural variant isotopic form is a pharmaceutically acceptable form. In one embodiment, a compound of the invention is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form. Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the Examples. Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions. In general, the compounds of formula (I) may be made according to the organic synthesis techniques known to those skilled in this field, as well as by the representative methods set forth below, those in the Examples, and modifications thereof. In the following schemes, reactive groups can be protected with protecting groups and deprotected according to established techniques well known to the skilled person. Generic Routes Generic routes by which compound examples of the invention may be conveniently prepared are summarised below. In the following description, the groups R₁, R₂, R₃, R₄, R₅ and B are as defined above for the compound of formula (I), unless otherwise stated. Scheme 1

Compounds of formula (I) may be prepared by reacting a compound of formula (II) with a compound of formula (III) under palladium-catalyzed cross coupling conditions, using a palladium pre-catalyst, such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd(dppf)Cl2^.CH2Cl2), in the presence of a base, such as triethylamine, and a suitable solvent, such as dimethylformamide (DMF). Scheme 2

Alternatively, compounds of formula (I) may be prepared by reacting a compound of formula (IV) with a compound of formula (V) under amidation conditions, using an amide coupling reagent, such as 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), in the presence of a base, such as N,N-diisopropylethylamine (DIPEA, also known as Hünig’s base), in a suitable solvent, such as DMF. Scheme 3

Compounds of formula (I) may also be prepared by reacting a compound of formula (VI) with a compound of (V) under basic conditions, using a base such as lithium bis(trimethylsilyl)amide (LiHMDS), in a suitable solvent, such as tetrahydrofuran (THF). Scheme 4

Compounds of formula (II) are commercially available. Compounds of formula (II) may also be prepared by reacting a compound of formula (V) with a compound of formula (VII) in the presence of a base, such as N,N-diisopropylethylamine, in a suitable solvent, such as dichloromethane (DCM). Scheme 5

Compounds of formula (VI) may be obtained by reacting a compound of formula (VIII) with a compound of formula (III) under palladium-catalyzed cross coupling conditions, using a palladium-precatalyst, such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd(dppf)Cl2^.CH2Cl2), in the presence of a base, such as triethylamine, and a suitable solvent, such as dimethylformamide (DMF). Compounds of the formula (VIII) are either commercially available or may be prepared by methods known to one skilled in the art. Scheme 6

Compounds of formula (IV) may be obtained by reacting a compound of formula (VI) under hydrolysis conditions, using a base, such as sodium hydroxide (NaOH), in a suitable solvent system, such as a mixture of methanol and water. Scheme 7

Compounds of formula (III), wherein B is group (Ba) and Y is N(R9c) may be prepared in three steps. Firstly, a compound of formula (IX) may be reacted with an amine in a suitable solvent, such as ethanol, to give a compound of formula (X). Subsequently, the compound of formula (X) may be subjected to reduction conditions using a metal, such as zinc, and an inorganic salt, such as ammonium chloride (NH₄Cl), in a suitable solvent, such as acetone, to afford a compound of formula (XI). Finally, the compound of formula (XI) may be reacted with a carbonylating agent, such as triphosgene, in a suitable solvent, such as dichloromethane (DCM), to afford the compound of formula (III). Scheme 8

Compounds of formula (III), wherein B is group (Ba) and Y is O or S (Y’), may be prepared in two steps. Firstly, the compound of formula (XII) may be subjected to reduction conditions using a metal, such as zinc, and an inorganic salt, such as ammonium chloride (NH₄Cl), in a suitable solvent, such as acetone, to afford a compound of formula (XIII). Subsequently, the compound of formula (XIII) may be reacted with a carbonylating agent, such as triphosgene, in a suitable solvent, such as dichloromethane (DCM), to afford the compound of formula (III). Therefore, in one embodiment the invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, which comprises reacting a compound of formula (II): wherein A, R_1a and R_1b are as defined for the compound of formula (I) or salt thereof, with a compound of formula (III):

wherein X is halo, such as bromo or iodo, and B is as defined for the compound of formula (I), or a salt thereof. The invention also provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, which comprises reacting a compound of formula (IV):

wherein R_1b and B are as defined for the compound of formula (I) or a salt thereof, with a compound of formula (V):

wherein A and R_1a are as defined for the compound of formula (I) or a salt thereof. The invention also provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, which comprises reacting a compound of formula (VI):

wherein R_1b and B are as defined for the compound of formula (I), or a salt thereof, with a compound of formula (V):

wherein A and R_1a are as defined for the compound of formula (I) or a salt thereof. In one embodiment, there is provided a compound of formula (II):

or a salt thereof, wherein A, R_1a, and R_1b are as defined elsewhere herein. In one embodiment, there is provided a compound of formula (IV):

or a salt thereof, wherein B and R1b are as defined elsewhere herein. In one embodiment, there is provided a compound of formula (VI):

or a salt thereof, wherein B and R1b are as defined elsewhere herein. The prodrugs of compounds of formula (I) (and compounds of formula (IA) and (IB)) in which an available nitrogen atom in group (Ba) or (Bb) is derivatized by the moiety -CH2-OP(=O)(OH)2 may be prepared as follows: Scheme 9

Compounds of formula (XV) may be prepared in two steps. Firstly, a compound of formula (I), wherein B is group (Ba), may be reacted with a base, such as caesium carbonate, sodium iodide and a dialkyl halomethyl phosphate, such as di-tert-butyl(chloromethyl)phosphate, in a suitable solvent, such as DMF, to give a compound of formula (XIV). Subsequently, the compound of formula (XIV) may be reacted under hydrolysis conditions using an acid, such as HCl, in a suitable solvent, such as dioxane, to afford a compound of formula (XV). Where Y represents NH the/a -CH₂-OP(=O)(OH)₂ group may alternatively attach to the Y N atom not the N atom as shown in the above scheme or it may attach to both N atoms. Wherein the Y group in group (Bb) is NH, this NH can be derivatised by the moiety -CH2-OP(=O)(OH)2 instead of or in addition to the NH group shown in the reaction scheme above. Scheme 10

Compounds of formula (XVIIa) and (XVIIb) may also be prepared in two steps. Firstly, a compound of formula (I), wherein B is group (Bb), may be reacted with a base, such as caesium carbonate, sodium iodide and a dialkyl halomethyl phosphate, such as di-tert-butyl(chloromethyl)phosphate, in a suitable solvent, such as DMF, to give a mixture of compounds of formula (XVIa) and/or formula (XVIb). Subsequently, the compounds of formula (XIVa) and formula (XVIb) may be reacted under hydrolysis conditions using an acid, such as HCl, in a suitable solvent, such as dioxane, to afford a mixture of compounds of formula (XVIIa) and formula (XVIIb). Compounds of formula (XVIIa) and formula (XVIIb) may be separated to provide the respective regioisomers as pure products. Novel compounds of formulae (II), (III), (IV), (V) and (VI) and salts thereof are also provided as an aspect of invention. Compounds of formula (III), (V), (VII), (VIII) and (IX) are either known or may be prepared by known methods. Therapeutic Methods Compounds of formula (I) of the present invention have utility as inhibitors of mPTP. Therefore, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use a pharmaceutical, in particular in the treatment or prophylaxis of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect, for example those diseases and disorders mentioned herein below. The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use a pharmaceutical, in particular in the treatment of a disease or disorder in which inhibition of mPTP provides a therapeutic effect, for example those diseases and disorders mentioned herein below. The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use a pharmaceutical, in particular in the prophylaxis of a disease or disorder in which inhibition of mPTP provides a prophylactic effect, for example those diseases and disorders mentioned herein below. The invention also provides use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect, for example those diseases and disorders mentioned herein below. The invention also provides use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder in which inhibition of mPTP provides a therapeutic effect, for example those diseases and disorders mentioned herein below. The invention also provides use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the prophylaxis of a disease or disorder in which inhibition of mPTP provides a prophylactic effect, for example those diseases and disorders mentioned herein below. The invention also provides a method of preventing or treating a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect in a subject, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for example those diseases and disorders mentioned herein below. The invention also provides a method of treating a disease or disorder in which inhibition of mPTP provides a therapeutic effect in a subject, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for example those diseases and disorders mentioned herein below. The invention also provides a method of preventing a disease or disorder in which inhibition of mPTP provides a prophylactic effect in a subject, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for example those diseases and disorders mentioned herein below. The terms ‘therapeutic effect’, ‘treatment’ or ‘treating’ as used herein includes the control, mitigation, reduction or modulation of the disease state or its symptoms. The terms ‘prophylactic effect’, ‘prophylaxis’ or ‘preventing’ are used herein to mean preventing symptoms of a disease or disorder in a subject or preventing recurrence of symptoms of a disease or disorder in an afflicted subject and is not limited to complete prevention of an affliction. In one embodiment, the disease or disorder is selected from degenerative or neurodegenerative diseases, disorders of the central nervous system, ischemia or re-perfusion injury, metabolic diseases, inflammatory or autoimmune diseases, diseases of aging and renal diseases. In one particular embodiment, the disease or disorder is a degenerative or neurodegenerative disease, such as Parkinson’s disease, dementia with Lewy bodies, Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, frontal temporal dementia, chemotherapy induced neuropathy, Huntington’s disease, spinocerebellar ataxias, progressive supranuclear palsy, hereditary spastic paraplegia, Duchenne muscular dystrophy, congenital muscular dystrophy, traumatic brain injury and Friedreich’s ataxia. In one preferred embodiment, the disease or disorder is Parkinson’s disease. In one preferred embodiment, the disease or disorder is Alzheimer’s disease. In one preferred embodiment, the disease or disorder is amyotrophic lateral sclerosis. In another particular embodiment, the disease or disorder is a disease of the central nervous system, such as AIDS dementia complex, depressive disorders, schizophrenia and epilepsy. In another embodiment, the disease or disorder is ischemia or re-perfusion injury, such as acute myocardial infarction, stroke, kidney ischemia reperfusion injury, and organ damage during transplantation. In another embodiment, the disease or disorder is a metabolic disease, such as hepatic steatosis, diabetes, diabetic retinopathy, cognitive decline and other diabetes associated conditions, obesity and feeding behaviours, and non-alcoholic fatty liver disease. In another embodiment, the disease or disorder is an inflammatory or autoimmune disease, such as acute pancreatitis, systemic lupus, organ failure in sepsis and hepatitis. In another embodiment the disease or disorder is a disease associated with mtDNA release and innate immune activation e.g. macular degeneration. In another embodiment, the disease or disorder is a disease of aging, such as bone repair, bone weakness in aging in osteoporosis and sarcopenia. In another embodiment, the disease or disorder is a renal disease, such as chronic kidney disease associated with APOL1 genetic variants and chronic kidney disease. In another embodiment, the disease or disorder is a pulmonary dysfunction or multi-organ failure associated with severe respiratory virus infections e.g. COVID19 infection. In another embodiment, the disease or disorder is adrenoleukodystrophy, in particular X-linked adrenoleukodystrophy. The compounds of formula (I) are expected to be useful in the treatment or prophylaxis of a mitochondrial disease. Therefore, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment or prophylaxis of a mitochondrial disease, for example those diseases and disorders mentioned herein below. The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment of a mitochondrial disease, for example those diseases and disorders mentioned herein below. The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the prophylaxis of a mitochondrial disease, for example those diseases and disorders mentioned herein below. The invention also provides use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the treatment or prophylaxis of a mitochondrial disease, for example those diseases and disorders mentioned herein below. The invention also provides use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the treatment of a mitochondrial disease, for example those diseases and disorders mentioned herein below. The invention also provides use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the prophylaxis of a mitochondrial disease, for example those diseases and disorders mentioned herein below. The invention also provides a method of treating or preventing a mitochondrial disease in a subject, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for example those diseases and disorders mentioned herein below. The invention also provides a method of treating a mitochondrial disease in a subject, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for example those diseases and disorders mentioned herein below. The invention also provides a method of preventing a mitochondrial disease in a subject, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for example those diseases and disorders mentioned herein below. Suitably, the mitochondrial disease is selected from Reye syndrome, Leber’s hereditary optic neuropathy and associated disorders and disorders, such as those diseases and disorders disclosed in CA2884607A1 (Stealth Peptides International Inc.) The compounds of formula (I) are expected to be useful in the treatment or prophylaxis of a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration. Therefore, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment or prophylaxis of a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, for example those diseases and disorders mentioned herein below. The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment of a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, for example those diseases and disorders mentioned herein below. The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the prophylaxis of a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, for example those diseases and disorders mentioned herein below. The invention also provides use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, for example those diseases and disorders mentioned herein below. The invention also provides use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, for example those diseases and disorders mentioned herein below. The invention also provides use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the prophylaxis of a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, for example those diseases and disorders mentioned herein below. The invention also provides a method of treating or preventing a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for example those diseases and disorders mentioned herein below. The invention also provides a method of treating a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for example those diseases and disorders mentioned herein below. The invention also provides a method of preventing a disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for example those diseases and disorders mentioned herein below. Suitably, the disease or disorder associated with TDP-43 proteinopathy such as TDP-43 associated neurodegeneration is selected from Amyotrophic Lateral Sclerosis, Frontotemporal dementia, Facial onset sensory and motor neuronopathy, Primary lateral sclerosis, Progressive muscular atrophy, Inclusion body myopathy associated with early-onset Paget disease of the bone and Frontotemporal lobar degeneration dementia, Perry disease, Chronic traumatic encephalopathy, Severe traumatic brain injury, Alzheimer’s disease, Hippocampal sclerosis dementia, Limbic-predominant age-related TDP-43 encephalopathy, and Cerebral age-related TDP-43 with sclerosis. The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment or prophylaxis of a disease or disorder associated with fibrosis. The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment of a disease or disorder associated with fibrosis. The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, for use in the prophylaxis of a disease or disorder associated with fibrosis. The invention also provides use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder associated with fibrosis. The invention also provides use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with fibrosis. The invention also provides use of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof, in the manufacture of a medicament for the prophylaxis of a disease or disorder associated with fibrosis. The invention also provides a method of treating or preventing a disease or disorder associated with fibrosis, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof. The invention also provides a method of treating a disease or disorder associated with fibrosis, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof. The invention also provides a method of preventing a disease or disorder associated with fibrosis, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof. Suitably, the disease or disorder associated with fibrosis is selected from chronic kidney disease, idiopathic pulmonary fibrosis, non-alcoholic steatohepatitis, primary biliary cholangitis and systemic sclerosis. Suitably the subject is a mammal, in particular the subject is a human. Pharmaceutical Compositions For use in therapy the compounds of the invention are usually administered as a pharmaceutical composition. The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate (e.g. salt) thereof, and a pharmaceutically acceptable carrier or excipient. In one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate (e.g. salt) thereof, for use in the treatment or prophylaxis of a disease or disorder as described herein. In one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate (e.g. salt) thereof, for use in the treatment of a disease or disorder as described herein. In one embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate (e.g. salt) thereof, for use in the prophylaxis of a disease or disorder as described herein. Pharmaceutical compositions of the invention may take the form of a pharmaceutical formulation as described below. In a further embodiment, there is provided a method for the treatment or prophylaxis of a disease or disorder as described herein, which comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) thereof. In a further embodiment, there is provided a method for the treatment of a disease or disorder as described herein, which comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) thereof. In a further embodiment, there is provided a method for the prophylaxis of a disease or disorder as described herein, which comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate (e.g. salt) thereof. Pharmaceutical compositions of the invention may take the form of a pharmaceutical formulation as described below. The invention also provides the use of a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof (e.g. salt) thereof, in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder as described herein. The invention also provides the use of a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof (e.g. salt) thereof, in the manufacture of a medicament for the treatment of a disease or disorder as described herein. The invention also provides the use of a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof (e.g. salt) thereof, in the manufacture of a medicament for the prophylaxis of a disease or disorder as described herein. Pharmaceutical compositions of the invention may take the form of a pharmaceutical formulation as described below. The amount of active ingredient which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment or prophylaxis, including the type, species, age, weight, sex, and medical condition of the subject and the renal and hepatic function of the subject, and the particular disorder or disease being treated or prevented, as well as its severity. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, suitably 0.01 mg per kg of body weight per day (mg/kg/day) to 10 mg/kg/day, and most suitably 0.1 to 5.0 mg/kg/day, for adult humans. For oral administration, the compositions are suitably provided in the form of tablets or other forms of presentation provided in discrete units containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, suitably from about 1 mg to about 100 mg of active ingredient. Intravenously, the most suitable doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. Advantageously, compounds of the invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, suitably compounds of the invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a trans- dermal delivery system, the dosage administration will, of course, be continuous rather than inter- mittent throughout the dosage regimen. The pharmaceutical formulations according to the invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous [bolus or infusion], and intraarticular), intranasal (also known as nasal administration), inhalation (including fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols, nebulizers or insufflators) insufflation, rectal, intraperitoneal, topical (including dermal, buccal, sublingual, and intraocular) and intrathecal administration, although the most suitable route may depend upon, for example, the condition and disorder of the recipient. Suitable pharmaceutical formulations according to the invention are those suitable for oral, intrathecal and parenteral administration; and more suitably are those suitable for oral or intrathecal administration. In one suitable embodiment a compound according to formula (I) is administered by intrathecal administration. Such a method of administration involves injection of the compound of the invention into the spinal canal, or into the subarachnoid space so that it reaches the cerebrospinal fluid. This is advantageous for the administration of compounds which may not be able to pass the blood brain barrier via other routes of administration, such as oral administration. Suitable pharmaceutical formulations may be administered intrathecally by continuous infusion such as with a catheter, or a pump, or intrathecally by a single bolus injection or by intermittent bolus injection. To be administered intrathecally, the pharmaceutical composition may be administered continuously or intermittently. The intermittent administration may be, for example, every thirty minutes, every hour, every several hours, every 24 hours, every couple of days (for example every 48 or 72 hours) or any combination thereof. When the pharmaceutical formulation of the invention is administered continuously, implantable delivery devices, such as an implantable pump, may be employed. Examples of such delivery devices include devices which can be implanted subcutaneously in the body or in the cranium, and provides an access port through which the pharmaceutical formulation may be delivered to the nerves or brain. Intrathecal dosages of the present invention, when used for the indicated effects, will typically be less than 1 mg, such as less than 500 µg, for example less than 250 µg per kg of body weight when administered in a single dose or intermittently for adult humans. When administered continuously, the intrathecal dosages of the present invention will typically be less than 250 µg per kg body weight per hour, such as less than 125 µg per kg body weight per hour for adult humans. In another suitable embodiment a compound according to formula (I) is administered by intranasal, inhalation (including fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols, nebulizers or insufflators) or insufflation administration. Such a method of administration allows for low doses of the compound of the invention to be administered, which can lead to a reduction in side-effects. For example, a daily dose of 10 to 0.01µg, suitably 1 to 0.01µg, and more suitably in the region of as low as 0.1µg (100ng) of compound of the invention may be used. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, pills or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non- aqueous liquid, for example as elixirs, tinctures, suspensions or syrups; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. The compounds of formula (I) can, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising a compound of the present invention, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The compounds of the invention may also be administered liposomally. Exemplary compositions for oral administration include suspensions which can contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavouring agents such as those known in the art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Disintegrators include without limitation starch, methylcellulose, agar, bentonite, xanthan gum and the like. The compounds of formula (I) can also be delivered through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used. Exemplary compositions include those formulating a compound of the present invention with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG). Such formulations can also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g. Carbopol 934). Lubricants, glidants, flavours, colouring agents and stabilizers may also be added for ease of fabrication and use. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. For oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. The compounds of formula (I) can also be administered In the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, 1,2-dipalmitoylphosphatidylcholine, phosphatidyl ethanolamine (cephaline), or phosphatidylcholine (lecithin). Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Exemplary compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer’s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor. Exemplary compositions for intranasal, aerosol or inhalation administration include solutions in saline, which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art. Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, synthetic glyceride esters or polyethylene glycol. Such carriers are typically solid at ordinary temperatures but liquefy and/or dissolve in the rectal cavity to release the drug. Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerine or sucrose and acacia. Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene). Suitable unit dosage formulations are those containing an effective dose, as hereinbefore recited, or an appropriate fraction thereof, of the active ingredient. It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents. The compounds of formula (I) are expected to display inhibitory activity of mPTP as demonstrated in the assay of Biological Example 1 (preferably with a pIC50 value of 7.0 and above). In addition to the property described above, certain compounds of formula (I) may also display one or more of the following advantageous properties: - low inhibition of CYP2D6 as demonstrated in the assays of Biological Example 2; - adequate solubility as demonstrated in the assay of Biological Example 3; - low intrinsic clearance (CLint) as demonstrated in the assays of Biological Example 4; - low efflux by multi-drug resistance protein 1 (MDR1) resulting in e.g. high oral bioavailability as demonstrated in the assay of Biological Example 5; - high systemic exposure and/or high brain penetration as demonstrated in the assays of Biological Examples 3, 4 and 5. The invention is further exemplified by the following non-limiting examples. EXAMPLES The invention is illustrated by the compounds described below. The following examples describe the laboratory synthesis of specific compounds of the invention and are not meant to limit the scope of the invention in any way with respect to compounds or processes. It is understood that, although specific reagents, solvents, temperatures and time periods are used, there are many possible equivalent alternatives that can be used to produce similar results. The invention is meant to include such equivalents. General Experimental Details Starting materials, reagents and solvents were obtained from commercial suppliers and used without further purification unless otherwise stated. Unless otherwise stated, all compounds with chiral centres are racemic. Where reactions are described as having been carried out in a similar manner to earlier, more completely described reactions, the general reaction conditions used were essentially the same. Work up conditions used were of the types standard in the art, but may have been adapted from one reaction to another. The starting material may not necessarily have been prepared from the batch referred to. Compounds synthesised may have various purities, ranging from for example 85% to 99%. Calculations of number of moles and yield are in some cases adjusted for this. Purity of final compounds was confirmed by HPLC/MS analysis and determined to be at least ≥ 90%, and in the significant majority of cases ≥ 95%. Analytical LCMS was conducted using the instrumentation shown in Table 1.¹H NMR were recorded at 300K in a Bruker 300MHz instruments (ADVANCE III and ADVANCE III HD). Flash prep HPLC was conducted using the following columns: Xbridge Prep C18 OBD Column, 5um, 19x150mm; Xbridge Prep C18 OBD Column, 5um, 30x150mm; Welch Xtimate C18, 21.2x250mm, 5um; SunFire Prep C18 OBD 19x150mmx5um. SFC purification was conducted using the following columns; (a) CHIRALPAK AS-H, 3*25cm, 5um (b) SFC-YMC Cellulose-SB, 4.6 x 100mm, 3um. Table 1: Analytical LC-MS conditions Instrument Column Mobile Phase Flow Rate ID LCMS01 Halo-C18, A:H2O/0.05%TFA; B:MeCN 1.5 mL/min 30*3.0mm, 2.0μm Instrument Column Mobile Phase Flow Rate ID LCMS02 Cortecs C18+, A:H2O/0.05%TFA; B:MeCN/0.05%TFA 1.5 mL/min 50*3.0mm, 2.7μm LCMS03 Halo-C18, A:H2O/0.1%TFA; B:MeCN/0.05%FA 1.5 mL/min 30*3.0mm, 2.0μm LCMS04 Kinetex XB-C18, A:H₂O/0.01%TFA; B: MeCN/0.01%FA 1.5 mL/min 50*3.0mm, 2.6μm LCMS05 Poroshell HPH- A:H₂O/5mM NH₄HCO₃; B:MeOH 1.0 mL/min C18, 50*3.0mm, 2.7μm LCMS06 Xbridge C18, A:H₂O/5mM NH₄HCO₃ +0.05% NH_3.H₂O; 1.2 mL/min 50*3.0mm, B:5%H2O in MeCN 3.5μm LCMS07 Poroshell HPH- A:H₂O/0.05% NH_3.H₂O; B: MeCN 1.2 mL/min C18, 50*3.0mm, 2.7μm LCMS08 Halo C18, A:H2O/0.05%TFA; B: MeCN 1.5 mL/min 50*3.0mm, 2.7μm LCMS09 Poroshell HPH- A:H2O/0.05% NH3.H2O; B: MeCN 1.2 mL/min C18, 50*3.0mm, 2.7μm Abbreviations AcOH Acetic Acid CDI Carbonyldiimidazole Cs2CO3 Cesium Carbonate DBU 1,8-Diazabicyclo(5.4.0)undec-7-ene DCM Dichloromethane DHP Dihydropyran DIEA N,N-Diisopropylethylamine DIPEA Diisopropylethylamine DMAc Dimethylacetamide DMF Dimethylformamide DMSO Dimethylsulfoxide ES Electrospray Et Ethyl Et3N Triethylamine EtOAc or AcOEt Ethyl Acetate EtOH Ethyl Alcohol eq equivalent g gram HNO₃ Nitric Acid HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate heps hepatocytes ¹H Proton HCl Hydrochloric acid HPLC High Performance Liquid Chromatography K Kelvin K₂CO₃ Potassium Carbonate K₃PO₄ Potassium Phosphate kg Kilogram LCMS Liquid Chromatography Mass Spectrometry LiHMDS Lithium bis(trimethylsilyl)amide LiOH Lithium Hydroxide M Molar quantity Me Methyl MeCN Acetonitrile MeI Methyl Iodide MeOH Methanol mg milligram mL millilitre mm millimetre mmol millimole MHz Megahertz m/z Mass-to-Charge ratio Na₂SO₄ Sodium Sulfate NaHCO₃ Sodium Bicarbonate NaOAc Sodium Acetate NaOH Sodium Hydroxide NBS N-Bromosuccinimide NCS N-Chlorosuccinimide ng nanogram NH2NH2 Hydrazine NH3 Ammonia NH4Cl Ammonium chloride NH4HCO3 Ammonium bicarbonate NMI 1-Methylimidazole NMR Nuclear Magnetic Resonance PE Petroleum ether Pd/C Palladium on carbon Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium Pd(OAc)₂ Palladium(II) Acetate Pd(dppf)Cl2.CH2Cl2 Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane Pd(dtbpf)Cl2 Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl2 Bis(diphenylphosphino)ferrocene]dichloropalladium(II) PPTS Pyridinium p-Toluenesulfonate RT room temperature o/n overnight (16h) TCFH Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran THP Tetrahydropyranyl TsOH p-Toluenesulfonic acid T₃P Propanephosphonic anhydride µg microgram µL microlitre µM micromolar Preparation of Comparative Example 1 Comparative Example 1: (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide

Comparative Example 1 was prepared according to methods described in Chen et al. (Assay and Drug Development Technologies, 2018, 16, 445-455). Preparation of Comparative Example 2 Comparative Example 2: (E)-3-(5-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3- yl)acrylamide

Comparative Example 2 may be prepared as described in Yannick LACROIX, “The design, synthesis and optimisation of calcium release-activated calcium (CRAC) channel inhibitors and mitochondrial permeability transition pore (mPTP) modulators, using phenotypic screening”, PhD Thesis. Preparation of Comparative Example 3 Comparative Example 3: (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide

Comparative Example 3 was prepared according to methods described in WO 2022/049377 (Example 28). Example 1: (2Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2- enamide Step 1. Preparation of 5-fluoro-2,4-dimethyl-3-nitropyridine

To a solution of 2,4-dibromo-5-fluoro-3-nitropyridine (1.00 g, 3.3 mmol) in 1,4-dioxane (10 mL) and H₂O (1 mL) was added 50% trimethyl-1,3,5,2,4,6-trioxatriborinane in THF (1.7 g, 6.6 mmol, 2 eq), Pd(dppf)Cl₂ (0.24 g, 0.3 mmol, 0.1 eq) and Cs₂CO₃ (2.17 g, 6.6 mmol, 2 eq). The mixture was stirred for 16 h at 100°C under N2 atmosphere. The reaction was cooled and diluted with water (20 mL), and the resulting mixture extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (3 x 5 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/AcOEt (9:1) to afford 5-fluoro-2,4-dimethyl-3- nitropyridine (0.46 g, 81% yield) as a light red oil. Step 2. Preparation of 5-fluoro-2,4-dimethylpyridin-3-amine To a solution of 5-fluoro-2,4-dimethyl-3-nitropyridine (0.46 g, 1.8 mmol) in MeOH (10 mL) was added 10% Pd/C (120 mg). The mixture was stirred for 2h at room temperature under H2 atmosphere. The resulting mixture was filtered, and the filter cake washed with MeOH (3 x 5 mL). The combined filtrate was concentrated under reduced pressure to afford 5-fluoro-2,4-dimethylpyridin-3-amine (0.32 g, 86% yield) as an off-white solid. LCMS (ES, m/z): 141 [M+H]⁺. Step 3. Preparation of (2Z)-2-fluoro-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]-N-(5-fluoro-2,4 dimethylpyridin-3-yl)prop-2-enamide (2)

To a stirred solution of methyl (2Z)-2-fluoro-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (prepared according to steps 1 and 2 of Example 6) (0.16 g, 0.49 mmol) and 5-fluoro-2,4- dimethylpyridin-3-amine (0.08 g, 0.59 mmol, 1.2 eq) in THF (3 mL) was added 1M LiHMDS in THF (0.99 mL, 0.99 mmol, 2 eq) dropwise at -30°C. The solution was stirred for 0.5 h, then quenched with sat. aqueous NH₄Cl solution at 0°C. The mixture was extracted with EtOAc (3 x 10 mL), and the combined organics were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/AcOEt (1:1) to afford (2Z)-2-fluoro-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]-N-(5-fluoro-2,4- dimethylpyridin-3-yl)prop-2-enamide (0.20 g, 93% yield) as a yellow solid. LCMS (ES, m/z): 431 [M+H]⁺. Step 4. Preparation of (2Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4- dimethylpyridin-3-yl)prop-2-enamide

To a stirred solution of (2Z)-2-fluoro-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]-N-(5-fluoro-2,4- dimethylpyridin-3-yl)prop-2-enamide (0.15g, 0.34 mmol) in DCM (1.5 mL) was added TFA (1.5 mL) and the mixture stirred for 1 h. The resulting mixture was concentrated, and the residue purified by Prep-HPLC with the following conditions (Xbridge C18, 19*150 mm, 5 μm; Mobile Phase: 5-95% MeCN / 20 mM NH4HCO3 + 0.05% NH3.H2O aqueous solution over 15 min.; Flow rate: 20 mL/min) to afford (2Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide (43 mg, 35% yield) as a white solid. LCMS (ES, m/z): 347 [M+H]⁺.¹H NMR (300 MHz, DMSO-d6, ppm) δ 8.38 (s, 1H), 8.25 (d, J = 3.5 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.58 (dd, J = 8.5, 5.9 Hz, 1H), 7.27 (d, J = 37.5 Hz, 1H), 2.38 (s, 3H), 2.15 (s, 3H). Example 2: (2Z)-2-fluoro-3-(3-fluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl) prop-2- enamide Step 1. Preparation of 6-bromo-3-fluoro-1H-indazole (2) A solution of 6-bromo-1H-indazole (10 g, 51 mmol) and Selectfluor (20 g, 56 mmol, 1.1 eq) in MeCN (100 mL) and AcOH (10 mL) was stirred for 3h at 90°C. The resulting mixture was diluted with EtOAc (300 mL) and basified with saturated aqueous NaHCO3 solution. The mixture was extracted with EtOAc (3 x 200 mL) and the combined organics were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/EA (1:1) to afford 6-bromo-3-fluoro-1H-indazole (2.0 g, 18% yield) as a yellow solid. LCMS (ES, m/z): 215, 217 [M+H]⁺. Step 2. Preparation of 6-bromo-3-fluoro-1-(oxan-2-yl) imidazole (3)

To a stirred solution of 6-bromo-3-fluoro-1H-indazole (2.0 g, 9.3 mmol) and DHP (1.56 g, 18.6 mmol, 2 eq) in DCM (20 mL) was added TsOH (0.80 g, 4.7 mmol, 0.5 eq) at 0°C. The resulting mixture was stirred for 2h, then concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/AcOEt (1:1) to afford 6-bromo-3-fluoro-1-(oxan-2-yl) imidazole (1.5 g, 53% yield) as a white solid. LCMS (ES, m/z): 299, 301 [M+H] ⁺. Step 3. Preparation of methyl (2Z)-2-fluoro-3-[3-fluoro-1-(oxan-2-yl) indazol-6-yl] prop-2-enoate (5)

A solution of 6-bromo-3-fluoro-1-(oxan-2-yl) indazole (1.0 g, 3.3 mmol), methyl 2-fluoroacrylate (0.42 g, 4.0 mmol, 1.2 eq), TEA (1.0 g, 10 mmol, 3 eq) and Pd(dppf)Cl2 (0.27 g, 0.3 mmol, 0.1 eq) in DMF (20 mL) was stirred for 1.5 h at 110°C. The resulting mixture was cooled, diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were washed with water (2 x 20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/AcOEt (4:1) to afford methyl (2Z)-2-fluoro-3-[3-fluoro-1-(oxan- 2-yl) indazol-6-yl] prop-2-enoate (700 mg, 64% yield) as a green solid. LCMS (ES, m/z): 323 [M+H] ⁺. Step 4. Preparation of (2Z)-2-fluoro-3-[3-fluoro-1-(oxan-2-yl) indazol-6-yl]-N-(5-fluoro-2,4- dimethylpyridin-3-yl) prop-2-enamide (7)

To a stirred solution of methyl (2Z)-2-fluoro-3-[3-fluoro-1-(oxan-2-yl) indazol-6-yl] prop-2-enoate (200 mg, 0.6 mmol) and 5-fluoro-2,4-dimethylpyridin-3-amine (96 mg, 0.7 mmol, 1.1 eq) in THF (4 mL) was added 1M LiHMDS in THF (1.9 mL, 1.9 mmol, 3 eq) dropwise at -30°C and the reaction stirred for 1h at this temperature. The reaction was quenched by the addition of aqueous sat. NH₄Cl solution (4 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 5 mL), and the combined organics were washed with brine (2 x 5 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/AcOEt (2:1) to afford (2Z)-2-fluoro- 3-[3-fluoro-1-(oxan-2-yl) indazol-6-yl]-N-(5-fluoro-2,4-dimethylpyridin-3-yl) prop-2-enamide (140 mg, 52% yield) as a green solid. LCMS (ES, m/z): 431 [M+H] ⁺. Step 5. Preparation of (2Z)-2-fluoro-3-(3-fluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4- dimethylpyridin-3-yl) prop-2-enamide

A solution of (2Z)-2-fluoro-3-[3-fluoro-1-(oxan-2-yl) indazol-6-yl]-N-(5-fluoro-2,4-dimethylpyridin-3-yl) prop-2-enamide (100 mg, 0.2 mmol) in DCM (2 mL) was treated with TFA (2 mL) and stirred for 2 h. The resulting mixture was concentrated and the residue purified by Prep-HPLC (Xbridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase: 0-100% MeCN / 10 mmol/L aqueous NH4HCO3 solution; Flow rate: 25 mL/min; detector, UV 254 nm) to afford (2Z)-2-fluoro-3-(3-fluoro-1H-indazol-6- yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl) prop-2-enamide (30 mg, 37% yield) as a white solid. LCMS (ES, m/z): 347 [M+H]⁺.¹H NMR: (400 MHz, DMSO-d_6, ppm) δ 12.79 (s, 1H), 10.40 (s, 1H), 8.39 (s, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.56 (dd, J = 8.6, 1.3 Hz, 1H), 7.25 (d, J = 38.3 Hz, 1H), 2.38 (s, 3H), 2.16 (s, 3H). Example 3: (2Z)-N-(2,5-dimethylpyridin-3-yl)-2-fluoro-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide Step 1. Preparation of (2Z)-N-(2,5-dimethylpyridin-3-yl)-2-fluoro-3-[3-methyl-1-(oxan-2- yl)indazol-6-yl]prop-2-enamide (3)

To a stirred solution of (2Z)-2-fluoro-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid (prepared according to step 1 of Example 5) (0.21g, 0.69 mmol), TCFH (0.38 g, 1.4 mmol, 2 eq) and NMI (0.11g, 1.4 mmol, 2 eq) in MeCN (4 mL) was added 2,5-dimethylpyridin-3-amine (0.10 g, 0.89 mmol, 1.3 eq) and the reaction was stirred for 2 h. The mixture was quenched with aqueous sat. NH₄Cl solution at 0°C, then extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with Petroleum ether/THF (2:1) to afford (2Z)-N-(2,5-dimethylpyridin-3-yl)-2- fluoro-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (0.19 g, 67% yield) as a yellow oil. LCMS (ES,m/z): 409 [M+H]⁺. Step 2. Preparation of (2Z)-N-(2,5-Dimethylpyridin-3-yl)-2-fluoro-3-(3-methyl-1H-indazol-6- yl)prop-2-enamide

To a stirred mixture of (2Z)-N-(2,5-dimethylpyridin-3-yl)-2-fluoro-3-[3-methyl-1-(oxan-2-yl)indazol-6- yl]prop-2-enamide (0.16 g, 0.39 mmol) in DCM (3 mL) was added TFA (1 mL) and the solution stirred for 2 h. The resulting mixture was concentrated under reduced pressure, and the residue purified by Prep-HPLC with the following conditions: (Xbridge C18, 19*150 mm, 5 μm; Mobile Phase: 5-50% MeCN / 20 mM aqueous NH4HCO3 + 0.05% NH3•H2O solution over 15 min.; Flow rate: 20 mL/min.) to afford (2Z)-N-(2,5-dimethylpyridin-3-yl)-2-fluoro-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide (28 mg, 21% yield) as a white solid. LCMS (ES, m/z): 325 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆, ppm) δ 12.84 (s, 1H), 10.16 (s, 1H), 8.22 (s, 1H), 7.84 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.18 (d, J = 38.6 Hz, 1H), 2.47 (s, 3H), 2.39 (s, 3H), 2.30 (s, 3H). Example 4: (2Z)-N-(5-chloro-2-methylpyridin-3-yl)-2-fluoro-3-(3-methyl-1H-indazol-6-yl)prop-2- enamide Step 1. Preparation of (2Z)-N-(5-Chloro-2-methylpyridin-3-yl)-2-fluoro-3-[3-methyl-1-(oxan-2- yl)indazol-6-yl]prop-2-enamide (3)

A mixture of (2Z)-2-fluoro-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid (prepared according to Step 1 of Example 5) (0.15 g, 0.5 mmol), 5-chloro-2-methylpyridin-3-amine (0.08 g, 0.6 mmol, 1.2 eq), TCFH (0.28 g, 1.0 mmol, 2 eq) and NMI (0.08 g, 1.0 mmol, 2 eq) in MeCN (3 mL) was stirred for 2 h at room temperature. The resulting mixture was diluted with water (5 mL) and extracted with DCM (3 x 10 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with Petroleum ether/EtOAc (1:1) to afford (2Z)-N-(5-chloro-2-methylpyridin-3-yl)-2-fluoro-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2- enamide (0.09 g, 42% yield) as a white solid. LCMS (ES, m/z): 429 [M+H]⁺. Step 2. Preparation of (2Z)-N-(5-chloro-2-methylpyridin-3-yl)-2-fluoro-3-(3-methyl-1H-indazol-6- yl)prop-2-enamide

A mixture of (2Z)-N-(5-chloro-2-methylpyridin-3-yl)-2-fluoro-3-[3-methyl-1-(oxan-2-yl)indazol-6- yl]prop-2-enamide (0.09 g, 0.2 mmol) and TFA (0.6 mL) in DCM (1.8 mL) was stirred for 2 h then diluted with water (5 mL) and neutralized to pH 7 with NH3•H2O. The mixture was extracted with DCM (3 x 6 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by Prep-HPLC (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase: 24-49% MeCN / 10 mmol/L NH₄HCO₃ + 0.1%NH₃•H₂O aqueous solution over 7 min.; Flow rate: 30 mL/min.) to afford (2Z)-N-(5- chloro-2-methylpyridin-3-yl)-2-fluoro-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide (0.02 g, 26% yield) as an off-white solid. LCMS (ES, m/z): 345 [M+H]⁺.¹H NMR (300 MHz, DMSO-d_6, ppm) δ 12.85 (s, 1H), 10.29 (s, 1H), 8.44 (d, J = 2.3 Hz, 1H), 7.95 (d, J = 2.3 Hz, 1H), 7.86 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 8.5, 1.4 Hz, 1H), 7.22 (d, J = 38.7 Hz, 1H), 2.52 (s, 3H), 2.45 (s, 3H). Example 5: (2Z)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2- enamide Step 1. Preparation of (2Z)-2-fluoro-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid (2)

A mixture of methyl (2Z)-2-fluoro-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (prepared according to steps 1 and 2 of Example 7) (0.41 g, 1.3 mmol), LiOH (0.06 g, 2.6 mmol, 2 eq), MeOH (3 mL) and H2O (3 mL) in THF (3 mL ) was stirred for 2 h, then concentrated. The resulting mixture was diluted with water (5 mL) and acidified to pH 5 with aqueous 1 M HCl. The precipitated solids were collected by filtration and washed with water (3 x 5 mL), then dried to afford (2Z)-2-fluoro-3-[3-methyl- 1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid (0.28 g, 71% yield) as a white solid. LCMS (ES, m/z): 305 [M+H]⁺. Step 2. Preparation of (2Z)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-[3-methyl-1- (oxan-2-yl)indazol-6-yl]prop-2-enamide (3)

A mixture of (2Z)-2-fluoro-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid (0.15 g, 0.5 mmol), 6-methoxy-2,4-dimethylpyridin-3-amine (0.09 g, 0.6 mmol, 1.2 eq), HATU (0.37 g, 0.9 mmol, 2 eq) and DIEA (0.13 g, 0.9 mmol, 2 eq) in DMF (3 mL) was stirred for 2 h at 60°C. The mixture was cooled and diluted with water (5 mL), then extracted with EtOAc (3 x 10 mL). The combined organics were washed with water (15 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (1:1) to afford (2Z)-2-fluoro-N-(6- methoxy-2,4-dimethylpyridin-3-yl)-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (0.14 g, 64% yield) as a white solid. LCMS (ES, m/z): 439 [M+H]⁺. Step 3. Preparation of (2Z)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-(3-methyl-1H- indazol-6-yl)prop-2-enamide

A mixture of (2Z)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-[3-methyl-1-(oxan-2-yl)indazol-6- yl]prop-2-enamide (0.09 g, 1 mmol) and TFA (0.6 mL) in DCM (1.2 mL) was stirred for 2 h at room temperature. The resulting mixture was diluted with water (5 mL) and was neutralized to pH7 with aqueous NH3•H2O. The mixture was extracted with DCM (3 x 5 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with Petroleum ether/EtOAc (1:2) to afford (2Z)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-(3- methyl-1H-indazol-6-yl)prop-2-enamide (0.03 g, 41% yield) as a white solid. LCMS (ES, m/z): 355 [M+H]⁺.¹H NMR: (300 MHz, DMSO-d6, ppm) δ 12.84 (s, 1H), 9.99 (s, 1H), 7.84 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.49-7.41 (m, 1H), 7.16 (d, J = 38.8 Hz, 1H), 6.63 (s, 1H), 3.83 (s, 3H), 2.52 (s, 3H), 2.29 (s, 3H), 2.15 (s, 3H).

-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(6-

2,4-dimethylpyridin-3-yl)prop-2- enamide Step 1. Preparation of 6-bromo-7-fluoro-1-(oxan-2-yl)indazole (2)

To a stirred solution of 6-bromo-7-fluoro-1H-indazole (1.0 g, 4.7 mmol) in DCM (10 mL) were added TsOH (0.32 g, 1.9 mmol, 0.4 eq) and DHP (1.2 g, 14 mmol, 3 eq). The reaction mixture was stirred for 2h, then concentrated. The residue was purified by silica gel column chromatography, eluting with n- hexane/AcOEt (10:1) to afford 6-bromo-7-fluoro-1-(oxan-2-yl)indazole (1g, 79% yield) as a white solid. LCMS (ES, m/z): 299, 301 [M+H]⁺. Step 2. Preparation of methyl (2Z)-2-fluoro-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (4)

To a solution of 6-bromo-7-fluoro-1-(oxan-2-yl)indazole (0.55 g, 1.8 mmol) and methyl 2-fluoroacrylate (0.58 g, 5.5 mmol, 3 eq) in DMF (5 mL) were added TEA (0.56 g, 5.5 mmol, 3 eq) and Pd(dppf)Cl2 (0.30 g, 0.4 mmol, 0.2 eq). The reaction mixture was stirred for 6 h at 110℃ under a nitrogen atmosphere. The resulting mixture was diluted with H₂O (50 mL) and was extracted with AcOEt (2 x 100 mL). The combined organics were washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with n- hexane/AcOEt (3:1) to afford methyl (2Z)-2-fluoro-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (180 mg, 30% yield) as a yellow solid. LCMS (ES, m/z): 323 [M+H]⁺. Step 3. Preparation of (2Z)-2-fluoro-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid (5) A solution of methyl (2Z)-2-fluoro-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (0.17 g, 0.5 mmol) in MeOH (2 mL) and H2O (2 mL) was treated with NaOH (63 mg, 1.6 mmol, 3 eq), and the reaction stirred for 2 h. The resulting mixture was concentrated, and washed with EtOAc (2 x 30 mL). The water phase was acidified to pH4 with 1 M HCl (aq.) and was extracted with EtOAc (4 x 30 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated to afford (2Z)-2-fluoro- 3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid (150 mg, 92% yield) as a yellow solid. LCMS (ES, m/z): 309 [M+H]⁺. Step 4. Preparation of (2Z)-2-fluoro-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]-N-(6-methoxy-2,4- dimethylpyridin-3-yl)prop-2-enamide (7)

To a solution of (2Z)-2-fluoro-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid (0.13 g, 0.4 mmol) in DCM (2 mL) was added DIEA (109 mg, 0.8 mmol, 2 eq), followed by 50% T3P in EtOAc (0.40 g, 1.3 mmol, 3 eq) at 0℃. The reaction mixture was stirred for 15 min. at room temperature, then 6-methoxy- 2,4-dimethylpyridin-3-amine (73 mg, 0.48 mmol, 1.2 eq) was added. The reaction was stirred for 2 h, then was concentrated. The residue was purified by silica gel column chromatography, eluting with n- hexane/AcOEt (1:2) to afford (2Z)-2-fluoro-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]-N-(6-methoxy-2,4- dimethylpyridin-3-yl)prop-2-enamide (150 mg, 80% yield). LCMS (ES, m/z): 443 [M+H]⁺. Step 5. Preparation of (2Z)-2-Fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4- dimethylpyridin-3-yl)prop-2-enamide

A mixture of (2Z)-2-fluoro-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]-N-(6-methoxy-2,4-dimethylpyridin-3- yl)prop-2-enamide (140 mg, 0.3 mmol) and TFA (0.5 mL) in DCM (0.5 mL) was stirred for 2h at room temperature. The resulting mixture was concentrated. The residue was purified by Pre-HPLC (Xbridge Shield C18, 50*3.0 mm, 3.5 μm, Mobile Phase: 5-100% MeCN / 0.05% aqueous ammonia over 2 min; Flow rate 1.50 mL/min.) to afford (2Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4- dimethylpyridin-3-yl)prop-2-enamide (31.5 mg, 28% yield) as a white solid. LCMS (ES, m/z): 359 [M+H]⁺.¹H NMR: (300 MHz, DMSO-d6, ppm) δ 10.10 (s, 1H), 8.25 (d, J = 3.5 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.56 (m, 1H), 7.23 (d, J = 37.6 Hz, 1H), 6.62 (s, 1H), 3.83 (s, 3H), 2.29 (s, 3H), 2.15 (s, 3H). Example 7: (2Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2- enamide Step 1. Preparation of 6-bromo-3-methyl-1-(oxan-2-yl)indazole (2)

To 6-bromo-3-methyl-1H-indazole (5.0 g, 24 mmol) and TsOH (0.82 g, 4.7 mmol, 0.2 eq) in DCM (50 mL) was added DHP (3.99 g, 4.7 mmol, 2 eq) and the reaction mixture was stirred for 3h. The resulting mixture was concentrated, and the residue purified by silica gel column chromatography, eluting with n-hexane/AcOEt (5:1) to afford 6-bromo-3-methyl-1-(oxan-2-yl)indazole (6.5 g, 93% yield) as a white solid. LCMS (ES, m/z): 295, 296 [M+H]⁺ Step 2. Preparation of methyl (2Z)-2-fluoro-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (3)

To 6-bromo-3-methyl-1-(oxan-2-yl)indazole (2.0 g, 6.8 mmol), methyl 2-fluoroacrylate (0.85 g, 8.1 mmol, 1.2 eq) in DMF (20 mL) was added Pd(dppf)Cl2 (1.5 g, 2.0 mmol, 0.3 eq) and TEA (2.1 g, 20 mmol, 3 eq). The reaction mixture was stirred for 2h at 110^°C under nitrogen atmosphere, then cooled and quenched with water. The precipitated solids were filtered and washed with EtOAc (3 x 30 mL). The combined filtrate was extracted with EtOAc (3 x 100 mL), and the combined organics were washed with brine (200 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/AcOEt (2:1) to afford methyl (2Z)-2-fluoro-3- [3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (960 mg, 44% yield) as a reddish brown yellow oil. LCMS (ES, m/z): 319 [M+H]⁺ Step 3. Preparation of (2Z)-2-Fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-[3-methyl-1-(oxan- 2-yl)indazol-6-yl]prop-2-enamide (4) A solution of methyl (2Z)-2-fluoro-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (120 mg, 0.4 mmol) and 5-fluoro-2,4-dimethylpyridin-3-amine (the product of Example 1 step 2) (63 mg, 0.5 mmol, 1.2 eq) in THF (1.2 mL) was stirred for 10 min at -30°C under nitrogen atmosphere.1M LiHMDS in THF (1.5 mL, 1.5 mmol, 4 eq) was added dropwise over 10 min at -30°C, and the reaction mixture was stirred for an additional 30 min at -30°C. The reaction was quenched with sat. aqueous NH₄Cl and extracted with EtOAc (3 x 50 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with n- hexane/AcOEt (1:2) to afford (2Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-[3-methyl-1-(oxan- 2-yl)indazol-6-yl]prop-2-enamide (100 mg, 62% yield) as a yellow solid. LCMS (ES, m/z): 427 [M+H]⁺. Step 4. Preparation of (2Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(3-methyl-1H- indazol-6-yl)prop-2-enamide

To (2Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2- enamide (100 mg, 0.2 mmol) in DCM (1 mL) was added TFA (1 mL), and the reaction mixture stirred for 2h. The resulting mixture was concentrated, and the residue purified by Pre-HPLC (Xbridge Shield C18, 50*3.0 mm, 3.5 μm, Mobile Phase: 5-100% MeCN / 0.05% aqueous ammonia over 2 min., Flow rate 1.50 mL/min). The appropriate fractions were concentrated to afford (2Z)-2-fluoro-N-(5-fluoro-2,4- dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide (22 mg, 28% yield) as a white solid. LCMS (ES, m/z): 343 [M+H]⁺.¹H NMR: (400 MHz, DMSO-d6, ppm) δ 12.83 (s, 1H), 10.32 (s, 1H), 8.37 (s, 1H), 7.84 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.44 (dd, J = 8.5, 1.4 Hz, 1H), 7.18 (d, J = 38.8 Hz, 1H), 2.48 (s, 3H), 2.36 (s, 3H), 2.13 (s, 3H). Example 8: (2E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide Step 1.6-bromo-3-methyl-1-(oxan-2-yl) indazole A solution of 6-bromo-3-methyl-1H-indazole (4.0 g, 19 mmol) in THF (80 mL) was treated with DHP (4.8 g, 57 mmol, 3.0 equiv) and PPTS (480 mg, 1.9 mmol, 0.1 equiv). The solution was stirred for 2 hours at 70°C, then cooled and quenched with water. The resulting mixture was extracted with CH₂Cl₂ (4 x 50 mL). The combined organics were dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with petroleum ether: THF (5:1) to afford 6-bromo-3-methyl-1-(oxan-2-yl) indazole (4.9 g, 88% yield) as an off-white solid. LC-MS (ES, m/z): 295 [M+H]⁺ Step 2. Preparation of methyl (2E)-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate

A solution of 6-bromo-3-methyl-1-(oxan-2-yl)indazole (4.9 g, 17 mmol) and methyl acrylate (5.7 g, 66 mmol, 4.0 equiv), Pd(dppf)Cl2•CH2Cl2 (2.7 g, 3.3 mmol, 0.2 equiv) and TEA (8.4 g, 83 mmol, 5.0 equiv) in DMF (100 mL) was stirred for 2 hours at 110°C under N2 atmosphere. The mixture was allowed to cool and was quenched with water. The resulting mixture was extracted with ethyl acetate (4x50 mL). The combined organics were washed with brine (3x5 mL) and dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (5:1) to afford methyl (2E)-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (4.0 g, 80% yield) as a yellow solid. LC-MS (ES, m/z): 301 [M+H]⁺ Step 3. Preparation of (2E)-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid

A solution of methyl (2E)-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (4.0 g, 13 mmol) in H₂O (27 mL), MeOH (27 mL) and THF (27 mL) was treated with NaOH (1.6 g, 40 mmol, 3 equiv). The mixture was stirred for 4 hours at room temperature, then acidified to pH6 with 1M HCl. The precipitated solids were collected by filtration and washed with THF (3x10 mL). Drying under vacuum gave (2E)-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid (3.2 g, 84% yield) as a white solid. LC-MS (ES, m/z): 287 [M+H]⁺. Step 4. Preparation of (2E)-N-(5-Chloro-2-methylpyridin-3-yl)-3-[3-methyl-1-(oxan-2-yl)indazol- 6-yl]prop-2-enamide (2)

To (2E)-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid (120 mg, 0.4 mmol), 5-chloro-2- methylpyridin-3-amine (120 mg, 0.8 mmol, 2 eq) and DIEA (0.22 g, 1.7 mmol, 4 eq) in DCM (1.2 mL) was added 50% T3P in EtOAc (0.53 g, 1.7 mmol, 4 eq). The reaction mixture was stirred for 3h at 40°C, then cooled and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/EtOAc (1:1) to afford (2E)-N-(5-chloro-2-methylpyridin-3-yl)-3-[3-methyl-1- (oxan-2-yl)indazol-6-yl]prop-2-enamide (80 mg, 46% yield) as a yellow solid. LCMS (ES, m/z): 411 [M+H]⁺. Step 5. Preparation of (2E)-N-(5-Chloro-2-methylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop- 2-enamide

To (2E)-N-(5-chloro-2-methylpyridin-3-yl)-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (60 mg, 0.2 mmol) in DCM (1 mL) was added 4M HCl in 1,4-dioxane (2 mL). The resulting mixture was stirred for 15 min at 60°C, then cooled and concentrated. The residue was triturated with EtOAc (10 mL) and the solids collected by filtration to afford (2E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-methyl- 1H-indazol-6-yl)prop-2-enamide (22 mg, 46% yield) as a white solid. LCMS (ES, m/z): 327 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆, ppm) δ 12.87 (s, 1H), 9.70 (s, 1H), 8.36 – 8.28 (m, 2H), 7.82 – 7.74 (m, 2H), 7.71 (s, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 15.7 Hz, 1H), 2.51 (s, 6H). Example 9: (2E)-3-(3-chloro-1H-indazol-6-yl)-N-[5-fluoro-2-(methoxymethyl)pyridin-3-yl]prop-2- enamide Step 1. Preparation of 5-Fluoro-2-(methoxymethyl)pyridin-3-amine (2) To a solution of 2-bromo-5-fluoropyridin-3-amine (0.50 g, 2.6 mmol) and tributyl(methoxymethyl)stannane (1.3 g, 3.9 mmol, 1.5 eq) in toluene (5 mL) was added PdP(Ph₃)₂Cl₂ (183 mg, 0.3 mmol, 0.1 eq). The mixture was stirred for 4h at 120°C under N₂ atmosphere, then was cooled, quenched with water and extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (3 x 10 mL), dried over anhydrous Na₂SO₄ and concentrated to afford 5-fluoro-2- (methoxymethyl)pyridin-3-amine (270 mg, 66% yield) as a colourless oil. LCMS (ES, m/z): 157 [M+H]⁺. Step 2. Preparation of N-[5-fluoro-2-(methoxymethyl)pyridin-3-yl]prop-2-enamide (3)

To a solution of 5-fluoro-2-(methoxymethyl)pyridin-3-amine (0.25 g, 1.6 mmol) and TEA (0.48 g, 4.8 mmol, 3 eq) in DCM (3 mL) was added acryloyl chloride (0.22 g, 2.4 mmol, 1.5 eq) at 0°C. The mixture was stirred for 2h at room temperature, then quenched by water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with n- hexane/EtOAc (1:3) to afford N-[5-fluoro-2-(methoxymethyl)pyridin-3-yl]prop-2-enamide (150 mg, 44% yield) as a yellow green solid. LCMS (ES, m/z): 211 [M+H]⁺. Step 3. Preparation of (2E)-3-(3-chloro-1H-indazol-6-yl)-N-[5-fluoro-2-(methoxymethyl)pyridin- 3-yl]prop-2-enamide

To a solution of N-[5-fluoro-2-(methoxymethyl)pyridin-3-yl]prop-2-enamide (100 mg, 0.5 mmol) in DMF (1 mL) was added 6-bromo-3-chloro-1H-indazole (132 mg, 0.6 mmol, 1.2 eq), TEA (0.16 g, 1.5 mmol, 3 eq) and Pd(dppf)Cl2 (110 mg, 0.1 mmol, 0.3 eq). The reaction was stirred for 2h at 110°C under N2 atmosphere, then cooled and quenched with water (10 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (15 mL), dried over anhydrous Na2SO4 and concentrated. The residue was dissolved in MeOH (2 mL) and purified by Prep-HPLC (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase: 24-50% MeCN / 10 mmol/L aqueous NH₄HCO₃ + 0.1% NH₃•H₂O over 7 min.; Flow rate: 30 mL/min.) to afford (2E)-3-(3-chloro- 1H-indazol-6-yl)-N-[5-fluoro-2-(methoxymethyl)pyridin-3-yl]prop-2-enamide (45 mg, 26 % yield) as a white solid. LCMS (ES, m/z): 361 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆, ppm) δ 13.52 (s, 1H), 9.67 (s, 1H), 8.41-8.28 (m, 2H), 7.88-7.83 (m, 1H), 7.83-7.69 (m, 2H), 7.59 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 15.7 Hz, 1H), 4.67 (s, 2H), 3.31(s, 3H). Example 10: (2E)-3-(3-chloro-1H-indazol-6-yl)-N-(5-fluoro-2-methylpyridin-3-yl)prop-2-enamide Step 1. Preparation of N-(5-Fluoro-2-methylpyridin-3-yl)prop-2-enamide (3)

A mixture of 5-fluoro-2-methylpyridin-3-amine (prepared from 5-fluoro-2-methyl-3-nitro-pyridine by a process analogous to that described in Example 1 step 2) (0.19 g, 1.5 mmol), TEA (0.46 g, 4.5 mmol, 3 eq) and DMAP (0.04 g, 0.3 mmol, 0.2 eq) in DCM (4 mL) was stirred for 5 min at 0°C. To this was added acryloyl chloride (0.31 g, 3.5 mmol, 2.3 eq) in portions over 5 min at 0°C. The resulting mixture was stirred for 10 min at 0°C, then was diluted with water (5 mL) and extracted with DCM (3 x 5 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with Petroleum ether/EtOAc (1:1) to afford N-(5- fluoro-2-methylpyridin-3-yl)prop-2-enamide (0.14 g, 52% yield) as a white solid. LCMS (ES, m/z): 181 [M+H]⁺. Step 2. Preparation of (2E)-3-(3-chloro-1H-indazol-6-yl)-N-(5-fluoro-2-methylpyridin-3-yl)prop- 2-enamide

A mixture of N-(5-fluoro-2-methylpyridin-3-yl)prop-2-enamide (0.10 g, 0.6 mmol), 6-bromo-3-chloro- 1H-indazole (0.15 g, 0.7 mmol, 1.2 eq), Pd(dppf)Cl2 (0.12 g, 0.2 mmol, 0.3 eq) and TEA (0.17 g, 1.7 mmol, 3 eq) in DMF (2 mL) was stirred for 2 hours at 110°C under N2 atmosphere. The mixture was cooled and diluted with water (3 mL), then extracted with EtOAc (3 x 10 mL). The combined organics were washed with water (10 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with Petroleum ether/EtOAc (1:2) to afford crude product. The residue was triturated with anhydrous ether (10 mL) and the solids removed, then dried to afford (2E)-3-(3-chloro-1H-indazol-6-yl)-N-(5-fluoro-2-methylpyridin-3-yl)prop-2-enamide (0.03 g, 20% yield) as a white solid. LCMS (ES, m/z): 331 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆, ppm) δ 13.45 (br, s, 1H), 9.70 (s, 1H), 8.27 (d, J = 2.7 Hz, 1H), 8.18 (dd, J = 10.9, 2.8 Hz, 1H), 7.87-7.72 (m, 3H), 7.55 (d, J = 8.6 Hz, 1H), 7.20 (d, J = 15.6 Hz, 1H), 2.50 (s, 3H). Example 11: (2E)-N-(5-fluoro-2-methylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide Step 1. Preparation of (2E)-N-(5-fluoro-2-methylpyridin-3-yl)-3-[3-methyl-1-(oxan-2-yl)indazol-6- yl]prop-2-enamide (3)

To a mixture of (2E)-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid (the product of Example 8 step 3) (0.13 g, 0.6 mmol), 5-fluoro-2-methylpyridin-3-amine (0.07 g, 0.5 mmol, 1.2 eq) and DIEA (0.18 g, 1.4 mmol, 3 eq) in DCM (2 mL) was added 50% T3P in EtOAc (0.43 g, 1.4 mmol, 3 eq), and the reaction stirred for 2 hours at 50°C. The mixture was cooled and concentrated, and the residue purified by silica gel column chromatography, eluting with Petroleum ether/EtOAc (2:1) to afford (2E)- N-(5-fluoro-2-methylpyridin-3-yl)-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (0.09 g, 50% yield) as a white solid. LCMS (ES, m/z): 395 [M+H]⁺. Step 2. Preparation of (2E)-N-(5-fluoro-2-methylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop- 2-enamide

To (2E)-N-(5-fluoro-2-methylpyridin-3-yl)-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (0.10, 0.3 mmol) in DCM (1.5 mL ) was added TFA (0.5 mL), and the reaction stirred for 2 h. The resulting mixture was diluted with water (2 mL) and was basified with aqueous NaHCO3. The mixture was extracted with DCM (3 x 5 mL), and the combined organics dried over anhydrous Na2SO4 before being concentrated. The residue was purified by Prep-HPLC with the following conditions (Xbridge C18, 19*150 mm, 5 μm; Mobile Phase: 5-60% MeCN / 20 mM NH4HCO3 + 0.05% NH3.H2O over 15 min.; Flow rate: 20 mL/min.) to afford (2E)-N-(5-fluoro-2-methylpyridin-3-yl)-3-(3-methyl-1H-indazol-6- yl)prop-2-enamide (20 mg, 25% yield) as a white solid. LCMS (ES, m/z): 311 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆, ppm) δ 12.88 (s, 1H), 9.67 (s, 1H), 8.26 (d, J = 2.8 Hz, 1H), 8.19 (dd, J = 10.9, 2.8 Hz, 1H), 7.88-7.65 (m, 3H), 7.41 (dd, J = 8.5, 1.4 Hz, 1H), 7.16 (d, J = 15.7 Hz, 1H), 2.51 (s, 3H) 2.49 (s, 3H). Example 12: (Z)-3-(7-chloro-1H-indazol-6-yl)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3- yl)acrylamide Step 1. Preparation of 4-bromo-3-chloro-2-fluorobenzaldehyde (2)

To 1-bromo-2-chloro-3-fluorobenzene (6.0 g, 29 mmol) in THF (80 mL) under N2 atmosphere at -78°C, was added 2M LDA in THF (17 mL, 34 mmol, 1.2 eq) dropwise. The resulting mixture was stirred for 2h at -78 °C, then DMF (2.5 g, 34 mmol, 1.2 eq) was added, and the mixture stirred at -78 °C for 1h. The reaction was quenched by the addition of saturated aqueous NH₄Cl solution at room temperature and was further diluted with H₂O (50 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organics were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with n- hexane/EtOAc (10:1) to afford 4-bromo-3-chloro-2-fluorobenzaldehyde (5.1 g, 74% yield) as a brown solid. LCMS (ES, m/z): 237, 239 [M+H]⁺. Step 2. Preparation of 6-bromo-7-chloro-1H-indazole (3)

4-Bromo-3-chloro-2-fluorobenzaldehyde (4.8 g, 20 mmol),

(2.0 g, 40 mmol, 2 eq), DBU (9.2 g, 61 mmol, 3 eq) in DMAc (80 mL) were stirred at 110 °C for 12h. The reaction was cooled and quenched with saturated aqueous citric acid and diluted with H2O (50 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/EtOAc (3:1) to afford 6-bromo-7-chloro-1H-indazole (675 mg, 14% yield) as a brown solid. LCMS (ES, m/z): 231, 233 [M+H]⁺ Step 3. Preparation of 6-bromo-7-chloro-1-(oxan-2-yl) indazole (4)

To 6-bromo-7-chloro-1H-indazole (0.67 g, 2.9 mmol), PPTS (0.88 g, 3.5 mmol, 1.2 eq) in DCM (10 mL) was added DHP (0.73 g, 8.7 mmol, 3 eq). The resulting solution was stirred at room temperature for 12 h. The reaction was diluted with H2O (10 mL) and extracted with DCM (3 x 30 mL). The combined organics were washed with brine (15 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/AcOEt (3:1) to afford 6-bromo-7-chloro-1-(oxan-2-yl) indazole (400 mg, 43% yield) as a white solid. LCMS (ES, m/z): 315, 317 [M+H]⁺. Step 4. Preparation of Methyl (2Z)-3-[7-chloro-1-(oxan-2-yl) indazol-6-yl]-2-fluoroprop-2-enoate (5)

To 6-bromo-7-chloro-1-(oxan-2-yl) indazole (0.40 g, 1.3 mmol), methyl 2-fluoroacrylate (0.39 g, 3.8 mmol, 3 eq) and Et₃N (0.38 g, 3.8 mmol, 3 eq) in DMF (10 mL) was added Pd(dtbpf)Cl₂ (0.25 g, 0.4 mmol, 0.3 eq). The resulting mixture was stirred for 2h at 110°C under nitrogen atmosphere, then cooled and quenched by water (20 mL), then extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with Petroleum ether/EtOAc (3:1) to afford methyl (2Z)-3-[7-chloro-1-(oxan-2-yl) indazol-6-yl]-2-fluoroprop-2-enoate (50 mg, 11% yield) as a brown solid. LCMS (ES, m/z): 339, 341 [M+H]⁺. Step 5. Preparation of (Z)-3-(7-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-2- fluoroacrylic acid (6)

Methyl (2Z)-3-[7-chloro-1-(oxan-2-yl) indazol-6-yl]-2-fluoroprop-2-enoate (50 mg, 0.14 mmol) and LiOH (11 mg, 0.4 mmol, 3 eq) in THF (2.5 mL) and H2O (0.5 mL) was stirred at room temperature for 2 h. The resulting mixture was washed with EtOAc (3 x 10 mL). The aqueous was acidified with citric acid and extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated to afford (2Z)-3-[7-chloro-1-(oxan-2-yl) indazol-6-yl]- 2-fluoroprop-2-enoic acid (40 mg, 83% yield) as a brown solid. LCMS (ES, m/z): 323 [M-H]- Step 6. Preparation of (2Z)-3-[7-chloro-1-(oxan-2-yl) indazol-6-yl]-2-fluoro-N-(6-methoxy-2,4- dimethylpyridin-3-yl) prop-2-enamide (8)

To (2Z)-3-[7-chloro-1-(oxan-2-yl) indazol-6-yl]-2-fluoroprop-2-enoic acid (40 mg, 0.12 mmol), 6- methoxy-2,4-dimethylpyridin-3-amine (23 mg, 0.14 mmol, 1.2 eq) and pyridine (1 mL) was added 50% T3P in EtOAc (1 mL). The resulting mixture was stirred at room temperature for 2h. The solvent was removed, and the residue was diluted with H2O (10 mL), then extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated to afford (2Z)-3-[7-chloro-1-(oxan-2-yl) indazol-6-yl]-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl) prop-2-enamide (30 mg, 53% yield) as a brown solid. LCMS (ES, m/z): 459, 461 [M+H]⁺. Step 7. Preparation of (Z)-3-(7-chloro-1H-indazol-6-yl)-2-fluoro-N-(6-methoxy-2,4- dimethylpyridin-3-yl)acrylamide

To (2Z)-3-[7-chloro-1-(oxan-2-yl) indazol-6-yl]-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl) prop-2- enamide (30 mg, 0.06 mmol) in DCM (2 mL) was added TFA (0.1 mL) at room temperature. The reaction was stirred for 1 h at room temperature, then concentrated. The residue was dissolved in MeCN (2 mL) and basified with NH₃•H₂O. The mixture was purified by Prep-HPLC with the following conditions (Column: SunFire Prep C18 OBD 5μm 30*150mm Column; Mobile Phase: 20-60% MeCN / 0.05% aqueous HCl over 10 min.; Flow rate: 60 mL/min mL/min) to afford (Z)-3-(7-chloro-1H-indazol- 6-yl)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide (6.0 mg, 25% yield) as a white solid. LCMS (ES, m/z): 375, 377 [M+H]⁺.¹H NMR (300 MHz, DMSO-d6, ppm) δ 13.80 (brs, 1H), 10.13 (s, 1H), 8.26 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 37.2 Hz, 1H), 6.63 (s, 1H), 3.84 (s, 3H), 2.30 (s, 3H), 2.16 (s, 3H). Example 13: (2E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(4-fluoro-1-methyl-2-oxo-3H-1,3-benzodiazol-5- yl)prop-2-enamide Step 1. Preparation of 4-bromo-3-fluoro-N-methyl-2-nitroaniline (2) A solution of 60% NaH/oil (2.0 g, 85 mmol, 2 eq) in DMF (20 mL) was treated with 4-bromo-3-fluoro- 2-nitroaniline (10 g, 43 mmol) for 30 min at 0°C. MeI (4.8 g, 34 mmol, 0.8 eq) was added dropwise at 0°C, and the reaction mixture was stirred for 30 min at room temperature. The reaction was quenched with water (50 mL) at 0°C, then extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (5:1) to afford 4- bromo-3-fluoro-N-methyl-2-nitroaniline (1.6 g, 14% yield) as a brown solid. LCMS (ES, m/z): 249, 251 [M+H]⁺. Step 2. Preparation of 4-bromo-3-fluoro-N1-methylbenzene-1,2-diamine (3)

To 4-bromo-3-fluoro-N-methyl-2-nitroaniline (1.6 g, 6.3 mmol), AcOH (3.0 g, 50 mmol, 8 eq) in EtOH (30 mL) at room temperature was added Zn (2.5 g, 38 mmol, 6 eq) in portions. The reaction mixture was stirred for 3 h, then filtered, and the filter cake was washed with MeOH (3 x 10 mL). The combined filtrate was concentrated and the residue suspended in saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (4:1) to afford 4-bromo-3-fluoro-N1- methylbenzene-1,2-diamine (900 mg, 65% yield) as a brown oil. LCMS (ES, m/z): 219, 221 [M+H]⁺. Step 3. Preparation of 5-bromo-4-fluoro-1-methyl-3H-1,3-benzodiazol-2-one (4)

A solution of 4-bromo-3-fluoro-N1-methylbenzene-1,2-diamine (0.90 g, 4.1 mmol) and CDI (2.7 g, 16 mmol, 4 eq) in DMAc (10 mL) was stirred for 3 h at 80°C. The resulting mixture was quenched by water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (1:1) to afford 5-bromo-4-fluoro-1-methyl- 3H-1,3-benzodiazol-2-one (500 mg, 49% yield) as a white solid. LCMS (ES, m/z): 245, 247 [M+H]⁺. Step 4. Preparation of methyl (2E)-3-(4-fluoro-1-methyl-2-oxo-3H-1,3-benzodiazol-5-yl)prop-2- enoate (5)

A solution of 5-bromo-4-fluoro-1-methyl-3H-1,3-benzodiazol-2-one (0.20 g, 0.8 mmol), Pd(dppf)Cl₂ (0.17 g, 0.2 mmol, 0.3 eq), methyl acrylate (0.14 g, 1.6 mmol, 2 eq) and TEA (0.24 g, 2.4 mmol, 3 eq) in DMF (8 mL) was stirred for 2 h at 110°C under nitrogen atmosphere. The resulting mixture was cooled and quenched by water (10 mL), then extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with CH2Cl2/MeOH (10:1) to afford methyl (2E)- 3-(4-fluoro-1-methyl-2-oxo-3H-1,3-benzodiazol-5-yl)prop-2-enoate (120 mg, 58% yield) as a dark solid. LCMS (ES, m/z): 251 [M+H]⁺. Step 5. Preparation of (2E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(4-fluoro-1-methyl-2-oxo-3H-1,3- benzodiazol-5-yl)prop-2-enamide

To a stirred mixture of methyl (2E)-3-(4-fluoro-1-methyl-2-oxo-3H-1,3-benzodiazol-5-yl)prop-2-enoate (100 mg, 0.4 mmol) and 5-chloro-2-methylpyridin-3-amine (94 mg, 0.6 mmol, 1.5 eq) in THF (2 mL) were added 1M LiHMDS in THF (1.7 mL, 1.7 mmol, 4 eq) dropwise at -78°C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at room temperature, then quenched by water (15 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated. The crude product was purified by Prep-HPLC (Column: Xbridge C18, 19*150 mm, 5 μm; Mobile Phase: 10-65% MeCN / 20 mM aqueous NH4HCO3 + 0.05% NH3•H2O over 9 min.; Flow rate: 60 mL/min) to afford (2E)-N-(5-chloro-2-methylpyridin-3-yl)- 3-(4-fluoro-1-methyl-2-oxo-3H-1,3-benzodiazol-5-yl)prop-2-enamide (35 mg, 22% yield) as a yellow solid. LCMS (ES, m/z): 361, 363 [M+H]⁺.¹H NMR (400 MHz, DMSO-d6, ppm) δ 11.57 (s, 1H), 9.70 (s, 1H), 8.27 (s, 2H), 7.66 (d, J = 15.8 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 7.08-7.00 (m, 2H), 3.30 (s, 3H), 2.47 (s, 3H). Example 14: (2Z)-2-fluoro-3-(4-fluoro-1-methyl-2-oxo-3H-1,3-benzodiazol-5-yl)-N-(5-fluoro-2,4- dimethylpyridin-3-yl)prop-2-enamide Step 1. Preparation of methyl (2Z)-2-fluoro-3-(4-fluoro-1-methyl-2-oxo-3H-1,3-benzodiazol-5- yl)prop-2-enoate (2)

A solution of 5-bromo-4-fluoro-1-methyl-3H-1,3-benzodiazol-2-one (the product of Example 13 step 3) (0.26 g, 1.0 mmol), methyl 2-fluoroacrylate (0.22 g, 2.1 mmol, 2 eq), Pd(dtbpf)Cl₂ (0.20 g, 0.3 mmol, 0.3 eq) and TEA (0.32 g, 3.1 mmol, 3 eq) in DMF (5 mL) was stirred for 2 h at 110°C under nitrogen atmosphere. The resulting mixture was cooled and quenched by water (10 mL), then extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with CH2Cl2/MeOH (10:1) to afford methyl (2Z)-2-fluoro-3-(4-fluoro-1-methyl-2-oxo-3H-1,3-benzodiazol-5- yl)prop-2-enoate (210 mg, 73% yield) as a dark solid. LCMS (ES, m/z): 269 [M+H]⁺. Step 2. Preparation of (2Z)-2-fluoro-3-(4-fluoro-1-methyl-2-oxo-3H-1,3-benzodiazol-5-yl)-N-(5- fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide

To a stirred solution of methyl (2Z)-2-fluoro-3-(4-fluoro-1-methyl-2-oxo-3H-1,3-benzodiazol-5-yl)prop- 2-enoate (0.20 g, 0.7 mmol) and 5-fluoro-2,4-dimethylpyridin-3-amine (the product of Example 1 step 2) (0.12 g, 0.8 mmol, 1.2 eq) in THF (3 mL) was added 1M LiHMDS in THF (3 mL, 3 mmol, 4 eq) dropwise at -78°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature, then quenched by water (15 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The crude product was purified by Prep-HPLC (Column: Xbridge C18, 19*150 mm, 5 μm; Mobile Phase: 10-65% MeCN / 20mM aqueous NH₄HCO₃ + 0.05% NH₃•H₂O over 8 min.; Flow rate: 60 mL/min) to afford (2Z)- 2-fluoro-3-(4-fluoro-1-methyl-2-oxo-3H-1,3-benzodiazol-5-yl)-N-(5-fluoro-2,4-dimethylpyridin-3- yl)prop-2-enamide (53 mg, 19% yield) as a yellow solid. LCMS (ES, m/z): 377 [M+H]⁺.¹H NMR (400 MHz, DMSO-d6, ppm) δ 11.60 (s, 1H), 10.33 (s, 1H), 8.36 (s, 1H), 7.58-7.54 (m, 1H), 7.17-7.02 (m, 2H), 3.30 (s, 3H), 2.34 (s, 3H), 2.12 (s, 3H). Example 15: (2Z)-3-(3-cyano-7-fluoro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3- yl)prop-2-enamide Step 1. Preparation of 6-Bromo-7-fluoro-3-iodo-1H-indazole (2)

To a stirred solution of 6-bromo-7-fluoro-1H-indazole (1.0 g, 4.7 mmol) in DMF (20 mL) was added NIS (2.1 g, 9.3 mmol, 2 eq). The reaction was stirred at 70°C for 1 h, then cooled and extracted with EtOAc (3x30 mL). The combined organics were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/EtOAc (6:1) to afford 6-bromo-7-fluoro-3-iodo-1H-indazole (1.5 g, 94% yield) as a yellow solid. LCMS (ES, m/z): 341, 343 [M+H]⁺. Step 2. Preparation of 6-bromo-7-fluoro-1H-indazole-3-carbonitrile (3)

To a stirred solution of 6-bromo-7-fluoro-3-iodo-1H-indazole (1.4g, 4.1 mmol) and Zn(CN)2 (0.48 g, 4.1 mmol, 1 eq) in DMF (15 mL) was added dppf (0.20 g, 0.37 mmol, 0.09 eq) and Pd₂(dba)₃ (0.37g, 0.41 mmol, 0.1 eq). The reaction was stirred at 60°C for 4 h, then cooled and extracted with EtOAc (3 x 40 mL). The combined organics were washed with brine (80 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with n- hexane/THF (10:1) to afford 6-bromo-7-fluoro-1H-indazole-3-carbonitrile (0.70 g, 71% yield) as a white solid. LCMS (ES, m/z): 240, 242 [M+H]⁺. Step 3. Preparation of 6-bromo-7-fluoro-1-(oxan-2-yl)indazole-3-carbonitrile (4)

To a stirred solution of 6-bromo-7-fluoro-1H-indazole-3-carbonitrile (0.70 g, 2.91 mmol) and DHP (0.49 g, 5.8 mmol, 2 eq) in DCM (10 mL) was added TsOH (0.15 g, 0.87 mmol, 0.3 eq) and the reaction stirred for 1 h. The mixture was basified with saturated NaHCO₃ (aq.) and the aqueous layer extracted with DCM (3 x 20 mL). The combined organics were washed with brine (40 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/THF (8:1) to afford 6-bromo-7-fluoro-1-(oxan-2-yl)indazole-3-carbonitrile (0.65 g, 68% yield) as a white solid. Step 4. Preparation of 2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide (7)

A solution of 5-fluoro-2,4-dimethylpyridin-3-amine (the product of Example 1 step 2) (0.5 g, 3.6 mmol) in THF (10 mL) was treated with methyl 2-fluoroacrylate (0.44 g, 4.3 mmol, 1.2 eq) at -30°C. 1M LiHMDS in THF (1 mL, 1 mmol) was added dropwise at -30°C and the reaction stirred for 0.5 h. The mixture was quenched by the addition of sat. NH4Cl (aq.) (10 mL) at 0°C, and extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated to afford 2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide (0.65 g, 85% yield) as a yellow solid. LCMS (ES, m/z): 213 [M+H]⁺. Step 5. (2Z)-3-[3-Cyano-7-fluoro-1-(oxan-2-yl)indazol-6-yl]-2-fluoro-N-(5-fluoro-2,4- dimethylpyridin-3-yl)prop-2-enamide (8)

To a stirred solution of 2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide (0.25 g, 1.2 mmol, 1.1 eq) and 6-bromo-7-fluoro-1-(oxan-2-yl)indazole-3-carbonitrile (as prepared according to Step 3) (0.36 g, 1.1 mmol) in DMF (6 mL) were added TEA (0.33 g, 3.3 mmol, 3 eq) and Pd(dppf)Cl2 (0.16 g, 0.22 mmol, 0.2 eq) at room temperature. The reaction was stirred at 100°C for 12 h under N2 atmosphere, then was cooled and extracted with DCM (3 x 30 mL). The combined organics were washed with brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/THF (3:1) to afford (2Z)-3-[3-cyano-7- fluoro-1-(oxan-2-yl)indazol-6-yl]-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide (0.08 g, 16% yield) as a yellow solid. LCMS (ES, m/z): 456 [M+H]⁺. Step 6. Preparation of (2Z)-3-(3-cyano-7-fluoro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4- dimethylpyridin-3-yl)prop-2-enamide

To a stirred solution of (2Z)-3-[3-cyano-7-fluoro-1-(oxan-2-yl)indazol-6-yl]-2-fluoro-N-(5-fluoro-2,4- dimethylpyridin-3-yl)prop-2-enamide (80 mg, 0.18 mmol) in DCM (2 mL) was added TFA (2 mL) dropwise at room temperature, and the mixture stirred for 2 h. The resulting mixture was concentrated and the residue dissolved into MeOH (3 mL), then basified with saturated NaHCO3 (aq.). The mixture was purified by Prep-HPLC with the following conditions (Xbridge C18, 19*150 mm, 5 μm; Mobile Phase: 15-65% MeCN / 20 mM aqueous NH₄HCO₃ + 0.05% NH_3.H₂O over 15 min.; Flow rate: 20 mL/min) to afford (2Z)-3-(3-cyano-7-fluoro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3- yl)prop-2-enamide (6 mg, 9% yield) as a white solid. LCMS (ES, m/z): 372 [M+H]⁺.¹H NMR (300 MHz, DMSO-d_6, ppm) δ 15.25 (s, 1H), 10.53 (s, 1H), 8.40 (s, 1H), 7.98-7.69 (m, 2H), 7.27 (d, J = 36.9 Hz, 1H), 2.38 (s, 3H), 2.16 (s, 3H). Example 16: (2E)-N-[5-chloro-2-(methoxymethyl)pyridin-3-yl]-3-(7-fluoro-1H-indazol-6-yl)prop-2- enamide Step 1. Preparation of methyl (2E)-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (2)

6-Bromo-7-fluoro-1-(oxan-2-yl)indazole (prepared from 6-bromo-7-fluoro-1H-indazole by an analogous method to Example 19 step 2) (1.0 g, 3.0 mmol) in DMF (10 mL) was treated with methyl acrylate (0.31 g, 3.6 mmol, 1.2 eq), Pd(dppf)Cl2 (0.66 g, 0.9 mmol, 0.3 eq) and TEA (0.91 g, 9.0 mmol, 3 eq). The reaction was stirred for 2h at 110°C under nitrogen atmosphere. The resulting mixture was cooled, quenched by water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/EtOAc (3:1) to afford methyl (2E)-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (600 mg, 59% yield) as a yellow green solid. LCMS (ES, m/z): 305 [M+H]⁺. Step 2. Preparation of 5-chloro-2-(methoxymethyl)pyridin-3-amine (4) To 2-bromo-5-chloropyridin-3-amine (0.50 g, 2.4 mmol) in DMF (5 mL) was added tributyl(methoxymethyl)stannane (1.2 g, 3.6 mmol, 1.5 eq) and Pd(PPh₃)₂Cl₂ (50 mg). The reaction was stirred overnight at 120°C, and the resulting mixture cooled and concentrated. The residue was dissolved in water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with hexane/EtOAc (2:1) to afford 5-chloro-2- (methoxymethyl)pyridin-3-amine (180 mg, 45% yield) as a light yellow solid. LCMS (ES, m/z): 173, 175 [M+H]⁺ Step 3. Preparation of (2E)-N-[5-chloro-2-(methoxymethyl)pyridin-3-yl]-3-[7-fluoro-1-(oxan-2- yl)indazol-6-yl]prop-2-enamide

To 5-chloro-2-(methoxymethyl)pyridin-3-amine (80 mg, 0.5 mmol) and methyl (2E)-3-[7-fluoro-1- (oxan-2-yl)indazol-6-yl]prop-2-enoate (as prepared according to Step 1) (141 mg, 0.5 mmol) in THF (3 mL) was added 1 M LiHMDS in THF (1.8 mL, 1.8 mmol, 4 eq) dropwise at -78°C. The reaction was stirred for 2h, then allowed to warm to room temperature. The reaction was quenched with MeOH at 0°C and concentrated. The residue triturated with hexane to give (2E)-N-[5-chloro-2- (methoxymethyl)pyridin-3-yl]-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (170 mg, 82% yield) as a grey solid. LCMS (ES, m/z): 445, 447 [M+H]⁺. Step 4. Preparation of (2E)-N-[5-Chloro-2-(methoxymethyl)pyridin-3-yl]-3-(7-fluoro-1H-indazol- 6-yl)prop-2-enamide

To (2E)-N-[5-chloro-2-(methoxymethyl)pyridin-3-yl]-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2- enamide (170 mg, 0.4 mmol) in DCM (2 mL) was added TFA (1 mL). the reaction was stirred for 1 h at room temperature, then concentrated. The residue was dissolved in MeCN (2 mL) and basified with NH3•H2O. The mixture was purified by Prep-HPLC with the following conditions (Column: SunFire Prep C18 OBD 5μm 30*150mm Column; Mobile Phase: 20-60% MeCN / 0.05% aqueous HCl over 10 min.; Flow rate: 60 mL/min mL/min) to afford (2E)-N-[5-chloro-2-(methoxymethyl)pyridin-3-yl]-3-(7-fluoro- 1H-indazol-6-yl)prop-2-enamide (40mg, 29% yield) as an off-white solid. LCMS (ES, m/z): 361, 363 [M+H]⁺.¹H NMR (300 MHz, DMSO-d6, ppm) δ 9.86 (s, 1H), 8.49 (s, 1H), 8.40 (s, 1H), 8.23 (d, J = 3.5 Hz, 1H), 7.88 (d, J = 15.8 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.50-7.40 (m, 1H), 7.23 (d, J = 15.8, 1H), 4.67 (s, 2H), 3.32 (s, 3H). Example 17: (2Z)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-cyano-1H-indazol-6-yl)-2-fluoroprop-2- enamide Step 1. Preparation of 6-bromo-3-iodo-1H-indazole (2)

To a solution of 6-bromo-1H-indazole (10 g, 51 mmol) in dry DMF (100 mL) was added I2 (28 g, 112 mmol, 2.2 eq) and KOH (6.8 g, 120 mmol, 2.4 eq). The mixture was stirred for 3h at room temperature, then partitioned between ethyl acetate and 1:1 mixture of aqueous saturated NaCl and saturated Na₂S₂O₃. The organics were removed and the aqueous layer extracted with ethyl acetate. The combined organics were washed with water and brine, dried with Na₂SO₄ and concentrated to give 6- bromo-3-iodo-1H-indazole (15 g, 91% yield) as a light yellow solid. LCMS (ES, m/z): 323, 325 [M+H]⁺ Step 2. Preparation of 6-bromo-1-(oxan-2-yl)indazole-3-carbonitrile (3)

To a solution of 6-bromo-3-iodo-1H-indazole (15g, 46 mmol) and TsOH (1.6 g, 9.1 mmol, 0.2 eq) in DCM (150 mL) was added DHP (7.8 g, 92 mmol, 2 eq). The mixture was stirred for 2h at room temperature, then concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/EtOAc (5:1) to afford 6-bromo-3-iodo-1-(oxan-2-yl)indazole (16 g, 84% yield) as a white solid. LCMS (ES, m/z): 407, 409 [M+H]⁺. Step 3. Preparation of 6-bromo-1-(oxan-2-yl)indazole-3-carbonitrile (4)

A solution of 6-bromo-3-iodo-1-(oxan-2-yl)indazole (5.0 g, 12 mmol) and Zn(CN)₂ (1.6 g, 15 mmol, 1.2 eq) in DMF (50 mL) was treated with dppf (0.67 g, 1.2 mmol, 0.1 eq) and Pd2(dba)3 (0.89 g, 0.9 mmol, 0.1 eq). The reaction was stirred for 1h at 80°C under N2 atmosphere, then cooled and quenched by water (60 mL). The mixture was extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/EtOAc (10:1) to afford 6-bromo-1-(oxan- 2-yl)indazole-3-carbonitrile) (2.2 g, 58% yield) as a white solid. Step 4. Preparation of methyl (2Z)-3-[3-cyano-1-(oxan-2-yl)indazol-6-yl]-2-fluoroprop-2-enoate (6)

To a solution of 6-bromo-1-(oxan-2-yl)indazole-3-carbonitrile (2.75 g, 9 mmol) and methyl 2- fluoroacrylate (1.1 g, 11 mmol, 1.2 eq) in DMF (20 mL) was added Pd(dppf)Cl₂ (2.0 g, 2.7 mmol, 0.3 eq) and TEA (2.7 g, 27 mmol, 3 eq). The reaction was stirred for 4h at 110°C under N₂ atmosphere. The resulting mixture was cooled, quenched by water and extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/EtOAc (3:1) to afford methyl (2Z)-3-[3-cyano-1-(oxan-2-yl)indazol-6-yl]-2-fluoroprop-2-enoate (800 mg, 26% yield) as a white solid. LCMS (ES, m/z): 330 [M+H]⁺. Step 5. Preparation of (2Z)-N-(5-Chloro-2-methylpyridin-3-yl)-3-[3-cyano-1-(oxan-2-yl)indazol-6- yl]-2-fluoroprop-2-enamide (8)

A solution of methyl (2Z)-3-[3-cyano-1-(oxan-2-yl)indazol-6-yl]-2-fluoroprop-2-enoate (150 mg, 0.4 mmol) and 5-chloro-2-methylpyridin-3-amine (82 mg, 0.5 mmol, 1.2 eq) in THF (1.5 mL) was treated with 1M LiHMDS in THF (1.9 mL, 1.9 mmol, 4 eq) at -78°C. The reaction was stirred for 1h at -78°C under N2 atmosphere, then quenched by the addition of water (20 mL) at 0°C. The mixture was extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated to afford (2Z)-N-(5-chloro-2-methylpyridin-3-yl)-3-[3-cyano-1- (oxan-2-yl)indazol-6-yl]-2-fluoroprop-2-enamide (150 mg, crude) as a white solid. LCMS (ES, m/z): 440 [M+H]⁺. Step 6. Preparation of (2Z)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-cyano-1H-indazol-6-yl)-2- fluoroprop-2-enamide

To a solution of (2Z)-N-(5-chloro-2-methylpyridin-3-yl)-3-[3-cyano-1-(oxan-2-yl)indazol-6-yl]-2- fluoroprop-2-enamide (150 mg, 0.4 mmol) in DCM (1 mL) was added TFA (1 mL). The mixture was stirred for 2h at room temperature, then concentrated. The residue was dissolved in MeOH (2 mL) and basified with NH3•H2O. The mixture was purified by Prep-HPLC (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase: 24-49% MeCN / 10 mmol/L aqueous NH4HCO3 + 0.1% NH3•H2O over 7 min.; Flow rate: 30 mL/min) to afford (2Z)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-cyano-1H- indazol-6-yl)-2-fluoroprop-2-enamide (24 mg, 19% yield) as a white solid. LCMS (ES, m/z): 356 [M+H]⁺.¹H NMR (300 MHz, DMSO-d6, ppm) δ 14.59 (s, 1H), 10.38 (s, 1H), 8.45 (d, J = 2.3 Hz, 1H), 8.15 (s, 1H), 8.05-7.92 (m, 2H), 7.76 (dd, J = 8.7, 1.3 Hz, 1H), 7.32 (d, J = 38.1 Hz, 1H), 2.45 (s, 3H). Example 18: (2Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(3-methyl-1H-indazol-6-yl)prop-2- enamide Step 1: Preparation of 5-chloro-3-nitropyridine-2,4-diol (2)

To a cooled solution of gimeracil (2.0 g, 14 mmol) in concentrated H₂SO₄ (20 mL) was added concentrated HNO3 (1.7 g, 27 mmol, 2 eq) dropwise under 0°C. The mixture was stirred in the ice bath for 1h and then allowed to stir to room temperature over 1 h. The reaction was poured into ice-water, and stirred vigorously for 10 min. The precipitate was collected by filtration, washed with water and dried under vacuum to give 5-chloro-3-nitropyridine-2,4-diol (1.4 g, 53% yield) as light yellow solid. LCMS (ES, m/z): 191 [M+H]⁺. Step 2. Preparation of methyl 2,4,5-trichloro-3-nitropyridine (3)

A solution of 5-chloro-3-nitropyridine-2,4-diol (1.3 g, 6.8 mmol) in POCl3 (15 mL) was heated at reflux for 2h. The mixture was cooled and concentrated, and the residue suspended in saturated aq. NaHCO3. The mixture was extracted with EtOAc (3 x 10 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography, eluting with n-hexane/EtOAc (10:1) to afford 2,4,5-trichloro-3-nitropyridine (900 mg, 58% yield) as a pale yellow solid. LCMS (ES, m/z): 227, 229 [M+H]⁺. Step 3. Preparation of 5-chloro-2,4-dimethyl-3-nitropyridine (4)

To a solution of 2,4,5-trichloro-3-nitropyridine (0.90 g, 3.9 mmol) and trimethyl-1,3,5,2,4,6- trioxatriborinane (5.0 g, 40 mmol, 10 eq) in dioxane (9 mL) and water (1 mL) were added Cs₂CO₃ (3.9 g, 12 mmol, 3 eq) and Pd(dppf)Cl₂•DCM (0.64 g, 0.8 mmol, 0.2 eq). After stirring for 16h at 100°C under a nitrogen atmosphere, the mixture was cooled and quenched by water (20 mL), then extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/ EtOAc (5:1) to afford 5-chloro-2,4-dimethyl-3-nitropyridine (310 mg, 41% yield) as a brown solid. LCMS (ES, m/z): 187, 189 [M+H]⁺. Step 4. Preparation of 5-chloro-2,4-dimethylpyridin-3-amine (5)

A solution of 5-chloro-2,4-dimethyl-3-nitropyridine (0.31 g, 1.6 mmol) in EtOH (3 mL) was treated with SnCl₂ (0.95 g, 4.9 mmol, 3 eq) and stirred for 16h at 80°C. The mixture was cooled and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/EtOAc (10:1) to afford 5-chloro-2,4-dimethylpyridin-3-amine (260 mg, 99% yield) as a white solid. LCMS (ES, m/z): 157, 159 [M+H]⁺. Step 5. Preparation of (2Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(3-methyl-1H- indazol-6-yl)prop-2-enamide (6) A solution of 5-chloro-2,4-dimethylpyridin-3-amine (0.29 g, 1.8 mmol) and methyl (2Z)-2-fluoro-3-(3- methyl-1H-indazol-6-yl)prop-2-enoate (0.52 g, 2.2 mmol, 1.2 eq) in THF (3 mL) was treated dropwise with 1M LiHMDS in THF (2.7 mL, 2.7 mmol, 1.5 eq) at -78°C under N₂ atmosphere. The reaction mixture was stirred at -78°C for 10 min., then quenched with water/sat. NH₄Cl (3 mL). The mixture was extracted with ether/EtOAc (2 x 15 mL). The combined organics were washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by flash chromatography, eluting with n-hexane/EtOAc (3:1) to give (2Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(3-methyl-1H- indazol-6-yl)prop-2-enamide (190 mg, 28% yield) as a yellow solid. LCMS (ES, m/z): 443 [M+H]⁺. Step 6: Preparation of (2Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(3-methyl-1H- indazol-6-yl)prop-2-enamide

To a solution of (2Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-[3-methyl-1-(oxan-2-yl)indazol-6- yl]prop-2-enamide (0.19g, 0.4 mmol) in DCM (1 mL) was added TFA (1 mL). The mixture was stirred for 2h then concentrated. The residue was dissolved in MeOH (2 mL) and was basified with NH3·H2O. The mixture was purified by Prep-HPLC (Column: Welch Xtimate C18 ExRS, 250 mm, 10μm; Mobile Phase: 25-75% MeCN / 0.05% NH₃•H₂O over 10 min.; Flow rate: 90 mL/min) to afford (2Z)-N-(5- chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide (55 mg, 36% yield) as a white solid. LCMS (ES, m/z): 359 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆ ppm ) δ 12.86 (s, 1H), 10.37 (s, 1H), 8.46 (s, 1H), 7.86 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 8.4, 1.3 Hz, 1H), 7.20 (d, J = 38.8 Hz, 1H), 2.50 (s, 3H), 2.39 (s, 3H), 2.26 (s, 3H). Example 19: (2Z)-3-(3-Chloro-7-fluoro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3- yl)prop-2-enamide Step 1. Preparation of 6-bromo-3-chloro-7-fluoro-1H-indazole (2) To a stirred solution of 6-bromo-7-fluoro-1H-indazole (1.0 g, 4.7 mmol) in DMF (20 mL) was added NCS (0.93 g, 7 mmol, 1.5 eq) and the reaction stirred at 80°C for 1 h. The mixture was cooled and diluted with H₂O (20 mL), then extracted with EtOAc (3 x 20 mL). The combined organics were dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/AcOEt (10:1) to afford 6-bromo-3-chloro-7-fluoro-1H-indazole (0.80 g, 68% yield) as a yellow solid. LCMS (ES, m/z): 249, 251 [M+H]⁺. Step 2. Preparation of 6-bromo-3-chloro-7-fluoro-1-(oxan-2-yl)indazole (3)

To a stirred solution of 6-bromo-3-chloro-7-fluoro-1H-indazole (0.80 g, 3.2 mmol) in THF (16 mL) was added PPTS (0.24 g, 0.96 mmol, 0.3 eq) and DHP (1.6g, 19 mmol, 6 eq). The reaction was stirred at 70°C for 4 h, then cooled and diluted with saturated brine (20 mL) and saturated aqueous NaHCO₃ (5 mL). The mixture was extracted with CH₂Cl₂ (3 x 20 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with petroleum ether: ethyl acetate (3:1) to afford 6-bromo-3-chloro-7-fluoro-1-(oxan-2- yl)indazole (0.70 g, 65% yield) as a white solid. LCMS (ES, m/z): 333, 335 [M+H]⁺. Step 3. Preparation of methyl (2Z)-3-[3-chloro-7-fluoro-1-(oxan-2-yl)indazol-6-yl]-2-fluoroprop- 2-enoate (5)

To a stirred solution of 6-bromo-3-chloro-7-fluoro-1-(oxan-2-yl)indazole (0.50 g, 1.5 mmol) and TEA (0.45 g, 4.5 mmol, 3 eq) in DMF (10 mL) were added methyl 2-fluoroacrylate (0.46 g, 4.5 mmol, 3 eq) and Pd(dppf)Cl₂ (0.10g, 0.1 mmol, 0.1 eq) under nitrogen atmosphere. The reaction was stirred at 100°C for 12 h, then cooled and diluted with water (10 mL). The mixture was extracted with EtOAc (3 x 20 mL). The combined organics were washed with water (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with Petroleum ether/THF (12:1) to afford methyl (2Z)-3-[3-chloro-7-fluoro-1-(oxan-2-yl)indazol-6-yl]-2-fluoroprop-2- enoate (0.15 g, 30% yield) as a yellow solid. LCMS (ES, m/z): 357 [M+H]⁺. Step 4: Preparation of (2Z)-3-[3-chloro-7-fluoro-1-(oxan-2-yl)indazol-6-yl]-2-fluoro-N-(5-fluoro- 2,4-dimethylpyridin-3-yl)prop-2-enamide (7)

To a stirred solution of methyl (2Z)-3-[3-chloro-7-fluoro-1-(oxan-2-yl)indazol-6-yl]-2-fluoroprop-2- enoate (0.15 g, 0.42 mmol) and 5-fluoro-2,4-dimethylpyridin-3-amine (the product of Example 1 step 2) (0.07 g, 0.5 mmol, 1.2 eq) in THF (3 mL) was added 1M LiHMDS in THF (0.84 mL, 0.84 mmol, 2 eq) dropwise at -30°C. The reaction was stirred for 30 min., then quenched at 0°C by the addition of sat. NH₄Cl (aq.) (10 mL). The mixture was extracted with EtOAc (3 x 10 mL). The combined organics were washed with water (20 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with Petroleum ether/THF (1:1) to afford (2Z)-3- [3-chloro-7-fluoro-1-(oxan-2-yl)indazol-6-yl]-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2- enamide (0.18 g, 92% yield) as a yellow solid. LCMS (ES, m/z): 465 [M+H]⁺. Step 5. Preparation of (2Z)-3-(3-chloro-7-fluoro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4- dimethylpyridin-3-yl)prop-2-enamide

To a stirred solution of (2Z)-3-[3-chloro-7-fluoro-1-(oxan-2-yl)indazol-6-yl]-2-fluoro-N-(5-fluoro-2,4- dimethylpyridin-3-yl)prop-2-enamide (0.18 g, 0.38 mmol) in DCM (4 mL) was added TFA (2 mL). The mixture was stirred for 1 h, then concentrated. The residue was dissolved into MeOH (2 mL) and basified with saturated NaHCO3 (aq.). The mixture was purified by Prep-HPLC with the following conditions (Column: Xbridge C18, 19*150 mm, 5 μm; Mobile Phase: 5-95% mEcn / 0.05% NH3•H2O over 15 min.; Flow rate: 80 mL/min.) to afford (2Z)-3-(3-chloro-7-fluoro-1H-indazol-6-yl)-2-fluoro-N-(5- fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide (36 mg, 24% yield) as a white solid. LCMS (ES, m/z): 381 [M+H]⁺.¹H NMR (300 MHz, DMSO-d6, ppm) δ 14.10 (s, 1H), 10.50 (s, 1H), 8.40 (s, 1H), 7.96- 7.57 (m, 2H), 7.26 (d, J = 37.1 Hz, 1H), 2.38 (d, J = 1.1 Hz, 3H), 2.16 (d, J = 1.9 Hz, 3H). Example 20: (2Z)-3-(3-cyano-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2- enamide Step 1. Preparation of (2Z)-3-[3-cyano-1-(oxan-2-yl)indazol-6-yl]-2-fluoro-N-(5-fluoro-2,4- dimethylpyridin-3-yl)prop-2-enamide (2) To a solution of methyl (2Z)-3-[3-cyano-1-(oxan-2-yl)indazol-6-yl]-2-fluoroprop-2-enoate (the product of Example 17 step 4) (150 mg, 0.5 mmol) and 5-fluoro-2,4-dimethylpyridin-3-amine (the product of Example 1 step 2) (80 mg, 0.5 mmol, 1.2 eq) in THF (1.5 mL) at -78°C was added 1M LiHMDS in THF (320 mg, 1.9 mmol, 4 eq) dropwise. The reaction was stirred for 1h at -78°C under N2 atmosphere, then quenched by the addition of water (10 mL) at 0°C. The mixture was extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated to afford (2Z)-3-[3-cyano-1-(oxan-2-yl)indazol-6-yl]-2-fluoro-N-(5-fluoro-2,4- dimethylpyridin-3-yl)prop-2-enamide (149 mg, crude) as a white solid. LCMS (ES, m/z): 438 [M+H]⁺. Step 2. Preparation of (2Z)-3-(3-cyano-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4- dimethylpyridin-3-yl)prop-2-enamide

A solution of (2Z)-3-[3-cyano-1-(oxan-2-yl)indazol-6-yl]-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3- yl)prop-2-enamide (149 mg, 0.3 mmol) in DCM (1 mL) was treated with TFA (1 mL). The mixture was stirred for 2h at room temperature, then concentrated. The residue was dissolved in MeOH (2 mL) and basified with NH₃•H₂O. The mixture was purified by Prep-HPLC (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase: 24-49% MeCN / 10 mmol/L aqueous NH₄HCO₃ + 0.1% NH₃•H₂O over 7 min.; Flow rate: 30 mL/min.) to afford (2Z)-3-(3-cyano-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4- dimethylpyridin-3-yl)prop-2-enamide (18 mg, 15% yield) as a white solid. LCMS (ES, m/z): 354 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d6, ppm) δ 14.54 (brs, 1H), 10.40 (s, 1H), 8.37 (s, 1H), 8.12 (s, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.27 (d, J = 38.3 Hz, 1H), 2.36 (s, 3H), 2.14 (s, 3H). Example 21: (2Z)-N-(2,5-dimethylpyridin-3-yl)-3-(3-cyano-1H-indazol-6-yl)-2-fluoroprop-2-enamide) Step 1. Preparation of (2Z)-3-[3-cyano-1-(oxan-2-yl)indazol-6-yl]-N-(2,5-dimethylpyridin-3-yl)-2- fluoroprop-2-enamide (2) To a solution of 6-[(1Z)-2-fluoro-3-oxobut-1-en-1-yl]-1-(oxan-2-yl)indazole-3-carbonitrile (the product of Example 17 step 4) (150 mg, 0.4 mmol) and 2,5-dimethylpyridin-3-amine (70 mg, 0.6 mmol, 1.2 eq) in THF (1.5 mL) was added 1M LiHMDS in THF (320 mg, 1.9 mmol, 4 eq) dropwise at -78°C. The reaction was stirred for 1h at -78°C under N₂ atmosphere, then quenched by the addition of water (20 mL) at 0°C. The mixture was extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated to afford (2Z)-3-[3-cyano-1-(oxan- 2-yl)indazol-6-yl]-N-(2,5-dimethylpyridin-3-yl)-2-fluoroprop-2-enamide (150 mg, crude) as a white solid. LCMS (ES, m/z): 420 [M+H]⁺. Step 2. Preparation of (2Z)-N-(2,5-dimethylpyridin-3-yl)-3-(3-cyano-1H-indazol-6-yl)-2- fluoroprop-2-enamide

A solution of (2Z)-3-[3-cyano-1-(oxan-2-yl)indazol-6-yl]-N-(2,5-dimethylpyridin-3-yl)-2-fluoroprop-2- enamide (150 mg, 0.4 mmol) in DCM (1 mL) and TFA (1 mL) was stirred for 2h, then concentrated. The residue was dissolved in MeOH (2 mL) and basified with NH3•H2O. The mixture was purified by Prep-HPLC (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase: 24-49% MeCN / 10 mmol/L aqueous NH₄HCO₃ + 0.1% NH₃•H₂O over 7 min.; Flow rate: 30 mL/min) to afford (2Z)-N-(2,5- dimethylpyridin-3-yl)-3-(3-cyano-1H-indazol-6-yl)-2-fluoroprop-2-enamide) (20 mg, 17% yield) as a white solid. LCMS (ES, m/z): 336 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆, ppm) δ14.49 (brs, 1H), 10.22 (s, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.25 (d, J = 38.2 Hz, 1H), 2.37 (s, 3H), 2.28 (s, 3H). Example 22: (2Z)-3-(3-chloro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2- enamide Step 1. Preparation of 6-bromo-3-chloro-1H-indazole (2) A solution of 6-bromo-1H-indazole (3.0 g, 15 mmol) and NCS (2.4 g, 18 mmol, 1.2 eq) in DCM (30 mL) was stirred for 5 h at 40°C. The reaction was cooled to 0°C and quenched by the addition of saturated aqueous sodium thiosulfate solution (15 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine (3 x 20 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/AcOEt (1:1) to afford 6-bromo-3-chloro-1H-indazole (2.4 g, 68% yield) as a yellow solid. LCMS (ES, m/z): 231, 233 [M+H]⁺. Step 2. Preparation of 6-bromo-3-chloro-1-(oxan-2-yl) indazole (3)

To a stirred solution of 6-bromo-3-chloro-1H-indazole (2.4 g, 10 mmol) and DHP (1.7 g, 21 mmol, 2 eq) in DCM (25 mL) was added TsOH•H₂O (0.99 g, 5.2 mmol, 0.5 eq) at 0°C. The resulting mixture was stirred for 2h at room temperature, then concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/AcOEt (1:1) to afford 6-bromo-3-chloro-1-(oxan-2-yl) indazole (2.0 g, 61% yield) as a white solid. LCMS (ES, m/z): 315, 317 [M+H]⁺. Step 3. Preparation of methyl (2Z)-3-[3-chloro-1-(oxan-2-yl)indazol-6-yl]-2-fluoroprop-2-enoate (4)

A solution of 6-bromo-3-chloro-1-(oxan-2-yl) imidazole (1.0 g, 3.2 mmol), methyl 2-fluoroacrylate (0.36 g, 3.5 mmol, 1.1 eq), TEA (0.96 g, 9.5 mmol, 3 eq) and Pd(dppf)Cl₂ (0.26 g, 0.3 mmol, 0.1 eq) in DMF (15 mL) was stirred for 1.5h at 110°C under nitrogen atmosphere. The resulting mixture was cooled and extracted with EtOAc (3 x 50 mL). The combined organics were washed with water (2 x 30 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with n-hexane/AcOEt (4:1) to afford methyl (2Z)-3-[3-chloro-1-(oxan-2-yl) indazol-6-yl]-2-fluoroprop-2-enoate (600 mg, 55% yield) as a green solid. LCMS (ES, m/z): 339 [M+H]⁺. Step 4. Preparation of (2Z)-3-[3-chloro-1-(oxan-2-yl)indazol-6-yl]-2-fluoro-N-(5-fluoro-2,4- dimethylpyridin-3-yl)prop-2-enamide (5)

To a stirred solution of methyl (2Z)-3-[3-chloro-1-(oxan-2-yl) indazol-6-yl]-2-fluoroprop-2-enoate (200 mg, 0.6 mmol) and 5-fluoro-2,4-dimethylpyridin-3-amine (the product of Example 1 step 2) (91 mg, 0.6 mmol, 1.1 eq) in THF (4 mL) was added 1M LiHMDS in THF (1.8 mL, 1.8 mmol, 3 eq) dropwise at - 30°C under nitrogen atmosphere. The reaction was stirred for 1h at -30°C then quenched at 0°C by the addition of sat. aqueous NH₄Cl solution (4 mL). The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organics were washed with brine (3 x 2 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with n- hexane/AcOEt to afford (2Z)-3-[3-chloro-1-(oxan-2-yl)indazol-6-yl]-2-fluoro-N-(5-fluoro-2,4- dimethylpyridin-3-yl)prop-2-enamide (120 mg, 45% yield) as a green solid. LCMS (ES, m/z): 447 [M+H]⁺. Step 5. Preparation of (2Z)-3-(3-chloro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4- dimethylpyridin-3-yl) prop-2-enamide

To a stirred solution of (2Z)-3-[3-chloro-1-(oxan-2-yl)indazol-6-yl]-2-fluoro-N-(5-fluoro-2,4- dimethylpyridin-3-yl)prop-2-enamide (120 mg, 0.3 mmol) in DCM (2 mL) was added TFA (1 mL) dropwise at room temperature. The resulting mixture was stirred for 2h, then concentrated. The residue was dissolved into 2 mL MeOH and was basified with saturated NaHCO3 (aq.). The mixture was purified by Pre-HPLC (Xbridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase: 0-100% MeCN / 10 mmol/L aqueous NH4HCO3 solution; Flow rate: 25 mL/min; detector, UV 254 nm) to afford (2Z)-3-(3-chloro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide (20 mg, 21% yield) as a white solid. LCMS (ES, m/z): 363 [M+H] ⁺.¹H NMR: (400 MHz, DMSO-d6, ppm) δ 13.51 (s, 1H), 10.40 (s, 1H), 8.39 (s, 1H), 7.97 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.61 (dd, J = 8.6, 1.3 Hz, 1H), 7.26 (d, J = 38.3 Hz, 1H), 2.38 (s, 3H), 2.16 (s, 3H). Example 23: (Z)-2-fluoro-3-(7-methoxy-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3- yl)acrylamide

Prepared using a similar approach as for Example 16. Step 1. Preparation of 6-Bromo-7-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2)

A solution of 6-bromo-7-methoxy-1H-indazole (0.40 g, 1.7 mmol), DHP (0.29 g, 3.5 mmol, 2 eq) and TsOH^.H₂O (67 mg, 0.3 mmol, 0.2 eq) in DCM (5 mL) was stirred for 2 h then concentrated. The residue was purified by silica chromatography, eluting with petroleum ether/ethyl acetate (5:1) to afford 6- bromo-7-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.40 g, 72% yield) as a brown solid. LCMS (ES, m/z): 311 [M+H]⁺ Step 2. Preparation of Methyl (Z)-2-fluoro-3-(7-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-6-yl)acrylate (3)

A solution of 6-bromo-7-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.40 g, 1.2 mmol), methyl 2-fluoroacrylate (0.40 g, 3.8 mmol, 3 eq), Pd(dtbpf)Cl2 (0.25 g, 0.3 mmol, 0.3 eq) and TEA (0.39 g, 3.8 mmol, 3 eq) in DMF (5 mL) was stirred for 2 h at 110°C under nitrogen atmosphere, then cooled. The reaction was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (3 x 100 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica chromatography, eluting with petroleum ether/ethyl acetate (1:1) to afford methyl (Z)-2-fluoro-3-(7-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (0.30 g, 69% yield) as a brown solid. LCMS (ES, m/z): 335 [M+H]⁺ Step 3. Preparation of (Z)-2-Fluoro-3-(7-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)- To a solution of methyl (Z)-2-fluoro-3-(7-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6- yl)acrylate (100 mg, 0.2 mmol) and 6-methoxy-2,4-dimethylpyridin-3-amine (54 mg, 0.3 mmol, 1.2 eq) in THF (2 mL) was added 1M LiHMDS in THF (0.6 mL, 0.6 mmol, 3 eq) at -78°C. The reaction mixture was stirred for 1 h at -78°C, then quenched with sat. aq. NH₄Cl solution (5 mL). The aqueous layer was extracted with EtOAc (3 x 5 mL). The combined organics were dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica chromatography, eluting with petroleum ether/ethyl acetate (1:1) to afford (Z)-2-fluoro-3-(7-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-(6- methoxy-2,4-dimethylpyridin-3-yl)acrylamide (80 mg, 58% yield) as a light yellow solid. LCMS (ES, m/z): 455 [M+H]⁺ Step 4. Preparation of (Z)-2-Fluoro-3-(7-methoxy-1H-indazol-6-yl)-N-(6-methoxy-2,4- dimethylpyridin-3-yl)acrylamide

(Z)-2-Fluoro-3-(7-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-(6-methoxy-2,4- dimethylpyridin-3-yl) acrylamide (80 mg, 0.1 mmol) in DCM (1 mL) was treated with 4N HCl in 1,4- dioxane (1 mL) and stirred for 1 h at room temperature. The resulting mixture was concentrated. The residue was dissolved in MeOH (3 mL) and purified by reverse phase chromatography with the following conditions (Column: Ultimate XB-C18, 30*250, 10um; Mobile Phase: 10-45% MeCN / 10mmol/L aqueous NH4HCO3 solution containing 0.1%NH3^.H2O over 20 min.; Flow rate: 60 mL/min mL/min; Wavelength: 254 nm /220 nm; Rt 14 min.) Concentration of the appropriate fractions gave (Z)-2-fluoro-3-(7-methoxy-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide (60 mg, 91% yield) as a white solid. LCMS (ES, m/z): 371 [M+H]⁺ ¹H NMR (400 MHz, DMSO-d₆, ppm): δ 13.54 (s, 1H), 9.98 (s, 1H), 8.17 (s, 1H), 7.58 (s, 2H), 7.35 (d, J = 39.4 Hz, 1H), 6.61 (s, 1H), 4.06 (s, 3H), 3.83 (s, 3H), 2.29 (s, 3H), 2.15 (s, 3H) Example 24: (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(2,4,5-trimethylpyridin-3-yl)acrylamide Prepared using a similar approach as for Example 16. Example 25: (Z)-2-fluoro-3-(7-methoxy-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)acrylamide

Prepared using a similar approach as for Example 23. Example 26: (E)-N-(4-(difluoromethyl)-5-fluoro-2-methylpyridin-3-yl)-3-(1H-indazol-6-yl)acrylamide Step 1. Preparation of Tert-butyl N-(2-chloro-5-fluoropyridin-3-yl)carbamate

To a stirred solution of 2-chloro-5-fluoropyridin-3-amine (4.0 g, 27 mmol) and BOC₂O (6.0 g, 27 mmol, 1 eq) in THF (40 mL) was added 1M LiHMDS in THF (109 mL, 109 mmol, 4 eq) dropwise at 0°C. The reaction mixture was stirred for 4 h at room temperature, then quenched by water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (3:1) to afford tert-butyl N-(2-chloro-5- fluoropyridin-3-yl)carbamate (2.4 g, 35% yield) as a light brown solid. LCMS (ES, m/z): 247 [M+H]⁺ Step 2. Preparation of 3-Amino-2-chloro-5-fluoropyridine-4-carbaldehyde

A solution of tert-butyl N-(2-chloro-5-fluoropyridin-3-yl)carbamate (2, 1.5 g, 6.0 mmol) in THF (20 mL) was treated with 1.6 M n-BuLi in hexanes (7.6 mL, 12 mmol, 2 eq) for 30 min at -78°C under nitrogen atmosphere, followed by the addition of DMF (0.88 g, 12 mmol, 2 eq) dropwise at -78°C. The cooling bath was removed and the mixture allowed to stir to RT over 2 h. The reaction was quenched with sat. NH₄Cl (aq.) (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated. The crude product was used in the next step directly without further purification. LCMS (ES, m/z): 175 [M+H]⁺ Step 3. Preparation of 2-Chloro-4-(difluoromethyl)-5-fluoropyridin-3-amine (4)

A solution of 3-amino-2-chloro-5-fluoropyridine-4-carbaldehyde (1.5 g, 8.5 mmol) in DCM (15 mL) was treated dropwise with DAST (2.8 g, 17 mmol, 2 eq) at -78°C. The reaction mixture was stirred overnight at room temperature, then quenched with saturated NaHCO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (4:1) to afford 2-chloro-4-(difluoromethyl)- 5-fluoropyridin-3-amine (0.20 g, 11% yield) as a brown oil. LCMS (ES, m/z): 197 [M+H]⁺ Step 4. Preparation of 4-(Difluoromethyl)-5-fluoro-2-methylpyridin-3-amine (5)

A solution of 2-chloro-4-(difluoromethyl)-5-fluoropyridin-3-amine (0.18 g, 0.9 mmol), trimethyl- 1,3,5,2,4,6-trioxatriborinane (1.1 g, 9.1 mmol, 10 eq), Pd(dppf)Cl₂ (0.22 g, 0.2 mmol, 0.3 eq) and Cs₂CO₃ (0.89 g, 2.7 mmol, 3 eq) in dioxane (2 mL) and H₂O (0.2 mL) was stirred for 4 h at 100°C under nitrogen atmosphere. The resulting mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (3:1) to afford 4-(difluoromethyl)-5-fluoro-2-methylpyridin-3-amine (0.10 g, 62% yield) as a brown oil. LCMS (ES, m/z): 177 [M+H]⁺ Step 5. Preparation of N-[4-(Difluoromethyl)-5-fluoro-2-methylpyridin-3-yl]prop-2-enamide (6) A solution of 4-(difluoromethyl)-5-fluoro-2-methylpyridin-3-amine (80 mg, 0.4 mmol) and TEA (0.22 g, 2.2 mmol, 5 eq) in DCM (2 mL) was treated with acryloyl chloride (82 mg, 0.9 mmol, 2 eq) at 0°C. The reaction mixture was stirred for 2 h at room temperature, then concentrated. The residue was purified by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (1:1) to afford N-[4- (difluoromethyl)-5-fluoro-2-methylpyridin-3-yl]prop-2-enamide (70 mg, 66% yield) as a light yellow solid. LCMS (ES, m/z): 231 [M+H]⁺ Step 6. Preparation of (2E)-N-[4-(Difluoromethyl)-5-fluoro-2-methylpyridin-3-yl]-3-[1-(oxan-2- yl)

A solution of N-[4-(difluoromethyl)-5-fluoro-2-methylpyridin-3-yl]prop-2-enamide (65 mg, 0.2 mmol) , 6-bromo-1-(oxan-2-yl)indazole (79 mg, 0.2 mmol, 1 eq), Pd(dppf)Cl2 (69 mg, 0.08 mmol, 0.3 eq) and TEA (85 mg, 0.8 mmol, 3 eq) in DMF (2 mL) was stirred for 1 h at 100°C under nitrogen atmosphere. The resulting mixture was quenched by water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (50mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (1:1) to afford (2E)-N-[4-(difluoromethyl)-5-fluoro-2-methylpyridin-3-yl]-3-[1-(oxan-2- yl)indazol-6-yl]prop-2-enamide (60 mg, 49% yield) as a white solid. LCMS (ES, m/z): 431 [M+H]⁺ Step 7. Preparation of (E)-N-(4-(difluoromethyl)-5-fluoro-2-methylpyridin-3-yl)-3-(1H-indazol-6- yl)acrylamide

A solution of (2E)-N-[4-(difluoromethyl)-5-fluoro-2-methylpyridin-3-yl]-3-[1-(oxan-2-yl)indazol-6- yl]prop-2-enamide (55 mg, 0.1 mmol, 1 eq) in DCM (1 mL) and trifluoroacetaldehyde (1 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The mixture was dissolved with MeOH (5 mL) and adjusted to PH=7 with NH3•H2O. The crude product was purified by Prep-HPLC (Column: XBridge C18, 19*150 mm, 5 μm; Mobile Phase: 10-65% MeCN / 20 mM NH4HCO3 containing 0.05% NH3•H2O over 8 min.; Flow rate: 60 mL/min.) to afford (E)-N-(4- (difluoromethyl)-5-fluoro-2-methylpyridin-3-yl)-3-(1H-indazol-6-yl)acrylamide (16 mg, 35% yield) as a white solid. LCMS (ES, m/z): 347.1 [M+H]⁺ ¹H NMR: (400 MHz, DMSO-d₆, ppm) δ 13.27 (s, 1H), 10.17 (s, 1H), 8.60 (s, 1H), 8.10 (s, 1H), 7.85- 7.73 (m, 3H), 7.43 (d, J = 8.5 Hz, 1H), 7.19-6.91 (m, 2H), 2.41 (s, 3H). Example 27: (Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)acrylamide Step 1. Preparation of (2Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-[7-fluoro-1-(oxan-2- yl)indazol-6-yl]prop-2-enamide (3)

To a stirred solution of methyl (2Z)-2-fluoro-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (0.20 g, 0.6 mmol) and 5-chloro-2,4-dimethylpyridin-3-amine (0.11 g, 0.7 mmol, 1.2 eq) in THF (2 mL) was added 1M LiHMDS in THF (2.4 mL, 2.4 mmol, 4 eq) dropwise at -78°C. The mixture was stirred at - 78 °C for 20 min., then extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (1:1) to afford (2Z)-N-(5- chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (160 mg, 57% yield) as a yellow solid. LCMS-3 (ES, m/z): 447 [M+H]⁺. Step 2. Preparation of (Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-1H-indazol- 6-yl)acrylamide

A solution of (2Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-[7-fluoro-1-(oxan-2-yl)indazol-6- yl]prop-2-enamide (120 mg, 0.2 mmol) in DCM (1 mL) was treated with 4N HCl (gas) in 1,4-dioxane (1.0 mL) and stirred for 1 h at room temperature. The resulting mixture was concentrated and the crude product purified by Prep-HPLC with the following conditions (Column: XBridge Prep C18 Column, 30*150 mm, 5μm; Mobile Phase: 30-50% MeCN / 0.1% aqueous NH3 over 10 min.; Flow rate: 60mL/min.) to afford (Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-1H-indazol-6- yl)acrylamide (35 mg, 36% yield) as a white solid. LCMS (ES, m/z): 363 [M+H]⁺ ¹H NMR (400 MHz, DMSO-d₆, ppm) δ 13.86 (s, 1H), 10.48 (s, 1H), 8.44 (s, 1H), 8.27-8.17 (m, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.56 (dd, J = 8.5, 5.8 Hz, 1H), 7.25 (d, J = 37.5 Hz, 1H), 2.37 (s, 3H), 2.24 (s, 3H). Example 28: (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)acrylamide Step 1. Preparation of 4-Bromo-5-fluoro-N-methyl-2-nitroaniline (2)

A solution of 4-bromo-5-fluoro-2-nitroaniline (1.0 g, 4.3 mmol) in DMF (10 mL) was treated with NaH (0.20 g, 8.5 mmol, 2 eq) for 30 min at 0°C under nitrogen atmosphere, followed by the addition of CH3I (0.72 g, 5.1 mmol, 1.2 eq) dropwise at 0°C. The reaction mixture was stirred for 30 min at 0°C, then quenched with sat. NH4Cl (aq.). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with Petroleum ether/EtOAc (5:1) to afford 4-bromo-5-fluoro-N-methyl-2-nitroaniline (510 mg, 48% yield) as an off-white solid. LCMS (ES, m/z): 249 [M+H]⁺ Step 2. Preparation of 4-Bromo-5-fluoro-N-methylbenzene-1,2-diamine (3)

To 4-bromo-5-fluoro-N-methyl-2-nitroaniline (570 mg, 2.3 mmol) in EtOH (12 mL) was added Zn (0.75 g, 11 mmol, 5 eq) and acetic acid (1.1 g, 18 mmol, 8 eq) at room temperature. The reaction mixture was stirred for 2 h at 50°C, then cooled and filtered, the filter cake being washed with MeOH (3 x 20 mL). The filtrate was concentrated and the residue purified by silica gel column chromatography, eluting with Petroleum ether/EtOAc (3:1) to afford 4-bromo-5-fluoro-N1-methylbenzene-1,2-diamine (360 mg, 72% yield) as a reddish brown solid. LCMS (ES, m/z): 219 [M+H]⁺ Step 3. Preparation of 5-Bromo-6-fluoro-1-methyl-3H-1,3-benzodiazol-2-one (4)

To a stirred solution of 4-bromo-5-fluoro-N1-methylbenzene-1,2-diamine (350 mg, 1.6 mmol) and TEA (485 mg, 4.8 mmol, 3 eq) in THF (3 mL) was added triphosgene (1.4 g, 4.8 mmol, 3 eq) in portions at 0°C. The reaction mixture was stirred overnight at room temperature then quenched with sat. NH4Cl (aq.) at 0°C. The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluting with Petroleum ether/EtOAc (1:1) to afford 5-bromo-6-fluoro-1-methyl-3H-1,3- benzodiazol-2-one (250 mg, 64% yield) as an off-white solid. LCMS (ES, m/z): 245 [M+H]⁺ Step 4. Preparation of Methyl (2E)-3-(6-fluoro-1-methyl-2-oxo-3H-1,3-benzodiazol-5-yl)prop-2- enoate (5)

To 5-bromo-6-fluoro-1-methyl-3H-1,3-benzodiazol-2-one (300 mg, 1.2 mmol) in DMF (3 mL) was added Pd(dppf)Cl2 (270 mg, 0.4 mmol, 0.3 eq), methyl acrylate (1.3 g, 1.5 mmol, 1.2 eq) and TEA (370 mg, 3.7 mmol, 3 eq) at room temperature. The reaction mixture was stirred for 2 h at 110°C under nitrogen atmosphere, then cooled and filtered. The residue was extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with CH₂Cl₂ / MeOH (5:1) to afford methyl (2E)-3-(6-fluoro-1-methyl-2-oxo-3H-1,3-benzodiazol-5-yl)prop-2-enoate (230 mg, 75% yield) as a reddish brown solid. LCMS (ES, m/z): 251 [M+H]⁺ Step 5. Preparation of (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(6-fluoro-1-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)acrylamide

To a stirred solution of methyl (2E)-3-(6-fluoro-1-methyl-2-oxo-3H-1,3-benzodiazol-5-yl)prop-2-enoate (170 mg, 0.7 mmol) and 5-chloro-2-methylpyridin-3-amine (116 mg, 0.8 mmol, 1.2 eq) in THF (3 mL) was added 1M LiHMDS in THF (2.7 mL, 2.7 mmol, 4 eq) dropwise at -78°C under nitrogen atmosphere. The reaction mixture was stirred for 1 h at -78°C under nitrogen atmosphere, then quenched with MeOH at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography with the following conditions: column: Xbridge Prep C185μm OBD 30*150mm Column; Mobile Phase: 30-65% MeCN / 10 mmol/L aqueous NH₄HCO₃ solution containing 0.05% NH₃ over 10 min_.; Flow rate: 45 mL/min.; Wavelength: 254nm/220nm nm; Rt 8.63). Concentration of the relevant fractions gave (E)-N-(5-chloro- 2-methylpyridin-3-yl)-3-(6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide (16 mg, 6.7% yield) as an off-white solid. LCMS (ES, m/z): 361 [M+H]⁺ ¹H NMR: (400 MHz, DMSO-d6, ppm) δ 8.26 (s, 2H), 7.89 (d, J = 15.8 Hz, 1H), 7.31 (d, J = 6.0 Hz, 1H), 7.05 (d, J = 10.6 Hz, 1H), 6.93 (d, J = 15.7 Hz, 1H), 3.39 (s, 3H), 2.52 (s, 3H). Example 29: (Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(7-fluoro-2-oxoindolin-6- yl)acrylamide Step 1. Preparation of (2E)-N-(3-Bromo-2-fluorophenyl)-2-(N-hydroxyimino)acetamide (2)

To 3-bromo-2-fluoroaniline (1 g, 5.3 mmol) in dioxane (3 mL) and H2O (24.4 mL) at 50°C was added chloral hydrate (1.4 g, 8.2 mmol, 1.6 eq), Na2SO4 (10.5 g, 74 mmol, 14 eq), 6M aqueous HCl (1.5 mL) and H₂O (24.4 mL). To this was added NH₂OH·HCl (1.7 g, 24 mmol, 4.6 eq) in H₂O (24.4 mL) and the reaction mixture was heated to 80°C for 1 h. After cooling, the precipitated solids were collected by filtration and washed with H₂O (3 x 30 mL) and air dried to give (2E)-N-(3-bromo-2-fluorophenyl)-2-(N- hydroxyimino)acetamide (1.2 g, 87% yield) as a yellow green solid. LCMS (ES, m/z): 261 [M+H]⁺ Step 2. Preparation of 6-Bromo-7-fluoro-1H-indole-2,3-dione (3)

To (2E)-N-(3-bromo-2-fluorophenyl)-2-(N-hydroxyimino)acetamide (1.1 g, 4.2 mmol) was added c.H₂SO₄ (10 mL) and the mixture heated at 90°C for 1h, then cooled. The reaction was quenched with ice water and the solid formed removed by filtration, the filter cake being washed with water (3 x 5 mL). Air drying gave 6-bromo-7-fluoro-1H-indole-2,3-dione (500 mg, 49% yield) as a red solid. LCMS (ES, m/z): 244 [M+H]⁺ Step 3. Preparation of 6-Bromo-7-fluoro-1,3-dihydroindol-2-one (4)

A solution of 6-bromo-7-fluoro-1H-indole-2,3-dione (490 mg, 2 mmol) in EtOH (8.5 mL) was treated with NH2NH2·H2O (0.05 mL, 1 mmol, 0.5 eq) and stirred for 30 min. at 90 °C. After cooling, the precipitated solids were collected by filtration. The collected solids were treated with t-BuOK (685 mg, 6.1 mmol, 3.1 eq) in EtOH (8.5 mL) and stirred for 1 h at 90°C. The resulting mixture was extracted with EtOAc (3 x 15mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to afford 6-bromo-7-fluoro-1,3- dihydroindol-2-one (200 mg, 43% yield) as a yellow solid. LCMS (ES, m/z): 230 [M+H]⁺ Step 4. Preparation of (Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(7-fluoro-2- oxoindolin-6-yl)acrylamide

To a stirred solution of 6-bromo-7-fluoro-1,3-dihydroindol-2-one (100 mg, 0.44 mmol) and TEA (132 mg, 1.3 mmol, 3 eq) in DMF (6 mL) were added 2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2- enamide (92 mg, 0.44 mmol, 1 eq) and Pd(dtbpf)Cl2 (85 mg, 0.13 mmol, 0.3 eq). The reaction mixture was stirred for 3h at 110°C under nitrogen atmosphere, then cooled and quenched with water (80mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na₂SO₄ and concentrated. The crude product was purified by Prep-HPLC with the following conditions (Column: Uitimate - XT-C18 Column, 30*150 mm, 10μm; Mobile Phase: 30-60% MeCN / 0.05% aqueous NH₃.H₂O; Flow rate: 35 mL/min; Wavelength: 254nm/220nm nm; Rt 8.2 min.). Concentration of the appropriate fractions gave (Z)-2- fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(7-fluoro-2-oxoindolin-6-yl)acrylamide (2.9 mg, 1.8% yield) as a white solid. LCMS (ES, m/z): 362 [M+H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.40 (s, 1H), 8.36 (s, 1H), 7.43 (t, J = 7.1 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 7.07 (d, J = 37.4 Hz, 1H), 3.61 (s, 2H), 2.34 (s, 3H), 2.12 (s, 3H). Example 30: (Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(1H-pyrazolo[3,4-b]pyridin-6- yl)acrylamide Step 1. Preparation of 6-Chloro-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine

To a solution of 6-chloro-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine (1.0 g, 4.2 mmol) in dioxane (20 mL) was added methyl 2-fluoroacrylate (0.53 g, 5.0 mmol, 1.2 eq) and tri-tert-butylphosphane (0.43 g, 2.1 mmol, 0.5 eq). The mixture was degassed with nitrogen before N-cyclohexyl-N-methylcyclohexanamine (0.90 g, 4.6 mmol, 1.1 eq) and Pd2(dba)3 (0.58 g, 0.63 mmol, 0.15 eq) were added. The reaction mixture was stirred for 12 h at 100 °C, then cooled and concentrated. The residue was purified by reverse phase flash with the following conditions: column, C18; Mobile Phase: 25-75% MeCN / 0.1% aqueous NH₄HCO₃ solution over 30 min.; Flow rate: 100 mL/min; Wavelength: 210 nm; Rt 22 min. Concentration of the appropriate fractions gave methyl (2Z)-2-fluoro-3-[1-(oxan-2-yl)pyrazolo[3,4- b]pyridin-6-yl]prop-2-enoate (200 mg, 16% yield) as a yellow solid. Step 2. Preparation of Methyl (2Z)-2-fluoro-3-[1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-6-yl]prop-2- enoate (2)

To a solution of 6-chloro-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine (1.0 g, 4.2 mmol) in dioxane (20 mL) was added methyl 2-fluoroacrylate (0.53 g, 5.0 mmol, 1.2 eq) and tri-tert-butylphosphane (0.43 g, 2.1 mmol, 0.5 eq). The mixture was degassed with nitrogen before N-cyclohexyl-N-methylcyclohexanamine (0.90 g, 4.6 mmol, 1.1 eq) and Pd₂(dba)₃ (0.58 g, 0.63 mmol, 0.15 eq) were added. The reaction mixture was stirred for 12 h at 100 °C, then cooled and concentrated. The residue was purified by reverse phase flash with the following conditions: column, C18; Mobile Phase: 25-75% MeCN / 0.1% aqueous NH4HCO3 solution over 30 min.; Flow rate: 100 mL/min; Wavelength: 210 nm; Rt 22 min. Concentration of the appropriate fractions gave methyl (2Z)-2-fluoro-3-[1-(oxan-2-yl)pyrazolo[3,4- b]pyridin-6-yl]prop-2-enoate (200 mg, 16% yield) as a yellow solid. Step 3. Preparation of (2Z)-2-Fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-[1-(oxan-2- yl)pyrazolo[3,4-b]pyridin-6-yl]prop-2-enamide (3) A solution of 5-fluoro-2,4-dimethylpyridin-3-amine (101 mg, 0.72 mmol, 1.1 eq) in THF (4 mL) was cooled to -70 °C and 1M LiHMDS in THF (0.8 mL, 0.8 mmol, 1.2 eq) was added dropwise. The mixture was stirred for 0.5 h at -70 °C then methyl (2Z)-2-fluoro-3-[1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-6- yl]prop-2-enoate (200 mg, 0.66 mmol, 1 eq) in THF (1 mL) was added at -70 °C. The reaction was stirred for 2 h at -70 °C before being quenched with water. The resulting mixture was extracted with EA (3 x 10 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified by reverse phase chromatography with the following conditions: column, C18; Mobile Phase: 25-70% MeCN / 0.1% aqueous NH4HCO3 solution over 30 min.; Flow rate: 100 mL/min; Wavelength: 210 nm; Rt 19 min. Concentration of the appropriate fractions gave (2Z)-2-fluoro-N-(5- fluoro-2,4-dimethylpyridin-3-yl)-3-[1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-6-yl]prop-2-enamide (120 mg, 44% yield) as a white solid. Step 4. Preparation of (Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(1H-pyrazolo[3,4- b]pyridin-6-yl)acrylamide

To (2Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-[1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-6-yl]prop- 2-enamide (125 mg, 0.30 mmol) in dioxane (1.3 mL) was added 4N HCl in 1,4-dioxane (0.65 mL). The mixture was stirred for 1 h at room temperature, then concentrated. The residue was suspended in saturated NaHCO₃ aqueous solution (5 mL) and extracted with EA (5 x 10 ml). The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified by HPLC with the following conditions: Column: C18; Mobile Phase: 20-70% MeCN / 0.1% aqueous NH4HCO3 solution; Flow rate: 80ml/min; Wavelength: 220 nm; Rt 16 min. Concentration of the appropriate fractions gave (Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide (14 mg, 18% yield) as a white solid. LCMS: (ES, m/z): 330.1[M+H]⁺ ¹H-NMR: (400 MHz, d₆-DMSO, ppm) δ 8.34 (2H, m), 8.20 (1H, s), 7.67 (1H, m), 7.12 (1H, d), 2.37 (3H, s), 2.14 (3H, s). ¹⁹F-NMR: (376 MHz, d₆-DMSO, ppm) δ -118.38, -134.86. Example 31: (Z)-3-(3-chloro-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin- 3-yl)acrylamide (Z)-3-(3-chloro-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3- yl)acrylamide

To (Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide (Example 30) (50 mg, 0.15 mmol) in EtOH (1 mL) was added NaClO solution (1.0 mL). The reaction mixture was stirred for overnight at room temperature, then concentrated. The residue was purified by HPLC with the following conditions: Column: C18; Mobile Phase: 10-60% MeCN / 0.1% aqueous NH₄HCO₃ solution over 30 min.; Flow rate: 80 mL/min; Wavelength: 220 nm; Rt 17 min. Concentration of the appropriate fractions gave (Z)-3-(3-chloro-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-fluoro-N-(5-fluoro- 2,4-dimethylpyridin-3-yl)acrylamide (15 mg, 26% yield) as a white solid. LCMS: (ES, m/z): 364.1 [M+H]⁺ ¹H-NMR: (400 MHz, d6-DMSO, ppm) δ 14.07 (1H, s), 10.55 (1H, s), 8.40 (1H, s), 8.32 – 8.28 (1H, m), 7.75 – 7.70 (1H, m), 7.17 (1H, d), 2.38 (3H, s), 2.16 (3H, s). ¹⁹F-NMR: (376 MHz, d₆-DMSO, ppm) δ -117.9, -134.5. Example 32: (Z)-3-(7-cyano-1H-indazol-6-yl)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3- yl)acrylamide Step 1. Preparation of Ethyl (2Z)-3-[7-cyano-1-(oxan-2-yl) indazol-6-yl]-2-fluoroprop-2-enoate (2)

A solution of methyl (2Z)-3-[7-chloro-1-(oxan-2-yl) indazol-6-yl]-2-fluoroprop-2-enoate (350 mg, 1.0 mmol), CuCN (278 mg, 3.1 mmol, 3 eq) and GPhos Pd G6 TES (98 mg, 0.10 mmol, 0.1 eq) in NMP (7 mL) was stirred overnight at 130 °C, then cooled and concentrated. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1). Concentration of the appropriate fractions gave (2Z)-3-[7-cyano-1-(oxan-2-yl) indazol-6-yl]-2-fluoroprop-2-enoate (200 mg, 49% yield) as a white solid. Step 2. Preparation of (2Z)-3-[7-Cyano-1-(oxan-2-yl) indazol-6-yl]-2-fluoro-N-(6-methoxy-2,4- dimethyl pyridin-3-yl) prop-2-enamide (3)

To a solution of 6-methoxy-2,4-dimethylpyridin-3-amine (100 mg, 0.66 mmol) in THF (3 mL) at -78 °C was slowly added 1M LiHMDS in THF (790 uL, 0.79 mmol, 1.2 eq) and the solution stirred for 30 min at -78 °C. Methyl ethyl (2Z)-3-[7-cyano-1-(oxan-2-yl)indazol-6-yl]-2-fluoroprop-2-enoate (271 mg, 0.79 mmol, 1.2 eq) was added in portions at -78 °C and the reaction mixture was stirred for 30 min. The reaction was quenched with water (1 mL) at -78 °C and extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (5 mL), dried over anhydrous MgSO4 and concentrated. The crude (2Z)-3-[7-cyano-1-(oxan-2-yl) indazol-6-yl]-2-fluoro-N-(6-methoxy-2,4-dimethyl pyridin-3-yl) prop-2-enamide isolated was used in the next step directly without further purification. Step 3. Preparation of (Z)-3-(7-cyano-1H-indazol-6-yl)-2-fluoro-N-(6-methoxy-2,4- dimethylpyridin-3-yl)acrylamide

To a solution of (2Z)-3-[7-cyano-1-(oxan-2-yl) indazol-6-yl]-2-fluoro-N-(6-methoxy-2,4-dimethyl pyridin-3-yl) prop-2-enamide (180 mg, 0.40 mmol) in DCM (3.6 mL) was added TFA (0.54 mL) at room temperature. The resulting mixture was stirred for 1 h, then concentrated and basified to pH 8 with saturated aqueous Na₂CO₃. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase: 20-50% MeCN / 0.1% aqueous NH₃.H₂O containing 10 mmol/L NH₄HCO₃ over 30 min; detector, UV 254 nm. Concentration of the appropriate fractions gave (Z)-3-(7-cyano-1H-indazol-6-yl)-2-fluoro-N-(6-methoxy-2,4- dimethylpyridin-3-yl)acrylamide (17 mg, 11% yield) as a white solid. LCMS: (ES, m/z): 366.1 [M+H]⁺ ¹H-NMR: (300 MHz, DMSO-d6, ppm) δ 13.98 (1H, s), 10.24 (1H, s), 8.39 (1H, s), 8.25 (1H, d), 7.77 (1H, d), 7.32 (1H, d), 6.63 (1H, s), 3.83 (3H, s), 2.30 (3H, s), 2.16 (3H, s). ¹⁹F-NMR: (300 MHz, d₆-DMSO, ppm) δ -119.26. Example 33: (Z)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-(7-methyl-1H-indazol-6- yl)acrylamide Step 1. Preparation of Methyl (2Z)-2-fluoro-3-[7-methyl-1-(oxan-2-yl) indazol-6-yl] prop-2-enoate (2)

To methyl (2Z)-3-[7-chloro-1-(oxan-2-yl) indazol-6-yl]-2-fluoroprop-2-enoate (400 mg, 1.2 mmol), Cs2CO3 (1.2 g, 3.5 mmol, 3.0 eq) and trimethyl boroxine (593 mg, 2.4 mmol, 2.0 eq) in DME (5 mL) and H2O (1 mL) was added Pd(dppf)Cl2 (86 mg, 0.12 mmol, 0.1 eq) and the reaction mixture was stirred overnight at 100 °C. The mixture was allowed to cool to room temperature and concentrated. The residue was purified by silica gel column chromatography, eluting with PE / EA (50 : 1). Concentration of the appropriate fractions gave methyl (2Z)-2-fluoro-3-[7-methyl-1-(oxan-2-yl) indazol- 6-yl] prop-2-enoate (153 mg, 41% yield) as a white solid. Step 2. Preparation of (Z)-2-Fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-(7-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (3)

6-Methoxy-2,4-dimethylpyridin-3-amine (153 mg, 1.0 mmol) in THF (3 mL) was cooled to -78 °C and treated with 1M LiHMDS in THF (1.2 mL, 1.2 mmol, 1.2 eq). The solution was stirred at -78 °C for 30 min., followed by the addition of methyl (2Z)-2-fluoro-3-[7-methyl-1-(oxan-2-yl) indazol-6-yl] prop-2- enoate (384 mg, 1.2 mmol, 1.2 eq) in portions. The reaction mixture was stirred for 30 min at -78 °C, then quenched with water (5 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (5 mL), dried over anhydrous MgSO4 and concentrated. The crude product was used in the next step directly without further purification. Step 3. Preparation of (Z)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-(7-methyl-1H- indazol-6-yl)acrylamide

To a solution of (2Z)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-[7-methyl-1-(oxan-2-yl) indazol-6-yl] prop-2-enamide (110 mg, 0.25 mmol) in DCM (2.4 mL) was added TFA (0.36 mL). The reaction mixture was stirred for 1 h at room temperature, then concentrated and basified to pH 8 with saturated aqueous Na₂CO₃. The solution was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase: 20-50% MeCN / 0.1% aqueous NH3.H2O containing 10 mmol/L NH4HCO3 over 30 min; detector, UV 254 nm. Concentration of the appropriate fractions gave (Z)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-(7-methyl-1H- indazol-6-yl)acrylamide (6.4 mg, 7.1% yield) as a white solid. LCMS: (ES, m/z): 355.2 [M+H]⁺ ¹H-NMR: (300 MHz, d₆-DMSO, ppm) δ 13.34 (1H, s), 9.99 (1H, s), 8.10 (1H, s), 7.67 (1H, d), 7.51 (1H, d), 7.25 (1H, d), 6.62 (1H, s), 3.83 (3H, s), 2.60 (3H, s), 2.30 (3H, s), 2.15 (3H, s). ¹⁹F-NMR: (300 MHz, d₆-DMSO, ppm) δ -126.56. Example 34: (E)-3-(3-chloro-5,7-difluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3- yl)acrylamide Step 1. Preparation of (2,3,5-Trifluorobenzylidene)hydrazine (2)

To 2,3,5-trifluorobenzaldehyde (10 g, 62 mmol) in EtOH (100 mL) was added N2H4 (80%wt, 5.8 g, 187 mmol, 3 eq) at room temperature. The mixture was stirred for 1 h, then quenched by the addition of water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were dried over anhydrous MgSO4 and concentrated to give crude (2,3,5-trifluorobenzylidene)hydrazine (8.9 g) which was used in the next step without purification. Step 2. Preparation of 5,7-Difluoro-1H-indazole (3)

(2,3,5-Trifluorobenzylidene)hydrazine (1.0 g, 5.7 mmol) in NMP (20 mL) was irradiated with microwave radiation for 20 min at 150 °C. This parallel reaction was repeated 9 times. All the resulting mixtures were quenched by the addition of water (200 mL) and extracted with EtOAc (4 x 100 mL). The combined organics were washed with brine (5 x 100 mL), dried over anhydrous MgSO₄ and concentrated. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1). Concentration of the appropriate fractions gave 5,7-difluoro-1H-indazole (801 mg, 10% yield) as a yellow solid. Step 3. Preparation of 5,7-Difluoro-1-(oxan-2-yl) indazole (4)

To 5,7-difluoro-1H-indazole (1.0 g, 6.5 mmol) and TsOH (0.22 g, 1.3 mmol, 0.2 eq) in DCM (20 mL) was added DHP (1.1 g, 13 mmol, 2 eq) at room temperature. The mixture was stirred for 3 h, then concentrated. The residue was purified by silica gel column chromatography, eluting with PE / EA (20:1). Concentration of the appropriate fractions gave 5,7-difluoro-1-(oxan-2-yl) indazole (1.1 g, 71% yield) as a white solid. Step 4. Preparation of 5,7-Difluoro-1-(oxan-2-yl) indazole-6-carbaldehyde (5)

A solution of 5,7-difluoro-1-(oxan-2-yl) indazole (640 mg, 2.7 mmol) in THF (8 mL) was cooled to - 78 °C.2M LDA in THF (2.0 mL, 4 mmol, 1.5 eq) was added dropwise and the mixture stirred at -78 °C for 30 min. DMF (1.96 g, 27 mmol, 10 eq) was added dropwise and the reaction stirred at -78 °C for 1 h. The resulting mixture was quenched by the addition of water (5 mL) and extracted with EA (3 x 10 mL). The combined organics were dried over anhydrous MgSO₄ and concentrated. The residue was purified by silica chromatography (PE / EA 3:1) to afford 5,7-difluoro-1-(oxan-2-yl) indazole-6- carbaldehyde (550 mg, 77% yield) as a white solid. Step 5. Preparation of Ethyl (2E)-3-[5,7-difluoro-1-(oxan-2-yl) indazol-6-yl] prop-2-enoate (6)

5,7-Difluoro-1-(oxan-2-yl) indazole-6-carbaldehyde (550 mg, 2.1 mmol) in THF (6 mL) was cooled to 0 °C and 60% NaH/oil (124 mg, 3.1 mmol, 1.5 eq) was added. The mixture was stirred at 0 °C for 30 min., then triethyl phosphonoacetate (509 mg, 2.3 mmol, 1.1 eq) was added, and this mixture stirred at 0 °C for 2 h. The reaction was quenched with water (5 mL) and extracted with EA (3 x 10 mL). The combined organics were dried over anhydrous MgSO4 and concentrated. The residue was purified by silica chromatography (PE / EA 1:1) to afford ethyl (2E)-3-[5,7-difluoro-1-(oxan-2-yl) indazol-6-yl] prop- 2-enoate (467 mg, 67% yield) as a white solid. Step 6. Preparation of (2E)-3-[5,7-Difluoro-1-(oxan-2-yl)indazol-6-yl]-N-(5-fluoro-2,4- dimethylpyridin-3-yl)prop-2-

5-Fluoro-2,4-dimethylpyridin-3-amine (156 mg, 1.1 mmol, 1 eq) in THF (5 mL) was cooled to -78 °C. 1M LiHMDS in THF (1.3 mL, 1.3 mmol, 1.2 eq) was added dropwise at -78 °C and stirred for 30 min. Ethyl (2E)-3-[5,7-difluoro-1-(oxan-2-yl) indazol-6-yl] prop-2-enoate (450 mg, 1.3 mmol, 1.2 eq) was added to the mixture at -78 °C and the reaction stirred for 1 h. The resulting mixture was quenched by the addition of water (2 mL) and extracted with EA (3 x 10 mL). The combined organics were dried over anhydrous MgSO4 and concentrated. The residue was purified by silica chromatography (PE / EA 1:1) to afford (2E)-3-[5,7-difluoro-1-(oxan-2-yl)indazol-6-yl]-N-(5-fluoro-2,4-dimethylpyridin-3- yl)prop-2-enamide (246 mg, 51% yield) as a white solid. Step 7. Preparation of (E)-3-(5,7-Difluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3- yl)acrylamide (8)

(2E)-3-[5,7-Difluoro-1-(oxan-2-yl)indazol-6-yl]-N-(5-fluoro-2,4-dimethyl-pyridin-3-yl)prop-2-enamide (240 mg, 0.56 mmol) in DCM (3 mL) was treated with 4N HCl in dioxane (3 mL). The mixture was stirred at room temperature for 1 h, then concentrated to give crude (E)-3-(5,7-difluoro-1H-indazol-6- yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)acrylamide (150 mg), which was used in the next step without purification. Step 8. Preparation of (E)-3-(3-chloro-5,7-difluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4- dimethylpyridin-3-yl)acrylamide

To (2E)-3-(5,7-difluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl) prop-2-enamide (150 mg, 0.43 mmol) in EtOH (2 mL) was added NaClO solution (3 mL) at 0 °C and the mixture stirred for 5 min. The reaction was quenched with water (2 mL) and extracted with EtOAc (3 x 10 mL). The combined organics were dried over anhydrous MgSO₄ and concentrated. The residue was purified by Prep-HPCL (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5 μm; Mobile Phase: 24-54% MeCN / 10 mmol/L aqueous NH₄HCO₃ solution containing 0.05%NH₃.H₂O over 10 min.; Flow rate: 60 mL/min; Wavelength: 254 nm/220 nm; Rt 7.8 min. Concentration of the appropriate fractions gave (E)- 3-(3-chloro-5,7-difluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)acrylamide (6.7 mg, 4.1% yield) as a wax. LCMS: (ES, m/z): 381.1 [M+H]⁺ ¹H-NMR: (300 MHz, d₆-DMSO, ppm) δ 14.19 (1H, s), 10.18 (1H, s), 8.35 (1H, s), 7.72 (1H, d), 7.55 (1H, d), 7.26 (1H, d), 2.37 (3H, s), 2.14 (3H, s). ¹⁹F-NMR: (300 MHz, d₆-DMSO, ppm) δ -119.81, -126.51, -134.75. Example 35: (Z)-1-(5-chloro-6-methoxy-2,4-dimethylpyridin-3-yl)-3-fluoro-4-(7-fluoro-1H-indazol-6- yl)but-3-en-2-one Step 1. Preparation of 3-Bromo-6-methoxy-2,4-dimethylpyridine (2)

To 3-bromo-6-chloro-2,4-dimethylpyridine (3.0 g, 14 mmol) was added MeONa (30 wt.% in MeOH, 30 mL) at room temperature. The reaction mixture was stirred for 2 h at 100 °C. The mixture was cooled and quenched with ice water, then extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (2 x 5 mL), dried over anhydrous MgSO4 and concentrated to give 3-bromo-6- methoxy-2,4-dimethylpyridine (2.2 g, 71% yield) as a light yellow solid. Step 2. Preparation of 3-Bromo-5-chloro-6-methoxy-2,4-dimethylpyridine (3)

To a solution of 3-bromo-6-methoxy-2,4-dimethylpyridine (2.1 g, 9.7 mmol) in DMF (11 mL) at room temperature was added NCS (1.9 g, 12 mmol, 1.2 eq). The reaction mixture was stirred overnight at 80 °C, then cooled and quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (2 x 5 mL), dried over anhydrous MgSO4 and concentrated. The crude product was used in the next step directly without further purification. Step 3. Preparation of 5-Chloro-6-methoxy-N-[(4-methoxyphenyl)methyl]-2,4-dimethylpyridin- 3-amine (4)

To a solution of 3-bromo-5-chloro-6-methoxy-2,4-dimethylpyridine (2.0 g, 8.0 mmol), (4- methoxyphenyl)methanamine (1.3 g, 9.6 mmol, 1.2 eq) and Cs2CO3 (7.8 g, 24 mmol, 3 eq) in dioxane (20 mL) was added GPhos Pd G6 TES (0.75 g, 0.8 mmol, 0.1 eq) at room temperature under nitrogen atmosphere. The reaction mixture was stirred overnight at 100 °C, then cooled and concentrated. The residue was purified by silica gel chromatography, eluting with PE / EA (10:1) to give 5-chloro-6- methoxy-N-[(4-methoxyphenyl)methyl]-2,4-dimethylpyridin-3-amine (991 mg, 34% yield) as a light yellow solid. Step 4. Preparation of 5-Chloro-6-methoxy-2,4-dimethylpyridin-3-amine (5)

To a solution of 5-chloro-6-methoxy-N-[(4-methoxyphenyl)methyl]-2,4-dimethylpyridin-3-amine (991 mg, 3.2 mmol) in DCM (10 mL) was added TFA (3 mL). The reaction mixture was stirred for 2 h at room temperature, then concentrated. The crude product was used in the next step directly without further purification. Step 5. Preparation of (Z)-N-(5-Chloro-6-methoxy-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro- 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (6)

To a solution of 5-chloro-6-methoxy-2,4-dimethylpyridin-3-amine (100 mg, 0.54 mmol) in THF (2 mL) at -78°C was slowly added 1M LHMDS in THF (0.64 mL, 0.64 mmol, 1.2 eq) over 30 min. Methyl (2Z)- 2-fluoro-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (207 mg, 0.64 mmol, 1.2 eq) in portions was then slowly added at -78 °C. The reaction mixture was stirred for 30 min. then quenched with water, still at -78 °C. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organics were washed with brine (5 mL), dried over anhydrous MgSO4 and concentrated. The crude product was used in the next step directly without further purification. Step 6. Preparation of (Z)-1-(5-chloro-6-methoxy-2,4-dimethylpyridin-3-yl)-3-fluoro-4-(7-fluoro- 1H-indazol-6-yl)but-3-en-2-one

To a solution of (2Z)-N-(5-chloro-6-methoxy-2,4-dimethylpyridin-3-yl)-2-fluoro-3-[7-fluoro-1-(oxan-2- yl)indazol-6-yl]prop-2-enamide (200 mg, 0.42 mmol) in DCM (2 mL) was added TFA (0.6 mL). The reaction mixture was stirred for 1 h at room temperature, then concentrated and basified to pH 8 with saturated aqueous Na2CO3. The residue was purified by reverse-phase chromatography with the following conditions: column, C18 silica gel; mobile phase: 20-50% MeCN in 0.1% aqueous NH3.H2O containing 10 mmol/L NH4HCO3 over 30 min; detector, UV 254 nm. Concentration of the appropriate fractions gave (Z)-1-(5-chloro-6-methoxy-2,4-dimethylpyridin-3-yl)-3-fluoro-4-(7-fluoro-1H-indazol-6- yl)but-3-en-2-one (14 mg, 8.1% yield) as a white solid. LCMS: (ES, m/z): 393.2 [M+H]⁺ ¹H-NMR: (300 MHz, d₆-DMSO, ppm) δ 13.88 (1H, s), 10.32 (1H, s), 8.25 (1H, s), 7.71 (1H, d), 7.63 – 7.52 (1H, m), 7.25 (1H, d), 3.95 (3H, s), 2.32 (3H, s), 2.24 (3H, s). ¹⁹F-NMR: (300 MHz, d6-DMSO, ppm) δ -123.47, -131.18. Example 36: (Z)-1-(5-chloro-2,4-dimethylpyridin-3-yl)-4-(3,7-difluoro-1H-indazol-6-yl)-3-fluorobut-3- en-2-one Step 1. Preparation of Methyl (2Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)prop-2-enoate (2)

To a solution of methyl (2Z)-2-fluoro-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (3.0 g, 9.3 mmol) in dioxane (30 mL) was added 4N HCl in 1,4-dioxane (15 mL) at 0 °C. The mixture was warmed to room temperature and stirred for 2 h, then basified to pH 8 with aq. NaHCO₃ solution and water (100 mL). The resulting mixture was extracted with EA (3 x 100 mL). The combined organics were dried over anhydrous Na₂SO₄ and concentrated to give crude methyl (2Z)-2-fluoro-3-(7-fluoro-1H- indazol-6-yl)prop-2-enoate (2.5 g) as an off-white solid. Step 2. Preparation of Methyl (Z)-3-(3,7-difluoro-1H-indazol-6-yl)-2-fluoroacrylate (3) To methyl (2Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)prop-2-enoate (1.5 g, 6.3 mmol) and AcOH (1.5 mL) in MeCN (15 mL) was added 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (3.4 g, 9.4 mmol, 1.5 eq). The mixture was warmed to 80 °C and stirred for 4 h. The resulting mixture was concentrated and the residue purified by Combi-Flash with the following conditions: Column: C18; Mobile Phase: 35-75% MeCN / 10 mmol/L aqueous NH4HCO3 solution over 20 min.; Flow rate: 100 mL/min; Wavelength: 254 nm/220 nm; Rt 17 min. Concentration of the appropriate fractions gave methyl (Z)-3-(3,7-difluoro-1H-indazol-6-yl)-2-fluoroacrylate (300 mg, 21% yield) as a yellow solid. Step 3. Preparation of (Z)-1-(5-chloro-2,4-dimethylpyridin-3-yl)-4-(3,7-difluoro-1H-indazol-6-yl)- 3-fluorobut-3-en-2-one

To a solution of 5-chloro-2,4-dimethylpyridin-3-amine (150 mg, 0.59 mmol) in THF (3 mL) at 0 °C was added 1M LiHMDS in THF (1.2 mL, 1.2 mmol, 2.0 eq). The reaction mixture was stirred for 0.5 h, then methyl (2Z)-3-(3,7-difluoro-1H-indazol-6-yl)-2-fluoroprop-2-enoate (246 mg, 0.59 mmol, 1.0 eq) was added. The reaction was warmed to room temperature and stirred for 2 h. The resulting mixture was concentrated and the residue purified by HPLC with the following conditions: Column: YMC-Actus Triart C18 ExRS 30 *150 mm, 5 m; Mobile Phase: 32-62% MeCN / aqueous 10 mmol/L NH4HCO3 containing 0.05%NH3 over 10 min.; Flow rate: 60 mL/min; Wavelength: 254 nm/220 nm; Rt 8.82 min.. Concentration of the appropriate fractions gave (Z)-1-(5-chloro-2,4-dimethylpyridin-3-yl)-4-(3,7- difluoro-1H-indazol-6-yl)-3-fluorobut-3-en-2-one (45 mg, 20% yield) as an off-white solid. LCMS: (ES, m/z): 381.00 [M+H]⁺ ¹H-NMR: (400 MHz, d₆-DMSO, ppm) δ 13.46 (1H, s), 10.55 (1H, s), 8.47 (1H, s), 7.69 – 7.57 (2H, m), 7.25 (1H, d), 2.39 (3H, s), 2.26 (3H, s). ¹⁹F-NMR: (376 MHz, d₆-DMSO, ppm) δ -122.20, -132.38, -135.48. Example 37: (E)-1-(2-cyclopropyl-5-fluoropyridin-3-yl)-4-(7-fluoro-1H-indazol-6-yl)but-3-en-2-one Step 1 Preparation of Methyl (E)-3-(7-fluoro-1H-indazol-6-yl)acrylate (5) A solution of methyl (2E)-3-[7-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (see Example 16, Step 1) (1.5 g, 4.9 mmol) in dioxane (15 mL) was treated with 4N HCl (gas) in 1,4-dioxane (15 mL). The mixture was stirred overnight then filtered. The solids were dried to give methyl (E)-3-(7-fluoro-1H- indazol-6-yl)acrylate (900 mg, 83% yield) as a white solid. Step 2. Preparation of 2-Cyclopropyl-5-fluoropyridin-3-amine (7)

To 2-chloro-5-fluoropyridin-3-amine (1 g, 6.8 mmol) and cyclopropylboronic acid (1.2 g, 14 mmol, 2 eq) in 1,4-dioxane (20 mL) was added K₂CO₃ (3.8 g, 27 mmol, 4 eq) and Pd(PPh₃)₄ (0.8 g, 0.68 mmol, 0.1 eq). The reaction was heated to 90 °C and stirred overnight. After cooling and concentration, the residue was purified by chromatography with the following conditions: Column: C18; Mobile Phase: 10-70% MeCN / aqueous 10 mmol/L NH4HCO3 over 30 min.; Flow rate: 100 mL/min; Wavelength: 254 nm / 210 nm; Rt 24 min. Concentration of the appropriate fractions gave 2-cyclopropyl-5-fluoropyridin- 3-amine (780 mg, 75% yield) as an orange oil. Step 3. Preparation of (E)-1-(2-cyclopropyl-5-fluoropyridin-3-yl)-4-(7-fluoro-1H-indazol-6- yl)but-3-en-2-one

A solution of 2-cyclopropyl-5-fluoropyridin-3-amine (70 mg, 0.46 mmol) in THF (0.7 mL) was cooled to 0 °C, then 1M LiHMDS in THF (0.92 mL, 0.92 mmol, 2 eq) was added dropwise to the mixture over 2 min. The mixture was stirred at 0 °C for 30 min., then a solution of methyl (2E)-3-(7-fluoro-1H-indazol- 6-yl)prop-2-enoate (101 mg, 0.46 mmol, 1 eq) in THF (0.7 mL) was added over 1 min. The reaction mixture was stirred for 1 h at 0 °C. The residue was diluted with water, and the solid was collected by filtration, then dried to give . (E)-1-(2-cyclopropyl-5-fluoropyridin-3-yl)-4-(7-fluoro-1H-indazol-6-yl)but- 3-en-2-one (90 mg, 56 % yield) as a white solid. LC-MS: (ES, m/z): 341.1 [M+H]⁺; ¹H-NMR: (400 MHz, d₆-DMSO, ppm) δ 13.87 (1H, s), 10.13 (1H, s), 8.31 – 8.17 (2H, m), 8.12 – 8.02 (1H, m), 7.88 (1H, d), 7.67 (1H, d), 7.45 – 7.35 (1H, m), 7.24 (1H, d), 2.43 – 2.28 (1H, m), 1.09 – 0.86 (4H, m). ¹⁹F-NMR: (376 MHz, d6-DMSO, ppm): δ -132.0, -133.2. Example 38: (Z)-1-(5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-fluoro-4-(7-fluoro-1H-indazol- 6-yl)but-3-en-2-one Step 1. Preparation of 5-Chloro-4-methyl-3-nitropyridin-2-amine (2)

To a solution of 4-methyl-3-nitropyridin-2-amine (14 g, 91 mmol) in MeCN (140 mL) was added NCS (19 g, 119 mmol, 1.3 eq) at room temperature. The mixture was stirred for 4 h at 70 °C, then cooled and concentrated. The residue was purified by silica gel chromatography, eluting with 8% EA:PE to give 5-chloro-4-methyl-3-nitropyridin-2-amine (13 g, 75% yield) as a yellow solid. Step 2. Preparation of 2-Bromo-5-chloro-4-methyl-3-nitropyridine (3)

To 5-chloro-4-methyl-3-nitropyridin-2-amine (13 g, 69 mmol) in 48% aqueous HBr (105 g, 624 mmol, 9 eq) at 0 °C was added Br2 (32 g, 200 mmol, 2.9 eq). NaNO2 (12 g, 172 mmol, 2.5 eq) was dissolved in H2O (52 mL) and added dropwise to the mixture at 0 °C. The reaction was stirred for 1 h at 0 °C, then NaOH (19 g) in water (60 mL) was gradually added. The resulting mixture was filtered, and the filter cake was washed with EA (3 x 100 mL). The filtrate was washed with H₂O (3 x 50 mL), dried with anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography, eluting with EA:PE (0-10%) to give 2-bromo-5-chloro-4-methyl-3-nitropyridine (8 g, 41% yield) as a yellow solid. Step 3. Preparation of 5-Chloro-4-methyl-3-nitro-2-(trifluoromethyl)pyridine (4)

To 2-bromo-5-chloro-4-methyl-3-nitropyridine (4.0 g, 16 mmol) in DMF (40 mL) was added methyl 2,2- difluoro-2-(fluorosulfonyl)acetate (4.6 g, 24 mmol, 1.5 eq) and CuI (3.6 g, 19 mmol, 1.2 eq) at room temperature. The reaction was stirred for 3 h at 100 °C, then cooled and filtered. The filter cake was washed with DMF (3 x 4 mL) and the combined filtrate was used for the next reaction. Step 4. Preparation of 5-Chloro-4-methyl-2-(trifluoromethyl)pyridin-3-amine (5)

To the DMF solution of crude 5-chloro-4-methyl-3-nitro-2-(trifluoromethyl)pyridine from the previous step was added B2(OH)4 (4.3 g, 48 mmol, 3 eq) at 0 °C.4-(Pyridin-4-yl)pyridine (0.12 g, 0.8 mmol, 0.05 eq) was dissolved in DMF and added dropwise to the solution at 0 °C. After stirring for 0.5 h at 0 °C, the reaction was basified with NaHCO3. The resulting solution was extracted with EA (100 mL), and the extracts washed with H2O (3 x 30 mL), dried with anhydrous Na2SO4 and concentrated. The residue was purified by reverse phase chromatography with the following conditions: column, C18; Mobile Phase: 15-60% MeCN / 0.1% aqueous formic acid over 30 min.; Flow rate: 100 mL/min; Wavelength: 210 nm; Rt 22 min. Concentration of the appropriate fractions gave 5-chloro-4-methyl-2- (trifluoromethyl)pyridin-3-amine (2 g, 53% yield) as a yellow solid. Step 5. Preparation of (Z)-N-(5-Chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-2-fluoro-3-(7- fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (6)

To a solution of 5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-amine (500 mg, 2.4 mmol), (Z)-2-fluoro- 3-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylic acid (732 mg, 2.4 mmol, 1 eq) and DIEA (1.8 g, 14 mmol, 6 eq) in DMF (5 mL) was added T3P (4.5 g, 14 mmol, 6 eq). The mixture was stirred overnight at 100 °C, then cooled and concentrated. The residue was purified by reverse phase chromatography with the following conditions: Column: C18; Mobile Phase: 35-85% MeCN / 0.1% aqueous formic acid over 25 min.; Flow rate: 100 mL/min; Wavelength: 254nm/220nm; Rt 22 min. Concentration of the appropriate fractions gave (Z)-N-(5-Chloro-4-methyl-2-(trifluoromethyl)pyridin-3- yl)-2-fluoro-3-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (550 mg, 46 % yield) as a yellow solid. Step 6. Preparation of (Z)-1-(5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-fluoro-4-(7- fluoro-1H-indazol-6-yl)but-3-en-2-one

To (Z)-N-(5-Chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-2-fluoro-3-(7-fluoro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-6-yl)acrylamide (550 mg, 1.1 mmol) in dioxane (5.5 mL) was added 4N HCl (gas) in 1,4-dioxane (5.5 mL) at 0 °C. The mixture was warmed to room temperature and stirred for 2 h, then concentrated. The residue was purified by reverse phase chromatography with the following conditions: Column: C18; Mobile Phase: 25-75% MeCN / 0.1% aqueous formic acid over 25 min.; Flow rate: 100 mL/min; Wavelength: 254nm/220nm; Rt 21 min. Concentration of the appropriate fractions (Z)-1-(5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-fluoro-4-(7-fluoro-1H-indazol-6- yl)but-3-en-2-one (144 mg, 31% yield) as a yellow solid. LC-MS: (ES, m/z): 417.1 [M+H]⁺ ¹H-NMR: (400 MHz, d6-DMSO, ppm) δ 13.92 (1H, s), 10.82 (1H, s), 8.82 (1H, s), 8.25 (1H, d), 7.71 (1H, d), 7.57 (1H, dd), 7.27 (1H, d), 2.34 (3H, s). ¹⁹F-NMR: (376 MHz, d6-DMSO, ppm) δ -63.7, -124.1, -130.9. Example 39: (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2-(trifluoromethyl)pyridin- 3-yl)acrylamide Step 1. Preparation of N-(5-Fluoro-4-methylpyridin-2-yl)nitramide (2)

To a solution of 5-fluoro-4-methylpyridin-2-amine (31 g, 246 mmol) in H2SO4 (310 mL) at 0 °C was added fuming HNO3 (11.3 mL, 270 mmol, 1.1 eq) dropwise. The reaction mixture was stirred for 10 minutes at 0 °C, then was poured into ice/water. The precipitated solids were collected by filtration and washed with ice water (3 x 100 mL). Air drying gave crude N-(5-fluoro-4-methylpyridin-2-yl)nitramide (16.9 g) as a white solid. Step 2. Preparation of 5-Fluoro-4-methyl-3-nitropyridin-2-amine (3)

A solution of N-(5-fluoro-4-methylpyridin-2-yl)nitramide (16.9 g, 99 mmol) in c.H2SO4 (85 mL) was heated at 50 °C for 1 h, then cooled. The mixture was basified to pH 9 with solid NaHCO3 then extracted with EA (3000 mL). The combined extracts were washed with H2O (3 x 1000 mL), dried with anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography, eluting with EA:PE (0-25%) to give 5-fluoro-4-methyl-3-nitropyridin-2-amine (6.5 g, 35% yield) as a yellow solid. Step 3. Preparation of 2-Bromo-5-fluoro-4-methyl-3-nitropyridine (4)

5-Fluoro-4-methyl-3-nitropyridin-2-amine (7.0 g, 41 mmol) in 48% aqueous HBr (62 g, 368 mmol, 9.0 eq) was cooled to 0 °C and Br₂ (19 g, 120 mmol, 2.9 eq) was slowly added dropwise. NaNO₂ (7.0 g, 101 mmol, 2.5 eq) was then dissolved in H2O (28 mL) and added to the mixture at 0 °C. The reaction was stirred for 2 h at 0 °C, then treated with a solution of NaOH (95 g) in water (300 mL). The resulting mixture was extracted with EA (3 x 100 mL), washed with H2O (3 x 100 mL) then dried with anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluting with EA:PE (0-15%) to give 2-bromo-5-fluoro-4-methyl-3-nitropyridine (5 g, 49% yield) as a yellow solid. Step 4. Preparation of 5-Fluoro-4-methyl-3-nitro-2-(trifluoromethyl)pyridine (5)

To 2-bromo-5-fluoro-4-methyl-3-nitropyridine (750 mg, 3.2 mmol) in DMF (7.5 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (920 mg, 4.8 mmol, 1.5 eq) and CuI (729 mg, 3.8 mmol, 1.2 eq). The mixture was stirred for 3 h at 100 °C, then cooled and filtered. The filter cake was washed with DMF (3 x 1 mL) and the combined filtrate was used in the next reaction. Step 5. Preparation of 5-Fluoro-4-methyl-2-(trifluoromethyl) pyridin-3-amine (6)

To the DMF solution of 5-fluoro-4-methyl-3-nitro-2-(trifluoromethyl)pyridine from the previous step at 0 °C was added B2(OH)4 (855 mg, 9.5 mmol, 3 eq).4-(Pyridin-4-yl) pyridine (25 mg, 0.16 mmol, 0.05 eq) was dissolved in DMF (1.0 mL) and added dropwise to the mixture at 0 °C. The reaction was stirred for 0.5 h at 0 °C, then basified with aqueous NaHCO3. The resulting solution was extracted with EA (10 mL), washed with H2O (3 x 5 mL) then dried with anhydrous Na2SO4 and concentrated. The residue was purified by reverse phase chromatography with the following conditions: column, C18; Mobile Phase: 10-60% MeCN / 0.1% aqueous formic acid over 30 min.; Flow rate: 100 mL/min; Wavelength: 210 nm; Rt 20 min. Concentration of the appropriate fractions gave 5-fluoro-4-methyl-2- (trifluoromethyl) pyridin-3-amine (300 mg, 44% yield) as a yellow solid. Step 6. Preparation of (Z)-2-Fluoro-3-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N- (5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)acrylamide (7)

To 5-fluoro-4-methyl-2-(trifluoromethyl) pyridin-3-amine (300 mg, 1.5 mmol) in DMF (3 mL) was added (Z)-2-fluoro-3-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylic acid (450 mg, 1.5 mmol, 0.9 eq), DIEA (1.2 g, 9.3 mmol, 6 eq) and 50% T3P in ethyl acetate (3 g, 9.3 mmol, 6 eq). The reaction mixture was stirred overnight at 100 °C, then cooled and concentrated. The residue was purified by reverse phase chromatography with the following conditions: Column: C18; Mobile Phase: 40-85% MeCN / 0.1% aqueous NH4HCO3 solution over 30 min.; Flow rate: 100 mL/min; Wavelength: 254 nm/220 nm; Rt 8 min. Concentration of the appropriate fractions gave (Z)-2-fluoro-3-(7-fluoro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3-yl) acrylamide (330 mg, 32% yield) as a yellow solid. Step 7. (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3- yl)acrylamide

(Z)-2-Fluoro-3-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2- (trifluoromethyl)pyridin-3-yl) acrylamide (320 mg, 0.66 mmol) in dioxane (3.2 mL) was cooled to 0 °C and treated with 4N HCl (gas) in 1,4-dioxane (3.2 mL). The mixture was warmed to room temperature and stirred for 2 h. The precipitate formed was recovered by filtration and purified by reverse phase chromatography with the following conditions: Column: C18; Mobile Phase: 25-75% MeCN / 0.1% aqueous NH4HCO3 solution over 25 min.; Flow rate: 100 mL/min; Wavelength: 254 nm/220 nm; Rt 18 min. Concentration of the appropriate fractions gave (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(5- fluoro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)acrylamide (100 mg, 37% yield) as a white solid. LC-MS: (ES, m/z): 401.0 [M+H]⁺; ¹H-NMR: (300 MHz, d₆-DMSO, ppm) δ 11.06 (1H, s), 8.66 (1H, s), 8.24 (1H, d), 7.69 (1H, d), 7.57 (1H, dd), 7.24 (1H, dd), 2.20 (3H, d). ¹⁹F-NMR: (282 MHz, d₆-DMSO, ppm) δ -63.35, -122.75, -123.59, -131.13. Example 40: (Z)-3-(3,7-difluoro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-4-methyl-2- (trifluoromethyl)pyridin-3-yl)acrylamide Step 1. Preparation of (Z)-3-(3,7-Difluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-2-fluoro- N-(5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)acrylamide (2)

To 5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3-amine (350 mg, 1.8 mmol) in DMF (3.5 mL) was added (Z)-3-(3,7-difluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-2-fluoroacrylic acid (500 mg, 1.5 mmol, 0.85 eq), DIEA (1.4 g, 11 mmol, 6 eq) and T3P (50% in ethyl acetate) (3.4 g, 11 mmol, 6 eq). The reaction mixture was stirred for 2 days at 100 °C, then cooled and concentrated. The residue was purified by reverse phase chromatography with the following conditions: Column: C18; Mobile Phase: 30-75% MeCN / 0.1% aqueous NH4HCO3 solution over 30 min.; Flow rate: 100 mL/min; Wavelength: 254 nm/220 nm; Rt 20 min. Concentration of the appropriate fractions gave (Z)-3-(3,7- difluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-4-methyl-2- (trifluoromethyl)pyridin-3-yl)acrylamide (350 mg, 31% yield) as a yellow solid. Step 2. Preparation of (Z)-3-(3,7-Difluoro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-4-methyl-2- (trifluoromethyl)pyridin-3-yl)acrylamide

To (Z)-3-(3,7-difluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-4-methyl-2- (trifluoromethyl)pyridin-3-yl)acrylamide (350 mg, 0.7 mmol) in DCM (3.5 mL) was added trifluoroacetic acid (3.5 mL). The mixture was stirred for 2 h, then concentrated. The residue was purified by HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 30*150 mm, 5 μm; Mobile Phase: 33-62% MeCN / 0.1% aqueous formic acid over 12 min.; Flow rate: 60 mL/min; Wavelength: 254 nm/220 nm; Rt 7.95 min. Concentration of the appropriate fractions gave (Z)-3-(3,7-difluoro-1H- indazol-6-yl)-2-fluoro-N-(5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)acrylamide (123 mg, 41% yield) as a white solid. LC-MS: (ES, m/z): 419.0 [M+H]⁺ _; ¹H-NMR: (300 MHz, d6-DMSO, ppm) δ 13.45 (1H, s), 10.93 (1H, s), 8.73 (1H, s), 7.74 – 7.48 (2H, m), 7.25 (1H, d), 2.22 (3H, d) ¹⁹F-NMR: (282 MHz, d6-DMSO, ppm) δ -63.37, -122.48, -123.02, -132.23, -135.50. Example 41: (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-ethynyl-1H-pyrazolo[3,4-b]pyridin-6- yl)acrylamide Step 1. Preparation of 6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (2)

To 6-chloro-1H-pyrazolo[3,4-b] pyridine (5.0 g, 32.558 mmol, 1.0 eq) in DCM (100 mL) was added TsOH (0.56 g, 3.3 mmol, 0.1 eq) and DHP (8.2 g, 98 mmol, 3 eq). The mixture was stirred for 2 h at room temperature, then concentrated. The residue was purified by silica gel chromatography, eluting with EA:PE (0-20%) to give 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (7 g,81% yield) as an oil. Step 2. Preparation of Methyl (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6- yl)acrylate (3)

To 6-chloro-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine (4.5 g, 19 mmol) in dioxane (90 mL) was added methyl acrylate (2.0 g, 23 mmol, 1.2 eq), N-cyclohexyl-N-methylcyclohexanamine (4.1 g, 21 mmol, 1.1 eq) and P(t-Bu)₃ (2.3 g, 11 mmol, 0.6 eq). The mixture was degassed with N₂ for 2 min., then Pd₂(dba)₃ (2.6 g, 2.8 mmol, 0.15 eq) was added. The reaction was stirred overnight at 100 °C, then cooled and concentrated. The residue was purified by reverse phase chromatography with the following conditions: column, C18; Mobile Phase: 25-70% MeCN / 0.1% aqueous NH4HCO3 solution over 35 min.; Flow rate: 100 mL/min; Wavelength: 210 nm; Rt 26 min. Concentration of the appropriate fractions gave methyl (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylate (4 g, 66% yield) as a yellow oil. Step 3. Preparation of Methyl (E)-3-(1H-pyrazolo[3,4-b]pyridin-6-yl)acrylate (4)

To methyl (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylate (2.0 g, 7 mmol) in dioxane (20 mL) at 0 °C was added 4N HCl (gas) in 1,4-dioxane (20 mL). The reaction was stirred for 1 h at room temperature, then concentrated. The residue was diluted with EA (30 mL) and washed with H₂O (3 x 10 mL), then dried with anhydrous Na₂SO₄ and concentrated. Methyl (E)-3-(1H- pyrazolo[3,4-b]pyridin-6-yl)acrylate (1.2 g, 84% yield) was isolated as a yellow solid. Step 4. Preparation of Methyl (E)-3-(3-iodo-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylate (5)

Methyl (E)-3-(1H-pyrazolo[3,4-b]pyridin-6-yl)acrylate (1.5 g, 7.4 mmol) in DMF (30 mL) was treated with NIS (2.0 g, 8.9 mmol, 1.2 eq) and the reaction stirred for 4 h at 40 °C. After concentration, the residue was purified by reverse phase chromatography with the following conditions: column, C18; Mobile Phase: 25-65% MeCN / 0.1% aqueous NH₄HCO₃ solution over 20 min.; Flow rate: 100 mL/min; Wavelength: 210 nm; Rt 17 min. Concentration of the appropriate fractions gave methyl (E)-3-(3-iodo- 1H-pyrazolo[3,4-b]pyridin-6-yl)acrylate (2 g, 78% yield) as a yellow solid. Step 5. Preparation of Methyl (E)-3-(3-((trimethylsilyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-6- yl)acrylate (6)

To methyl (E)-3-(3-iodo-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylate (2.0 g, 6.1 mmol) in DMF (20 mL) was added trimethylsilylacetylene (1.2 g, 12 mmol, 2 eq) and TEA (1.8 g, 18 mmol, 3 eq) The mixture was degassed with N2 for 10 min., then CuI (0.12 g, 0.61 mmol, 0.1 eq) and Pd(PPh3)2Cl2 (0.43 g, 0.61 mmol, 0.1 eq) were added. The reaction mixture was stirred for 2 h at 60 °C, then cooled and concentrated. The residue was purified by reverse phase chromatography with the following conditions: Column: C18; Mobile Phase: 35-85% MeCN / 0.1% aqueous formic acid over 28 min.; Flow rate: 100 mL/min; Wavelength: 210 nm; Rt 23 min. Concentration of the appropriate fractions gave methyl (E)-3-(3-((trimethylsilyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylate (1.5 g, 82% yield) as a yellow solid. Step 6. Preparation of (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-((trimethylsilyl)ethynyl)-1H- pyrazolo[3,4-b]pyridin-6-yl)acrylamide (7)

To methyl (E)-3-(3-((trimethylsilyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylate (950 mg, 3.2 mmol) in THF (19 mL) at 0 °C was added 1M LiHMDS in THF (6.3 mL, 6.3 mmol, 2 eq) and the resulting mixture was stirred for 0.5 h at 0 °C.5-Chloro-2-methylpyridin-3-amine (452 mg, 3.2 mmol, 1 eq) in THF (5 mL) was added dropwise, and the reaction mixture was removed from the cooling bath and stirred overnight at room temperature. The reaction was quenched with H₂O at 0 °C and extracted with EA (20 mL). The combined extracts were washed with H₂O (3 x 10 mL), dried with anhydrous Na₂SO₄ and concentrated. The residue was purified by HPLC with the following conditions: Column: C18; Mobile Phase: 35-75% MeCN / 0.1% aqueous formic acid over 20 min.; Flow rate: 100 mL/min; Wavelength: 210 nm; Rt 18 min. Concentration of the appropriate fractions gave (E)-N-(5-chloro-2- methylpyridin-3-yl)-3-(3-((trimethylsilyl) ethynyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide (120 mg, 9% yield) as a yellow solid. Step 7. Preparation of (E)-N-(5-Chloro-2-methylpyridin-3-yl)-3-(3-ethynyl-1H-pyrazolo[3,4- b]pyridin-6-yl)acrylamide To (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-((trimethylsilyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-6-yl) acrylamide (120 mg, 0.29 mmol) in MeOH (1.2 mL) was added K₂CO₃ (49 mg, 0.35 mmol, 1.2 eq) and the reaction stirred overnight at room temperature. The resulting mixture was filtered and the filter cake was washed with cold MeOH (3 x 3 mL). Concentration of the combined filtrate gave (E)-N-(5- chloro-2-methylpyridin-3-yl)-3-(3-ethynyl-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide (18 mg, 19% yield) as a white solid. LCMS: (ES, m/z): 338.0 [M+H]⁺; ¹H-NMR: (400 MHz, d₆-DMSO, ppm) δ 14.10 (1H, s), 10.03 (1H, s), 8.56 – 7.98 (3H, m), 7.78 (1H, d), 7.68 – 7.44 (2H, m), 4.62 (1H, s), 2.50 (3H, s). Example 42: (Z)-3-(3,7-difluoro-1H-indazol-6-yl)-2-fluoro-N-(6-(methoxy-d3)-2,4-dimethylpyridin-3- yl)acrylamide Step 1. Preparation of 2-Hydroxy-4,6-dimethyl-5-nitronicotinonitrile (2)

To 2-hydroxy-4,6-dimethyl-5-nitropyridine-3-carbonitrile (22 g, 114 mmol) and c.H₂SO₄ (110 mL) was added c.HNO₃ (14.35 g, 230 mmol, 2 eq) dropwise over 5 mins at 80°C. The reaction mixture was stirred for 2 h at 80°C, then cooled and quenched with water/ice (100 mL). The resulting mixture was filtered, and the filter cake was washed with H₂O (20 mL). The solid was dried under vacuum to give 2-hydroxy-4,6-dimethyl-5-nitronicotinonitrile (14 g, 84 % yield) as a yellow solid. LCMS (ES, m/z): 194 [M+H]⁺ Step 2. Preparation of 4,6-Dimethyl-5-nitropyridin-2-ol (3)

To 2-hydroxy-4,6-dimethyl-5-nitronicotinonitrile (14 g, 74 mmol) and H₂O (57 mL) was added c.H₂SO₄ (98%, 142 mL) and the reaction stirred for 4 h at 150°C. The reaction was cooled, and ice/H2O (200 mL) was added. The resulting mixture was filtered, and the filter cake was washed with H2O (20 mL). The solid was dried under vacuum to give 4,6-dimethyl-5-nitropyridin-2-ol (8.4 g, 67% yield) as a yellow solid. LCMS (ES, m/z): 169 [M+H]⁺ Step 3. Preparation of 6-(Methoxy-d3)-2,4-dimethyl-3-nitropyridine (4)

To 4,6-dimethyl-5-nitropyridin-2-ol (3.0 g, 18 mmol) and AgCO3 (9.8 g, 36 mmol, 2 eq) in DCM (60 mL) was added iodomethane-d3 (5.2 g, 36 mmol, 2 eq). The resulting suspension was stirred for 14 h then filtered. The filtrate was concentrated and the residue purified by silica gel chromatography, eluting with n-hexane/ EtOAc (5 :1) to afford 6-(methoxy-d3)-2,4-dimethyl-3-nitropyridine (2.3 g, 70% yield) as a yellow solid. LCMS (ES, m/z): 186 [M+H]⁺ Step 4. Preparation of 6-(Methoxy-d3)-2,4-dimethylpyridin-3-amine (5)

6-(Methoxy-d3)-2,4-dimethyl-3-nitropyridine (2.3 g) and 10% Pd/C (400 mg) in MeOH (35 mL) was hydrogenated at atmospheric pressure for 3 h at room temperature. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 2 mL). The filtrate was concentrated to afford 6- (methoxy-d3)-2,4-dimethylpyridin-3-amine (1.9 g, 95% yield) as a brown oil. LCMS (ES, m/z): 156 [M+H]⁺ ¹H NMR (300 MHz, Chloroform-d) δ 6.44-6.33 (m, 1H), 2.36 (d, J = 0.6 Hz, 3H), 2.17 (d, J = 0.8 Hz, 3H) Step 5. Preparation of (Z)-3-(3,7-difluoro-1H-indazol-6-yl)-2-fluoro-N-(6-(methoxy-d3)-2,4- dimethylpyridin-3-yl)acrylamide

A solution of 6-(methoxy-d3)-2,4-dimethylpyridin-3-amine (400 mg, 2.6 mmol) in THF (8 mL) at -78 °C was treated with 1M LiHMDS in THF (5.2 mL, 5.2 mmol, 2 eq) for 30 min. Methyl (Z)-3-(3,7-difluoro- 1H-indazol-6-yl)-2-fluoroacrylate (660 mg, 2.6 mmol, 1 eq) was added in portions at -78 °C, and the resulting mixture stirred for 1 h at low temperature. The reaction was quenched with water (2 mL) and stirred to room temperature for 0.5 h. The resulting mixture was extracted with EtOAc (3 x 10 mL) and the combined organics were washed with brine (5 mL), dried over anhydrous MgSO4 and concentrated. The residue was purified by reverse-phase chromatography with the following conditions: Column: XSelect CSH Prep C18 OBD, 30*150 mm, 5μm; Mobile Phase: 30-60% MeCN / 0.1% aqueous formic acid over 12 min.; Flow rate: 60 mL/min; Wavelength: 254 nm/220 nm; Rt 7.35 min. Concentration of the appropriate fractions gave (Z)-3-(3,7-difluoro-1H-indazol-6-yl)-2-fluoro-N-(6- (methoxy-d3)-2,4-dimethylpyridin-3-yl)acrylamide (63 mg, 6.4% yield) as a white solid. LC-MS: (ES, m/z): 380.2 [M+H]⁺; ¹H-NMR: (300 MHz, d₆-DMSO, ppm) δ 13.41 (1H, s), 10.12 (1H, s), 7.67 - 7.56 (2H, m), 7.21 (1H, d), 6.62 (1H, s), 2.14 (3H, s), 2.07 (3H, s). ¹⁹F-NMR: (300 MHz, d6-DMSO, ppm) δ -121.84, -132.57, -135.55. Example 43: (Z)-3-(3-(1-cyanocyclopropyl)-7-fluoro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4- dimethylpyridin-3-yl)acrylamide Step 1. Preparation of 1-(6-Bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3- yl)cyclopropane-1-carbonitrile (2)

To Zn (0.69 g, 11 mmol, 2.3 eq) in THF (10 mL) was added Br₂ (0.56 g, 3.5 mmol, 0.75 eq) and 1- bromocyclopropane-1-carbonitrile (1.0 g, 7.1 mmol, 1.5 eq) at room temperature. The resulting mixture was stirred at 60 °C for 3 h, then cooled to room temperature.6-Bromo-7-fluoro-3-iodo-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazole (2.0 g, 4.7 mmol) in THF (10 mL) was added followed by Pd₂(dba)₃CHCl₃ (0.12 g, 0.12 mmol, 0.025 eq) and SPhos (0.10 g, 0.24 mmol, 0.05 eq). The resulting mixture was stirred overnight at 60 °C, then cooled and concentrated. The residue was purified by silica gel chromatography, eluting with PE / EA (1: 1) to afford 1-(6-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-3-yl)cyclopropane-1-carbonitrile (590 mg, 34% yield) as a yellow solid. Step 2. Preparation of Methyl (Z)-3-(3-(1-cyanocyclopropyl)-7-fluoro-1-(tetrahydro-2H-pyran-2- yl)-1H-indazol-6-yl)

To 1-(6-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)cyclopropane-1-carbonitrile (590 mg, 1.6 mmol), methyl 2-fluoroacrylate (202 mg, 1.9 mmol, 1.2 eq) and TEA (492 mg, 4.9 mmol, 3 eq) in DMF (11.8 mL) was added Pd(dtbpf)Cl₂ (317 mg, 0.49 mmol, 0.3 eq) at room temperature under nitrogen atmosphere. The reaction mixture was stirred overnight at 90 °C then cooled and concentrated. The residue was purified by silica gel chromatography, eluting with PE / EA (2:1) to afford methyl (Z)-3-(3-(1-cyanocyclopropyl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-2- fluoroacrylate (130 mg, 21% yield) as a yellow solid. Step 3. Preparation of (Z)-3-(3-(1-Cyanocyclopropyl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)acrylamide (4)

To methyl (Z)-3-(3-(1-cyanocyclopropyl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-2- fluoroacrylate (130 mg, 0.34 mmol) in THF (2.6 mL) at -78 °C was added 1M LiHMDS in THF (0.67 mL, 0.67 mmol, 2 eq) dropwise, and the solution stirred at low temperature for 30 min.5-Fluoro-2,4- dimethylpyridin-3-amine (56 mg, 0.40 mmol, 1.2 eq) in THF (1 mL) was added dropwise to the mixture and stirred for another 30 min. The reaction was quenched with water (5 mL) at room temperature and extracted with EtOAc (2 x 10 mL). The combined organics were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluting with PE / EA (2:1) to afford (Z)-3-(3-(1-cyanocyclopropyl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl) acrylamide (120 mg, 72% yield) as a white solid. Step 4. Preparation of (Z)-3-(3-(1-Cyanocyclopropyl)-7-fluoro-1H-indazol-6-yl)-2-fluoro-N-(5- fluoro-2,4-dimethylpyridin-3-yl)acrylamide

To (Z)-3-(3-(1-cyanocyclopropyl)-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-2-fluoro-N-(5- fluoro-2,4-dimethylpyridin-3-yl) acrylamide (120 mg, 0.29 mmol) in DCM (1.2 mL) was added 4N HCl in dioxane (1.2 mL). The resulting mixture was stirred for 1 h then concentrated. The mixture was neutralized to pH 7 with saturated aqueous NaHCO and extracted with EtOAc (2 x 10 mL). The combined organics were dried over anhydrous MgSO₄ and concentrated. The residue was purified by reverse-phase chromatography with the following Column: Xbridge Prep OBD C18 Column, 30*150 mm, 5 m; Mobile Phase: 33-53% MeCN / 10 mmol/L aqueous NH₄HCO₃ solution containing 0.05%NH3.H2O over 15 min.; Flow rate: 60 mL/min; Wavelength: 254 nm/220 nm; Rt 7.3 min. Concentration of the appropriate fractions gave (Z)-3-(3-(1-cyanocyclopropyl)-7-fluoro-1H-indazol-6- yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)acrylamide (23 mg, 19% yield) as a white solid. LC-MS: (ES, m/z): 412.2 [M+H]⁺; ¹H-NMR: (300 MHz, d6-DMSO, ppm) δ 13.62 (1H, s), 8.39 (1H, s), 7.84 (1H, d), 7.67 (1H, t), 7.33 - 7.21 (1H, d), 2.39 (3H, s), 2.17 (3H, s), 1.88 (2H, s), 1.75 (2H, s). ¹⁹F-NMR: (300 MHz, d6-DMSO, ppm) δ -122.67, -130.69, -134.55. Example 44: (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-chloro-5-fluoro-1H-pyrazolo[3,4-b]pyridin-6- yl)acrylamide Step 1. Preparation of 5-Fluoro-1H-pyrazolo[3,4-b]pyridine 7-oxide (2)

To 5-fluoro-1H-pyrazolo[3,4-b]pyridine (4.5 g, 33 mmol) in EA (45 mL) was added 85 wt % m-CPBA (8.3 g, 41 mmol, 1.3 eq). The mixture was stirred overnight, and the precipitated solids were collected by filtration and washed with EA (2 x 20 mL). The solids were air dried to give 5-fluoro-1H-pyrazolo[3,4- b]pyridine 7-oxide (4.3 g, 86% yield) as a yellow solid. Step 2. Preparation of 6-Bromo-5-fluoro-1H-pyrazolo[3,4-b]pyridine (3)

5-Fluoro-1H-pyrazolo[3,4-b]pyridine 7-oxide (4.3 g, 28 mmol) in CHCl₃ (172 mL) was treated with POBr₃ (12 g, 42 mmol, 1.5 eq) and the reaction was stirred for 2 h at 60 °C. The mixture was cooled to 0 °C and quenched with H₂O, then extracted with DCM (4 x 200 mL). The organics were dried with anhydrous Na₂SO₄ and concentrated. The residue was purified by reverse phase chromatography with the following conditions: column, C18; Mobile Phase: 15-65% MeCN / 0.1% aqueous NH4HCO3 solution over 25 min.; Flow rate: 100 mL/min; Wavelength: 210 nm; Rt 16 min. Concentration of the appropriate fractions gave 6-bromo-5-fluoro-1H-pyrazolo[3,4-b]pyridine (1.4 g, 23% yield) as a yellow solid. Step 3. Preparation of 6-Bromo-5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4- b]pyridine (4)

To 6-bromo-5-fluoro-1H-pyrazolo[3,4-b]pyridine (1.4 g, 6.5 mmol, 1 eq) in DCM (28 mL) at 0 °C was added TsOH (0.11 g, 0.65 mmol, 0.1 eq), followed by DHP (1.6 g, 19 mmol, 3 eq). The mixture was stirred overnight at room temperature then concentrated. The residue was purified by reverse phase chromatography with the following conditions: column, C18; Mobile Phase: 50-90% MeCN / 0.1% aqueous NH4HCO3 solution over 20 min.; Flow rate: 100 mL/min; Wavelength: 210 nm; Rt 15 min. Concentration of the appropriate fractions gave 6-bromo-5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazolo[3,4-b]pyridine (1.7 g, 87% yield) as a yellow oil. Step 4. Preparation of Methyl (E)-3-(5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4- b]pyridin-6-yl)acrylate (5)

6-Bromo-5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (1.7 g, 5.7 mmol) in dioxane (17 mL) was treated with methyl acrylate (0.59 g, 6.8 mmol, 1.2 eq), N,N- dicyclohexylmethylamine (1.2 g, 6.2 mmol, 1.1 eq) and P(t-Bu)₃ (0.69 g, 3.4 mmol, 0.6 eq). The mixture was degassed with N₂ for 10 min., then Pd₂(dba)₃ (0.78 g, 0.85 mmol, 0.15 eq) was added. The reaction was stirred overnight at 100 °C, then cooled and concentrated. The residue was purified by reverse phase chromatography with the following conditions: column, C18; Mobile Phase: 30-70% MeCN / 0.1% aqueous formic acid over 30 min.; Flow rate: 100 mL/min; Wavelength: 210 nm; Rt 22 min. Concentration of the appropriate fractions gave methyl (E)-3-(5-fluoro-1-(tetrahydro-2H-pyran-2- yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylate (1.2 g, 64% yield) as a yellow solid. Step 5. Preparation of (E)-N-(5-Chloro-2-methylpyridin-3-yl)-3-(5-fluoro-1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide (6)

5-Chloro-2-methylpyridin-3-amine (103 mg, 0.72 mmol, 1.1 eq) in THF (1 mL) at 0 °C was treated with 1M LiHMDS in THF (1.3 mL, 1.3 mmol, 2 eq) dropwise over 2 min. The mixture was stirred at 0 °C for 30 min., then a solution of (E)-3-(5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6- yl)acrylate (200 mg, 0.66 mmol, 1 eq) in THF (1 mL) was added to the mixture over 1 min. The reaction was stirred for 2 h at room temperature, then quenched with H₂O (5 mL) and extracted with EA (2 x 5 mL). The organics were dried with anhydrous Na₂SO₄ and concentrated. The residue was purified by reverse flash chromatography with the following conditions: column, C18; Mobile Phase: 60-100% MeCN / 0.1% aqueous NH4HCO3 solution over 20 min.; Flow rate: 100 mL/min; Wavelength: 210 nm; Rt 13 min. Concentration of the appropriate fractions gave (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(5- fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide (140 mg, 48% yield) as a yellow solid. Step 6. Preparation of (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(5-fluoro-1H-pyrazolo[3,4- b]pyridin-6-yl)acrylamide (7) (E)-N-(5-Chloro-2-methylpyridin-3-yl)-3-(5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4- b]pyridin-6-yl)acrylamide (120 mg, 0.29 mmol) in dioxane (1.2 mL) was treated with 4N HCl (gas) in 1,4-dioxane (1.2 mL) and stirred for 2 h. The resulting mixture was triturated with hexane (10 mL) and the precipitated solids collected by filtration and washed with hexane (2 x 5 mL). Air drying gave (E)- N-(5-chloro-2-methylpyridin-3-yl)-3-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide (40 mg, 42% yield) as a yellow oil. Step 7. Preparation of (E)-N-(5-Chloro-2-methylpyridin-3-yl)-3-(3-chloro-5-fluoro-1H- pyrazolo[3,4-b]pyridin-6-yl)acrylamide

(E)-N-(5-Chloro-2-methylpyridin-3-yl)-3-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide (30 mg, 0.09 mmol) in EtOH (0.6 mL) was treated with NaOCl solution (0.3 mL). The mixture was stirred for 2 h, then concentrated. The resulting mixture was purified by HPLC with the following conditions: Column: XBridge Prep Shield RP18 OBD Column, 19*250 mm, 5 μm; Mobile Phase: 35-55% MeCN / 10 mmol/L aqueous NH4HCO3 solution over 12 min.; Flow rate: 25 mL/min; Wavelength: 254 nm/220 nm; Rt 12.6 min. Concentration of the appropriate fractions gave (E)-N-(5-chloro-2-methylpyridin-3- yl)-3-(3-chloro-5-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide (15 mg, 45% yield) as a white solid. LC-MS: (ES, m/z): 366.1 [M+H]⁺; ¹H-NMR: (400 MHz, d₆-DMSO, ppm) δ 14.09 (1H, s), 10.16 (1H, s), 8.51 – 8.16 (3H, m), 7.83 (1H, d), 7.64 (1H, d), 2.51 (3H, s). ¹⁹F-NMR: (376 MHz, d6-DMSO, ppm) δ -133.21. Example 45: (Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-3-(2-hydroxypropan-2-yl)- 1H-indazol-6-yl)acrylamide Step 1. Preparation of Methyl (Z)-2-fluoro-3-(7-fluoro-3-iodo-1H-indazol-6-yl)acrylate (2)

To methyl (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)acrylate (0.6 g, 2.5 mmol) in MeCN (6 mL) was added NIS (0.62 g, 2.8 mmol, 1.1 eq). The reaction was stirred at 60 °C for 3 h, then cooled and quenched with H₂O (10 mL). The resulting mixture was extracted with EA (3 x 10 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate and concentrated to give methyl (Z)-2-fluoro-3-(7-fluoro-3-iodo-1H-indazol-6-yl)acrylate (810 mg, 88% yield) as a yellow oil. Step 2. Preparation of Methyl (Z)-3-(3-(1-ethoxyvinyl)-7-fluoro-1H-indazol-6-yl)-2-fluoroacrylate (3)

To methyl (Z)-2-fluoro-3-(7-fluoro-3-iodo-1H-indazol-6-yl)acrylate (760 mg, 2.1 mmol) and tributyl(1- ethoxyethenyl) stannane (1.5 g, 4.2 mmol, 2 eq) in DMF (15 mL) was added dichlorobis(triphenylphosphine)palladium(II) (147 mg, 0.21 mmol, 0.1 eq) at room temperature under nitrogen atmosphere. The reaction was stirred for 12 h at 90 °C, then cooled and quenched with water (15 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (20 mL), dried over anhydrous MgSO4 and concentrated. The residue was purified by silica gel chromatography, eluting with PE/EA (20:1) to give methyl (Z)-3-(3-(1-ethoxyvinyl)-7-fluoro- 1H-indazol-6-yl)-2-fluoroacrylate (350 mg, 54% yield) as a white solid. Step 3. Preparation of (Z)-3-(3-acetyl-7-fluoro-1H-indazol-6-yl)-N-(5-chloro-2,4-dimethylpyridin-

5-Chloro-2,4-dimethylpyridin-3-amine (120 mg, 0.77 mmol) in THF (2.4 mL) at -78 °C was treated dropwise with 1M LiHMDS in THF (0.92 mL, 0.92 mmol, 1.2 eq) and stirred for 30 min. Methyl (Z)-3- (3-(1-ethoxyvinyl)-7-fluoro-1H-indazol-6-yl)-2-fluoroacrylate (260 mg, 0.84 mmol, 1.1 eq) was added in portions at -78 °C, and the reaction was stirred for 1 h, then quenched with water (5 mL), still at - 78 °C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (5 mL), dried over anhydrous MgSO4 and concentrated. The crude product was purified by silica gel chromatography, eluting with PE/EA (3:1) to give (Z)-3-(3-acetyl-7-fluoro-1H- indazol-6-yl)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoroacrylamide (120 mg, 76% yield) as a white solid. Step 4. Preparation of (Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-3-(2- hydroxypropan-2-yl)-1H-indazol-6-yl)acrylamide

To (Z)-3-(3-acetyl-7-fluoro-1H-indazol-6-yl)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoroacrylamide (200 mg, 0.49 mmol) in THF (4 mL) 0 °C was slowly added 3M CH3MgBr in diethyl ether (0.83 mL, 2.5 mmol, 5 eq). The reaction was stirred for 1 h at 0 °C and quenched by the addition of aqueous NH4Cl (1 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (5 mL), dried over anhydrous MgSO4 and concentrated. The residue was purified by reverse-phase chromatography with the following conditions: Column: Xselect CSH F-Phenyl OBD column30*150 mm, 5 μm; Mobile Phase: 32-62% MeCN / 0.05% aqueous TFA over 8 min.; Flow rate: 60 mL/min; Wavelength: 254 nm; Rt 7 min. Concentration of the appropriate fractions gave (Z)-N-(5- chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-3-(2-hydroxypropan-2-yl)-1H-indazol-6- yl)acrylamide (40 mg, 19% yield) as a white solid. LC-MS: (ES, m/z): 421.2 [M+H]⁺; ¹H-NMR: (300 MHz, d6-DMSO, ppm) δ 13.42 (1H, s), 10.49 (1H, s), 8.46 (1H, s), 7.92 (1H, d), 7.55 - 7.50 (1H, m), 7.26 (1H, d), 5.34 (1H, s), 2.39 (3H, s), 2.26 (3H, s), 1.61 (6H, s). ¹⁹F-NMR: (300 MHz, d6-DMSO, ppm) δ -123.65, -131.89. Example 46: (E)-3-(3-chloro-1H-pyrazolo[3,4-b]pyridin-6-yl)-N-(5-chloro-2-cyclopropylpyridin-3- yl)acrylamide Step 1. Preparation of Methyl (E)-3-(3-chloro-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylate (2)

Methyl (E)-3-(1H-pyrazolo[3,4-b]pyridin-6-yl)acrylate (800 mg, 3.9 mmol) in DMF (16 mL) was treated with a solution of NCS (627 mg, 3.9 mmol, 1 eq) in DMF (1 mL). The reaction was stirred overnight, then concentrated. The residue was purified by reverse phase chromatography with the following conditions: Column: C18; Mobile Phase: 20-80% MeCN / 10 mmol/L aqueous NH4HCO3 solution over 30 min.; Flow rate: 100 mL/min; Wavelength: 254 nm/210 nm; Rt 20 min. Concentration of the appropriate fractions gave methyl (E)-3-(3-chloro-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylate (425 mg, 45% yield) as an off-white solid. Step 2. Preparation of Methyl (E)-3-(3-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4- b]pyridin-6-yl)acrylate (3)

Methyl (E)-3-(3-chloro-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylate (330 mg, 1.4 mmol) in DCM (6.6 mL) was treated with TsOH (24 mg, 0.14 mmol, 0.1 eq) and DHP (350 mg, 4.2 mmol, 3 eq). The reaction mixture was stirred for 2 h at room temperature, then diluted with DCM (30 ml) and washed with H2O (3 x 10 ml). The organic phase was dried with anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluting with EA:PE (0-10%). Concentration of the appropriate fractions gave methyl (2E)-3-[3-chloro-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-6-yl]prop-2-enoate (400 mg, 80% yield) as a yellow solid. Step 3. Preparation of (E)-3-(3-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6- yl)-N-(5-chloro-2-cyclopropylpyridin-3-yl)acrylamide (4)

5-Chloro-2-cyclopropylpyridin-3-amine (131 mg, 0.78 mmol) in THF (4 mL) at 0 °C was treated with 1M LiHMDS in THF (0.93 mL, 0.93 mmol, 1.2 eq). The resulting mixture was stirred for 0.5 h at 0 °C, then methyl (2E)-3-[3-chloro-1-(oxan-2-yl)pyrazolo[3,4-b]pyridin-6-yl]prop-2-enoate (250 mg, 0.78 mmol, 1 eq) in THF (1 mL) was added at 0 °C. The reaction mixture was stirred for 2 h at room temperature, then quenched with NH₄Cl at 0 °C. The mixture was extracted with EA (30 mL) and washed with H₂O (3 x 10 mL), dried with anhydrous Na₂SO₄ and concentrated. The residue was purified by HPLC with the following conditions: C18; Mobile Phase: 35-100% MeCN / 10 mmol/L aqueous formic acid over 26 min.; Flow rate: 100 mL/min; Wavelength: 254 nm/220 nm; Rt 24 min. Concentration of the appropriate fractions gave (E)-3-(3-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazolo[3,4-b]pyridin-6-yl)-N-(5-chloro-2-cyclopropyl pyridin-3-yl)acrylamide (100 mg, 28% yield) as a yellow solid. Step 4. Preparation of (E)-3-(3-Chloro-1H-pyrazolo[3,4-b]pyridin-6-yl)-N-(5-chloro-2- cyclopropylpyridin-3-yl)acrylamide

(E)-3-(3-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-N-(5-chloro-2- cyclopropyl pyridin-3-yl)acrylamide (90 mg, 0.2 mmol) in DCM (0.9 mL) was treated with TFA (0.9 mL) and stirred for 2 h. After concentration, the solid was slurried with a small amount of MeCN and filtered. The solid was washed with EA (3 x 8 mL) and dried to give (E)-3-(3-chloro-1H-pyrazolo[3,4-b]pyridin- 6-yl)-N-(5-chloro-2-cyclopropylpyridin-3-yl)acrylamide (15 mg, 20% yield) as a green solid. LCMS: (ES, m/z): 374.1 [M+H]⁺; ¹H-NMR: (300 MHz, d6-DMSO, ppm) δ 13.98 (1H, s), 10.33 (1H, s), 8.45 – 8.07 (3H, m), 7.78 (1H, d), 7.68 – 7.48 (2H, m), 3.33 (1H, s), 1.00 (4H, t). Example 47: (E)-N-(5-chloro-2-cyclopropylpyridin-3-yl)-3-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-6- yl)acrylamide Step 1. Preparation of (E)-3-(5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6- yl)acrylic acid (2)

Methyl (E)-3-(5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylate (200 mg, 0.66 mmol) in THF (2 mL) was treated with a solution of LiOH (24 mg, 0.98 mmol, 1.5 eq) in H₂O (2 mL) at 0 °C. The reaction was stirred for 2 h then diluted with water and adjusted to pH 3-4 with saturated citric acid solution. The mixture was extracted with EA (2 x 10 ml). The combined organics were washed with brine (10 ml), dried over sodium sulfate and concentrated to give crude (E)-3-(5- fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylic acid (180 mg) as a white solid. Step 2. Preparation of (E)-N-(5-Chloro-2-cyclopropylpyridin-3-yl)-3-(5-fluoro-1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide (3)

(E)-3-(5-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylic acid (180 mg, 0.62 mmol), DIEA (479 mg, 3.7 mmol, 6 eq) and 5-chloro-2-cyclopropylpyridin-3-amine (83 mg, 0.49 mmol, 0.8 eq) in DMF (1.8 mL) were cooled to 0 °C and T3P (50% in ethyl acetate) (1.2 g, 3.7 mmol, 6 eq) was added. The mixture was stirred for 3 h then concentrated. The residue was purified by reverse phase chromatography with the following conditions: column, C18; Mobile Phase: 30-70% MeCN / 0.1% aqueous NH₄HCO₃ solution over 30 min.; Flow rate: 100 mL/min; Wavelength: 210 nm; Rt 13 min. Concentration of the appropriate fractions gave (E)-N-(5-chloro-2-cyclopropylpyridin-3-yl)-3-(5- fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide (100 mg, 34% yield over 2 steps) as a yellow solid. Step 3. Preparation of (E)-N-(5-Chloro-2-cyclopropylpyridin-3-yl)-3-(5-fluoro-1H-pyrazolo[3,4- b]pyridin-6-yl)acrylamide

(E)-N-(5-Chloro-2-cyclopropylpyridin-3-yl)-3-(5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4- b]pyridin-6-yl)acrylamide (90 mg, 0.2 mmol) in dioxane (0.9 mL) was treated with 4N HCl (gas) in 1,4- dioxane (0.9 mL). The mixture was stirred for 2 h then triturated with hexane (10 mL). The solids were collected by filtration and purified by HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase: 35-60% 1:3 MeCN:IPA / 10 mmol aqueous NH4HCO3 solution containing 0.05% NH3H2O over 8 min.; Flow rate: 60 mL/min; Wavelength: 210 nm; Rt 7.5 min. Concentration of the appropriate fractions gave (E)-N-(5-chloro-2-cyclopropylpyridin-3-yl)-3-(5- fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide (25 mg, 34.% yield) as a white solid. LC-MS: (ES, m/z): 358.1 [M+H]⁺; ¹H-NMR: (400 MHz, d₆-DMSO, ppm) δ 13.82 (1H, s), 10.43 (1H, s), 8.46 – 8.05 (4H, m), 7.85 (1H, s), 7.63 (1H, d), 2.48 – 2.28 (1H, m), 1.16 – 0.89 (4H, m). ¹⁹F-NMR: (376 MHz, d₆-DMSO, ppm) δ -134.94. Example 48: (Z)-N-(2,5-difluoro-4-methylpyridin-3-yl)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)acrylamide Step 1. Preparation of Tert-butyl N-(2,5-difluoropyridin-4-yl) carbamate (2)

2,5-Difluoropyridine-4-carboxylic acid (4.0 g, 25 mmol) in tert-butanol (80 mL) was treated with Et₃N (3.6 g, 35 mmol, 1.4 eq) and DPPA (7.6 g, 28 mmol, 1.1 eq). The reaction mixture was stirred overnight at 85 °C, then cooled and concentrated. The residue was purified by silica gel chromatography, eluting with EA:PE (0-10%) to give tert-butyl N-(2,5-difluoropyridin-4-yl) carbamate (5 g, 86% yield) as a white solid. Step 2. Preparation of 2,5-Difluoropyridin-4-amine (3)

Tert-butyl N-(2,5-difluoropyridin-4-yl) carbamate (5.0 g, 22 mmol) in 1,4-dioxane (50 mL) was treated with 4N HCl in 1,4-dioxane (50 mL) and the reaction mixture was stirred overnight at room temperature. The precipitated solids were collected by filtration and washed with MTBE (3 x 20 mL). Air drying gave 2,5-difluoropyridin-4-amine (2.6 g, 92% yield) as a yellow solid. Step 3. Preparation of N-(2,5-Difluoropyridin-4-yl)nitramide (4)

2,5-Difluoropyridin-4-amine (2.6 g, 20 mmol) in conc. H₂SO₄ (26 mL) was cooled in an ice bath and 65-68% conc. HNO₃ (10.4 mL) was slowly added to the mixture at 0 °C. The mixture was heated at 80 °C for 2 h, then cooled. The reaction was poured into saturated aqueous NaHCO₃ solution at 0 °C. The precipitated solids were collected by filtration and washed with H2O (3 x 10 mL). Drying gave N- (2,5-difluoropyridin-4-yl)nitramide (2.5 g, 71% yield) as a yellow solid. Step 4. Preparation of 2,5-Difluoro-3-nitropyridin-4-amine (5)

N-(2,5-Difluoropyridin-4-yl)nitramide (2.5 g, 14 mmol) was taken up in conc. H2SO4 (12.5 mL) and stirred for 2 h at 100 °C. The mixture was cooled and added to saturated aqueous NaHCO3 solution slowly. The precipitated solids were collected by filtration and washed with H2O (2 x 20 mL). Drying gave 2,5-difluoro-3-nitropyridin-4-amine (1.1 g, 44% yield) as a yellow solid. Step 5. Preparation of 4-Bromo-2,5-difluoro-3-nitropyridine (6)

2,5-Difluoro-3-nitropyridin-4-amine (1.2 g, 7.1 mmol) in MeCN (25 mL) was treated with CuBr₂ (1.9 g, 8.5 mmol, 1.2 eq) and the mixture was heated to 65 °C.2-Tert-butyl nitrite (1.1 g, 11 mmol, 1.5 eq) was added dropwise and the reaction mixture stirred for 2 h at 65 °C. The mixture was cooled and quenched with 2 M HCl aqueous solution (10 mL), then extracted with EA (3 x 15 mL). The combined organics were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluting with EA/PE (0~5%) to give 4-bromo-2,5-difluoro-3-nitropyridine (1 g, 59% yield) as a yellow solid. Step 6. Preparation of 2,5-Difluoro-4-methyl-3-nitropyridine (7)

4-Bromo-2,5-difluoro-3-nitropyridine (500 mg, 2.1 mmol) in 1,4-dioxane (10 mL) and H2O (2.5 mL) was treated with trimethyl-1,3,5,2,4,6-trioxatriborinane (525 mg, 4.2 mmol, 2 eq), K2CO3 (868 mg, 6.3 mmol, 3 eq) and Pd(dppf)Cl2 (230 mg, 0.31 mmol, 0.15 eq) and the mixture was degassed with nitrogen. The reaction mixture was stirred for 2 h at 90 °C, then cooled and diluted with EA (15 mL). The organics were washed with water (3 x 15 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluting with EA/PE (0~5%) to give 2,5-difluoro- 4-methyl-3-nitropyridine (160 mg, 43% yield) as a yellow oil. Step 7. Preparation of 2,5-Difluoro-4-methylpyridin-3-amine (8) To 2,5-difluoro-4-methyl-3-nitropyridine (160 mg, 0.92 mmol) in DMF (3.2 mL) at 0 °C was added dihydroxyboranyl)boronic acid (410mg, 4.6 mmol, 5 eq).4-(Pyridin-4-yl)pyridine (14 mg, 0.092 mmol, 0.1 eq) in DMF (0.5 ml) was added dropwise and the reaction mixture stirred for 0.5 h at 0 °C. EA (10 mL) was added and the organic layer was washed with brine (6 x 15 mL), dried over anhydrous Na₂SO₄ and concentrated. Crude 2,5-difluoro-4-methylpyridin-3-amine (125 mg) was isolated as a yellow solid. Step 8. Preparation of (Z)-N-(2,5-difluoro-4-methylpyridin-3-yl)-2-fluoro-3-(7-fluoro-1H-indazol- 6-yl)acrylamide

2,5-Difluoro-4-methylpyridin-3-amine (100 mg, 0.69 mmol) in THF (2 mL) was cooled to -70 °C and 1M LiHMDS in hexanes (1.3 mL, 1.3 mmol, 2 eq) was added dropwise. The reaction mixture was stirred at -70 °C for 0.5 h, when methyl (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)acrylate (165 mg, 0.69 mmol, 1 eq) in THF (0.5 mL) was added. The mixture was removed from the cooling bath and allowed to stir to room temperature over 1.5 h. The reaction was quenched with water (10 mL) and extracted with EA (3 x 15 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified by HPLC with the following conditions: Column: Xselect CSH F-Phenyl OBD 30*150 mm, 5μm; Mobile Phase: 15-40% MeCN / 0.1% aqueous formic acid over 8 min.; Flow rate: 60 mL/min; Wavelength: 254 nm/220 nm; Rt 7 min. Concentration of the appropriate fractions gave (Z)-N-(2,5-difluoro-4-methylpyridin-3-yl)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)acrylamide (60 mg, 45% yield over two steps) as a white solid. LC-MS: (ES, m/z): 351.1 [M+H]⁺; ¹H-NMR: (400 MHz, d₆-DMSO, ppm) δ 13.93 (1H, s), 10.67 (1H, s), 8.26 (1H, d), 8.20 (1H, d), 7.71 (1H, d), 7.56 -7.50 (1H, m), 7.29 (1H, d), 2.25 (3H, s). ¹⁹F-NMR: (376 MHz, d6-DMSO, ppm) δ -77.92, -123.79, -130.79, -133.64. Example 49: (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(2-fluoro-6-methoxy-4-methylpyridin-3- yl)acrylamide Step 1. Preparation of 2,6-Difluoro-4-methylpyridine (2) A mixture of 4-bromo-2,6-difluoropyridine (5.0 g, 26 mmol), methylboronic acid (3.1 g, 52 mmol, 2 eq), K2CO3 (11 g, 77 mmol, 3 eq) and Pd(dppf)Cl2 (1.9 g, 2.6 mmol, 0.1 eq) in DME (40 mL) and H2O (10 mL) was degassed with nitrogen and heated overnight at 90 °C. The reaction was cooled and concentrated. The residue was purified by silica gel chromatography, eluting with PE / EA (100:1) to afford 2,6-difluoro-4-methylpyridine (1.1 g, 33% yield) as a light yellow oil. Step 2. Preparation of 2,6-Difluoro-4-methyl-3-nitropyridine (3)

To a solution of 2,6-difluoro-4-methylpyridine (1.1 g, 8.5 mmol) in TFAA (5.5 mL) at 0 °C was added c.HNO₃ (0.55 mL) dropwise. The reaction mixture was stirred overnight at room temperature, then poured into water/ice and extracted with EtOAc (3 x 20 mL). The combined organics were washed with saturated aqueous NaHCO₃ (10 mL), dried over anhydrous Na₂SO₄ and concentrated. The crude 2,6-difluoro-4-methyl-3-nitropyridine was used in the next step directly without further purification. Step 3. Preparation of 2-Fluoro-6-methoxy-4-methyl-3-nitropyridine (4)

To a solution of 2,6-difluoro-4-methyl-3-nitropyridine (1.5 g, 8.4 mmol) in MeOH (30 mL) cooled to - 78 °C was added sodium methoxide (0.39 g, 7.1 mmol, 0.85 eq) in portions over 2 min. The reaction mixture was stirred at -78 °C for 1 h, then quenched with water (30 mL) and extracted with EtOAc (3 x 15 mL). The combined organics were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica chromatography (PE / EA 10:1) to afford 2-fluoro-6- methoxy-4-methyl-3-nitropyridine (181 mg, 12% yield) as an off-white solid. Step 4. Preparation of 2-Fluoro-6-methoxy-4-methylpyridin-3-amine (5)

2-Fluoro-6-methoxy-4-methyl-3-nitropyridine (181 mg, 0.97 mmol) and B2(OH)4 (262 mg, 2.9 mmol, 3 eq) in DMF (2 mL) at 0 °C were treated with 4-(pyridin-4-yl)pyridine (7.6 mg, 0.049 mmol, 0.05 eq) in DMF (2 mL) dropwise over 2 min. The reaction mixture was stirred at 0 °C for 15 min. then quenched with water (5 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (5 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica chromatography (PE / EA 2:1) to afford 2-fluoro-6-methoxy-4-methylpyridin-3-amine (112 mg, 74% yield) as a yellow oil. Step 5. Preparation of (Z)-2-Fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(2-fluoro-6-methoxy-4- methylpyridin-3-yl)acrylamide

2-Fluoro-6-methoxy-4-methylpyridin-3-amine (100 mg, 0.64 mmol) in THF (2 mL) was cooled to -78 °C and treated with 1M LiHMDS in THF (214 mg, 1.3 mmol, 2 eq) dropwise over 30 min. Methyl (Z)-2- fluoro-3-(7-fluoro-1H-indazol-6-yl)acrylate (183 mg, 0.77 mmol, 1.2 eq) in THF (2 mL) was then added dropwise and the reaction mixture stirred at -78 °C for 30 min. The reaction was quenched with water (4 mL) and the resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organics were washed with brine (5 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by reverse-phase chromatography with the following conditions: Column: YMC-Actus Triart C18 ExRS30*150 mm, 5 μm; Mobile Phase: 25-57% MeCN / 10 mmol/L aqueous NH₄HCO₃ solution containing 0.05%NH₃.H₂O over 10 min.; Flow rate: 60 mL/min; Wavelength: 254 nm/220 nm; Rt 8.8 min. Concentration of the appropriate fractions gave (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(2- fluoro-6-methoxy-4-methylpyridin-3-yl)acrylamide (10 mg, 4.4% yield) as a white solid. LC-MS: (ES, m/z): 363.1 [M+H]⁺; ¹H-NMR: (300 MHz, d6-DMSO, ppm) δ 13.89 (1H, s), 10.20 (1H, s), 8.26 (1H, d), 7.71 (1H, d), 7.55 (1H, d), 7.24 (1H, d), 6.78 (1H, s), 3.84 (3H, s), 2.25 (3H, s). ¹⁹F-NMR: (300 MHz, d₆-DMSO, ppm) δ -78.61, -123.80, 131.09. Example 50: (Z)-N-(5-cyano-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(3,7-difluoro-1H-indazol-6-yl)- 2-fluoroacrylamide Step 1. Preparation of 5-Chloro-4-methyl-3-nitro-2-(trifluoromethyl)pyridine (2)

2-Bromo-5-chloro-4-methyl-3-nitropyridine (4.0 g, 16 mmol) in DMF (40 mL) were treated with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (4.6 g, 24 mmol, 1.5 eq) and CuI (3.6 g, 19 mmol, 1.2 eq). The reaction was heated at 100 °C for 1 h, then cooled and quenched with H₂O (200 mL). The resulting mixture was extracted with MTBE (2 x 150 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluting with 0-8% EA: PE to give 5-chloro-4-methyl-3-nitro-2-(trifluoromethyl)pyridine (2.7 g, 71% yield) as a yellow solid. Step 2. Preparation of 4-Methyl-5-nitro-6-(trifluoromethyl)pyridine-3-carbonitrile (3)

To 5-chloro-4-methyl-3-nitro-2-(trifluoromethyl)pyridine (2.3 g, 9.6 mmol) in DMA (23 mL) was added zinc (II) cyanide (1.1 g, 9.6 mmol, 1 eq) and Zn (63 mg, 0.96 mmol, 0.1 eq). X-Phos (912 mg, 1.9 mmol, 0.2 eq) and Pd₂(dba)₃ (876 mg, 0.96 mmol, 0.1 eq) were added and the reaction heated at 100 °C for 1 h. The mixture was cooled and concentrated, and the residue purified by reverse phase chromatography with the following conditions: Column: C18; Mobile Phase: 20-100% MeCN / 0.1% aqueous formic acid over 40 min.; Flow rate: 100 mL/min; Wavelength: 254 nm/220 nm; Rt 25 min. Concentration of the appropriate fractions gave 4-methyl-5-nitro-6-(trifluoromethyl)pyridine-3- carbonitrile (700 mg, 32% yield) as a brown solid. Step 3. Preparation of 5-Amino-4-methyl-6-(trifluoromethyl)nicotinonitrile (4)

4-Methyl-5-nitro-6-(trifluoromethyl)pyridine-3-carbonitrile (700 mg, 3.0 mmol) and (dihydroxyboranyl) boronic acid (815 mg, 9.1 mmol, 3 eq) in DMF (14 mL) were cooled to 0 °C and 4-(pyridin-4-yl)pyridine (24 mg, 0.15 mmol, 0.05 eq) in DMF (4 mL) was added dropwise. The mixture was stirred at 0°C for 0.5 h, then concentrated. The residue was purified by reverse phase chromatography with the following conditions: Column: C18; Mobile Phase: 20-100% MeCN / 0.1% aqueous NH4HCO3 solution over 17 min.; Flow rate: 100 mL/min; Wavelength: 254 nm/220 nm; Rt 8.5 min. Concentration of the appropriate fractions gave 5-amino-4-methyl-6-(trifluoromethyl)nicotinonitrile (500 mg, 82% yield) as a yellow solid. Step 4. Preparation of (Z)-N-(5-Cyano-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(3,7-difluoro- 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-2-fluoroacrylamide (5)

To a solution of 5-amino-4-methyl-6-(trifluoromethyl)pyridine-3-carbonitrile (93 mg, 0.46 mmol) and (Z)-3-(3,7-difluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-2-fluoroacrylic acid (150 mg, 0.46 mmol, 1 eq) in DMF (1.5 mL) at 0°C was added DIEA (357 mg, 2.8 mmol, 6 eq) and T3P (878 mg, 2.8 mmol, 6 eq). The reaction was heated at 100°C overnight then cooled and concentrated. The residue was poured into ice water (10 mL), then extracted with EA (2 x 10 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica chromatography (1:2 EA:PE) to afford (Z)-N-(5-cyano-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(3,7-difluoro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-2-fluoroacrylamide (50 mg, 21% yield) as a yellow solid. Step 5. Preparation of (Z)-N-(5-cyano-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(3,7-difluoro- 1H-indazol-6-yl)-2-fluoroacrylamide

(Z)-N-(5-Cyano-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(3,7-difluoro-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-6-yl)-2-fluoroacrylamide (48 mg, 0.094 mmol) in DCM (960 μL) was treated with trifluoroacetic acid (480 μL) at 0 °C, then stirred at room temperature overnight. After concentration, the residue was purified by reverse phase chromatography with the following conditions: Column: Xselect CSH Prep C18 OBD Colum, 19*250nm, 5μm; Mobile Phase: 30-55% MeCN / 10 mmol/L aqueous NH₄HCO₃ solution over 12 min.; Flow rate: 25 mL/min; Wavelength: 254 nm/220 nm; Rt 13.2 min. Concentration of the appropriate fractions gave (Z)-N-(5-cyano-4-methyl-2- (trifluoromethyl)pyridin-3-yl)-3-(3,7-difluoro-1H-indazol-6-yl)-2-fluoroacrylamide (15 mg, 37% yield) as a white solid. LC-MS: (ES, m/z): 426.1 [M+H]⁺; ¹H-NMR: (400 MHz, d6-DMSO, ppm) δ 13.47 (1H, s), 10.87 (1H, s), 9.11 (1H, s), 7.66 (1H, d), 7.63 – 7.55 (1H, m), 7.25 (1H, d), 2.50 – 2.45 (3H, m). ¹⁹F-NMR: (376 MHz, d₆-DMSO, ppm) δ -64.26, -122.60, -132.20, -135.47. Example 51: (Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(7-fluoro-3-propyl-1H-indazol-6- yl)acrylamide Step 1. Preparation of (Z)-2-Fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(7-fluoro-3-iodo-1H- indazol-6-yl)acrylamide (2)

(Z)-2-Fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)acrylamide (420 mg, 1.2 mmol) and NIS (300 mg, 1.3 mmol, 1.1 eq) in MeCN (4.2 mL) were stirred overnight at room temperature. The reaction mixture was quenched by the addition of H₂O (10 mL) and extracted with EA (3 x 50 mL). The combined organics were dried over anhydrous MgSO4 and concentrated to give (Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(7-fluoro-3-iodo-1H-indazol-6-yl)acrylamide (342 mg, 60% yield) as a white solid. Step 2. Preparation of (Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(7-fluoro-3-propyl-1H- indazol-6-yl)acrylamide

(Z)-2-Fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(7-fluoro-3-iodo-1H-indazol-6-yl)acrylamide (1.0 g, 2.1 mmol), 0.5M 2-propylzinc bromide in THF (6.3 mL, 3.2 mmol, 1.5 eq), Pd2(dba)3.CHCl3 (0.05 g, 0.053 mmol, 0.025 eq) and SPhos (0.04 g, 0.11 mmol, 0.05 eq) in THF (10 mL) were stirred at 60 °C for 6 h. The mixture was cooled and concentrated. The residue was purified by supercritical fluid chromatography with the following conditions (Column: DAICEL DCpak P4VP 3*25 cm, 5 μm; Mobile Phase: 35% 20 mM NH₃ in MeOH / CO₂; Flow rate: 60 mL/min; Column Temperature: 35℃; Back Pressure: 100 bar; Wavelength: 254 nm; Rt 4.54 min. to afford (Z)-2-fluoro-N-(5-fluoro-2,4- dimethylpyridin-3-yl)-3-(7-fluoro-3-propyl-1H-indazol-6-yl)acrylamide (9.5 mg, 1.2% yield) as a white solid. LC-MS: (ES, m/z): 389.2 [M+H]⁺; ¹H-NMR: (300 MHz, d₆-DMSO, ppm) δ 13.48 (1H, s), 10.46 (1H, s), 8.39 (1H, s), 7.68 (1H, d), 7.53 (1H, d), 7.33 – 7.20 (1H, d), 2.92 (2H, t), 2.38 (3H, s), 2.16 (3H, s), 1.77 (2H, h), 0.96 (3H, t). ¹⁹F-NMR: (300 MHz, d₆-DMSO, ppm) δ -123.62, -131.66, -134.56. Example 52: (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-ethynyl-5-fluoro-1H-pyrazolo[3,4-b]pyridin-6- yl)acrylamide Step 1. Preparation of Methyl (E)-3-(5-fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylate (2)

To methyl (E)-3-(5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylate (740 mg, 3.3 mmol) in DMF (15 mL) was added N-iodosuccinimide (903 mg, 4.0 mmol, 1.2 eq) and the reaction stirred for 12 h at 40 °C. After cooling and concentration the residue was purified by reverse phase chromatography with the following conditions: column, C18; Mobile Phase: 30-70% MeCN / 0.1% aqueous NH4HCO3 solution over 30 min.; Flow rate: 100 mL/min; Wavelength: 210 nm; Rt 18 min. Concentration of the appropriate fractions gave methyl (E)-3-(5-fluoro-3-iodo-1H-pyrazolo[3,4- b]pyridin-6-yl)acrylate (800 mg, 68% yield) as a white solid. Step 2. Preparation of Methyl (E)-3-(5-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazolo[3,4-b]pyridin-6-yl)acrylate (3)

To methyl (E)-3-(5-fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylate (450 mg, 1.3 mmol) in DCM (4.5 mL) was added 3,4-dihydro-2H-pyran (131 mg, 1.6 mmol, 1.2 eq) and TsOH (45 mg, 0.26 mmol, 0.2 eq). The mixture was stirred for 2 h at room temperature, then concentrated. The residue was purified by silica gel chromatography, eluting with 0-10% EA/PE. Concentration of the appropriate fractions gave methyl (E)-3-(5-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6- yl)acrylate (530 mg, 94% yield) as a white solid. Step 3. Preparation of (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(5-fluoro-3-iodo-1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazolo [3,4-b]pyridin-6-yl)acrylamide (4)

A solution of 5-chloro-2-methylpyridin-3-amine (159 mg, 1.1 mmol) in THF (10 mL) was cooled at - 70 °C and 1M LiHMDS in hexanes (2.2 mL, 2.2 mmol, 2 eq) was added dropwise. The mixture was stirred at -70 °C for 0.5 h, then methyl (2E)-3-[5-fluoro-3-iodo-1-(oxan-2-yl) pyrazolo[3,4-b]pyridin-6- yl]prop-2-enoate (480 mg, 1.1 mmol) in THF (1 mL) was added slowly at -70 °C. The mixture was stirred for 2 h at -70 °C, then concentrated. The residue was purified by reverse phase chromatography with the following conditions: column, C18; Mobile Phase: 40-90% MeCN / 0.1% aqueous formic acid over 30 min., Mobile Phase B: ACN; Flow rate: 100 mL/min; Gradient: 40% B to 90% B in 30 min; Wavelength: 210 nm; Rt 25 min. Concentration of the appropriate fractions gave (E)-N-(5-chloro-2- methylpyridin-3-yl)-3-(5-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6- yl)acrylamide (300 mg, 49% yield) as a yellow solid. Step 4. Preparation of (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(5-fluoro-1-(tetrahydro-2H-pyran- 2-yl)-3-((trimethylsilyl) ethynyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide (5)

To (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(5-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo [3,4-b]pyridin-6-yl)acrylamide (300 mg, 0.55 mmol) in DMF (3 mL) was added trimethylsilylacetylene (109 mg, 1.1 mmol, 2 eq), Et3N (168 mg, 1.7 mmol, 3 eq) and CuI (11 mg, 0.055 mmol, 0.1 eq). The mixture was degassed with N₂ for 10 min. then Pd(PPh₃)₂Cl₂ (57 mg, 0.08 mmol, 0.1 eq) was added, and the reaction stirred for 2 h at 60 °C. The resulting mixture was cooled and concentrated, and the residue purified by reverse phase chromatography with the following conditions: column, C18; Mobile Phase: 60-100% MeCN / 0.1% aqueous formic acid over 30 min.; Flow rate: 100 mL/min; Wavelength: 210 nm; Rt 17 min. Concentration of the appropriate fractions gave (E)-N-(5-chloro-2-methylpyridin- 3-yl)-3-(5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3-((trimethylsilyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-6- yl)acrylamide (200 mg, 70% yield) as a yellow solid. Step 5. Preparation of (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-ethynyl-5-fluoro-1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide (6)

(E)-N-(5-Chloro-2-methylpyridin-3-yl)-3-(5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-3- ((trimethylsilyl)ethynyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide (200 mg, 0.39 mmol) in methanol (2 mL) was treated with K2CO3 (65 mg, 0.47 mmol, 1.2 eq) and stirred overnight at room temperature. The resulting mixture was concentrated and diluted with water (10 mL), before being extracted with EA (3 x 10 mL). The combined organics were dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography, eluting with EA/PE (0~10%). Concentration of the appropriate fractions gave (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-ethynyl-5-fluoro-1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide (150 mg, 87% yield) as a yellow solid. Step 6. Preparation of (E)-N-(5-Chloro-2-methylpyridin-3-yl)-3-(3-ethynyl-5-fluoro-1H- pyrazolo[3,4-b]pyridin-6-yl)acrylamide

(E)-N-(5-Chloro-2-methylpyridin-3-yl)-3-(3-ethynyl-5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazolo[3,4-b]pyridin-6-yl)acrylamide (150 mg, 0.35 mmol) in dioxane (1.5 mL) was treated with 4N HCl (gas) in dioxane (1.5 mL). The mixture was stirred overnight at room temperature, then triturated with hexanes. The precipitated solids were collected by filtration and washed with hexane (3 x 10 mL). Air drying gave (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-ethynyl-5-fluoro-1H-pyrazolo[3,4-b]pyridin- 6-yl)acrylamide (16 mg, 13% yield) as a yellow solid. LC-MS: (ES, m/z): 356.1 [M+H]⁺ _; ¹H-NMR: (400 MHz, d₆-DMSO, ppm) δ 14.26 (1H, s), 10.15 (1H, s), 8.27 – 8.20 (3H, m), 7.83 (1H, d), 7.63 (1H, d), 4.66 (1H, s), 2.50 (3H, s). ¹⁹F-NMR: (376 MHz, d₆-DMSO, ppm) δ -132.82. Example 53: (Z)-N-(2-(difluoromethyl)-5-fluoro-4-methylpyridin-3-yl)-2-fluoro-3-(7-fluoro-1H-indazol- 6-yl)acrylamide Step 1. Preparation of 5-Fluoro-4-methyl-3-nitropyridin-2-amine (2) To a solution of 5-fluoro-4-methylpyridin-2-amine (20 g, 158 mmol) in conc. H₂SO₄ (250 mL) was added 65-68% conc. HNO₃ (12 g, 190 mmol, 1.2 eq) at -10 °C. The mixture was stirred to 25°C for 3 h, then slowly poured into ice water. The mixture was neutralized with NH3·H2O and extracted with DCM (3 x 150 mL). The combined organics were washed with brine (2 x 90 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluting with PE/THF (4/1) to afford 5-fluoro-4-methyl-3-nitropyridin-2-amine (9 g, 32% yield) as a yellow solid. ¹H NMR: ¹H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.03 (s, 2H), 2.30 (d, J = 2.3 Hz, 3H). Step 2. Preparation of 2-Bromo-5-fluoro-4-methyl-3-nitropyridine (3)

To a solution of 5-fluoro-4-methyl-3-nitropyridin-2-amine (4 g, 12 mmol) in MeCN (50 mL) was added CuBr2 (7.9 g, 35 mmol, 3 eq) and tert-butylnitrite (3.7 g, 35 mmol, 3 eq). The mixture was stirred at 60 °C for 1 h, then cooled and diluted with H₂O, and extracted with EA (3 x 80 mL). The combined organics were washed with brine (2 x 30 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography, eluting with PE/THF (5/1) to afford 2-bromo-5- fluoro-4-methyl-3-nitropyridine (2 g, 36% yield) as an off-white solid. Step 3. Preparation of 2-Ethenyl-5-fluoro-4-methyl-3-nitropyridine (4)

To a solution of 2-bromo-5-fluoro-4-methyl-3-nitropyridine (1.5 g, 6.1 mmol) and 2-ethenyl-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (1.05 g, 6.7 mmol, 1.1 eq) in 1,4-dioxane (20 mL) and H2O (4 mL) were added K2CO3 (2.6 g, 19 mmol, 3 eq) and Pd(dppf)Cl2 (453 mg, 0.6 mmol, 0.1 eq). The mixture was stirred at 90 °C for 4 h under a nitrogen atmosphere. The resulting mixture was cooled, diluted with H₂O and extracted with EA (3 x 50 mL). The combined organics were washed with brine (2 x 20 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography, eluting with PE / THF (5:1) to afford 2-ethenyl-5-fluoro-4-methyl-3-nitropyridine (730 mg, 64% yield) as a yellow oil. ¹H NMR (300 MHz, DMSO-d6) δ 8.81 (s, 1H), 6.68 (dd, J = 16.7, 10.6 Hz, 1H), 6.43 (dd, J = 16.7, 1.9 Hz, 1H), 5.78 – 5.67 (m, 1H), 2.26 (d, J = 2.0 Hz, 3H). Step 4. Preparation of 5-Fluoro-4-methyl-3-nitropyridine-2-carbaldehyde (5)

To a solution of 2-ethenyl-5-fluoro-4-methyl-3-nitropyridine (730 mg, 4.0 mmol) in THF (8 mL) and H2O (8 mL) was added potassium osmate dihydrate (73 mg, 0.2 mmol, 0.05 eq) and 4-methylmorpholine (704 mg, 6.0 mmol, 1.5 eq) and the mixture stirred at RT for 1 h. NaIO4 (2.6 g, 12 mmol, 3 eq) was added and the mixture was stirred for 3 h, then quenched with sat. Na₂S₂O₃ solution. The resulting mixture was extracted with DCM (3 x 30 mL). The combined organics were washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography, eluting with PE/THF (5/1) to afford 5-fluoro-4-methyl-3-nitropyridine-2-carbaldehyde (500 mg, 67% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.04 (s, 1H), 2.28 (d, J = 2.0 Hz, 3H). Step 5. Preparation of 2-(Difluoromethyl)-5-fluoro-4-methyl-3-nitropyridine (6)

Diethylaminosulfur trifluoride (4.4 g, 27 mmol, 10 eq) was added dropwise to 5-fluoro-4-methyl-3- nitropyridine-2-carbaldehyde (500 mg, 2.7 mmol) in DCM (2 mL) at 0 °C over a period of 10 minutes. The reaction mixture was stirred at 40°C for 12 h. The reaction was quenched by the addition of ice water (20 mL). The resulting mixture was extracted with DCM (3 x 20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluting with PE / THF (4:1) to afford 2-(difluoromethyl)-5-fluoro-4-methyl-3-nitropyridine (330 mg, 58% yield) as a yellow oil. Step 6. Preparation of 2-(Difluoromethyl)-5-fluoro-4-methylpyridin-3-amine (7)

To a solution of 2-(difluoromethyl)-5-fluoro-4-methyl-3-nitropyridine (330 mg, 1.4 mmol) in methanol (8 mL) was added 10% Pd/C (100 mg) in a pressure tank. The mixture was hydrogenated at room temperature under 10 atm of hydrogen pressure overnight, filtered through a Celite pad and concentrated. The crude product 2-(difluoromethyl)-5-fluoro-4-methylpyridin-3-amine (250 mg) was used in the next step directly without further purification. LCMS (ES, m/z): 177 [M+H]⁺ 1H NMR: ¹H NMR (300 MHz, Methanol-d₄) δ 8.72 (s, 1H), 6.90 (t, J = 53.6 Hz, 1H), 2.38 (d, J = 2.0 Hz, 3H). Step 7. Preparation of (Z)-N-(2-(difluoromethyl)-5-fluoro-4-methylpyridin-3-yl)-2-fluoro-3-(7- fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (8)

To a solution of 2-(difluoromethyl)-5-fluoro-4-methylpyridin-3-amine (70 mg, 0.3 mmol) and methyl (Z)- 2-fluoro-3-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (92 mg, 0.2 mmol, 0.8 eq) in THF (2 mL) was added 1M LiHMDS in THF (1.0 mL, 1.0 mmol, 3 eq) at -78 °C. The reaction was stirred at -78 °C for 20 min., then quenched with sat. NH4Cl (aq.). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica chromatography (PE/THF = 4:1) to afford (Z)-N-(2-(difluoromethyl)-5-fluoro-4-methylpyridin-3-yl)-2-fluoro-3-(7-fluoro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (35 mg, 20% yield) as a white solid. LCMS (ES, m/z): 467 [M+H]⁺ Step 8. Preparation of (Z)-N-(2-(difluoromethyl)-5-fluoro-4-methylpyridin-3-yl)-2-fluoro-3-(7- fluoro-1H-indazol-6-yl)acrylamide

To a solution of (Z)-N-(2-(difluoromethyl)-5-fluoro-4-methylpyridin-3-yl)-2-fluoro-3-(7-fluoro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (35 mg, 0.06 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.3 mL). The mixture was stirred at 20°C for 2 h then concentrated. The mixture was neutralised with NH₃·H₂O and purified by Prep-HPLC with the following conditions: Column: Uitimate - XB-C18 Column, 30*150 mm, 10μm; Mobile Phase: 5% MeCN for 2 min, then 5-50% MeCN over 10 min. / 0.05% aqueous NH3·H2O; Flow rate: 90 mL/min; Wavelength: 254nm/220nm nm; RT 11.5 min. Concentration of the appropriate fractions gave (2Z)-N-[2-(difluoromethyl)-5-fluoro-4- methylpyridin-3-yl]-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)prop-2-enamide (6.9 mg, 26% yield) as a white solid. LCMS (ES, m/z): 383 [M+H]⁺ ¹H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.26 (d, J = 3.5 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 8.6, 5.8 Hz, 1H), 7.34 – 6.88 (m, 2H), 2.19 (d, J = 2.0 Hz, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ -115.98, -126.26, -131.11. Example 54: (Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-3-methyl-1H-indazol-6- yl)acrylamide Step 1.6-Bromo-7-fluoro-3-iodo-1H-indazole

To 6-bromo-7-fluoro-1H-indazole (2.0 g, 9.3 mmol) in DMF (20 mL) was added I₂ (5.2 g, 20 mmol, 2.2 eq) and KOH (1.3 g, 22 mmol, 2.4 eq) at room temperature, and resulting mixture was stirred overnight. The reaction was cooled to 0°C and quenched with aqueous sat. Na2SO3 solution (200 mL). The precipitated solids were collected by filtration and washed with water (3x10 mL). Drying gave 6-bromo- 7-fluoro-3-iodo-1H-indazole (2.8 g, 88% yield) as an off-white solid. LCMS (ES, m/z): 341 [M+H]⁺ Step 2.6-Bromo-7-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

A solution of 6-bromo-7-fluoro-3-iodo-1H-indazole (2.9 g, 8.4 mmol) in DCM (30 mL) was treated with TsOH (0.44 g, 2.5 mmol, 0.3 eq) and DHP (1.4 g, 17 mmol, 2 eq), and the reaction stirred for 1h. The resulting mixture was concentrated, and the residue purified by silica chromatography, eluting with n- hexane/AcOEt (2:1) to afford 6-bromo-7-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.6 g, 72% yield) as a light brown solid. LCMS (ES, m/z): 425 [M+H]⁺ Step 3.6-Bromo-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

To 6-bromo-7-fluoro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.0 g, 2.3 mmol), 2,4,6- trimethyl-1,3,5,2,4,6-trioxatriborinane (0.28 g, 2.3 mmol, 1 eq) and Cs2CO3 (2.3 g, 7 mmol, 3 eq) in dioxane (10 mL) and H2O (1 mL) was added Pd(dppf)Cl2 (0.17 g, 0.2 mmol, 0.1 eq) and the reaction mixture stirred for 6 h at 80°C under nitrogen atmosphere. The mixture was cooled and quenched by water (20 mL), then extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica chromatography, eluting with n-hexane/AcOEt (5:1) to afford 6-bromo-7-fluoro-3-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazole (0.46 g, 59% yield) as a yellow solid. LCMS (ES, m/z): 313 [M+H]⁺ Step 4. Methyl (Z)-2-fluoro-3-(7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6- yl)acrylate

To 6-bromo-7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (180 mg, 0.6 mmol), methyl 2-fluoroacrylate (74 mg, 0.8 mmol, 1.5 eq), and TEA (174 mg, 1.7 mmol, 3 eq) in DMF (3.6 mL) was added Pd(dtpf)Cl2 (84 mg, 0.1 mmol, 0.2 eq). The reaction mixture was stirred for 4 h at 90°C under nitrogen atmosphere, then cooled and quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (10 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica chromatography, eluting with n-hexane/AcOEt (3:1) to afford methyl (Z)-2-fluoro-3-(7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-6-yl)acrylate (150 mg, 77% yield) as a yellow solid. LCMS (ES, m/z): 337 [M+H]⁺ Step 5. Preparation of (Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-3-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (2)

To a solution of 5-chloro-2,4-dimethylpyridin-3-amine (39 mg, 0.2 mmol, 1.2 eq) and methyl (Z)-2- fluoro-3-(7-fluoro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (70 mg, 0.03 mmol) in THF (2 mL) was added 1M LiHMDS in THF (0.8 mL, 0.8mmol 4 eq) dropwise at -78°C. The reaction mixture was stirred for 1 h at -78°C, then quenched with water and extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine (3 x 50 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica chromatography, eluting with petroleum ether/ethyl acetate (1:1) to afford (Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-3-methyl-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (80 mg, 83% yield) as a light yellow solid. LCMS (ES, m/z): 461 [M+H]⁺ Step 6. Preparation of (Z)-N-(5-Chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-3-methyl- 1H-indazol-6-yl)acrylamide

A solution of (Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-3-methyl-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-6-yl)acrylamide (70 mg, 0.1 mmol) in DCM (1 mL) was treated with 4N HCl in 1,4-dioxane (1 mL) and stirred for 1 h. The resulting mixture was concentrated, and the residue dissolved in MeOH (3 mL) and purified by reverse phase chromatography with the following conditions (Column: XBridge Prep C18 Column, 30*150 mm, 5μm; Mobile Phase: 30-50% MeCN / 0.1% aqueous NH₃ ^.H₂O over 10 min.; Flow rate: 60mL/min.). Concentration of the appropriate fractions gave (2Z)-N- (5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-3-methyl-1H-indazol-6-yl) prop-2-enamide (31 mg, 54% yield) as a white solid. LCMS (ES, m/z): 377 [M+H]⁺ ¹H NMR (400 MHz, DMSO-d6, ppm) δ 13.42 (s, 1H), 10.45 (s, 1H), 8.44 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.52 (dd, J = 8.5, 5.7 Hz, 1H), 7.23 (d, J = 37.6 Hz, 1H), 2.51 (s, 3H), 2.37 (s, 3H), 2.24 (s, 3H). Example 55: (E)-3-(7-fluoro-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3- yl)acrylamide Step 1. Preparation of (E)-3-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-(5-fluoro- 4-methyl-2-(trifluoromethyl)pyridin-3-yl)acrylamide (3)

To 5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3-amine (0.07 g, 0.36 mmol), (2E)-3-[7-fluoro-1-(oxan- 2-yl) indazol-6-yl]prop-2-enoic acid (0.12 g, 0.4 mmol, 1.1 eq) and DIEA (0.37g, 2.9 mmol, 8 eq) in DMF (2 mL) was added 50% T3P in EA (1.4 g, 2.1mmol, 6 eq) and the reaction stirred for 14 h at 120°C. The mixture was cooled and diluted with H₂O (5 mL), then extracted with EtOAc (3 x 8 mL). The combined organics were dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography, eluting with Petroleum ether/ EtOAc (1:1) to afford (E)-3-(7- fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3- yl)acrylamide (0.098 g, 58% yield) as a yellow oil. LCMS (ES, m/z): 467 [M+H]⁺ Step 2. Preparation of (E)-3-(7-Fluoro-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2- (trifluoromethyl)pyridin-3-yl)acrylamide

To (E)-3-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2- (trifluoromethyl)pyridin-3-yl)acrylamide (0.098g, 0.21 mmol) in DCM (1.5 mL) was added TFA (0.5 mL) and the solution stirred for 3 h, before being concentrated. The resulting mixture was diluted with ice- water (5 mL) and neutralized to pH 8 with NaHCO₃ solution. This was extracted with DCM (3x5 mL), dried over anhydrous Na2SO4 and concentrated. The residue was dissolved in MeOH (3 mL) and purified by Prep-HPLC with the following conditions: Column XBridge C18, 19*150 mm, 5 μm; Mobile Phase: 5-95% MeCN / 20 mM aqueous NH4HCO3 solution containing 0.05%NH3.H2O over 15 min.; Flow rate: 20 mL/min. Concentration of the appropriate fractions gave (E)-3-(7-Fluoro-1H-indazol-6- yl)-N-(5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)acrylamide (41 mg, 51% yield) as a white solid. LCMS: (ES, m/z): 383 [M+H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ 13.90 (s, 1H), 10.36 (s, 1H), 8.70 (s, 1H), 8.24 (s, 1H), 7.86 (d, J = 15.9 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.10 (d, J = 15.9 Hz, 1H), 2.20 (s, 3H). Example 56: (E)-3-(5-fluoro-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3- yl)acrylamide Step 1. Preparation of (E)-3-(5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-(5-fluoro- 4-methyl-2-(trifluoromethyl)pyridin-3-yl)acrylamide (2)

To (E)-3-(5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylic acid (90 mg, 0.3 mmol), 5- fluoro-4-methyl-2-(trifluoromethyl)pyridin-3-amine (60 mg, 0.3 mmol, 1 eq) and DIEA (400 mg, 3.1 mmol, 10 eq) in DMF (2 mL) was added 50% T₃P in EA (1.2 g, 1.8 mmol, 6 eq), and the reaction stirred at 120°C for 12 h. After cooling, the resulting mixture was diluted with H₂O (10 mL) and extracted with EtOAc (3x 10 mL). The combined organics were washed with brine (3x10 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluting with n- hexane/AcOEt(1:1) to afford (E)-3-(5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-(5-fluoro- 4-methyl-2-(trifluoromethyl)pyridin-3-yl)acrylamide (52 mg, 36% yield) as an oil. LCMS (ES, m/z): 467 [M+H]⁺ Step 2. Preparation of (E)-3-(5-Fluoro-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2- (trifluoromethyl)pyridin-3-yl)acrylamide

To (E)-3-(5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2- (trifluoromethyl)pyridin-3-yl)acrylamide (52 mg, 0.1 mmol) in DCM (1.2 mL) was added TFA (0.3 mL) and the mixture stirred for 2 h before being concentrated. The residue was quenched with ice-water (5 mL) and basified to pH 8 with NaHCO₃ solution, then extracted with DCM (2x10 mL). The combined organics were dried over anhydrous Na₂SO₄ and concentrated. The residue was dissolved in MeOH (2 mL) and purified by Prep-HPLC using the following conditions: column, C18 silica gel; mobile phase 10-50% MeCN / 0.1% aqueous NH3.H2O over 10 min; detector, UV 254 nm. Concentration of the appropriate fractions gave (E)-3-(5-fluoro-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2- (trifluoromethyl)pyridin-3-yl)acrylamide (12 mg, 25% yield) as a white solid. LCMS: (ES, m/z): 383 [M+H]⁺ ¹H NMR: (400 MHz, DMSO-d6) δ 13.41 (s, 1H), 10.31 (s, 1H), 8.70 (s, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 7.79 (d, J = 15.9 Hz, 1H), 7.68 (d, J = 11.4 Hz, 1H), 7.14 (d, J = 16.0 Hz, 1H), 2.20 (s, 3H). Example 57: (E)-N-(5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(5-fluoro-1H-indazol-6- yl)acrylamide Step 1. Preparation of (E)-N-(5-Chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(5-fluoro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (2)

To (E)-3-(5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylic acid (0.09 g, 0.31 mmol), 5- chloro-4-methyl-2-(trifluoromethyl) pyridin-3-amine (0.07 g, 0.34 mmol, 1.1 eq) and DIEA (0.31 g, 2.4 mmol, 8 eq) in DMF (2 mL) was added 50% T3P in EA (1.2 g, 1.9 mmol, 6 eq) and the reaction stirred for 12 h at 120°C. After cooling the mixture was diluted with H2O (8 mL) and extracted with EtOAc (3 x 10 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluting with Petroleum ether/ EtOAc (1:1) to afford (E)-N- (5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(5-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-6-yl)acrylamide (0.09 g, 65% yield) as a yellow oil. LCMS (ES, m/z): 483 [M+H]⁺ Step 2. Preparation of (E)-N-(5-Chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(5-fluoro-1H- indazol-6-yl)acrylamide

To a solution (E)-N-(5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(5-fluoro-1-(tetrahydro-2H- pyran-2-yl)-1H-indazol-6-yl)acrylamide (0.09 g, 0.20 mmol) in DCM (1.2 mL) was added TFA (0.3 mL) and the reaction stirred for 2 h before being concentrated. The residue was quenched ice-water (5 mL) and basified to pH 8 with NaHCO₃ solution, then extracted with DCM (2 x 6 mL). The extracts were dried over anhydrous Na₂SO₄ and concentrated. The residue was dissolved in MeOH (3 mL) and purified by Prep-HPLC (XBridge C18, 19*150 mm, 5 μm; Mobile Phase: 5-97% MeCN / 20 mM aqueous NH4HCO3 solution containing 0.05% NH3.H2O over 15 min.; Flow rate: 20 mL/min; detector, UV 254 nm). Concentration of the appropriate fractions gave (E)-N-(5-chloro-4-methyl-2- (trifluoromethyl)pyridin-3-yl)-3-(5-fluoro-1H-indazol-6-yl)acrylamide (16 mg, 20% yield ) as a white solid. LCMS: (ES, m/z):399 [M+H]⁺ ¹H NMR (300 MHz, DMSO-d6) δ 13.40 (s, 1H), 10.34 (s, 1H), 8.76 (s, 1H), 8.10 (s, 1H), 7.92 (d, J = 5.9 Hz, 1H), 7.76 (d, J = 16.0 Hz, 1H), 7.66 (d, J = 11.4 Hz, 1H), 7.12 (d, J = 16.0 Hz, 1H), 2.29 (s, 3H). Example 58: (E)-N-(5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(7-fluoro-1H-indazol-6- yl)acrylamide Step 1. Preparation of (E)-N-(5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(7-fluoro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (2)

To 5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-amine (218 mg, 0.2 mmol, 1.5 eq), (E)-3-(7-fluoro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylic acid (300 mg, 0.1 mmol) and DIEA (1.3 g 1.0 mmol, 10 eq) in DMF (5 mL) was added T3P (3.9 g, 0.6 mmol, 6 eq). The reaction mixture was stirred at 120°C for 10 h, then cooled and diluted with H2O (15 mL). The resulting mixture was extracted with EtOAc (3x 15 mL). The combined organics were washed with brine (3x10 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluting with n- hexane/AcOEt (3:1) to afford (E)-N-(5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(7-fluoro-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (90 mg, 20% yield) as a yellow oil. LCMS (ES, m/z): 483 [M+H]⁺ Step 2. Preparation of (E)-N-(5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(7-fluoro-1H- indazol-6-yl)acrylamide

(E)-N-(5-Chloro-4-methyl-2-(trifluoromethyl) pyridin-3-yl)-3-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-6-yl) acrylamide (90 mg, 0.4 mmol) in DCM (1.2 mL) was treated with TFA (0.3 mL) and stirred for 1 h.. The resulting mixture was concentrated and diluted with ice-water (5 mL). The mixture was basified to pH 8 with NaHCO₃ solution and extracted with DCM (2x5 mL). The combined extracts were dried over anhydrous Na₂SO₄ and concentrated. The residue was dissolved in MeOH (3 mL) and purified by reverse phase chromatography (C18 silica gel; mobile phase, 10-60% MeCN / 0.1% aqueous NH3.H2O over 10 min; detector, UV 254 nm.) to afford (E)-N-(5-chloro-4-methyl-2- (trifluoromethyl)pyridin-3-yl)-3-(7-fluoro-1H-indazol-6-yl)acrylamide (14 mg, 8% yield) as a white solid. LCMS: (ES, m/z): 399 [M+H]⁺ ¹H NMR (300 MHz, DMSO-d₆) δ 13.91 (s, 1H), δ 10.34 (s, 1H), δ 8.78 (s, 1H), 8.24 (d, J = 3.3 Hz, 1H), 7.86 (d, J = 15.9 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.52-7.37 (m, 1H), 7.10 (d, J = 15.9 Hz, 1H), 2.31 (s, 3H). Example 59: (Z)-N-(5-cyano-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(3-ethynyl-7-fluoro-1H- indazol-6-yl)-2-fluoroacrylamide Step 1. Preparation of Methyl (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)acrylate (2)

To a solution of methyl (Z)-2-fluoro-3-(7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (1.0 g, 3.1 mmol) in DCM (15 mL) was added 4N HCl in 1,4-dioxane (5 mL) and the reaction stirred for 12 h at room temperature. The precipitated solids were collected by filtration and washed with DCM (2 x 3 mL) to afford methyl (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)acrylate (0.66 g, 84% yield) as a white solid. LCMS (ES, m/z): 239 [M+H]⁺ Step 2. Preparation of Methyl (Z)-2-fluoro-3-(7-fluoro-3-iodo-1H-indazol-6-yl)acrylate (3) To a solution of methyl (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)acrylate (660 mg, 2.7 mmol) in DMF (12 mL) was added NIS (655 mg, 2.9 mmol, 1 eq) and the reaction stirred at 60°C for 12 h. After cooling, the mixture was diluted with H₂O (30 mL) and extracted with EtOAc (3 x 40 mL). The combined organics were washed with brine (2x30 mL), dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica chromatography, eluting with n-hexane/AcOEt (5:1) to afford methyl (Z)- 2-fluoro-3-(7-fluoro-3-iodo-1H-indazol-6-yl)acrylate (750 mg, 74% yield) as a white solid. LCMS (ES, m/z): 365 [M+H]⁺ Step 3. Preparation of Methyl (Z)-2-fluoro-3-(7-fluoro-3-((trimethylsilyl)ethynyl)-1H-indazol-6- yl)acrylate (4)

To a solution of methyl (Z)-2-fluoro-3-(7-fluoro-3-iodo-1H-indazol-6-yl)acrylate (0.70 g, 1.9 mmol) in DMF (13 mL) was added trimethylsilylacetylene (0.28 g, 2.8 mmol, 1.5 eq), DIEA (0.49 g, 3.84 mmol, 2 eq), Pd(PPh3)2Cl2 (0.02 g, 0.04 mmol, 0.02 eq) and CuI (0.014 g, 0.08 mmol, 0.04 eq). The reaction was stirred at 50°C for 3 h under N2, then cooled and diluted with H2O (30 mL). The resulting mixture was extracted with EtOAc (3x20 mL). The combined organics were washed with brine (2x10 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica chromatography, eluting with n-hexane/AcOEt (5:1) to afford methyl (Z)-2-fluoro-3-(7-fluoro-3-((trimethylsilyl)ethynyl)-1H- indazol-6-yl)acrylate (0.60 g, 93% yield) as an off-white solid. LCMS (ES, m/z): 335[M+H]⁺ Step 4. Preparation of (Z)-3-(3-Ethynyl-7-fluoro-1H-indazol-6-yl)-2-fluoroacrylic acid (5)

A solution of methyl (Z)-2-fluoro-3-(7-fluoro-3-((trimethylsilyl)ethynyl)-1H-indazol-6-yl) acrylate (0.50 g, 1.4 mmol, 1 equiv), LiOH (0.11 g, 2.8 mmol, 2 equiv) in H2O (5 mL) and THF (5 mL) was stirred for 4 h at room temperature. The mixture was neutralized to pH 6 with 1M HCl. The precipitated solids were collected by filtration and washed with H2O (2x1 mL) afford (Z)-3-(3-ethynyl-7-fluoro-1H-indazol-6-yl)- 2-fluoroacrylic acid (0.2 g, 54% yield) as an off-white solid. LCMS-(ES, m/z): [M+H]⁺=249 Step 5. Preparation of (Z)-N-(5-Cyano-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(3-ethynyl-7- fluoro-1H-indazol-6-yl)-2-fluoroacrylamide

To (Z)-3-(3-ethynyl-7-fluoro-1H-indazol-6-yl)-2-fluoroacrylic acid (0.05 g, 0.2 mmol), 5-amino-4- methyl-6-(trifluoromethyl)nicotinonitrile (0.04 g,0.2 mmol, 1.1 eq) and DIEA (0.05 g, 0.4 mmol, 2 eq) in DMF (1mL) was added T3P (0.25 g, 0.4 mmol, 2 eq) and the reaction stirred for 14 h at 100°C. The mixture was cooled and concentrated, and the residue dissolved in MeOH (3 mL) and purified by reverse phase chromatography (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase: 20-56% MeCN / 10 mmol/L aqueous NH₄HCO₃ solution containing 0.1%NH₃ • H₂O over 45 min.; Flow rate: 60 mL/min.). Concentration of the appropriate fractions gave (Z)-N-(5-cyano-4-methyl- 2-(trifluoromethyl)pyridin-3-yl)-3-(3-ethynyl-7-fluoro-1H-indazol-6-yl)-2-fluoroacrylamide (2.1 mg, 2% yield) as a white solid. LCMS: (ES, m/z): 432 [M+H]⁺ ¹H NMR (400 MHz, DMSO-d6) δ 13.45 (s, 1H), δ10.71 (s, 1H), δ 9.04 (s, 1H), 7.75-7.62 (m, 2H), 7.23 (d, J = 37.1 Hz, 1H), 4.65 (s, 1H), 2.46 (s, 3H). Examples 60-89: Examples 60, 63, 64, 65, 66, 67, 75, 80, 82 and 87 were synthesized using a similar procedure to the one used for Example 8. Examples 61, 62 and 68 were synthesized using a similar procedure to the one used for Example 20 Examples 69, 70, 73, 76, 77, 78, 79, 81, 83, 84, 85, 86, 88 and 89 were synthesized using a similar procedure to the one used for Example 1. Example 71 was synthesized using a similar procedure to the one used for Example 12. Example 72 was synthesized using a similar procedure to the one used for Example 32. Example 74 was synthesized using a similar procedure to the one used for Example 15. LCMS Example number/name/ Retenti LCMS LCMS Method ¹H NMR Structure on time m/z / min. (300 MHz, d6- Example 60 5-95% MeCN / DMSO, ppm) δ (E)-N-(5-fluoro-2,6-dimethylpyridin-3- 0.05% aqueous 12.88 (1H, s), 9.63 yl)-3-(3-methyl-1H-indazol-6- TFA over 2 min.; 325.2 (1H, s), 8.05 (1H, yl)acrylamide Column HALO 0.798 [M+H] d), 7.68-7.84 (3H, AQ-C18, 30*3.0 + m), 7.42 (1H, d), mm, 2 um; 7.11 (1H, d), 2.52 Flowrate 1.5 (3H, s), 2.47 (3H, ml/min. s), 2.40 (3H, d). 1H NMR: (400 MHz, DMSO-d6, ppm) δ 14.56 (s, 1H), 9.61 (s, 1H), Example 61 5-95% MeCN / 8.12-8.07 (m, 1H), (E)-3-(3-cyano-1H-indazol-6-yl)-N- 0.05% aqueous 7.99 (s, 1H), 7.95 (2,5-dimethylpyridin-3-yl)acrylamide TFA over 2 min.; 318.1 (d, J = 8.6 Hz, Column Cortecs 0.651 [M+H] 1H), 7.86 (d, J = C18+, 30*3.0 + 2.0 Hz, 1H), 7.77 mm, 2.7 um; (d, J = 15.7 Hz, Flowrate 1.5 1H), 7.67 (dd, J = ml/min. 8.5, 1.3 Hz, 1H), 7.14 (d, J = 15.7 Hz, 1H), 2.41 (s, 3H), 2.26 (s, 3H). 1H NMR (400 Example 62 MHz, Methanol-d4) (E)-N-(5-chloro-2-methylpyridin-3-yl)- 30%-95% MeCN δ 9.05 (s, 1H), 3-(3-cyano-1H-indazol-6- / 0.05% NH3·H2O 8.66 (d, J = 2.2 yl)acrylamide over 3 min.; 336.0 Hz, 1H), 8.00 – Column EVO 1.167 [M-H]- 7.90 (m, 3H), 7.76 C18, 50*3.0 mm, (d, J = 8.6 Hz, 2.6 um; Flowrate 1H), 7.17 (d, J = 1.2 ml/min. 15.6 Hz, 1H), 2.76 (s, 3H). LCMS Example number/name/ Retenti LCMS LCMS Method ¹H NMR Structure on time m/z / min. 1H NMR (300 Example 63 10%-95% MeCN MHz, DMSO-d₆, (E)-3-(3-chloro-1H-indazol-6-yl)-N-(5- / 5 mM NH₄HCO₃ ppm) δ 13.41 (br cyano-2-methylpyridin-3- over 2 min.; s, 1H), 9.89 (br s, yl)acrylamide Column L- 336.2 1H), 8.71 (s, 1H), 0.887 column3 C18 [M-H]- 8.60 (s, 1H), 7.89- 3.0*30mm 3um; 7.68 (m, 3H), Flowrate 1.5 7.62-7.45 (m, 1H), ml/min. 7.33-7.12 (m, 1H), 2.61 (s, 3H). 1H NMR: (300 MHz, DMSO-d6, ppm) δ 8.68-8.58 Example 64 5-95% MeCN / (m, 2H), 7.90 (d, J (E)-N-(5-cyano-2-methylpyridin-3-yl)- 0.05% aqueous = 15.6 Hz, 1H), 3-(3-methyl-1H-indazol-6- TFA over 2 min.; 318.0 7.79 (d, J = 8.5 yl)acrylamide Column Cortecs 0.917 [M+H] Hz, 1H), 7.70 (s, C18+, 30*3.0 + 1H), 7.50 (d, J = mm, 2.7 um; 8.3 Hz, 1H), 7.06 Flowrate 1.5 (d, J = 15.6 Hz, ml/min. 1H), 2.67 (s, 3H), 2.65-2.62 (m, 1H), 2.59 (s, 3H). 1H NMR (300 Example 65 MHz, DMSO-d6, (E)-3-(3-chloro-1H-indazol-6-yl)-N-(5- 5%-95% MeCN / ppm) δ 13.57 (br, chloro-2-cyanopyridin-3- 0.05% NH3·H2O s, 1H), 10.71 (br, yl)acrylamide over 3 min.; s, 1H) 8.67-8.57 356.0 Column EVO 1.522 (m, 1H), 8.54-8.43 [M-H]- C18, 50*3.0 mm, (m, 1H), 8.00-7.80 2.6 um; Flowrate (m, 2H), 7.78-7.68 1.2 ml/min. (m, 1H), 7.64-7.53 (m, 1H), 7.23-7.10 (m, 1H). LCMS Example number/name/ Retenti LCMS LCMS Method ¹H NMR Structure on time m/z / min. 1H NMR (400 Example 66 MHz, DMSO-d₆, (E)-N-(5-chloro-2-cyanopyridin-3-yl)- 5%-95% MeCN ppm) δ 12.88 (s, 3-(3-methyl-1H-indazol-6- /0.05% NH₃·H₂O 1H), 10.67 (br, s, yl)acrylamide over 3 min.; 338.1 1H), 8.65-8.57 (m, Column EVO 1.416 [M+H] 1H), 8.57-8.48 (m, C18, 50*3.0 mm, + 1H), 7.87-7.78 (m, 2.6 um; Flowrate 2H), 7.74 (s, 1H), 1.2 ml/min. 7.45-7.39 (m, 1H), 7.13-7.05 (m, 1H), 2.45 (s, 3H). 1H NMR (300 MHz, Methanol-d4) Example 67 5%-(30-60)-95% δ 8.29 (q, J = 2.3 (E)-N-(5-chloro-2-methylpyridin-3-yl)- MeCN /0.1% Hz, 2H), 8.07 (d, J 3-(7-fluoro-3-methyl-1H-indazol-6- aqueous TFA = 15.8 Hz, 1H), 345.3 yl)acrylamide over 3 min.; 7.58 (d, J = 8.5 1.933 [M+H] Column SB-Aq + Hz, 1H), 7.43 (dd, 4.6*50mm, J = 8.5, 5.8 Hz, 1.8um; Flowrate 1H), 7.11 (d, J = 1.5 ml/min. 15.8 Hz, 1H), 2.57 (d, J = 9.9 Hz, 6H). 1H NMR (300 Example 68 5-95% MeCN / MHz, DMSO- (E)-N-(5-chloro-2- 0.05% aqueous d6) δ 9.70 (s, 1H), (methoxymethyl)pyridin-3-yl)-3-(3- FA over 3 min.; 8.44 (dd, J = 40.0, cyano-1H-indazol-6-yl)acrylamide Column SB-Aq 368.3 2.3 Hz, 3H), 8.03 4.6*50mm 1.738 [M+H] (s, 1H), 7.84 1.8um, 30*3.0 + (dd, J = 23.1, 12.0 mm, 2 um; Hz, 2H), 7.63 Flowrate 1.5 (d, J = 8.5 Hz, ml/min. 1H), 7.16 (d, J = 15.7 Hz, 1H), 4.66 LCMS Example number/name/ Retenti LCMS LCMS Method ¹H NMR Structure on time m/z / min. (s, 2H), 3.32 (s, 3H). 10-90% MeCN / (400 MHz, d6- Example 69 5 mM aqueous DMSO, ppm) δ (Z)-N-(5-cyano-2,4-dimethylpyridin-3- NH4HCO3 over 2 13.87 (1H, s), yl)-2-fluoro-3-(7-fluoro-1H-indazol-6- min.; Column 354.1 10.54 (1H, s), 8.81 yl)acrylamide Shim-pack 0.93 [M+H] (1H, s), 8.25 (1H, Scepter C18, + d), 7.71 (1H, d), 33*2.1 mm, 2 7.57 (1H, dd), 7.27 um; Flowrate 1.2 (1H, d), 2.49 (3H, ml/min. s), 2.39 (3H, s). Example 70 5-100% MeCN / (Z)-3-(3-chloro-7-fluoro-1H-indazol-6- (400 MHz, d6- 0.05% aqueous yl)-N-(5-cyano-2,4-dimethylpyridin-3- DMSO, ppm) δ TFA over 2 min.; yl)-2-fluoroacrylamide 388.1 8.80 (1H, s), 7.69 Column XSelect 0.886 [M+H] – 7.59 (2H, m), HSS T3 C18, + 7.25 (1H, d), 2.48 30*3.0 mm, 2.5 (3H, s), 2.39 (3H, um; Flowrate 1.5 s). ml/min. (300 MHz, d6- Example 71 5-95% MeCN / DMSO, ppm) δ (Z)-3-(7-chloro-1H-indazol-6-yl)-2- 0.05% aqueous 13.82 (1H, s), fluoro-N-(5-fluoro-2,4- TFA, 2 min.; 363.1 10.51 (1H, s), 8.39 dimethylpyridin-3-yl)acrylamide Column XSelect 0.751 [M+H] (1H, s), 8.27 (1H, HSS T3, 30*3.0 + s), 7.88 (1H, d), mm, 2.5 um; 7.70 (1H, d), 7.41 Flowrate 1.5 (1H, d), 2.39 (3H, ml/min. s), 2.16 (3H, s). 5-95% MeCN / (300 MHz, d6- Example 72 0.05% aqueous DMSO, ppm) δ 354.1 (Z)-3-(7-cyano-1H-indazol-6-yl)-2- TFA, 2 min.; 14.19 (1H, s), 0.708 [M+H] fluoro-N-(5-fluoro-2,4- Column XSelect + 10.59 (1H, s), 8.40 dimethylpyridin-3-yl)acrylamide HSS T3, 30*3.0 (2H, s), 8.27 (1H, mm, 2.5 um; d), 7.79 (1H, d), LCMS Example number/name/ Retenti LCMS LCMS Method ¹H NMR Structure on time m/z / min. Flowrate 1.5 7.35 (1H, d), 2.39 ml/min. (3H, s), 2.17 (3H, s). 20-90% MeCN / Example 73 (400 MHz, d6- 5mM aqueous (Z)-3-(3,7-difluoro-1H-indazol-6-yl)-2- DMSO, ppm) δ NH₄HCO₃ over 3 fluoro-N-(6-methoxy-2,4- 10.14 (1H, s), 7.69 min.; dimethylpyridin-3-yl)acrylamide 377.0 – 7.48 (2H, m), Column Shim- 1.571 [M+H] 7.21 (1H, d), 6.62 Pack Velox SP- + (1H, s), 3.83 (3H, C18, 33*2.1 mm, s), 2.29 (3H, s), 3.0 um; Flowrate 2.15 (3H, s). 1.2 ml/min. Example 74 0-90% MeCN / 5 (400 MHz, d6- (Z)-N-(5-chloro-2,4-dimethylpyridin- mM aqueous DMSO, ppm) δ 3-yl)-3-(3-cyano-7-fluoro-1H-indazol- NH4HCO3 over 2 388.0 15.24 (1H, s), 6-yl)-2-fluoroacrylamide min.; 5 10.56 (1H, s), 8.47 Column Kinetex 0.850 [M+H] (1H, s), 7.86 – EVO C18 -100A, + 7.75 (2H, m), 7.26 30*3.0 mm, 2.6 (1H, d), 2.39 (3H, um; Flowrate 1.2 s), 2.26 (3H, s). ml/min. (300 MHz, d6- 5-95% MeCN / DMSO, ppm) δ Example 75 0.05% aqueous 10.03 (1H, s), 8.30 (E)-N-(2-cyclopropylpyridin-3-yl)-3- TFA, 3 min.; – 8.19 (2H, m), (7-fluoro-1H-indazol-6-yl)acrylamide 323.1 Column XSelect 7.98 –7.85 (2H, 0.809 [M+H] HSS T3, 30*3.0 + m), 7.66 (1H, d), mm, 2.5 um; 7.39 (1H, d), 7.24 – Flowrate 1.5 7.12 (2H, m), 2.33 ml/min. (1H, q), 1.02 – 0.92 (4H, m). Example 76 5-95% MeCN / 359.2 (300 MHz, d6- 0.925 (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6- 0.05% aqueous [M+H] DMSO, ppm) δ LCMS Example number/name/ Retenti LCMS LCMS Method ¹H NMR Structure on time m/z / min. yl)-N-(5-methoxy-2,4-dimethylpyridin- TFA, 3 min.; ⁺ 13.88 (1H, s), 3-yl)acrylamide Column XSelect 10.32 (1H, s), 8.24 HSS T3, 30*3.0 (1H, d), 8.15 (1H, mm, 2.5 um; s), 7.71 (1H, d), Flowrate 1.5 7.57 (1H, d), 7.24 ml/min. (1H, d), 3.91 (3H, s), 2.33 (3H, s), 2.04 (3H, s). Example 77 25-90% MeCN / (300 MHz, d6- (Z)-3-(3,7-difluoro-1H-indazol-6-yl)-2- 5 mM NH₄HCO₃ DMSO, ppm) δ fluoro-N-(5-fluoro-2,4- in water, 2 min.; 13.19 (1H, s), dimethylpyridin-3-yl)acrylamide 365.0 Column Shim- 10.54 (1H, s), 8.39 0.888 [M+H] pack Scepter + (1H, s), 7.67 - 7.57 C18, 30*2.1 mm, (2H, m), 7.23 (1H, 3.0 um; Flowrate d), 2.38 (3H, s), 1.5 ml/min. 2.08 (3H, s). (300 MHz, d6- Example 78 10-90% MeCN / DMSO, ppm) δ (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6- 5 mM NH₄HCO₃ 8.24 (1H, d), 7.70 yl)-N-(6-(methoxy-d₃)-2,4- in water, 3 min.; 362.1 (1H, d), 7.58 - 7.54 Column Shim- dimethylpyridin-3-yl)acrylamide 1.331 [M+H] (1H, m), 7.20 (1H, pack Scepter + d), 6.62 (1H, s), C18, 30*2.1 mm, 6.03 (1H, s), 2.29 3.0 um; Flowrate (3H, s), 2.15 (3H, 1.5 ml/min. s). Example 79 0-90% MeCN / 5 (400 MHz, d6- (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6- mM aqueous DMSO, ppm) δ yl)-N-(4-methyl-2- NH₄HCO₃ over 3 383.0 8.60 (1H, d), 8.26 (trifluoromethyl)pyridin-3- min.; 5 (1H, d), 7.82 – 7.67 yl)acrylamide Column Kinetex 1.230 [M+H] (2H, m), 7.61 – EVO C18 -100A, + 7.51 (1H, m), 7.26 30*3.0 mm, 2.6 (1H, d), 2.31 (3H, um; Flowrate 1.2 s). ml/min. LCMS Example number/name/ Retenti LCMS LCMS Method ¹H NMR Structure on time m/z / min. (300 MHz, d6- Example 80 5-95% MeCN / DMSO, ppm) δ (E)-3-(3-chloro-1H-indazol-6-yl)-N-(5- 0.1% aqueous 13.50 (1H, s), chloro-2-cyclopropylpyridin-3- FA, 3 min.; 10.06 (1H, s), 8.29 yl)acrylamide 373.1 Column Luna (1H, d), 8.20 (1H, 1.440 [M+H] Omega PS C18, + d), 7.83 – 7.73 (3H, 50*3.0 mm, 3.0 m), 7.53 (1H, d), um; Flowrate 1.5 7.18 (1H, d), 2.41 – ml/min. 2.30 (1H, m), 1.05 – 1.00 (4H, m). Example 81 30-90% MeCN / (Z)-N-(5-chloro-4-methyl-2- 5 mM aqueous (trifluoromethyl)pyridin-3-yl)-3-(3,7- (400 MHz, d6- NH₄HCO₃ over 3 difluoro-1H-indazol-6-yl)-2- 434.9 DMSO, ppm) δ min.; fluoroacrylamide 5 13.22 (1H, s), 8.75 Column Shim- 1.564 [M+H] (1H, s), 7.74 – 7.46 pack Scepter + (2H, m), 7.23 (1H, C18, 30*2.1 mm, d), 2.32 (3H, s). 3.0 um; Flowrate 1.2 ml/min. (300 MHz, d6- DMSO, ppm) δ Example 82 10-90% MeCN / 13.27 (1H, s), (E)-N-(5-chloro-2-cyclopropylpyridin- 5 mM NH₄HCO₃ 10.45 (1H, s), 8.40 3-yl)-3-(3-fluoro-1H-indazol-6- in water, 3 min.; (1H, d), 8.13 (1H, yl)acrylamide 357.0 Column Shim- s), 7.94 (1H, s), 1.571 [M+H] pack Scepter + 7.88 – 7.83 (2H, C18, 30*2.1 mm, m), 7.52 – 7.44 3.0 um; Flowrate (1H, m), 7.23 (1H, 1.5 ml/min. d), 2.29 – 2.18 (1H, m), 1.06 – 0.91 (4H, m). Example 83 5-95% MeCN / 372.1 (300 MHz, d6- 1.186 (Z)-N-(5-cyano-2,4-dimethylpyridin-3- 0.05% aqueous [M+H] DMSO, ppm) δ LCMS Example number/name/ Retenti LCMS LCMS Method ¹H NMR Structure on time m/z / min. yl)-3-(3,7-difluoro-1H-indazol-6-yl)-2- TFA, 3 min.; ⁺ 13.51 (1H, s), fluoroacrylamide Column XSelect 10.69 (1H, s), 8.82 HSS T3, 30*3.0 (1H, s), 7.72 – 7.55 mm, 2.5 um; (2H, m), 7.26 (1H, Flowrate 1.5 d), 2.51 (3H, s), ml/min. 2.40 (3H, s). Example 84 (Z)-3-(3-chloro-7-fluoro-1H-indazol-6- 35-90% MeCN / (300 MHz, d6- yl)-2-fluoro-N-(6-methoxy-2,4- 6.5 mM DMSO, ppm) δ dimethylpyridin-3-yl)acrylamide(Z)-3- NH₄HCO₃ in 14.13 (1H, s), (3-chloro-7-fluoro-1H-indazol-6-yl)-2- H₂O/ACN 393.0 10.12 (1H, s), 7.99 fluoro-N-(6-methoxy-2,4- (9:1,v/v), pH=10; 5 1.020 – 7.47 (2H, m), dimethylpyridin-3-yl)acrylamide over 3 min.; [M+H] 7.22 (1H, d), 6.62 Column HPH- + (1H, s), 3.83 (3H, C18, 30*3.0 mm, s), 2.29 (3H, s), 1.9 um; Flowrate 2.15 (3H, s). 1.0 ml/min. Example 85 (300 MHz, d6- (Z)-3-(3-chloro-7-fluoro-1H-indazol-6- 20-90% MeCN / DMSO, ppm) δ yl)-2-fluoro-N-(6-(methoxy-d₃)-2,4- 5 mM NH4HCO3, 14.15 (1H, s), dimethylpyridin-3-yl)acrylamide 3 min.; Column 396.1 10.14 (1H, s), 7.68 cortecs shield 1.633 [M+H] - 7.59 (2H, m), rp18, 30*2.1 mm, + 7.22 (1H, d), 6.62 2.7 um; Flowrate (1H, s), 2.29 (3H, 1.5 ml/min. s), 2.15 (3H, s). 20-90% MeCN / (300 MHz, d6- 5 mM NH₄HCO₃ Example 86 DMSO, ppm) δ in water, 3 min.; (Z)-3-(3-chloro-7-fluoro-1H-indazol-6- 14.16 (1H, s), Column 439.9 yl)-N-(5-cyano-4-methyl-2- 1.980 10.94 (1H, s), 9.15 Poroshell HPH- [M-H]- (trifluoromethyl)pyridin-3-yl)-2- (1H, s), 7.70 - 7.61 C18, 30*3.0 mm, fluoroacrylamide (2H, m), 7.27 (1H, 1.9 um; Flowrate d), 2.49 (3H, s). 1.5 ml/min. LCMS Example number/name/ Retenti LCMS LCMS Method ¹H NMR Structure on time m/z / min. 20-90% MeCN / Example 87 6.5 mM (E)-3-(3-chloro-1H-indazol-6-yl)-N-(5- (300 MHz, d6- NH₄HCO₃ in fluoro-4-methyl-2- DMSO, ppm) δ H2O/ACN (trifluoromethyl)pyridin-3- 399.0 13.53 (1H, s), (9:1,v/v), pH=10; yl)acrylamide 5 10.22 (1H, s), 8.70 over 3 min.; 1.576 [M+H] (1H, s), 8.07 – 7.72 Column Shim + (3H, m), 7.56 (1H, Pack Scepter dd), 7.07 (1H, d), C18, 33*3.0 mm, 2.20 (3H, d). 3.0 um; Flowrate 1.2 ml/min. 1H NMR (300 MHz, DMSO-d₆) δ Example 88 5-95% MeCN / 8.24 (dd, J = 5.3, (Z)-N-(2-chloro-4-methylpyridin-3-yl)- 0.05% aqueous 4.2 Hz, 2H), 7.70 2-fluoro-3-(7-fluoro-1H-indazol-6- TFA over 2 min.; 349.0 (d, J = 8.5 Hz, yl)acrylamide Column SB-Aq, 0.887 [M+H] 1H), 7.57 (dd, J = 3.0*30 mm, 1.8 + 8.5, 5.8 Hz, 1H), um; Flowrate 1.5 7.40 (d, J = 4.9 ml/min. Hz, 1H), 7.26 (d, J = 37.5 Hz, 1H), 2.27 (s, 3H). 10%-(30%-60%)- ¹H NMR (300 Example 89 95% MeCN /5 MHz, DMSO-d6) δ (Z)-3-(3,7-difluoro-1H-indazol-6-yl)- 401.1 mM NH4HCO3 12.15 (br s, 1H), N-(2-(difluoromethyl)-5-fluoro-4- 1.330 [M+H] over 3 min.; + 8.49 (s, 1H), 7.68 methylpyridin-3-yl)-2- Column L- – 7.55 (m, 2H), fluoroacrylamide column3 C18, 7.27 – 6.84 (m, LCMS Example number/name/ Retenti LCMS LCMS Method ¹H NMR Structure on time m/z / min. 3.0*30 mm, 3 2H), 2.14 (d, J = um; Flowrate 1.2 2.0 Hz, 3H). ml/min. Example 90 & 91: (Z)-(3-chloro-6-(3-((5-cyano-2,4-dimethylpyridin-3-yl)amino)-2-fluoro-3-oxoprop-1- en-1-yl)-7-fluoro-2H-indazol-2-yl)methyl dihydrogen phosphate and (Z)-(3-chloro-6-(3-((5-cyano-2,4- dimethylpyridin-3-yl)amino)-2-fluoro-3-oxoprop-1-en-1-yl)-7-fluoro-1H-indazol-1-yl)methyl dihydrogen phosphate Step 1. Preparation of di-tert-butyl {3-chloro-6-[(1Z)-2-[(5-cyano-2,4-dimethylpyridin-3- yl)carbamoyl]-2-fluoroeth-1-en-1-yl]-7-fluoroindazol-2-yl}methyl phosphate

To (2Z)-3-(3-chloro-7-fluoro-2H-indazol-6-yl)-N-(5-cyano-2,4-dimethylpyridin-3-yl)-2-fluoroprop-2- enamide (100 mg, 0.25 mmol) and Cs₂CO₃ (101 mg, 0.31 mmol, 1.2 equiv) in DMA (1 mL) was added di-tert-butyl chloromethyl phosphate (73 mg, 0.28 mmol) and the mixture was heated at 60^°C overnight. After cooling, the resulting mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organics were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated to give crude di-tert-butyl {3-chloro-6-[(1Z)-2-[(5-cyano-2,4-dimethylpyridin-3-yl) carbamoyl]-2-fluoroeth-1-en-1-yl]-7-fluoroindazol-2-yl} methyl phosphate as a yellow solid. LCMS (ES, m/z): [M+H]⁺=610. Step 2. Preparation of (Z)-(3-Chloro-6-(3-((5-cyano-2,4-dimethylpyridin-3-yl)amino)-2-fluoro-3- oxoprop-1-en-1-yl)-7-fluoro-2H-indazol-2-yl)methyl dihydrogen phosphate＆ (Z)-(3-chloro-6-(3- ((5-cyano-2,4-dimethylpyridin-3-yl)amino)-2-fluoro-3-oxoprop-1-en-1-yl)-7-fluoro-1H-indazol-1- yl)methyl dihydrogen phosphate

Di-tert-butyl {3-chloro-6-[(1Z)-2-[(5-cyano-2,4-dimethylpyridin-3-yl) carbamoyl]-2-fluoroeth-1-en-1-yl]- 7-fluoroindazol-2-yl} methyl phosphate (200 mg, 0.32 mmol) in acetone (2 mL) and H2O (2 mL) was heated at 40^°C overnight. After cooling to room temperature, the resulting mixture was purified by reverse phase chromatography with the following conditions: Column: YMC-Actus Triart C18 ExRS30*150 mm, 5μm; Mobile Phase: 3-36% MeCN / 10 mmol/L aqueous NH4HCO3 solution containing 0.05% NH₃ ^.H₂O over 10 min.; Flow rate: 60mL/min; Wavelength: 254 nm/220 nm. Concentration of the appropriate fractions gave: First eluting product, Rt 7.42 min: (Z)-(3-chloro-6-(3-((5-cyano-2,4-dimethylpyridin-3-yl)amino)-2-fluoro-3-oxoprop-1-en-1-yl)-7-fluoro- 2H-indazol-2-yl)methyl dihydrogen phosphate (45 mg, 35% yield for 2 steps) as a white solid. LC-MS (ES, m/z): 498.05 [M+H]⁺ ¹H-NMR: (400 MHz, DMSO-d6, ppm): δ 8.77 (s, 1H), 7.66-7.47 (m, 3H), 5.90 (d, J = 8.4 Hz, 2H), 2.45 (s, 3H), 2.35 (s, 3H). ¹⁹F-NMR: (376 MHz, DMSO-d6, ppm): δ -120.94, -128.01. ³¹P-NMR: (162 MHz, DMSO-d₆, ppm): δ -3.46. Second eluting product, Rt 8.95 min: (Z)-(3-chloro-6-(3-((5-cyano-2,4-dimethylpyridin-3-yl)amino)-2-fluoro-3-oxoprop-1-en-1-yl)-7-fluoro- 1H-indazol-1-yl)methyl dihydrogen phosphate (8.0 mg, 6% yield for 2 steps) as a white solid. LC-MS (ES, m/z): 498.05 [M+H]⁺ ¹H-NMR: (400 MHz, DMSO-d6, ppm): δ 8.79 (s, 1H), 7.50-7.44 (m, 2H), 7.19 (d, J = 37.3 Hz, 1H), 5.87 (d, J = 6.4 Hz, 2H), 2.47 (s, 3H), 2.37 (s, 3H). ¹⁹F-NMR: (376 MHz, DMSO-d6, ppm): δ -122.67, -128.42. ³¹P-NMR: (162 MHz, DMSO-d6, ppm): δ -3.01. Example 92: (Z)-(7-fluoro-6-(2-fluoro-3-((6-methoxy-2,4-dimethylpyridin-3-yl)amino)-3-oxoprop-1-en- 1-yl)-2H-indazol-2-yl)methyl dihydrogen phosphate Step 1. Preparation of Di-tert-butyl {7-fluoro-6-[(1Z)-2-fluoro-2-[(6-methoxy-2,4-dimethylpyridin- 3-yl)carbamoyl]eth-1-en-1-yl]indazol-2-yl}methyl phosphate (2)

To (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide (200 mg, 0.5 mmol) and di-tert-butyl chloromethyl phosphate (216 mg, 0.8 mmol, 1.5 eq) in DMF (3 mL) was added Cs₂CO₃ (545 mg, 1.6 mmol, 3 eq) and NaI (92 mg, 0.6 mmol, 1.1 eq). The mixture was stirred at 50 °C for 2 h, then cooled and extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluting with PE/THF (10/1) to afford the product. The crude product was purified further by reverse phase chromatography with the following conditions (Column: Uitimate - XB-C18, 30*150 mm, 10μm; Mobile Phase: 30-80% MeCN / 0.05% aqueous NH3·H2O over 12 min.; Flow rate: 90mL/min; Wavelength: 254nm/220nm; Rt 11.5 min. Concentration of the appropriate fractions gave di-tert-butyl {7-fluoro-6-[(1Z)-2-fluoro-2-[(6-methoxy-2,4-dimethylpyridin-3- yl)carbamoyl]eth-1-en-1-yl]indazol-2-yl}methyl phosphate (80 mg, 24% yield) as a colourless oil. LCMS (ES, m/z): 581 [M+H]⁺ Step 2. Preparation of (Z)-(7-fluoro-6-(2-fluoro-3-((6-methoxy-2,4-dimethylpyridin-3-yl)amino)- 3-oxoprop-1-en-1-yl)-2H-indazol-2-yl)methyl dihydrogen phosphate

To a solution of di-tert-butyl {7-fluoro-6-[(1Z)-2-fluoro-2-[(6-methoxy-2,4-dimethylpyridin-3- yl)carbamoyl]eth-1-en-1-yl]indazol-2-yl}methyl phosphate (80 mg, 0.1 mmol) in DCM (2 mL) was added TFA (0.3 mL). The mixture was stirred at 25 °C for 2 h, then basified to pH 7 with NH₃·H₂O. The resulting mixture was concentrated and the residue purified by reverse phase chromatography with the following conditions (Column: XBridge Prep OBD C18, 30*150 mm, 5μm; Mobile Phase: 5-25% MeCN / 0.05% aqueous NH3·H2O over 10 min.; Flow rate: 35 mL/min; Wavelength: 254nm/220nm; Rt 8.5 min. Concentration of the appropriate fractions gave (Z)-(7-fluoro-6-(2-fluoro-3-((6-methoxy-2,4- dimethylpyridin-3-yl)amino)-3-oxoprop-1-en-1-yl)-2H-indazol-2-yl)methyl dihydrogen phosphate (11 mg, 18% yield) as a white solid. LCMS (ES, m/z): 469 [M+H]⁺ ¹H NMR: (300 MHz, DMSO-d₆, ppm) δ 8.68 (d, J = 2.8 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.46 (dd, J = 8.9, 5.9 Hz, 1H), 7.41 (s, 1H), 7.24 (d, J = 37.5 Hz, 1H), 6.10 (d, J = 10.9 Hz, 2H), 4.08 (s, 3H), 2.45 (s, 3H), 2.36 (s, 3H).¹⁹F NMR (282 MHz, DMSO-d6) δ -75.25, -123.42, -127.73. Biological Examples Biological Example 1 – mPTP activity assay in isolated rat liver mitochondria and isolated rat brain mitochondria Rat liver mitochondria assay Pharmacological inhibition or modulation of the mPTP can be measured in well characterised ‘Ca²⁺ retention’ assays performed in isolated mitochondria. In vitro, isolated mitochondria rapidly sequester exogenous Ca²⁺ until the intramitochondrial Ca²⁺ concentration reaches the threshold for mPTP activation. Once the pore is activated, mitochondrial integrity is compromised and the stored Ca²⁺ is released. The distribution of Ca²⁺ between extra- and intra-mitochondrial compartments can be measured in real time with the use of membrane-impermeant Ca²⁺ sensitive fluorescent dyes. Depending on the configuration of the assay, inhibition or modulation of the mPTP either delays the opening of the pore or increases the concentration of Ca²⁺ required to induce mPTP opening. MPTP activity was measured in mitochondria freshly isolated from female Sprague Dawley (250 to 300 gram) rat livers using the following method. Cervical dislocation was performed on the rat. The liver was then perfused in-situ with ~40 ml cold Dulbecco’s Phosphate Buffered Saline (DPBS) prior to dissection and transferred into 30 ml Isolation Buffer (250mM Sucrose, 10mM KCl, 1mM EGTA, 1mM EDTA, 25mM HEPES, adjusted to pH 7.5 with 1M NaOH). Each lobe of the liver was then removed from the buffer, minced using tweezers and a scalpel into ~5mm pieces then transferred into a 50 ml Potterton dounce homogenization tube on ice containing 30 ml ice-cold centrifugation buffer (300mM Trehalose, 25mM HEPES, 1mM EGTA, 1mM EDTA, 10mM KCl, adjusted to pH 7.5 with 1M NaOH and supplemented with 0.1% bovine serum albumin (BSA) and complete protease inhibitor cocktail (one tablet of inhibitor per 50mls of buffer). Homogenisation was carried out using a Teflon pestle at 1800 rpm. The slurry was centrifuged at 800 g for 10 min at 4 ^oC, then the supernatant centrifuged at 10,000 g for 10 min. The pellet was washed once with FLIPR assay buffer (75mM Mannitol, 25mM Sucrose, 5mM Potassium Phosphate Monobasic, 20mM Tris base, 100mM KCl, 0.1 % BSA adjusted to pH 7.4 with 5M HCl) centrifuged again, then resuspended in FLIPR assay buffer to a concentration of 8.8 mg/ml protein. Tested compounds (10 mM stock in DMSO) were serially diluted in DMSO in half log steps to generate 10 test concentrations (final concentrations in assay 30 µM to 1 nM). An intermediate dilution of 5 µl DMSO samples into 247 µl FLIPR assay buffer was carried out prior to transfer of 5 µl into duplicate wells of a 384 well polypropylene assay plate. Control wells were 0.5 % (v/v) DMSO and 5 µM cyclosporin A. A stock mitochondria/Fluo5N assay solution was prepared in 5.6 ml FLIPR assay buffer (at RT) supplemented with succinate disodium salt (10mM), rotenone (1µM), Fluo5N pentapotassium salt (2 µM) and 1 ml mitochondria suspension, then transferred (15 µl) into the assay plate containing test compounds and incubated for 10 min at RT. Assay plates were then transferred to a FLIPR Tetra plate reader (Molecular Devices). Dye fluorescence was then measured every 3 sec for a total of 10 min. After 12 sec, a 2.5 µl bolus of CaCl2 (75 µM) was added from a source plate containing 675 µM CaCl2 in FLIPR assay buffer. IC50 values for tested compounds were calculated using the fluorescence value collected at the 10 min timepoint with % inhibition calculated using the DMSO control and cyclosporin A values as 100 and 0 %, respectively. Rat brain mitochondria assay mPTP activity was measured in brain mitochondria freshly isolated from female Sprague Dawley (250 to 300 gram) rats. Anaesthetised rats were perfused in-situ with ~40 ml cold Dulbecco’s Phosphate Buffered Saline (DPBS), then brains dissected and transferred into 30 ml Isolation Buffer (225mM mannitol, 75 mM sucrose, 1mM EGTA, adjusted to pH 7.4 with 1M NaOH). The brain was minced using tweezers and a scalpel into ~5mm pieces then transferred into a 50 ml Potterton Dounce homogenization tube on ice containing 10 ml ice-cold isolation buffer (as above with addition of Complete Protease inhibitor; 1 tablet per 50 ml buffer). Homogenisation was carried out using a Teflon pestle at 1800 rpm. The slurry was centrifuged at 2000 g for 10 min at 4 ^oC, then the supernatant centrifuged at 12,000 g for 9 min. The pellet was resuspended with a dounce homogeniser in isolation buffer as above but with the addition of 0.02 % digitonin, centrifuged at 12,000g for 11 min and finally resuspended in 5 ml modified isolation buffer (as above but with EGTA reduced to 0.1 mM). Test compounds were prepared in 384 well polypropylene assay plates as described above for the liver mitochondria assay. A stock mitochondria/Fluo5N assay solution was prepared in 5.6 ml assay buffer (120 mM mannitol, 40 mM MOPS, 5 mM KH2PO4, 60 mM KCl, 10 mM pyruvate, 2 mM malate, 2 mM MgCl2, 20 µM ADP, 1.26 µM oligomycin A, adjusted to pH 7.4) supplemented with Fluo5N pentapotassium salt (2 µM) and 1 ml mitochondria suspension, then transferred (15 µl) into the assay plate containing test compounds and incubated for 10 min at RT. Assay plates were then transferred to a FLIPR Tetra plate reader (Molecular Devices). Dye fluorescence was then measured every 3 sec for a total of 10 min. After 12 sec, a 2.5 µl bolus of Ca2+ (75 µM) was added from a source plate containing 675 µM CaCl₂ in FLIPR assay buffer. IC50 values for test compounds were calculated using the fluorescence value collected at the 10 min timepoint with % inhibition calculated using the DMSO control and cyclosporin A values at 100 % and 0 %, respectively. General cytotoxicity was assessed using standard cell viability methods (Cell Titre Glo; Promega) in HEK293 and SHSY5Y cells, following incubation of test compound for between 24 and 96 hours. Results: mPTP pIC₅₀ values for certain Example compounds of the invention in a range of mPTP assays are provided in Table 3 below. Table 3 also provides the pIC₅₀ values for Comparative Examples 1,2 and 3. The results indicate that the tested compounds of the invention display inhibition of mPTP from isolated rat liver mitochondria and isolated rat brain mitochondria, with many Example compounds displaying pIC50 values of 7.0 or greater. Biological Example 2 – Cytochrome P450 Assays Studies to assess tested compound mediated inhibition of cytochrome P450 enzyme isoform CYP2D6 were performed using human liver microsomes (BD Gentest) using either a single concentration (1 µM) of test compound or concentration response (0.1, 0.3, 1, 3, 10 and 30 µM) to derive an IC50. Tested compound solutions were prepared from 10 mM stocks in DMSO and diluted to 200 µM in DMSO. Reactions were prepared in a 96 deep well plate by combining 1 µl test compound with 179 µl reaction mixture (100 mM phosphate buffered saline (PBS), 0.2 mg/mL microsomes and 2 µM Dextromethorphan prepared from stocks as detailed below). Table 2: Summary of incubation mixtures Buffer Stock Concentration Volume Final Concentration Microsomes 20 mg/mL 2 μL 0.2 mg/mL Phosphate buffer 100 mM 176 μL 100 mM Substrate - 1 μL - The positive control inhibitor, quinidine, was used at a final concentration of 0.5 µM when used at a single concentration. The final concentrations of quinidine used to derive an IC50 were 0, 0.1, 0.3, 1, 3, 10 and 30 μM. Plates were warmed at 37 °C for 15 min before starting reactions with 20 µl 10 mM NADPH solution in PBS and incubated for 20 min at 37^oC. The assay is performed in duplicate. Reactions were quenched with 200 µl cold acetonitrile containing internal standards (200 nM labetalol, 200 nM alprazolam and 100 nM tolbutamide). The plate was centrifuged at 4000 rpm for 30 minutes, placed on ice for 20 minutes and then centrifuged at 4000 rpm for 30 minutes again to precipitate protein.100 μL of the supernatant was transferred to a new plate and diluted with 100 μL pure water before being analysed using UPLC/MS/MS. The products of the transformation for dextromethorphan to dextrophan was monitored by UPLC-MS/MS. The inhibition of CYP2D6 in human liver microsomes was measured as the percentage decrease in the activity of dextrophan formation compared to non- inhibited controls (= 100% activity). The IC₅₀ value was calculated (test compound concentration which produces 50% inhibition) by using Excel Xlfit. Results: CYP2D6 % inhibition values for certain compounds of the invention are presented in Table 3. Table 3 also presents the CYP2D6 % inhibition value for Comparative Example 1. The results indicate that the tested compounds display a significantly reduced inhibition of CYP2D6 compared to Comparative Examples 1 and 2. The results show that Comparative Example 1 is a highly potent inhibitor of CYP2D6, and significantly more potent than the tested Example compounds. Therefore, the tested compounds of the invention are expected to display improved in vivo properties as compared with Comparative Examples 1 and 2, such as the reduction of deleterious drug-drug interactions and reduced inhibition in the production of neurotransmitters in the central nervous system, in particular dopamine. Table 3: Summary of results from Biological Examples 1 and 2 Example No. mPTP Rat liver mPTP Rat CYP2D6 % CYP2D6 IC50 pIC50* brain pIC50 inhibition @ 1 µM µM** Comparative 7.8 7.5 86.5 0.074 Example 1 Comparative 7.9 7.7 NT 21 Example 2 Example No. mPTP Rat liver mPTP Rat CYP2D6 % CYP2D6 IC50 pIC50* brain pIC50 inhibition @ 1 µM µM** Comparative 8.1 NT NT NT Example 3 1 7.9 7.7 18 NT 2 7.0 6.4 NT NT 3 7.0 6.4 NT NT 4 7.2 6.8 NT NT 5 6.9 6.8 NT >50 6 7.5 7.7 NT >50 7 7.0 6.5 NT NT 8 7.5 7.5 <1 NT 9 7.5 6.9 NT NT 10 7.2 7.3 NT NT 11 6.8 6.5 NT NT 12 7.7 7.4 NT NT 13 7.7 7.3 NT NT 14 7.3 6.5 <1 NT 15 7.4 7.7 3 NT 16 7.9 8.0 NT NT 17 7.2 7.3 NT NT 18 7.3 8.3 6 NT 7.7*** 19 7.9 7.8 5 NT 20 7.1 7.0 NT NT 21 6.8 6.9 NT NT 22 7.5 7.1 NT NT 23 5.8 5.3 NT NT 24 7.7 7.4 NT NT 25 5.7 5.1 NT NT 26 6.4 5.8 NT NT 27 8.2 8.3 NT NT 28 7.1 6.5 NT NT 29 5.1 4.5 NT NT 30 6.4 5.9 NT NT 31 7.2 7.0 NT NT 32 7.3 7.1 NT NT 33 6.4 6.1 NT NT Example No. mPTP Rat liver mPTP Rat CYP2D6 % CYP2D6 IC50 pIC50* brain pIC50 inhibition @ 1 µM µM** 34 8.1 8.3 NT NT 35 7.7 8.0 NT NT 36 7.9 8.2 NT NT 37 8.2 8.3 NT NT 38 7.9 8.0 NT NT 39 7.8 7.5 NT NT 40 7.5 7.6 NT NT 41 8.1 7.8 NT NT 42 7.2 7.7 NT 15 43 6.3 6.0 NT NT 44 7.7 7.6 NT NT 45 5.8 5.8 NT NT 46 8.1 8.2 NT NT 47 8.4 8.4 NT NT 48 7.4 7.2 NT NT 49 7.6 7.6 NT NT 50 7.0 7.1 NT NT 51 7.1 6.8 NT NT 52 8.3 8.3 NT NT 53 7.7 7.4 NT NT 54 8.2 8.3 NT NT 55 7.6 7.3 NT NT 56 7.4 7.0 NT NT 57 7.5 7.5 NT NT 58 7.8 8.1 NT NT 59 7.2 7.6 NT NT 60 6.8 6.6 NT NT 61 7.4 7.7 NT NT 62 7.7 7.8 <1 NT 63 7.0 7.1 NT NT 64 6.7 6.5 NT NT 65 6.6 6.7 NT NT 66 6.4 6.4 NT NT 67 8.2 8.3 NT NT 68 7.7 7.7 NT NT 69 7.6 7.3 NT NT Example No. mPTP Rat liver mPTP Rat CYP2D6 % CYP2D6 IC50 pIC50* brain pIC50 inhibition @ 1 µM µM** 70 7.8 7.8 NT NT 71 8.0 7.8 NT NT 72 7.0 6.7 NT NT 73 7.4 7.6 NT NT 74 7.8 8.1 NT NT 75 7.6 7.5 NT NT 76 7.2 6.9 NT NT 77 8.2 8.0 NT NT 78 7.8 7.6 NT NT 79 7.3 7.1 NT NT 80 8.0 8.0 NT NT 81 7.4 7.7 NT NT 82 8.6 8.3 NT NT 83 8.0 7.9 NT NT 84 7.5 7.9 NT NT 85 7.1 7.8 NT NT 86 7.0 7.3 NT NT 87 7.5 7.5 NT NT 88 7.3 7.1 NT NT 89 7.6 7.6 NT NT 90 NT NT NT NT 91 NT NT NT NT 92 NT NT NT NT *average value from multiple experiments (n≥2) **average value from two experiments ***average value from four experiments NT – not tested. Biological Example 3 – FaSSIF Solubility Test compounds were prepared as 10 mM stocks in DMSO and 15 µl samples transferred in duplicate into 1.5 mL glass flat bottom vials (BioTech Solutions). Fasted state simulated intestinal fluid (FaSSIF) was added to each vial to final volume of 500 µl. One PTFE encapsulated stir stick (V&P Scientific) was placed in each vial before sealing with PTFE/SIL plugs (BioTech Solutions). Vials were shaken at 1100 rpm for 2 hr at 25°C. Samples were then filtered through MultiScreen Solvinert filter plates (Millipore) via vacuum filtration. Aliquots of filtrate (5 µl) plus 5 µl DMSO were diluted in 490 µl 50 % acetonitrile in water containing internal standard. The filtrate was analysed and quantified against a standard of known concentration using LC-MS/MS. Solubility values of the test compound and control compound were calculated as follows: [Sample] = (Area ratiosample * INJ VOL STD * DFSample * [STD])/(Area ratio STD * INJ VOLSample). Results: The solubility values for certain compounds of the invention are provided in Table 4 below. Table 4 also presents results for Comparative Examples 1,2 and 3. The results indicate that certain compounds of the invention display higher solubility in FaSSIF than Comparative Examples 1 and 3. Therefore, certain compounds of the invention may be expected to display improved bioavailability and/or improved systemic exposure than Comparative Examples 1 and 3, particularly when said compounds are dosed orally. Biological Example 4 – Hepatocyte intrinsic clearance assays Hepatocyte clearance assay In vitro clearance studies were performed in primary human hepatocytes (BioIVT). Vials of cryopreserved human hepatocytes were thawed in a 37°C water bath for 2 min. Cells were transferred into thawing medium (Williams’ Medium E containing 30% Percoll, 1 x GlutaMAX-1, 15 mM HEPES, 5 % fetal bovine serum (FBS), 4 µg/ml insulin, 1 µM dexamethasone), centrifuged at 100 g for 10 min then resuspended in culture medium (Leibovitz’s L-15 Medium) at a concentration of 0.5 × 10⁶ viable cells/mL (number of viable cells assessed using AO/PI staining). Hepatocytes (198 μL) were transferred into wells of a 96-well non-coated plate and placed in a 37°C incubator for 10 min. Test compound solutions were prepared from 10 mM stocks in DMSO, diluted to 100 µM in 50 % (v/v in water) acetonitrile. Test compound samples (2 µl) were added to each well of hepatocytes and incubated at 37°C. Samples (25 µl) were collected at t=0, 15, 30, 60, 60 and 120 min, mixed with 6 volumes (150 µl) of acetonitrile containing internal standard (100 nM alprazolam, 200 nM caffeine and 100 nM tolbutamide), vortexed for 5 min and centrifuged for 45 min at 3220 g. An aliquot of supernatant (100 µL) was diluted with 100 µL ultra-pure water, and the mixture was used for LC/MS/MS analysis. All incubations were performed in duplicate. Peak areas were determined from extracted ion chromatograms. The slope value, k, was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug vs. incubation time curve. The in vitro half-life (in vitro t1/2) was determined from the slope value: in vitro t1/2 = 0.693 / k. Conversion of the in vitro t1/2 (in min) into the in vitro intrinsic clearance (in vitro Cl_int, in µL/min/1×10⁶ cells) was done using the following equation (mean of duplicate determinations): in vitro CL_int = kV/N V = incubation volume (0.2 mL) N = number of hepatocytes per well (0.1 × 10⁶cells). Results: Intrinsic clearance values in human hepatocytes are presented in Table 4. Table 4 also presents intrinsic clearance values for Comparative Examples 1, 2 and 3. These results indicate that certain compounds of the invention exhibited lower intrinsic clearance (Clint) values in human hepatocytes when compared to Comparative Examples 1 and 3 and thus may be expected to have improved (i.e. higher) oral bioavailability and/or improved (i.e. higher) systemic exposure when compared to Comparative Examples 1 and 3. Table 4: Summary of results from Biological Examples 3 and 4 Example No. Solubility FaSSIF Human heps Clint µM µL/min/10⁶ cells* Comparative 4 13 Example 1 Comparative 58 <3 Example 2 Comparative 6 21 Example 3 1 35 4 2 8 <3 3 65 <3 4 10 6 5 30 <3 6 7 4 7 NT NT 8 23 <3 9 3 6 10 4 7 11 4 5 12 NT NT 13 2 4 14 18 <3 15 15 <3 16 5 16 17 4 7 18 11 5 19 20 <3 20 11 <3 21 NT NT 22 5 <3 Example No. Solubility FaSSIF Human heps Clint µM µL/min/10⁶ cells* 23 NT NT 24 27 7 25 NT NT 26 NT NT 27 8 9 28 NT NT 29 NT NT 30 263 3 31 4 5 32 90 3 33 NT NT 34 58 17 35 5 15 36 8 3 37 1 9 38 18 5 39 68 3 40 75 3 41 0 36 42 21 3 43 NT NT 44 36 15 45 NT NT 46 1798 15 47 67 17 48 NT NT 49 NT 15 50 14 3 51 NT NT 52 NT NT 53 11 12 54 3 11 55 43 8 56 41 8 57 NT 13 58 NT 9 Example No. Solubility FaSSIF Human heps Clint µM µL/min/10⁶ cells* 59 NT NT 60 NT NT 61 2 3 62 NT NT 63 7 8 64 NT NT 65 NT NT 66 NT 8 67 2 17 68 NT NT 69 4 3 70 0 3 71 3 7 72 NT NT 73 18 3 74 4 3 75 2 6 76 88 3 77 24 3 78 9 3 79 26 4 80 51 7 81 12 3 82 7 9 83 1 3 84 22 6 85 14 3 86 NT NT 87 NT 9 88 32 8 89 9 6 90 1801 NT 91 NT NT 92 NT NT * average value from two experiments. NT – not tested. Biological Example 5 – MDCK-MDR1 Efflux Assay The bidirectional permeability and absorption mechanisms of test compounds was analysed using MDCK-MDR1 Cell Monolayers. Cell Seeding Preparation MDCK-MDR1 cell culture medium was prepared consisting of Dulbecco’s Modified Eagle’s Medium (DMEM) with high glucose and L-glutamine supplemented with 10% FBS, 1× penicillin-streptomycin mixture. 50 μL of culture medium was added to each well of a Transwell insert. A further 25 mL of culture medium was added to the Transwell insert and it was incubated at 37 °C, 5% CO2 for 1 hour to be ready for cell seeding. Cells were cultivated in T-75 flasks in a cell culture incubator set at 37°C, 5% CO2, 95% relative humidity. Cells were allowed to reach 80-90% confluence before detaching and splitting. The cultivated cells were rinsed in T-75 flasks with 5 mL PBS. After aspirating off, 1.5 mL trypsin/EDTA, was added and then the cells were allowed to incubate at 37 °C for approximately 5 to 10 minutes or until the cells detach and float. The trypsin/EDTA was inactivated by adding excess serum containing medium. The cell suspension was removed to a conical tube and the cells pelleted by centrifugation at 120 x g for 10 minutes. The cells were resuspended in seeding medium at a density of 7.8 × 10⁵ cells/mL and 50 μL of the cell suspension was added to each well of a previously prepared Transwell plate to yield the final cell monolayer density of 2.72 × 10⁵ cells/cm². Seeding and Feeding of MDCK-MDR1 Cells into Transwell Plates 50 μL of cell suspension was added to each well of a Transwell plate and incubated for 4-7 days. The medium was replaced every other day. Assessment of Cell Monolayer Integrity When the 4–7-day MDCK-MDR1 cultured cells had reached confluence and were differentiated, they were used for transport studies. The medium was removed from the reservoir and Transwell inserts and 75 μL of prewarmed culture medium was added to each transwell insert and 25 mL of receiver plate. The electrical resistance across the monolayer was measured using Millicell Epithelial Volt-Ohm measuring system. Performing the Drug Transport Assay The MDCK-MDR1 plate was removed from the incubator. The monolayers were washed and the volume exchanged twice using pre-warmed HBSS (10 mM HEPES, pH 7.4), followed by incubation at 37 °C for 30 minutes. Stock solutions of the test compounds and control compounds in DMSO were prepared by diluting with HBSS (10 mM HEPES, pH 7.4) to reach the final concentration of 1 μM. The final concentration of DMSO in the incubation system was 0.5%. To determine the rate of drug transport in the apical to basolateral direction: 125 μL of working solution of compounds was added to the Transwell insert (apical compartment), followed by immediate transfer of a 50 μL sample (D0 sample) from the apical compartment to a new 96-well plate containing 200 μL cold acetonitrile containing internal standards (IS: 2 µM ketoprofen, 200 nM labetalol, 200 nM caffeine and 100 nM alprazolam). The wells in the receiver plate were filled with 235 μL of prewarmed HBSS (10 mM HEPES, pH 7.4). To determine the rate of drug transport in the basolateral to apical direction: 285 μL of working solution of compounds was added to the receiver plate wells (basolateral compartment), followed by immediate transfer of a 50 μL sample (D0 sample) from the basolateral compartment to a new 96-well plate containing 200 μL cold acetonitrile containing internal standards (IS: 2 µM ketoprofen, 200 nM labetalol, 200 nM caffeine and 100 nM alprazolam). The Transwell insert (apical compartment) was filled with 75 μL of prewarmed HBSS (10 mM HEPES, pH 7.4). The multiwell insert plate was placed into the basolateral plate, transferred into the incubator and incubated at 37 °C for 2 hours. After the incubation, the multiwell cell insert plate was removed from the basolateral receiver plate and place it into an empty basolateral plate.50 μL Aliquots from both basolateral donor well and apical receiver well were transferred into a new 96-well plates, 200 μL of cold acetonitrile containing appropriate internal standards (IS: 2 µM ketoprofen, 200 nM labetalol, 200 nM caffeine and 100 nM alprazolam) was added into each well of the plate. Samples were vortexed for 10 minutes and then centrifuged at 3,220 g for 30 minutes.100 μL of the supernatant was transferred to a new 96-well plate and 100 μL of pure water was added for analysis by UPLC-MS/MS. The Lucifer Yellow leakage was determined after a 2-hour transport period, using Lucifer yellow working solutions, prepared by diluting the stock solution with transport buffer to reach the final concentration of 100 μM. The remaining transfer buffer was aspirated, and 100 μL of the Lucifer yellow solution to the Transwell insert (apical compartment) was added. The wells in the receiver plate (basolateral compartment) were filled with 300 μL of transport buffer, which were incubated at 37 °C for 30 minutes.80 μL was removed directly from the basolateral wells and transferred to new 96 wells plates. The Lucifer Yellow fluorescence (to monitor monolayer integrity) was measured in a fluorescence plate reader at 485 nm excitation and 530 nm emission. Data Analysis All calculations were carried out using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The Lucifer yellow leakage of MDCK-MDR1 cell monolayers was calculated using the following equation:

Where Iacceptor is the fluorescence intensity in the acceptor well (0.3 mL), and Idonor is the fluorescence intensity in the donor well (0.1 mL) and expressed as % leakage. Any monolayer that produces a Lucifer yellow leakage > 1%, indicating poor monolayer formation, will be excluded from the evaluation. The apparent permeability (Papp), in units of centimetre per second, was calculated for MDCK-MDR1 drug transport assays using the following equation:

Where VA is the volume (in mL) in the acceptor well (0.235 mL for Ap→Bl flux and 0.075 mL for Bl→Ap flux), Area is the surface area of the membrane (0.143 cm² for Transwell-96 Well Permeable Supports), and time is the total transport time in seconds. The efflux ratio was determined using the following equation:

Where Papp (B-A) indicates the apparent permeability coefficient in basolateral to apical direction, and Papp (A-B) indicates the apparent permeability coefficient in apical to basolateral direction. The control compound was included in the assay. Any value of the compounds that was not within the specified limits was rejected and the experiment was repeated. Results: Apparent permeability (from Apical to Basolateral direction) and the efflux ratio measured in the MDCK-MDR1 assay are presented in Table 5. Table 5 also presents apparent permeability and efflux ratio values for Comparative Examples 1, 2 and 3. These results indicate that certain compounds of the invention have increased apparent permeability and/or reduced efflux ratio when compared to Comparative Example 2. These results indicate that certain compounds of the invention may be expected to have improved oral bioavailability and/or improved systemic exposure and/or brain penetration than Comparative Example 2. Table 5: Summary of results from Biological Examples 5 Example No. Papp A-B Efflux ratio 10^-6 cm.s^-1 Comparative 16 0.4 Example 1 Comparative 4 10 Example 2 Comparative 9 2.2 Example 3 Example No. Papp A-B Efflux ratio 10^-6 cm.s^-1 1 12 1.8 2 10 1.6 3 20 1.0 4 10 0.5 5 10 1.5 6 9 1.6 7 NT NT 8 7 2.2 9 9 0.9 10 6 2.2 11 NT NT 12 15 0.7 13 4 9 14 6 9 15 5 3.8 16 9 1.4 17 6 0.9 18 8 1.8 19 9 1.6 20 3 8.1 21 NT NT 22 8 2.0 23 NT NT 24 9 2.7 25 NT NT 26 4 9.2 27 13 1.3 28 NT NT 29 NT NT 30 13 2.3 31 11 1.5 32 5 6.2 33 NT NT 34 2 16.5 35 8 1.3 36 10 1.8 Example No. Papp A-B Efflux ratio 10^-6 cm.s^-1 37 9 1.2 38 9 0.9 39 10 1 40 9 0.9 41 1 2.6 42 16 0.5 43 NT NT 44 4 2.2 45 NT NT 46 0 3.2 47 7 1.2 48 NT NT 49 NT NT 50 9 0.7 51 NT NT 52 NT NT 53 12 1.2 54 13 1 55 9 3.4 56 7 3.9 57 NT NT 58 8 2 59 NT NT 60 NT NT 61 1 15.7 62 1 12.1 63 3 7.7 64 NT NT 65 NT NT 66 NT NT 67 4 1.7 68 NT NT 69 5 6.4 70 10 1.4 71 14 1.1 72 NT NT Example No. Papp A-B Efflux ratio 10^-6 cm.s^-1 73 12 0.5 74 4 4.9 75 13 2.2 76 8 3.4 77 9 1.6 78 13 1.1 79 13 1.3 80 2 0.9 81 8 0.8 82 6 0.7 83 7 2.6 84 15 0.5 85 12 0.6 86 NT NT 87 7 2.1 88 15 1.5 89 15 0.8 90 NT NT 91 NT NT 92 NT NT NT – not tested. Conclusion from Biological Examples: The results of Biological Examples 1 and 2 demonstrate that the tested compounds of the invention are inhibitors of mPTP in a range of mPTP assays. The tested compounds of the invention also showed a reduced inhibition of CYP2D6 compared to Comparative Example 1 (Biological Example 2). The results of Biological Example 3, 4 and 5 demonstrate certain compounds of the invention show improved solubility and/or intrinsic clearance compared to Comparative Example 1 and 3 and lower efflux ratio in the MDCK MDR1 Efflux assay compared to Comparative Example 2 and as such, are expected to display improved overall pharmacokinetic properties e.g. in respect of oral bioavailability and/or improved systemic exposure and/or brain penetration compared to Comparative Examples 1, 2 and/or 3. Therefore, the compounds of the invention are believed to be useful pharmaceuticals, particularly for the treatment or prophylaxis of diseases and disorders in which inhibition of mPTP provides a therapeutic or prophylactic effect. Throughout the specification and the claims which follow, unless the context requires otherwise, the word ‘comprise’, and variations such as ‘comprises’ and ‘comprising’, will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps. The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the claims which follow. All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth. REFERENCES Yu et al., TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS, Cell, Volume 183, Issue 3, 2020, pages 636-649.e18. Jang et al., Proximal tubule cyclophilin D mediates kidney fibrogenesis in obstructive nephropathy, 2021, American Journal of Physiology: Renal physiology, doi: 10.1152/ajprenal.00171.2021. Epub ahead of print. PMID: 34396791. Plyte et al., Cinnamic Anilides as New Mitochondrial Permeability Transition Pore Inhibitors Endowed with Ischemia-Reperfusion Injury Protective Effect in Vivo, J. Med Chem.2014, 57, 5333-47 Chen et al., Probing Mitochondrial Permeability Transition Pore Activity in Nucleated Cells and Platelets by High-Throughput Screening Assays Suggests Involvement of Protein Phosphatase 2B in Mitochondrial Dynamics, Assay and Drug Development Technologies, 2018, 16, 445-45. Yannick LACROIX, “The design, synthesis and optimisation of calcium release-activated calcium (CRAC) channel inhibitors and mitochondrial permeability transition pore (mPTP) modulators, using phenotypic screening”, PhD Thesis, University of Strathclyde (released 1 November 2021).

Claims

CLAIMS 1. A compound of formula (I):

wherein: R₁ is H or F; wherein: R2 is C1-3alkyl, -CH2OC1-3alkyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; R3 is H, C1-3alkyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; R4 is H, C1-3alkyl, -CH2OC1-3alkyl, C1-3fluoroalkyl, C1-3alkoxy, C1-3fluoroalkoxy, -CN, halo or C3- 5cycloalkyl; and R₅ is H, C_1-3alkyl, -CH₂OC_1-3alkyl, C_1-3fluoroalkyl, C_1-3alkoxy, -CN, halo or C_3-5cycloalkyl; provided that when R₅ is H then R₁ is F; B is group (Ba) or (Bb): wherein group (Ba) is: (Ba); wherein: Y is C(R9a)(R9b), O or N(R9c); R9a, R9b and R9c are independently H or C1-3alkyl or R9a and R9b together with the carbon atom to which they are attached form a C3-6cycloalkyl group; and R₆, R₇ and R₈ are independently H, C_1-3alkyl, C_2-3alkynyl, C_1-3fluoroalkyl, C_1-3alkoxy, -CN, halo or C_3-5cycloalkyl; wherein group (Bb) is:

wherein: R10 is H, C1-3alkyl, C2-3alkynyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; D is N or C(R11) and R11, R12 and R13 are independently H, C1-3alkyl, C2-3alkynyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; or a prodrug thereof in which an available nitrogen atom in group Ba or Bb is derivatised by the moiety -CH2-OP(=O)(OH)2; or a pharmaceutically acceptable salt and/or solvate thereof.

2. A compound of formula (I) according to claim 1 which is a compound of formula (IA):

wherein: R₂ is C_1-3alkyl, -CH₂OC_1-3alkyl, C_1-3fluoroalkyl, C_1-3alkoxy, -CN, halo or C_3-5cycloalkyl; R₃ is H, C_1-3alkyl, C_1-3fluoroalkyl, C_1-3alkoxy, -CN, halo or C_3-5cycloalkyl; R₄ is H, C_1-3alkyl, -CH₂OC_1-3alkyl, C_1-3fluoroalkyl, C_1-3alkoxy, C_1-3fluoroalkoxy, -CN, halo or C_3- ₅cycloalkyl; and R5 is H, C1-3alkyl, -CH2OC1-3alkyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; B is group (Ba) or (Bb): wherein group (Ba) is:

wherein: Y is C(R9a)(R9b), O or N(R9c); R_9a, R_9b and R_9c are independently H or C_1-3alkyl or R_9a and R_9b together with the carbon atom to which they are attached form a C_3-6cycloalkyl group; and R₆ and R₈ are independently H, C_1-3alkyl, C_2-3alkynyl, C_1-3fluoroalkyl, C_1-3alkoxy, -CN, halo or C_3-5cycloalkyl; wherein group (Bb) is:

(Bb1); wherein: R10 is H, C1-3alkyl, C2-3alkynyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; D is N or C(R11) and R11 and R13 are independently H, C1-3alkyl, C2-3alkynyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; or a prodrug thereof in which an available nitrogen atom in group Ba or Bb is derivatised by the moiety -CH₂-OP(=O)(OH)₂; or a pharmaceutically acceptable salt and/or solvate thereof.

3. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to claim 1 or claim 2, wherein B is group (Ba1).

4. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to claim 2 or claim 3, wherein R8 is F.

5. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to claim 2 or claim 3, wherein R₈ is H.

6. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 2 to 5, wherein R6 is H.

7. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 2 to 6, wherein Y is CH2.

8. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 2 to 6, wherein Y is NMe.

9. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to claim 1 or claim 2, wherein B is group (Bb1).

10. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to claim 2 or claim 9, wherein R11 is C1-3alkyl, C2-3alkynyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C_3-5cycloalkyl.

11. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to claim 2 or claim 9, wherein D is N.

12. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to claim 2 or claim 9, wherein D is C(R11) and R11 is F, Cl, -CN, OMe, preferably D is C(R11) and R11 is F.

13. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to claim 2 or claim 9, wherein D is C(R11) and R11 is H.

14. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to claim 2 or claims 9 to 13, wherein R₁₃ is H.

15. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 2 or claims 9 to 14, wherein R₁₀ is H, Cl, F, Me or -CN, preferably H, Cl, Me or -CN.

16. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 2 or 9 to 15, wherein R2 is Me.

17. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 2 or 9 to 15, wherein R₅ is C_1-3alkyl, -CH₂OMe, C_1-3fluoroalkyl, C_1- ₃alkoxy, -CN, halo or C_3-5cycloalkyl, preferably is Me, F or Cl more preferably is Me or Cl.

18. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to claim 17, wherein R3 is Me, R4 is H and R5 is Me, F or Cl e.g. is Me or Cl.

19. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to claim 16, wherein R2 is Me, R3 is Me, R4 is methoxy and R5 is H.

20. A compound of formula (I) according to claim 1 which is a compound of formula (IB):

wherein: R10 is H, C1-3alkyl, C2-3alkynyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C3-5cycloalkyl; D is N or C(R11) and R11, R12 and R13 are independently H, C1-3alkyl, C2-3alkynyl, C1-3fluoroalkyl, C1-3alkoxy, -CN, halo or C_3-5cycloalkyl; or a prodrug thereof in which an available nitrogen atom in group Ba or Bb is derivatised by the moiety -CH₂-OP(=O)(OH)₂; or a pharmaceutically acceptable salt and/or solvate thereof.

21. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to claim 20, wherein B is group (Ba).

22. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to claim 20 or claim 21, wherein R₇ is F and R₆ and R₈ are each H

23. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 20 to 22, wherein R8 is F and R6 and R7 are each H.

24. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 20 to 23, wherein Y is N(Me).

25. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to claim 20, wherein B is group (Bb).

26. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to claim 20, wherein B is group (Bbx):

27. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof. according to claim 26 wherein: (i) R10 is H and R13 is H; (ii) R10 is F and R13 is H; or (iii) R10 is Cl and R13 is H.

28. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to claim 20 or claim 25, wherein D is C(R₁₁) and R₁₁ is F.

29. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to claim 20 or claim 25, wherein D is C(R₁₁) and R₁₁ is H.

30. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof, according to any one of claims 20, 25, 28 or 29, wherein R12 and R13 are H.

31. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 20, 25 or 28 to 30, wherein R₁₀ is selected from H, Cl, Me and -CN.

32. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 20 to 31, wherein R₂ is Me, -(CH₂)OMe or -CN.

33. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof according to claim 32, wherein R2 is Me, R3 is H, R4 is H and R5 is Cl.

34. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof. according to claim 32, wherein (i) R₂ is Me, R₃ is H, R₄ is H and R₅ is F; (ii) R₂ is -(CH₂)OMe, R₃ is H, R₄ is H and R₅ is F; (iii) R₂ is -(CH₂)OMe, R₃ is H, R₄ is H and R₅ is Cl; (iv) R₂ is Me, R₃ is H, R₄ is H and R₅ is -CN; (v) R₂ is -CN, R₃ is H, R₄ is H and R₅ is Cl or (vi) R₂ is Me, R₃ is H, R₄ is H and R5 is Me.

35. A compound or a prodrug thereof or a pharmaceutically acceptable salt and/or solvate thereof. according to any of claims 20 to 31, wherein: (i) R2 is Me, R3 is Me, R4 is H and R5 is F; (ii) R2 is Me, R3 is Me, R4 is H and R5 is Cl; (iii) R2 is CF3, R3 is Me, R4 is H and R5 is F; (iv) R2 is Me, R3 is Me, R4 is OMe and R₅ is H; or (v) R₂ is Me, R₃ is Me, R₄ is OCD₃ and R₅ is H.

36. A compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 35.

37. A prodrug of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 35 wherein B is group (Bb) and the 1-N or 2-N atom of group (Bb) is derivatised by the moiety CH2-OP(=O)(OH)2.

38. The compound, prodrug, pharmaceutically acceptable salt and/or solvate thereof according to claim 1, which is selected from the group consisting of: (2Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2Z)-2-fluoro-3-(3-fluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl) prop-2-enamide; (2Z)-N-(2,5-dimethylpyridin-3-yl)-2-fluoro-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2Z)-N-(5-chloro-2-methylpyridin-3-yl)-2-fluoro-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2Z)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2E)-3-(3-chloro-1H-indazol-6-yl)-N-[5-fluoro-2-(methoxymethyl)pyridin-3-yl]prop-2-enamide; (2E)-3-(3-chloro-1H-indazol-6-yl)-N-(5-fluoro-2-methylpyridin-3-yl)prop-2-enamide; (2E)-N-(5-fluoro-2-methylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (Z)-3-(7-chloro-1H-indazol-6-yl)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (2E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(4-fluoro-1-methyl-2-oxo-3H-1,3-benzodiazol-5-yl)prop-2- enamide; (2Z)-2-fluoro-3-(4-fluoro-1-methyl-2-oxo-3H-1,3-benzodiazol-5-yl)-N-(5-fluoro-2,4-dimethylpyridin-3- yl)prop-2-enamide; (2Z)-3-(3-cyano-7-fluoro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2- enamide; (2E)-N-[5-chloro-2-(methoxymethyl)pyridin-3-yl]-3-(7-fluoro-1H-indazol-6-yl)prop-2-enamide; (2Z)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-cyano-1H-indazol-6-yl)-2-fluoroprop-2-enamide; (2Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2Z)-3-(3-chloro-7-fluoro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2- enamide; (2Z)-3-(3-cyano-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2Z)-N-(2,5-dimethylpyridin-3-yl)-3-(3-cyano-1H-indazol-6-yl)-2-fluoroprop-2-enamide); (2Z)-3-(3-chloro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide; (Z)-2-fluoro-3-(7-methoxy-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(2,4,5-trimethylpyridin-3-yl)acrylamide; and (Z)-2-fluoro-3-(7-methoxy-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)acrylamide or a pharmaceutically acceptable prodrug, salt and/or solvate of any one thereof.

39. The compound, prodrug, pharmaceutically acceptable salt and/or solvate thereof according to claim 1, which is selected from the group consisting of: (E)-N-(4-(difluoromethyl)-5-fluoro-2-methylpyridin-3-yl)-3-(1H-indazol-6-yl)acrylamide; (Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)acrylamide; (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(6-fluoro-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5- yl)acrylamide; (Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(7-fluoro-2-oxoindolin-6-yl)acrylamide; (Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide; (Z)-3-(3-chloro-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3- yl)acrylamide; (Z)-3-(7-cyano-1H-indazol-6-yl)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-(7-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-chloro-5,7-difluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-1-(5-chloro-6-methoxy-2,4-dimethylpyridin-3-yl)-3-fluoro-4-(7-fluoro-1H-indazol-6-yl)but-3-en-2- one; (Z)-1-(5-chloro-2,4-dimethylpyridin-3-yl)-4-(3,7-difluoro-1H-indazol-6-yl)-3-fluorobut-3-en-2-one; (E)-1-(2-cyclopropyl-5-fluoropyridin-3-yl)-4-(7-fluoro-1H-indazol-6-yl)but-3-en-2-one; (Z)-1-(5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-fluoro-4-(7-fluoro-1H-indazol-6-yl)but-3-en- 2-one; (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3- yl)acrylamide; (Z)-3-(3,7-difluoro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3- yl)acrylamide; (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-ethynyl-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide; (Z)-3-(3,7-difluoro-1H-indazol-6-yl)-2-fluoro-N-(6-(methoxy-d3)-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-3-(3-(1-cyanocyclopropyl)-7-fluoro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3- yl)acrylamide; (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-chloro-5-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide; (Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-3-(2-hydroxypropan-2-yl)-1H-indazol-6- yl)acrylamide; (E)-3-(3-chloro-1H-pyrazolo[3,4-b]pyridin-6-yl)-N-(5-chloro-2-cyclopropylpyridin-3-yl)acrylamide; (E)-N-(5-chloro-2-cyclopropylpyridin-3-yl)-3-(5-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide; (Z)-N-(2,5-difluoro-4-methylpyridin-3-yl)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)acrylamide; (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(2-fluoro-6-methoxy-4-methylpyridin-3-yl)acrylamide; (Z)-N-(5-cyano-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(3,7-difluoro-1H-indazol-6-yl)-2- fluoroacrylamide; (Z)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(7-fluoro-3-propyl-1H-indazol-6-yl)acrylamide; (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-ethynyl-5-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide; (Z)-N-(2-(difluoromethyl)-5-fluoro-4-methylpyridin-3-yl)-2-fluoro-3-(7-fluoro-1H-indazol-6- yl)acrylamide; (Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(7-fluoro-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)acrylamide; (E)-3-(5-fluoro-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)acrylamide; (E)-N-(5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(5-fluoro-1H-indazol-6-yl)acrylamide; (E)-N-(5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(7-fluoro-1H-indazol-6-yl)acrylamide; (Z)-N-(5-cyano-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(3-ethynyl-7-fluoro-1H-indazol-6-yl)-2- fluoroacrylamide; (E)-N-(5-fluoro-2,6-dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2,5-dimethylpyridin-3-yl)acrylamide; (E)-N-(5-chloro-2-methylpyridin-3-yl)-3-(3-cyano-1H-indazol-6-yl)acrylamide; (E)-3-(3-chloro-1H-indazol-6-yl)-N-(5-cyano-2-methylpyridin-3-yl)acrylamide; (E)-N-(5-cyano-2-methylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-chloro-1H-indazol-6-yl)-N-(5-chloro-2-cyanopyridin-3-yl)acrylamide; (E)-N-(5-chloro-2-cyanopyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N -(5-chloro-2-methylpyridin-3-yl)-3-(7-fluoro-3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(5-chloro-2-(methoxymethyl)pyridin-3-yl)-3-(3-cyano-1H-indazol-6-yl)acrylamide; (Z)-N-(5-cyano-2,4-dimethylpyridin-3-yl)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)acrylamide; (Z)-3-(3-chloro-7-fluoro-1H-indazol-6-yl)-N-(5-cyano-2,4-dimethylpyridin-3-yl)-2-fluoroacrylamide; (Z)-3-(7-chloro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-3-(7-cyano-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-3-(3,7-difluoro-1H-indazol-6-yl)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-N-(5-chloro-2,4-dimethylpyridin-3-yl)-3-(3-cyano-7-fluoro-1H-indazol-6-yl)-2-fluoroacrylamide; (E)-N-(2-cyclopropylpyridin-3-yl)-3-(7-fluoro-1H-indazol-6-yl)acrylamide; (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(5-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-3-(3,7-difluoro-1H-indazol-6-yl)-2-fluoro-N-(5-fluoro-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(6-(methoxy-d₃)-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)-N-(4-methyl-2-(trifluoromethyl)pyridin-3-yl)acrylamide; (E)-3-(3-chloro-1H-indazol-6-yl)-N-(5-chloro-2-cyclopropylpyridin-3-yl)acrylamide; (Z)-N-(5-chloro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-3-(3,7-difluoro-1H-indazol-6-yl)-2- fluoroacrylamide; (E)-N-(5-chloro-2-cyclopropylpyridin-3-yl)-3-(3-fluoro-1H-indazol-6-yl)acrylamide; (Z)-N-(5-cyano-2,4-dimethylpyridin-3-yl)-3-(3,7-difluoro-1H-indazol-6-yl)-2-fluoroacrylamide; (Z)-3-(3-chloro-7-fluoro-1H-indazol-6-yl)-2-fluoro-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (Z)-3-(3-chloro-7-fluoro-1H-indazol-6-yl)-2-fluoro-N-(6-(methoxy-d₃)-2,4-dimethylpyridin-3- yl)acrylamide; (Z)-3-(3-chloro-7-fluoro-1H-indazol-6-yl)-N-(5-cyano-4-methyl-2-(trifluoromethyl)pyridin-3-yl)-2- fluoroacrylamide; (E)-3-(3-chloro-1H-indazol-6-yl)-N-(5-fluoro-4-methyl-2-(trifluoromethyl)pyridin-3-yl)acrylamide; (Z)-N-(2-chloro-4-methylpyridin-3-yl)-2-fluoro-3-(7-fluoro-1H-indazol-6-yl)acrylamide; and (Z)-3-(3,7-difluoro-1H-indazol-6-yl)-N-(2-(difluoromethyl)-5-fluoro-4-methylpyridin-3-yl)-2- fluoroacrylamide; or a pharmaceutically acceptable prodrug, salt and/or solvate of any one thereof. 37. The compound, prodrug, pharmaceutically acceptable salt and/or solvate thereof according to claim 1, which is selected from the group consisting of: (Z)-(3-chloro-6-(3-((5-cyano-2,4-dimethylpyridin-3-yl)amino)-2-fluoro-3-oxoprop-1-en-1-yl)-7-fluoro- 2H-indazol-2-yl)methyl dihydrogen phosphate; (Z)-(3-chloro-6-(3-((5-cyano-2,4-dimethylpyridin-3-yl)amino)-2-fluoro-3-oxoprop-1-en-1-yl)-7-fluoro- 1H-indazol-1-yl)methyl dihydrogen phosphate; and (Z)-(7-fluoro-6-(2-fluoro-3-((6-methoxy-2,4-dimethylpyridin-3-yl)amino)-3-oxoprop-1-en-1-yl)-2H- indazol-2-yl)methyl dihydrogen phosphate; or a pharmaceutically acceptable salt and/or solvate of any one thereof.

40. A pharmaceutical composition comprising a compound or a prodrug according to any one of claims 1 to 39 and a pharmaceutically acceptable carrier or excipient.

41. The compound, prodrug, pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 39, or the pharmaceutical composition according to claim 40 for use as a pharmaceutical.

42. The compound, prodrug, pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 39, or the pharmaceutical composition according to claim 40 for use in the treatment or prophylaxis of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect.

43. Use of a compound, prodrug, pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 39 or a pharmaceutical composition according to claim 40 in the manufacture of a medicament for treating or preventing a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect.

44. A method of treating or preventing a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect, which comprises administrating to a subject in need thereof an effective amount of a compound, prodrug, pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 39 or a pharmaceutical composition according to claim 40.

45. The compound, prodrug, pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method, according to any one of claims 1 to 44, wherein the disease or disorder is selected from degenerative or neurodegenerative diseases (such as Parkinson’s disease, dementia with Lewy bodies, Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, frontal temporal dementia, chemotherapy induced neuropathy, Huntington’s disease, spinocerebellar ataxias, progressive supranuclear palsy, hereditary spastic paraplegia, Duchenne muscular dystrophy, congenital muscular dystrophy, traumatic brain injury and Friedreich’s ataxia, in particular Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis), disorders of the central nervous system (such as AIDS dementia complex, depressive disorders, schizophrenia and epilepsy), ischemia and re-perfusion injury (such as acute myocardial infarction, stroke, kidney ischemia reperfusion injury, and organ damage during transplantation), metabolic diseases (such as hepatic steatosis, diabetes, diabetic retinopathy, cognitive decline and other diabetes associated conditions, obesity and feeding behaviours, and non-alcoholic fatty liver disease), inflammatory or autoimmune diseases (such as acute pancreatitis, systemic lupus, organ failure in sepsis and hepatitis), diseases of aging (such as bone repair, bone weakness in aging in osteoporosis and sarcopenia), renal diseases (such as chronic kidney disease associated with APOL1 genetic variants and chronic kidney disease), mitochondrial diseases (such as Reye syndrome, Leber’s hereditary optic neuropathy and associated disorders and disorders), and TDP-43 diseases or disorders, such as TDP-43 associated neurodegeneration (e.g. Amyotrophic Lateral Sclerosis, Frontotemporal dementia, Facial onset sensory and motor neuronopathy, Primary lateral sclerosis, Progressive muscular atrophy, Inclusion body myopathy associated with early-onset Paget disease of the bone and Frontotemporal lobar degeneration dementia, Perry disease, Chronic traumatic encephalopathy, Severe traumatic brain injury, Alzheimer’s disease, Hippocampal sclerosis dementia, Limbic-predominant age-related TDP-43 encephalopathy, and Cerebral age-related TDP-43 with sclerosis).

46. The compound, prodrug, pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to any one of claims 1 to 45, wherein the compound is for administration to a human subject.

47. The compound, prodrug, pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to any one of claims 1 to 46, for use in combination with a further therapeutic agent.