New regulations for compounds

Abstract

The present invention provides compounds of formula (I): [Formula 1] TIFF2023539695000234.tif20170 and related aspects.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to novel compounds that are inhibitors of the mitochondrial permeability transition pore (mPTP), and in particular to such compounds for use as pharmaceuticals, especially 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 technology]

[0002] BACKGROUND OF THE INVENTION The mitochondrial permeability transition pore (mPTP) is activated under certain conditions of cellular stress, particularly when excessive Ca 2+ It is a high-conductance channel located on the inner mitochondrial membrane that is activated under load and oxidative stress. It is permeable to solutes with molecular weights <1.5 kDa and is sensitive to voltage and Ca. 2+ Activation of mitochondrial membrane potential (MTP)-dependent mitochondrial ATPases (MTPs) is dependent on mitochondrial activity and exhibits a characteristically large conductance. Upon activation, oxidative phosphorylation is uncoupled, resulting in loss of mitochondrial membrane potential and perturbation of mitochondrial metabolism. In addition, solutes enter the mitochondrial matrix, causing swelling and consequent release of apoptotic factors and sequestered Ca2+, which leads to rupture of the outer membrane. 2+ This is accompanied by the release of ATP, which results in cell death by apoptosis or necrosis depending on the cell type and physiology, and has therefore been implicated as a key pathological event in several degenerative and metabolic diseases.

[0003] Under normal physiological conditions, mitochondria are responsible for cellular Ca 2+ It plays an important role in regulating homeostasis. Ca enters cells through cell surface channels, a common mechanism of cell signaling. 2+ is rapidly sequestered by mitochondria and absorbs excessive and toxic Ca in the cytoplasm. 2+ Accumulation of high levels of Ca is prevented. 2+In cell types such as neurons, skeletal muscle fibers, and cardiomyocytes, where there is a flux of Ca, this Ca flux is transported from mitochondria to the mitochondrion. 2+ The "buffering" function is crucial for maintaining cellular health. However, mitochondria do not retain Ca 2+ Mitochondrial Ca sequestering capacity is limited. 2+ When the level reaches a certain threshold, Ca 2+ The activation of sensitive mPTP leads to mitochondrial breakdown and initiation of cell death. Activation of mPTP in degenerative diseases can occur in various ways depending on the disease, for example: 1) excessive intracellular Ca 2+ Entry of Ca into mitochondria 2+ overload, 2) dysfunctional mitochondrial Ca 2+ Efflux mechanisms, especially Ca 2+ Ca overload 2+ 3) decreased activity of the efflux transporter NCLX, and 3) Ca in mitochondria 2+ 4) oxidative stress; and 5) sensitization of mPTP due to impaired mitochondrial function, i.e., lower intramitochondrial Ca. 2+ Activation of mPTP at high concentrations, 6) excessive Ca transport from the endoplasmic reticulum into mitochondria at the junction between two organelles known as the mitochondrial-associated membrane. 2+ This can occur when moving.

[0004] While the properties and functions of mPTP can be investigated in simple in vitro assays in isolated mitochondria, the molecular identity of mPTP remains unknown. Although multiple proteins, including ATP synthase and the adenine nucleotide translocator (ANT) protein family, have been proposed to comprise the pore-forming complex, no single protein has been widely accepted as being responsible for pore formation. However, peptidyl prolyl cis-trans isomerase F (Ppif), also known as cyclophilin D, is well accepted as a key regulator of the pore, even though it does not form a transmembrane channel by itself. Genetic or pharmacological inhibition of Ppif results in Ca 2+ It significantly reduces the sensitivity of pore opening in response to stress and other mPTP activators. Therefore, genetic disruption or pharmacological inhibition of Ppif has been utilized to evaluate the involvement of mPTP in pathological pathways in cellular and animal disease models. Thus, inhibition of mPTP has been shown to be a potential therapeutic approach for a number of diseases, particularly those related to Ca 2+ It has been shown to be protective in models of diseases in which dysregulation and oxidative stress are known to contribute to cellular degeneration. In particular, genetic knockout of Ppif was shown to be protective in various presymptomatic in vivo transgenic models of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and motor neuron disease. This demonstrates the therapeutic potential of mPTP inhibition. In each of these diseases, genetic mutations, particularly proteins that cause inherited forms of the disease (i.e., amyloid precursor protein, α-synuclein, and superoxide dismutase 1, respectively) and are expressed in mouse models, inhibit the transport of Ca into mitochondria. 2+ It has been shown that mitochondrial Ca2+ induces either overload or sensitization of the mPTP. Recent evidence suggests that this may occur by a common mechanism in Alzheimer's disease, Parkinson's disease, and Friedreich's ataxia. In each case, mitochondrial Ca2+ is increased in cells expressing mutant disease-associated proteins (amyloid precursor protein, PINK1, and frataxin, respectively).2+ The activity or expression of the efflux transporter NCLX is reduced, which prevents the entry of Ca into mitochondria. 2+ In the case of Parkinson's disease, it has also been shown that pathological aggregated forms of the protein α-synuclein, a misfolded protein commonly found in sporadic and inherited cases of Parkinson's disease, sensitize or activate the mPTP.

[0005] Genetic disruption of Ppif has been shown to be beneficial in presymptomatic models of a number of other degenerative diseases, thus indicating the potential of mPTP inhibitors in Duchenne and congenital forms of muscular dystrophy, ischemia-reperfusion injury, bone repair, pancreatitis, and other related disorders, among others.

[0006] In addition to the demonstrated benefits of Ppif inhibition in presymptomatic models, mPTP function has been shown to be dysregulated in multiple other disease indications. In particular, in several diseases, Ca 2+ The threshold for mPTP activation in response to stress appears to be sensitized, suggesting that aberrant mPTP activation can occur under physiological conditions and that mPTP activation drives tissue degeneration. For example, in muscle mitochondria from aged human muscle biopsies, the threshold for mPTP activation is reduced compared to healthy controls. This sensitization of mPTP activity in these diseases provides an additional rationale for the therapeutic potential of mPTP inhibitors.

[0007] In addition, mPTP inhibitors may be effective in preventing mitochondrial dysfunction, oxidative stress, inflammatory stress, or Ca 2+ It may also have therapeutic potential in other diseases where dysregulation occurs during the pathogenesis of the disease.

[0008] The discovery and development of mPTP inhibitors has primarily focused on identifying Ppif inhibitors. Cyclosporin A (CsA), originally identified as an immunosuppressant due to its inhibitory activity against calcineurin, was also found to inhibit Ppif, as well as other members of the peptidyl prolyl cis-trans isomerase (Ppi) enzyme family. Subsequently, several cyclosporin A derivatives, e.g., Debio-25 and NIM811, were developed that exhibit broad activity against the Ppi enzyme family without inhibiting calcineurin. However, none of these have been marketed. To date, no potent, brain-penetrant, selective Ppif inhibitors have been reported. Another, more recent approach to discovering mPTP inhibitors utilizes phenotypic screening in isolated mitochondria. These have been successful in identifying potent small-molecule mPTP inhibitors with Ppif-independent modes of action.

[0009] Yu et al. (2020, Cell, 183, 1-14) discusses the relationship between mPTP activation and the mechanisms of TDP-43 proteinopathies, such as TDP-43-associated neurodegeneration. Cytoplasmic neuronal accumulation of TDP-43, a normally nuclear protein, characterizes almost all ALS cases 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 associated with upregulation of the NF-κB and type I IFN pathways, directly suggesting a role for TDP-43 in neuroinflammation. Mutant or overexpressed wild-type TDP-43 in neurons mislocalizes to mitochondria and induces the release of mitochondrial DNA (mtDNA) into the cytoplasm. This mtDNA then activates cGAS-STING, an immune sensor that triggers the induction of innate immune genes such as IL-6, TNFα, and interferon-β. Inhibition of mPTP with cyclosporine A or by CypD knockout prevents TDP-43-induced release of mtDNA and the subsequent induction of innate immune response genes. Furthermore, inhibition of cGAS-STING extends the survival of mutant mice expressing mutant TDP-43. This data implicates mPTP activation in mediating the toxic effects of TDP-43 in ALS and other diseases in which either mutations in the TDP-43 gene cause the disease or TDP-43 proteinopathy is present.

[0010] A paper by Jang et al. (2021 American Journal of Physiology: Renal physiology, doi: 10.1152 / ajprenal.00171.2021. Epub ahead of print. PMID: 34396791) highlights the potential therapeutic benefit of mPTP inhibition (via CypD knockout) in a mouse model of renal fibrosis. Renal fibrosis was induced in wild-type and CypD-KO mice using unilateral ureteral obstruction. Markers of inflammation, proximal tubular atrophy, and fibrosis were reduced in CypD-KO mice compared with wild-type mice. Measures of fibrosis included collagen deposition, α-SMA and TGF-β expression, and interstitial cell proliferation. This highlights the potential role of mPTP in cell injury / death-mediated tissue remodeling and fibrosis. Therefore, mPTP inhibitors may be beneficial in diseases in which fibrosis is a key pathological mechanism, such as chronic kidney disease, idiopathic pulmonary fibrosis, nonalcoholic steatohepatitis, primary biliary cholangitis, and systemic sclerosis.

[0011] WO2010 / 049768 relates to acrylamide derivatives and their use as therapeutic agents, particularly for the prevention and / or treatment of diseases associated with mPTP activity (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 of mPTP modulators using platelets and discloses additional acrylamide derivatives, including (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide. CA2884607A1 relates to acrylamide and maleimide compounds said to be useful in the treatment of mitochondrial diseases.

[0012] When administered orally, the oral bioavailability and systemic exposure of a drug are largely determined by the extent of absorption from the gastrointestinal tract and the extent of first-pass metabolism in the liver. Therefore, properties such as high solubility (measured in phosphate-buffered saline (PBS) or the more biologically relevant fasting simulated intestinal fluid (FaSSIF)) and high metabolic stability (measured in vitro in either isolated liver microsomes or hepatocytes from rats and humans) can be used to predict improved oral bioavailability and / or systemic exposure in patients.

[0013] There remains a need to discover additional compounds that are inhibitors of mPTP, particularly those that combine inhibition of mPTP with other desirable pharmacological properties, such as improved oral bioavailability and / or improved systemic exposure. Summary of the Invention

[0014] (Summary of the Invention) The present invention relates to a compound of formula (I): [ka] (In the formula: R 1a is H or methyl; R 1b is H or fluoro; A is a group (Aa), (Ab), (Ac), or (Ad): wherein the group (Aa) is: [ka] and; (In the formula: R2 is H, C 1-4 Alkyl, C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene (C 3-6 cycloalkyl), C 1-4 Alkylene (4-7 membered heterocycloalkyl), C 1-4 Alkoxy, OC 1-4Alkylene (aryl), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 AlkyleneO(4-7 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), C 3-6 Alkynyl, or C 1-4 Alkylene O(C 3-6 alkynyl); wherein the aryl, heterocycloalkyl, and cycloalkyl are C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 2a R 2b , SO2R 2c , and NHSO2R 2c optionally substituted by 1, 2, or 3 substituents each independently selected from R 2a is H and C 1-4 alkyl; R 2b is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 7-membered heterocycloalkyl; R 2c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 7-membered heterocycloalkyl; each R3 is independently halo, methyl, ethyl, or n-propyl; m is 0, 1, 2, 3, or 4); The group (Ab) is: [ka] and; (In the formula: R4 is H, C 1-4 Alkyl or C 1-4 alkylene(aryl); wherein the aryl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 4a R 4b , SO2R 4c , and NHSO2R 4c optionally substituted by 1, 2, or 3 substituents each independently selected from R 4a is H and C 1-4 alkyl; R 4b is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 7-membered heterocycloalkyl; R 4c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 7-membered heterocycloalkyl; R5 is H or C 1-4 is alkyl; Each R6 is independently 1-4 alkyl or halo; n is 0, 1, 2, or 3); The group (Ac) is: [ka] and; (In the formula: R7 is C 1-4 Alkyl, C 1-4 Alkylene (OH) or C 1-4 Alkylene OC 1-4 is alkyl; o is 1 or 2); The group (Ad) is: [ka] and; (In the formula: X is a bond, O, or CH; Each R8 is independently halo, C 1-4 Alkyl, C 1-4 Alkoxy, OC 1-4 Haloalkyl, OC 1-4 Alkylene (C 3-6 Cycloalkyl), OC 1-4 alkylene (4- to 7-membered heterocycloalkyl), or OH; wherein the heterocycloalkyl and cycloalkyl are C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 8a R 8b , SO2R 8c , and NHSO2R 8c optionally substituted by 1, 2, or 3 substituents independently selected from R 8a is H and C 1-4 alkyl; R 8b is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 7-membered heterocycloalkyl; R 8c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 7-membered heterocycloalkyl; Each R9 is independently halo or C 1-4 is alkyl; p is 0, 1, or 2; q is 0, 1, 2, 3, or 4); B is: [ka] and; (In the formula: R 10 is H, halo, or C 1-4 is alkyl; D, E, and F each independently represent C(R 10 ) or one of D, E, and F is N and the remaining two of D, E, and F groups are independently C(R 10 ) is); with the proviso that the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide; or a pharmaceutically acceptable salt and / or solvate thereof.

[0015] The present invention also provides a compound of formula (I): [ka] (In the formula: R 1a is H or methyl; R 1b is H or fluoro; A is a group (Aa), (Ab), (Ac), or (Ad): wherein the group (Aa) is: [ka] and; (In the formula: R2 is H, C 1-4 Alkyl, C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene (C 3-6 cycloalkyl), C 1-4 Alkylene (4-7 membered heterocycloalkyl), C 1-4 Alkoxy, OC 1-4 Alkylene (aryl), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC3-6 Cycloalkyl, C 1-4 AlkyleneO(4-7 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), C 3-6 Alkynyl, or C 1-4 Alkylene O(C 3-6 alkynyl); wherein the aryl, heterocycloalkyl, or cycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 optionally substituted with up to three substituents each independently selected from haloalkyl, halo, and CN; each R3 is independently halo, methyl, ethyl, or n-propyl; m is 0, 1, 2, 3, or 4); The group (Ab) is: [ka] and; (In the formula: R4 is H, C 1-4 Alkyl or C 1-4 alkylene(aryl); wherein the aryl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 optionally substituted with up to three substituents each independently selected from haloalkyl, halo, and CN; R5 is H or C 1-4 is alkyl; Each R6 is independently 1-4 alkyl or halo; n is 0, 1, 2, or 3); The group (Ac) is: [ka] and; (In the formula: R7 is C 1-4 Alkyl, C 1-4 Alkylene (OH) or C1-4 Alkylene OC 1-4 is alkyl; o is 1 or 2); The group (Ad) is: [ka] and; (In the formula: X is a bond, O, or CH; Each R8 is independently halo, C 1-4 Alkyl, C 1-4 alkoxy, or OH; Each R9 is independently halo or C 1-4 is alkyl; p is 0, 1, or 2; q is 0, 1, 2, 3, or 4); B is: [ka] and; (In the formula: R 10 is H, halo, or C 1-4 is alkyl; D, E, and F each independently represent C(R 10 ) or one of D, E, and F is N and the remaining two of D, E, and F groups are independently C(R 10 ) is); with the proviso that the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide; or a pharmaceutically acceptable salt and / or solvate thereof.

[0016] In one embodiment, the compound of formula (I) is provided in the form of a pharmaceutically acceptable salt. In one embodiment, the compound of formula (I) is provided in the form of a solvate. In one embodiment, the compound of formula (I) is provided.

[0017] The present invention further provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0018] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect.

[0019] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the manufacture of a medicament for the treatment or prevention of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect.

[0020] The present invention also provides methods for preventing or treating disorders in which inhibition of mPTP provides a therapeutic or prophylactic effect in a subject.

[0021] Preferably, the disease or disorder is selected from a degenerative or neurodegenerative disease, a disorder of the central nervous system, ischemia and reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, an age-related disease, and a renal disease.

[0022] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of mitochondrial diseases.

[0023] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the manufacture of a medicament for the treatment or prevention of mitochondrial diseases.

[0024] The present invention also provides a method for preventing or treating a mitochondrial disease in a subject, the method comprising 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.

[0025] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration.

[0026] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration.

[0027] The present invention also provides a method for treating or preventing a disease or disorder associated with TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, comprising 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.

[0028] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of a disease or disorder associated with fibrosis.

[0029] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with fibrosis.

[0030] The present invention also provides a method for treating or preventing a disease or disorder associated with fibrosis, comprising 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. DETAILED DESCRIPTION OF THE INVENTION

[0031] (Detailed Description of the Invention) C 1-4The term "alkyl," as used herein, whether alone or forming part of a larger group, refers to a linear or branched, fully saturated hydrocarbon chain containing the specified number of carbon atoms. 1-4 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl. Reference to "propyl" includes n-propyl and isopropyl. Reference to "butyl" includes n-butyl, isobutyl, tert-butyl, and sec-butyl.

[0032] C 1-4 The term "alkylene" as used herein, such as alkylene, whether alone, can be used to form a larger group, e.g., C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene (C 3-6 Cycloalkyl), OC 1-4 Alkylene (C 3-6 cycloalkyl), C 1-4 Alkylene (4-7 membered heterocycloalkyl), OC 1-4 Alkylene (4-7 membered heterocycloalkyl), C 1-4 Alkoxy, OC 1-4 Alkylene (aryl), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 AlkyleneO(4-7 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), or C 1-4 Alkylene O(C 3-6 alkynyl), e.g., C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene (C 3-6 cycloalkyl), C 1-4 Alkylene (4-7 membered heterocycloalkyl), C 1-4 Alkoxy, OC 1-4 Alkylene (aryl), C1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 AlkyleneO(4-7 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), or C 1-4 Alkylene O(C 3-6 C is a difunctional linear or branched, fully saturated hydrocarbon group containing the specified number of carbon atoms, whether forming part of a cyclic alkyl group (alkynyl). 1-4 Examples of alkylene groups include methylene (i.e., -CH2-), ethylene (i.e., -CH2CH2-), n-propylene (i.e., (-CH2)3-), and n-butylene (i.e., (-CH2)4-). 1-4 An example of a branched alkylene group is i-propylene (ie, -CH(Me)CH2-).

[0033] C 1-4 The term alkylene (OH) refers to a C group substituted by OH, such as CHOH. 1-4 It means an alkyl group.

[0034] C 1-4 The term "alkoxy" as used herein, such as in alkoxy, refers to an alkyl group as defined above, single-bonded to an oxygen atom (e.g., C 1-4 C 1-4 Examples of alkoxy groups include methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy, and 3-butoxy, especially methoxy.

[0035] The term "halo" or "halogen" as used herein means fluorine, chlorine, bromine, or iodine. Particular examples of halo are bromine, fluorine, and chlorine, especially fluorine.

[0036] C 1-4 The term "haloalkyl" as used herein, such as in haloalkyl, whether alone or as O-C 1-4A linear or branched alkyl group containing the specified number of carbon atoms substituted by one or more halo atoms, whether forming part of a larger group such as haloalkyl, for example, fluoromethyl (CHF), di-fluoromethyl (CHF), tri-fluoromethyl (CF), 1-fluoroethyl (CHFCH), and 2-fluoroethyl (CHCHF).

[0037] C 3-6 The term "cycloalkyl" as used herein, such as in cycloalkyl, whether alone, refers to a C 1-4 Alkylene (C 3-6 cycloalkyl) or C 1-4 Alkylene OC 3-6 A fully saturated hydrocarbon ring containing the specified number of carbon atoms, whether it forms part of a larger group such as cycloalkyl. 3-6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, especially cyclopropyl. Cycloalkyl may be optionally substituted as defined herein.

[0038] The term "heterocycloalkyl" as used herein, such as in 4- to 7-membered heterocycloalkyl, whether alone or in combination with C 1-4 Alkylene (4-7 membered heterocycloalkyl) and C 1-4 A fully saturated hydrocarbon ring containing the specified number of ring atoms, whether forming part of a larger group such as alkyleneO (4- to 7-membered heterocycloalkyl), wherein at least one of the carbon atoms is replaced by a heteroatom such as N, S, or O. Optionally, heterocycloalkyl may be substituted as defined herein.

[0039] Examples of 4- to 7-membered heterocycloalkyl groups include those containing one heteroatom, such as one heteroatom (e.g., nitrogen) or two or more heteroatoms (e.g., two nitrogen atoms or one nitrogen atom and one oxygen atom). Examples of 4- to 7-membered heterocycloalkyl groups containing one nitrogen atom include azetidinyl, pyrrolidinyl, piperidinyl, and azepanyl. Examples of 4- to 7-membered heterocycloalkyl groups containing two nitrogen atoms include diazetidinyl, imidazolidinyl, pyrazolidinyl, diazinanyl, and diazepanyl.

[0040] Further examples of 4- to 7-membered heterocycloalkyl groups include oxetanyl, thietanyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, triazinanyl, trioxanyl, trithianyl, oxepanyl, and thiepanyl.

[0041] The term "aryl" as used herein refers to a group, whether alone or in combination with a larger group, e.g., C 1-4 Alkylene (aryl), OC 1-4 Alkylene (aryl), or C 1-4 It refers to a phenyl ring whether it forms part of an alkylene O (aryl), which may optionally be substituted as defined herein.

[0042] C 3-6 The term "alkynyl" as used herein, whether alone or as in alkynyl, 1-4 Alkylene O(C 3-6 A linear or branched divalent hydrocarbon chain containing at least one carbon-carbon triple bond, whether it forms part of a larger group such as alkynyl. 3-6Examples of alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, pentynyl, and hexynyl.

[0043] C 1-4 An example of alkylene(aryl) is CHPh (where Ph means phenyl). 1-4 Alkylene OC 1-4 Examples of alkyl include CHOMe, CHOEt, and CHOPr. 1-4 Alkylene OC 3-6 Examples of cycloalkyl include CHO-Ccycloalkyl and CHO-Ccycloalkyl, such as CHO-cyclopropyl or CHO-cyclobutyl. 1-4 Examples of alkylene(4-7 membered heterocycloalkyl) include CH2(4 membered heterocycloalkyl), such as CH2-azetidinyl, CH2CH2-azetidinyl. 1-4 Examples of alkyleneO(4-7 membered heterocycloalkyl) include C 2 O-azetidinyl, etc. 1-4 Examples of alkylOC4 heterocycloalkyl include C 1-4 Alkylene O(C 3-6 An example of an alkynyl is CH2OCH2C≡CH.

[0044] In the embodiments and options described below, when a substituent is shown as being optionally substituted in Formula (I), the optional substituent may be attached to a carbon atom that is bonded to a hydrogen atom, i.e., an available carbon atom, which refers to a CH group, or the optional substituent may be attached to a nitrogen atom that is bonded to a hydrogen atom, i.e., an available nitrogen atom, which refers to an NH group. The optional substituent replaces a hydrogen atom that is bonded to a carbon atom or a hydrogen atom that is bonded to a nitrogen atom.

[0045] In one embodiment, R 1a is H. In a second embodiment, R 1a is methyl.

[0046] In one embodiment, R 1b is H. In a second embodiment, R 1b is fluoro.

[0047] In one preferred embodiment, A is a group (Aa): [ka] is.

[0048] In one embodiment, R2 is a C aryl group such as methyl, ethyl, propyl, or butyl. 1-4 Alkyl, especially methyl; C such as benzyl 1-4 Alkylene (aryl); C such as CH2OH 1-4 Alkylene (OH); C such as CHOMe, CHOEt, or CHOPr 1-4 Alkylene OC 1-4 alkyl, in particular CHOMe; CHO-Ccycloalkyl or CHO-Ccycloalkyl, for example CHO-cyclopropyl or CHO-cyclobutyl; 1-4 Alkylene OC 3-6 Cycloalkyl; C such as CH2OPh 1-4 C such as alkylene O(aryl); CH2(4-membered heterocycloalkyl), e.g., CH2-azetidinyl, or CH2CH2(4-membered heterocycloalkyl), e.g., CH2CH2-azetidinyl 1-4 Alkylene (4-7 membered heterocycloalkyl); C 1-4 C alkyl OC heterocycloalkyl etc. 1-4 AlkyleneO(4-7 membered heterocycloalkyl), especially CHO-azetidinyl; or C such as CHOCHC≡CH 1-4 Alkylene O(C 3-6 Preferably, R2 is methyl, CH2OH, or CHOMe, especially methyl.

[0049] Aryl, heterocycloalkyl, and cycloalkyl groups present in R2 are C 1-4Alkyl; C such as cyclopropyl 3-6 Cycloalkyl; C such as OMe 1-4 Alkoxy; C such as CF3 1-4 Haloalkyl; halo such as chloro or fluoro; CN; OH; NR 2a R 2b ;SO2R 2c ; and NHSO2R 2c Suitably, the aryl, heterocycloalkyl, and cycloalkyl groups present in R2 are selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , C 50 , C 51 , C 52 , C 53 , C 54 , C 55 , C 56 , C 57 , C 58 , C 59 , C 60 , C 61 , C 62 , C 63 , C 64 , C 65 , C 66 , C 67 , C 68 , C 69 , C 70 , C 71 , C 72 , C 73 , C 74 , C 75 , C 76 , C 77 , C 78 , C 79 , C 79 , C 71 , C 72 , C 73 1-4 Alkyl; C such as cyclopropyl 3-6 Cycloalkyl; C such as OMe 1-4 Alkoxy; C such as CF3 1-4 and CN. Suitably, the aryl, heterocycloalkyl, and cycloalkyl groups present in R2 are optionally substituted by up to three substituents, such as one, two, or three, such as one or two, for example, one, each independently selected from haloalkyl; halo, such as chloro or fluoro; and CN. Suitably, the aryl, heterocycloalkyl, and cycloalkyl groups present in R2 are selected from the group consisting of OH; NR 2a R 2b ;SO2R 2c ; and NHSO2R 2c may be optionally substituted by up to three substituents each independently selected from, such as one, two, or three, such as one or two, for example, one substituent.

[0050] In one embodiment, R 2a is H. In a second embodiment, R 2a is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 2a is H or methyl.

[0051] In one embodiment, R 2b is H. In a second embodiment, R 2bis C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 2b C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a fourth embodiment, R 2b C such as OMe or OEt 1-4 In a fifth embodiment, R 2b is C such as CF3 1-4 In a sixth embodiment, R 2b is aryl, such as phenyl. In a seventh embodiment, R 2b is a 4- to 7-membered heterocycloalkyl such as azetidinyl or oxetanyl. In an eighth embodiment, R 2b is H or methyl.

[0052] In one embodiment, R 2c is C such as methyl, ethyl, or propyl 1-4 In a second embodiment, R 2c C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a third embodiment, R 2c C such as OMe or OEt 1-4 In a fourth embodiment, R 2c is C such as CF3 1-4 In a fifth embodiment, R 2c is aryl, such as phenyl. In a sixth embodiment, R 2c is a 4- to 7-membered heterocycloalkyl such as azetidinyl or oxetanyl. In a seventh embodiment, R 2c is methyl.

[0053] Suitably, the aryl is substituted with one, two, or three substituents, such as one or two, for example one substituent, each independently selected from methyl, chloro, and fluoro. In one embodiment, the aryl is unsubstituted.

[0054] Suitably, the heterocycloalkyl is substituted with one, two, or three substituents, such as one or two, for example one, each independently selected from CH2CH2F (particularly as a substituent on a nitrogen atom) and fluoro (particularly as a substituent on a carbon atom). In one embodiment, the heterocycloalkyl is unsubstituted.

[0055] Suitably, when the heterocycloalkyl is azetidinyl, the nitrogen atom is in the 1- or 3-position relative to the point of attachment to the remainder of the R2 group (i.e., 1-azetidinyl or 3-azetidinyl), for example: [ka] is.

[0056] Suitably, R2 is C such as CH2-azetidinyl or CH2CH2-azetidinyl. 1-4 When R is alkylene (4-7 membered heterocycloalkyl), the azetidinyl is 1-azetidinyl. Suitably, R is C 2 O-azetidinyl, such as C 1-4 When alkyleneO(4-7 membered heterocycloalkyl), the azetidinyl is 3-azetidinyl. For example: [ka] is.

[0057] Suitably, when a heterocycloalkyl contains one or more nitrogen atoms, the nitrogen atom(s) may be bonded to a hydrogen atom to form an NH group, where valence requires. Alternatively, the nitrogen atom(s) may be, for example, C 1-4 C alkyl, such as CH2CH2F 1-4Haloalkyl, C(O)H, C(O)C 1-4 C(O)OC such as alkyl, C(O)OtBu 1-4 C(O)OC such as alkyl, C(O)OBz 1-4 Alkylene (aryl), C(O)NHC 1-4 Alkyl, C(O)NHC such as C(O)NHBz 1-4 Alkylene (aryl), Fmoc group, C(O)C 1-4 Haloalkyl, C(O)OC 1-4 Haloalkyl, or C(O)NHC 1-4 It may be substituted with haloalkyl (e.g., one nitrogen atom is substituted). Preferably, when the heterocycloalkyl contains one or more S atoms, the S atom(s) are substituted with one or two oxygen atoms (i.e., S(O) or S(O)2) (e.g., one S atom is substituted). Alternatively, none of the sulfur atoms in the heterocycloalkyl ring are substituted.

[0058] One or more (e.g., one) nitrogen atoms are C 1-4 C alkyl, such as CH2CH2F 1-4 Haloalkyl, C(O)H, C(O)C 1-4 C(O)OC such as alkyl, C(O)OtBu 1-4 C(O)OC such as alkyl, C(O)OBz 1-4 Alkylene (aryl), C(O)NHC 1-4 Alkyl, C(O)NHC such as C(O)NHBz 1-4 Alkylene (aryl), Fmoc group, C(O)C 1-4 Haloalkyl, C(O)OC 1-4 Haloalkyl, or C(O)NHC 1-4 When substituted by haloalkyl, these substituents may be present in addition to the optional substituents described above in connection with heterocycloalkyl. Such substituents on a nitrogen atom may also be referred to as or function as protecting groups, which may be added and removed by methods known to those skilled in the art.

[0059] Preferably, the cycloalkyl is one, two, or three C 1-4 Alkyl substituents, such as one or two, for example, one C 1-4 It is substituted with alkyl substituents (such as methyl, ethyl, and propyl, especially methyl). In one embodiment, the cycloalkyl is unsubstituted.

[0060] Preferably, R2 is H, C 1-4 Alkyl, C 1-4 Alkylene (OH), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene O (aryl), OC 1-4 Alkylene (aryl), C 1-4 Alkylene (4-7 membered heterocycloalkyl), C 1-4 alkyleneO(4-7 membered heterocycloalkyl), or C 1-4 Alkylene O(C 3-6 More preferably, m is 0 except when R is H, methyl, CHOH, CHOMe, CHOPh, OCHPh, CHO(1-(2-fluoroethyl)azetidin-3-yl, CH(3-fluoroazetidin-1-yl), CHCH(3-fluoroazetidin-1-yl), or CHOCHC≡CH.

[0061] Preferably, when m is 0, R2 is C 1-4 Preferably, when m is 0, R2 is not CH2CH2(3-fluoroazetidin-1-yl). Preferably, when R2 is H and m is 1, R3 is not fluoro at the 3-position.

[0062] When present, in one embodiment, each R3 is independently fluoro or methyl, particularly fluoro.

[0063] In one embodiment, m is 1 or 2.

[0064] In one preferred embodiment, m is 1 and R3 is in the 3 position. In another preferred embodiment, m is 1 and R3 is in the 6 position. In another preferred embodiment, m is 2, one R3 is in the 3 position and the other R3 is in the 6 position. In one embodiment, R2 is H, m is 1 and R3 is in the 3 position. In one embodiment, m is 0. In one embodiment, R2 is H and R3 is in the 3 position.

[0065] References to substituent positions are with respect to the bond to the amide moiety, for example: [ka] is.

[0066] Examples of suitable substituents include 2-OCHPh; 2-CHOPh; 2-CHO(cyclobutyl), 2-CHOH; 2-CHOMe; 2-CHO(1-(2-fluoroethyl)azetidin-3-yl); 2-CH(3-fluoroazetidin-1-yl); 2-CHCH(3-fluoroazetidin-1-yl); 2-CHOCHC≡CH; 3-methyl; 3-chloro; 3-fluoro; 3-fluoro-2-methyl; 6-fluoro-2-methyl; 2,6-dimethyl; and 3-fluoro-2,6-dimethyl. In one embodiment, each R is the same. In one embodiment, each R is different.

[0067] In one embodiment, A is a group (Ab): [ka] is.

[0068] In one embodiment, R4 is H. In a second embodiment, R4 is C, such as methyl. 1-4 In a third embodiment, R4 is C alkyl, such as benzyl. 1-4In a preferred embodiment, R4 is H, methyl, or benzyl, in particular methyl or benzyl. Suitably, aryl is C such as methyl. 1-4 Alkyl; C such as cyclopropyl 3-6 Cycloalkyl; C such as OMe 1-4 Alkoxy; C such as CF3 1-4 Haloalkyl; halo such as chloro or fluoro; CN; OH; NR 4a R 4b ;SO2R 4c ; and NHSO2R 4c Suitably, the aryl is substituted by one, two, or three substituents, such as one or two, for example one substituent, each independently selected from C 1-4 Alkyl; C such as cyclopropyl 3-6 Cycloalkyl; C such as OMe 1-4 Alkoxy; C such as CF3 1-4 Preferably, the aryl is substituted by one, two, or three substituents, such as one or two, for example one, each independently selected from haloalkyl; halo, such as chloro or fluoro; and CN. Suitably, the aryl is substituted by one, two, or three substituents, such as one or two, for example one, each independently selected from haloalkyl; OH; NR 4a R 4b ;SO2R 4c ; and NHSO2R 4c

[0039] The aryl is substituted with one, two, or three substituents, such as one or two, for example, one substituent, each independently selected from the following:

[0040] Preferably, the aryl is substituted with one, two, or three substituents, such as one or two, for example, one, each independently selected from methyl, chloro, and fluoro. In one embodiment, the aryl is substituted with one, two, or three, such as one or two, for example, one methyl group. In one embodiment, the aryl is substituted with one, two, or three, such as one or two, for example, one chloro group. In one embodiment, the aryl is substituted with one, two, or three, such as one or two, for example, one fluoro group. Preferably, the aryl is unsubstituted.

[0069] In one embodiment, R 4a is H. In a second embodiment, R 4a is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 4a is H or methyl.

[0070] In one embodiment, R 4b is H. In a second embodiment, R 4b is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 4b C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a fourth embodiment, R 4b C such as OMe or OEt 1-4 In a fifth embodiment, R 4b is C such as CF3 1-4 In a sixth embodiment, R 4b is aryl, such as phenyl. In a seventh embodiment, R 4b is a 4- to 7-membered heterocycloalkyl such as azetidinyl or oxetanyl. In an eighth embodiment, R 4b is H or methyl.

[0071] In one embodiment, R 4c is C such as methyl, ethyl, or propyl 1-4 In a second embodiment, R 4c C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a third embodiment, R 4c C such as OMe or OEt 1-4 In a fourth embodiment, R 4c is C such as CF31-4 In a fifth embodiment, R 4c is aryl, such as phenyl. In a sixth embodiment, R 4c is a 4- to 7-membered heterocycloalkyl such as azetidinyl or oxetanyl. In a seventh embodiment, R 4c is H or methyl.

[0072] In one embodiment, R 5 is H.

[0073] When present, in one embodiment, each R6 is independently fluoro or methyl. Suitably, n is 1, 2 or 3, such as 1 or 2, for example 1.

[0074] In one embodiment, n is 0.

[0075] In one embodiment, the group A is the group (Ac): [ka] is.

[0076] In one embodiment, R7 is methyl, CH2OH, or CH2OMe.

[0077] In one embodiment, o is 2.

[0078] Suitably, the stereochemistry of R7 is trans with respect to the bond connecting the (Ac) group to the amide moiety, for example, the following two stereochemical configurations: [ka] The ion implantation device has one of the following:

[0079] In one preferred embodiment, A is a group (Ad): [ka] is.

[0080] In one embodiment, X is a bond or O. Preferably, X is a bond. Preferably, X is O. In a second embodiment, X is CH2.

[0081] In one embodiment, R8 is halo. 1-4 In one embodiment, R is C 1-4 In one embodiment, R8 is OH.

[0082] When present, in one embodiment, each R is independently methyl, OMe, or fluoro. In one embodiment, each R is independently OCH-cyclopropyl, OCH-oxetanyl, OCHCHF, methyl, OMe, OEt, or fluoro, e.g., OCHCHF, OMe, or OEt, particularly OMe. In another embodiment, each R is independently OCH-cyclopropyl, OCH-oxetanyl, OCHCHF, or OEt, such as OCH-cyclopropyl, OCH-oxetanyl, or OCHCHF.

[0083] Suitably, each cycloalkyl and heterocycloalkyl present in R is independently selected from C methyl, 1-4 Alkyl; C such as cyclopropyl 3-6 Cycloalkyl; C such as OMe 1-4 Alkoxy; C such as CF3 1-4 Haloalkyl; halo such as chloro or fluoro; CN; OH; NR 8a R 8b ;SO2R 8c ; and NHSO2R 8c Preferably, the cycloalkyl and heterocycloalkyl are each independently substituted by one, two, or three substituents, such as one or two, for example one substituent, each independently selected from C, such as methyl. 1-4 Alkyl; C such as cyclopropyl 3-6 Cycloalkyl; C such as OMe 1-4 Alkoxy; C such as CF31-4 Preferably, the cycloalkyl and heterocycloalkyl are each independently substituted by 1, 2, or 3 substituents, such as 1 or 2, for example 1 substituent, each independently selected from haloalkyl; halo, such as chloro or fluoro; and CN. Suitably, the cycloalkyl and heterocycloalkyl are each independently substituted by OH; NR 8a R 8b ;SO2R 8c ; and NHSO2R 8c Substituted by 1, 2, or 3 substituents each independently selected from, for example, 1 or 2, such as 1 substituent.

[0084] In one embodiment, R 8a is H. In a second embodiment, R 8a is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 8a is H or methyl.

[0085] In one embodiment, R 8b is H. In a second embodiment, R 8b is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 8b C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a fourth embodiment, R 8b C such as OMe or OEt 1-4 In a fifth embodiment, R 8b is C such as CF3 1-4 In a sixth embodiment, R 8b is aryl, such as phenyl. In a seventh embodiment, R 8b is a 4- to 7-membered heterocycloalkyl such as azetidinyl or oxetanyl. In an eighth embodiment, R 8b is H or methyl.

[0086] In one embodiment, R 8c is C such as methyl, ethyl, or propyl 1-4 In a second embodiment, R 8c C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a third embodiment, R 8c C such as OMe or OEt 1-4 In a fourth embodiment, R 8c is C such as CF3 1-4 In a fifth embodiment, R 8c is aryl, such as phenyl. In a sixth embodiment, R 8c is a 4- to 7-membered heterocycloalkyl such as azetidinyl or oxetanyl. In a seventh embodiment, R 8c is methyl.

[0087] Suitably, the cycloalkyl (e.g., cyclopropyl) present in R8 has one, two, or three C 1-4 Alkyl substituents, such as one or two, for example, one methyl, ethyl, and propyl, especially methyl, C 1-4 It is substituted by an alkyl substituent. In one embodiment, the cycloalkyl is unsubstituted.

[0088] Suitably, heterocycloalkyl present in R (e.g., oxetanyl) is selected from C 11 alkyl, C 21 alkyl, C 31 alkyl, C 41 alkyl, C 51 alkyl, C 61 alkyl, C 71 alkyl, C 81 alkyl, C 91 alkyl, C 101 alkyl, C 111 alkyl, C 121 alkyl, C 131 alkyl, C 141 alkyl, C 151 alkyl, C 161 alkyl, C 171 alkyl, C 181 alkyl, C 191 alkyl, C 21 ... 1-4 In one embodiment, the heterocycloalkyl is unsubstituted.

[0089] Suitably, when the heterocycloalkyl is oxetanyl, the oxygen atom is in the 2- or 3-position relative to the point of attachment to the remainder of the R group (i.e., 2-oxetanyl or 3-oxetanyl), for example: [ka] is.

[0090] Preferably, R8 is OC such as OCH2-oxetanyl. 1-4 When alkylene(4-7 membered heterocycloalkyl), the oxetanyl may be 3-oxetanyl, for example: [ka] is.

[0091] When p is 1 or 2, R8 may be in the 2-position and / or the 3-position. In one embodiment, p is 1 and R8 is in the 2-position. In a second embodiment, p is 1 and R8 is in the 3-position. In a third embodiment, p is 2, one R8 is in the 2-position and one R8 is in the 3-position. For example: [ka] is.

[0092] Examples of suitable R8 substituents include 2-methyl, 2-methoxy, 2-ethoxy, 2-OCH2CH2F, 2-OCH2-cyclopropyl, and 2-OCH2-oxetanyl, such as 2-methyl and 2-methoxy.

[0093] Preferably, when X is a bond, R8 is not in position 3. Preferably, when X is a bond, R8 is in position 2.

[0094] Suitable examples of substituents are 2-methyl, 2-methoxy and 3-fluoro.

[0095] In one embodiment, p is 0 or 1.

[0096] Preferably, when X is a bond and p is 0, the compound has the (R) stereochemical configuration. Preferably, when X is as defined above and p is 1, the stereochemistry of R is trans with respect to the bond connecting the (Ad) group to the amide substituent, for example, the following stereochemical configuration: [ka] The ion implantation device has one of the following:

[0097] When present, in one embodiment, each R9 is independently fluoro.

[0098] Suitably, when q is 1, 2, 3, or 4, R9 may be in the 5, 6, 7, and / or 8 positions. In one embodiment, q is 1 and R9 is in the 5 position. In a second embodiment, q is 1 and R9 is in the 6 position. For example: [ka] is.

[0099] Preferably, R9 is not at position 8. Preferably, R9 is at position 7. Preferably, R9 is at position 6. Preferably, R9 is at position 5.

[0100] In embodiments where X is a bond, it will be understood that the substituent position numbering will scale with the total number of atoms in the bicyclic ring system. For example: [ka] is.

[0101] Suitable examples of R9 substituents when X is a bond are 4-fluoro and 5-fluoro.

[0102] In one embodiment, q is 1 or 2.

[0103] In one embodiment, D, E, and F are C(R10 In a second embodiment, D is N and E and F are C(R 10 In a third embodiment, E is N and D and F are C(R 10 In a fourth embodiment, F is N and D and E are C(R 10 )

[0104] Preferably, D and F are C(R 10 ), then E cannot be N.

[0105] In one embodiment, R 10 is H. In a second embodiment, R 10 is halo, such as fluoro or chloro, and in particular chloro. In a third embodiment, R 10 is C such as methyl 1-4 Preferably, each R 10 is independently H, fluoro, chloro, or methyl.

[0106] In one preferred embodiment, the compound of the present invention has formula (Ia): [ka] (In the formula, A is a group (Aa'), (AdI'), or (AdII'); R 10a is H, fluoro, chloro, or methyl; wherein the group (Aa') is: [ka] and; (In the formula: R 2d is methyl, CHOMe, or CHOCHC≡CH; Each R 3a are independently H, methyl, or fluoro; and The group (AdI') is: [ka] and; (In the formula: R 8d is H, methyl, or OMe; R 9a is H or F); The group (AdII') is: [ka] and (In the formula: X is O; and R 8a’ is methyl); provided that A is a group (AdI′) and R 10a When one of R is fluoro or chloro, the other two R 10a groups are independently H); or a pharmaceutically acceptable salt and / or solvate thereof.

[0107] In one embodiment, the compound of formula (I) is: (E)-N-(3-fluoro-2-methylphenyl)-3-(7-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide (racemic mixture); (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide (enantiomer 1); (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide (enantiomer 2); (E)-N-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-indazol-6-yl)acrylamide; (E)-3-(5-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(4-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (mixture of stereoisomers); (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 1); (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 2); (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 3); (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 4); (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (mixture of stereoisomers); (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (stereoisomer 1); (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (stereoisomer 2); (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (stereoisomer 3); (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (stereoisomer 4); (E)-N-(2-(benzyloxy)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(2-(phenoxymethyl)phenyl)acrylamide; (E)-N-(2-(cyclobutoxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(1-benzyl-1H-indazol-7-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(m-tolyl)acrylamide; (E)-N-(3-chlorophenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(3-fluorophenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-((1R,3R)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide (mixture of stereoisomers); (E)-N-((1R,3R)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide (stereoisomer 1); (E)-N-((1R,3S)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide (stereoisomer 2); (E)-N-(2-(hydroxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(2-(methoxymethyl)phenyl)acrylamide; (E)-N-(2-(((1-(2-fluoroethyl)azetidin-3-yl)oxy)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide hydrochloride; (E)-N-(2-((3-fluoroazetidin-1-yl)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2-(2-(3-fluoroazetidin-1-yl)ethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2-fluoro-6-methylphenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-pyrazolo[4,3-b]pyridin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[4,3-c]pyridin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(7-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(3-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; and (E)-3-(1H-indazol-6-yl)-N-(2-((prop-2-yn-1-yloxy)methyl)phenyl)acrylamide; or a pharmaceutically acceptable salt and / or solvate of any one of these.

[0108] The definition of a compound of formula (I) is intended to include all tautomers of the compound.

[0109] The compounds of the present invention may be provided in the form of their pharmaceutically acceptable salts and / or solvates. In particular, the compounds of formula (I) may be provided in the form of their pharmaceutically acceptable salts and / or solvates, e.g., pharmaceutically acceptable salts.

[0110] It will be recognized that for use in medicine, salts of compounds of formula (I) should be pharmaceutically acceptable. Non-pharmaceutically acceptable salts of compounds of formula (I) may be useful in other contexts, such as during the preparation of compounds of formula (I). Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described in Berge et al. (1977). Such pharmaceutically acceptable salts include acid and base addition salts. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, and organic acids, such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, or naphthalenesulfonic acid. Other salts, such as oxalates or formates, may be used, for example, in the isolation of compounds of formula (I) and are within the scope of the present invention.

[0111] Certain compounds of formula (I) may form acid or base addition salts with one or more equivalents of the acid or base, and the present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

[0112] The compounds of formula (I) may be prepared in crystalline or non-crystalline form. If crystalline, the compounds of formula (I) may optionally be solvated, for example as hydrates. The present invention includes within its scope stoichiometric solvates (e.g., hydrates) as well as compounds containing variable amounts of solvent (e.g., water).

[0113] The present invention should be understood to encompass all isomers of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric, and optical forms, and mixtures thereof (e.g., racemic mixtures). When additional chiral centers 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. Alternatively, any isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

[0114] The present disclosure includes all isotopic forms of the compounds of the present invention provided herein, whether (i) in a form in which all atoms of a given atomic number have a mass number (or mixture of mass numbers) that is predominant in nature (referred to herein as a "natural isotopic form") or (ii) in a form in which one or more atoms are replaced by an atom having the same atomic number but a mass number that is different from the mass number of the atom that is predominant in nature (referred to herein as a "non-natural variant isotopic form"). It is understood that atoms may naturally occur as a mixture of mass numbers. The term "non-natural variant isotopic form" also includes embodiments in which the proportion of atoms of a given atomic number that have mass numbers that are less common in nature (referred to herein as "rare isotopes") is increased compared to the proportion occurring in nature, for example, to a level of >20%, >50%, >75%, >90%, >95%, or >99% of the number of atoms of that atomic number (the latter embodiment being referred to as an "isotopically enriched variant form"). The term "non-natural variant isotopic form" also includes embodiments in which the proportion of a rare isotope is reduced compared to the proportion occurring in nature. Isotopic forms can include radioactive forms (i.e., which incorporate a radioactive isotope) and non-radioactive forms. Radioactive forms are typically isotopically enriched variant forms.

[0115] Thus, non-naturally occurring variant isotopic forms of a compound may contain deuterium ( 2 H or D), carbon-11 (11 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-15( 15 N), oxygen-15( 15 O), oxygen-17( 17 O), oxygen-18( 18 O), phosphorus-32( 32 P), sulfur-35( 35 S), chlorine-36( 36 Cl), chlorine-37( 37 Cl), fluorine-18( 18 F), iodine-123( 123 I), iodine-125( 125 It may contain one or more artificial or rare isotopes, such as I), or may contain an increased proportion of such isotopes at one or more atoms compared to the proportion that predominates in nature.

[0116] Non-natural variant isotopic forms containing radioactive isotopes may be used, for example, for drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. 2 Non-natural variant isotopic forms incorporating H or D may offer certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in certain circumstances. 11 C. 18 F, 15 O, and 13 Non-natural variant isotopic forms can be prepared incorporating positron emitting isotopes, such as N, which can be useful in positron emission tissue distribution (PET) studies to examine substrate receptor occupancy.

[0117] In one embodiment, the compounds of the invention are provided in natural isotopic form.

[0118] In one embodiment, the compounds of the present invention are provided in non-natural variant isotopic forms. In a specific embodiment, non-natural variant isotopic forms are those in which deuterium (i.e., 2 In one embodiment, the atoms of the compounds of the present invention are in a non-radioactive isotopic form. In one embodiment, one or more atoms of the compounds of the present invention are in a radioactive isotopic form. Preferably, the radioisotope is a stable isotope. Preferably, the non-natural variant isotopic form is a pharmaceutically acceptable form.

[0119] In one embodiment, compounds of the present invention are provided in which a single atom of the compound exists in a non-natural variant isotopic form. In another embodiment, compounds of the present invention are provided in which two or more atoms exist in a non-natural variant isotopic form.

[0120] Non-natural isotopically variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein, for example, processes similar to those described in the Examples below for preparing natural isotopically variant forms. Thus, non-natural isotopically variant forms could be prepared by substituting appropriate isotopically variant (or labeled) reagents for the conventional reagents employed in the Examples. Because the compounds of formula (I) are intended for use in pharmaceutical compositions, it will be readily understood that they are each preferably provided in substantially pure form, e.g., at least 60% pure, more preferably at least 75% pure, and preferably at least 85%, particularly at least 98% pure (percentages weight by weight). Impure preparations of the compounds may be used to prepare purer forms for use in pharmaceutical compositions.

[0121] In general, compounds of formula (I) can be made by organic synthesis techniques known to those skilled in the art, as well as by the representative methods described below, those in the Examples, and modifications thereof. In the following schemes, reactive groups can be protected with protecting groups and deprotected by established techniques well known to those skilled in the art.

[0122] (General route) General routes by which examples of compounds of the invention can be conveniently prepared are outlined below. In the following description, the group R 1a , R 1b , A, and B are as defined above in relation to compounds of formula (I) unless otherwise specified.

[0123] (Scheme 1) [ka] Compounds of formula (I) may be prepared by reacting compounds of formula (II) with compounds of formula (III) under palladium-catalyzed cross-coupling conditions using a palladium catalyst precursor such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane complex (Pd(dppf)Cl2·CH2Cl2) in the presence of a base such as triethylamine and a suitable solvent such as dimethylformamide (DMF).

[0124] (Scheme 2) [ka] 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-oxide hexafluorophosphate (HATU) in the presence of a base such as N,N-diisopropylethylamine (DIPEA, also known as Hunig's base) in a suitable solvent such as DMF.

[0125] (Scheme 3) [ka] Compounds of formula (I) may also be prepared by reacting compounds of formula (VI) with compounds of formula (V) under basic conditions using a base such as lithium bis(trimethylsilyl)amide (LiHMDS) in a suitable solvent such as tetrahydrofuran (THF).

[0126] (Scheme 4) [ka] Compounds of formula (II) are commercially available. Compounds of formula (II) can also be prepared by reacting compounds of formula (VII) with compounds of formula (VIII) in the presence of a base such as N,N-diisopropylethylamine in a suitable solvent such as dichloromethane (DCM).

[0127] (Scheme 5) [ka] Compounds of formula (VI) can be obtained by reacting compounds of formula (IX) with compounds of formula (III) under palladium-catalyzed cross-coupling conditions using a palladium catalyst precursor such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane complex (Pd(dppf)Cl2·CH2Cl2) in the presence of a base such as triethylamine and a suitable solvent such as dimethylformamide (DMF).

[0128] (Scheme 6) [ka] Compounds of formula (IV) can be obtained by reacting compounds of formula (VI) under hydrolysis conditions with a base such as sodium hydroxide (NaOH) in a suitable solvent system such as a mixture of methanol and water.

[0129] (Scheme 7) [ka] R 1a is H, A is a group (Aa), and R2 is C 1-4 alkyl, m is 2, and R3 is C 1-4 Compounds of formula (VII), which are alkyl or halo, can be prepared in two steps. A nitro compound of formula (XVI) can be reacted under palladium-catalyzed cross-coupling conditions using a palladium catalyst precursor such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane complex (Pd(dppf)Cl2·CHCl2), an organoboron compound such as trimethyl-1,3,5,2,4,6-trioxatriborinane, a base such as cesium carbonate (Cs2CO3), and a suitable solvent system such as a mixture of water and 1,4-dioxane to give compounds of formula (XVII). Compounds of formula (XVII) can then be reacted with a metal such as iron in the presence of an acid such as acetic acid to give compounds of formula (VII).

[0130] (Scheme 8) [ka] A is a group (Ad), X is a bond, q is 0, p is 1, and R8 is OC 1-4 Haloalkyl, OC 1- Alkylene (4-7 membered heterocycloalkyl), or C 1-4 A compound of formula (V) where PG is a nitrogen protecting group such as tert-butoxycarbonyl (BOC) can be prepared by reacting a compound of formula (XXI) where C is C in the presence of a base such as NaH in a suitable solvent such as THF. 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4The compound of formula (V) can be prepared by reacting a compound of formula (XXII) with a compound of formula (XXII) which is alkylene(4-7 membered heterocycloalkyl) to give a compound of formula (XXIII). Deprotection of the compound of formula (XXIII) with an aqueous acid, such as 2M HCl, in a suitable solvent, such as methanol, gives a compound of formula (V).

[0131] (Scheme 9) [ka] A is a group (Ad), X is a bond, q is 0, p is 1, and R8 is OC 1-4 Alkylene (C 3-6 Compounds of formula (V), where PG is a nitrogen protecting group such as tert-butoxycarbonyl (BOC), can be prepared by treating a compound of formula (XXIV), where PG is a nitrogen protecting group such as tert-butoxycarbonyl (BOC), with a suitable reagent, for example, diiodomethane, in the presence of an organometallic reagent, for example, ZnEt, in a suitable solvent, such as dichloromethane, to give compounds of formula (XXV). Deprotection of compound of formula (XXV) with an aqueous acid, for example, 2 M HCl, in a suitable solvent, such as methanol, gives compounds of formula (V).

[0132] Thus, in one embodiment, the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, comprising: Compounds of formula (II): [ka] (In the formula, A, R 1a and R 1b is as defined in relation to compounds of formula (I); or a salt thereof; Compounds of formula (III): [ka] wherein X is halo, such as bromo or iodo, and B is as defined in relation to compounds of formula (I); or a salt thereof; The above process is provided, with the proviso that the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide.

[0133] The present invention also provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, comprising the steps of: Compounds of formula (IV): [ka] (In the formula, R 1b and B are as defined in relation to the compounds of formula (I); or a salt thereof; Compounds of formula (V): [ka] (Wherein, A and R 1a is as defined in relation to compounds of formula (I); or a salt thereof; Also provided is the above process, wherein the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide.

[0134] The present invention also provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, comprising the steps of: Compounds of formula (VI): [ka] (In the formula, R 1b and B are as defined in relation to the compounds of formula (I); or a salt thereof; Compounds of formula (V): [ka] (Wherein, A and R 1a is as defined in relation to compounds of formula (I); or a salt thereof; Also provided is the above process, wherein the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide.

[0135] (Treatment method) The compounds of formula (I) of the present invention are useful as inhibitors of mPTP.

[0136] Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, as a medicament, in particular for use in the treatment or prevention of diseases or disorders in which inhibition of mPTP provides a therapeutic or prophylactic effect, such as the diseases and disorders mentioned herein below.

[0137] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, as a medicament, in particular for use in the treatment of diseases or disorders in which inhibition of mPTP provides a therapeutic effect, such as the diseases and disorders mentioned herein below.

[0138] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use as a medicament, in particular in the prevention of diseases or disorders in which inhibition of mPTP provides a preventive effect, such as the diseases and disorders mentioned herein below.

[0139] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the manufacture of a medicament for the treatment or prevention of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect, such as the diseases and disorders mentioned herein below.

[0140] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the manufacture of a medicament for the treatment of a disease or disorder in which inhibition of mPTP provides a therapeutic effect, such as the diseases and disorders mentioned herein below.

[0141] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the manufacture of a medicament for the prevention of diseases or disorders in which inhibition of mPTP provides a preventive effect, such as the diseases and disorders mentioned herein below.

[0142] The present invention also provides a method for preventing or treating a disease or disorder in a subject in which inhibition of mPTP provides a therapeutic or prophylactic effect, such as the diseases and disorders mentioned herein below, which method 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.

[0143] The present invention also provides a method for treating a disease or disorder in a subject in which inhibition of mPTP provides a therapeutic effect, such as the diseases and disorders mentioned herein below, comprising 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.

[0144] The present invention also provides a method for preventing a disease or disorder in a subject in which inhibition of mPTP provides a preventive effect, such as the diseases and disorders mentioned herein below, comprising 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.

[0145] As used herein, the term "treatment" or "treating" includes controlling, alleviating, reducing, or modulating a disease state or its symptoms.

[0146] The term "prevention" or "preventing" as used herein shall mean preventing the symptoms of a disease or disorder in a subject or preventing the recurrence of symptoms of a disease or disorder in an affected subject, and is not limited to complete prevention of disease.

[0147] In one embodiment, the disease or disorder is selected from a degenerative or neurodegenerative disease, a disorder of the central nervous system, an ischemia or reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, an age-related disease, and a renal disease.

[0148] In a particular embodiment, the disease or disorder is degenerative or neurodegenerative disease, such as Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal dementia, chemotherapy-induced neuropathy, Huntington's disease, spinocerebellar ataxia, progressive supranuclear palsy, hereditary spastic paraplegia, Duchenne muscular dystrophy, congenital muscular dystrophy, traumatic brain injury, and Friedreich's ataxia.In a preferred embodiment, the disease or disorder is Parkinson's disease.In a preferred embodiment, the disease or disorder is Alzheimer's disease.In a preferred embodiment, the disease or disorder is amyotrophic lateral sclerosis.

[0149] In another particular embodiment, the disease or disorder is a disease of the central nervous system, such as AIDS dementia complex, depressive disorder, schizophrenia, and epilepsy.

[0150] In another embodiment, the disease or disorder is ischemia or reperfusion injury, such as acute myocardial infarction, stroke, renal ischemia-reperfusion injury, and organ damage during transplantation.

[0151] In another embodiment, the disease or disorder is a metabolic disease such as fatty liver, diabetes, diabetic retinopathy, cognitive decline and other diabetes-related conditions, obesity and eating behavior, and non-alcoholic fatty liver disease.

[0152] 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.

[0153] In another embodiment, the disease or disorder is a disease of aging, such as bone repair, bone frailty in aging in osteoporosis, and sarcopenia.

[0154] In another embodiment, the disease or disorder is a kidney disease, such as chronic kidney disease and chronic kidney disease associated with APOL1 gene variants.

[0155] The compounds of formula (I) are expected to be useful in the treatment or prevention of mitochondrial diseases.

[0156] Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of mitochondrial diseases, such as the diseases and disorders mentioned herein below.

[0157] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of mitochondrial diseases, such as the diseases and disorders mentioned herein below.

[0158] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the prevention of mitochondrial diseases, such as the diseases and disorders mentioned herein below.

[0159] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the manufacture of a medicament for the treatment or prevention of mitochondrial diseases, such as the diseases and disorders mentioned herein below.

[0160] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the manufacture of a medicament for the treatment of mitochondrial diseases, such as the diseases and disorders mentioned herein below.

[0161] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the manufacture of a medicament for the prevention of mitochondrial diseases, such as the diseases and disorders mentioned herein below.

[0162] The present invention also provides a method for treating or preventing a mitochondrial disease, such as the diseases and disorders mentioned herein below, in a subject, said method comprising 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.

[0163] The present invention also provides a method of treating a mitochondrial disease in a subject, such as the diseases and disorders mentioned herein below, comprising 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.

[0164] The present invention also provides a method for preventing a mitochondrial disease in a subject, such as the diseases and disorders mentioned herein below, which method 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.

[0165] Preferably, the mitochondrial disease is selected from Reye's syndrome, Leber's hereditary optic neuropathy and related disorders, and the disorders disclosed in CA2884607A1 (Stealth Peptides International).

[0166] The compounds of formula (I) are expected to be useful in the treatment or prevention of diseases or disorders associated with TDP-43 proteinopathies, such as TDP-43 associated neurodegeneration.

[0167] Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, for example the diseases and disorders mentioned herein below.

[0168] The present 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 a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, for example the diseases and disorders mentioned herein below.

[0169] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the prevention of a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, for example the diseases and disorders mentioned herein below.

[0170] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, such as the diseases and disorders mentioned herein below.

[0171] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the manufacture of a medicament for the treatment of a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, for example the diseases and disorders mentioned herein below.

[0172] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the manufacture of a medicament for the prevention of a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, such as the diseases and disorders mentioned herein below.

[0173] The present invention also provides a method for treating or preventing a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, such as the diseases and disorders mentioned herein below, which method 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.

[0174] The present invention also provides a method for treating a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, for example the diseases and disorders mentioned herein below, comprising 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.

[0175] The present invention also provides a method for preventing a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, such as the diseases and disorders mentioned herein below, comprising 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.

[0176] 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 sensorimotor neuropathy, primary lateral sclerosis, progressive muscular atrophy, early-onset Paget's disease of bone and inclusion body myopathy associated with frontotemporal lobar degeneration dementia, Perry's disease, chronic traumatic brain injury, 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.

[0177] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of a disease or disorder associated with fibrosis.

[0178] The present 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.

[0179] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the prevention of a disease or disorder associated with fibrosis.

[0180] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with fibrosis.

[0181] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the manufacture of a medicament for the treatment of a disease or disorder associated with fibrosis.

[0182] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the manufacture of a medicament for the prevention of a disease or disorder associated with fibrosis.

[0183] The present invention also provides a method for treating or preventing a disease or disorder associated with fibrosis, comprising 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.

[0184] The present invention also provides a method of treating a disease or disorder associated with fibrosis, comprising 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.

[0185] The present invention also provides a method for preventing a disease or disorder associated with fibrosis, comprising 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.

[0186] Suitably, the fibrosis-related disease or disorder is selected from chronic kidney disease, idiopathic pulmonary fibrosis, non-alcoholic steatohepatitis, primary biliary cholangitis, and systemic sclerosis.

[0187] Preferably, the subject is a mammal, and in particular, the subject is a human.

[0188] (Pharmaceutical composition) For use in therapy, the compounds of the present invention are usually administered as pharmaceutical compositions. The present invention also provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof (e.g., a salt), and a pharmaceutically acceptable carrier or excipient. The pharmaceutical compositions of the present invention may take the form of pharmaceutical formulations as described below.

[0189] 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 prevention 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 prevention of a disease or disorder as described herein.

[0190] In a further embodiment, there is provided a method for the treatment or prevention of a disease or disorder as described herein, comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., a salt) thereof. In a further embodiment, there is provided a method for the treatment of a disease or disorder as described herein, comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., a salt) thereof. In a further embodiment, there is provided a method for the prevention of a disease or disorder as described herein, comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., a salt) thereof.

[0191] The present invention also provides the use of a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof, in the manufacture of a medicament for the treatment or prevention of a disease or disorder as described herein. The present invention also provides the use of a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof, in the manufacture of a medicament for the treatment of a disease or disorder as described herein. The present invention also provides the use of a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof, in the manufacture of a medicament for the prevention of a disease or disorder as described herein.

[0192] Of course, the amount of active ingredient required to achieve a therapeutic effect will vary depending on the subject being treated or prevented, including the particular compound, the route of administration, the type, species, age, weight, sex, and medical condition of the subject, and the particular disorder or disease being treated or prevented, and its severity, including the renal and hepatic function of the subject. A physician, veterinarian, or clinician of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, or halt the progress of the disease.

[0193] Oral dosages of the present invention, when used for the indicated effects, will range from about 0.01 mg / kg body weight per day (mg / kg / day) to about 100 mg / kg / day for adult humans, preferably from 0.01 mg / kg body weight per day (mg / kg / day) to 10 mg / kg / day, and most preferably from 0.1 to 5.0 mg / kg / day. For oral administration, the compositions are preferably provided in the form of tablets or other presentations provided as individually 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 active ingredient for symptomatic adjustment of dosage to the patient being treated. Pharmaceutical preparations typically contain from about 0.01 mg to about 500 mg of active ingredient, preferably from about 1 mg to about 100 mg. Intravenously, the most preferred dosages will be in the range of about 0.1 to about 10 mg / kg / minute during a constant rate infusion. Advantageously, compounds of the present 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 per day. Furthermore, compounds of the present invention can be preferably administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patch forms well known to those skilled in the art. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

[0194] Although the most suitable route will depend, for example, on the condition and disorder of the recipient, pharmaceutical formulations according to the present invention include those suitable for oral administration, parenteral administration (including subcutaneous, intradermal, intramuscular, intravenous (bolus or infusion), and intraarticular), intranasal (also known as intranasal), inhalation administration (including fine particle dusts or mists that may be generated by various types of pressurized metered dose aerosols, nebulizers, or inhalers), insufflation, rectal, intraperitoneal, topical administration (including cutaneous, buccal, sublingual, and intraocular), and intrathecal administration.

[0195] Preferred pharmaceutical formulations according to the present invention are those suitable for oral, intrathecal, and parenteral administration; more preferably, those suitable for oral or intrathecal administration.

[0196] In a preferred embodiment, the compound according to formula (I) is administered by intrathecal administration.This method of administration involves injecting the compound of the present invention into the spinal canal or intrathecal space, so that it reaches the cerebrospinal fluid.This is advantageous for administering compounds that may not be able to cross the blood-brain barrier by other routes of administration, such as oral administration.

[0197] Suitable pharmaceutical formulations can be administered intrathecally by continuous infusion, such as with a catheter or pump, or by single bolus injection or intermittent bolus injection. For intrathecal administration, the pharmaceutical composition can be administered continuously or intermittently. Intermittent administration can be, for example, every 30 minutes, every hour, every few hours, every 24 hours, every few days (e.g., every 48 hours or 72 hours), or any combination thereof.

[0198] When the pharmaceutical formulations of the present invention are administered continuously, an implantable delivery device, such as an implantable pump, can be employed. Examples of such delivery devices include devices that can be implanted subcutaneously in the body or skull and provide an access port through which the pharmaceutical formulation can be delivered to a nerve or the brain.

[0199] When used for the indicated effects, the intrathecal dosage of the present invention will typically be less than 1 mg, such as less than 500 μg / kg body weight, for example, less than 250 μg / kg, when administered in a single dose or intermittently to an adult human. When administered continuously, the intrathecal dosage of the present invention will typically be less than 250 μg / kg body weight per hour, such as less than 125 μg / kg body weight per hour, for an adult human.

[0200] In another preferred embodiment, the compounds according to Formula (I) are administered intranasally, by inhalation (including fine particle dusts or mists that can be generated by various types of pressurized metered-dose aerosols, nebulizers, or inhalers), or by insufflation. Such methods of administration allow for lower doses of the compounds of the invention to be administered, which may lead to fewer side effects. For example, daily doses of the compounds of the invention ranging from 10 to 0.01 μg, preferably 1 to 0.01 μg, and more preferably about 0.1 μg (100 ng) may be used.

[0201] The formulations can be conveniently provided in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy.All methods include the step of combining the active ingredient with the carrier, which constitutes one or more accessory ingredients.In general, the formulations are prepared by uniformly and intimately combining the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation.

[0202] 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 suspension in an aqueous liquid or non-aqueous liquid, for example, an elixir, tincture, suspension, or syrup; or as an oil-in-water or water-in-oil emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0203] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricant, surfactant, or dispersant, in a suitable machine. Molded tablets may be made by molding a mixture of powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored, and may be formulated to provide slow or controlled release of the active ingredient therein. The compounds of formula (I) can be administered, for example, in a form suitable for immediate release or sustained release. Immediate release or sustained release can be achieved by using a suitable pharmaceutical composition containing the compound of the present invention, or, particularly in the case of sustained release, by using devices such as subcutaneous implants or osmotic pumps. The compounds of the present invention may also be administered liposomally.

[0204] Exemplary compositions for oral administration include suspensions, which may contain, for example, microcrystalline cellulose to provide bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents known in the art; and immediate-release tablets, which may 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 known in the art. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic and tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. The compound 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 that can be used. Exemplary compositions include those in which the compound of the present invention is formulated with a fast-dissolving diluent such as mannitol, lactose, sucrose, and / or cyclodextrin. Such formulations can also include high molecular weight excipients such as cellulose (avicel) or polyethylene glycol (PEG). Such formulations can also include excipients that aid adhesion to the mucosa, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymers (e.g., Gantrez), and release-controlling agents such as polyacrylic acid copolymers (e.g., Carbopol 934). Lubricants, glidants, flavors, colors, and stabilizers can also be added for ease of production and use.Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. 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, etc.

[0205] 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 various phospholipids, 1,2-dipalmitoylphosphatidylcholine, phosphatidylethanolamine (cephalin), or phosphatidylcholine (lecithin).

[0206] Preparations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, 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 contain suspending agents and thickening agents. The preparations may be presented in single-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a 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, for example, suitable non-toxic parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents such as synthetic mono- or diglycerides, and injectable solvents or suspensions which may contain fatty acids such as oleic acid or Cremaphor.

[0207] Exemplary compositions for intranasal, aerosol, or inhalation administration include solutions in saline, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, and / or other solubilizing or dispersing agents such as those known in the art.

[0208] Formulations for rectal administration can be presented as suppositories using conventional carriers such as cocoa butter, synthetic glyceride esters, or polyethylene glycols. Such carriers are usually solid at room temperature but liquefy and / or melt in the rectal cavity to release the drug.

[0209] Formulations for topical administration in the mouth, e.g., buccal or sublingual administration, include lozenges comprising the active ingredient in a base such as flavored sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a base such as gelatin and glycerin or sucrose and acacia. Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).

[0210] Suitable unit dosage formulations are those containing an effective dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0211] It should be understood that the formulations of the present invention, in addition to the ingredients particularly mentioned above, may contain other agents conventionally used in the art, taking into account the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0212] The compounds of formula (I) have the following advantageous properties: - mPTP inhibitory activity as demonstrated in the assay of Biological Example 1; and - improved solubility and / or improved intrinsic clearance (CL) resulting in, for example, improved oral bioavailability and / or improved systemic exposure, as demonstrated in the assays of Biological Examples 2 and 3. int ) It is expected that you will demonstrate one or more of the following:

[0213] The present invention is further illustrated by the following non-limiting examples. [Example]

[0214] (Example) The present invention is exemplified by the compounds described below. The following examples describe the laboratory synthesis of specific compounds of the present invention and are in no way intended to limit the scope of the present invention with respect to the compounds or processes. Although specific reagents, solvents, temperatures, and time periods are used, it is understood that there are many possible equivalent alternatives that can be used to produce similar results. The present invention is intended to encompass such equivalents.

[0215] (General experimental details) Starting materials, reagents, and solvents were obtained from commercial suppliers and used without further purification unless otherwise noted. All compounds containing a chiral center were racemic unless otherwise noted. Where reactions are described as being carried out in a manner similar to earlier, more fully described reactions, the general reaction conditions used were essentially the same. Workup conditions used were of a type standard in the art but may have varied from one reaction to another. Starting materials may not necessarily have been prepared from the batch described. Synthesized compounds may have varying purities, for example, ranging from 85% to 99%. In some cases, mole and yield calculations have been adjusted for this.

[0216] The purity of the final compounds was confirmed by HPLC / MS analysis and determined to be at least ≥90%, and frequently ≥95%. Analytical LCMS was performed using the instrumentation shown in Table 1. 1H NMR was recorded at 300 K on a Bruker 300 MHz instrument (ADVANCE III and ADVANCE III HD). Flash preparative HPLC was performed using the following columns: XBridge Prep C18 OBD column, 5 μm, 19 × 150 mm; Welch Xtimate C18, 21.2 × 250 mm, 5 μm; SunFire Prep C18 OBD 19 × 150 mm × 5 μm. SFC purification was performed using the following columns: (a) CHIRALPAK AS-H, 3 × 25 cm, 5 μm; (b) SFC-YMC Cellulose-SB, 4.6 × 100 mm, 3 μm. (Table 1: LC-MS conditions for analysis) [Table 1] (abbreviation) [Table 2] TIFF0007784431000048.tif39170

[0217] (Preparation of Comparative Example 1) (Comparative Example 1: (E)-N-(2-methyl-3-fluorophenyl)-3-(1H-indazol-6-yl)acrylamide) [ka] Comparative Example 1 was prepared according to the method described in Chen et al. (Assay and Drug Development Technologies, 2018, 16, 445-455) and may also be prepared using synthetic methods similar to those described herein for Examples 1-40.

[0218] (Preparation of Examples 1 to 40) (Intermediate 1: N-(3-fluoro-2-methylphenyl)acrylamide) [ka] To a stirred solution of 3-fluoro-2-methyl-aniline (1.0 g, 7.991 mmol, 1.00 equiv.) and N,N-diisopropylethylamine (3.1 g, 23.972 mmol, 3.00 equiv.) in DCM (40 mL) was added acryloyl chloride (0.7 mL, 8.790 mmol, 1.10 equiv.) dropwise at 0° C. under an inert atmosphere of nitrogen. The resulting mixture was stirred at 25° C. under an inert atmosphere of nitrogen for 3 hours. The resulting mixture was washed with 2×30 mL of water, and the organic layer was concentrated. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (1:5). This afforded 1.04 g (73%) of N-(3-fluoro-2-methylphenyl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =180

[0219] (Intermediate 2: N-(3-chloro-2-methylphenyl)acrylamide) [ka] A 50 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 3-chloro-2-methyl-aniline (300 mg, 2.12 mmol, 1.00 equiv.), DCM (15 mL), and EtN (1.0 mL, 7.19 mmol, 3.00 equiv.). Subsequently, acryloyl chloride (260 mg, 2.88 mmol, 1.20 equiv.) was added dropwise with stirring at 25 °C. The resulting solution was stirred for 5 h at 25 °C. The resulting mixture was washed with 2 × 10 mL of water, and the organic layer was concentrated. The residue was purified by silica gel chromatography eluting with EtOAc / PE (1:5). This afforded 300 mg (74%) of N-(3-chloro-2-methylphenyl)prop-2-enamide as a pale yellow solid. LC-MS (ES, m / z): [M+H] + =196

[0220] (Intermediate 3: (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylic acid) [ka] (Process 1) A 500 mL three-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with 6-bromo-1H-indazole (19.6 g, 100.00 mmol, 1.00 equiv.), 3,4-dihydro-2H-pyran (12.6 g, 150.00 mmol, 1.50 equiv.), and TsOH (1.7 g, 10.00 mmol, 0.10 equiv.) in DCM (200 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was concentrated. The residue was loaded onto a silica gel column using PE / EtOAc (1:0 to 3:1). This afforded 23.9 g (85%) of methyl 3-(1H-indazol-6-yl)acrylate as a solid. LC-MS (ES, m / z): [M+H] + =281

[0221] [ka] (Process 2) A 500 mL three-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with methyl 3-(1H-indazol-6-yl)acrylate (23.9 g, 85.00 mmol, 1.00 equiv.), methyl acrylate (10.98 g, 127.50 mmol, 1.50 equiv.), EtN (23.7 mL, 170.00 mmol, 2.00 equiv.), and Pd(dppf)Cl (1.87 g, 2.55 mmol, 0.03 equiv.) in DMF (200 mL). The resulting solution was stirred at 110 °C for 2 h. The resulting solution was cooled to room temperature and diluted with 300 mL of H2O. The mixture was extracted with 3 x 500 mL of EtOAc. The organic layer was concentrated, and the residue was loaded onto a silica gel column using PE / EtOAc (1:0 to 3:1). This gave 20.20 g (83%) of (E)-methyl 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate as a solid. LC-MS (ES, m / z): [M+H] + =287

[0222] [ka] (Step 3) A 500 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with (E)-methyl 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (11.44 g, 40.00 mmol, 1.00 equiv.) in MeOH / HO (80:40 mL). To this was added NaOH (3.20 g, 80.00 mmol, 2.00 equiv.). The resulting solution was stirred for 6 hours at 50° C. The resulting solution was concentrated to remove MeOH. The pH of the aqueous phase was adjusted to 4 with AcOH. The solid was collected by filtration. This afforded 8.16 g (75%) of methyl 3-(1H-indazol-6-yl)acrylate as a yellow solid. LC-MS (ES, m / z): [M+H] + =273

[0223] Example 1: (E)-N-(3-fluoro-2-methylphenyl)-3-(7-methyl-1H-indazol-6-yl)acrylamide [ka] An 8 mL vial purged and maintained under an inert atmosphere of nitrogen was charged with N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 40.00 mg, 0.22 mmol, 1.00 equiv.), DMF (2 mL), 6-bromo-7-methyl-1H-indazole (47.1 mg, 0.22 mmol, 1.00 equiv.), EtN (0.09 mL, 0.67 mmol, 3.00 equiv.), and Pd(dppf)Cl·CHCl (9.11 mg, 0.011 mmol, 0.05 equiv.). The resulting solution was stirred at 120 °C for 12 h. The crude product was purified by preparative HPLC. This gave 13 mg (19%) of (2E)-N-(3-fluoro-2-methylphenyl)-3-(7-methyl-1H-indazol-6-yl)prop-2-enamide as a white solid. LC-MS (ES, m / z): [M+H] + =310 [ka]

[0224] Example 2: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide [ka] An 8 mL vial purged and maintained under an inert atmosphere of nitrogen was charged with (2E)-3-(1H-indazol-6-yl)prop-2-enoic acid (40 mg, 0.21 mmol, 1.00 equiv.), DMF (3 mL), T3P (88 mg, 0.28 mmol, 1.30 equiv.), DIPEA (55 mg, 0.43 mmol, 2.00 equiv.), and indanamine (31 mg, 0.23 mmol, 1.10 equiv.). The resulting solution was stirred for 3 hours at 25°C. The mixture was purified by preparative HPLC. This afforded 12 mg (19%) of (2E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)prop-2-enamide as a white solid. LC-MS (ES, m / z): [M+H] + =304 [ka]

[0225] Example 3: (R,E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide [ka] An 8 mL sealed tube was charged with methyl 3-(1H-indazol-6-yl)prop-2-enoate (110 mg, 0.54 mmol, 1.00 equiv.), (1R)-2,3-dihydro-1H-inden-1-amine hydrochloride (92 mg, 0.54 mmol, 1.00 equiv.), and THF (2 mL). Subsequently, LiHMDS (3.2 mL, 3.26 mmol, 6.00 equiv.) was added at 0 °C. The resulting solution was stirred at room temperature for 3 h. The resulting solution was diluted with 10 mL of EtOAc. The reaction was then quenched by the addition of 15 mL of saturated NH4Cl. The organic layer was washed with 15 mL of water and concentrated in an oven under reduced pressure. The crude product was purified by flash preparative HPLC. This gave 72 mg (43%) of N-[(1R)-2,3-dihydro-1H-inden-1-yl]-3-(1H-indazol-6-yl)prop-2-enamide as a white solid. LC-MS (ES, m / z): [M+H] + =304 [ka]

[0226] Example 4: (racemic) (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide [ka] An 8 mL vial purged and maintained under an inert atmosphere of nitrogen was charged with (2E)-3-(1H-indazol-6-yl)prop-2-enoic acid (30 mg, 0.16 mmol, 1.00 equiv.), DCM (4 mL), HATU (79 mg, 0.21 mmol, 1.30 equiv.), 2-methylcyclohexane-1-amine (20 mg, 0.18 mmol, 1.10 equiv.), and DIPEA (41 mg, 0.32 mmol, 2.00 equiv.). The resulting solution was stirred for 5 hours at 25°C. The reaction was then quenched by the addition of 4 mL of water. The resulting solution was extracted with 5 mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative HPLC. This gave 10 mg (22%) of (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide (trans isomer) as an off-white solid and 10 mg (22%) of (E)-3-(1H-indazol-6-yl)-N-((1S,2R)-2-methylcyclohexyl)acrylamide (cis isomer) as an off-white solid. (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide (trans isomer) LC-MS (ES, m / z): [M+H] + =284 [ka] (E)-3-(1H-indazol-6-yl)-N-((1S,2R)-2-methylcyclohexyl)acrylamide (cis isomer) LC-MS (ES, m / z): [M+H] + =284 [ka]

[0227] [ka] 550 mg of (E)-3-(1H-indazol-6-yl)-N-(2-methylcyclohexyl)acrylamide obtained in Example 4 was purified by SFC (CHIRALPAK IG-3, 100 × 4.6 mm, 3 μm IG30CS-UL011 column, eluted with hexane (0.1% DEA), EtOH / MeOH) to give 60 mg (11%) of trans-(2E)-3-(1H-indazol-6-yl)-N-[(1S,2S)-2-methylcyclohexyl]prop-2-enamide and 80 mg (15%) of trans-(2E)-3-(1H-indazol-6-yl)-N-[(1R,2R)-2-methylcyclohexyl]prop-2-enamide as white solids. Example 4a: Enantiomer 1; LC-MS (ES, m / z): [M+H]+=284 [ka] Example 4b: Enantiomer 2; LC-MS (ES, m / z): [M+H]+=284 [ka]

[0228] Example 5: (E)—N-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide [ka] (Process 1) A 100 mL sealed tube was charged with 6-bromo-1H-indazole (3.1 g, 15.80 mmol, 1.00 equiv.), methyl acrylate (1.5 g, 17.40 mmol, 1.10 equiv.), EtN (19.6 mL, 140.80 mmol, 2.00 equiv.), and Pd(dppf)Cl (345 mg, 4.70 mmol, 0.03 equiv.) in DMF (50 mL). The resulting solution was stirred at 110 °C for 2 h. The resulting solution was concentrated. The residue was loaded onto a silica gel column using THF / hexane (35 / 65). This afforded 2.3 g (70%) of methyl 3-(1H-indazol-6-yl)acrylate as a yellow solid. LC-MS (ES, m / z): [M+H] + =203

[0229] [ka] (Process 2) A 40 mL sealed tube was charged with 7-fluoro-2,3-dihydroinden-1-one (800.0 mg, 5.33 mmol, 1.00 equiv), NaOAc (874.1 mg, 10.66 mmol, 2.00 equiv), MeOH (15.00 mL), and hydroxylamine hydrochloride (1.1 g, 15.98 mmol, 3.00 equiv). The resulting solution was stirred at 60 °C for 16 h. The resulting mixture was concentrated. The crude product was diluted with EtOAc (30.00 mL) and HO (15.00 mL). The organic layer was separated, washed with 20 mL of HO, and concentrated. This afforded 810 mg (92%) of 7-fluoro-2,3-dihydroinden-1-one oxime as an off-white solid. LC-MS (ES, m / z): [M+H] + =166

[0230] [ka] (Step 3) A 50 mL round-bottom flask was charged with 7-fluoro-2,3-dihydroinden-1-one oxime (810.0 mg, 4.90 mmol, 1.00 equiv) and MeOH (20.0 mL). Subsequently, Pd / C (104.4 mg) was added. The resulting solution was stirred at room temperature under atmospheric H2 for 16 hours. The solid was filtered off and washed with 10 mL of MeOH. The combined solution was concentrated. This afforded 530 mg (71%) of 7-fluoro-2,3-dihydro-1H-inden-1-amine as an off-white solid. LC-MS (ES, m / z): [M+H] + =152

[0231] [ka] (Step 4) Into an 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen were placed 7-fluoro-2,3-dihydro-1H-inden-1-amine (55.0 mg, 0.36 mmol, 1.00 equiv.), methyl 3-(1H-indazol-6-yl)prop-2-enoate (73.6 mg, 0.36 mmol, 1.00 equiv.), and THF (3.00 mL). Subsequently, LiHMDS (1.5 mL, 1.45 mmol, 4.00 equiv.) was added at 0 °C. The resulting solution was stirred at room temperature for 30 minutes. The reaction was then quenched by the addition of 15 mL of saturated NH4Cl. The organic layer was washed with 15 mL of water and dried under reduced pressure in an oven. The crude product was purified by flash preparative HPLC. This gave 18 mg (15%) of (7-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =322 [ka]

[0232] Example 6: (E)—N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide [ka] (Process 1) A 40 mL sealed tube was charged with 6-fluoro-2,3-dihydroinden-1-one (800.0 mg, 5.33 mmol, 1.00 equiv.), NaOAc (874.1 mg, 10.656 mmol, 2.00 equiv.), MeOH (15.0 mL), and hydroxylamine hydrochloride (1.1 g, 15.98 mmol, 3.00 equiv.). The resulting solution was stirred at 60 °C for 16 h. The resulting mixture was concentrated. The crude product was diluted with EtOAc (30.0 mL) and HO (15.0 mL). The organic phase was washed with 20 mL of HO. The solid was dried in an oven under reduced pressure. This afforded 810 mg (92%) of N-[6-fluoro-2,3-dihydroinden-1-ylidene]hydroxylamine as an off-white solid. LC-MS (ES, m / z): [M+H] + =166

[0233] [ka] (Process 2) A 50 mL round-bottom flask was charged with N-[6-fluoro-2,3-dihydroinden-1-ylidene]hydroxylamine (810.0 mg, 4.90 mmol, 1.00 equiv.) and MeOH (20.0 mL). This was followed by the addition of Pd / C (104.4 mg, 0.98 mmol, 0.20 equiv.). The resulting solution was stirred at room temperature under atmospheric H2 for 16 hours. The solid was filtered off and washed with 10 mL of MeOH. The combined solution was concentrated. This afforded 530 mg (71%) of 6-fluoro-2,3-dihydro-1H-inden-1-amine as an off-white solid. LC-MS (ES, m / z): [M+H] + =152

[0234] [ka] (Step 3) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with 6-fluoro-2,3-dihydro-1H-inden-1-amine (55.0 mg, 0.36 mmol, 1.00 equiv.), methyl 3-(1H-indazol-6-yl)prop-2-enoate (Example 5, Step 1, 73.6 mg, 0.36 mmol, 1.00 equiv.), and THF (3.0 mL). Subsequently, LiHMDS (1.5 mL, 1.45 mmol, 4.00 equiv.) was added at 0° C. The resulting solution was stirred at room temperature for 30 minutes. The reaction was then quenched by the addition of 15 mL of saturated NH4Cl. The organic layer was washed with 15 mL of water and dried under reduced pressure in an oven. The crude product was purified by flash preparative HPLC. This gave 15 mg (13%) of (6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide as a white solid. LC MS: (ES, m / z): [M+H] + =322 [ka]

[0235] Example 7: (E)—N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide [ka] (Process 1) A 40 mL sealed tube was charged with 5-fluoro-2,3-dihydroinden-1-one (800.0 mg, 5.33 mmol, 1.00 equiv), NaOAc (874.1 mg, 10.66 mmol, 2.00 equiv), MeOH (15.0 mL), and hydroxylamine hydrochloride (1.11 g, 15.98 mmol, 3.00 equiv). The resulting solution was stirred at 60 °C for 16 h. The resulting mixture was concentrated. The crude product was diluted with EtOAc (30.0 mL) and HO (15.0 mL). The organic layer was separated, washed with 20 mL of HO, and concentrated. This afforded 810 mg (92%) of 5-fluoro-2,3-dihydroinden-1-one oxime as an off-white solid. LC-MS (ES, m / z): [M+H] + =166

[0236] [ka] (Process 2) A 50 mL round-bottom flask was charged with 5-fluoro-2,3-dihydroinden-1-one oxime (810.0 mg, 4.90 mmol, 1.00 equiv) and MeOH (20.0 mL). Subsequently, Pd / C (104.38 mg) was added. The resulting solution was stirred under H2 at room temperature for 16 hours. The solid was filtered off and washed with 10 mL of MeOH. The combined solution was concentrated. This afforded 530 mg (71%) of 5-fluoro-2,3-dihydro-1H-inden-1-amine as an off-white solid. LC-MS (ES, m / z): [M+H] + =152

[0237] [ka] (Step 3) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with 5-fluoro-2,3-dihydro-1H-inden-1-amine (55.0 mg, 0.36 mmol, 1.00 equiv.), methyl 3-(1H-indazol-6-yl)prop-2-enoate (73.6 mg, 0.36 mmol, 1.00 equiv.), and THF (3.00 mL). LiHMDS (1.5 mL, 1.45 mmol, 4.00 equiv.) was then added at 0° C. The resulting solution was stirred at room temperature for 30 minutes. The reaction was then quenched by the addition of 15 mL of saturated NH4Cl. The organic layer was washed with 15 mL of water and dried under reduced pressure in an oven. The crude product was purified by flash preparative HPLC. This gave 13 mg (12%) of (5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide as a white solid. LC-MS: (ES, m / z): [M+H] + =322 [ka]

[0238] Example 8: (E)—N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide [ka] (Process 1) A 40 mL sealed tube was charged with 4-fluoro-2,3-dihydroinden-1-one (800.0 mg, 5.33 mmol, 1.00 equiv), NaOAc (874.1 mg, 10.66 mmol, 2.00 equiv), MeOH (15.0 mL), and hydroxylamine hydrochloride (1.11 g, 15.98 mmol, 3.00 equiv). The resulting solution was stirred at 60 °C for 16 h. The resulting mixture was concentrated. The crude product was diluted with EtOAc (30.00 mL) and HO (15.00 mL). The organic layer was separated, washed with 20 mL of HO, and concentrated. This afforded 810 mg (92%) of 4-fluoro-2,3-dihydroinden-1-one oxime as an off-white solid. LC-MS (ES, m / z): [M+H] + =166

[0239] [ka] (Process 2) A 50 mL round-bottom flask was charged with 4-fluoro-2,3-dihydroinden-1-one oxime (810.0 mg, 4.90 mmol, 1.00 equiv) and MeOH (20.0 mL). Subsequently, Pd / C (104.38 mg) was added. The resulting solution was stirred under H2 for 16 h at room temperature. The solid was filtered off and washed with 10 mL of MeOH. The combined solution was concentrated. This afforded 530 mg (71%) of 4-fluoro-2,3-dihydro-1H-inden-1-amine as an off-white solid. LC-MS (ES, m / z): [M+H] + =152

[0240] [ka] (Step 3) Into an 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen were placed 4-fluoro-2,3-dihydro-1H-inden-1-amine (55.0 mg, 0.36 mmol, 1.00 equiv.), methyl 3-(1H-indazol-6-yl)prop-2-enoate (73.6 mg, 0.36 mmol, 1.00 equiv.), and THF (3.00 mL). Subsequently, LiHMDS (1.5 mL, 1.45 mmol, 4.00 equiv.) was added at 0 °C. The resulting solution was stirred at room temperature for 30 minutes. The reaction was then quenched by the addition of 15 mL of saturated NH4Cl. The organic layer was washed with 15 mL of water and dried under reduced pressure in an oven. The crude product was purified by flash preparative HPLC. This gave 19 mg (16%) of (4-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide as a white solid. LC-MS: (ES, m / z): [M+H] + =322 [ka]

[0241] Example 9: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-indazol-6-yl)acrylamide [ka] (Process 1) In a 500 mL three-necked round-bottom flask, acryloyl chloride (6.80 g, 75.08 mmol, 1.0 equiv.) was added to indanamine (10.0 g, 75.08 mmol, 1.0 equiv.) and EtN (20.9 mL, 150.16 mmol, 2.0 equiv.) in DCM (200.0 mL) at 0 °C. The resulting solution was stirred for 15 h at 25 °C. The reaction was then quenched by the addition of 100 mL of water / ice. The resulting solution was extracted with 2 × 100 mL of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was subjected to a silica gel column using EtOAc / PE (10 / 1) to give 7.3 g (52%) of N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide as a white solid. LC-MS (ES, m / z): [M+H] + =188

[0242] [ka] (Process 2) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (100.0 mg, 0.53 mmol, 1.00 equiv.), 6-bromo-7-fluoro-1H-indazole (137.8 mg, 0.64 mmol, 1.2 equiv.), Pd(dppf)Cl·CHCl (43.61 mg, 0.05 mmol, 0.10 equiv.), DMF (4 mL), and EtN (0.22 mL, 1.60 mmol, 3.00 equiv.). The resulting solution was stirred at 120 °C overnight. The reaction mixture was cooled to room temperature. The crude mixture was purified by flash preparative HPLC. This gave 67 mg (39%) of (2E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-indazol-6-yl)prop-2-enamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =322 [ka]

[0243] Example 10: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-indazol-6-yl)acrylamide [ka] An 8 mL round-bottom flask was charged with 6-bromo-5-fluoro-1H-indazole (100.00 mg, 0.46 mmol, 1.00 equiv.), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 9, Step 1, 87.08 mg, 0.46 mmol, 1.00 equiv.), Pd(dppf)Cl (34.03 mg, 0.046 mmol, 0.1 equiv.), EtN (141.2 mg, 1.39 mmol, 3.00 equiv.), and DMF (3.00 mL). The resulting solution was stirred in an oil bath at 120 °C for 15 hours. The mixture was cooled to room temperature and loaded onto a silica gel column with THF / PE (1 / 1). This gave 80 mg (54%) of (2E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-indazol-6-yl)prop-2-enamide as a white solid. LC-MS (ES, m / z): [M+H] + =322 [ka]

[0244] Example 11: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-indazol-6-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 9, Step 1, 100.0 mg, 0.53 mmol, 1.00 equiv.), 6-bromo-4-fluoro-1H-indazole (137.8 mg, 0.64 mmol, 1.20 equiv.), Pd(dppf)Cl·CHCl (87.2 mg, 0.11 mmol, 0.2 equiv.), DMF (4.0 mL), and EtN (0.22 mL, 1.60 mmol, 3.00 equiv.). The resulting solution was stirred at 120 °C overnight. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This gave 63.6 mg (37%) of (2E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-indazol-6-yl)prop-2-enamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =322 [ka]

[0245] Example 12: (E)-3-(5-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 9, Step 1, 100.0 mg, 0.53 mmol, 1.00 equiv.), 6-bromo-5-chloro-1H-indazole (148.4 mg, 0.64 mmol, 1.20 equiv.), Pd(dppf)Cl.CHCl (43.6 mg, 0.05 mmol, 0.10 equiv.), DMF (4.0 mL), and EtN (0.22 mL, 1.60 mmol, 3.00 equiv.). The resulting solution was stirred at 120 °C overnight. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This gave 38.4 mg (21%) of (2E)-3-(5-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =338 [ka]

[0246] Example 13: (E)-3-(4-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (100.0 mg, 0.53 mmol, 1.00 equiv.), 6-bromo-4-chloro-1H-indazole (148.4 mg, 0.64 mmol, 1.20 equiv.), Pd(dppf)Cl.CHCl (43.6 mg, 0.053 mmol, 0.10 equiv.), DMF (4.0 mL), and EtN (0.22 mL, 1.60 mmol, 3.00 equiv.). The resulting solution was stirred at 120 °C overnight. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This gave 57.2 mg (32%) of (2E)-3-(4-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =338 [ka]

[0247] Example 14: (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (mixture of stereoisomers) [ka] (Process 1) A 100 mL round-bottom flask was charged with 2-methyl-2,3-dihydroinden-1-one (2.00 g, 13.68 mmol, 1.00 equiv), NHOH.HCl (0.95 g, 13.68 mmol, 1.00 equiv), EtN (5.7 mL, 41.04 mmol, 3.00 equiv), and MeOH (30.00 mL). The resulting solution was stirred in an oil bath at 70 °C for 15 h. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The residue was applied to a silica gel column using EtOAc / hexane (1 / 1). This afforded 1.8 g (82%) of N-[(1Z)-2-methyl-2,3-dihydroinden-1-ylidene]hydroxylamine as a solid. LC-MS (ES, m / z): [M+H] + =162

[0248] [ka] (Process 2) A 100 mL round-bottom flask was charged with 4 M HCl in MeOH (20.00 mL) and N-[(1Z)-2-methyl-2,3-dihydroinden-1-ylidene]hydroxylamine (1.8 g, 11.166 mmol, 1.00 equiv.) and Pd / C (0.59 g) in MeOH (50.00 mL). The resulting solution was stirred under H (30 psi (207 kPa)) for 15 hours at 20°C. The solution was filtered, and the organic layer was concentrated. This afforded 1.5 g (73.14%) of 2-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride as a solid. LC-MS-PH-NRG0310-2 (ES, m / z): [M+H] + =148

[0249] [ka] (Step 3) An 8 mL round-bottom flask was charged with (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (Example 5, Step 1, 100.0 mg, 0.35 mmol, 1.00 equiv), 2-methyl-2,3-dihydro-1H-inden-1-amine (51.42 mg, 0.35 mmol, 1.00 equiv), and THF (2.0 mL). LiHMDS (1.1 mL, 1.05 mmol, 3.00 equiv) was added, and the resulting solution was stirred in a water / ice bath at 0° C. for 1 h. The reaction was quenched with 1 mL of NH4Cl, extracted with 2×5 mL of EtOAc, and the organic layer was concentrated. This gave 100 mg (crude) of (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide as a solid. LC-MS (ES, m / z): [M+H] + =402

[0250] [ka] (Step 4) An 8 mL vial was charged with 4 M HCl in MeOH (1.0 mL) and (2E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (100.0 mg, crude) in MeOH (1.0 mL). The mixture was stirred for 15 hours at 20°C. The mixture was concentrated, and the crude mixture was purified by flash preparative HPLC. This afforded 6.5 mg of (2E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)prop-2-enamide as a white solid. LC-MS (ES, m / z): [M+H] + =318 [ka]

[0251] (Examples 14a, 14b, 14c, and 14d) Separation of (£)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide by SFC (column: IG 100 × 4.6 mm 3.0 um; solvent: MeOH (20 mM NH)) gave the four individual isomers. [ka]

[0252] Example 14a: (E)-3-(1H-indazol-6-yl)-N-((1S,2S)-2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 1) LC-MS (ES, m / z): [M+H] + =318 [ka]

[0253] Example 14b: (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 2) LC-MS (ES, m / z): [M+H] + =318 [ka]

[0254] Example 14c: (E)-3-(1H-indazol-6-yl)-N-((1R,2S)-2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 3) LC-MS (ES, m / z): [M+H] + =318 [ka]

[0255] Example 14d: (E)-3-(1H-indazol-6-yl)-N-((1S,2R)-2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 4) LC-MS (ES, m / z): [M+H] + =318 [ka]

[0256] Example 15: (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (mixture of stereoisomers) [ka] (Process 1) A 500 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2,3-dihydro-1-benzopyran-4-one (15.0 g, 101.24 mmol, 1.00 equiv.) and THF (200.0 mL). Subsequently, LiHMDS (121.5 mL, 121.48 mmol, 1.20 equiv.) was added dropwise at −78° C. with stirring. The resulting solution was stirred at −78° C. for 40 minutes. To this was added dropwise a solution of MeI (17.2 g, 121.49 mmol, 1.20 equiv.) in THF (10 mL) with stirring at −78° C. The resulting solution was allowed to react for an additional hour at 25° C. with stirring. The reaction was then quenched by the addition of 150 mL of saturated NH4Cl. The resulting solution was extracted with 2 x 150 mL of EtOAc, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1 / 10). This gave 5 g (30%) of 3-methyl-2,3-dihydro-1-benzopyran-4-one as a pale yellow oil.

[0257] [ka] (Process 2) A 40 mL vial purged and maintained under an inert atmosphere of nitrogen was charged with 3-methyl-2,3-dihydro-1-benzopyran-4-one (1.1 g, 6.78 mmol, 1.00 equiv.), MeOH (20.0 mL), NHOH.HCl (1.4 g, 20.35 mmol, 3.00 equiv.), and EtN (2.8 mL, 20.35 mmol, 3.00 equiv.). The resulting solution was stirred at 70 °C for 15 h. The resulting mixture was concentrated. The residue was diluted with 10 mL of water. The resulting solution was extracted with 2 × 10 mL of ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The resulting mixture was concentrated. This afforded 1 g (83%) of N-[(4E)-3-methyl-2,3-dihydro-1-benzopyran-4-ylidene]hydroxylamine as a white solid.

[0258] [ka] (Step 3) In a 100 mL vial purged and maintained with an inert atmosphere of H2, N-[(4E)-3-methyl-2,3-dihydro-1-benzopyran-4-ylidene]hydroxylamine (0.70 g, 3.95 mmol, 1.00 equiv.), MeOH (20.00 mL), and Pd / C (0.06 g) were placed. The resulting solution was stirred for 12 h at 40 °C. The solids were removed by filtration. The resulting mixture was concentrated. This afforded 530 mg (82%) of 3-methyl-3,4-dihydro-2H-1-benzopyran-4-amine as a pale yellow oil. [ka]

[0259] (Step 4) An 8 mL sealed tube was charged with methyl 3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (Example 5, Step 1, 150 mg, 0.52 mmol, 1.00 equiv.), 7-methyl-2,3-dihydro-1H-inden-1-amine (154.3 mg, 1.04 mmol, 2.00 equiv.), and THF (3.0 mL). Subsequently, LiHMDS (2.1 mL, 2.09 mmol, 4.00 equiv.) was added at 0 °C. The resulting solution was stirred at room temperature for 0.5 h. The reaction was then quenched by the addition of 2 mL of saturated NH4Cl. The resulting solution was extracted with 2 × 15 mL of EtOAc. The organic phase was dried over Na2SO4 and concentrated. This gave 130 mg (crude) of N-(7-methyl-2,3-dihydro-1H-inden-1-yl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =418

[0260] [ka] (Step 5) A 40 mL sealed tube was charged with N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (130 mg, crude), MeOH (4.0 mL), and 4 M HCl / MeOH (4.00 mL). The resulting solution was stirred at room temperature for 5 hours. The resulting mixture was concentrated. The crude product was purified by flash preparative HPLC. This afforded 19 mg of 3-(1H-indazol-6-yl)-N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)prop-2-enamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =334 [ka]

[0261] (Examples 15a, 15b, 15c, and 15d) Separation of (£)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide by SFC (column: SB 100 × 4.6 mm 3.0 um; solvent: MeOH (20 mM NH)) gave four individual isomers. [ka]

[0262] Example 15a (stereoisomer 1): LC-MS (ES, m / z): [M+H] + =334 [ka]

[0263] Example 15b (stereoisomer 2): (ES, m / z): [M+H] + =334 [ka]

[0264] Example 15c (stereoisomer 3): LC-MS): [M+H] + =334 [ka]

[0265] Example 15d (stereoisomer 4): LC-MS-PH-NRG0375-0 (ES, m / z): [M+H] + =334 [ka]

[0266] Example 16: (E)—N-(2-(benzyloxy)phenyl)-3-(1H-indazol-6-yl)acrylamide [ka] (Process 1) A 50 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with methyl (2E)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (Example 5, Step 1, 330.0 mg, 1.15 mmol, 1.00 equiv.), THF (20.0 mL), and 2-(benzyloxy)aniline (298.5 mg, 1.50 mmol, 1.30 equiv.). Subsequently, LiHMDS (3.5 mL, 1 M in THF, 3.00 equiv.) was added dropwise with stirring at 0° C. The resulting solution was stirred for 2 hours at 25° C. The reaction was then quenched by the addition of 10 mL of NH4Cl. The resulting solution was extracted with 2×30 mL of EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated. This gave 310 mg (crude) of (2E)-N-[2-(benzyloxy)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as a pale yellow solid.

[0267] [ka] (Process 2) In a 50 mL three-necked round-bottom flask was placed (2E)-N-[2-(benzyloxy)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (100.0 mg, crude). HCl in MeOH (4 M, 10.00 mL) was introduced at 25 °C. The resulting solution was stirred for 30 minutes at 40 °C. The resulting mixture was concentrated. The crude product was purified by preparative HPLC. This afforded 20 mg of (2E)-N-[2-(benzyloxy)phenyl]-3-(1H-indazol-6-yl)prop-2-enamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =370 [ka]

[0268] Example 17: (E)-3-(1H-indazol-6-yl)-N-(2-(phenoxymethyl)phenyl)acrylamide [ka] (Process 1) In a 20 mL sealed tube, add methyl 3-(1H-indazol-6-yl)acrylate (Intermediate 3 、 A mixture of 3-[1-(oxan-2-yl)indazol-6-yl]-N-[2-(phenoxymethyl)phenyl]prop-2-enamide (150.0 mg, 0.55 mmol, 1.00 equiv.), 2-(phenoxymethyl)aniline (109.8 mg, 0.55 mmol, 1.00 equiv.), MeOH (5.0 mL), and DMT-MM (228.7 mg, 0.83 mmol, 1.50 equiv.) was added. The resulting solution was stirred for 16 hours at room temperature. Water (6.00 mL) was added dropwise with stirring. The solid was collected by filtration. This afforded 130 mg (52%) of 3-[1-(oxan-2-yl)indazol-6-yl]-N-[2-(phenoxymethyl)phenyl]prop-2-enamide as a white solid. LC-MS (ES, m / z): [M+H] + =454

[0269] [ka] (Process 2) A 20 mL sealed tube was charged with (E)-N-(2-(phenoxymethyl)phenyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (50.0 mg, 0.11 mmol, 1.00 equiv), MeOH (4.0 mL), and HCl / MeOH (4.0 mL, 4 M). The resulting solution was stirred for 5 h at room temperature and concentrated. The crude product was purified by flash preparative HPLC. This afforded 29 mg (71%) of 3-(1H-indazol-6-yl)-N-[2-(phenoxymethyl)phenyl]prop-2-enamide as a white solid. LC-MS (ES, m / z): [M+H] + =370 [ka]

[0270] Example 18: (E)—N-(2-(cyclobutoxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide [ka] (Process 1) A 50 mL three-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with cyclobutanol (1.0 g, 13.86 mmol, 1.00 equiv.), 3,3,3-trichloropropanenitrile (2.2 g, 13.86 mmol, 1.00 equiv.), and DCM (20.0 mL). Subsequently, DBU (0.21 g, 1.38 mmol, 0.10 equiv.) was added at 0 °C. The resulting solution was stirred for 1 h at 0–5 °C. The resulting mixture was concentrated in the cold. The residue was applied to a silica gel column using EtOAc / PE (5:95). This afforded 1.3 g (43%) of cyclobutyl-2,2,2-trichloroethaneimidate as a pale pink oil. LC-MS (ES, m / z): [M+H] + =216

[0271] [ka] (Process 2) In a 50 mL three-necked round-bottom flask, 2-nitrobenzyl alcohol (679.1 mg, 3.69 mmol, 1.20 equiv) and DCM (20.01 mL) were placed. Subsequently, cyclobutyl 2,2,2-trichloroethaneimidate (800.0 mg, 3.69 mmol, 1.00 equiv) was added at 0 °C. After stirring for 10 min at 0 °C, BF3.Et2O (472.0 mg, 3.33 mmol, 0.90 equiv) was added. The resulting solution was stirred for 1 h at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was loaded onto a silica gel column using THF:PE = 5:95. This afforded 530 mg (69%) of 1-(cyclobutoxymethyl)-2-nitrobenzene as a pale pink solid.

[0272] [ka] (Step 3) A 40 mL sealed tube was charged with 1-(cyclobutoxymethyl)-2-nitrobenzene (500.0 mg, 2.41 mmol, 1.00 equiv), MeOH (10.0 mL), HO (2.0 mL), Zn (789.1 mg, 2.06 mmol, 5.00 equiv), and NHCl (1.3 g, 24.13 mmol, 10.00 equiv). The resulting solution was stirred for 3 h at room temperature. The solids were filtered off. The filtrate was concentrated. The residue was diluted with 50 mL of EtOAc. The resulting mixture was washed with 20 mL of HO. The organic phase was concentrated. The crude product was purified by flash preparative HPLC. This afforded 160 mg (37%) of 2-(cyclobutoxymethyl)aniline as an off-white solid. LC-MS (ES, m / z): [M+H]=178

[0273] [ka] (Step 4) An 8 mL sealed tube was charged with methyl (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (60.0 mg, 0.21 mmol, 1.00 equiv), 2-(cyclobutoxymethyl)aniline (37.1 mg, 0.21 mmol, 1.00 equiv), and THF (4.00 mL). Subsequently, LiHMDS (0.63 mL, 0.63 mmol, 3.00 equiv, 1 M in THF) was added at 0 °C. The resulting solution was stirred for 0.5 h at room temperature. The reaction mixture was quenched by the addition of 10 mL of saturated NH4Cl. The resulting solution was extracted with 2 × 15 mL of EtOAc. The organic phase was dried over Na2SO4 and concentrated. This gave 83 mg (crude) of N-[2-(cyclobutoxymethyl)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid. LC-MS (ES, m / z): [M+H]+=432

[0274] [ka] (Step 5) An 8 mL sealed tube was charged with (E)-N-(2-(cyclobutoxymethyl)phenyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (83.00 mg, crude), DCM (2.00 mL), and TFA (2.00 mL). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated in the cold. The crude product was purified by flash preparative HPLC. This afforded 18 mg of N-[2-(cyclobutoxymethyl)phenyl]-3-(1H-indazol-6-yl)prop-2-enamide as a white solid. LC-MS (ES, m / z): [M+H] + =348 [ka]

[0275] Example 19: (E)—N-(1-benzyl-1H-indazol-7-yl)-3-(1H-indazol-6-yl)acrylamide [ka] (Process 1) A 100 mL round-bottom flask was charged with 7-nitroindazole (3.0 g, 18.39 mmol, 1.00 equiv.), K2CO3 (7.6 g, 55.17 mmol, 3.00 equiv.), CH3CN (50.0 mL), and PhCH2Br (4.7 g, 27.58 mmol, 1.50 equiv.). The resulting solution was stirred for 16 hours at room temperature. The resulting solution was poured into 150 mL of water. The solid was collected by filtration. The residue was loaded onto a silica gel column. This afforded 1.60 g (34%) of 1-benzyl-7-nitroindazole as a red solid and 1.40 g (30%) of 2-benzyl-7-nitroindazole as a red solid.

[0276] [ka] (Process 2) A 50 mL round-bottom flask was charged with 1-benzyl-7-nitroindazole (820.0 mg, 3.24 mmol, 1.00 equiv), Zn (1.1 g, 16.19 mmol, 5.00 equiv), NH4Cl (1.7 g, 32.38 mmol, 10.00 equiv), MeOH (30.0 mL), and HO (5.0 mL). The resulting solution was stirred for 3 h at room temperature. The solids were filtered off. The resulting solution was concentrated. The residue was diluted with 50 mL of EtOAc. The resulting mixture was washed with 20 mL of HO and 20 mL of brine. The organic phase was concentrated. This afforded 650 mg (89%) of 1-benzylindazol-7-amine as an off-white solid. LC-MS (ES, m / z): [M+H] + =224

[0277] [ka] (Step 3) An 8 mL sealed tube was charged with methyl (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (Example 5, Step 1, 150.0 mg, 0.52 mmol, 1.00 equiv.), THF (3.00 mL), and 1-benzylindazol-7-amine (175.5 mg, 0.78 mmol, 1.50 equiv.). Subsequently, LiHMDS (2.10 mL, 2.10 mmol, 4.00 equiv.) was added at 0° C. The resulting solution was stirred at room temperature for 0.5 h. The reaction was then quenched by the addition of 5 mL of saturated NH4Cl. The resulting solution was extracted with 2×15 mL of EtOAc. The organic phase was dried over sodium sulfate and concentrated. This gave 120 mg (crude) of N-(1-benzylindazol-7-yl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =478

[0278] [ka] (Step 4) A 20 mL sealed tube was charged with (E)-N-(1-benzyl-1H-indazol-7-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (120.0 mg, crude), MeOH (4.0 mL), and 4 M HCl / MeOH (4.0 mL). The resulting solution was stirred at room temperature for 5 hours, and the resulting mixture was concentrated. The crude product was purified by flash preparative HPLC. This afforded 17 mg of N-(1-benzylindazol-7-yl)-3-(1H-indazol-6-yl)prop-2-enamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =394 [ka]

[0279] Example 20: (E)-3-(1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide [ka] (Process 1) A 50 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (220.0 mg, 0.77 mmol, 1.00 equiv), THF (20.0 mL), 1-methylindazol-7-amine (147.0 mg, 1.00 mmol, 1.30 equiv), and LiHMDS (2.3 mL, 2.31 mmol, 3.00 equiv). The resulting solution was stirred for 2 hours at 25° C. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 100 mL of EtOAc, dried over anhydrous sodium sulfate, and concentrated. This gave 220 mg (crude) of (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-(1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide as a solid. [ka]

[0280] (Process 2) Into a 50 mL three-necked round-bottom flask was placed (2E)-(1-(tetrahydro-2H-pyran-2-yl)-N-(1-methylindazol-7-yl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (80.00 mg, crude). To this was introduced 4 M HCl / MeOH (10.00 mL) at 25° C. The resulting solution was stirred for 30 minutes at 40° C. The resulting mixture was concentrated. The crude product was purified by preparative HPLC. This afforded 20 mg of (2E)-3-(1H-indazol-6-yl)-N-(1-methylindazol-7-yl)prop-2-enamide as an off-white solid. LC-MS (ES, m / z): [M+H] + = 318 [ka]

[0281] Example 21: (E)-3-(1H-indazol-6-yl)-N-(m-tolyl)acrylamide [ka] (Process 1) An 8 mL sealed tube was charged with methyl (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (Example 5, Step 1, 150.0 mg, 0.52 mmol, 1.00 equiv.), m-toluidine (84.2 mg, 0.78 mmol, 1.50 equiv.), THF (3.00 mL), and LiHMDS (2.1 mL, 2.09 mmol, 4.00 equiv., 1 M in THF). The resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition of 5 mL of saturated NH4Cl. The resulting solution was extracted with 2 x 15 mL of ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. This gave 130 mg (crude) of (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-(m-tolyl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =362

[0282] [ka] (Process 2) An 8 mL sealed tube was charged with (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-(m-tolyl)acrylamide (130.00 mg, crude), MeOH (2.00 mL), and HCl / MeOH (2.00 mL, 4 M). The resulting solution was stirred for 5 hours at room temperature. The resulting mixture was concentrated in the cold. The crude product was purified by flash preparative HPLC. This afforded 35 mg of (E)-3-(1H-indazol-6-yl)-N-(m-tolyl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =278 [ka]

[0283] Example 22: (E)-N-(3-chlorophenyl)-3-(1H-indazol-6-yl)acrylamide [ka] (Process 1) An 8 mL sealed tube was charged with methyl (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (Example 5, Step 1, 130.0 mg, 0.45 mmol, 1.00 equiv.), 3-chloroaniline (86.9 mg, 0.68 mmol, 1.50 equiv.), THF (3.0 mL), and LiHMDS (1.8 mL, 1.82 mmol, 4.00 equiv., 1 M in THF). The resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition of 5 mL of saturated NH4Cl. The resulting solution was extracted with 2 x 15 mL of EtOAc. The organic phase was dried over Na2SO4 and concentrated. This gave 135 mg (crude) of N-(3-chlorophenyl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid. LC-MS-PH-NRG0319-1 (ES, m / z): [M+H] + =382

[0284] [ka] (Process 2) An 8 mL sealed tube was charged with (N-(3-chlorophenyl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (130 mg crude), MeOH (2.00 mL), and 4 M HCl / MeOH (2.00 mL). The resulting solution was stirred for 5 h at room temperature. The resulting mixture was concentrated in the cold. The crude product was purified by flash preparative HPLC. This afforded 42 mg of (£)-N-(3-chlorophenyl)-3-(1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =298 [ka]

[0285] Example 23: (E)—N-(3-fluorophenyl)-3-(1H-indazol-6-yl)acrylamide [ka] (Process 1) An 8 mL sealed tube was charged with methyl (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (150.0 mg, 0.52 mmol, 1.00 equiv), 3-fluoroaniline (87.3 mg, 0.78 mmol, 1.50 equiv), THF (3.0 mL), and LiHMDS (2.1 mL, 2.10 mmol, 4.00 equiv). The resulting solution was stirred for 1 hour at room temperature. The reaction was then quenched by the addition of 5 mL of saturated NH4Cl. The resulting solution was extracted with 2 x 15 mL of EtOAc. The organic phase was dried over sodium sulfate and concentrated. This gave 128 mg (crude) of N-(3-fluorophenyl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =366

[0286] [ka] (Process 2) An 8 mL sealed tube was charged with N-(3-fluorophenyl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (120.0 mg, crude), MeOH (2.0 mL), and 4 M HCl / MeOH (2.0 mL). The resulting solution was stirred at room temperature for 5 hours. The resulting mixture was concentrated in the cold. The crude product was purified by flash preparative HPLC. This afforded 33 mg of (E)-N-(3-fluorophenyl)-3-(1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =282 [ka]

[0287] Example 24: (E)-N-(2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide [ka] (Process 1) A 50 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2,6-dimethylaniline (160.0 mg, 1.32 mmol, 1.00 equiv.), DCM (10.0 mL), and triethylamine (0.55 mL, 3.96 mmol, 3.00 equiv.). Subsequently, acryloyl chloride (143.40 mg, 1.58 mmol, 1.20 equiv.) was added dropwise at 0°C with stirring. The resulting solution was stirred for 3 hours at 25°C. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 2 × 10 mL of dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column using EtOAc / PE (1 / 3). This afforded 150 mg (65%) of N-(2,6-dimethylphenyl)prop-2-enamide as a white solid. LC-MS (ES, m / z): [M+H] + =176

[0288] [ka] (Process 2) An 8 mL vial purged and maintained under an inert atmosphere of nitrogen was charged with N-(2,6-dimethylphenyl)prop-2-enamide (50.0 mg, 0.29 mmol, 1.00 equiv.), DMF (4.0 mL), 6-bromo-1H-indazole (61.8 mg, 0.31 mmol, 1.10 equiv.), EtN (0.12 mL, 0.86 mmol, 3.00 equiv.), and Pd(dppf)Cl·CHCl (11.7 mg, 0.014 mmol, 0.05 equiv.). The resulting solution was stirred at 120 °C for 5 h. The reaction mixture was cooled to 25 °C in a water bath. The crude mixture was purified by flash preparative HPLC. This gave 30 mg (36%) of (£)-N-(2,6-dimethylphenyl)-3-(lH-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =292 [ka]

[0289] (Examples 25 and 26: (E)-N-((1R,3R)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide, Isomer 1; (E)-N-((1R,3S)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide, Isomer 2) [ka] (Process 1) A 100 mL round-bottom flask was charged with benzaldehyde (5.5 g, 51.83 mmol, 1.00 equiv), EtOH (30.0 mL), NHOAc (8.0 g, 103.65 mmol, 2.00 equiv), and malonic acid (5.4 g, 51.83 mmol, 1.00 equiv). The resulting solution was stirred for 12 hours at 80 °C. The solid was collected by filtration. This afforded 5 g (58%) of 3-amino-3-phenylpropanoic acid as a white solid. [ka]

[0290] (Process 2) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 3-amino-3-phenylpropanoic acid (4.9 g, 29.66 mmol, 1.00 equiv.) and DCM (40.0 mL). Subsequently, trifluoroacetic anhydride (6.9 g, 32.63 mmol, 1.10 equiv.) was added dropwise at 0° C. with stirring. The resulting solution was stirred for 30 minutes at 0° C. The solid was collected by filtration. This afforded 4 g (52%) of 3-phenyl-3-(2,2,2-trifluoroacetamido)propanoic acid as a white solid.

[0291] [ka] (Step 3) A 100 mL round-bottom flask was charged with 3-phenyl-3-(2,2,2-trifluoroacetamido)propanoic acid (5.0 g, 19.14 mmol, 1.00 equiv.) and thionyl chloride (30 mL). The resulting solution was stirred at 70° C. for 3 hours. The resulting mixture was concentrated to afford 4.5 g (84%) of 3-phenyl-3-(2,2,2-trifluoroacetamido)propanoyl chloride as a white solid.

[0292] [ka] (Step 4) A 100 mL three-necked round-bottom flask was charged with AlCl (4.29 g, 32.18 mmol, 2.00 equiv.) and DCM (30.00 mL). Subsequently, a solution of 3-phenyl-3-(2,2,2-trifluoroacetamido)propanoyl chloride (4.5 g, 16.09 mmol, 1.00 equiv.) in DCM (20 mL) was added dropwise at 0 °C with stirring. The resulting solution was stirred at 40 °C for 12 h. The reaction mixture was cooled to 25 °C. The solid was filtered off. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column using EtOAc / PE (1 / 2). This afforded 3.4 g (87%) of 2,2,2-trifluoro-N-(3-oxo-1,2-dihydroinden-1-yl)acetamide as a white solid. LC-MS (ES, m / z): [M+H] + =244

[0293] [ka] (Step 5) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2,2,2-trifluoro-N-(3-oxo-1,2-dihydroinden-1-yl)acetamide (3.0 g, 12.34 mmol, 1.00 equiv.) and MeOH (30.00 mL). Subsequently, NaBH4 (1.40 g, 37.01 mmol, 3.00 equiv.) was added portionwise at 0 °C. The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 2 × 40 mL of DCM. The mixture was dried over anhydrous sodium sulfate and concentrated. This afforded 2 g (66%) of 2,2,2-trifluoro-N-(3-hydroxy-2,3-dihydro-1H-inden-1-yl)acetamide as a white solid.

[0294] [ka] (Step 6) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2,2,2-trifluoro-N-(3-hydroxy-2,3-dihydro-1H-inden-1-yl)acetamide (2.0 g, 8.16 mmol, 1.00 equiv.) and DCM (30.00 mL). Subsequently, diethylsulfur trifluoride (1.71 g, 10.60 mmol, 1.30 equiv.) was added dropwise at 0° C. with stirring. The resulting solution was stirred for 2 hours at 0° C. The reaction was then quenched by the addition of 50 mL of aqueous NaHCO3 solution. The resulting solution was extracted with 2×50 mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The residue was loaded onto a silica gel column using EtOAc / PE (1 / 5). This gave 810 mg (40%) of 2,2,2-trifluoro-N-(3-fluoro-2,3-dihydro-1H-inden-1-yl)acetamide as a pale yellow solid.

[0295] [ka] (Step 7) A 40 mL vial was charged with 2,2,2-trifluoro-N-(3-fluoro-2,3-dihydro-1H-inden-1-yl)acetamide (800.0 mg, 3.24 mmol, 1.00 equiv.), MeOH / HO (10.0 mL / 5.0 mL), and NaOH (258.9 mg, 6.472 mmol, 2.00 equiv.). The resulting solution was stirred for 5 hours at room temperature. The resulting solution was extracted with 2 × 20 mL of EtOAc, and the organic layer was dried over anhydrous sodium sulfate and concentrated. This afforded 450 mg (92%) of 3-fluoro-2,3-dihydro-1H-inden-1-amine as a pale yellow solid.

[0296] [ka] (Step 8) A 50 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 3-fluoro-2,3-dihydro-1H-inden-1-amine (410.0 mg, 2.71 mmol, 1.00 equiv.), DCM (15.00 mL), and EtN (0.76 mL, 5.42 mmol, 2.00 equiv.). Subsequently, acryloyl chloride (294.55 mg, 3.25 mmol, 1.20 equiv.) was added dropwise at 0° C. with stirring. The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 2×10 mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative HPLC. This gave 230 mg (41%) of N-(3-fluoro-2,3-dihydro-1H-inden-1-yl)prop-2-enamide as a pale yellow solid.

[0297] [ka] (Step 9) A 20 mL vial purged and maintained under an inert atmosphere of nitrogen was charged with N-(3-fluoro-2,3-dihydro-1H-inden-1-yl)prop-2-enamide (80.0 mg, 0.39 mmol, 1.00 equiv.), DMF (8.0 mL), 6-bromo-1H-indazole (84.5 mg, 0.43 mmol, 1.10 equiv.), EtN (0.14 mL, 0.98 mmol, 2.50 equiv.), and Pd(dppf)Cl.CHCl (25.40 mg, 0.03 mmol, 0.08 equiv.). The resulting solution was stirred at 120 °C for 12 h. The reaction mixture was cooled to 25 °C. The resulting solution was diluted with 8 mL of water. The resulting solution was extracted with 2 × 10 mL of EtOAc. The resulting mixture was washed with 2 × 15 mL of brine. The resulting mixture was concentrated. The crude product was purified by SFC to give 11 mg (9%) of trans-(2E)-N-[(1R,3R)-3-fluoro-2,3-dihydro-1H-inden-1-yl]-3-(1H-indazol-6-yl)prop-2-enamide (isomer 1) as an off-white solid and 13 mg (10%) of cis-(2E)-N-[(1R,3S)-3-fluoro-2,3-dihydro-1H-inden-1-yl]-3-(1H-indazol-6-yl)prop-2-enamide (isomer 2) as an off-white solid. The stereochemistry was arbitrarily assigned: Isomer 1: LC-MS (ES, m / z): [M+H] + =322 [ka] Isomer 2: LC-MS (ES, m / z): [M+H] + =322 [ka]

[0298] Example 27: (E)—N-(2-(hydroxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide [ka] (Process 1) An 8 mL sealed tube was charged with methyl (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (Example 5, Step 1, 150.0 mg, 0.52 mmol, 1.00 equiv.), THF (3.00 mL), 2-(phenoxymethyl)aniline (125.2 mg, 0.62 mmol, 1.20 equiv.), and LiHMDS (2.62 mL, 2.62 mmol, 5.00 equiv.). The resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition of 5 mL of saturated NH4Cl. The resulting solution was extracted with 2 x 15 mL of EtOAc. The organic phase was dried over sodium sulfate and concentrated. This gave 78 mg (crude) of N-[2-(hydroxymethyl)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid. LC-MS-PH-NRG0347-1 (ES, m / z): [M+H] + =378

[0299] [ka] (Process 2) An 8 mL sealed tube was charged with (N-[2-(hydroxymethyl)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (75 mg, crude), THF (2 mL), and TFA (2 mL). The resulting solution was stirred for 3 h at room temperature. The resulting mixture was concentrated in the cold. The crude product was purified by flash preparative HPLC. This afforded 38 mg of (E)-N-(2-(hydroxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =294 [ka]

[0300] Example 28: (E)—N-(3-fluoro-2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide [ka] An 8 mL vial was charged with 6-bromo-1H-indazole (100.0 mg, 0.51 mmol, 1.00 equiv.), N-(3-fluoro-2,6-dimethylphenyl)prop-2-enamide (prepared similarly to Intermediate 1 using 3-fluoro-2,6-dimethylaniline and acryloyl chloride, 98.1 mg, 0.51 mmol, 1.00 equiv.), Pd(dppf)Cl (37.1 mg, 0.051 mmol, 0.10 equiv.), and EtN (0.21 mL, 1.52 mmol, 3.00 equiv.) in DMF (4.0 mL). The resulting solution was stirred at 120 °C in an oil bath for 2 hours. The reaction mixture was cooled. The residue was loaded onto a silica gel column using THF / PE (1 / 1). This gave 20 mg (13%) of (£)-N-(3-fluoro-2,6-dimethylphenyl)-3-(lH-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =310 [ka]

[0301] Example 29: (E)-3-(1H-indazol-6-yl)-N-(2-(methoxymethyl)phenyl)acrylamide [ka] (Process 1) A 40 mL sealed tube was charged with 2-nitrobenzyl alcohol (500.00 mg, 3.26 mmol, 1.00 equiv.), MeCN (20.00 mL), and K2CO3 (676.80 mg, 4.89 mmol, 1.50 equiv.). Subsequently, methyl iodide (1.40 g, 9.79 mmol, 3.00 equiv.) was added at 0 °C. The resulting solution was stirred at room temperature for 3 h. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 2 × 30 mL of EtOAc. The organic phase was washed with 2 × 20 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. This afforded 510 mg (93%) of 1-(methoxymethyl)-2-nitrobenzene as a pale yellow oil.

[0302] [ka] (Process 2) A 40 mL sealed tube was charged with 1-(methoxymethyl)-2-nitrobenzene (510.0 mg, 3.05 mmol, 1.00 equiv), EtOH (10.0 mL), HO (2.0 mL), NHCl (1.3 mg, 24.50 mmol, 8.03 equiv), and Zn (997.8 mg, 15.25 mmol, 5.00 equiv). The resulting solution was stirred at room temperature for 1 h. The resulting solution was diluted with 50 mL of DCM. The solid was filtered off. The filtrate was dried over anhydrous sodium sulfate and concentrated in vacuo. This afforded 380 mg (90%) of 2-(methoxymethyl)aniline as a pale yellow solid. LC-MS (ES, m / z): [M+H]+ = 138

[0303] [ka] (Step 3) An 8 mL sealed tube was charged with methyl (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (50.0 mg, 0.17 mmol, 1.00 equiv), 2-(methoxymethyl)aniline (23.3 mg, 0.17 mmol, 1.00 equiv), and THF (3.00 mL). Subsequently, LiHMDS (0.70 mL, 0.70 mmol, 4.00 equiv) was added at 0 °C. The resulting solution was stirred at room temperature for 0.5 h. The reaction was then quenched by the addition of 5 mL of saturated NH4Cl. The resulting solution was extracted with 2 × 10 mL of EtOAc. The organic phase was dried over sodium sulfate and concentrated. This gave 51 mg (crude) of (2E)-N-[2-(methoxymethyl)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as a white solid. LC-MS (ES, m / z): [M+H]+=392

[0304] [ka] (Step 4) An 8 mL sealed tube was charged with (2E)-N-[2-(methoxymethyl)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (51.0 mg, 0.13 mmol, 1.00 equiv), MeOH (2.0 mL), and 4 M HCl / MeOH (2.0 mL). The resulting solution was stirred at room temperature for 5 hours. The resulting mixture was concentrated in the cold. The crude product was purified by flash preparative HPLC. This afforded 38 mg of (E)-3-(1H-indazol-6-yl)-N-(2-(methoxymethyl)phenyl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =308 [ka]

[0305] Example 30: (E)—N-(2-(((1-(2-fluoroethyl)azetidin-3-yl)oxy)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide hydrochloride [ka] (Process 1) A 100 mL three-necked round-bottom flask was charged with tert-butyl 3-hydroxyazetidine-1-carboxylate (4.0 g, 23.09 mmol, 1.00 equiv.), DMF (50.0 mL), KCO (4.8 g, 34.64 mmol, 1.50 equiv.), and 1-(bromomethyl)-2-nitrobenzene (4.99 g, 23.09 mmol, 1.00 equiv.). The resulting solution was stirred at 50 °C for 3 h. The resulting solution was diluted with 150 mL of EtOAc. The solids were filtered off. The filtrate was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column using EtOAc / PE (20:80). This afforded 3.5 g (49%) of tert-butyl 3-[(2-nitrophenyl)methoxy]azetidine-1-carboxylate as a colorless solid.

[0306] [ka] (Process 2) A 50 mL round-bottom flask was charged with tert-butyl 3-[(2-nitrophenyl)methoxy]azetidine-1-carboxylate (3.0 g, 9.73 mmol, 1.00 equiv.), DCM (10.0 mL), and TFA (10.0 mL). The resulting solution was stirred at room temperature for 3 hours. The resulting mixture was concentrated. The crude product was purified by recrystallization from EtO. This afforded 2.7 g (91%) of 3-((2-nitrobenzyl)oxy)azetidine trifluoroacetate as a white solid. LC-MS (ES, m / z): [M+H] + =209

[0307] [ka] (Step 3) A 40 mL sealed tube was charged with 3-((2-nitrobenzyl)oxy)azetidine trifluoroacetate (1.00 g, 3.28 mmol, 1.00 equiv), MeCN (20.00 mL), KCO (0.91 g, 6.57 mmol, 2.00 equiv), KI (0.55 g, 3.31 mmol, 1.01 equiv), and 1-bromo-2-fluoroethane (0.63 g, 4.93 mmol, 1.50 equiv). The resulting solution was stirred at 50 °C for 3 h. The resulting solution was diluted with 50 mL of EA. The solid was removed by filtration. The filtrate was concentrated. The residue was loaded onto a silica gel column using THF:PE=32:68. This gave 0.75 g (89%) of 1-(2-fluoroethyl)-3-[(2-nitrophenyl)methoxy]azetidine as a pale yellow solid.

[0308] [ka] (Step 4) A 40 mL sealed tube was charged with 1-(2-fluoroethyl)-3-[(2-nitrophenyl)methoxy]azetidine (500.0 mg, 1.96 mmol, 1.00 equiv), MeOH (10.0 mL), HO (2.0 mL), NHCl (841.5 mg, 15.72 mmol, 8.00 equiv), and Zn (643.1 mg, 9.80 mmol, 5.00 equiv). The resulting solution was stirred at room temperature for 3 h. The resulting solution was diluted with 50 mL of DCM. The solids were removed by filtration. The filtrate was concentrated. This afforded 300 mg (68%) of 2-([[1-(2-fluoroethyl)azetidin-3-yl]oxy]methyl)aniline as an off-white solid. LC-MS (ES, m / z): [M+H] + =225

[0309] [ka] (Step 5) An 8 mL sealed tube was charged with methyl (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (100.0 mg, 0.35 mmol, 1.00 equiv), 2-([[1-(2-fluoroethyl)azetidin-3-yl]oxy]methyl)aniline (78.3 mg, 0.35 mmol, 1.00 equiv), and THF (3.00 mL). Subsequently, LiHMDS (1.7 mL, 1.75 mmol, 5.00 equiv) was added at 0 °C. The resulting solution was stirred at room temperature for 1 h. The reaction was then quenched by the addition of 5 mL of saturated NH4Cl. The resulting solution was extracted with 2 × 10 mL of ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. This gave 105 mg (crude) of (2E)-N-[2-([[1-(2-fluoroethyl)azetidin-3-yl]oxy]methyl)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =479

[0310] [ka] (Step 6) An 8 mL sealed tube was charged with (2E)-N-[2-([[1-(2-fluoroethyl)azetidin-3-yl]oxy]methyl)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (100.0 mg, crude), DCM (5.0 mL), and TFA (119.13 mg, 1.05 mmol, 5.00 equiv). The resulting solution was stirred at room temperature for 3 hours. The resulting mixture was concentrated. The crude product was purified by flash preparative HPLC. This afforded 73 mg of (E)-N-(2-(((1-(2-fluoroethyl)azetidin-3-yl)oxy)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide hydrochloride as an off-white solid. LC-MS (ES, m / z): [M+H] + =395 [ka]

[0311] Example 31: (E)—N-(2-((3-fluoroazetidin-1-yl)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide [ka] (Process 1) A 40 mL sealed tube was charged with 1-(bromomethyl)-2-nitrobenzene (500.0 mg, 2.31 mmol, 1.00 equiv.), CHCN (10.0 mL), EtN (0.64 mL, 4.63 mmol, 2.00 equiv.), and 3-fluoroazetidine hydrochloride (309.8 mg, 2.77 mmol, 1.20 equiv.). The resulting solution was stirred at room temperature for 16 hours. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2 × 20 mL of EtOAc. The organic phase was washed with 20 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was loaded onto a silica gel column using 20:80 EtOAc / PE. This afforded 380 mg (78%) of 3-fluoro-1-[(2-nitrophenyl)methyl]azetidine as an off-white solid.

[0312] [ka] (Process 2) A 40 mL vial was charged with 3-fluoro-1-[(2-nitrophenyl)methyl]azetidine (380.0 mg, 1.81 mmol, 1.00 equiv.), MeOH (8.0 mL), HO (1.0 mL), NHCl (773.6 mg, 14.46 mmol, 8.00 equiv.), and Zn (591.2 mg, 9.04 mmol, 5.00 equiv.). The resulting solution was stirred at room temperature for 2 hours and diluted with 30 mL of DCM. The solid was removed by filtration. The filtrate was dried over anhydrous sodium sulfate and concentrated in vacuo. This afforded 310 mg (95%) of 2-[(3-fluoroazetidin-1-yl)methyl]aniline as an off-white solid. LC-MS (ES, m / z): [M+H] + =181

[0313] [ka] (Step 3) An 8 mL sealed tube was charged with methyl (2E)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (Example 5, Step 1, 70.0 mg, 0.244 mmol, 1.00 equiv.), THF (2.0 mL), and 2-[(3-fluoroazetidin-1-yl)methyl]aniline (52.9 mg, 0.29 mmol, 1.20 equiv.). Subsequently, LiHMDS (1.2 mL, 1.22 mmol, 5.00 equiv.) was added at 0 °C. The resulting solution was stirred at room temperature for 1 hour. The reaction was then quenched by the addition of 5 mL of saturated NH4Cl. The resulting solution was extracted with 2 × 10 mL of EtOAc. The organic phase was dried over sodium sulfate and concentrated. This gave 55 mg (crude) of (2E)-N-[2-[(3-fluoroazetidin-1-yl)methyl]phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =435

[0314] [ka] (Step 4) An 8 mL sealed tube was charged with (2E)-N-[2-[(3-fluoroazetidin-1-yl)methyl]phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (55.0 mg, crude), DCM (2.0 mL), and TFA (2.0 mL). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by flash preparative HPLC. This afforded 18 mg of (E)-N-(2-((3-fluoroazetidin-1-yl)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =351 [ka]

[0315] Example 32: (E)—N-(2-(2-(3-fluoroazetidin-1-yl)ethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide [ka] (Process 1) A 50 mL round-bottom flask was charged with 2-nitrobenzaldehyde (0.90 g, 5.95 mmol, 1.00 equiv.), bromo(methyl)triphenyl-lambda-5-phosphane (3.20 g, 8.93 mmol, 1.50 equiv.), and THF (30.0 mL). Subsequently, t-BuOK (1.0 g, 8.93 mmol, 1.50 equiv.) was added at 0° C. The resulting solution was stirred at room temperature for 16 hours. The reaction was then quenched by the addition of 30 mL of 2 M HCl. The resulting solution was extracted with 50 mL of EtOAc. The organic phase was washed with 20 mL of brine. The resulting solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (5:95). This gave 270 mg (30%) of 1-ethenyl-2-nitrobenzene as a pale yellow solid.

[0316] [ka] (Process 2) An 8 mL sealed tube was charged with 1-ethenyl-2-nitrobenzene (270.0 mg, 1.81 mmol, 1.00 equiv.), MeOH (4.0 mL), EtN (0.5 mL, 3.62 mmol, 2.00 equiv.), and 3-fluoroazetidine (149.5 mg, 1.99 mmol, 1.10 equiv.). The resulting solution was stirred at room temperature for 20 hours. The resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column using EtOAc / PE (20:80). This afforded 190 mg (46%) of 3-fluoro-1-[2-(2-nitrophenyl)ethyl]azetidine as a pale yellow solid.

[0317] [ka] (Step 3) A 40 mL sealed tube was charged with 3-fluoro-1-[2-(2-nitrophenyl)ethyl]azetidine (190.0 mg, 0.85 mmol, 1.00 equiv), MeOH (6.0 mL), HO (1.0 mL), NHCl (362.6 mg, 6.77 mmol, 8.00 equiv), and Zn (277.1 mg, 4.24 mmol, 5.00 equiv). The resulting solution was stirred at room temperature for 2 hours. The resulting solution was diluted with 20 mL of DCM. The solids were removed by filtration. The filtrate was dried over anhydrous sodium sulfate and concentrated. This afforded 150 mg (91%) of 2-[2-(3-fluoroazetidin-1-yl)ethyl]aniline as an off-white solid. LC-MS (ES, m / z): [M+H] + =195

[0318] [ka] (Step 4) An 8 mL sealed tube was charged with (E)-methyl 3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylate (60.0 mg, 0.21 mmol, 1.00 equiv), 2-[2-(3-fluoroazetidin-1-yl)ethyl]aniline (40.7 mg, 0.21 mmol, 1.00 equiv), and THF (2.0 mL). Subsequently, LiHMDS (0.84 mL, 0.84 mmol, 4.00 equiv) was added at 0 °C. The resulting solution was stirred at room temperature for 0.5 h. The reaction was then quenched by the addition of 5 mL of saturated NH4Cl. The resulting solution was extracted with 2 × 10 mL of EtOAc. The organic phase was dried over Na2SO4 and concentrated. This gave 51 mg (crude) of N-[2-[2-(3-fluoroazetidin-1-yl)ethyl]phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as a solid. LC-MS (ES, m / z): [M+H]+=449

[0319] [ka] (Step 5) An 8 mL sealed tube was charged with N-[2-[2-(3-fluoroazetidin-1-yl)ethyl]phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (51.00 mg, crude), DCM (1.00 mL), and TFA (1.00 mL). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by flash preparative HPLC. This afforded 18 mg of (E)-N-(2-(2-(3-fluoroazetidin-1-yl)ethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =365 [ka]

[0320] Example 33: (E)—N-(2-fluoro-6-methylphenyl)-3-(1H-indazol-6-yl)acrylamide [ka] (Process 1) A 25 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2-fluoro-6-methylaniline (160.0 mg, 1.28 mmol, 1.00 equiv.), DCM (6.0 mL), and EtN (0.45 mL, 3.20 mmol, 2.50 equiv.). Subsequently, acryloyl chloride (138.86 mg, 1.54 mmol, 1.20 equiv.) was added dropwise at 0° C. with stirring. The resulting solution was stirred for 2 hours at 0° C. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×10 mL of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column using EtOAc / PE (1 / 6). This gave 120 mg (52%) of N-(2-fluoro-6-methylphenyl)prop-2-enamide as a pale yellow solid. LC-MS-PH-NRG0405-1 (ES, m / z): [

[0321] [ka] (Process 2) An 8 mL vial purged and maintained under an inert atmosphere of nitrogen was charged with N-(2-fluoro-6-methylphenyl)prop-2-enamide (120.0 mg, 0.67 mmol, 1.00 equiv.), DMF (5.0 mL), 6-bromo-1H-indazole (145.1 mg, 0.74 mmol, 1.10 equiv.), EtN (0.28 mL, 2.01 mmol, 3.00 equiv.), and Pd(dppf)Cl.CHCl (27.28 mg, 0.034 mmol, 0.05 equiv.). The resulting solution was stirred at 120 °C for 12 h. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This gave 30 mg (15%) of (£)-N-(2-fluoro-6-methylphenyl)-3-(lH-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =296 [ka]

[0322] Example 34: (E)—N-(3-fluoro-2-methylphenyl)-3-(1H-pyrazolo[4,3-b]pyridin-6-yl)acrylamide [ka] To a microwave vial containing N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 100.00 mg, 0.558 mmol, 1.00 equiv.), 6-bromo-1H-pyrazolo[4,3b]pyridine (110 mg, 0.558 mmol, 1.00 equiv.), Pd(OAc) (19 mg, 0.084 mmol, 0.15 equiv.), tris(2-methylphenyl)phosphane (34 mg, 0.112 mmol, 0.20 equiv.), and tetrabutylammonium chloride (155 mg, 0.558 mmol, 1.00 equiv.) was added DMF (1.5 mL). The resulting solution was stirred at 115 °C for 12 h. The resulting mixture was diluted with 20 mL of EtOAc and washed with 2 × 10 mL of 1 M aqueous KCO solution. The organic layer was concentrated, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column. The resulting crude product was purified by flash preparative HPLC. This gave 23 mg (14%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-pyrazolo[4,3-b]pyridin-6-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =297 [ka]

[0323] Example 35: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[4,3-c]pyridin-6-yl)acrylamide [ka] An 8 mL vial was charged with 6-bromo-1H-pyrazolo[4,3-c]pyridine (Example 9, Step 1, 200.0 mg, 1.01 mmol, 1.00 equiv.), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (189.1 mg, 1.01 mmol, 1.00 equiv.), Pd(dppf)Cl (73.9 mg, 0.10 mmol, 0.10 equiv.), and EtN (0.42 mL, 3.03 mmol, 3.00 equiv.) in DMF (5.00 mL). The resulting solution was stirred at 120 °C in an oil bath for 15 h. The reaction mixture was cooled. The crude mixture was purified by flash preparative HPLC. This gave 15 mg (5%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[4,3-c]pyridin-6-yl)acrylamide as a white solid. LC MS (ES, m / z): [M+H] + =305 [ka]

[0324] Example 36: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide [ka] An 8 mL round-bottom flask was charged with 6-bromo-1H-pyrazolo[3,4-b]pyridine (Example 9, Step 1, 200.0 mg, 1.01 mmol, 1.00 equiv.), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (189.1 mg, 1.01 mmol, 1.00 equiv.), Pd(dppf)Cl2CH2Cl2 (82.5 mg, 0.10 mmol, 0.10 equiv.), Et3N (0.42 mL, 3.03 mmol, 3.00 equiv.), and DMF (4.00 mL). The resulting solution was stirred at 120 °C in an oil bath for 15 h. The reaction mixture was cooled. The crude mixture was purified by flash preparative HPLC. This gave 15 mg (5%) of (£)-N-(2,3-dihydro-lH-inden-l-yl)-3-(lH-pyrazolo[3,4-b]pyridin-6-yl)acrylamide as a solid. LC-MS (ES, m / z): [M+H] + =305 [ka]

[0325] Example 37: (E)-3-(1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide [ka] (Process 1) A 250 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with (1S,2S)-1-amino-2,3-dihydro-1H-inden-2-ol (2.6 g, 17.43 mmol, 1.00 equiv.), DMF (50.0 mL), EtN (4.9 mL, 34.85 mmol, 2.00 equiv.), and phthalic anhydride (3.9 g, 26.14 mmol, 1.50 equiv.). The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 200 mL of water. The pH of the solution was adjusted to 5-6 with 2 N HCl. The resulting solution was extracted with 3 × 100 mL of EtOAc. The resulting mixture was washed with 1 × 100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column with EtOAc-PE (1:5 to 1:3) to give 3.60 g (74%) of 2-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]isoindole-1,3-dione as an off-white solid.

[0326] [ka] (Process 2) A 100 mL three-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with 2-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]isoindole-1,3-dione (2.0 g, 7.16 mmol, 1.00 equiv.), DMF (30.0 mL), BaO (13.2 g, 85.93 mmol, 12.00 equiv.), Ba(OH) (7.4 g, 42.97 mmol, 6.00 equiv.), and CHCl (6.1 g, 42.98 mmol, 6.00 equiv.). The resulting solution was stirred at room temperature overnight. The solids were removed by filtration. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using THF:PE (1:6 to 1:4). This gave 1.60 g (76%) of 2-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]isoindole-1,3-dione as an off-white solid.

[0327] [ka] (Step 3) A 250 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]isoindole-1,3-dione (1.60 g, 5.46 mmol, 1.00 equiv), EtOH (50.0 mL), and NH2NH2.HO (80%, 15 mL). The resulting solution was heated at reflux overnight. The reaction mixture was cooled to room temperature. The solids were filtered off. The resulting mixture was concentrated. The resulting solution was diluted with 200 mL of EtOAc. The resulting mixture was washed with 2 × 100 mL of HO and 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column using THF:PE (1:3 to 1:1). This gave 250 mg (28%) of (1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-amine as an off-white solid.

[0328] [ka] (Step 4) A 40 mL sealed tube purged with and maintained under an inert atmosphere of nitrogen was charged with (1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-amine (250.0 mg, 1.53 mmol, 1.00 equiv.), (2E)-3-methyl 3-(1H-indazol-6-yl)acrylate (Intermediate 3, 458.8 mg, 1.69 mmol, 1.10 equiv.), HATU (873.6 mg, 2.30 mmol, 1.50 equiv.), DMF (10 mL), and DIPEA (593.88 mg, 4.60 mmol, 3.00 equiv.). The resulting solution was stirred at room temperature for 4 hours. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3 x 60 mL of EtOAc. The organic layer was washed with 1×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated. The residue was loaded onto a silica gel column using THF:PE (1:3 to 1:1). This afforded 200 mg (31%) of (2E)-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid.

[0329] [ka] (Step 5) A 50 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with (2E)-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (200.0 mg, 0.48 mmol, 1.00 equiv.) and 4 M HCl in EtOAc (10.00 mL). The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated. The crude product was purified by preparative HPLC. This afforded 27 mg (17%) of (E)-3-(1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =334 [ka]

[0330] Example 38: (E)-3-(1H-indazol-6-yl)-N-(7-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide [ka] (Process 1) An 8 mL sealed tube was charged with methyl 3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (150.0 mg, 0.52 mmol, 1.00 equiv.), 7-methyl-2,3-dihydro-1H-inden-1-amine (154.3 mg, 1.05 mmol, 2.00 equiv.), and THF (3.00 mL). Subsequently, LiHMDS (2.1 mL, 2.09 mmol, 4.00 equiv.) was added at room temperature. The resulting solution was stirred at room temperature for 0.5 hours. The reaction was then quenched by the addition of 20 mL of saturated NH4Cl. The resulting solution was extracted with 2 × 15 mL of EtOAc. The organic phase was dried over Na2SO4 and concentrated. This gave 130 mg (crude) of N-(7-methyl-2,3-dihydro-1H-inden-1-yl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as an off-white solid.

[0331] [ka] (Process 2) A 20 mL round-bottom flask was charged with N-(7-methyl-2,3-dihydro-1H-inden-1-yl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (130.0 mg, crude), MeOH (4.00 mL), and 4 M HCl in dioxane (4.00 mL). The resulting solution was stirred at room temperature for 5 hours. The resulting mixture was concentrated. The crude product was purified by flash preparative HPLC. This afforded 21 mg of (E)-3-(1H-indazol-6-yl)-N-(7-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =318 [ka]

[0332] Example 39: (E)-3-(1H-indazol-6-yl)-N-(3-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide [ka] (Process 1) A 40 mL vial was charged with 3-methyl-2,3-dihydroinden-1-one (500.0 mg, 3.42 mmol, 1.00 equiv.), NHOH.HCl (237.7 mg, 3.42 mmol, 1.00 equiv.), and EtN (1.4 mL, 10.26 mmol, 3.00 equiv.) in MeOH (12.00 mL). The resulting solution was stirred at 70 °C in an oil bath for 10 h. The reaction mixture was cooled and concentrated. The residue was applied to a silica gel column with EtOAc / PE (1 / 1). This afforded 400 mg (72%) of N-[(1Z)-3-methyl-2,3-dihydroinden-1-ylidene]hydroxylamine as a white solid.

[0333] [ka] (Process 2) A 50 mL round-bottom flask was charged with N-[(1Z)-3-methyl-2,3-dihydroinden-1-ylidene]hydroxylamine (400.0 mg, 2.481 mmol, 1.00 equiv.) in 4 M HCl / MeOH (2.0 mL) and MeOH (10.0 mL). Pd / C (264 mg) was added. The resulting solution was stirred under H2 (30 Psi (207 kPa)) for 10 hours at 20 °C. The solution was collected by filtration. The resulting mixture was concentrated. This afforded 350 mg (77%) of 3-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride as a white solid.

[0334] [ka] (Step 3) An 8 mL round-bottom flask was charged with 3-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride (100.0 mg, 0.54 mmol, 1.00 equiv.), methyl 3-(1H-indazol-6-yl)acrylate (Intermediate 3, 148.3 mg, 0.54 mmol, 1.00 equiv.), HATU (310.5 mg, 0.82 mmol, 1.50 equiv.), and EtN (0.23 mL, 1.63 mmol, 3.00 equiv.) in DMF (2.0 mL). The resulting solution was stirred for 2 hours at 20 °C. The residue was applied to a silica gel column using THF / PE (1 / 1). This gave 110 mg (50%) of (2E)-N-(3-methyl-2,3-dihydro-1H-inden-1-yl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide as a white solid.

[0335] [ka] (Step 4) An 8 mL vial was charged with (2E)-N-(3-methyl-2,3-dihydro-1H-inden-1-yl)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (100.00 mg, 0.25 mmol, 1.00 equiv), 4 M HCl / MeOH (2.00 mL), and MeOH (2.00 mL). The resulting solution was stirred for 2 hours at 20°C. The mixture was purified by flash preparative HPLC using HCl. This afforded 20 mg (25%) of (E)-3-(1H-indazol-6-yl)-N-(3-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide as a solid. LC-MS (ES, m / z): [M+H] + =318 [ka]

[0336] Example 40: (E)-3-(1H-indazol-6-yl)-N-(2-((prop-2-yn-1-yloxy)methyl)phenyl)acrylamide [ka] (Process 1) A 25 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with (2E)-N-[2-(hydroxymethyl)phenyl]-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (Example 27, 200.0 mg, 0.53 mmol, 1.00 equiv.) and THF (5.00 mL). Subsequently, NaH (19.1 mg, 0.80 mmol, 1.50 equiv.) was added at 0° C. The resulting solution was stirred for 10 minutes at 0° C. To this was added propargyl bromide (63.0 mg, 0.53 mmol, 1.00 equiv.) at 0° C. The resulting solution was allowed to warm to room temperature and stirred for 2 hours. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 2×8 mL of EtOAc and dried over anhydrous sodium sulfate. The resulting mixture was concentrated, and the residue was purified by preparative HPLC to give 55 mg (25%) of (2E)-3-[1-(oxan-2-yl)indazol-6-yl]-N-[2-[(prop-2-yn-1-yloxy)methyl]phenyl]prop-2-enamide as a pale yellow solid.

[0337] [ka] (Process 2) A 20 mL vial was charged with (2E)-3-[1-(oxan-2-yl)indazol-6-yl]-N-[2-[(prop-2-yn-1-yloxy)methyl]phenyl]prop-2-enamide (55.00 mg, 0.13 mmol, 1.00 equiv.) and 4 M HCl / dioxane (5.00 mL). The resulting solution was stirred for 3 h at room temperature. The pH of the solution was adjusted to 8 with 2 M Na2CO3. The resulting solution was extracted with 2 × 10 mL of EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by preparative HPLC. This afforded 5.1 mg (12%) of (E)-3-(1H-indazol-6-yl)-N-(2-((prop-2-yn-1-yloxy)methyl)phenyl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =332 [ka]

[0338] Biological Examples Biological Example 1 - mPTP Activity Assay in Isolated Rat Liver Mitochondria, Human Platelet Mitochondria, and Isolated Rat Brain Mitochondria (Rat liver mitochondrial assay) Pharmacological inhibition or modulation of mPTP has been demonstrated using well-characterized "Ca"-dependent ATPases performed in isolated mitochondria. 2+ In vitro, isolated mitochondria can measure intramitochondrial Ca retention in a mitochondrial Ca2+ / Ca ... 2+ Exogenous Ca concentration is increased until it reaches the threshold for mPTP activation. 2+ When the pore is activated, mitochondrial integrity is compromised and stored Ca is released. 2+ Ca is released from inside and outside the mitochondrial compartment. 2+ The partitioning of Ca into membrane-impermeable Ca 2+ Depending on the assay configuration, inhibition or modulation of mPTP can delay pore opening or increase the Ca concentration required to induce mPTP opening. 2+ or increasing the concentration of

[0339] mPTP activity was measured in mitochondria freshly isolated from female Sprague Dawley (250-300 gram) rat livers using the following method. Cervical dislocation was performed on the rats. The livers were then perfused in situ with approximately 40 ml of cold Dulbecco's phosphate-buffered saline (DPBS) and then dissected and transferred to 30 ml of isolation buffer (250 mM sucrose, 10 mM KCl, 1 mM EGTA, 1 mM EDTA, 25 mM HEPES, pH adjusted to 7.5 with 1 M NaOH). Each liver lobe was then removed from the buffer and minced into approximately 5 mm pieces using forceps and a scalpel, then transferred to a 50 ml Potterton-Dounce homogenization tube on ice containing 30 ml of ice-cold centrifugation buffer (300 mM trehalose, 25 mM HEPES, 1 mM EGTA, 1 mM EDTA, 10 mM KCl, pH adjusted to 7.5 with 1 M NaOH, and supplemented with 0.1% bovine serum albumin (BSA) and complete protease inhibitor cocktail (one inhibitor tablet per 50 ml of buffer)). Homogenization was performed at 1800 rpm using a Teflon pestle. The slurry was centrifuged at 800 g for 10 min at 4°C, and the supernatant was then centrifuged at 10,000 g for 10 min. The pellet was washed once with FLIPR assay buffer (75 mM mannitol, 25 mM sucrose, 5 mM potassium phosphate monobasic, 20 mM Tris base, 100 mM KCl, 0.1% BSA, pH adjusted to 7.4 with 5 M HCl), centrifuged again, and then resuspended in FLIPR assay buffer to a concentration of 8.8 mg / ml protein.

[0340] Test compounds (10 mM stock in DMSO) were serially diluted in half-log increments into DMSO to generate 10 test concentrations (final concentrations in the assay, 30 μM to 1 nM). Intermediate dilutions of 5 μl of DMSO sample into 247 μl of FLIPR assay buffer were performed, followed by transfer of 5 μl to duplicate wells of a 384-well polypropylene assay plate. Control wells contained 0.5% (v / v) DMSO and 5 μM cyclosporine A.

[0341] A mitochondria / Fluo5N assay stock solution was prepared in 5.6 ml of FLIPR assay buffer (room temperature) supplemented with succinic acid disodium salt (10 mM), rotenone (1 μM), Fluo5N pentapotassium salt (2 μM), and 1 ml of mitochondrial suspension. 15 μl was then transferred into the assay plate containing the test compound and incubated for 10 minutes at room temperature. The assay plate was then transferred to a FLIPR Tetra plate reader (Molecular Devices). Dye fluorescence was then measured every 3 seconds for a total of 10 minutes. After 12 seconds, a 2.5 μl bolus of CaCl (75 μM) was added from the source plate containing 675 μM CaCl in FLIPR assay buffer. IC values ​​for test compounds were calculated using the fluorescence values ​​collected at 10 minutes. Percent inhibition was calculated using the DMSO control and cyclosporine A values ​​as 100 and 0%, respectively.

[0342] (Human platelet mitochondrial assay) The mPTP cell-based assay was performed in stimulated human platelets using a mitochondrial membrane potential flow cytometry assay. Platelets were simulated by Ca transport across the platelet membrane. 2+ This then leads to a rapid influx of Ca 2+ is sequestered by mitochondria until a threshold for mPTP opening is reached, at which point a pore opens and the mitochondrial membrane potential is lost. Changes in mitochondrial membrane potential due to mPTP opening can be quantified in living platelets using standard mitochondrial membrane potential dyes, such as 3,3'-dihexyloxacarbocyanine iodide (DiOC6(3)), allowing for the pharmacological characterization of mPTP inhibitors.

[0343] Fresh human blood (20 ml) was collected from consenting donors in 3.2% sodium citrate. Platelets were isolated by centrifugation at 200 g for 20 minutes at room temperature, and the platelet-rich plasma layer was then transferred to a new tube. Prostaglandin 12 was added to the platelets at a final concentration of 20 ng / ml. After centrifugation at 640 g for 10 minutes, the platelet-rich pellet was resuspended in 4 ml of HEPES assay buffer (137 mM NaCl, 2.7 mM KCl, 11.9 mM NaHCO 3 , 0.42 mM NaH 2 PO 4 , 1 mM MgCl 2 , 5.5 mM glucose, 0.1% bovine serum albumin, 10 mM HEPES, pH adjusted to 7.4) and stored on ice.

[0344] Test compounds were prepared from 10 mM stocks in DMSO and serially diluted in assay buffer containing 0.4% DMSO. 25 μl was transferred to a 96-well plate. Platelets were loaded with the mitochondrial membrane potential dye DiOC6(3) (3,3'-dihexyloxacarbocyanine iodide; Invitrogen) at 200 nM for 30 minutes. 50 μl was then plated into each well of the 96-well plate containing the diluted test compound and incubated for 15 minutes. Control wells contained DMSO (0.1% final concentration) only or 5 μM cyclosporin A. Platelets were then stimulated with the addition of 25 μl of assay buffer containing CaCl, α-thrombin, and convulxin at final concentrations of 2 mM, 0.017 U / ml, and 0.167 μg / ml, respectively, and incubated for 14 minutes. The reaction was stopped by adding 25 μl of 15 mM EDTA in assay buffer. The mitochondrial membrane potential of the entire platelet population in each well was then quantified by flow cytometry using a Guava easyCyte 5 benchtop flow cytometer with 3000 events per well. The percentage of platelets with depolarized mitochondrial membrane potential was calculated for each well. The pIC50 of each compound was then calculated using a standard four-parameter curve-fitting model (GraphPad Prism).

[0345] (Rat brain mitochondrial assay) mPTP activity was measured in freshly isolated brain mitochondria from female Sprague-Dawley (250-300 grams) rats. Anesthetized rats were perfused in situ with approximately 40 ml of cold Dulbecco's phosphate-buffered saline (DPBS), and then the brains were dissected and transferred to 30 ml of isolation buffer (225 mM mannitol, 75 mM sucrose, 1 mM EGTA, pH 7.4 adjusted with 1 M NaOH). Brains were minced into approximately 5 mm fragments using forceps and a scalpel and then transferred to a 50 ml Potterton-Dounce homogenization tube on ice containing 10 ml of ice-cold isolation buffer (supplemented with complete protease inhibitors as described above; 1 tablet per 50 ml of buffer). Homogenization was performed at 1800 rpm using a Teflon pestle. The slurry was centrifuged at 2000 g for 10 min at 4° C., and the supernatant was then centrifuged at 12,000 g for 9 min. The pellet was resuspended using a Dounce homogenizer in the same isolation buffer as above, but with the addition of 0.02% digitonin, centrifuged at 12,000 g for 11 min, and finally resuspended in 5 ml of modified isolation buffer (as above, but with EGTA reduced to 0.1 mM).

[0346] Test compounds were prepared in 384-well polypropylene assay plates as described above for the liver mitochondrial assay. A stock mitochondrial / Fluo5N assay solution was prepared in 5.6 ml of 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, pH adjusted to 7.4) supplemented with Fluo5N pentapotassium salt (2 μM) and 1 ml of mitochondrial suspension. 15 μl was then transferred to the assay plate containing the test compound and incubated for 10 minutes at room temperature. The assay plate was then transferred to a FLIPR Tetra plate reader (Molecular Devices). Dye fluorescence was then measured every 3 seconds for a total of 10 minutes. After 12 seconds, a 2.5 μl bolus of Ca (75 μM) was added from the source plate containing 675 μM CaCl in FLIPR assay buffer. IC values ​​for test compounds were calculated using fluorescence values ​​collected at 10 minutes. Percent inhibition was calculated using the DMSO control and cyclosporine A values ​​as 100% and 0%, respectively.

[0347] After 24-96 hours of incubation with test compounds, general cytotoxicity was assessed in HEK293 and SHSY5Y cells using a standard cell viability method (Cell Titre Glo; Promega).

[0348] (result) mPTP pIC for specific example compounds within the mPTP assay 50 The values ​​are shown in Table 2 below. Table 2 also shows the pIC for Comparative Example 1. 50 The results show that the compounds of the present invention tested exhibited inhibition of mPTP, with many example compounds exhibiting PIC values ​​of 6.0 or greater. 50Table 2 also shows the mPTP human platelet pIC values ​​for certain Example compounds and Comparative Example 1. Examples 28 and 14c showed the highest activity in the rat liver mitochondrial assay, and Example 14c also showed the highest activity in the rat brain mitochondrial assay. Table 2 also shows the mPTP human platelet pIC values ​​for certain Example compounds and Comparative Example 1. 50 Table 2 also shows the mPTP rat brain mitochondrial pIC values ​​for certain example compounds and Comparative Example 1. 50 These results demonstrate that the tested Example compounds are active on isolated rat liver mitochondria, isolated rat brain mitochondria, and human platelet mitochondria.

[0349] Biological Example 2 - PBS and FaSSIF Solubility Test compounds were prepared as 10 mM stocks in DMSO, and 15 μl samples were transferred in duplicate to 1.5 mL flat-bottom glass vials (BioTech Solutions). Fasting simulated intestinal fluid (FaSSIF) or PBS (pH 7.4) was added to each vial to a final volume of 500 μl. One PTFE-sealed stir bar (V&P Scientific) was placed in each vial, which was then sealed with a PTFE / SIL plug (BioTech Solutions). The vials were shaken at 1100 rpm for 2 hours at 25°C. The samples were then filtered through a MultiScreen Solvinert filter plate (Millipore) by vacuum filtration. An aliquot (5 μl) of the filtrate and 5 μl of DMSO were diluted in 50% acetonitrile in water (490 μl) containing an internal standard. The filtrates were analyzed and quantified against standards of known concentration using LC-MS / MS. Solubility values ​​for the test and control compounds were calculated as follows: [Sample] = (area ratio 試料 *INJ VOL STD*DF 試料 *[STD]) / (Area ratio STD*INJ VOL 試料 ).

[0350] (result) Solubility values ​​for certain compounds of the invention are shown in Table 2 below. Table 2 also shows the results for Comparative Example 1. The results demonstrate that certain Example compounds exhibit higher solubility in PBS and / or FaSSIF than Comparative Example 1. Certain compounds of the invention exhibit higher solubility values ​​in either PBS or FaSSIF, and certain compounds of the invention exhibit higher solubility values ​​in both PBS and FaSSIF. Therefore, certain compounds of the invention can be expected to exhibit improved bioavailability and / or improved systemic exposure than Comparative Example 1, particularly when the compound is administered orally. Table 2: Results of Biological Examples 1 and 2 [Table 3] TIFF0007784431000214.tif159170*Average value from multiple experiments (n≥2).

[0351] Biological Example 3 - Liver Microsomal and Hepatocyte Intrinsic Clearance Assays (Hepatocyte clearance assay) In vitro clearance studies were performed on primary rat and human hepatocytes (BioIVT). Vials of cryopreserved rat or human hepatocytes were thawed in a 37°C water bath for 2 minutes. Cells were transferred to thawing medium (Williams medium E containing 30% Percoll, 1x GlutaMAX-1, 15 mM HEPES, 5% fetal bovine serum (FBS), 4 μg / ml insulin, and 1 μM dexamethasone), centrifuged at 100g for 10 minutes, and then thawed at 0.5x10 6Hepatocytes were resuspended in culture medium (Leibovitz's L-15 medium) at a concentration of 10 ... Samples (25 μl) were collected at t = 0, 15, 30, 60, 60, and 120 min and mixed with 6 volumes (150 μl) of acetonitrile containing internal standards (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide), vortexed for 5 min, and centrifuged at 3220 g for 45 min. An aliquot (100 μl) of the supernatant was diluted with 100 μl of ultrapure 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 curve of the natural logarithm of the percentage of parent drug remaining versus incubation time. The in vitro half-life (in vitro t) was determined from the slope value: in vitro t = 0.693 / k. In vitro t (unit: min) and in vitro intrinsic clearance (in vitro CL int , unit: μL / min / 1×10 6 Conversion to saturation (cells) was performed using the following equation (average of duplicate measurements): In vitro CL int =kV / N V = incubation volume (0.2 mL) N = number of hepatocytes per well (0.1 x 10 6 cell).

[0352] (Microsomal clearance assay) Rat liver microsomes (BioIVT) were used with and without the cofactors nicotinamide adenine dinucleotide phosphate (NADPH) and uridine diphosphate glucuronic acid (UDPGA) to assess the microsomal stability of test compounds. Reactions were performed in a final volume of 250 μl of preheated (37°C) 100 mM phosphate buffer containing 5 mM MgCl, 0.025 mg / ml alamethicin, and 0.5 mg / ml rat liver microsomes. Where appropriate, NADPH and UDPGA were included at 1 mM and 2 mM, respectively. Reactions were initiated with the addition of 1 μM (final concentration) of test compound. Verapamil was used as a positive control. Solutions were incubated in a 37°C water bath, and aliquots were taken at 0.5, 5, 15, 30, and 60 minutes. The reaction was stopped by the addition of 5 volumes of cold acetonitrile containing internal standards (200 nM caffeine and 100 nM tolbutamide). Samples were centrifuged at 3220 g for 40 minutes. An aliquot of the supernatant was diluted 1:1 in ultrapure water and then used for LC-MS / MS analysis. Peak areas were determined from extracted ion chromatograms. The slope value k was determined by linear regression of the curve of the natural logarithm of the percentage of parent drug remaining versus incubation time. The in vitro half-life (in vitro t1 / 2) was determined from the slope value: in vitro t1 / 2 = 0.693 / k. The in vitro intrinsic clearance (in vitro CL) of in vitro t1 / 2 (min) was int Conversion to RT (units: μL / min / mg protein) was performed using the following equation (average of duplicate measurements): In vitro Clint = (0.693 / t1 / 2) * (volume of incubation (μl) / amount of protein (mg)).

[0353] (result) Intrinsic clearance values ​​for certain Example compounds are shown in Table 3. Table 3 also shows the intrinsic clearance value for Comparative Example 1. These results indicate that certain Example compounds can be expected to exhibit improved oral bioavailability and / or improved systemic exposure when compared to Comparative Example 1, i.e., they will exhibit lower intrinsic clearance (CL) in at least the human or rat species. int ) values. Certain Example compounds exhibited lower intrinsic clearance (CL ) values ​​than Comparative Example 1 in both human and rat species. int ) values ​​were shown. Table 3: Results of Biological Example 3 [Table 4] *Average value from two experiments.

[0354] (Conclusion) The results of Biological Examples 1-3 demonstrate that the tested compounds of the present invention are inhibitors of mPTP within the mPTP assay. Certain tested compounds of the present invention also exhibited improved solubility and / or reduced intrinsic clearance compared to Comparative Example 1. Accordingly, certain compounds of the present invention are expected to have improved pharmacokinetic profiles, such as improved oral bioavailability and / or improved systemic exposure, compared to Comparative Example 1, and are expected to be useful pharmaceuticals, particularly for the treatment or prevention of diseases and disorders in which inhibition of mPTP provides a therapeutic or prophylactic effect.

[0355] Unless the context requires otherwise, throughout this specification and the claims that follow, the word "comprise" and variations such as "comprises" and "comprising" shall be understood to imply the inclusion of a stated integer, step, group of integers, or group of steps, but not the exclusion of any other integer, step, group of integers, or group of steps.

[0356] This application of which this specification and claims form 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. These may take the form of product, composition, process, or use claims and may include, by way of example and not limitation, the following claims:

[0357] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference herein as if fully set forth.

[0358] (References) [Table 5] The present application provides the following aspects of the invention. (Aspect 1) Formula (I): (chemical 1) TIFF0007784431000217.tif24170 (In the formula: R 1a is H or methyl; R 1b is H or fluoro; A is a group (Aa), (Ab), (Ac), or (Ad): wherein the group (Aa) is: (chemical 2) TIFF0007784431000218.tif33170 and; (In the formula: R 2 is H, C 1-4 Alkyl, C 1-4 Alkylene (aryl), C1-4 Alkylene (OH), C 1-4 Alkylene (C 3-6 cycloalkyl), C 1-4 Alkylene (4-7 membered heterocycloalkyl), C 1-4 Alkoxy, OC 1-4 Alkylene (aryl), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 AlkyleneO(4-7 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), C 3-6 Alkynyl, and C 1-4 Alkylene O(C 3-6 alkynyl); wherein the aryl, heterocycloalkyl, or cycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 2a R 2b , SO 2 R 2c , and NHSO 2 R 2c optionally substituted by 1, 2, or 3 substituents each independently selected from R 2a is H and C 1-4 alkyl; R 2b is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 7-membered heterocycloalkyl; R 2c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 7-membered heterocycloalkyl; Each R 3 is independently halo, methyl, ethyl, or n-propyl; m is 0, 1, 2, 3, or 4); The group (Ab) is: (C3) TIFF0007784431000219.tif35170 and; (In the formula: R 4 is H, C 1-4 Alkyl or C 1-4 alkylene(aryl); wherein the aryl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 4a R 4b , SO 2 R 4c , and NHSO 2 R 4c optionally substituted by 1, 2, or 3 substituents each independently selected from R 4a is H and C 1-4 alkyl; R 4b is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 7-membered heterocycloalkyl; R 4c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 7-membered heterocycloalkyl; R 5 is H or C 1-4 is alkyl; Each R 6 are independent, C 1-4 alkyl or halo; n is 0, 1, 2, or 3); The group (Ac) is: (C4) TIFF0007784431000220.tif21170 and; (In the formula: R 7 is C 1-4 Alkyl, C 1-4 Alkylene (OH) or C 1-4 Alkylene OC 1-4 is alkyl; o is 1 or 2); The group (Ad) is: (C5) TIFF0007784431000221.tif27170 and; (In the formula: X is a bond, O, or CH 2 and; Each R 8 are independently, halo, C 1-4 Alkyl, C 1-4 Alkoxy, OC 1-4 Haloalkyl, OC 1-4 Alkylene (C 3-6 Cycloalkyl), OC 1-4 alkylene (4- to 7-membered heterocycloalkyl), or OH; wherein the heterocycloalkyl and cycloalkyl are C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 8a R 8b , SO 2 R 8c , and NHSO 2 R 8c optionally substituted by 1, 2, or 3 substituents independently selected from R 8a is H and C 1-4 alkyl; R 8b is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 7-membered heterocycloalkyl; R 8c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 7-membered heterocycloalkyl; Each R 9 are independently halo or C 1-4 is alkyl; p is 0, 1, or 2; q is 0, 1, 2, 3, or 4); B is: (6) TIFF0007784431000222.tif23170 and; (In the formula: R 10 is H, halo, or C 1-4 is alkyl; D, E, and F each independently represent C(R 10 ) or one of D, E, and F is N and the remaining two of D, E, and F groups are independently C(R 10 ) is); with the proviso that the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide; or a pharmaceutically acceptable salt and / or solvate thereof. (Aspect 2) Formula (I): (7) TIFF0007784431000223.tif23170 (In the formula: R 1a is H or methyl; R 1b is H or fluoro; A is a group (Aa), (Ab), (Ac), or (Ad): wherein the group (Aa) is: (C8) TIFF0007784431000224.tif31170 and; (In the formula: R 2 is H, C 1-4 Alkyl, C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene (C 3-6 cycloalkyl), C 1-4 Alkylene (4-7 membered heterocycloalkyl), C 1-4 Alkoxy, OC 1-4 Alkylene (aryl), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 AlkyleneO(4-7 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), C 3-6 Alkynyl, or C 1-4 Alkylene O(C 3-6 alkynyl); wherein the aryl, heterocycloalkyl, or cycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 optionally substituted with up to three substituents each independently selected from haloalkyl, halo, and CN; Each R 3 is independently halo, methyl, ethyl, or n-propyl; m is 0, 1, 2, 3, or 4); The group (Ab) is: (9) TIFF0007784431000225.tif35170 and; (In the formula: R 4 is H, C 1-4 Alkyl or C 1-4 alkylene(aryl); wherein the aryl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 optionally substituted with up to three substituents each independently selected from haloalkyl, halo, and CN; R 5 is H or C 1-4 is alkyl; Each R 6 are independent, C 1-4 alkyl or halo; n is 0, 1, 2, or 3); The group (Ac) is: (C10) TIFF0007784431000226.tif22170 and; (In the formula: R 7 is C 1-4 Alkyl, C 1-4 Alkylene (OH) or C 1-4 Alkylene OC 1-4 is alkyl; o is 1 or 2); The group (Ad) is: (Chem.11) TIFF0007784431000227.tif28170 and; (In the formula: X is a bond, O, or CH 2 and; Each R 8 are independently, halo, C 1-4 Alkyl, C 1-4 alkoxy, or OH; Each R 9 are independently halo or C1-4 is alkyl; p is 0, 1, or 2; q is 0, 1, 2, 3, or 4); B is: (C12) TIFF0007784431000228.tif21170 and; (In the formula: R 10 is H, halo, or C 1-4 is alkyl; and D, E, and F each independently represent C(R 10 ) or one of D, E, and F is N and the remaining two of D, E, and F groups are independently C(R 10 ) is); with the proviso that the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide; or a pharmaceutically acceptable salt and / or solvate thereof. (Aspect 3) A is a group (Aa): (C13) TIFF0007784431000229.tif31170 2. The compound of embodiment 1, wherein (Aspect 4) R 2 But C 1-4 Alkyl, C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 Alkylene O (aryl), C 1-4 Alkylene (4-7 membered heterocycloalkyl), C 1-4 Alkylene O(4-7 membered heterocycloalkyl), and C 1-4 Alkylene O(C 3-6 alkynyl); wherein the aryl, heterocycloalkyl, or cycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl; C 1-4 Alkoxy, C 1-4 The compound according to any one of embodiments 1 to 3, optionally substituted with up to three substituents each independently selected from haloalkyl, halo, and CN. (Aspect 5) The compound of embodiment 4, wherein said aryl is unsubstituted. (Aspect 6) The compound of embodiment 4, wherein said aryl is substituted with one, two, or three substituents independently selected from methyl, chloro, and fluoro. (Aspect 7) The compound of embodiment 4, wherein said heterocycloalkyl is unsubstituted. (Aspect 8) The heterocycloalkyl is CH 2 CH 2 The compound according to embodiment 4, wherein the compound is substituted with one, two, or three substituents independently selected from F and fluoro. (Aspect 9) Each R 3 The compound according to any one of embodiments 1 to 8, wherein is independently fluoro or methyl. (Aspect 10) The compound according to any one of embodiments 1 to 9, wherein m is 1 or 2. (Aspect 11) m is 1 and R 3 is at the 3-position. (Aspect 12) m is 1 and R 3 is at the 6-position. (Aspect 13) m is 2, and one R 3 is in third place and the other R 3 is at the 6-position. (Aspect 14) A is a group (Ab): (C14) TIFF0007784431000230.tif34170 2. The compound of embodiment 1, wherein (Aspect 15) R 4 15. The compound according to embodiment 14, wherein is H, methyl, or benzyl. (Aspect 16) R 5 16. The compound according to any one of aspects 14 to 15, wherein (Aspect 17) Each R 6 17. The compound according to any one of embodiments 14 to 16, wherein is independently fluoro or methyl. (Aspect 18) The compound according to any one of embodiments 14 to 17, wherein n is 0. (Aspect 19) A is a group (Ac): (C15) TIFF0007784431000231.tif22170 2. The compound of embodiment 1, wherein (Aspect 20) R 7 But methyl, CH 2 OH or CH 2 20. The compound of embodiment 19, wherein said compound is OMe. (Aspect 21) 21. The compound of embodiment 19 or 20, wherein o is 2. (Aspect 22) A is a group (Ad): (C16) TIFF0007784431000232.tif28170 2. The compound of embodiment 1, wherein (Aspect 23) 23. The compound according to embodiment 22, wherein X is a bond or O. (Aspect 24) Each R 8 24. The compound according to embodiment 22 or 23, wherein is independently methyl, OMe, or fluoro. (Aspect 25) The compound according to any one of embodiments 22 to 24, wherein p is 0 or 1. (Aspect 26) Each R 9 26. The compound of any one of embodiments 22-25, wherein is independently fluoro. (Aspect 27) The compound according to any one of aspects 22 to 26, wherein q is 1 or 2. (Aspect 28) D, E, and F are C(R 10 28. The compound according to any one of embodiments 1 to 27, wherein (Aspect 29) D is N and E and F are C(R 10 28. The compound according to any one of embodiments 1 to 27, wherein (Aspect 30) E is N and D and F are C(R 10 28. The compound according to any one of embodiments 1 to 27, wherein (Aspect 31) F is N and D and E are C(R 10 28. The compound according to any one of embodiments 1 to 27, wherein (Aspect 32) Each R 10 32. The compound according to any one of embodiments 1 to 31, wherein is independently H, fluoro, chloro, or methyl. (Aspect 33) below: (E)-N-(3-fluoro-2-methylphenyl)-3-(7-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide (racemic mixture); (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide (enantiomer 1); (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide (enantiomer 2); (E)-N-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-indazol-6-yl)acrylamide; (E)-3-(5-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(4-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (mixture of stereoisomers); (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 1); (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 2); (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 3); (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 4); (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (mixture of stereoisomers); (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (stereoisomer 1); (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (stereoisomer 2); (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (stereoisomer 3); (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (stereoisomer 4); (E)-N-(2-(benzyloxy)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(2-(phenoxymethyl)phenyl)acrylamide; (E)-N-(2-(cyclobutoxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(1-benzyl-1H-indazol-7-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(m-tolyl)acrylamide; (E)-N-(3-chlorophenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(3-fluorophenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-((1R,3R)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide (mixture of stereoisomers); (E)-N-((1R,3R)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide (stereoisomer 1); (E)-N-((1R,3S)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide (stereoisomer 2); (E)-N-(2-(hydroxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(2-(methoxymethyl)phenyl)acrylamide; (E)-N-(2-(((1-(2-fluoroethyl)azetidin-3-yl)oxy)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide hydrochloride; (E)-N-(2-((3-fluoroazetidin-1-yl)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2-(2-(3-fluoroazetidin-1-yl)ethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2-fluoro-6-methylphenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-pyrazolo[4,3-b]pyridin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[4,3-c]pyridin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(7-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(3-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; and (E)-3-(1H-indazol-6-yl)-N-(2-((prop-2-yn-1-yloxy)methyl)phenyl)acrylamide; or a pharmaceutically acceptable salt and / or solvate of any one of them. (Aspect 34) A compound according to any one of embodiments 1 to 33 for use as a medicament. (Aspect 35) A compound according to any one of aspects 1 to 33 for use in the treatment or prevention of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect. (Aspect 36) A compound according to any one of aspects 1 to 33 for use in the treatment of a disease or disorder in which inhibition of mPTP provides a therapeutic effect. (Aspect 37) A compound according to any one of aspects 1 to 33 for use in the prevention of a disease or disorder in which inhibition of mPTP confers a preventative effect. (Aspect 38) 38. The compound for use according to any one of aspects 35 to 37, wherein the disease or disorder is selected from a degenerative or neurodegenerative disease, a disorder of the central nervous system, ischemia and reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, an age-related disease, and a renal disease. (Aspect 39) 39. The compound for use according to aspect 38, wherein 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, frontotemporal dementia, chemotherapy-induced neuropathy, Huntington's disease, spinocerebellar ataxia, progressive supranuclear palsy, hereditary spastic paraplegia, Duchenne muscular dystrophy, congenital muscular dystrophy, traumatic brain injury, and Friedreich's ataxia. (Aspect 40) 39. The compound for use according to embodiment 38, wherein said disease or disorder is a disease of the central nervous system, such as AIDS dementia complex, depressive disorder, schizophrenia, and epilepsy. (Aspect 41) 39. The compound for use according to embodiment 38, wherein said disease or disorder is ischemia or reperfusion injury, such as acute myocardial infarction, stroke, renal ischemia-reperfusion injury, and organ damage during transplantation. (Aspect 42) 39. The compound for use according to aspect 38, wherein the disease or disorder is a metabolic disease such as fatty liver, diabetes, diabetic retinopathy, cognitive decline and other diabetes-related conditions, obesity and eating behavior, and non-alcoholic fatty liver disease. (Aspect 43) 39. The compound for use according to embodiment 38, wherein the disease or disorder is an inflammatory or autoimmune disease, such as acute pancreatitis, systemic lupus, organ failure in sepsis, and hepatitis. (Aspect 44) 39. The compound for use according to embodiment 38, wherein said disease or disorder is an age-related disease such as bone repair, bone frailty in aging in osteoporosis, and sarcopenia. (Aspect 45) 39. The compound for use according to embodiment 38, wherein said disease or disorder is a kidney disease, such as chronic kidney disease and chronic kidney disease associated with APOL1 gene variants. (Aspect 46) A compound according to any one of aspects 1 to 33 for use in the treatment or prevention of a mitochondrial disease. (Aspect 47) A compound according to any one of embodiments 1 to 33 for use in the treatment of a mitochondrial disease. (Aspect 48) A compound according to any one of embodiments 1 to 33 for use in the prevention of a mitochondrial disease. (Aspect 49) 34. A compound according to any one of aspects 1 to 33 for use in the treatment or prevention of a disease or disorder associated with a TPD-43 proteinopathy, such as TDP-43 associated neurodegeneration. (Aspect 50) 50. The compound for use according to aspect 49, wherein the disease or disorder is selected from amyotrophic lateral sclerosis, frontotemporal dementia, facial-onset sensorimotor neuropathy, primary lateral sclerosis, progressive muscular atrophy, early-onset Paget's disease of bone and inclusion body myopathy associated with frontotemporal lobar dementia, Perry's disease, chronic traumatic brain injury, 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. (Aspect 51) A compound according to any one of aspects 1 to 33 for use in the treatment or prevention of a disease or disorder associated with fibrosis. (Aspect 52) 52. The compound of embodiment 51, wherein the disease or disorder is selected from chronic kidney disease, idiopathic pulmonary fibrosis, nonalcoholic steatohepatitis, primary biliary cholangitis, and systemic sclerosis. (Aspect 53) A pharmaceutical composition comprising a compound according to any one of Aspects 1 to 33, or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier or excipient. (Aspect 54) A compound according to any one of Aspects 1 to 52, or a solvate thereof. (Aspect 55) A compound according to any one of Aspects 1 to 52, or a pharmaceutically acceptable salt thereof. (Aspect 56) 53. The compound according to any one of embodiments 1 to 52.

Claims

1. Formula (I): 【Chemistry 1】 (In the formula: R 1a is H or methyl; R 1b is H or fluoro; A is a group (Aa), (Ab), (Ac), or (Ad): wherein the group (Aa) is: 【Chemistry 2】 and; (In the formula: R 2 is H, C 1-4 Alkyl, C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene (C 3-6 cycloalkyl), C 1-4 Alkylene (4-7 membered heterocycloalkyl), C 1-4 Alkoxy, OC 1-4 Alkylene (aryl), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 AlkyleneO(4-7 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), C 3-6 Alkynyl, and C 1-4 Alkylene O(C 3-6 alkynyl); wherein the aryl, heterocycloalkyl, or cycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 2a R 2b , SO 2 R 2c , and NHSO 2 R 2c optionally substituted by 1, 2, or 3 substituents each independently selected from R 2a is H and C 1-4 alkyl; R 2b is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 7-membered heterocycloalkyl; R 2c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 7-membered heterocycloalkyl; Each R 3 is independently halo, methyl, ethyl, or n-propyl; m is 0, 1, 2, 3, or 4); The group (Ab) is: 【Transformation 3】 and; (In the formula: R 4 is H, C 1-4 Alkyl or C 1-4 alkylene(aryl); wherein the aryl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 4a R 4b , SO 2 R 4c , and NHSO 2 R 4c optionally substituted by 1, 2, or 3 substituents each independently selected from R 4a is H and C 1-4 alkyl; R 4b is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 7-membered heterocycloalkyl; R 4c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 7-membered heterocycloalkyl; R 5 is H or C 1-4 is alkyl; Each R 6 are independent, C 1-4 alkyl or halo; n is 0, 1, 2, or 3); The group (Ac) is: 【Chemistry 4】 and; (In the formula: R 7 is C 1-4 Alkyl, C 1-4 Alkylene (OH) or C 1-4 Alkylene OC 1-4 is alkyl; o is 1 or 2); The group (Ad) is: 【Transformation 5】 and; (In the formula: X is a bond, O, or CH 2 and; Each R 8 are independently, halo, C 1-4 Alkyl, C 1-4 Alkoxy, OC 1-4 Haloalkyl, OC 1-4 Alkylene (C 3-6 Cycloalkyl), OC 1-4 alkylene (4- to 7-membered heterocycloalkyl), or OH; wherein the heterocycloalkyl and cycloalkyl are C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 8a R 8b , SO 2 R 8c , and NHSO 2 R 8c optionally substituted by 1, 2, or 3 substituents independently selected from R 8a is H and C 1-4 alkyl; R 8b is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 7-membered heterocycloalkyl; R 8c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 7-membered heterocycloalkyl; Each R 9 are independently halo or C 1-4 is alkyl; p is 0, 1, or 2; q is 0, 1, 2, 3, or 4); B is: 【Transformation 6】 and; (In the formula: R 10 is H, halo, or C 1-4 is alkyl; D, E, and F each independently represent C(R 10 ) or one of D, E, and F is N and the remaining two of D, E, and F groups are independently C(R 10 ) is); with the proviso that the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide; or a pharmaceutically acceptable salt and / or solvate thereof.

2. Formula (I): 【Transformation 7】 (In the formula: R 1a is H or methyl; R 1b is H or fluoro; A is a group (Aa), (Ab), (Ac), or (Ad): wherein the group (Aa) is: 【Transformation 8】 and; (In the formula: R 2 is H, C 1-4 Alkyl, C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene (C 3-6 cycloalkyl), C 1-4 Alkylene (4-7 membered heterocycloalkyl), C 1-4 Alkoxy, OC 1-4 Alkylene (aryl), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 AlkyleneO(4-7 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), C 3-6 Alkynyl, or C 1-4 Alkylene O(C 3-6 alkynyl); wherein the aryl, heterocycloalkyl, or cycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 optionally substituted with up to three substituents each independently selected from haloalkyl, halo, and CN; Each R 3 is independently halo, methyl, ethyl, or n-propyl; m is 0, 1, 2, 3, or 4); The group (Ab) is: 【Chemistry 9】 and; (In the formula: R 4 is H, C 1-4 Alkyl or C 1-4 alkylene(aryl); wherein the aryl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 optionally substituted with up to three substituents each independently selected from haloalkyl, halo, and CN; R 5 is H or C 1-4 is alkyl; Each R 6 are independent, C 1-4 alkyl or halo; n is 0, 1, 2, or 3); The group (Ac) is: 【Chemistry 10】 and; (In the formula: R 7 is C 1-4 Alkyl, C 1-4 Alkylene (OH) or C 1-4 Alkylene OC 1-4 is alkyl; o is 1 or 2); The group (Ad) is: 【Chemistry 11】 and; (In the formula: X is a bond, O, or CH 2 and; Each R 8 are independently, halo, C 1-4 Alkyl, C 1-4 alkoxy, or OH; Each R 9 are independently halo or C 1-4 is alkyl; p is 0, 1, or 2; q is 0, 1, 2, 3, or 4); B is: 【Chemistry 12】 and; (In the formula: R 10 is H, halo, or C 1-4 is alkyl; and D, E, and F each independently represent C(R 10 ) or one of D, E, and F is N and the remaining two of D, E, and F groups are independently C(R 10 ) is); with the proviso that the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide; 2. The compound according to claim 1, or a pharmaceutically acceptable salt and / or solvate thereof,

3. A is a group (Aa): 【Chemistry 13】 (In the formula, R 2 But C 1-4 Alkyl, C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 Alkylene O (aryl), C 1-4 Alkylene (4-7 membered heterocycloalkyl), C 1-4 alkyleneO(4- to 7-membered heterocycloalkyl), and C 1-4 Alkylene O(C 3-6 alkynyl); wherein the aryl, heterocycloalkyl, or cycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl; C 1-4 Alkoxy, C 1-4 and optionally substituted with up to three substituents each independently selected from haloalkyl, halo, and CN.

2. The compound according to claim 1, or a pharmaceutically acceptable salt and / or solvate thereof, wherein:

4. Each R 3 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt and / or solvate thereof, wherein is independently fluoro or methyl.

5. The compound according to any one of claims 1 to 4, wherein m is 1 or 2, or a pharmaceutically acceptable salt and / or solvate thereof.

6. A is a group (Ab): 【Chemistry 14】 2. The compound according to claim 1, wherein:

7. R 4 is H, methyl, or benzyl, and R 5 The compound of claim 6, or a pharmaceutically acceptable salt and / or solvate thereof, wherein is H.

8. Each R 6 is independently fluoro or methyl, and 8. The compound according to claim 6 or 7, wherein n is 0, or a pharmaceutically acceptable salt and / or solvate thereof.

9. A is a group (Ac): 【Chemistry 15】 2. The compound according to claim 1, or a pharmaceutically acceptable salt and / or solvate thereof, wherein:

10. R 7 But methyl, CH 2 OH or CH 2 OMe, and 10. The compound of claim 9, or a pharmaceutically acceptable salt and / or solvate thereof, wherein o is 2.

11. A is a group (Ad): 【Chemistry 16】 2. The compound according to claim 1, or a pharmaceutically acceptable salt and / or solvate thereof, wherein:

12. X is a bond or O; p is 1, and R 8 12. The compound of claim 11, or a pharmaceutically acceptable salt and / or solvate thereof, wherein is independently methyl, OMe, or fluoro.

13. Each R 9 are independently fluoro, and 13. The compound according to claim 11 or 12, or a pharmaceutically acceptable salt and / or solvate thereof, wherein q is 1 or 2.

14. D, E, and F are C(R 10 14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt and / or solvate thereof, wherein

15. Each R 10 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt and / or solvate thereof, wherein is independently H, fluoro, chloro, or methyl.

16. Compounds of formula (Ia): 【Chemistry 17】 (In the formula, A is a group (Aa'), (AdI'), or (AdII'), R 10a is H, fluoro, chloro, or methyl; wherein the group (Aa') is [Chemistry 18] and (In the formula, R 2d is methyl, CH 2 OMe or CH 2 OCH 2 C≡CH, Each R 3a are independently H, methyl, or fluoro. The group (AdI') is: 【Chemistry 19】 and; (In the formula: R 8d is H, methyl, or OMe; R 9a is H or F); The group (AdII') is: 【Chemistry 20】 and (In the formula: X is O; and R 8a’ is methyl); provided that A is a group (AdI′) and R 10a When one of R is fluoro or chloro, the other two R 10a groups are independently H); or a pharmaceutically acceptable salt and / or solvate thereof, 2. The compound of claim 1, or a pharmaceutically acceptable salt and / or solvate thereof.

17. below: (E)-N-(3-fluoro-2-methylphenyl)-3-(7-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((1R * ,2R * )-2-methylcyclohexyl)acrylamide (racemic mixture); (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((1S,2S)-2-methylcyclohexyl)acrylamide; (E)-N-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-indazol-6-yl)acrylamide; (E)-3-(5-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(4-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((1S,2S)-2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((1R,2S)-2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((1S,2R)-2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((3S,4S)-3-methylchroman-4-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((3R,4R)-3-methylchroman-4-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((3R,4S)-3-methylchroman-4-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((3S,4R)-3-methylchroman-4-yl)acrylamide; (E)-N-(2-(benzyloxy)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(2-(phenoxymethyl)phenyl)acrylamide; (E)-N-(2-(cyclobutoxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(1-benzyl-1H-indazol-7-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(m-tolyl)acrylamide; (E)-N-(3-chlorophenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(3-fluorophenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-((1R,3R)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-((1R,3S)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2-(hydroxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(2-(methoxymethyl)phenyl)acrylamide; (E)-N-(2-(((1-(2-fluoroethyl)azetidin-3-yl)oxy)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2-((3-fluoroazetidin-1-yl)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2-(2-(3-fluoroazetidin-1-yl)ethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2-fluoro-6-methylphenyl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-pyrazolo[4,3-b]pyridin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[4,3-c]pyridin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(7-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(1H-indazol-6-yl)-N-(3-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; and (E)-3-(1H-indazol-6-yl)-N-(2-((prop-2-yn-1-yloxy)methyl)phenyl)acrylamide; or a pharmaceutically acceptable salt and / or solvate of any one of these 2. The compound of claim 1, selected from the group consisting of:

18. 18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt and / or solvate thereof, for use as a medicine.

19. 19. A pharmaceutical composition according to claim 18 for use in the treatment or prevention of a disease or disorder, comprising: the disease or disorder is selected from a degenerative or neurodegenerative disease, a disorder of the central nervous system, ischemia and reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, an age-related disease, and a renal disease; wherein the degenerative disease or neurodegenerative disease is selected from Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal dementia, chemotherapy-induced neuropathy, Huntington's disease, spinocerebellar ataxia, progressive supranuclear palsy, hereditary spastic paraplegia, Duchenne muscular dystrophy, congenital muscular dystrophy, traumatic brain injury, and Friedreich's ataxia.

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