New regulations for compounds

Abstract

The present invention relates to a compound of formula (I): [Formula 1] TIFF2023539694000311.tif20170 and related embodiments.

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] CYP2D6 is one of the major members of the human drug-metabolizing cytochrome P450 enzyme system. It is responsible for the hepatic metabolism of a significant proportion of clinically used drugs. Inhibition of CYP2D6 can promote drug-drug interactions with co-prescribed drugs metabolized by the same enzyme, potentially resulting in increased plasma concentrations to levels that can cause adverse effects. CYP2D6 is primarily expressed in the liver and, to a lesser extent, in the central nervous system (CNS). In the CNS, it is involved in the synthesis of various neurotransmitters, including dopamine. Consequently, inhibition of CYP2D6, particularly at the CNS level, can potentially have adverse effects through impaired pathways such as dopamine production. In Parkinson's disease, characterized by loss of dopaminergic neurons in the substantia nigra, further depletion of dopamine levels through CYP2D6 inhibition may not be tolerated.

[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] 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. CA2884607A1 relates to acrylamide and maleimide compounds said to be useful in the treatment of mitochondrial diseases.

[0014] There remains a need to discover additional compounds that are inhibitors of mPTP, particularly those that combine mPTP inhibition with low CYP2D6 inhibition. Such compounds may also exhibit other desirable pharmacological properties, such as improved oral bioavailability and / or improved systemic exposure. Summary of the Invention

[0015] (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 1bis H or F; 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 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 Alkenyl 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 1-4selected 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 C1-4 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 3-6Cycloalkyl, 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 a group (Ba), (Bb), or (Bc): where the group (Ba) is: [ka] and; (In the formula: Y is C(R 11 )(R 12 ), N(R 13 ), O, or S; Each R 10 are independently halo or C 1-4 is alkyl; r is 0, 1, 2, or 3; R 11 is H or C 1-4 is alkyl; R 12 is H or C 1-4 alkyl; or R 11 and R 12 together with the carbon atoms to which they are attached, form C 3-6 Forming a cycloalkyl; R 13 is H, C 1-4 Alkyl or C 3-6 is cycloalkyl; wherein the cycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C1-4 Haloalkyl, Halo, CN, OH, NR 13a R 13b , SO2R 13c , and NHSO2R 13c optionally substituted by 1, 2, or 3 substituents independently selected from R 13a is H and C 1-4 alkyl; R 13b 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 13c 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; The group (Bb) is: [ka] and; (In the formula: Each R 14 are independently halo or C 1-4 is alkyl; s is 0, 1, 2, or 3); The group (Bc) is: [ka] and; (In the formula: R 15 is C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 1-4 haloalkyl, halo, or CN; wherein the cycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4Haloalkyl, Halo, CN, OH, NR 15a R 15b , SO2R 15c , and NHSO2R 15c optionally substituted by 1, 2, or 3 substituents independently selected from R 15a is H and C 1-4 alkyl; R 15b 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 15c 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 16 is H, halo, or C 1-4 is alkyl; and D, E, and F each independently represent C(R 16 ) or one of D, E, and F is N and the remaining two of D, E, and F groups are independently C(R 16 )is)); or a pharmaceutically acceptable salt and / or solvate thereof.

[0016] Preferably, the compound of formula (I): [ka] (In the formula: R 1a is H or methyl; R 1b is H or F; 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), for example, C 1- Alkylene (4-7 membered heterocycloalkyl), etc., 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, and cycloalkyl are 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 1-4Alkoxy, 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 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, 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 a group (Ba), (Bb), or (Bc): where the group (Ba) is: [ka] and; (In the formula: Y is C(R 11 )(R 12 ), N(R 13 ), O, or S; Each R 10are independently halo or C 1-4 is alkyl; r is 0, 1, 2, or 3; R 11 is H or C 1-4 is alkyl; R 12 is H or C 1-4 alkyl; or R 11 and R 12 together with the carbon atoms to which they are attached, form C 3-6 Forming a cycloalkyl; R 13 is H, C 1-4 Alkyl or C 3-6 is cycloalkyl); The group (Bb) is: [ka] and; (In the formula: Each R 14 are independently halo or C 1-4 is alkyl; s is 0, 1, 2, or 3); The group (Bc) is: [ka] and; (In the formula: R 15 is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 haloalkyl, or CN; R 16 is H, halo, or C 1-4 is alkyl; and D, E, and F each independently represent C(R 16 ) or one of D, E, and F is N and the remaining two of D, E, and F groups are independently C(R 16 )is)); or a pharmaceutically acceptable salt and / or solvate thereof.

[0017] 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.

[0018] 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.

[0019] 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.

[0020] 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.

[0021] 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.

[0022] 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, a disease of aging, and a renal disease.

[0023] 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.

[0024] 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.

[0025] 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.

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

[0028] 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.

[0029] 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

[0030] (Detailed Description of the Invention) C 1-4 The 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.

[0031] 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 1-4Alkoxy, 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 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-).

[0032] 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.

[0033] 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.

[0034] 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.

[0035] C 1-4The term "haloalkyl" as used herein, such as in haloalkyl, whether alone or as O-C 1-4 A 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).

[0036] 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.

[0037] 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 carbon 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] C 1-4 An example of an 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.

[0043] 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 an available carbon atom that is bonded to a hydrogen atom, i.e., a CH group, or the optional substituent may be attached to an available nitrogen atom that is bonded to a hydrogen atom, i.e., an NH group, and 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.

[0044] In one embodiment, A is a group (Aa): [ka] is.

[0045] 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 CH2Ome; CH2O-C3 cycloalkyl or CH2O-C4 cycloalkyl, for example C2O-cyclopropyl or CH2O-cyclobutyl; 1-4 Alkylene OC 3-6 Cycloalkyl; C such as CH2OPh 1-4 alkylene O(aryl); CH2(4-membered heterocycloalkyl), e.g., CH2-azetidinyl, or CH2CH2(4-membered heterocycloalkyl), e.g., CH2CH2-azetidinyl, etc. 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.

[0046] Aryl, heterocycloalkyl, and cycloalkyl groups present in R2 are C 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 2a R 2b ;SO2R 2c ; and NHSO2R 2cSuitably, 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.

[0047] 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.

[0048] In one embodiment, R 2b is H. In a second embodiment, R 2b is 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 1-4In 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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 1-4 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)NHBz1-4 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.

[0055] 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.

[0056] 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.

[0057] Preferably, R2 is H, C 1-4 Alkyl or C 1-4 Alkylene OC 1-4 Except when R2 is alkyl, m is 0. More preferably, m is 0 except when R2 is H, methyl, or CHOMe.

[0058] When present, in one embodiment, each R3 is independently fluoro or methyl, in particular fluoro.

[0059] In one embodiment, m is 1 or 2.

[0060] 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 and one R3 is in the 3 position and the other R3 is in the 6 position. In one embodiment, m is 3 and one R3 is in the 3 position, one R3 is in the 4 position and one R3 is in the 6 position. In one embodiment, m is 3 and one R3 is in the 3 position, one R3 is in the 5 position and one R3 is in the 6 position.

[0061] Preferably, when R2 is methyl, m is 1, and R3 is chloro, R3 is not at the 5-position. Preferably, when R2 is methyl, m is 1, and R3 is chloro, R3 is at the 3-, 4-, or 6-position. Preferably, when R2 is H, m is 1, and R3 is C 1-4 When alkyl, R3 is not at position 3 or 5. Preferably, R2 is H, m is 1, and R3 is C 1-4 When alkyl, R3 is in the 4- or 6-position. Preferably, when m is 2, the two R3 groups are not in the 3- and 5-positions. Preferably, when m is 2, the two R3 groups are in the 4- and 6-positions.

[0062] References to substituent positions are with respect to the bond to the amide moiety, for example: [ka] is.

[0063] Examples of suitable substituents include 3-fluoro-2-methyl; 3-fluoro-2-CHOCH; 3-chloro-2-methyl-; 4,5-difluoro-2-methyl; 5-chloro-2-isopropyl; 5-fluoro-2-methyl; 2-isopropyl-6-methyl; 2,6-dimethyl; 2-methyl; 2-isopropyl; 4-fluoro-3-methyl; 3-fluoro-4-methyl; 3,4-difluoro-2,6-dimethyl; 3,5-difluoro-2,6-dimethyl; and 3-fluoro-2,6-dimethyl.In one embodiment, each R is the same.In one embodiment, each R is different.

[0064] In one embodiment, A is a group (Ab): [ka] is.

[0065] 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. 1-4 In a preferred embodiment, R4 is H, methyl, or benzyl, in particular methyl or benzyl. Suitably, the aryl present in R4 is C aryl, 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 4cPreferably, the aryl present in R4 is substituted by one, two, or three substituents, such as one or two, for example one substituent, each independently selected from 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. Preferably, the aryl present in R4 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 present in R4 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 present in R4 is substituted by one, two, or three, such as one or two, for example one, substituent ..., substituent, each 4a R 4b ;SO2R 4c ; and NHSO2R 4c The aryl is substituted by one, two, or three substituents, such as one or two, for example, one substituent, each independently selected from the following: aryl, chloro, and fluoro. Preferably, the aryl is substituted by one, two, or three, such as one or two, for example, one, substituent, each independently selected from methyl, chloro, and fluoro. In one embodiment, the aryl is substituted by one, two, or three, such as one or two, for example, one methyl group. In one embodiment, the aryl is substituted by one, two, or three, such as one or two, for example, one chloro group. In one embodiment, the aryl is substituted by one, two, or three, such as one or two, for example, one fluoro group. Preferably, the aryl is unsubstituted.

[0066] 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.

[0067] In one embodiment, R 4b is H. In a second embodiment, R4b 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.

[0068] 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 CF3 1-4 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 methyl.

[0069] In one embodiment, R 5 is H.

[0070] When present, in one embodiment, each R6 is independently fluoro or methyl. Suitably, n may be 1, 2 or 3, such as 1 or 2, for example 1.

[0071] In one embodiment, n is 0.

[0072] In one embodiment, the group A is the group (Ac): [ka] is.

[0073] In one embodiment, R7 is methyl, CH2OH, or CH2OMe.

[0074] In one embodiment, o is 2. Suitably, when o is 2, B is not a group (Ba).

[0075] 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:

[0076] In one embodiment, A is a group (Ad): [ka] is.

[0077] In one embodiment, X is a bond or O. Suitably, X is a bond. Alternatively, X is O. In a second embodiment, X is CH2.

[0078] In one embodiment, R8 is halo. In a second embodiment, R8 is C 1-4 In a third embodiment, R8 is C 1-4In a fourth embodiment, R8 is OH.

[0079] 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.

[0080] 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 present in R8 are 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 CF3 1-4 Preferably, the cycloalkyl and heterocycloalkyl present in R8 are each independently selected from OH; NR8; NR8; and NR8. 8a R 8b ;SO2R 8c ; and NHSO2R8c Substituted by 1, 2, or 3 substituents each independently selected from, for example, 1 or 2, such as 1 substituent.

[0081] 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.

[0082] 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.

[0083] 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 8cC 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.

[0084] Suitably, cycloalkyl (e.g., cyclopropyl) present in R8 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 201 alkyl, C 211 alkyl, C 221 alkyl, C 231 alkyl, C 241 alkyl, C 251 alkyl, C 261 alkyl, C 271 alkyl, C 281 alkyl, C 311 alkyl, C 291 alkyl, C 321 alkyl, C 331 alkyl, C 341 alkyl, C 351 alkyl, C 4 1-4 In one embodiment, the cycloalkyl is substituted with 1, 2, or 3 substituents, such as 1 or 2, for example, 1 substituent, each independently selected from alkyl. In one embodiment, the cycloalkyl is unsubstituted.

[0085] 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.

[0086] 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.

[0087] Preferably, R8 is OC such as OCH2-oxetanyl. 1-4When alkylene(4-7 membered heterocycloalkyl), the oxetanyl may be 3-oxetanyl, for example: [ka] is.

[0088] 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.

[0089] 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.

[0090] In one embodiment, p is 0 or 1.

[0091] Preferably, when X is O, p is 1 or 2. Preferably, when X is a bond and the group B is (Ba), Y is C(R 11 )(R 12 ) and R 11 and R 12 are both H and p is 1 or 2. Preferably, when X is CH2, B is not (Ba).

[0092] 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:

[0093] When present, in one embodiment, each R9 is independently fluoro.

[0094] 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.

[0095] 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.

[0096] Suitable examples of R9 substituents when X is a bond are 4-fluoro and 5-fluoro.

[0097] In one embodiment, q is 1 or 2.

[0098] In one embodiment, the group B is (Ba): [ka] is.

[0099] Y is C(R 11 )(R 12 ), in one embodiment, R 11 is H. In a second embodiment, R 11 is C such as methyl 1-4 It is alkyl.

[0100] Y is C(R 11 )(R 12 ), in one embodiment, R 12 is H. In a second embodiment, R 12 is C such as methyl 1-4 It is alkyl.

[0101] In a preferred embodiment, Y is C(R 11 )(R 12 ), then R 11 is H or methyl, and R 12 is H. In a second preferred embodiment, R 11 and R 12 are both H. In a third embodiment, R 11 and R 12 together with the carbon atoms to which they are attached form a cyclopropyl ring. Preferably, the cyclopropyl ring contains one, two, or three C 1-4 Alkyl substituents, such as one or two, for example, one C 1-4 It is substituted with an alkyl substituent (such as methyl). In one embodiment, the cyclopropyl ring is unsubstituted.

[0102] Preferably, Y is C(R 11 )(R 12 ), then R 11 is methyl and R 12 is H and A is not a group (Aa).

[0103] In one embodiment, Y is N(R 13 ). Preferably, R 13 C such as methyl, ethyl, propyl, or butyl 1-4 In a second embodiment, R 13 is C such as cyclopropyl 3-6 Preferably, R 13 C present in 3-6 Cycloalkyl, e.g., cyclopropyl rings, are C 1-4 Alkyl, C3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 13a R 13b , SO2R 13c , and NHSO2R 13c and R is substituted by one, two, or three, such as one or two, for example one, substituent independently selected from 13 C present in 3-6 Cycloalkyl, e.g., cyclopropyl rings, are C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Substituted by 1, 2, or 3, such as 1 or 2, for example, 1 substituent independently selected from haloalkyl, halo, and CN. 13 C present in 3-6 Cycloalkyl, e.g., cyclopropyl rings, can be OH, NR 13a R 13b , SO2R 13c , and NHSO2R 13c and is substituted by one, two, or three, such as one or two, for example one, substituent independently selected from 3-6 A cycloalkyl, e.g., cyclopropyl, ring may contain one, two, or three C 1-4 Alkyl substituents, such as one or two, for example, one C 1-4 Substituted by alkyl substituents (such as methyl). In one embodiment, C 3-6 Cycloalkyl groups, such as cyclopropyl rings, are unsubstituted.

[0104] In one embodiment, R 13a is H. In a second embodiment, R 13a is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 13a is H or methyl.

[0105] In one embodiment, R 13b is H. In a second embodiment, R 13b is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 13b C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a fourth embodiment, R 13b C such as OMe or OEt 1-4 In a fifth embodiment, R 13b is C such as CF3 1-4 In a sixth embodiment, R 13b is aryl, such as phenyl. In a seventh embodiment, R 13b is a 4- to 7-membered heterocycloalkyl such as azetidinyl or oxetanyl. In an eighth embodiment, R 13b is H or methyl.

[0106] In one embodiment, R 13c is C such as methyl, ethyl, or propyl 1-4 In a second embodiment, R 13c C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a third embodiment, R 13c C such as OMe or OEt 1-4 In a fourth embodiment, R 13c is C such as CF3 1-4 In a fifth embodiment, R 13c is aryl, such as phenyl. In a sixth embodiment, R 13c is a 4- to 7-membered heterocycloalkyl such as azetidinyl or oxetanyl. In a seventh embodiment, R 13c is H or methyl.

[0107] In one embodiment, Y is O or S.

[0108] When present, in one embodiment, each R 10 is independently fluoro, chloro, or methyl.

[0109] In one embodiment, r is 0 or 1, in particular 0.

[0110] When r is 1, 2, or 3, R 10 may be at position 7, 5, and / or 4. In one embodiment, r is 1 and R 10 is at position 7. In a second embodiment, r is 1 and R 10 is at position 5. In one embodiment, r is 1 and R 10 is in fourth place. For example: [ka] is.

[0111] Suitable R 10 Examples of substituents include 4-fluoro and 7-fluoro.

[0112] In one embodiment, the group B is (Bb): [ka] is.

[0113] When present, in one embodiment, each R 14 is independently fluoro or methyl.

[0114] In one embodiment, s is 0 or 1, in particular 0.

[0115] Preferably, when s is 1, 2, or 3, R 14 may be at positions 7, 5, and / or 4. In one embodiment, s is 1 and R 14 is at position 5. In a second embodiment, s is 2 and one R14 is in 7th place and has one R 14 is in 4th place. For example: [ka] is.

[0116] Preferably, R 14 is not at position 7. Preferably, R 14 is not in fourth place.

[0117] Suitable R 14 An example of a substituent is 5-fluoro.

[0118] In one embodiment, the group B is (Bc): [ka] is.

[0119] R 15 is C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 1-4 haloalkyl, halo, or CN; wherein the cycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 15a R 15b , SO2R 15c , and NHSO2R 15c and optionally substituted with 1, 2, or 3 substituents independently selected from:

[0120] In one embodiment, R 15 is methyl, ethyl, cyclopropyl, CF3, or CN, for example methyl or CN, especially methyl. In a second embodiment, R 15is methyl, ethyl, cyclopropyl, CF3, CN, OMe, chloro, or fluoro, for example methyl, CN, chloro, or fluoro, in particular chloro or fluoro. In a third embodiment, R 15 is OMe, chloro, or fluoro. In a fourth embodiment, R 15 is methyl, CN, chloro, or fluoro.

[0121] Preferably, R 15 C present in 3-6 Cycloalkyl, e.g., cyclopropyl rings, are C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 15a R 15b , SO2R 15c , and NHSO2R 15c and R is substituted by one, two, or three, such as one or two, for example one, substituent independently selected from 15 C present in 3-6 Cycloalkyl, e.g., cyclopropyl rings, are C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Substituted by 1, 2, or 3, such as 1 or 2, for example, 1 substituent independently selected from haloalkyl, halo, and CN. 15 C present in 3-6 Cycloalkyl, e.g., cyclopropyl rings, can be OH, NR 15a R 15b , SO2R 15c , and NHSO2R 15c and is substituted by one, two, or three, such as one or two, for example one, substituent independently selected from 3-6 A cycloalkyl, e.g., cyclopropyl, ring may contain one, two, or three C 1-4 Alkyl substituents, such as one or two, for example, one C 1-4Substituted by alkyl substituents (such as methyl). In one embodiment, C 3-6 Cycloalkyl groups, such as cyclopropyl rings, are unsubstituted.

[0122] In one embodiment, R 15a is H. In a second embodiment, R 15a is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 15a is H or methyl.

[0123] In one embodiment, R 15b is H. In a second embodiment, R 15b is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 15b C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a fourth embodiment, R 15b C such as OMe or OEt 1-4 In a fifth embodiment, R 15b is C such as CF3 1-4 In a sixth embodiment, R 15b is aryl, such as phenyl. In a seventh embodiment, R 15b is a 4- to 7-membered heterocycloalkyl such as azetidinyl or oxetanyl. In an eighth embodiment, R 15b is H or methyl.

[0124] In one embodiment, R 15c is C such as methyl, ethyl, or propyl 1-4 In a second embodiment, R 15c C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a third embodiment, R 15cC such as OMe or OEt 1-4 In a fourth embodiment, R 15c is C such as CF3 1-4 In a fifth embodiment, R 15c is aryl, such as phenyl. In a sixth embodiment, R 15c is a 4- to 7-membered heterocycloalkyl such as azetidinyl or oxetanyl. In a seventh embodiment, R 15c is methyl.

[0125] In one embodiment, D, E, and F are C(R 16 In a second embodiment, D is N and E and F are C(R 16 In a third embodiment, E is N and D and F are C(R 16 In a fourth embodiment, F is N and D and E are C(R 16 )

[0126] In one embodiment, R 16 is H. In a second embodiment, R 16 is halo, such as fluoro or chloro, and in particular chloro. In a third embodiment, R 16 is C such as methyl 1-4 Preferably, each R 16 is independently H, fluoro, chloro, or methyl.

[0127] In a preferred embodiment of the present invention, the compound of the present invention has the formula (Ia'): [ka] (In the formula: A is a group (Aa'), a group (Ab'), a group (Ad'), or a group (Ad''); R 15d is methyl, ethyl, cyclopropyl, CN, CF3, OMe, chloro, or fluoro; wherein the group (Aa') is: [ka] and (In the formula: R 2d is H, methyl, or CHOMe; Each R 3a are independently H, fluoro, or methyl; and The group (Ab') is: [ka] and (In the formula: R 4d is methyl); The group (Ad') is: [ka] and (In the formula: R 8d is H, methyl, OCH2-cyclopropyl, OCH2-oxetanyl, OCH2CH2F, OMe, or OEt; Each R 9a are independently H or fluoro; The group (Ad'') is: [ka] and (In the formula: R 8d is methyl; and Each R 9a are independently H or fluoro); or a pharmaceutically acceptable salt and / or solvate thereof.

[0128] In a preferred embodiment of the invention, the compound of the invention has formula (Ia): [ka] (In the formula: A is a group (Aa'), a group (Ab'), or a group (Ad'); wherein the group (Aa') is: [ka] and (In the formula: R 2d is H, methyl, or CHOMe; Each R 3a is independently H, fluoro, or methyl; and R 15d is methyl or CN); The group (Ab') is: [ka] and (In the formula: R 4d is methyl); The group (Ad') is: [ka] and (In the formula: R 8d is H or methyl; and Each R 9a are independently H or fluoro); or a pharmaceutically acceptable salt and / or solvate thereof.

[0129] In one preferred embodiment, A is group (Aa) and B is group (Ba). In a second preferred embodiment, A is group (Aa) and B is group (Bb). In a third preferred embodiment, A is group (Ad) and B is group (Bc).

[0130] In one embodiment, the compound of formula (I) is: (E)-3-(1H-benzo[d][1,2,3]triazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)acrylamide; (E)-3-(3,3-dimethyl-2-oxoindolin-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2'-oxospiro[cyclopropane-1,3'-indoline]-6'-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(7-fluoro-2-oxoindolin-6-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-2-oxoindolin-6-yl)acrylamide; (E)-N-(3-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(o-tolyl)acrylamide; (E)-N-(2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(2-isopropyl-6-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(5-chloro-2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(4,5-difluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(5-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(4-fluoro-2-oxoindolin-6-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-3-(1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-3-(1-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-(trifluoromethyl)-1H-indazol-6-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-ethyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(3,5-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3,4-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide; (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(4-fluoro-3-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(3-fluoro-4-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; Racemic -(E)-3-(3-methyl-1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (Z)-2-fluoro-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3-chloro-2-methylphenyl)-N-methyl-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(2-methylcyclopentyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-(methoxymethyl)phenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide; (E)-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(chroman-4-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)acrylamide; (E)-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3,5-difluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide; (E)-N-(5-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; and (E)-N-(2-methylcyclohexyl)-3-(2-oxoindolin-6-yl)acrylamide; or a pharmaceutically acceptable salt and / or solvate of any one of these.

[0131] In one embodiment, the compound of formula (I) is: (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4S)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4R)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4R)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4S)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-((1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-((1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-((1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-methoxy-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-chloro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-fluoro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; and (E)-3-(3-cyano-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; or a pharmaceutically acceptable salt and / or solvate of any one of these.

[0132] The definition of a compound of formula (I) is intended to include all tautomers of the compound.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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).

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] In one embodiment, the compounds of the invention are provided in natural isotopic form.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] (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 , R2, R3, R 13 , A, and B are as defined above in relation to compounds of formula (I) unless otherwise specified.

[0147] (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).

[0148] (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.

[0149] (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).

[0150] (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).

[0151] (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).

[0152] (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.

[0153] (Scheme 7) [ka] R 1a is H, A is a group (Aa), and R2 is C 1-4 alkyl, m is 3, and R3 is C 1-4 Compounds of formula (VII), which are alkyl or halo, can be prepared in two steps. First, compounds of formula (X) are reacted with a brominating agent such as N-bromosuccinimide (NBS) in a solvent such as acetonitrile to give dibrominated compounds of formula (XI). Compounds of formula (VII) can be further 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 such as 1,4-dioxane to give compounds of formula (VII).

[0154] (Scheme 8) [ka] R 1a is H, A is a group (Aa), and R2 is C 1-4 alkyl, m is 3, and R3 is C 1-4The alkyl or halo compound of formula (VII) can be prepared in four steps. First, a compound of formula (XII) is reacted with a chlorinating agent such as N-chlorosuccinimide (NCS) in a solvent such as acetonitrile to give a compound of formula (XIII). Then, a compound of formula (XIII) is reacted with a brominating agent such as N-bromosuccinimide (NBS) in a solvent such as acetonitrile to give a trihalogenated compound of formula (XIV). Compounds of formula (XIV) can be further 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 such as 1,4-dioxane to give compounds of formula (XV). Compounds of formula (XV) can be further reacted under reductive dehalogenation conditions using a hydrogen atmosphere such as 30 atm hydrogen, a palladium catalyst such as palladium on carbon (Pd / C), an acid such as hydrochloric acid, and a solvent such as ethanol (EtOH) to give compounds of formula (VII).

[0155] (Scheme 9) [ka] R 1a is H, A is a group (Aa), and R2 is C 1-4 alkyl, m is 2, and R3 is C 1-4Compounds 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).

[0156] (Scheme 10) [ka] B is a group (Ba) and Y is N(R 13 Compounds of formula (III), wherein r is 0, can be prepared in three steps. First, compounds of formula (XVIII) can be reacted with an amine in a suitable solvent, such as ethanol, to give compounds of formula (XIX). Subsequently, compounds of formula (XIX) can be subjected to reducing conditions using a metal, such as zinc, and an inorganic salt, such as ammonium chloride (NH4Cl), in a suitable solvent, such as acetone, to give compounds of formula (XX). Finally, compounds of formula (XX) can be reacted with a carbonylating agent, such as triphosgene, in a suitable solvent, such as dichloromethane (DCM), to give compounds of formula (III).

[0157] (Scheme 11) [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 1-4A 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 1-4 The 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).

[0158] (Scheme 12) [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).

[0159] 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.

[0160] 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 the compounds of formula (I); or a salt thereof The process also includes reacting

[0161] 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 the compounds of formula (I); or a salt thereof The process also includes reacting

[0162] (Treatment method) The compounds of formula (I) of the present invention are useful as inhibitors of mPTP.

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] As used herein, the term "treatment" or "treating" includes controlling, alleviating, reducing, or modulating a disease state or its symptoms.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] In another embodiment, the disease or disorder is a disease of aging, such as bone repair, bone frailty in aging in osteoporosis, and sarcopenia.

[0181] 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.

[0182] The compounds of formula (I) are expected to be useful in the treatment or prevention of mitochondrial diseases.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] Suitably, the mitochondrial disease is selected from disorders such as Reye's syndrome, Leber's hereditary optic neuropathy and related disorders, and diseases and disorders disclosed in CA2884607A1 (Stealth Peptides International).

[0193] 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.

[0194] 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.

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] 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.

[0214] Preferably, the subject is a mammal, and in particular, the subject is a human.

[0215] (Pharmaceutical composition) For use in therapy, the compounds of the invention are typically administered as pharmaceutical compositions. The invention also provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g., a salt) thereof, and a pharmaceutically acceptable carrier or excipient.

[0216] 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.

[0217] 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. The pharmaceutical compositions of the present invention may take the form of pharmaceutical formulations as described below.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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).

[0233] 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.

[0234] 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.

[0235] 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.

[0236] 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).

[0237] Suitable unit dosage formulations are those containing an effective dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0238] 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.

[0239] The compounds of formula (I) have the following advantageous properties: - inhibitory activity of mPTP (preferably pIC) as demonstrated in the assay of Biological Example 1 50 value is 6.0 or greater); and - Low inhibition of CYP2D6 as demonstrated in the assay of Biological Example 2 It is expected that you will demonstrate one or more of the following:

[0240] In addition to the properties mentioned above, certain compounds of formula (I) have the following advantageous properties: - 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 3 and 4. int ) may also indicate one or more of:

[0241] The present invention is further illustrated by the following non-limiting examples. [Example]

[0242] (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.

[0243] (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.

[0244] 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. 1 H 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]

[0245] (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 1-64.

[0246] (Preparation of Examples 1 to 74) (Intermediate 1: N-(3-fluoro-2-methylphenyl)acrylamide) [ka] To a stirred solution of 3-fluoro-2-methylaniline (1.0 g, 8.0 mmol, 1.0 equiv.) and DIPEA (3.1 g, 23.9 mmol, 3.0 equiv.) in DCM (40 mL) under nitrogen at 0° C., acryloyl chloride (0.71 mL, 8.8 mmol, 1.1 equiv.) was added dropwise. The resulting mixture was stirred at 25° C. under an inert atmosphere of nitrogen for 3 h. 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

[0247] (Intermediate 2: N-(3-chloro-2-methylphenyl)acrylamide) [ka] Into a 50 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 3-chloro-2-methyl-aniline (300 mg, 2.12 mmol, 1.0 equiv.), DCM (15 mL), and EtN (1 mL, 7.19 mmol, 3.0 equiv.) were placed. Subsequently, acryloyl chloride (260 mg, 2.9 mmol, 1.2 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)acrylamide as a pale yellow solid. LC-MS (ES, m / z): [M+H] + =196

[0248] Example 1: (E)-3-(1H-benzo[d][1,2,3]triazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide [ka] To a microwave vial containing N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 100 mg, 0.56 mmol, 1.0 equiv.), 5-bromo-3H-1,2,3-benzotriazole (110 mg, 0.56 mmol, 1.0 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, 1.0 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. The organic layer was concentrated, dried over anhydrous sodium sulfate, and concentrated. The residue was loaded onto a silica gel column. The crude product was purified by flash preparative HPLC to give 9 mg (5%) of (£)-3-(1H-benzo[d][1,2,3]triazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide as a pale gray solid. LC-MS (ES, m / z): [M+H] + =297; [ka]

[0249] (Intermediate 3: (E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid) [ka] (Process 1) A 250 mL three-necked round-bottom flask was charged with 6-bromo-3-methyl-1H-indazole (2.50 g, 11.84 mmol, 1.00 equiv.), methyl acrylate (1.53 g, 17.76 mmol, 1.50 equiv.), EtN (3.60 g, 35.53 mmol, 3.00 equiv.), Pd(dppf)Cl (0.87 g, 1.18 mmol, 0.10 equiv.), and DMF (100.00 mL). The resulting solution was stirred at 120 °C for 10 h. The mixture was concentrated, and the residue was applied to a silica gel column using THF / PE (1 / 1). This afforded 0.9 g (35% yield) of methyl (2E)-3-(3-methyl-1H-indazol-6-yl)prop-2-enoate as a pale yellow solid. [ka]

[0250] (Process 2) A 40 mL vial was charged with methyl (2E)-3-(3-methyl-1H-indazol-6-yl)prop-2-enoate (890.00 mg, 4.12 mmol, 1.00 equiv.), NaOH (329.24 mg, 8.23 ​​mmol, 2.00 equiv.) in HO (10.00 mL), and MeOH (10.00 mL). The resulting solution was stirred for 2 hours at 20 °C. The pH of the solution was adjusted to 3 with HCl (1 mol / L). The solid was collected by filtration. This afforded 500 mg (60% yield) of (E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid as an off-white solid.

[0251] Example 2: (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)acrylamide [ka] To a microwave vial containing N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 180 mg, 1.0 mmol, 1.0 equiv.), 5-bromo-3H-1,3-benzothiazol-2-one (231 mg, 1.0 mmol, 1.0 equiv.), Pd(OAc) (34 mg, 0.151 mmol, 0.15 equiv.), tris(2-methylphenyl)phosphane (62 mg, 0.201 mmol, 0.20 equiv.), and tetrabutylammonium chloride (279 mg, 1.0 mmol, 1.0 equiv.) was added DMF (2.8 mL). The resulting solution was stirred at 115 °C for 12 h. The resulting mixture was diluted with 30 mL of EtOAc and washed with 2 × 15 mL of 1 M aqueous KCO. The organic layer was concentrated, dried over anhydrous sodium sulfate, and concentrated. The residue was loaded onto a silica gel column. The resulting crude product was purified by flash preparative HPLC to give 6 mg (2%) of (£)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =329 [ka]

[0252] Example 3: (E)-3-(3,3-dimethyl-2-oxoindolin-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide [ka] To a microwave vial containing N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 185 mg, 1.03 mmol, 1.0 equiv.), 6-bromo-3,3-dimethyl-1H-indol-2-one (240 mg, 1.03 mmol, 1.0 equiv.), Pd(OAc) (35 mg, 0.155 mmol, 0.15 equiv.), tris(2-methylphenyl)phosphane (63 mg, 0.206 mmol, 0.20 equiv.), and tetrabutylammonium chloride (286 mg, 1.03 mmol, 1.0 equiv.) was added DMF (2.9 mL). The resulting solution was stirred at 115 °C for 12 h. The resulting mixture was diluted with 30 mL of EtOAc and washed with 2 × 15 mL of 1 M aqueous KCO. The organic layer was concentrated, dried over anhydrous sodium sulfate, and concentrated. The residue was loaded onto a silica gel column. The resulting crude product was purified by flash preparative HPLC to give 76 mg (22%) of (E)-3-(3,3-dimethyl-2-oxoindolin-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =339 [ka]

[0253] Example 4: (E)-N-(3-fluoro-2-methylphenyl)-3-(2'-oxospiro[cyclopropane-1,3'-indoline]-6'-yl)acrylamide [ka] To a microwave vial containing N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 130 mg, 0.725 mmol, 1.0 equiv.), 6'-bromo-1'H-spiro[cyclopropane-1,3'-indol]-2'-one (172 mg, 0.725 mmol, 1.0 equiv.), Pd(OAc) (24 mg, 0.109 mmol, 0.15 equiv.), tris(2-methylphenyl)phosphane (44 mg, 0.145 mmol, 0.20 equiv.), and tetrabutylammonium chloride (278 mg, 0.725 mmol, 1.0 equiv.) was added DMF (2 mL). The resulting solution was stirred at 115 °C for 12 h. The resulting mixture was diluted with 30 mL of EtOAc, washed with 2 × 15 mL of 1 M aqueous KCO, and the organic layer was concentrated, dried over anhydrous sodium sulfate, and concentrated. The residue was loaded onto a silica gel column. The resulting crude product was purified by flash preparative HPLC. This afforded 10 mg (4%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(2'-oxospiro[cyclopropane-1,3'-indoline]-6'-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =337 [ka]

[0254] Example 5: (E)—N-(3-fluoro-2-methylphenyl)-3-(7-fluoro-2-oxoindolin-6-yl)acrylamide [ka] Prepared by the method described above using intermediate 1 and 6-bromo-7-fluoro-1,3-dihydro-2H-indol-2-one. LC-MS (ES, m / z): 327 [M−H] + [ka]

[0255] Example 6: (E)—N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] Into an 8 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 50 mg, 0.28 mmol, 1.0 equiv.), DMF (4 mL), 5-bromo-2-benzoxazolinone (66 mg, 0.31 mmol, 1.10 equiv.), EtN (0.12 mL, 0.84 mmol, 3.0 equiv.), and Pd(dppf)Cl CHCl (11 mg, 0.014 mmol, 0.05 equiv.). The resulting solution was stirred at 120° C. for 12 hours. The reaction was then quenched by the addition of 3 mL of water. The resulting solution was extracted with 5 mL of DCM, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash preparative HPLC. This afforded 21 mg (24%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a white solid. LC MS (ES, m / z): [M+H] + =313 [ka]

[0256] Example 7: (E)—N-(3-fluoro-2-methylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-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, 90 mg, 0.50 mmol, 1.0 equiv.), DMF (5 mL), 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (137 mg, 0.60 mmol, 1.20 equiv.), EtN (0.21 mL, 1.51 mmol, 3.0 equiv.), and Pd(dppf)Cl·CHCl (20 mg, 0.025 mmol, 0.05 equiv.). The resulting solution was stirred at 120 °C for 12 h and cooled to 25 °C. The mixture was purified by preparative HPLC. This gave 7 mg (4%) of (£)-N-(3-fluoro-2-methylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide as an off-white solid. LC MS (ES, m / z): [M+H] + =326 [ka]

[0257] Example 8: (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-2-oxoindolin-6-yl)acrylamide [ka] (Process 1) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 6-bromo-1H-indole-2,3-dione (3.5 g, 15.48 mmol, 1.0 equiv.) and THF (70 mL). 3 M methylmagnesium bromide (5.2 mL, 15.48 mmol, 1.0 equiv.) was added dropwise over 0.5 h at −78° C. The resulting solution was stirred for an additional 5 h at −78° C., after which the temperature was raised to 25° C. The reaction was then quenched by the addition of 10 mL of 0.2 M HCl. The resulting solution was extracted with 2×50 mL of EtOAc, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column using 35 / 65 EtOAc / PE. This gave 3 g (80%) of 6-bromo-3-hydroxy-3-methyl-1H-indol-2-one as an off-white solid. LC-MS (ES, m / z): [MH] + =240

[0258] [ka] (Process 2) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 6-bromo-3-hydroxy-3-methyl-1H-indol-2-one (2.0 g, 8.26 mmol, 1.0 equiv.) and THF (30 mL). Subsequently, diethylaminosulfur trifluoride (DAST) (2.0 g, 12.39 mmol, 1.50 equiv.) was added at −78° C. The resulting solution was stirred from −78° C. for 1 hour and warmed to 25° C. The reaction was then quenched by the addition of 10 mL of saturated NaHCO3. The resulting solution was extracted with 2×50 mL of EtOAc, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column using 25 / 75 EtOAc / PE. This gave 1.65 g (82%) of 6-bromo-3-fluoro-3-methyl-1H-indol-2-one as a white solid. LC-MS (ES, m / z): [MH] + =242

[0259] [ka] (Step 3) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with 6-bromo-3-fluoro-3-methyl-1H-indol-2-one (200 mg, 0.82 mmol, 1.0 equiv.), N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 147 mg, 0.82 mmol, 1.0 equiv.), Pd(dppf)Cl.CHCl (13 mg, 0.02 mmol, 0.02 equiv.), DMF (4 mL), and EtN (0.23 mL, 1.64 mmol, 2.0 equiv.). The resulting solution was stirred at 110 °C for 2 h. The solids were removed by filtration. The filtrate was concentrated. The crude product was purified by flash preparative HPLC. This gave 13 mg (4.5%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(3-fluoro-3-methyl-2-oxoindolin-6-yl)acrylamide and 12 mg (4%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-2-oxoindolin-6-yl)acrylamide. (E)-N-(3-fluoro-2-methylphenyl)-3-(3-fluoro-3-methyl-2-oxoindolin-6-yl)acrylamide LC-MS (ES, m / z): [M+H] + =343 [ka] E) -N-(3-fluoro-2-methylphenyl)-3-(3-methyl-2-oxoindolin-6-yl)acrylamide LC-MS (ES, m / z): [M+H] + =325 [ka]

[0260] Example 9: (E)—N-(3-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(3-chloro-2-methylphenyl)prop-2-enamide (Intermediate 2, 55 mg, 0.28 mmol, 1.0 equiv.), DMF (4 mL), 2-benzoxazolinone, 5-bromo- (66 mg, 0.31 mmol, 1.10 equiv.), EtN (0.12 mL, 0.84 mmol, 3.0 equiv.), and Pd(dppf)Cl.CHCl (11 mg, 0.014 mmol, 0.05 equiv.). The resulting solution was stirred at 120 °C for 12 h. The reaction was then quenched by the addition of 3 mL of water. The resulting solution was extracted with 5 mL of DCM, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash preparative HPLC. This gave 21 mg (24%) of (£)-N-(3-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a white solid. LC MS (ES, m / z): [M+H] + =329 [ka]

[0261] Example 10: (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide [ka] A 40 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was charged with N-(3-fluoro-2-methylphenyl)prop-2-enamide (Intermediate 1, (500 mg, 2.79 mmol, 1.0 equiv.), 6-bromo-1,3-dihydroindol-2-one (592 mg, 2.79 mmol, 1.0 equiv.), DMF (20 mL), EtN (1.2 mL, 8.37 mmol, 3.0 equiv.), and Pd(dppf)Cl (41 mg, 0.05 mmol, 0.02 equiv.). The reaction mixture was stirred for 2 h at 110 °C. The resulting mixture was concentrated. The crude product was purified by flash preparative HPLC. This afforded 102 mg (11%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide as a white solid. LC-MS (ES, m / z): [MH] + =309 [ka]

[0262] Example 11: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] (Process 1) A 500 mL sealed tube was charged with 5-bromobenzo[d]oxazol-2(3H)-one (10.0 g, 46.96 mmol, 1.0 equiv.), methyl acrylate (12.1 g, 140.8 mmol, 3.0 equiv.), EtN (19.6 mL, 140.8 mmol, 3.0 equiv.), and Pd(dppf)Cl (350 mg, 4.7 mmol, 0.01 equiv.) in DMF (200 mL). The resulting solution was stirred at 120 °C for 2 h. The resulting solution was concentrated. The residue was loaded onto a silica gel column eluted with THF / hexane (20 / 80). This gave 11 g (82%) of methyl (E)-3-(3-(3-methoxy-3-oxopropyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate as a yellow solid.

[0263] [ka] (Process 2) A 500 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with THF (300 mL), methyl (E)-3-(3-(3-methoxy-3-oxopropyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate (11.0 g, 36.1 mmol, 1.0 equiv.), and t-BuOK (13.2 g, 108.2 mmol, 3.0 equiv.). The resulting solution was stirred for 2 hours at 60°C. The reaction was then quenched by the addition of 600 mL of saturated NH4Cl. The resulting solution was extracted with 2 x 300 mL of EtOAc. The organic layer was washed with 2 x 400 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting solution was concentrated. The residue was loaded onto a silica gel column using 40 / 60 EtOAc / hexanes. This gave 5.5 g (69%) of methyl (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate as a pale red solid.

[0264] [ka] (Step 3) A purged 100 mL three-neck round-bottom flask was charged with THF (20 mL), methyl (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate (2.5 g, 11.4 mmol, 1.0 equiv.), and 2 M NaOH (17.1 mL, 34.2 mmol, 3.0 equiv.). The resulting solution was stirred for 2 h at 25 °C. The reaction mixture was concentrated at low temperature (<30 °C). The residue was dissolved in water (30 mL) and the pH was adjusted to 2-3 with 2 M HCl. The solid was collected. This afforded 2.5 g (65%) of (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylic acid as an off-white solid.

[0265] [ka] (Step 4) Each vial was charged with (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylic acid (30 mg, 0.146 mmol, 1.0 equiv.) in DMF (2 mL). Then, T3P (70 mg, 0.22 mmol, 1.50 equiv.), DIPEA (28 mg, 0.22 mmol, 1.50 equiv.), and 1-indanamine (0.161 mmol, 1.1 equiv.) were added. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with water, extracted with EtOAc, and the organic layer was concentrated in vacuo to give the crude product. The crude product was then directly purified by preparative HPLC. The collected fractions were lyophilized to give the final compound. LC-MS (ES, m / z): 321 [M+H] + [ka]

[0266] (General Procedure A) [ka] Each vial was charged with methyl (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate (Example 11, Step 2, 30 mg, 0.14 mmol, 1.0 equiv.) in THF (2 mL). Amine (0.18 mmol, 1.30 equiv.) was added, and the reaction mixture was cooled to 0° C. 1M LiHMDS (0.68 mL, 0.68 mmol, 5.0 equiv.) was then added. The reaction mixture was stirred for 1 hour at 25° C. The reaction mixture was quenched with water, extracted with EtOAc, and the organic layer was concentrated in vacuo to give the crude product, which was then purified by preparative HPLC. The collected fractions were lyophilized to give the final compound.

[0267] Example 12: (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(o-tolyl)acrylamide [ka] Synthesis using general procedure A with 2-methylaniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate gave (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(o-tolyl)acrylamide as a solid. LC-MS (ES, m / z): 295 [M+H] + [ka]

[0268] Example 13: (E)-N-(2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] Synthesis using general procedure A with 2-isopropylaniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate gave (E)-N-(2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a solid. LC-MS (ES, m / z): 323 [M+H] + [ka]

[0269] Example 14: (E)-N-(2-isopropyl-6-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] Synthesis using 2-isopropyl-6-methylaniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate using general procedure A gave (E)-N-(2-isopropyl-6-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a solid. LC-MS (ES, m / z): 337 [M+H] + [ka]

[0270] Example 15: (E)-N-(5-chloro-2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] Synthesis using general procedure A with 5-chloro-2-isopropylaniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate gave (E)-N-(5-chloro-2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a solid. LC-MS (ES, m / z): 357 [M+H] + [ka]

[0271] Example 16: (E)—N-(4,5-difluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] Synthesis using 4,5-difluoro-2-methylaniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate according to general procedure A gave (E)-N-(4,5-difluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a solid. LC-MS (ES, m / z): 331 [M+H] + , 373 [M+CH3CN] + .

[0272] Example 17: (E)—N-(5-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] Synthesis using general procedure A with 5-fluoro-2-methylaniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate gave (E)-N-(5-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a solid. LC-MS (ES, m / z): 311 [M+H] +

[0273] Example 18: (E)—N-(3-fluoro-2-methylphenyl)-3-(4-fluoro-2-oxoindolin-6-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(3-fluoro-2-methylphenyl)acrylamide (60.0 mg, 0.34 mmol, 1.0 equiv.), 6-bromo-4-fluoroindolin-2-one (78 mg, 0.34 mmol, 1.0 equiv.), EtN (0.14 mL, 1.0 mmol, 3.0 equiv.), DMF (4.0 mL), and Pd(dppf)Cl (25.2 mg, 0.034 mmol, 0.10 equiv.). The resulting solution was stirred at 120 °C for 2 h. The crude mixture was purified by flash preparative HPLC. This afforded 11.8 mg (11%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(4-fluoro-2-oxoindolin-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =329 [ka]

[0274] Example 19: (E)—N-(2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide [ka] (Process 1) A 500 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 6-bromo-1,3-dihydroindol-2-one (20.0 g, 94.32 mmol, 1.0 equiv.), DMF (350 mL), methyl acrylate (6.50 g, 75.50 mmol, 0.80 equiv.), EtN (26.3 mL, 188.64 mmol, 2.0 equiv.), and Pd(dppf)Cl.CHCl (0.77 g, 0.94 mmol, 0.01 equiv.). The resulting solution was stirred at 120 °C for 2 h. The reaction mixture was cooled to room temperature. The mixture was loaded onto a silica gel column using THF / PE (2 / 1). This gave 7.4 g (36%) of methyl (2E)-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2-enoate as a pale yellow solid.

[0275] [ka] (Process 2) A 250 mL round-bottom flask was charged with methyl (2E)-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2-enoate (3.0 g, 13.81 mmol, 1.0 equiv.), MeOH / HO (80 / 40 mL), and NaOH (1.7 g, 41.43 mmol, 3.0 equiv.). The resulting solution was stirred for 12 hours at 25 °C. The resulting mixture was concentrated. The resulting solution was diluted with 40 mL of water. The resulting solution was extracted with 2 × 50 mL of DCM. The pH of the aqueous phase was adjusted to 5 with 2 M HCl. The solid was collected by filtration. This afforded 1.8 g (64%) of (2E)-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2-enoic acid as a pale yellow solid.

[0276] [ka] (Step 3) To an 8 mL vial purged and maintained under an inert atmosphere of nitrogen was added (E)-3-(2-oxoindolin-6-yl)acrylic acid (60.0 mg, 0.30 mmol, 1.0 equiv.) in DMF (4.0 mL). HATU (167.6 mg, 0.44 mmol, 1.50 equiv.), DIPEA (56.8 mg, 0.44 mmol, 1.50 equiv.), and 2,6-dimethylbenzenamine (39.5 mg, 0.33 mmol, 1.10 equiv.) were then added. The reaction mixture was stirred for 2 hours at room temperature. The crude mixture was then purified by preparative HPLC. This afforded 12 mg (13%) of (E)-N-(2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =307 [ka]

[0277] Example 20: (E)—N-(3-fluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide [ka] An 8 mL round-bottom flask was charged with 6-bromoindolin-2-one (100 mg, 0.47 mmol, 1.0 equiv.), N-(3-fluoro-2,6-dimethylphenyl)prop-2-enamide (prepared by the procedure described for Intermediate 1 from 2,6-dimethyl-3-fluoroaniline and acryloyl chloride; 90.7 mg, 0.47 mmol, 1.0 equiv.), Pd(dppf)Cl (34.4 mg, 0.047 mmol, 0.10 equiv.), EtN (0.2 mL, 1.41 mmol, 3.0 equiv.), and DMF (4.0 mL). The resulting solution was stirred in an oil bath at 120 °C for 2 hours. The mixture was loaded onto a silica gel column using PE / THF (1 / 1). This gave 11 mg (7%) of (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide as a solid. LC-MS (ES, m / z): [M+H] + =325 [ka]

[0278] Example 21: (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide [ka] An 8 mL vial was charged with (£)-3-(2-oxoindolin-6-yl)acrylic acid (50.0 mg, 0.25 mmol, 1.0 equiv.), 2-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride (45.20 mg, 0.25 mmol, 1.0 equiv.), HATU (141.38 mg, 0.37 mmol, 1.50 equiv.), and DIPEA (95.41 mg, 0.74 mmol, 3.0 equiv.) in DMF (2.0 mL). The resulting solution was stirred for 2 hours at 20°C. The mixture was purified by flash preparative HPLC. This gave 27 mg (33%) of ((E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =333 [ka]

[0279] Example 22: (E)-3-(1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide [ka] (Process 1) A 100 mL sealed tube was charged with 4-bromo-1-fluoro-2-nitrobenzene (2.0 g, 9.09 mmol, 1.0 equiv.), EtOH (8.0 mL, 1.0 equiv.), and ethylamine (22.73 mL, 45.45 mmol, 5.0 equiv., 2M in ethanol). The resulting solution was stirred for 4 h at 50 °C. The resulting mixture was concentrated. The residue was diluted with 15 mL of HO and stirred for 15 min. The solid was collected by filtration. This afforded 2.2 g (98%) of 4-bromo-N-ethyl-2-nitroaniline as a red solid. LC-MS (ES, m / z): [M+H] + =245

[0280] [ka] (Process 2) A 50 mL round-bottom flask was charged with 4-bromo-N-ethyl-2-nitroaniline (2.0 g, 8.16 mmol, 1.0 equiv), acetone (16.0 mL), HO (2.0 mL), NHCl (4.37 g, 81.61 mmol, 10.0 equiv), and Zn (2.67 g, 40.80 mmol, 5.0 equiv). The resulting solution was stirred for 3 h at room temperature. The solid was removed by filtration. The filtrate was concentrated. The residue was diluted with 20 mL of HO and stirred for 15 min. The solid was collected by filtration. This afforded 1.1 g (63%) of 4-bromo-N 1 -ethylbenzene-1,2-diamine was obtained as a pale yellow solid. LC-MS (ES, m / z): [M+H] + =215

[0281] [ka] (Step 3) In a 50 mL three-neck round-bottom flask purged and maintained under an inert atmosphere of nitrogen, 4-bromo-N 1A mixture of 1,2-ethylbenzene-1,2-diamine (400.0 mg, 1.86 mmol, 1.0 equiv.), DCM (8.0 mL), and triphosgene (441.5 mg, 1.48 mmol, 0.80 equiv.) was added. Subsequently, EtN (0.8 mL, 5.58 mmol, 3.0 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 5 mL of water. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column using (THF / PE=18 / 82). This afforded 210 mg (47%) of 5-bromo-1-ethyl-3H-1,3-benzodiazol-2-one as a light brown solid. LC-MS (ES, m / z): [M+H] + =240

[0282] [ka] (Step 4) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(3-fluoro-2-methylphenyl)acrylamide (120.0 mg, 0.67 mmol, 1.0 equiv.), 5-bromo-1-ethyl-3H-1,3-benzodiazol-2-one (161.5 mg, 0.67 mmol, 1.0 equiv.), EtN (0.28 mL, 2.01 mmol, 3.0 equiv.), DMF (5.0 mL), and Pd(dppf)Cl (9.8 mg, 0.01 mmol, 0.02 equiv.). The resulting solution was stirred at 120 °C for 2 h. The crude mixture was purified by flash preparative HPLC. This gave 25 mg (11%) of (£)-3-(1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =340 [ka]

[0283] Example 23: (E)-3-(1-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide [ka] (Process 1) A 40 mL sealed tube was charged with 4-bromo-1-fluoro-2-nitrobenzene (2.0 g, 9.09 mmol, 1.0 equiv.), aminocyclopropane (2.60 g, 45.45 mmol, 5.0 equiv.), and EtOH (20.0 mL). The resulting solution was stirred for 4 hours at 50 °C. The resulting mixture was concentrated. The residual compound was diluted with 15 mL of HO and stirred for 15 minutes. The solid was collected by filtration. The solid was dried in an oven under reduced pressure. This afforded 2.4 g (96%) of 4-bromo-N-cyclopropyl-2-nitroaniline as a red solid. LC-MS (ES, m / z): [M+H] + =257

[0284] [ka] (Process 2) A 40 mL sealed tube was charged with 4-bromo-N-cyclopropyl-2-nitroaniline (2.0 g, 7.8 mmol, 1.0 equiv), acetone (16.0 mL), HO (2.0 mL), Zn (2.54 g, 38.89 mmol, 5.0 equiv), and NHCl (4.16 g, 77.8 mmol, 10.0 equiv). The resulting solution was stirred for 3 h at 25 °C. The solid was removed by filtration. The filtrate was concentrated. The residue was diluted with 20 mL of HO and stirred for 15 min. The solid was collected by filtration. This afforded 1 g (56%) of 4-bromo-N 1 -Cyclopropylbenzene-1,2-diamine was obtained as a light brown solid. LC-MS (ES, m / z): [M+H] + =227

[0285] [ka] (Step 3) In a 50 mL three-neck round-bottom flask purged and maintained under an inert atmosphere of nitrogen, 4-bromo-N 1 A mixture of 1,2-cyclopropylbenzene-1,2-diamine (300.0 mg, 1.32 mmol, 1.0 equiv.), triphosgene (313.60 mg, 1.06 mmol, 0.80 equiv.), and DCM (6.0 mL) was added. This was followed by the addition of EtN (0.6 mL, 3.96 mmol, 3.0 equiv.) at 0° C. The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by the addition of 5 mL of water. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. This afforded 180 mg (53%) of 5-bromo-1-cyclopropyl-3H-1,3-benzodiazol-2-one as a light brown solid. LC-MS (ES, m / z): [M+H] + =253

[0286] [ka] (Step 4) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(3-fluoro-2-methylphenyl)acrylamide (120.0 mg, 0.67 mmol, 1.0 equiv.), 5-bromo-1-cyclopropyl-3H-1,3-benzodiazol-2-one (169.5 mg, 0.67 mmol, 1.0 equiv.), EtN (0.2 mL, 1.34 mmol, 2.0 equiv.), DMF (5.0 mL), and Pd(dppf)Cl (9.80 mg, 0.013 mmol, 0.02 equiv.). The resulting solution was stirred at 120 °C for 2 h. The solids were removed by filtration. The crude mixture was purified by flash preparative HPLC. This gave 21 mg (9%) of (E)-3-(1-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =352 [ka]

[0287] Example 24: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-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

[0288] [ka] An 8 mL vial was charged with N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (100.0 mg, 0.53 mmol, 1.0 equiv.), 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (121.27 mg, 0.53 mmol, 1.0 equiv.), Pd(dppf)Cl (39.08 mg, 0.05 mmol, 0.10 equiv.), and EtN (0.22 mL, 1.60 mmol, 3.0 equiv.) in DMF (4.0 mL, 25.844 mmol). 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 7.8 mg (4%) of (£)-N-(2,3-dihydro-lH-inden-l-yl)-3-(l-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =334 [ka]

[0289] Example 25: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-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 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv.), 6-bromo-3-methyl-1H-indazole (135.27 mg, 0.64 mmol, 1.20 equiv.), Pd(dppf)Cl.CHCl (87.23 mg, 0.11 mmol, 0.20 equiv.), DMF (4.0 mL), and EtN (0.22 mL, 1.60 mmol, 3.0 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 64 mg (38%) of (£)-N-(2,3-dihydro-lH-inden-l-yl)-3-(3-methyl-lH-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =318 [ka]

[0290] Example 26: (E)-3-(3-cyano-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 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv.), 6-bromo-1H-indazole-3-carbonitrile (142.30 mg, 0.64 mmol, 1.20 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, 3.0 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 24 mg (14%) of (£)-3-(3-cyano-lH-indazol-6-yl)-N-(2,3-dihydro-lH-inden-l-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =329 [ka]

[0291] Example 27: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-benzo[d][1,2,3]triazol-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 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv.), 5-bromo-6-fluoro-3H-1,2,3-benzotriazole (138.44 mg, 0.64 mmol, 1.20 equiv.), Pd(dppf)Cl·CHCl (43.61 mg, 0.05 mmol, 0.10 equiv.), DMF (4.0 mL), and EtN (0.22 mL, 1.60 mmol, 3.0 equiv.). The resulting solution was stirred at 140 °C overnight. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This gave 6.3 mg (4%) of (£)-N-(2,3-dihydro-lH-inden-l-yl)-3-(5-fluoro-lH-benzo[d][l,2,3]triazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =323 [ka]

[0292] Example 28: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(3-(trifluoromethyl)-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 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv.), 6-bromo-3-(trifluoromethyl)-1H-indazole (169.9 mg, 0.64 mmol, 1.20 equiv.), Pd(dppf)Cl·CHCl (43.61 mg, 0.05 mmol, 0.10 equiv.), DMF (4.0 mL), and EtN (0.22 mL, 1.60 mmol, 3.0 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 80 mg (40%) of (£)-N-(2,3-dihydro-lH-inden-l-yl)-3-(3-(trifluoromethyl)-lH-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =372 [ka]

[0293] Example 29: (E)—N-(2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide [ka] 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, 1.0 equiv. (prepared similarly to Intermediate 1 from acroyl chloride and 2,6-dimethylaniline), DMF (4.0 mL), 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (71.3 mg, 0.31 mmol, 1.10 equiv.), EtN (0.12 mL, 0.86 mmol, 3.0 equiv.), and Pd(dppf)Cl.CHCl (11.65 mg, 0.014 mmol, 0.05 equiv.). The resulting solution was stirred at 120 °C for 5 h. The reaction mixture was cooled to room temperature. The crude mixture was loaded onto a silica gel column using 1 / 1 EtOAc / PE. This gave 20 mg (22%) of (E)-N-(2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =322 [ka]

[0294] Example 30: (E)—N-(3-fluoro-2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide [ka] (Process 1) A 40 mL vial was charged with 1-bromo-4-fluoro-3-methyl-2-nitrobenzene (500.0 mg, 2.14 mmol, 1.0 equiv.), trimethyl-1,3,5,2,4,6-trioxatriborinane (268.20 mg, 2.13 mmol, 1.0 equiv.), KCO (590.6 mg, 4.27 mmol, 2.0 equiv.), and Pd(dppf)Cl (156.3 mg, 0.21 mmol, 0.10 equiv.) in dioxane (10.0 mL) and HO (2.0 mL). The resulting solution was stirred at 110 °C in an oil bath for 1 h. The crude mixture was applied to a silica gel column using EtOAc / PE (1 / 10). This afforded 250 mg (69%) of 1-fluoro-2,4-dimethyl-3-nitrobenzene as a solid.

[0295] [ka] (Process 2) A 40 mL vial was charged with 1-bromo-4-fluoro-3-methyl-2-nitrobenzene (0.50 g, 2.14 mmol, 1.0 equiv.) in AcOH (10.0 mL), and Fe (596.6 mg, 10.68 mmol, 5.0 equiv.) was added. The resulting solution was stirred for 1 h at room temperature. The solid was filtered off. The resulting solution was diluted with 20 mL of water and extracted with 40 mL of EtOAc. The organic layer was dried and concentrated. This afforded 250 mg (84%) of 3-fluoro-2,6-dimethylaniline as a solid. LC-MS (ES, m / z): [M+H] + =140

[0296] [ka] (Step 3) In an 8 mL vial, 6-bromo-3-fluoro-2-methylaniline (100.0 mg, 0.49 mmol, 1.0 equiv.) and EtN (0.2 mL, 1.47 mmol, 3.0 equiv.) were placed in DCM (4 mL), and acryloyl chloride (53.2 mg, 0.59 mmol, 1.20 equiv.) was added. The resulting solution was stirred for 1 h at 0 °C. The resulting mixture was concentrated in vacuo. The residue was purified by flash chromatography (PE / EA = 10 / 1). This afforded 120 mg (126.72%) of N-(3-fluoro-2,6-dimethylphenyl)prop-2-enamide as a white solid. LC-MS (ES, m / z): [M+H] + =194

[0297] [ka] (Step 4) An 8 mL round-bottom flask was charged with 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (100 mg, 0.44 mmol, 1.0 equiv.), N-(3-fluoro-2,6-dimethylphenyl)prop-2-enamide (85.1 mg, 0.44 mmol, 1.0 equiv.), Pd(dppf)Cl (32.2 mg, 0.044 mmol, 0.10 equiv.), EtN (0.18 mL, 1.32 mmol, 3.0 equiv.), and DMF (4.0 mL). The resulting solution was stirred in an oil bath at 120 °C for 2 hours. The mixture was loaded onto a silica gel column using PE / THF (1 / 1). This gave 45 mg (30%) of (£)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide as a solid. LC-MS (ES, m / z): [M+H] + =340 [ka]

[0298] Example 31: (E)-N-(2,6-dimethylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] 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, 1.0 equiv.), DCM (10.0 mL), and EtN (0.55 mL, 3.96 mmol, 3.0 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 at 25°C for 3 hours. The reaction was then quenched by the addition of 15 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 / 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

[0299] [ka] 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, 1.0 equiv.), DMF (5.0 mL), 6-bromo-3-methyl-1H-indazole (66.3 mg, 0.31 mmol, 1.10 equiv.), EtN (0.12 mL, 0.86 mmol, 3.0 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. The crude mixture was purified by flash preparative HPLC. This gave 30 mg (34%) of (£)-N-(2,6-dimethylphenyl)-3-(3-methyl-lH-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =306 [ka]

[0300] Example 32: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(3-ethyl-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 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv.), 6-bromo-3-ethyl-1H-indazole (144.3 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, 3.0 equiv.). The resulting solution was stirred overnight at 120 °C. The reaction mixture was cooled to room temperature. The crude product was purified by preparative HPLC. This gave 86 mg (49%) of (£)-N-(2,3-dihydro-lH-inden-l-yl)-3-(3-ethyl-lH-indazol-6-yl)acrylamide as an off-white solid. LC MS (ES, m / z): [M+H] + =332 [ka]

[0301] Example 33: (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide [ka] An 8 mL vial was charged with N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv), 6-bromo-3-cyclopropyl-1H-indazole (126.6 mg, 0.53 mmol, 1.0 equiv), Pd(dppf)Cl (39.1 mg, 0.05 mmol, 0.10 equiv), EtN (0.22 mL, 1.60 mmol, 3.0 equiv), and DMF (4 mL). The resulting solution was stirred in an oil bath at 120 °C for 2 hours. The reaction mixture was cooled. The mixture was loaded onto a silica gel column using PE / THF (1 / 1). This gave 15 mg (8%) of (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide as a solid. LC MS (ES, m / z): [M+H] + =344 [ka]

[0302] Example 34: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-3-methyl-1H-indazol-6-yl)acrylamide [ka] An 8 mL vial was charged with 6-bromo-4-fluoro-3-methyl-1H-indazole (Example 24, Step 1, 100.0 mg, 0.44 mmol, 1.0 equiv.), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (81.8 mg, 0.44 mmol, 1.0 equiv.), Pd(dppf)Cl (31.9 mg, 0.04 mmol, 0.10 equiv.), EtN (0.18 mL, 1.31 mmol, 3.0 equiv.), and DMF (4.0 mL). The resulting solution was stirred in an oil bath at 120° C. for 2 hours. The reaction mixture was cooled. The residue was applied to a silica gel column using PE / THF (1 / 1). This gave 17 mg (12%) of (£)-N-(2,3-dihydro-lH-inden-l-yl)-3-(4-fluoro-3-methyl-lH-indazol-6-yl)acrylamide as a solid. LC MS (ES, m / z): [M+H] + =336 [ka]

[0303] Example 35: (E)—N-(3,5-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide [ka] (Process 1) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 3,5-difluoroaniline (1.0 g, 7.8 mmol, 1.0 equiv.), CHCN (30 mL), and NCS (1.1 g, 8.16 mmol, 1.05 equiv.). The resulting solution was stirred at 80 °C for 5 h. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The residue was applied to a silica gel column using THF:PE (1:4 to 1:1). This afforded 500 mg (39%) of 4-chloro-3,5-difluoroaniline as a gray solid.

[0304] [ka] (Process 2) A 50 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 4-bromo-3,5-difluoroaniline (500.0 mg, 2.40 mmol, 1.0 equiv.), CHCN (20.0 mL), and NBS (1.3 g, 7.21 mmol, 3.0 equiv.). The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using THF:PE (1:5 to 1:3). This afforded 700 mg (91%) of 2,6-dibromo-4-chloro-3,5-difluoroaniline as a yellow solid.

[0305] [ka] (Step 3) A 250 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2,6-dibromo-4-chloro-3,5-difluoroaniline (3.0 g, 9.36 mmol, 1.0 equiv.), Pd(dppf)Cl.CHCl (0.76 g, 0.94 mmol, 0.10 equiv.), dioxane (60.0 mL), CsCO (12.20 g, 37.46 mmol, 4.0 equiv.), and trimethyl-1,3,5,2,4,6-trioxatriborinane (8.23 g, 32.77 mmol, 3.50 equiv., 50%). The resulting solution was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The crude mixture was purified by preparative HPLC. This gave 600 mg (33%) of 4-chloro-3,5-difluoro-2,6-dimethylaniline as an off-white solid.

[0306] [ka] (Step 4) A 100 mL pressure tank reactor was charged with 4-chloro-3,5-difluoro-2,6-dimethylaniline (280.0 mg, 1.46 mmol, 1.0 equiv), EtOH (20.0 mL), HCl (1.0 mL), and Pd / C (77.76 mg). The flask was evacuated and flushed with nitrogen three times, followed by hydrogen. The resulting solution was stirred at 70 °C under an atmosphere of hydrogen (30 atm) overnight. The reaction mixture was cooled to room temperature. The solids were filtered off, and the resulting mixture was concentrated. This afforded 220 mg (crude) of 3,5-difluoro-2,6-dimethylaniline hydrochloride as an off-white solid.

[0307] [ka] (Step 5) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 3,5-difluoro-2,6-dimethylaniline hydrochloride (220.0 mg, 1.14 mmol, 1.0 equiv.), DCM (20.0 mL), and EtN (0.48 mL, 3.41 mmol, 3.0 equiv.). Subsequently, acryloyl chloride (123.4 mg, 1.36 mmol, 1.20 equiv.) was added dropwise with stirring at 0 °C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using THF:PE (1:5 to 1:3). This afforded 160 mg (67%) of N-(3,5-difluoro-2,6-dimethylphenyl)prop-2-enamide as an off-white solid.

[0308] [ka] (Step 6) In an 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen, N-(3,5-difluoro-2,6-dimethylphenyl)prop-2-enamide (160.0 mg, 0.76 mmol, 1.0 equiv.), 6-bromo-1,3-dihydroindol-2-one (192.8 mg, 0.91 mmol, 1.20 equiv.), Pd(dppf)Cl·CHCl (61.7 mg, 0.076 mmol, 0.10 equiv.), DMF (5.0 mL), and EtN (0.32 mL, 2.27 mmol, 3.0 equiv.) were added. The resulting solution was stirred at 100 °C for 2 h, and the reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This gave 14.8 mg (6%) of (E)-N-(3,5-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide as a solid. LC MS (ES, m / z): [M+H] + =343 [ka]

[0309] Example 36: (E)—N-(3,4-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide [ka] (Process 1) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with benzeneamine, 3,4-difluoro- (1.0 g, 7.75 mmol, 1.0 equiv.), CHCN (30.0 mL), and NBS (2.9 g, 16.27 mmol, 2.10 equiv.). The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using THF:PE (1:5 to 1:3). This afforded 1.4 g (63%) of 2,6-dibromo-3,4-difluoroaniline as a dark brown solid.

[0310] [ka] (Process 2) A 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2,6-dibromo-3,4-difluoroaniline (1.20 g, 4.18 mmol, 1.0 equiv.), Pd(dppf)Cl2·CHCl2 (340.7 mg, 0.42 mmol, 0.10 equiv.), CsCO3 (4.8 g, 14.64 mmol, 3.50 equiv.), dioxane (50.0 mL), and trimethyl-1,3,5,2,4,6-trioxatriborinane (3.2 g, 12.55 mmol, 3.0 equiv., 50%). The resulting solution was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The crude mixture was purified by preparative HPLC. This gave 350 mg (53%) of 3,4-difluoro-2,6-dimethylaniline as an off-white solid.

[0311] [ka] (Step 3) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 3,4-difluoro-2,6-dimethylaniline (210.0 mg, 1.34 mmol, 1.0 equiv.), DCM (20 mL), and EtN (0.28 mL, 2.0 mmol, 1.50 equiv.). Subsequently, acryloyl chloride (145.13 mg, 1.60 mmol, 1.20 equiv.) was added dropwise at 0 °C with stirring. The resulting solution was stirred at room temperature for 2 h. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using THF:PE (1:5 to 1:3). This afforded 180 mg (64%) of N-(3,4-difluoro-2,6-dimethylphenyl)prop-2-enamide as an off-white solid.

[0312] [ka] (Step 4) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(3,4-difluoro-2,6-dimethylphenyl)prop-2-enamide (100.0 mg, 0.47 mmol, 1.0 equiv.), 6-bromo-1,3-dihydroindol-2-one (120.47 mg, 0.57 mmol, 1.20 equiv.), Pd(dppf)Cl·CHCl (38.57 mg, 0.05 mmol, 0.10 equiv.), DMF (4.0 mL), and EtN (0.2 mL, 1.42 mmol, 3.0 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 11.3 mg (7%) of (E)-N-(3,4-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide as an off-white solid. LCMS (ES, m / z): [M+H] + =343 [ka]

[0313] Example 37: (E)—N-(3-fluoro-2-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 110.0 mg, 0.61 mmol, 1.0 equiv.), 6-bromo-3-methyl-1H-indazole (155.47 mg, 0.74 mmol, 1.20 equiv.), Pd(dppf)Cl.CHCl (100.01 mg, 0.12 mmol, 0.20 equiv.), DMF (4.0 mL), and EtN (0.26 mL, 1.84 mmol, 3.0 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 26 mg (14%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC MS (ES, m / z): [M+H] + =310 [ka]

[0314] Example 38: (E)-3-(3-methyl-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide [ka] An 8 mL vial was charged with 6-bromo-3-methyl-1H-indazole (40.0 mg, 0.19 mmol, 1.0 equiv.), N-(2-methyl-2,3-dihydro-1H-inden-1-yl)prop-2-enamide (prepared using 2-methylindanamine according to Example 24, Step 1, 38.14 mg, 0.19 mmol, 1.0 equiv.), Pd(dppf)Cl (13.87 mg, 0.02 mmol, 0.10 equiv.), and EtN (0.8 mL, 0.57 mmol, 3.0 equiv.) in DMF (2.0 mL). The resulting solution was stirred in an oil bath at 120 °C for 2 hours. The reaction solution was cooled to room temperature. The crude mixture was purified by flash preparative HPLC. This gave 29 mg (44%) of (E)-3-(3-methyl-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC MS (ES, m / z): [M+H] + =332 [ka]

[0315] Example 39: (E)-3-(3-methyl-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 1-methylindazol-7-amine (400.0 mg, 2.71 mmol, 1.0 equiv.), DCM (10.0 mL), and EtN (0.6 mL, 4.07 mmol, 1.50 equiv.). Subsequently, acryloyl chloride (246 mg, 2.71 mmol, 1.0 equiv.) was added at −30° C. The resulting solution was stirred for 10 minutes at −30° C. The reaction was then quenched by the addition of 8 mL of water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was loaded onto a silica gel column using EtOAc / PE (15:85). This afforded 120 mg (21%) of N-(1-methylindazol-7-yl)prop-2-enamide as an off-white solid. LC MS (ES, m / z): [M+H] + =202

[0316] [ka] (Process 2) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(1-methylindazol-7-yl)prop-2-enamide (100.0 mg, 0.49 mmol, 1.0 equiv.), 6-bromo-3-methyl-1H-indazole (104.8 mg, 0.49 mmol, 1.0 equiv.), DMF (4.0 mL), EtN (0.14 mL, 0.99 mmol, 2.0 equiv.), and Pd(dppf)Cl CHCl (41 mg, 0.05 mmol, 0.10 equiv.). The resulting solution was stirred at 120 °C for 2 h. The crude mixture was purified by flash preparative HPLC. This gave 33 mg (20%) of (E)-3-(3-methyl-1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide as an off-white solid. LC MS (ES, m / z): [M+H] + =332 [ka]

[0317] Example 40: (E)—N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-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, 1.0 equiv), NaOAc (874.14 mg, 10.66 mmol, 2.0 equiv), MeOH (15.0 mL), and hydroxylamine hydrochloride (1.10 g, 15.98 mmol, 3.0 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 organic layer was concentrated. This afforded 810 mg (92%) of N-[5-fluoro-2,3-dihydroinden-1-ylidene]hydroxylamine as an off-white solid. LC MS (ES, m / z): [M+H] + =166

[0318] [ka] (Process 2) A 50 mL round-bottom flask was charged with N-[5-fluoro-2,3-dihydroinden-1-ylidene]hydroxylamine (810.0 mg, 4.90 mmol, 1.0 equiv) and MeOH (20.0 mL). Subsequently, Pd / C (104.38 mg) was added under H2. The resulting solution was stirred 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

[0319] [ka] (Step 3) A 25 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 5-fluoro-2,3-dihydro-1H-inden-1-amine (210.0 mg, 1.38 mmol, 1.0 equiv.), DCM (5.0 mL), and EtN (0.4 mL, 2.77 mmol, 2.0 equiv.). Subsequently, acryloyl chloride (188.58 mg, 2.08 mmol, 1.50 equiv.) was added at −30° C. The resulting solution was stirred for 10 minutes at −30° C. The reaction was then quenched by the addition of 5 mL of water. The organic layer was separated and concentrated. The residue was loaded onto a silica gel column using EtOAc / PE (80:20). This gave 200 mg (70%) of N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)prop-2-enamide as an off-white solid. LC MS (ES, m / z): [M+H] + =206

[0320] [ka] (Step 4) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)acrylamide (100.0 mg, 0.48 mmol, 1.0 equiv.), 6-bromo-3-methyl-1H-indazole (102.8 mg, 0.48 mmol, 1.0 equiv.), EtN (0.14 mL, 0.97 mmol, 2.0 equiv.), DMF (5.0 mL), and Pd(dppf)Cl·CHCl (39.69 mg, 0.05 mmol, 0.10 equiv.). The resulting solution was stirred at 120 °C for 2 h. The reaction solution was cooled to room temperature. The crude mixture was purified by flash preparative HPLC. This gave 34 mg (20%) of (£)-N-(5-fluoro-2,3-dihydro-lH-inden-l-yl)-3-(3-methyl-lH-indazol-6-yl)acrylamide as a white solid. LC MS (ES, m / z): [M+H] + =336 [ka]

[0321] Example 41: (E)-N-(4-fluoro-3-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] (Process 1) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 4-fluoro-3-methylaniline (600.0 mg, 4.79 mmol, 1.0 equiv.), DCM (20.0 mL), and EtN (2.0 mL, 14.38 mmol, 3.0 equiv.). Subsequently, acryloyl chloride (520.73 mg, 5.75 mmol, 1.20 equiv.) was added dropwise at 0 °C with stirring. The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using THF:PE (1:5 to 1:3). This afforded 400 mg (56%) of N-(4-fluoro-3-methylphenyl)prop-2-enamide as a pale yellow solid.

[0322] [ka] (Process 2) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(4-fluoro-3-methylphenyl)prop-2-enamide (110.0 mg, 0.61 mmol, 1.0 equiv.), 6-bromo-3-methyl-1H-indazole (155.47 mg, 0.74 mmol, 1.20 equiv.), Pd(dppf)Cl.CHCl (100.01 mg, 0.12 mmol, 0.20 equiv.), DMF (4.0 mL), and EtN (0.26 mL, 1.84 mmol, 3.0 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 20.4 mg (11%) of (E)-N-(4-fluoro-3-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC MS (ES, m / z): [M+H] + =310 [ka]

[0323] Example 42: (E)—N-(3-fluoro-4-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] (Process 1) A 100 mL three-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with 3-fluoro-4-methylaniline (550.0 mg, 4.40 mmol, 1.0 equiv.), DCM (20.0 mL), and EtN (1.2 mL, 8.79 mmol, 2.0 equiv.). Subsequently, acryloyl chloride (477.34 mg, 5.27 mmol, 1.20 equiv.) was added dropwise at 0 °C with stirring. The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using THF:PE (1:5 to 1:3). This afforded 450 mg (57%) of N-(3-fluoro-4-methylphenyl)prop-2-enamide as an off-white solid.

[0324] [ka] (Process 2) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(3-fluoro-4-methylphenyl)prop-2-enamide (110.0 mg, 0.61 mmol, 1.0 equiv.), 6-bromo-3-methyl-1H-indazole (155.5 mg, 0.74 mmol, 1.20 equiv.), Pd(dppf)Cl.CHCl (100.0 mg, 0.12 mmol, 0.20 equiv.), DMF (4.0 mL), and EtN (0.26 mL, 1.84 mmol, 3.0 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 35.8 mg (19%) of (E)-N-(3-fluoro-4-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC MS (ES, m / z): [M+H] + =310 [ka]

[0325] Example 43: Racemic (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide [ka] (Process 1) A 25 mL three-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with racemic trans-(1R,2R)-2-methylcyclohexan-1-amine hydrochloride (300.0 mg, 2.0 mmol, 1.0 equiv.), DCM (6.0 mL), and EtN (0.84 mL, 6.01 mmol, 3.0 equiv.). Subsequently, acryloyl chloride (181.43 mg, 2.0 mmol, 1.0 equiv.) was added at 0°C. The resulting solution was stirred at room temperature for 40 minutes. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was diluted with 10 mL of DCM. The resulting mixture was washed with 10 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (22:78). This gave 200 mg (60%) of N-[(1R,2R)-2-methylcyclohexyl]prop-2-enamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =168

[0326] [ka] (Process 2) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with DMF (4.0 mL), N-[(1R,2R)-2-methylcyclohexyl]prop-2-enamide (100.0 mg, 0.60 mmol, 1.0 equiv.), 6-bromo-3-methyl-1H-indazole (126.0 mg, 0.60 mmol, 1.0 equiv.), EtN (0.25 mL, 1.79 mmol, 3.0 equiv.), and Pd(dppf)Cl CHCl (48.71 mg, 0.06 mmol, 0.10 equiv.). The resulting solution was stirred at 120 °C for 2 h. The crude mixture was purified by flash preparative HPLC. This gave 41 mg (23%) of racemic (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide as an off-white solid. LC MS (ES, m / z): [M+H] + =298 [ka]

[0327] Example 44: (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide [ka] An 8 mL vial was charged with 6-bromo-1H-indazole-3-carbonitrile (40.0 mg, 0.18 mmol, 1.0 equiv.), N-(2-methyl-2,3-dihydro-1H-inden-1-yl)prop-2-enamide (prepared using 2-methylindanamine according to Example 24, Step 1, 36.26 mg, 0.18 mmol, 1.0 equiv.), Pd(dppf)Cl (13.18 mg, 0.018 mmol, 0.10 equiv.), and EtN (0.075 mL, 0.54 mmol, 3.0 equiv.) in DMF (2.0 mL). The resulting solution was stirred at 120 °C in an oil bath for 2 hours. The mixture was cooled to room temperature. The crude mixture was purified by flash preparative HPLC. This gave 16 mg (26%) of (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC MS (ES, m / z): [M+H] + =343 [ka]

[0328] Example 45: (E)—N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide [ka] An 8 mL vial was charged with 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (50.0 mg, 0.22 mmol, 1.0 equiv.), N-(2-methyl-2,3-dihydro-1H-inden-1-yl)prop-2-enamide (prepared using 2-methylindanamine according to Example 24, Step 1, 44.3 mg, 0.22 mmol, 1.0 equiv.), Pd(dppf)Cl (16.1 mg, 0.022 mmol, 0.10 equiv.), and EtN (0.092 mL, 0.66 mmol, 3.0 equiv.) in DMF (2.0 mL). The resulting solution was stirred at 120 °C in an oil bath for 2 hours. The reaction solution was cooled to room temperature. The crude mixture was purified by flash preparative HPLC. This gave 29 mg (38%) of (£)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide as an off-white solid. LC MS (ES, m / z): [M+H] + =348 [ka]

[0329] Example 46: (E)—N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] An 8 mL vial was charged with 2-benzoxazolinone, 5-bromo- (50.0 mg, 0.23 mmol, 1.0 equiv.), N-(2-methyl-2,3-dihydro-1H-inden-1-yl)prop-2-enamide (prepared using 2-methylindanamine according to Example 24, Step 1, 47.0 mg, 0.23 mmol, 1.0 equiv.), Pd(dppf)Cl (17.1 mg, 0.023 mmol, 0.10 equiv.), and EtN (0.098 mL, 0.70 mmol, 3.0 equiv.) in DMF (2.0 mL). The resulting solution was stirred in an oil bath at 120 °C for 2 hours. The reaction solution was cooled to room temperature. The crude mixture was purified by flash preparative HPLC. This gave 29 mg (37%) of (£)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as an off-white solid. LCMS (ES, m / z): [M+H] + =335 [ka]

[0330] Example 47: (Z)-2-fluoro-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide [ka] (Process 1) A 40 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with DMF (20.0 mL), 6-bromo-1,3-dihydroindol-2-one (1.0 g, 4.72 mmol, 1.0 equiv), methyl 2-fluoroacrylate (0.59 g, 5.66 mmol, 1.20 equiv), Pd(dppf)Cl.CHCl (77.0 mg, 0.094 mmol, 0.02 equiv), and EtN (1.3 mL, 9.43 mmol, 2.0 equiv). The resulting solution was stirred at 110 °C for 2 h. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using (25 / 75) elution. This gave 420 mg (37%) of methyl 2-fluoro-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2-enoate as a yellow solid. LC-MS-PH-NRG0255-1 (ES, m / z): [MH] + =234

[0331] [ka] (Process 2) An 8 mL sealed tube was charged with methyl 2-fluoro-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2-enoate (150.0 mg, 0.64 mmol, 1.0 equiv.), 3-fluoro-2-methyl-aniline (239.42 mg, 1.91 mmol, 3.0 equiv.), and THF (3.0 mL). Subsequently, LiHMDS (1.92 mL, 1.92 mmol, 3.0 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 HO. The resulting solution was extracted with 2 × 10 mL of EtOAc. The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash preparative HPLC. This gave 28 mg (13%) of (Z)-2-fluoro-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide as a white solid. LC MS (ES, m / z): [M+H] + =329 [ka]

[0332] Example 48: (E)-N-(3-chloro-2-methylphenyl)-N-methyl-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was charged with (E)-methyl 3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate (prepared by Example 11, Step 2, 30.0 mg, 0.14 mmol, 1.0 equiv.) in THF (2.0 mL). 3-Chloro-N,2-dimethylbenzenamine (27.60 mg, 0.18 mmol, 1.30 equiv.) was then added. The reaction mixture was cooled to 0° C. 1 M LiHMDS (0.68 mL, 0.68 mmol, 5.0 equiv.) was then added. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was quenched with 1 mL of water, extracted with 2×5 mL of EtOAc, and the organic layer was concentrated in vacuo to give the crude product. The crude product was then purified by preparative HPLC. This gave 9.6 mg (21%) of (£)-N-(3-chloro-2-methylphenyl)-N-methyl-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =343

[0333] Example 49: (E)—N-(2-methylcyclopentyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was charged with (E)-methyl 3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate (prepared by Example 11, Step 2, 30.0 mg, 0.14 mmol, 1.0 equiv.) in THF (2.0 mL). 2-Methylcyclopentanamine (17.6 mg, 0.18 mmol, 1.30 equiv.) was then added. The reaction mixture was cooled to 0° C. 1 M LiHMDS (0.68 mL, 0.68 mmol, 5.0 equiv.) was then added. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was quenched with 1 mL of water, extracted with 2×5 mL of EtOAc, and the organic layer was concentrated in vacuo to give the crude product. The crude product was then purified by preparative HPLC. This gave 19 mg (48%) of (E)-N-(2-methylcyclopentyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =287

[0334] Example 50: (E)—N-(3-fluoro-2-(methoxymethyl)phenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] (Process 1) A 250 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with THF (50.0 mL) and 2-fluoro-6-nitrobenzoic acid (2.0 g, 10.80 mmol, 1.0 equiv.). Subsequently, borane (32.41 mL, 32.41 mmol, 3.0 equiv., 1 M / THF) was added at 0° C. The resulting solution was stirred for 10 hours at 50° C. The reaction was then quenched by the addition of 20 mL of 3 M HCl. The resulting solution was diluted with 50 mL of EtOAc. The organic layer was washed with 2×30 mL of brine. The solution was dried over sodium sulfate and evaporated under reduced pressure. This afforded 1.3 g (70%) of (2-fluoro-6-nitrophenyl)methanol as a light brown solid.

[0335] [ka] (Process 2) A 40 mL sealed tube was charged with (2-fluoro-6-nitrophenyl)methanol (1.30 g, 7.59 mmol, 1.0 equiv.), DMF (20.0 mL), and methyl iodide (5.39 g, 37.98 mmol, 5.0 equiv.). Subsequently, Cs2CO3 (3.71 g, 11.39 mmol, 1.50 equiv.) was added at 0 °C. The resulting solution was stirred at 50 °C for 5 h. The solid was filtered off. The filtrate solution was diluted with 100 mL of EtOAc. The resulting mixture was washed with 3 × 50 mL of H2O and 50 mL of brine. The organic layer was dried over sodium sulfate and evaporated. The crude product was purified by flash preparative HPLC. This afforded 0.91 g (64%) of 1-fluoro-2-(methoxymethyl)-3-nitrobenzene as a yellow oil.

[0336] [ka] (Step 3) A 40 mL sealed tube was charged with 1-fluoro-2-(methoxymethyl)-3-nitrobenzene (0.70 g, 3.78 mmol, 1.0 equiv.), MeOH (20.0 mL), HO (3.0 mL), and NHCl (1.21 g, 22.68 mmol, 6.0 equiv.). Zn (1.24 g, 18.90 mmol, 5.0 equiv.) was then added at 10 °C. The resulting solution was stirred at 25 °C for 1 h. The solid was filtered off. The resulting solution was diluted with 20 mL of DCM. The mixture was dried over anhydrous sodium sulfate and concentrated (cold). This afforded 0.21 g (35%) of 3-fluoro-2-(methoxymethyl)aniline as a light brown oil (this amine was unstable and was used immediately in the next step). LC-MS (ES, m / z): [M+H] + =156

[0337] [ka] (Step 4) An 8 mL sealed tube was charged with 3-fluoro-2-(methoxymethyl)aniline (200.0 mg, 1.28 mmol, 1.0 equiv.), DCM (4.0 mL), and EtN (0.36 mL, 2.57 mmol, 2.0 equiv.). Subsequently, acryloyl chloride (116.6 mg, 1.28 mmol, 1.0 equiv.) was added at 0° C. The resulting solution was stirred for 0.5 h at 0° C. The reaction was then quenched by the addition of 2 mL of water. The resulting mixture was washed with 2 mL of brine. The organic layer was dried over sodium sulfate and concentrated. This afforded 160 mg (59%) of N-[3-fluoro-2-(methoxymethyl)phenyl]prop-2-enamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =210

[0338] [ka] (Step 5) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-[3-fluoro-2-(methoxymethyl)phenyl]prop-2-enamide (100.0 mg, 0.47 mmol, 1.0 equiv.), DMF (4.0 mL), 6-bromo-3-methyl-1H-indazole (100.88 mg, 0.47 mmol, 1.0 equiv.), EtN (0.2 mL, 1.43 mmol, 3.0 equiv.), and Pd(dppf)Cl·CHCl (38.94 mg, 0.048 mmol, 0.10 equiv.). The resulting solution was stirred at 120 °C for 2 h. The crude mixture was purified by flash preparative HPLC. This gave 71 mg (43%) of (E)-N-(3-fluoro-2-(methoxymethyl)phenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =340 [ka]

[0339] Example 51: (E)-3-(3-cyano-1H-indazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide [ka] (Process 1) A 40 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with 6-bromo-1H-indazole-3-carbonitrile (220.0 mg, 0.99 mmol, 1.0 equiv), dihydropyran (416.7 mg, 4.95 mmol, 5.0 equiv), DCM (10.0 mL), and TsOH (34.1 mg, 0.20 mmol, 0.20 equiv). The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using THF:PE (1:20 to 1:8). This afforded 300 mg (99%) of 6-bromo-1-(oxan-2-yl)indazole-3-carbonitrile as an off-white solid.

[0340] [ka] (Process 2) In an 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen, N-(3-fluoro-2-methylphenyl)acrylamide (150.0 mg, 0.84 mmol, 1.0 equiv.), 6-bromo-1-(oxan-2-yl)indazole-3-carbonitrile (307.5 mg, 1.0 mmol, 1.20 equiv.), Pd(dppf)Cl₂·CHCl₂ (68.2 mg, 0.08 mmol, 0.10 equiv.), DMF (4.0 mL), and EtN (0.35 mL, 2.51 mmol, 3.0 equiv.) were added. The resulting solution was stirred at 120 °C for 3 h. The reaction mixture was cooled to room temperature. The mixture was loaded onto a silica gel column using THF:PE (1:4 to 1:1). This gave 150 mg (44%) of (2E)-3-[3-cyano-1-(oxan-2-yl)indazol-6-yl]-N-(3-fluoro-2-methylphenyl)acrylamide as a light brown solid.

[0341] [ka] (Step 3) A 40 mL sealed tube was charged with (2E)-3-[3-cyano-1-(oxan-2-yl)indazol-6-yl]-N-(3-fluoro-2-methylphenyl)acrylamide (150.0 mg, 0.37 mmol, 1.0 equiv.) and 4 M HCl / dioxane (10 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 12.5 mg (11%) of (E)-3-(3-cyano-1H-indazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =321 [ka]

[0342] Example 52: (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-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 3-methyl-3,4-dihydro-2H-1-benzopyran-4-amine (110.0 mg, 0.67 mmol, 1.0 equiv.), DCM (10.0 mL), and EtN (0.19 mL, 1.35 mmol, 2.0 equiv.). Subsequently, acryloyl chloride (67.10 mg, 0.74 mmol, 1.10 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 10 mL of water. The resulting solution was extracted with 2×15 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 110 mg (75%) of N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)prop-2-enamide as a pale yellow solid. LC-MS (ES, m / z): [M+H] + =218

[0343] [ka] (Process 2) An 8 mL vial purged and maintained under an inert atmosphere of nitrogen was charged with N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)prop-2-enamide (120.0 mg, 0.55 mmol, 1.0 equiv.), DMF (5.0 mL), 6-bromo-3-methyl-1H-indazole (116.6 mg, 0.55 mmol, 1.0 equiv.), EtN (0.23 mL, 1.66 mmol, 3.0 equiv.), and Pd(dppf)Cl.CHCl (22.50 mg, 0.028 mmol, 0.05 equiv.). The resulting solution was stirred at 120 °C for 5 h. The reaction mixture was cooled to room temperature. The residue was loaded onto a silica gel column using EtOAc (1 / 3). This gave 55 mg (29%) of (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =348 [ka]

[0344] Example 53: (E)—N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-methyl-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-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (160.0 mg, 0.99 mmol, 1.0 equiv.), DCM (10.0 mL), and EtN (0.28 mL, 1.98 mmol, 2.0 equiv.). Subsequently, acryloyl chloride (98.79 mg, 1.09 mmol, 1.10 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 DCM, 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 / 5). This gave 140 mg (66%) of N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)prop-2-enamide as a pale yellow solid. LC-MS (ES, m / z): [M+H] + =216

[0345] [ka] (Process 2) An 8 mL vial purged and maintained under an inert atmosphere of nitrogen was charged with N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)prop-2-enamide (140.0 mg, 0.65 mmol, 1.0 equiv.), DMF (5.0 mL), 6-bromo-3-methyl-1H-indazole (137.3 mg, 0.65 mmol, 1.0 equiv.), EtN (0.27 mL, 1.95 mmol, 3.0 equiv.), and Pd(dppf)Cl.CHCl (26.5 mg, 0.033 mmol, 0.05 equiv.). The resulting solution was stirred at 120 °C for 5 h. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This gave 30 mg (13%) of (£)-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H]+=346 [ka]

[0346] Example 54: (E)—N-((1S,2S)-2-Methoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] (Process 1) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with (1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-amine hydrochloride (300.0 mg, 1.50 mmol, 1.0 equiv.), DCM (20.0 mL), and EtN (0.31 mL, 2.25 mmol, 1.50 equiv.). Subsequently, acryloyl chloride (163.2 mg, 1.80 mmol, 1.20 equiv.) was added dropwise at 0°C with stirring. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using THF:PE (1:5 to 1:3). This gave 200 mg (61%) of N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide as an off-white solid.

[0347] [ka] (Process 2) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (140.0 mg, 0.64 mmol, 1.0 equiv.), 6-bromo-3-methyl-1H-indazole (163.2 mg, 0.77 mmol, 1.20 equiv.), Pd(dppf)Cl·CHCl (52.5 mg, 0.064 mmol, 0.10 equiv.), DMF (4 mL), and EtN (0.27 mL, 1.93 mmol, 3.0 equiv.). The resulting solution was stirred at 120 °C for 1 h. The reaction mixture was cooled to room temperature. The crude mixture was purified by flash preparative HPLC. This gave 28.6 mg (13%) of (E)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =348 [ka]

[0348] Example 55: (R,E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] (Process 1) An 8 mL sealed tube was charged with (1R)-2,3-dihydro-1H-inden-1-amine (100.0 mg, 0.75 mmol, 1.0 equiv.), DCM (5.0 mL), and EtN (0.21 mL, 1.50 mmol, 2.0 equiv.). Subsequently, acryloyl chloride (81.54 mg, 0.90 mmol, 1.20 equiv.) was added at −30° C. The resulting solution was stirred for 10 minutes at −30° C. The reaction was then quenched by the addition of 5 mL of water. The organic phase was dried over NaSO and concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (15:75). This afforded 93 mg (66%) of N-[(1R)-2,3-dihydro-1H-inden-1-yl]prop-2-enamide as a white solid. LC-MS-PH-NRG0457-1 (ES, m / z): [M+H] + =188

[0349] [ka] (Process 2) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-[(1R)-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (60.0 mg, 0.32 mmol, 1.0 equiv.), 6-bromo-3-methyl-1H-indazole (67.63 mg, 0.32 mmol, 1.0 equiv.), DMF (2.0 mL), EtN (0.09 mL, 0.64 mmol, 2.0 equiv.), and Pd(dppf)Cl·CHCl (5.2 mg, 0.06 mmol, 0.02 equiv.). The resulting solution was stirred at 120 °C for 2 h. The crude mixture was purified by flash preparative HPLC. This gave 41 mg (40%) of (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =318 [ka]

[0350] Example 56: (E)-N-(chroman-4-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] Prepared according to Example 11, step 4 using (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylic acid and chroman-4-amine to give (E)-N-(chroman-4-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =337

[0351] Example 57: (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)acrylamide [ka] Prepared according to example 11, step 4 using (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylic acid and 1,2,3,4-tetrahydronaphthalen-1-amine to give (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =335

[0352] Example 58: (E)—N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-oxoindolin-6-yl)acrylamide [ka] An 8 mL vial was charged with (£)-3-(2-oxoindolin-6-yl)acrylic acid (50.0 mg, 0.25 mmol, 1.00 equiv.), 2-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (40.3 mg, 0.25 mmol, 1.00 equiv.), HATU (141.4 mg, 0.37 mmol, 1.50 equiv.), and DIPEA (95.4 mg, 0.74 mmol, 3.00 equiv.) in DMF (2.00 mL). The resulting solution was stirred for 2 hours at 20°C. The mixture was purified by flash preparative HPLC. This gave 19 mg (22%) of (£)-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-oxoindolin-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H]+=347 [ka]

[0353] Example 59: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide [ka] An 8 mL vial was charged with (E)-3-(2-oxoindolin-6-yl)acrylic acid (50.0 mg, 0.25 mmol, 1.00 equiv.), 2,3-dihydro-1H-inden-1-amine (33.3 mg, 0.25 mmol, 1.00 equiv.), HATU (141.4 mg, 0.37 mmol, 1.50 equiv.), and DIPEA (95.4 mg, 0.74 mmol, 3.00 equiv.) in DMF (2.00 mL). The resulting solution was stirred for 2 hours at 20°C. The mixture was purified by flash preparative HPLC. This afforded 15 mg (19%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H]+=319 [ka]

[0354] Example 60: (E)—N-(3,5-difluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide [ka] (Process 1) A 100 mL pressure tank reactor was charged with 4-chloro-3,5-difluoro-2-methylaniline (160.00 mg, 0.90 mmol, 1.00 equiv), EtOH (30.00 mL), 4 M HCl / EtOH (1.00 mL), and Pd / C (47.94 mg). The flask was evacuated and flushed with nitrogen three times, followed by hydrogen. The resulting solution was stirred at 70 °C under an atmosphere of hydrogen (30 atm) overnight. The reaction mixture was cooled to room temperature. The solids were removed by filtration. The resulting mixture was concentrated. This afforded 120 mg (crude) of 3,5-3,5-difluoro-2-methylaniline hydrochloride.

[0355] [ka] (Process 2) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 3,5-difluoro-2-methylaniline hydrochloride (120.00 mg, 0.67 mmol, 1.00 equiv.), DCM (20 mL), and EtN (0.28 mL, 2.01 mmol, 3.00 equiv.). Subsequently, acryloyl chloride (90.7 mg, 1.00 mmol, 1.50 equiv.) was added dropwise at 0 °C with stirring. The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using THF:PE (1:5 to 1:3). This afforded 120 mg (91%) of N-(3,5-difluoro-2-methylphenyl)prop-2-enamide as an off-white solid.

[0356] [ka] (Step 3) In an 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen, N-(3,5-difluoro-2-methylphenyl)prop-2-enamide (120.00 mg, 0.61 mmol, 1.00 equiv.), 6-bromo-1,3-dihydroindol-2-one (154.9 mg, 0.73 mmol, 1.20 equiv.), Pd(dppf)Cl.CHCl (49.6 mg, 0.06 mmol, 0.10 equiv.), DMF (4.00 mL), and EtN (0.25 mL, 1.83 mmol, 3.00 equiv.) were added. The resulting solution was stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This gave 11.3 mg (6%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =329 [ka]

[0357] Example 61: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide [ka] An 8 mL round-bottom flask was charged with 5-bromo-4-fluoro-3H-1,2,3-benzotriazole (50.0 mg, 0.23 mmol, 1.00 equiv.), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (43.3 mg, 0.23 mmol, 1.00 equiv.), Pd(dppf)Cl (16.9 mg, 0.023 mmol, 0.10 equiv.), EtN (0.096 mL, 0.70 mmol, 3.00 equiv.), and DMF (3.00 mL). The resulting solution was stirred in an oil bath at 120 °C for 2 hours. The reaction mixture was cooled. The residue was applied to a silica gel column using PE / THF (1 / 1). This gave 19 mg (25%) of (£)-N-(2,3-dihydro-lH-inden-l-yl)-3-(7-fluoro-lH-benzo[d][l,2,3]triazol-6-yl)acrylamide as a solid. LC-MS (ES, m / z): [M+H] + =323 [ka]

[0358] Example 62: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide [ka] An 8 mL round-bottom flask was charged with 6-bromo-4-fluoro-1H-1,2,3-benzotriazole (40.00 mg, 0.18 mmol, 1.00 equiv.), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (34.7 mg, 0.18 mmol, 1.00 equiv.), Pd(dppf)Cl (13.6 mg, 0.019 mmol, 0.10 equiv.), and EtN (0.077 mL, 0.55 mmol, 3.00 equiv.) in DMF (2.00 mL). The resulting solution was stirred in an oil bath at 120 °C for 1 hour. The reaction mixture was cooled. The mixture was loaded onto a silica gel column using PE / THF (1 / 1). This gave 17.8 mg (30%) of (£)-N-(2,3-dihydro-lH-inden-l-yl)-3-(4-fluoro-lH-benzo[d][l,2,3]triazol-6-yl)acrylamide as a white solid. LC MS (ES, m / z): [M+H] + =323 [ka]

[0359] Example 63: (E)—N-(5-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with (E)-methyl 3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate (30.0 mg, 0.14 mmol, 1.00 equiv.) in THF (2.00 mL). 5-Chloro-2-methylbenzenamine (25.4 mg, 0.18 mmol, 1.30 equiv.) was then added. The reaction mixture was cooled to 0° C. 1 M LiHMDS (0.68 mL, 0.68 mmol, 5.00 equiv.) was then added. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was quenched with 1 mL of water, extracted with 2×5 mL of ETOAc, and the organic layer was concentrated in vacuo to give the crude product. The crude product was then purified by preparative HPLC. This gave 5 mg (11%) of (£)-N-(5-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =329 [ka]

[0360] Example 64: (E)-N-(2-methylcyclohexyl)-3-(2-oxoindolin-6-yl)acrylamide [ka] An 8 mL vial was charged with (E)-3-(2-oxoindolin-6-yl)acrylic acid (50.00 mg, 0.25 mmol, 1.00 equiv.), 2-methylcyclohexanamine (28.25 mg, 0.25 mmol, 1.00 equiv.), HATU (141.38 mg, 0.37 mmol, 1.50 equiv.), and DIPEA (95.41 mg, 0.74 mmol, 3.00 equiv.) in DMF (2.00 mL). The resulting solution was stirred for 2 hours at 20°C. The mixture was purified by flash preparative HPLC. This afforded 8.3 mg (11%) of (E)-N-(2-methylcyclohexyl)-3-(2-oxoindolin-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =299

[0361] Example 65: (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide [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 (15.00 g, 101.24 mmol, 1.00 equiv.) and THF (200 mL). Subsequently, LiHMDS (1 M in THF, 1.20 equiv.) was added dropwise with stirring at −78° C. The resulting solution was stirred at −78° C. for 40 minutes. To this was added a solution of MeI (17.24 g, 121.49 mmol, 1.20 equiv.) in THF (10 mL) dropwise with stirring at −78° C. The resulting solution was allowed to react at −78° C. for an additional 40 minutes with stirring, followed by stirring at 25° C. for an additional hour. The reaction was then quenched by the addition of 150 mL of NH4Cl. The resulting solution was extracted with 2 x 150 mL of ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1 / 10). This afforded 5 g (30% yield) of 3-methyl-2,3-dihydro-1-benzopyran-4-one as a pale yellow oil.

[0362] [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 (1.10 g, 6.78 mmol, 1.00 equiv.), MeOH (20.00 mL), NHOH.HCl (1.41 g, 20.35 mmol, 3.00 equiv.), and EtN (2.06 g, 20.35 mmol, 3.00 equiv.). The resulting solution was stirred at 70 °C for 15 hours. The resulting mixture was concentrated. The resulting solution 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% yield) of N-[(4E)-3-methyl-2,3-dihydro-1-benzopyran-4-ylidene]hydroxylamine as a white solid.

[0363] [ka] (Step 3) A 100 mL single-neck round-bottom flask purged and maintained with an inert atmosphere of H was charged with 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). The resulting solution was stirred for 12 hours at 40 °C. The solids were removed by filtration. The resulting mixture was concentrated. This afforded 530 mg (82% yield) of 3-methyl-3,4-dihydro-2H-1-benzopyran-4-amine as a pale yellow oil.

[0364] [ka] (Step 4) A 40 mL vial was charged with 3-methyl-3,4-dihydro-2H-1-benzopyran-4-amine (300.00 mg, 1.838 mmol, 1.00 equiv.), DCM (10.00 mL), and EtN (371.98 mg, 3.676 mmol, 2.00 equiv.). Subsequently, a solution of acryloyl chloride (182.99 mg, 2.022 mmol, 1.10 equiv.) in DCM (2 mL) was added dropwise with stirring at 0°C. The resulting solution was stirred for 5 hours at 0°C. The reaction was then quenched by the addition of 8 mL of water. The resulting solution was extracted with 2 × 15 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 ethyl acetate / petroleum ether (1 / 2). This gave 280 mg (70% yield) of N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)prop-2-enamide as an off-white solid.

[0365] [ka] (Step 5) A 20 mL vial purged and maintained under an inert atmosphere of nitrogen was charged with N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)prop-2-enamide (150.00 mg, 0.690 mmol, 1.00 equiv.), DMF (6.00 mL), 6-bromo-3-methyl-1H-indazole (145.72 mg, 0.690 mmol, 1.00 equiv.), EtN (174.65 mg, 1.725 mmol, 2.50 equiv.), and Pd(dppf)Cl.CHCl (33.74 mg, 0.041 mmol, 0.06 equiv.). The resulting solution was stirred overnight at 120 °C. The reaction mixture was cooled to room temperature. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1 / 1). This gave 110 mg of a racemic mixture of cis / trans isomers as a pale yellow solid. This mixture was purified by chiral preparative HPLC to give four separate stereoisomers, including (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4R)-3-methylchroman-4-yl)acrylamide (Example 65c). The cis-trans isomers were assigned using NOESY NMR. The stereochemistry of each enantiomeric pair has been arbitrarily assigned.

[0366] Example 65a: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4S)-3-methylchroman-4-yl)acrylamide LC-MS (ES, m / z): [M+H] + =348 [ka]

[0367] Example 65b: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4R)-3-methylchroman-4-yl)acrylamide LC-MS1 (ES, m / z): [M+H] + =348 [ka]

[0368] Example 65c: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4R)-3-methylchroman-4-yl)acrylamide LC-MS (ES, m / z): [M+H] + =348 [ka]

[0369] Example 65d: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4S)-3-methylchroman-4-yl)acrylamide LC-MS (ES, m / z): [M+H] + =348 [ka]

[0370] Example 66: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl)acrylamide [ka] (Process 1) A 100 mL three-necked round-bottom flask was charged with oxetan-3-ylmethanol (2.00 g, 22.70 mmol, 1.00 equiv), trifluoromethanesulfonic anhydride (9.61 g, 34.050 mmol, 1.50 equiv), EtN (4.59 g, 45.40 mmol, 2.00 equiv), and DCM (50.00 mL). The resulting solution was stirred for 10 h at 20 °C. The resulting mixture was washed with 2 × 50 mL of aqueous NaCO and 1 × 50 mL of aqueous NaCl. The organic layer was dried over anhydrous sodium sulfate, concentrated, and used in the next step without purification.

[0371] [ka] (Process 2) A 100 mL three-necked round-bottom flask was charged with tert-butyl N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamate (1.00 g, 4.01 mmol, 1.00 equiv.), oxetan-3-ylmethyl trifluoromethanesulfonate (0.88 g, 4.01 mmol, 1.00 equiv.), and NaH (0.14 g, 6.01 mmol, 1.50 equiv.) in THF (20.00 mL). The resulting solution was stirred for 10 hours at 20 °C. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 2 × 20 mL of ethyl acetate, and the organic layers were combined. The organic layer was concentrated, and the residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1 / 1). This gave 150 mg of tert-butyl N-[(1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl]carbamate as a solid.

[0372] [ka] (Step 3) An 8 mL vial was charged with MeOH (2.00 mL) and tert-butyl N-[(1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl]carbamate (140.00 mg, 0.438 mmol, 1.00 equiv.) in 2 M HCl (g) in MeOH (2.00 mL). The resulting solution was stirred for 2 hours at 10° C. The resulting mixture was concentrated. This afforded 35 mg of (1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-amine as a solid.

[0373] [ka] (Step 4) An 8 mL vial was charged with (1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-amine (25.00 mg, 0.114 mmol, 1.00 equiv.), (E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid (Intermediate 3, 22.83 mg, 0.114 mmol, 1.00 equiv.), HATU (65.02 mg, 0.171 mmol, 1.50 equiv.), and EtN (34.61 mg, 0.342 mmol, 3.00 equiv.) in DMF (3.00 mL). The resulting solution was stirred for 2 hours at 20 °C. The crude mixture was purified by preparative HPLC. This gave 15 mg of (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =404 [ka]

[0374] Example 67: (E)—N-((1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] (Process 1) An 8 mL vial was charged with tert-butyl N-(2-hydroxy-octahydro-1H-inden-1-yl)carbamate (200.00 mg, 0.783 mmol, 1.00 equiv.), allyl bromide (94.75 mg, 0.783 mmol, 1.00 equiv.), and NaH (5.00 mg, 0.783 mmol, 60%) in THF (3.00 mL). The resulting solution was stirred for 10 hours at 20° C. The reaction was then quenched by the addition of 0.5 mL of water. The mixture was concentrated, and the residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1 / 1). This gave 150 mg (66% yield) of tert-butyl N-[(1S,2S)-2-(prop-2-en-1-yloxy)-2,3-dihydro-1H-inden-1-yl]carbamate as a pale yellow solid.

[0375] [ka] (Process 2) A 40 mL vial was charged with tert-butyl N-[2-(prop-2-en-1-yloxy)-octahydro-1H-inden-1-yl]carbamate (140.00 mg, 0.474 mmol, 1.00 equiv.), 1 M ZnEt (4.74 mL, 4.739 mmol, 10.00 equiv.), CHCl (1015.41 mg, 3.791 mmol, 8.00 equiv.), and TFA (432.28 mg, 3.791 mmol, 8.00 equiv.) in DCM (5.00 mL). The resulting solution was stirred for 10 hours at 20 °C. The mixture was concentrated, and the residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (10 / 1). This gave 70 mg (48% yield) of tert-butyl N-[(1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl]carbamate as a solid.

[0376] [ka] (Step 3) An 8 mL vial was charged with MeOH (3.00 mL) and tert-butyl N-[2-(cyclopropylmethoxy)-octahydro-1H-inden-1-yl]carbamate (50.00 mg, 1.00 equiv.) in 2 M HCl (g) in MeOH (3.00 mL). The resulting solution was stirred for 2 hours at 20° C. The resulting mixture was concentrated. This afforded 30 mg of (1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-amine as an off-white solid.

[0377] [ka] (Step 4) An 8 mL vial was charged with (1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-amine (20.00 mg, 0.098 mmol, 1.00 equiv.), (E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid (19.70 mg, 0.098 mmol, 1.00 equiv.), HATU (56.11 mg, 0.148 mmol, 1.50 equiv.), and EtN (29.87 mg, 0.295 mmol, 3.00 equiv.) in DMF (2.00 mL). The resulting solution was stirred for 2 hours at 20 °C. The mixture was purified by flash preparative HPLC. This gave 20 mg (52% yield) of (E)-N-((1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =388 [ka]

[0378] Example 68: (E)—N-((1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] (Process 1) A 100 mL three-necked round-bottom flask was charged with 2-fluoroethanol (3.20 g, 49.95 mmol, 1.00 equiv.), trifluoromethanesulfonic anhydride (14.09 g, 49.95 mmol, 1.00 equiv.), and EtN (10.11 g, 99.91 mmol, 2.00 equiv.) in DCM (60.00 mL). The resulting solution was stirred at −78° C. for 10 hours in a liquid nitrogen bath. The resulting mixture was washed with 2×50 mL of aqueous NaCO and 1×50 mL of aqueous NaCl. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 9.7 g, which was used in the next step without purification.

[0379] [ka] (Process 2) A 20 mL vial was charged with tert-butyl N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamate (400.00 mg, 1.60 mmol, 1.00 equiv.), 2-fluoroethyl trifluoromethanesulfonate (629.32 mg, 3.21 mmol, 2.00 equiv.), and NaH (77.01 mg, 3.21 mmol, 2.00 equiv.) in THF (10.00 mL). The resulting solution was stirred for 10 hours at 20°C. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 2 x 20 mL of ethyl acetate, and the organic layers were combined. The organic layer was concentrated, and the residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1 / 1). This gave 300 mg (63% yield) of tert-butyl N-[(1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]carbamate as a pale yellow solid.

[0380] [ka] (Step 3) A 20 mL vial was charged with MeOH (5.00 mL) and tert-butyl N-[(1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]carbamate (300.00 mg) in 2 M HCl (g) in MeOH (5.00 mL) and stirred for 10 hours at 20° C. The resulting mixture was concentrated to give 120 mg of (1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-amine as a pale yellow solid.

[0381] [ka] (Step 4) In an 8 mL vial, (1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-amine (40.00 mg, 0.205 mmol, 1.00 equiv.), ((E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid (Intermediate 3, 41.03 mg, 0.205 mmol, 1.00 equiv.), HATU (116.85 mg, 0.307 mmol, 1.50 equiv.), DIPEA (79.44 mg, 0.000 equiv.), and HCl were added. 0.615 mmol, 3.00 equiv.) and DMF (2.00 mL) were added. The resulting solution was stirred for 10 h at 20° C. The mixture was purified by flash preparative HPLC. This gave 21 mg of (E)-N-((1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =380 [ka]

[0382] Example 69: (E)—N-((1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] (Process 1) A 20 mL vial was charged with tert-butyl N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamate (400.00 mg, 1.604 mmol, 1.00 equiv.), ethyl iodide (500.47 mg, 3.209 mmol, 2.00 equiv.), and NaH (128.36 mg, 3.209 mmol, 2.00 equiv., 60%) in THF (10.00 mL). The resulting solution was stirred for 10 hours at 20 °C. The mixture was quenched with 5 mL of HO and extracted with 30 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1 / 1). This gave 200 mg (45% yield) of tert-butyl N-[(1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]carbamate as a pale yellow solid.

[0383] [ka] (Process 2) A 20 mL vial was charged with MeOH (5.00 mL) and tert-butyl N-[(1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]carbamate (170.00 mg) in 2 M HCl (g) in MeOH (5.00 mL) and stirred for 10 hours at 20° C. The resulting mixture was concentrated to give 80 mg of (1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-amine as a pale yellow solid.

[0384] [ka] (Step 3) An 8 mL vial was charged with (1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-amine (40.00 mg, 0.226 mmol, 1.00 equiv.), (E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid (Intermediate 3, 45.19 mg, 0.226 mmol, 1.00 equiv.), HATU (128.71 mg, 0.339 mmol, 1.50 equiv.), and DIPEA (87.50 mg, 0.677 mmol, 3.00 equiv.) in DMF (2.00 mL). The resulting solution was stirred at 20° C. for 2 hours. The mixture was purified by preparative HPLC. This gave 25 mg of (E)-N-((1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =362 [ka]

[0385] Example 70: (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide [ka] An 8 mL vial was charged with N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (see Example 54, Step 1, 60.00 mg, 0.276 mmol, 1.00 equiv.), 6-bromo-3-cyclopropyl-1H-indazole (65.48 mg, 0.276 mmol, 1.00 equiv.), Pd(dppf)Cl (20.21 mg, 0.028 mmol, 0.10 equiv.), and EtN (83.83 mg, 0.828 mmol, 3.00 equiv.) in DMF (2.00 mL). The resulting solution was stirred at 120° C. for 3 hours. The mixture was purified by preparative HPLC. This gave 31 mg of (E)-3-(3-cyclopropyl-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] + =374 [ka]

[0386] Example 71: (E)-3-(3-methoxy-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide [ka] An 8 mL vial was charged with N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (see Example 54, Step 1, 60.00 mg, 0.276 mmol, 1.00 equiv.), 6-bromo-3-methoxy-1H-indazole (62.70 mg, 0.276 mmol, 1.00 equiv.), Pd(dppf)Cl (20.21 mg, 0.028 mmol, 0.10 equiv.), and EtN (83.83 mg, 0.828 mmol, 3.00 equiv.) in DMF (2.00 mL). The resulting solution was stirred at 120° C. for 3 hours. The mixture was purified by preparative HPLC. This gave 33 mg of (E)-3-(3-methoxy-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. This compound was converted to HCl. LC-MS (ES, m / z): [M+H] + =364 [ka]

[0387] Example 72: (E)-3-(3-chloro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide [ka] An 8 mL vial was charged with N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (60.00 mg, 0.276 mmol, 1.00 equiv.), 6-bromo-3-chloro-1H-indazole (63.92 mg, 0.276 mmol, 1.00 equiv.), Pd(dppf)Cl (20.21 mg, 0.028 mmol, 0.10 equiv.), and EtN (83.83 mg, 0.828 mmol, 3.00 equiv.) in DMF (4.00 mL). The resulting solution was stirred at 120 °C for 3 h. The mixture was purified by preparative HPLC. This gave 32 mg of (E)-3-(3-chloro-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] + =368 [ka]

[0388] Example 73: (E)-3-(3-fluoro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide [ka] (Process 1) A 40 mL vial was charged with 6-bromo-1H-indazole (500.00 mg, 2.54 mmol, 1.00 equiv.) and Selectfluor (1797.95 mg, 5.075 mmol, 2.00 equiv.) in CHCN (10.00 mL) and AcOH (1.00 mL). The resulting solution was stirred at 95 °C for 15 hours. The mixture was applied to a silica gel column using ethyl acetate / petroleum ether (1 / 1). This afforded 110 mg (20% yield) of 6-bromo-3-fluoro-1H-indazole as a pale yellow solid.

[0389] [ka] (Process 2) An 8 mL vial was charged with N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (see Example 54, Step 1, 60.00 mg, 0.276 mmol, 1.00 equiv.), 6-bromo-3-fluoro-1H-indazole (59.38 mg, 0.276 mmol, 1.00 equiv.), Pd(dppf)Cl (20.21 mg, 0.028 mmol, 0.10 equiv.), and EtN (83.83 mg, 0.828 mmol, 3.00 equiv.) in DMF (2.00 mL). The resulting solution was stirred at 120° C. for 14 hours. The mixture was purified by preparative HPLC. This gave 34 mg of (E)-3-(3-fluoro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC-MS1 (ES, m / z): [M+H] + =352 [ka]

[0390] Example 74: (E)-3-(3-cyano-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide [ka] (Process 1) An 8 mL vial was charged with N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (see Example 54, Step 1, 70.0 mg, 0.322 mmol, 1.00 equiv.), 6-bromo-1-(oxan-2-yl)indazole-3-carbonitrile (98.64 mg, 0.322 mmol, 1.00 equiv.), Pd(dppf)Cl (23.57 mg, 0.032 mmol, 0.10 equiv.), and EtN (97.81 mg, 0.967 mmol, 3.00 equiv.) in DMF (4.00 mL). The resulting solution was stirred at 120 °C for 3 h. The mixture was loaded onto a silica gel column and eluted with ethyl acetate / petroleum ether (1 / 1). This gave 60 mg (42% yield) of (E)-3-(3-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide as a pale yellow solid.

[0391] [ka] (Process 2) An 8 mL vial was charged with MeOH (2.00 mL) and (E)-3-(3-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide (60.00 mg, 0.136 mmol, 1.00 equiv) in 2 M HCl (g) in MeOH (2.00 mL). The resulting solution was stirred for 2 hours at 10° C. The resulting mixture was concentrated. The residue was purified by preparative HPLC. This afforded 31 mg of (E)-3-(3-cyano-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] + =359 [ka]

[0392] 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

[0393] 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.

[0394] 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.

[0395] 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 the 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.

[0396] (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.

[0397] 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.

[0398] 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).

[0399] (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).

[0400] 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.

[0401] 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).

[0402] (result) mPTP pIC for specific example compounds of the present invention within the mPTP assay 50 The values ​​are shown in Table 3 below. Table 3 also shows the pIC for Comparative Example 1. 50 The results show that the compounds of the present invention that were tested exhibited inhibition of mPTP, with many example compounds exhibiting pIC values ​​of 6.0 or greater. 50Table 3 also shows the mPTP human platelet pIC values ​​for certain Example compounds and Comparative Example 1. Examples 37 and 51 showed the highest activity in the rat liver mitochondrial assay, and Example 51 also showed the highest activity in the rat brain mitochondrial assay. Table 3 also shows the mPTP human platelet pIC values ​​for certain Example compounds and Comparative Example 1. 50 Table 3 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.

[0403] Biological Example 2 - Cytochrome P450 Assay Tests evaluating test compound-mediated inhibition of the cytochrome P450 enzyme isoform CYP2D6 were performed using human liver microsomes (BD Gentest) using either a single test compound concentration (1 μM) or a concentration response (0.1, 0.3, 1, 3, 10, and 30 μM) to derive IC50 values. Test compound solutions were prepared from 10 mM stocks in DMSO and diluted to 200 μM with DMSO. Reactions were set up in 96-deep-well plates by combining 1 μl of test compound with 179 μl of reaction mixture (100 mM phosphate-buffered saline (PBS), 0.2 mg / mL microsomes, and 2 μM dextromethorphan, prepared from stocks detailed below).

[0404] Table 2: Summary of incubation mixtures [Table 3]

[0405] The positive control inhibitor, quinidine, was used at a final concentration of 0.5 μM when used at a single concentration. The final concentrations of quinidine used to derive IC50s were 0, 0.1, 0.3, 1, 3, 10, and 30 μM. Plates were warmed to 37°C for 15 minutes, and then the reaction was initiated with 20 μl of 10 mM NADPH solution in PBS and incubated for 20 minutes at 37°C. Assays were performed in duplicate. Reactions were quenched with 200 μl of cold acetonitrile containing internal standards (200 nM labetalol, 200 nM alprazolam, and 100 nM tolbutamide). Plates were centrifuged at 4000 rpm for 30 minutes, placed on ice for 20 minutes, and then centrifuged again at 4000 rpm for 30 minutes to precipitate proteins. 100 μL of the supernatant was transferred to a new plate, diluted with 100 μL of pure water, and then analyzed using UPLC / MS / MS. The products of the conversion of dextromethorphan to dextrorphan were monitored by UPLC-MS / MS. Inhibition of CYP2D6 in human liver microsomes was measured as the percentage reduction in activity of dextrorphan production compared to the uninhibited control (=100% activity). IC 50 Values ​​(concentration of test compound producing 50% inhibition) were calculated using Excel XLfit.

[0406] (result) CYP2D6 % inhibition values ​​for certain compounds of the present invention are shown in Table 3. Table 3 also shows the CYP2D6 % inhibition value for Comparative Example 1. The results show that the test compounds exhibited significantly reduced inhibition of CYP2D6 compared to Comparative Example 1. Negative values ​​indicate no effective inhibition of CYP2D6 at a test compound concentration of 1 uM. Table 3 also shows the CYP2D6 IC values ​​for certain example compounds and Comparative Example 1. 50The % CYP2D6 inhibition values ​​are also shown. The results indicate that Comparative Example 1 is a highly potent inhibitor of CYP2D6 and is significantly more potent than the tested Example compounds. This is consistent with the potent CYP2D6 % inhibition value shown for Comparative Example 1. Therefore, the tested compounds of the present invention are expected to exhibit improved in vivo properties, such as reduced adverse drug-drug interactions and reduced inhibition of neurotransmitter production in the central nervous system, particularly dopamine.

[0407] Table 3: Summary of results from Biological Examples 1 and 2 [Table 4] TIFF0007784430000281.tif248170TIFF0007784430000282.tif139170*Average value from multiple experiments (n≧2) **Average value from two experiments.

[0408] Biological Example 3 - 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 ).

[0409] (result) Solubility values ​​for certain compounds of the present invention are shown in Table 4 below. Table 4 also shows the results for Comparative Example 1. The results demonstrate that certain compounds of the present invention exhibit higher solubility in PBS and / or FaSSIF than Comparative Example 1. Certain compounds of the present invention exhibit solubility in either PBS or FaSSIF, and certain compounds exhibit higher solubility values ​​in both PBS and FaSSIF. Therefore, certain compounds of the present invention can be expected to exhibit improved bioavailability and / or improved systemic exposure than Comparative Example 1, particularly when the compound is administered orally.

[0410] Biological Example 4 - 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).

[0411] (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)).

[0412] (result) Intrinsic clearance values ​​for certain compounds of the invention are shown in Table 4. Table 4 also shows the intrinsic clearance value for Comparative Example 1. These results indicate that certain compounds of the invention can be expected to have improved oral bioavailability and / or improved systemic exposure when compared to Comparative Example 1, i.e., they will have a lower intrinsic clearance (CL) in at least the human or rat species. int ) values ​​in both human and rat species. Certain compounds exhibited lower intrinsic clearance (CL ) values ​​than Comparative Example 1. int ) values ​​were shown. Table 4: Summary of results from Biological Examples 3 and 4 [Table 5] TIFF0007784430000284.tif248170TIFF0007784430000285.tif62170*Average value from two experiments.

[0413] (Conclusion) The results of Biological Examples 1 and 2 demonstrate that the tested compounds of the invention are inhibitors of mPTP within the mPTP assay. The tested compounds of the invention also exhibited reduced inhibition of CYP2D6 compared to Comparative Example 1. The results of Biological Examples 3 and 4 demonstrate that certain compounds of the invention exhibit improved solubility and / or reduced intrinsic clearance compared to Comparative Example 1, and are therefore expected to exhibit improved oral bioavailability and / or improved systemic exposure compared to Comparative Example 1.

[0414] Accordingly, the compounds of the present invention are believed to be useful pharmaceutical agents, particularly for the treatment or prevention of diseases and disorders in which inhibition of mPTP provides a therapeutic or prophylactic effect.

[0415] 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.

[0416] 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:

[0417] 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.

[0418] (References) [Table 6] The present application provides the following aspects of the invention. (Aspect 1) Formula (I): (chemical 1) TIFF0007784430000287.tif24170 (In the formula: R 1a is H or methyl; R 1b is H or F; A is a group (Aa), (Ab), (Ac), or (Ad): wherein the group (Aa) is: (chemical 2) TIFF0007784430000288.tif33170 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 Alkenyl 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 , 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, C1-4 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) TIFF0007784430000289.tif34170 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, C1-4 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) TIFF0007784430000290.tif23170 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) TIFF0007784430000291.tif29170 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 a group (Ba), (Bb), or (Bc): where the group (Ba) is: (6) TIFF0007784430000292.tif28170 and; (In the formula: Y is C(R 11 )(R 12 ), N(R13 ), O, or S; Each R 10 are independently halo or C 1-4 is alkyl; r is 0, 1, 2, or 3; R 11 is H or C 1-4 is alkyl; R 12 is H or C 1-4 alkyl; or R 11 and R 12 together with the carbon atoms to which they are attached, form C 3-6 Forming a cycloalkyl; R 13 is H, C 1-4 Alkyl or C 3-6 is cycloalkyl; wherein the cycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 13a R 13b , SO 2 R 13c , and NHSO 2 R 13c optionally substituted by 1, 2, or 3 substituents independently selected from R 13a is H and C 1-4 alkyl; R 13b 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 13c 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; The group (Bb) is: (7) TIFF0007784430000293.tif28170 and; (In the formula: Each R 14 are independently halo or C 1-4 is alkyl; s is 0, 1, 2, or 3); The group (Bc) is: (C8) TIFF0007784430000294.tif32170 and; (In the formula: R 15 is C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 1-4 haloalkyl, halo, or CN; wherein the cycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 15a R 15b , SO 2 R 15c , and NHSO 2 R 15c optionally substituted by 1, 2, or 3 substituents independently selected from R 15a is H and C 1-4 alkyl; R 15b 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 15c 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 16 is H, halo, or C 1-4 is alkyl; and D, E, and F each independently represent C(R 16 ) or one of D, E, and F is N and the remaining two of D, E, and F groups are independently C(R 16 )is)); or a pharmaceutically acceptable salt and / or solvate thereof. (Aspect 2) Formula (I): (9) TIFF0007784430000295.tif23170 (In the formula: R 1a is H or methyl; R 1b is H or F; A is a group (Aa), (Ab), (Ac), or (Ad): wherein the group (Aa) is: (C10) TIFF0007784430000296.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 (C3-6 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 Alkenyl O(C 3-6 alkynyl); wherein the aryl, heterocycloalkyl, and cycloalkyl are C 1-4 Alkyl, C 3-6 Cycloacyl (C 3-6 cycloaklyl), 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: (Chem.11) TIFF0007784430000297.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: (C12) TIFF0007784430000298.tif23170 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: (C13) TIFF0007784430000299.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 C 1-4 is alkyl; p is 0, 1, or 2; q is 0, 1, 2, 3, or 4); B is a group (Ba), (Bb), or (Bc): where the group (Ba) is: (C14) TIFF0007784430000300.tif29170 and; (In the formula: Y is C(R 11 )(R 12 ), N(R 13 ), O, or S; Each R10 are independently halo or C 1-4 is alkyl; r is 0, 1, 2, or 3; R 11 is H or C 1-4 is alkyl; R 12 is H or C 1-4 alkyl; or R 11 and R 12 together with the carbon atoms to which they are attached, form C 3-6 Forming a cycloalkyl; R 13 is H, C 1-4 Alkyl or C 3-6 is cycloalkyl); The group (Bb) is: (C15) TIFF0007784430000301.tif29170 and; (In the formula: Each R 14 are independently halo or C 1-4 is alkyl; s is 0, 1, 2, or 3); The group (Bc) is: (C16) TIFF0007784430000302.tif31170 and; (In the formula: R 15 is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 haloalkyl, or CN; R 16 is H, halo, or C 1-4 is alkyl; and D, E, and F each independently represent C(R 16 ) or one of D, E, and F is N and the remaining two of D, E, and F groups are independently C(R 16 )is)); or a pharmaceutically acceptable salt and / or solvate thereof. (Aspect 3) A is a group (Aa): (C17) TIFF0007784430000303.tif32170 3. The compound of embodiment 1 or 2, 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 alkyleneO(4-7 membered heterocycloalkyl), 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 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): (C18) TIFF0007784430000304.tif36170 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 1. (Aspect 19) The group A is the group (Ac): (C19) TIFF0007784430000305.tif24170 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): (20) TIFF0007784430000306.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 Independently, OCH 2 -cyclopropyl, OCH 2 -Oxetanyl, OCH 2 CH 2 24. The compound according to embodiment 22 or 23, which is F, methyl, OMe, OEt, or fluoro, such as methyl, OMe, or fluoro. (Aspect 25) Each R 8 Independently, OCH 2 -cyclopropyl, OCH 2 -Oxetanyl, OCH 2 CH 2 25. The compound of embodiment 24, wherein said compound is F, or OEt. (Aspect 26) Each R 8 Independently, OCH 2 CH 2 25. The compound according to embodiment 24, which is F, OMe, or OEt, in particular OMe. (Aspect 27) The compound according to any one of embodiments 23 to 26, wherein p is 0 or 1. (Aspect 28) Each R 9 The compound of any one of embodiments 23-27, wherein is independently fluoro. (Aspect 29) The compound according to any one of aspects 23 to 28, wherein q is 1 or 2. (Aspect 30) The group B is (Ba): (21) TIFF0007784430000307.tif29170 30. The compound according to any one of embodiments 1 to 29, wherein: (Aspect 31) Y is C(R 11 )(R 12 ) or N(R 13 31. The compound of embodiment 30, wherein (Aspect 32) R 11 is H or methyl, and R 12 is H. (Aspect 33) R 11 and R 12 and R are both H. (Aspect 34) R 11 and R 12 together with the carbon atom to which they are attached form a cyclopropyl ring. (Aspect 35) R 13 However, methyl, ethyl, propyl, or butyl, especially methyl, etc. 1-4 alkyl; or C such as cyclopropyl 3-6 32. The compound of embodiment 31, wherein said compound is cycloalkyl. (Aspect 36) 31. The compound according to embodiment 30, wherein Y is O or S. (Aspect 37) Each R 10 The compound according to any one of embodiments 30 to 36, wherein is independently fluoro, chloro, or methyl. (Aspect 38) The compound according to any one of aspects 30 to 37, wherein r is 0 or 1. (Aspect 39) The group B is (Bb): (22) TIFF0007784430000308.tif29170 30. The compound according to any one of embodiments 1 to 29, wherein: (Aspect 40) Each R 14 is independently fluoro or methyl. (Aspect 41) 41. The compound according to embodiment 39 or 40, wherein s is 0 or 1. (Aspect 42) The group B is a group (Bc): (23) TIFF0007784430000309.tif32170 30. The compound according to any one of embodiments 1 to 29, wherein: (Aspect 43) R 15 However, methyl, ethyl, cyclopropyl, CF 3 , CN, OMe, chloro, or fluoro, e.g., methyl, ethyl, cyclopropyl, CF 3 or CN. (Aspect 44) R 15 44. The compound of embodiment 43, wherein is OMe, chloro, or fluoro. (Aspect 45) R 15 44. The compound according to embodiment 43, wherein is methyl, CN, chloro, or fluoro. (Aspect 46) D, E, and F are C(R 16 46. ​​The compound of any one of embodiments 42 to 45, wherein (Aspect 47) D is N and E and F are C(R 16 46. ​​The compound of any one of embodiments 42 to 45, wherein (Aspect 48) E is N and D and F are C(R 16 46. ​​The compound of any one of embodiments 42 to 45, wherein (Aspect 49) F is N and D and E are C(R 16 46. ​​The compound of any one of embodiments 42 to 45, wherein (Aspect 50) Each R 16 50. The compound according to any one of embodiments 42 to 49, wherein is independently H, fluoro, chloro, or methyl. (Aspect 51) (E)-3-(1H-benzo[d][1,2,3]triazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)acrylamide; (E)-3-(3,3-dimethyl-2-oxoindolin-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2'-oxospiro[cyclopropane-1,3'-indoline]-6'-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(7-fluoro-2-oxoindolin-6-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-2-oxoindolin-6-yl)acrylamide; (E)-N-(3-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(o-tolyl)acrylamide; (E)-N-(2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(2-isopropyl-6-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(5-chloro-2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(4,5-difluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(5-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(4-fluoro-2-oxoindolin-6-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-3-(1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-3-(1-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-(trifluoromethyl)-1H-indazol-6-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-ethyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(3,5-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3,4-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide; (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(4-fluoro-3-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(3-fluoro-4-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; Racemic -(E)-3-(3-methyl-1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (Z)-2-fluoro-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3-chloro-2-methylphenyl)-N-methyl-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(2-methylcyclopentyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-(methoxymethyl)phenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide; (E)-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(chroman-4-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)acrylamide; (E)-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3,5-difluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide; (E)-N-(5-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(2-methylcyclohexyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4S)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4R)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4R)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4S)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-((1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-((1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-((1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-methoxy-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-chloro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-fluoro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; and (E)-3-(3-cyano-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; or a pharmaceutically acceptable salt and / or solvate of any one of them. (Aspect 52) A compound according to any one of embodiments 1 to 51 for use as a medicament. (Aspect 53) A compound according to any one of aspects 1 to 51 for use in the treatment or prevention of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect. (Aspect 54) A compound according to any one of embodiments 1 to 51 for use in the treatment of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect. (Aspect 55) 52. A compound according to any one of aspects 1 to 51 for use in the prevention of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect. (Aspect 56) 56. The compound for use according to any one of aspects 53 to 55, 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 57) 57. The compound for use according to aspect 56, 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 58) 57. The compound for use according to embodiment 56, wherein said disease or disorder is a disease of the central nervous system, such as AIDS dementia complex, depressive disorder, schizophrenia, and epilepsy. (Aspect 59) 57. The compound for use according to embodiment 56, 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 60) 57. The compound for use according to aspect 56, 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 61) 57. The compound for use according to embodiment 56, wherein the disease or disorder is an inflammatory or autoimmune disease, such as acute pancreatitis, systemic lupus, organ failure in sepsis, and hepatitis. (Aspect 62) 57. The compound for use according to embodiment 56, wherein said disease or disorder is an age-related disease such as bone repair, bone frailty in aging in osteoporosis, and sarcopenia. (Aspect 63) 57. The compound for use according to embodiment 56, wherein said disease or disorder is a kidney disease, such as chronic kidney disease and chronic kidney disease associated with APOL1 gene variants. (Aspect 64) A compound according to any one of aspects 1 to 51 for use in the treatment or prevention of a mitochondrial disease. (Aspect 65) 52. The compound according to any one of embodiments 1 to 51, for use in the treatment or prevention of a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration. (Aspect 66) 66. The compound for use according to aspect 65, 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 67) A compound according to any one of aspects 1 to 51 for use in the treatment or prevention of a disease or disorder associated with fibrosis. (Aspect 68) 70. The compound of embodiment 67, wherein the disease or disorder is selected from chronic kidney disease, idiopathic pulmonary fibrosis, nonalcoholic steatohepatitis, primary biliary cholangitis, and systemic sclerosis. (Aspect 69) A pharmaceutical composition comprising a compound of formula (I) according to any one of Aspects 1 to 51 or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier or excipient. (Aspect 70) A compound according to any one of aspects 1 to 69, or a solvate thereof. (Aspect 71) 70. A compound according to any one of aspects 1 to 69, or a pharmaceutically acceptable salt thereof. (Aspect 72) 70. The compound according to any one of embodiments 1 to 69.

Claims

1. Formula (I): 【Chemistry 1】 (In the formula: R 1a is H or methyl; R 1b is H or F; 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, or C 1-4 Alkenyl 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 , 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 a group (Ba), (Bb), or (Bc): Here, the group (Ba) is 【Transformation 6】 and; (In the formula: Y is C(R 11 )(R 12 ), N(R 13 ), O, or S; Each R 10 are independently halo or C 1-4 is alkyl; r is 0, 1, 2, or 3; R 11 is H or C 1-4 is alkyl; R 12 is H or C 1-4 alkyl; or R 11 and R 12 together with the carbon atoms to which they are attached, form C 3-6 Forming a cycloalkyl; R 13 is H, C 1-4 Alkyl or C 3-6 is cycloalkyl; wherein the cycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 13a R 13b , SO 2 R 13c , and NHSO 2 R 13c optionally substituted by 1, 2, or 3 substituents independently selected from R 13a is H and C 1-4 alkyl; R 13b 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 13c 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; The group (Bb) is 【Transformation 7】 and; (In the formula: Each R 14 are independently halo or C 1-4 is alkyl; s is 0, 1, 2, or 3); The group (Bc) is 【Transformation 8】 and; (In the formula: R 15 is C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 1-4 haloalkyl, halo, or CN; wherein the cycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 15a R 15b , SO 2 R 15c , and NHSO 2 R 15c optionally substituted by 1, 2, or 3 substituents independently selected from R 15a is H and C 1-4 alkyl; R 15b 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 15c 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 16 is H, halo, or C 1-4 is alkyl; and D, E, and F each independently represent C(R 16 ) or one of D, E, and F is N and the remaining two of D, E, and F groups are independently C(R 16 )is)); or a pharmaceutically acceptable salt and / or solvate thereof.

2. Formula (I): 【Chemistry 9】 (In the formula: R 1a is H or methyl; R 1b is H or F; A is a group (Aa), (Ab), (Ac), or (Ad): wherein group (Aa) is: 【Chemistry 10】 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 Alkenyl 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 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 11】 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 12】 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 13】 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 a group (Ba), (Bb), or (Bc): where the group (Ba) is: 【Chemistry 14】 and; (In the formula: Y is C(R 11 )(R 12 ), N(R 13 ), O, or S; Each R 10 are independently halo or C 1-4 is alkyl; r is 0, 1, 2, or 3; R 11 is H or C 1-4 is alkyl; R 12 is H or C 1-4 alkyl; or R 11 and R 12 together with the carbon atoms to which they are attached, form C 3-6 Forming a cycloalkyl; R 13 is H, C 1-4 Alkyl or C 3-6 is cycloalkyl); The group (Bb) is 【Chemistry 15】 and; (In the formula: Each R 14 are independently halo or C 1-4 is alkyl; s is 0, 1, 2, or 3); The group (Bc) is 【Chemistry 16】 and; (In the formula: R 15 is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 haloalkyl, or CN; R 16 is H, halo, or C 1-4 is alkyl; and D, E, and F each independently represent C(R 16 ) or one of D, E, and F is N and the remaining two of D, E, and F groups are independently C(R 16 )is)); or a pharmaceutically acceptable salt and / or solvate thereof, 2. The compound of claim 1, or a pharmaceutically acceptable salt and / or solvate thereof.

3. A is a group (Aa): 【Chemistry 17】 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt and / or solvate thereof, wherein:

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 alkyleneO(4- to 7-membered heterocycloalkyl), 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 The compound of any one of claims 1 to 3, optionally substituted with up to three substituents each independently selected from haloalkyl, halo, and CN, or a pharmaceutically acceptable salt and / or solvate thereof.

5. R 2 But methyl, CH 2 OH or CH 2 2. The compound of claim 1, which is OMe, a pharmaceutically acceptable salt and / or solvate thereof.

6. Each R 3 The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt and / or solvate thereof, wherein is independently fluoro or methyl.

7. The compound according to any one of claims 1 to 6, wherein m is 1 or 2, or a pharmaceutically acceptable salt and / or solvate thereof.

8. m is 1 and R 3 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt and / or solvate thereof, wherein: is at the 3-position.

9. m is 1 and R 3 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt and / or solvate thereof, wherein: is at the 6-position.

10. m is 2, and one R 3 is in third place and the other R 3 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt and / or solvate thereof, wherein: is at the 6-position.

11. The group B is a group (Bc): [Chemistry 18] The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt and / or solvate thereof, wherein

12. R 15 However, methyl, ethyl, cyclopropyl, CF 3 12. The compound of claim 11, or a pharmaceutically acceptable salt and / or solvate thereof, wherein R is CN, OMe, chloro, or fluoro.

13. R 15 13. The compound of claim 12, a pharmaceutically acceptable salt and / or solvate thereof, wherein is OMe, chloro, or fluoro.

14. R 15 13. The compound of claim 12, a pharmaceutically acceptable salt and / or solvate thereof, wherein is methyl, CN, chloro, or fluoro.

15. D, E, and F are C(R 16 15. The compound according to any one of claims 11 to 14, or a pharmaceutically acceptable salt and / or solvate thereof, wherein

16. Each R 16 16. The compound of any one of claims 11-15, wherein is independently H, fluoro, chloro, or methyl.

17. Formula (Ia'): 【Chemistry 19】 (In the formula: A is a group (Aa'), a group (Ab'), a group (Ad'), or a group (Ad''); R 15d is methyl, ethyl, cyclopropyl, CN, CF 3 , OMe, chloro, or fluoro; wherein the group (Aa') is: 【Chemistry 20】 and (In the formula: R 2d is H, methyl, or CH 2 OMe; Each R 3a are independently H, fluoro, or methyl; and The group (Ab') is: 【Chemistry 21】 and (In the formula: R 4d is methyl); The group (Ad') is: 【Chemistry 22】 and (In the formula: R 8d is H, methyl, OCH 2 -cyclopropyl, OCH 2 -Oxetanyl, OCH 2 CH 2 F, OMe, or OEt; Each R 9a are independently H or fluoro; The group (Ad'') is: 【Chemistry 23】 and (In the formula: R 8d is methyl; and Each R 9a are independently H or fluoro) or a pharmaceutically acceptable salt and / or solvate thereof, 2. The compound of claim 1, or a pharmaceutically acceptable salt and / or solvate thereof.

18. (E)-3-(1H-benzo[a]pyridin-3-yl] [d][1,2,3]triazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)acrylamide; (E)-3-(3,3-dimethyl-2-oxoindolin-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2'-oxospiro[cyclopropane-1,3'-indoline]-6'-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(7-fluoro-2-oxoindolin-6-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-2-oxoindolin-6-yl)acrylamide; (E)-N-(3-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(o-tolyl)acrylamide; (E)-N-(2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(2-isopropyl-6-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(5-chloro-2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(4,5-difluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(5-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(4-fluoro-2-oxoindolin-6-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-3-(1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-3-(1-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-benzo[b] [d][1,2,3]triazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-(trifluoromethyl)-1H-indazol-6-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-ethyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(3,5-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3,4-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide; (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(4-fluoro-3-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(3-fluoro-4-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; Racemic -(E)-3-(3-methyl-1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (Z)-2-fluoro-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3-chloro-2-methylphenyl)-N-methyl-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(2-methylcyclopentyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-(methoxymethyl)phenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide; (E)-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(chroman-4-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)acrylamide; (E)-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3,5-difluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-benzo[b] [d][1,2,3]triazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-benzo[b] [d][1,2,3]triazol-6-yl)acrylamide; (E)-N-(5-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(2-methylcyclohexyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4S)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4R)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4R)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4S)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-((1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-((1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-((1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-methoxy-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-chloro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-fluoro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; and (E)-3-(3-cyano-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; or a pharmaceutically acceptable salt and / or solvate thereof, according to claim 1, selected from the group consisting of:

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

20. 20. A pharmaceutical composition for use according to claim 19 for use in the prevention or treatment 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 the group consisting of 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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