Novel compounds

Abstract

The present invention relates to compounds of Formula (I) and related aspects.

Description

Invention Field

[0001] This invention relates to novel compounds as inhibitors of the mitochondrial permeability transition pore (mPTP). The invention also particularly relates to such compounds used as medicines, especially for the treatment or prevention of degenerative diseases, neurodegenerative diseases, or mitochondrial diseases, or for other diseases or conditions where inhibition of mPTP provides therapeutic or preventative effects. Background of the Invention

[0003] The mitochondrial permeability transition pore (mPTP) is a highly conductive channel located on the inner mitochondrial membrane. It plays a crucial role in certain cellular stress conditions, particularly under conditions requiring calcium. 2+ It is activated under overload and oxidative stress conditions. It can penetrate solutes with a molecular weight <1.5 kDa, and is effective against voltage and Ca2+. 2+ It is mitochondrial-dependent and exhibits a characteristic high conductivity. Once activated, oxidative phosphorylation uncouples, leading to loss of mitochondrial membrane potential and disruption of mitochondrial metabolism. Furthermore, solute influx into the mitochondrial matrix causes swelling, eventually rupturing the outer membrane and releasing apoptosis factors and isolated Ca2+. 2+ And, depending on the cell type and physiology, it ultimately leads to cell death through apoptosis or necrosis. Therefore, it is considered a key pathological event in many degenerative and metabolic diseases.

[0004] Under normal physiological conditions, mitochondria play a crucial role in regulating cellular calcium levels. 2+ It plays a crucial role in homeostasis. Ca2+ enters the cell through cell surface channels. 2+ (This is a common mechanism in cell signaling) It is rapidly isolated by mitochondria to prevent excessive and toxic calcium from entering the cytoplasm. 2+ Accumulation. After experiencing high-level Ca... 2+ In cell types with high flux, such as neurons, skeletal muscle fibers, and cardiomyocytes, this Ca2+ in mitochondria... 2+ The "buffering" effect is crucial for maintaining cell health. However, mitochondria isolate Ca... 2 + The capacity is limited; if mitochondrial Ca... 2+ When the level reaches a certain threshold, Ca 2+ Sensitive mPTPs are activated, leading to mitochondrial breakdown and cell death. Depending on the disease, mPTP activation in degenerative diseases can occur in several ways, such as: 1) excessive calcium... 2+ Ca enters cells and mitochondria 2+ Overload, 2) Dysfunctional mitochondrial Ca 2+ Extrinsic mechanisms, especially Ca 2+ Decreased activity of the efflux transporter NCLX leads to Ca 2+ Overload, 3) Ca in mitochondria 2+4) Overactive or upregulated uptake mechanisms, 5) Oxidative stress, and 6) MPTP sensitivity due to impaired mitochondrial function, i.e., MPTP is present in lower mitochondrial Ca2+ levels. 2+ Activated at a certain concentration, 6) at the contact point between two organelles called the mitochondrial-associated membrane, Ca 2+ They are translocated from the endoplasmic reticulum to the mitochondria.

[0005] Although the properties and functions of mPTPs can be studied in isolated mitochondria using simple in vitro assays, their molecular biological characterization remains unclear. Several proteins have been proposed to constitute the pore-forming complex, including ATP synthases and the adenine nucleotide transporter (ANT) protein family, but none is widely accepted as responsible for pore formation. However, peptidyl prolyl cis-trans isomerase F (Ppif), also known as cyclic protein D, is recognized as a key regulator of pores, although it does not itself form transmembrane channels. Genetic or pharmacological inhibition of Ppif significantly reduces its response to Ca2+. 2+ Sensitivity to overload and pore opening by other mPTP activators. Therefore, genetic ablation or pharmacological inhibition of Ppif has been used to assess the involvement of mPTP in pathological pathways in cellular and animal disease models. In this way, inhibition of mPTP has been shown to have a protective effect in many disease models, particularly those with known calcium deficiency. 2+ Dysregulation and oxidative stress can lead to disease models of cellular degeneration. Notably, Ppif gene knockout has shown protective effects in various preclinical in vivo transgenic models of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and motor neuron disease, demonstrating the therapeutic potential of mPTP inhibition. In each of these diseases, mutations in the genes of specific proteins (amyloid precursor protein, α-synuclein, and superoxide dismutase 1, respectively) that cause the genetic form of the disease and are expressed in mouse models have been shown to lead to mitochondrial calcium deficiency. 2+ Overload or mPTP sensitization. Recent evidence suggests that it may occur through a common mechanism in Alzheimer's disease, Parkinson's disease, and Friedreich's ataxia. In each case, it has been reported that in cells expressing mutated disease-related proteins (amyloid precursor protein, PINK1, and frataxin, respectively), mitochondrial Ca2+... 2+ Decreased activity or expression of the efflux transporter NCLX leads to mitochondrial calcium deficiency. 2+ Overload. In cases of Parkinson's disease, the pathological aggregated form of α-synuclein (a misfolded protein commonly found in sporadic and hereditary Parkinson's disease) has also been shown to sensitize and activate mPTP.

[0006] Ppif gene ablation has been shown to be beneficial in many other preclinical models of degenerative diseases, thus demonstrating the potential of mPTP inhibitors in Duchenne and congenital muscular dystrophy, ischemia-reperfusion injury, bone repair, pancreatitis and other related diseases.

[0007] In addition to demonstrating the benefits of Ppif inhibition in preclinical models, mPTP dysfunction has been confirmed in a variety of other disease indications. In particular, in many diseases, the response to Ca... 2+ The overloaded mPTP activation threshold appears to become sensitive, suggesting that mPTP activation may occur aberrantly under physiological conditions and drive tissue degeneration. For example, in muscle mitochondria from muscle biopsies of older adults, the mPTP activation threshold was lowered compared to healthy controls. This sensitization of mPTP activity in these diseases forms another theoretical basis for the therapeutic potential of mPTP inhibitors.

[0008] mPTP inhibitors may also cause mitochondrial dysfunction, oxidative stress, inflammatory stress, or calcium-related stress during disease development. 2+ It has therapeutic potential in other disorders.

[0009] The discovery and development of mPTP inhibitors has primarily focused on the identification of Ppif inhibitors. Cyclosporine A (CsA), initially identified as an immunosuppressant due to its inhibitory activity against calcineurin, has also been found to inhibit Ppif and other members of the peptidyl-prolyl cis-trans isomerase (Ppi) family. Several cyclosporine A derivatives, such as Debio-25 and NIM811, which retain broad activity against the Ppi enzyme family but do not inhibit calcineurin, have subsequently been developed, but none have reached the market. To date, no effective brain-osmotically selective Ppif inhibitors have been reported. Other newer methods for discovering mPTP inhibitors utilize phenotypic screening in isolated mitochondria. These methods have successfully identified effective small-molecule mPTP inhibitors with Ppif-independent modes of action.

[0010] Yu et al. (2020, Cell, 183, 1-14) investigated the link between mPTP activation and TDP-43 proteopathies, such as TAR DNA-binding protein 43 (TDP-43)-related neurodegeneration. Cytoplasmic accumulation of the normal nuclear protein TDP-43 is a disease marker in almost all ALS cases and 40-50% of frontotemporal degeneration (FTLD) cases, with some familial cases caused by mutant forms of this protein. Both diseases are associated with a spectrum of neuroinflammatory cytokines related to upregulation of the NF-κB and type I IFN pathways, directly indicating the role of TDP-43 in neuroinflammation. Mutated or overexpressed WT TDP-43 in neurons mislocalizes to mitochondria and induces the release of mitochondrial DNA (mtDNA) into the cytoplasm. This mtDNA then activates the immune sensor cGAS-STING, triggering the induction of innate immune genes such as IL-6, TNFα, and interferon β. Inhibition of mPTP with cyclosporine A or by CypD knockout prevents TDP-43-induced mtDNA release and subsequent induction of innate immune response genes. Furthermore, inhibition of cGAS-STING prolongs the survival of mutant mice expressing mutant TDP-43. These data suggest that mPTP activation mediates the toxic effects of TDP-43 in ALS and other diseases in which TDP-43 gene mutations lead to disease or in which TDP-43 protein disorders are observed.

[0011] Jang et al. (2021 American Journal of Physiology: Renal Physiology, doi:10.1152 / ajprenal.00171.2021. Published online prior to print, PMID:34396791.) highlighted the potential therapeutic benefits of mPTP inhibition (via CypD knockout) in a mouse model of renal fibrosis. Renal fibrosis was induced in WT and CypD KO mice using unilateral ureteral obstruction. Compared to WT, CypD KO mice showed reduced inflammation, proximal tubular atrophy, and fibrosis markers. Measurements of fibrosis included collagen deposition, α-SMA and TGFβ expression, and interstitial cell proliferation. This highlights the potential role of mPTP in cell damage / death-mediated tissue remodeling and fibrosis. Therefore, mPTP inhibitors may be beneficial for diseases where fibrosis is a key pathological mechanism, such as chronic kidney disease, idiopathic pulmonary fibrosis, non-alcoholic steatohepatitis, primary biliary cholangitis, and systemic sclerosis.

[0012] WO2010 / 049768 relates to acryloylamino 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 further acryloylamino derivatives, including (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide. CA2884607A1 relates to acrylamide and maleimide compounds, which are claimed to be useful for the treatment of mitochondrial diseases.

[0013] When administered orally, the oral bioavailability and systemic exposure of a drug depend largely on the extent of absorption in the gastrointestinal tract and the degree of first-pass metabolism in the liver. Properties such as high solubility (measured in phosphate-buffered saline (PBS) or, more biologically relevant, fasting-state simulated intestinal fluid (FaSSIF)) and high metabolic stability (measured in vitro in isolated liver microsomes or hepatocytes in rats and humans) can therefore predict improvements in patient oral bioavailability and systemic exposure.

[0014] There is still a need to find other compounds that can act as mPTP inhibitors, especially those that combine mPTP inhibition with other desired pharmacological properties, such as improved oral bioavailability and / or improved systemic exposure. Invention Overview

[0016] This invention relates to compounds of formula (I):

[0017]

[0018] in:

[0019] R 1a It is H or methyl;

[0020] R 1b It is H or fluorine;

[0021] A is a group (Aa), (Ab), (Ac), or (Ad):

[0022] The group (Aa) is:

[0023]

[0024] in:

[0025] R2 is H, C 1-4 Alkyl, C 1-4Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene (C 3-6 cycloalkyl), C 1-4 Alkylene (4-7 membered heterocyclic alkyl), 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 Alkylene O (4-7 membered heterocyclic alkyl), C 1-4 Alkylene O (aryl), C 3-6 alkynyl or C 1-4 Alkylene O(C) 3-6 (alkynyl); wherein the aryl, heterocyclic alkyl, and cycloalkyl groups are optionally selected by one, two, or three independently from C10. 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, halogenated, CN, OH, NR 2a R 2b SO2R 2c and NHSO2R 2c Substituents of the substituents;

[0026] R 2a Selected from H and C 1-4 alkyl;

[0027] R 2b Selected from H, C 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl groups, aryl groups, and 4-7 membered heterocyclic alkyl groups;

[0028] R 2c Selected from C 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl groups, aryl groups, and 4-7 membered heterocyclic alkyl groups;

[0029] Each R3 is independently of the other: halo, methyl, ethyl, or n-propyl.

[0030] m is 0, 1, 2, 3 or 4;

[0031] The group (Ab) is:

[0032]

[0033] in:

[0034] R4 is H, C 1-4 Alkyl or C 1-4 Alkylene (aryl); wherein the aryl group is optionally composed of 1, 2, or 3 each independently selected from C10. 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, halogenated, CN, OH, NR 4a R 4b SO2R 4c and NHSO2R 4c Substituents of the substituents;

[0035] R 4a Selected from H and C 1-4 alkyl;

[0036] R 4b Selected from H, C 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl groups, aryl groups, and 4-7 membered heterocyclic alkyl groups;

[0037] R 4c Selected from C 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl groups, aryl groups, and 4-7 membered heterocyclic alkyl groups;

[0038] R5 is H or C 1-4 alkyl;

[0039] Each R6 is independently C 1-4 Alkyl or halogenated;

[0040] n is 0, 1, 2, or 3;

[0041] The group (Ac) is:

[0042]

[0043] in:

[0044] R7 is C 1-4 Alkyl, C 1-4 alkylene (OH) or C 1-4 Alkylene OC 1-4 alkyl;

[0045] o is 1 or 2;

[0046] The group (Ad) is:

[0047]

[0048] in:

[0049] X is a bond, O, or CH2;

[0050] Each R8 is independently halogenated, C 1-4 Alkyl, C 1-4 Alkoxy OC 1-4 Halogenated alkyl, OC 1-4 Alkylene (C 3-6 cycloalkyl), OC 1-4 Alkylene (4-7 membered heterocyclic alkyl) or OH; wherein the heterocyclic alkyl and cycloalkyl groups are optionally selected independently by 1, 2 or 3 C14 groups. 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, halogenated, CN, OH, NR 8a R 8b SO2R 8c and NHSO2R 8c Substituents of the substituents;

[0051] R 8a Selected from H and C 1-4 alkyl;

[0052] R 8b Selected from H, C 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl groups, aryl groups, and 4-7 membered heterocyclic alkyl groups;

[0053] R 8c Selected from C 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl groups, aryl groups, and 4-7 membered heterocyclic alkyl groups;

[0054] Each R9 is independently halogenated or C-substituted. 1-4 alkyl;

[0055] p is 0, 1, or 2;

[0056] q is 0, 1, 2, 3, or 4;

[0057] Where B is:

[0058]

[0059] in:

[0060] R 10 Is it H, halogenated, or C? 1-4 alkyl;

[0061] D, E, and F are each independently C(R) 10 ); or one of D, E, and F is N and the remaining two of the D, E, and F groups are independently C(R) 10 );and

[0062] The condition is that the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide;

[0063] Or its pharmaceutically acceptable salts and / or solvates.

[0064] The present invention also provides compounds of formula (I):

[0065]

[0066] in:

[0067] R 1a It is H or methyl;

[0068] R 1b It is H or fluorine;

[0069] A is a group (Aa), (Ab), (Ac), or (Ad):

[0070] The group (Aa) is:

[0071]

[0072] in:

[0073] 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 heterocyclic alkyl), 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 Alkylene O (4-7 membered heterocyclic alkyl), C 1-4 Alkylene O (aryl), C 3-6 alkynyl or C 1-4 Alkylene O(C) 3-6(alkynyl); wherein the aryl, heterocyclic, or cycloalkyl group may optionally be selected from up to three independently selected C14 groups. 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, halogenated and CN substituents;

[0074] Each R3 is independently of the other: halo, methyl, ethyl, or n-propyl.

[0075] m is 0, 1, 2, 3 or 4;

[0076] The group (Ab) is:

[0077]

[0078] in:

[0079] R4 is H, C 1-4 Alkyl or C 1-4 Alkylene (aryl); wherein the aryl group may optionally be composed of up to three independently selected C14 groups. 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, halogenated and CN substituents;

[0080] R5 is H or C 1-4 alkyl;

[0081] Each R6 is independently C 1-4 Alkyl or halogenated;

[0082] n is 0, 1, 2, or 3;

[0083] The group (Ac) is:

[0084]

[0085] in:

[0086] R7 is C 1-4 Alkyl, C 1-4 alkylene (OH) or C 1-4 Alkylene OC 1-4 alkyl;

[0087] o is 1 or 2;

[0088] The group (Ad) is:

[0089]

[0090] in:

[0091] X is a bond, O, or CH2;

[0092] Each R8 is independently halogenated, C 1-4 Alkyl, C 1-4 alkoxy or OH;

[0093] Each R9 is independently halogenated or C-substituted. 1-4 alkyl;

[0094] p is 0, 1, or 2;

[0095] q is 0, 1, 2, 3, or 4;

[0096] Where B is:

[0097]

[0098] in:

[0099] R 10 Is it H, halogenated, or C? 1-4 alkyl;

[0100] D, E, and F are each independently C(R) 10 ); or one of D, E, and F is N and the remaining two of the D, E, and F groups are independently C(R) 10 );and

[0101] The condition is that the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide;

[0102] Or its pharmaceutically acceptable salts and / or solvates.

[0103] 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, a compound of formula (I) is provided.

[0104] The present invention also provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

[0105] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for the treatment or prevention of diseases or conditions in which inhibition of mPTP provides therapeutic or preventive effects.

[0106] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for use in the preparation of medicaments for treating or preventing diseases or conditions in which inhibition of mPTP provides therapeutic or preventative effects.

[0107] The present invention also provides a method for preventing or treating diseases in which inhibition of mPTP provides therapeutic or preventive effects in an individual.

[0108] Suitablely, the disease or condition is selected from degenerative or neurodegenerative diseases, central nervous system diseases, ischemia and reperfusion injury, metabolic diseases, inflammatory or autoimmune diseases, age-related diseases, and kidney diseases.

[0109] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for the treatment or prevention of mitochondrial diseases.

[0110] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for use in the preparation of medicaments for the treatment or prevention of mitochondrial diseases.

[0111] The present invention also provides a method for preventing or treating mitochondrial diseases in an individual, the method comprising administering to the individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0112] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for the treatment or prevention of diseases or conditions associated with TDP-43 protein pathologies, such as TDP-43-associated neurodegeneration.

[0113] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for use in the preparation of medicaments for the treatment or prevention of diseases or conditions associated with TDP-43 protein disorders, such as TDP-43-associated neurodegeneration.

[0114] The present invention also provides a method for treating or preventing diseases or conditions associated with TDP-43 protein disorders, such as TDP-43-associated neurodegeneration, comprising administering to an individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0115] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for the treatment or prevention of diseases or conditions associated with fibrosis.

[0116] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for use in the preparation of medicaments for the treatment or prevention of diseases or conditions associated with fibrosis.

[0117] The present invention also provides a method for treating or preventing diseases or conditions associated with fibrosis, comprising administering to an individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof. Invention Details

[0119] The term "alkyl" as used in this article, such as C 1-4 Alkyl groups, whether used alone or as part of a larger group, are fully saturated hydrocarbon chains, either straight or branched, containing a specified number of carbon atoms. C 1-4 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl. The term "propyl" includes both n-propyl and isopropyl. The term "butyl" includes n-butyl, isobutyl, tert-butyl, and sec-butyl.

[0120] The term "alkylene" as used in this article, such as C 1-4 -alkylene groups, whether used alone or as part of a larger group, such as 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 heterocyclic alkyl), OC 1-4 Alkylene (4-7 membered heterocyclic alkyl), 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 Alkylene O (4-7 membered heterocyclic alkyl), C 1-4 Alkylene O (aryl) or C 1-4 Alkylene O(C) 3-6 (Alkyne group), for example, 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 heterocyclic alkyl), 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 Alkylene O (4-7 membered heterocyclic alkyl), C 1-4 Alkylene O (aryl) or C 1-4 Alkylene O(C) 3-6 Alkyne (C) is a divalent, straight-chain or branched, fully saturated hydrocarbon group containing a specified number of carbon atoms. 1-4Examples 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-). The C-axis of the branched chain... 1-4 An example of an alkylene group is isopropylene (i.e., -CH(Me)CH2-).

[0121] Term C 1-4 Alkylene (OH) refers to C atoms that have been substituted with OH radicals. 1-4 Alkyl groups, such as CH2OH.

[0122] The term "alkoxy" as used in this article, such as C 1-4 An alkoxy group is an alkyl group as defined above (e.g., C10) that is monovalently bonded to an oxygen atom. 1-4 Alkyl). C 1-4 Examples of alkoxy groups include methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy, and 3-butoxy, especially methoxy.

[0123] As used in this article, the term "halogenated" or "halogen" refers to fluorine, chlorine, bromine, or iodine. Specific examples of halogenation are bromine, fluorine, and chlorine, especially fluorine.

[0124] The term "haloalkyl" as used in this article, such as C 1-4 Haloalkyl groups, whether alone or forming larger groups such as OC 1-4 A portion of haloalkyl groups are straight-chain or branched alkyl groups containing a specified number of carbon atoms that are substituted with one or more halogen atoms, such as fluoromethyl (CH2F), difluoromethyl (CHF2), trifluoromethyl (CF3), 1-fluoroethyl (CH2FCH2), and 2-fluoroethyl (CH2CH2F).

[0125] The term "cycloalkyl" as used in this article, such as C16, refers to cycloalkyl groups. 3-6 Cycloalkyl groups, whether alone or forming larger groups such as C 1-4 Alkylene (C 3-6 cycloalkyl) or C 1-4 Alkylene OC 3-6 A portion of cycloalkyl groups are fully saturated hydrocarbon rings containing a specified number of carbon atoms. C 3-6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, especially cyclopropyl. Optionally, cycloalkyl groups may be substituted as defined herein.

[0126] The term “heterocyclic alkyl” as used herein refers to 4-7 membered heterocyclic alkyl groups, whether alone or forming larger groups such as C. 1-4 Alkylene (4-7 membered heterocyclic alkyl) and C 1-4A subset of alkylene oxides (4-7 membered heterocyclic alkyl groups) is a fully saturated hydrocarbon ring containing a specified number of ring atoms, wherein at least one carbon atom is replaced by a heteroatom such as N, S, or O. Optionally, heterocyclic alkyl groups may be substituted as defined herein.

[0127] Examples of 4-7 membered heterocyclic alkyl groups include those containing 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 4-7 membered heterocyclic alkyl groups containing one nitrogen atom include azircyclic butyl, pyrrolidinyl, piperidinyl, and azircyclic heptyl. Examples of 4-7 membered heterocyclic alkyl groups containing two nitrogen atoms include diazacyclic butyl, imidazoalkyl, pyrazolyl, diazinyl, and diazacyclic heptyl.

[0128] Other examples of 4-7 membered heterocyclic alkyl groups include oxetane, thiohepane, dioxetane, dithiohepane, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrahydropyranyl, thiohexyl, morpholinyl, thiomorpholinyl, dioxetane, dithiohexyl, triazine, trioxetane, trithiohexyl, oxetaneheptyl, and thiohepane.

[0129] The term "aryl" as used in this article, whether alone or forming a larger group such as C, refers to aryl. 1-4 Alkylene (aryl), OC 1-4 alkylene (aryl) or C 1-4 A portion of alkylene O (aryl) refers to a benzene ring. Optionally, the aryl group may be substituted as defined herein.

[0130] The term "alkynyl" as used in this article, such as C 3-6 Alkyne groups, whether alone or forming larger groups such as C 1-4 Alkylene O(C) 3-6 A part of the alkynyl group is a straight-chain or branched divalent hydrocarbon chain having at least one carbon-carbon triple bond. 3-6 Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, pentynyl, and hexynyl.

[0131] C 1-4 An example of an alkylene (aryl) group is CH2Ph, where Ph represents phenyl. 1-4 Alkylene OC 1-4 Examples of alkyl groups include CH2OMe, CH2OEt, and CH2OPr. C 1-4 Alkylene OC 3-6 Examples of cycloalkyl groups include CH2OC3-cycloalkyl and CH2OC4-cycloalkyl, such as CH2O-cyclopropyl or CH2O-cyclobutyl.1-4 Examples of alkylene (4-7-membered heterocyclic alkyl) include CH2 (4-membered heterocyclic alkyl), such as CH2-azacyclobutane and CH2CH2-azacyclobutane. 1-4 Examples of alkylene O (4-7 membered heterocyclic alkyl) include C 1-4 Alkyl OC4 heterocyclic alkyl, such as CH2O-azacyclic butyl. C 1-4 Alkylene O(C) 3-6 An example of an alkynyl group is CH2OCH2C≡CH.

[0132] In the following embodiments and preferred embodiments, when the substituent in formula (I) is indicated as optionally substituted, the optional substituent may be attached to a available carbon atom, wherein the available carbon atom refers to a carbon atom attached to a hydrogen atom, i.e., a CH group, or the optional substituent may be attached to a available nitrogen atom, wherein the available nitrogen atom refers to a nitrogen atom attached to a hydrogen atom, i.e., an NH group. The optional substituent replaces the hydrogen atom attached to the carbon atom or the hydrogen atom attached to the nitrogen atom.

[0133] In one implementation, R 1a It is H. In the second implementation scheme, R 1a It is a methyl group.

[0134] In one implementation, R 1b It is H. In the second implementation scheme, R 1b It's fluorine.

[0135] In a preferred embodiment, A is a group (Aa):

[0136]

[0137] In one implementation, R2 is C 1-4 Alkyl groups, such as methyl, ethyl, propyl, or butyl, especially methyl; C 1-4 Alkylene (aryl), such as benzyl; C 1-4 Alkylene (OH), for example CH2OH; C 1-4 Alkylene OC 1-4 Alkyl groups, such as CH2OMe, CH2OEt, or CH2OPr, especially CH2OMe; C 1-4 Alkylene OC 3-6 Cycloalkyl, such as CH2O-C3 cycloalkyl or CH2O-C4 cycloalkyl, such as CH2O-cyclopropyl or CH2O-cyclobutyl; C 1-4 Alkylene O (aryl), for example CH2OPh; C 1-4Alkylene (4-7-membered heterocyclic alkyl), such as CH2 (4-membered heterocyclic alkyl), such as CH2-azacyclobutane or CH2CH2 (4-membered heterocyclic alkyl), such as CH2CH2-azacyclobutane; C 1-4 Alkylene O (4-7 membered heterocyclic alkyl), such as C 1-4 Alkyl OC4 heterocyclic alkyl, especially CH2O-azacyclic butyl; or C 1-4 Alkylene O(C) 3-6 (Alkyne group), for example, CH2OCH2C≡CH. Suitably, R2 is methyl, CH2OH, or CH2OMe, especially methyl.

[0138] The aryl, heterocyclic, and cycloalkyl groups present in R2 may optionally be substituted by up to three substituents, such as one, two, or three substituents, such as one or two substituents, such as one substituent, each of which is independently selected from C10. 1-4 Alkyl, such as methyl; C 3-6 Cycloalkyl, such as cyclopropyl; C 1-4 Alkoxy groups, such as OMe; C 1-4 Haloalkyl, such as CF3; halogenated, such as chlorine or fluorine; CN; OH; NR 2a R 2b SO2R 2c ; and NHSO2R 2c Suitably, the aryl, heterocyclic, and cycloalkyl groups present in R2 may optionally be substituted by up to three substituents, such as one, two, or three substituents, such as one or two substituents, such as one substituent, each of which is independently selected from C10. 1-4 Alkyl, such as methyl; C 3-6 Cycloalkyl, such as cyclopropyl; C 1-4 Alkoxy groups, such as OMe; C 1-4 Halogenated alkyl groups, such as CF3; halogenated groups, such as chlorine or fluorine; and CN. Suitably, the aryl, heterocyclic, and cycloalkyl groups present in R2 may optionally be substituted by up to three substituents, such as one, two, or three substituents, such as one or two substituents, such as one substituent, each of which is independently selected from OH; NR 2a R 2b SO2R 2c ; and NHSO2R 2c .

[0139] In one implementation, R 2a It is H. In the second implementation scheme, R 2a It is C 1-4 Alkyl groups, such as methyl, ethyl, or propyl, especially methyl. In the third embodiment, R 2a It is H or methyl.

[0140] In one implementation, R 2b It is H. In the second implementation scheme, R 2b It is C 1-4 Alkyl groups, such as methyl, ethyl, or propyl, especially methyl. In the third embodiment, R 2b It is C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, and cyclopentyl, especially cyclopropyl. In the fourth embodiment, R 2b It is C 1-4 Alkyl groups, such as OMe or OEt, especially OMe. In the fifth embodiment, R 2b It is C 1-4 Halogenated alkyl groups, such as CF3. In the sixth embodiment, R 2b It is an aryl group, such as a phenyl group. In the seventh embodiment, R 2b It is a 4-7 membered heterocyclic alkyl group, such as an azirmonobutylene or an oxobutylene. In the eighth embodiment, R 2b It is H or methyl.

[0141] In one implementation, R 2c It is C 1-4 Alkyl groups, such as methyl, ethyl, or propyl, especially methyl. In the second embodiment, R 2c It is C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, and cyclopentyl, especially cyclopropyl. In the third embodiment, R 2c It is C 1-4 Alkyl groups, such as OMe or OEt, especially OMe. In the fourth embodiment, R 2c It is C 1-4 Halogenated alkyl groups, such as CF3. In the fifth embodiment, R 2c It is an aryl group, such as a phenyl group. In the sixth embodiment, R 2c It is a 4-7 membered heterocyclic alkyl group, such as an azirrobutane or an oxacyclobutane. In the seventh embodiment, R 2c It is a methyl group.

[0142] Suitably, the aryl group is substituted by one, two, or three substituents, for example, one or two substituents, such as one substituent, each of which is independently selected from methyl, chlorine, and fluorine. In one embodiment, the aryl group is unsubstituted.

[0143] Suitably, the heterocyclic alkyl group is substituted with one, two, or three substituents, for example, one or two substituents, such as one substituent, each substituent being independently selected from CH2CH2F (particularly as a substituent on the nitrogen atom) and fluorine (particularly as a substituent on the carbon atom). In one embodiment, the heterocyclic alkyl group is unsubstituted.

[0144] Suitably, when the heterocyclic alkyl group is an azircyclic butyl group, the nitrogen atom is located at the 1 or 3 position relative to the connection point with the remainder of the R2 group (i.e., 1-azircyclic butyl or 3-azircyclic butyl), for example:

[0145]

[0146] Suitablely, when R2 is C 1-4 When R2 is an alkylene group (4-7-membered heterocyclic alkyl group), such as CH2-azacyclobutane or CH2CH2-azacyclobutane, the azacyclobutane is 1-azacyclobutane. Suitably, when R2 is C 1-4 When the alkylene group is O (4-7-membered heterocyclic alkyl), such as CH2O-azacyclic butyl, the azacyclic butyl is 3-azacyclic butyl. For example:

[0147]

[0148] Suitablely, when a heterocyclic alkyl group contains one or more nitrogen atoms, the nitrogen atom may be attached to a hydrogen atom to form an NH group, depending on the required valence. Alternatively, the nitrogen atom may be substituted (e.g., one nitrogen atom is substituted), for example, by C… 1-4 Alkyl, C 1-4 Haloalkyl groups such as CH2CH2F, C(O)H, C(O)C 1-4 Alkyl, C(O)OC 1-4 Alkyl groups such as C(O)OtBu and C(O)OC 1-4 Alkylene (aryl) compounds such as C(O)OBz, C(O)NHC 1-4 Alkyl, C(O)NHC 1-4 Alkylene (aryl) groups such as C(O)NHBz, Fmoc groups, C(O)C 1-4 Haloalkyl, C(O)OC 1-4 Halogenated alkyl or C(O)NHC 1-4 Halogenated alkyl groups. Suitably, when the heterocyclic alkyl group contains one or more sulfur atoms, the sulfur atoms are substituted with one or two oxygen atoms (e.g., one sulfur atom is substituted) (i.e., S(O) or S(O)2). Alternatively, any sulfur atom in the heterocyclic alkyl ring is unsubstituted.

[0149] When one or more nitrogen atoms are C 1-4 Alkyl, C 1-4 Haloalkyl groups such as CH2CH2F, C(O)H, C(O)C 1-4 Alkyl, C(O)OC 1-4 Alkyl groups such as C(O)OtBu and C(O)OC 1-4 Alkylene (aryl) compounds such as C(O)OBz, C(O)NHC1-4 Alkyl, C(O)NHC 1-4 Alkylene (aryl) groups such as C(O)NHBz, Fmoc groups, C(O)C 1-4 Haloalkyl, C(O)OC 1-4 Halogenated alkyl or C(O)NHC 1-4 When alkyl halogens are substituted, in addition to the optional substituents described above for heterocyclic alkyl groups, these substituents may also be present. Substituents on the nitrogen atom may be called protecting groups or function as protecting groups, and they can be added and removed by methods known to those skilled in the art.

[0150] Suitably, the cycloalkyl group is formed by 1, 2, or 3 C atoms. 1-4 Alkyl substituents, such as 1 or 2, for example, 1 C 1-4 Alkyl substituents, such as methyl, ethyl, and propyl, especially methyl-substituted. In one embodiment, the cycloalkyl group is unsubstituted.

[0151] Suitable, unless R2 is H, C 1-4 Alkyl, C 1-4 Alkylene (OH), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene O (aryl), OC 1-4 Alkylene (aryl), C 1-4 Alkylene (4-7 membered heterocyclic alkyl), C 1-4 Alkylene O (4-7 membered heterocyclic alkyl) or C 1-4 Alkylene O(C) 3-6 (Alkyne), otherwise m is 0. More preferably, unless R2 is H, methyl, CH2OH, CH2OMe, CH2OPh, OCH2Ph, CH2O(1-(2-fluoroethyl)azacyclobutane-3-yl, CH2(3-fluoroazacyclobutane-1-yl), CH2CH2(3-fluoroazacyclobutane-1-yl) or CH2OCH2C≡CH, m is 0.

[0152] Suitablely, when m is 0, R2 is not C. 1-4 Alkenyl O (4-7-membered heterocyclic alkyl). Suitably, when m is 0, R2 is not CH2CH2 (3-fluoroazacyclobutane-1-yl). Suitably, when R2 is H and m is 1, R3 is not fluorine at the 3-position.

[0153] In one implementation, when present, each R3 is independently fluorine or methyl, particularly fluorine.

[0154] In one implementation, m is 1 or 2.

[0155] In one preferred embodiment, m is 1 and R3 is in 3 bits. In another preferred embodiment, m is 1 and R3 is in 6 bits. In yet another preferred embodiment, m is 2, one R3 is in 3 bits and the other R3 is in 6 bits. In one embodiment, R2 is H, m is 1 and R3 is in 3 bits. In one embodiment, m is 0. In one embodiment, R2 is H and R3 is in 3 bits.

[0156] The positions of the substituents mentioned are relative to their connection positions with the amide moiety, for example:

[0157]

[0158] Examples of suitable substituents include 2-OCH2Ph; 2-CH2OPh; 2-CH2O (cyclobutyl); 2-CH2OH; 2-CH2OMe; 2-CH2O (1-(2-fluoroethyl)azacyclobutane-3-yl); 2-CH2 (3-fluoroazacyclobutane-1-yl); 2-CH2CH2 (3-fluoroazacyclobutane-1-yl); 2-CH2OCH2C≡CH; 3-methyl; 3-chloro; 3-fluoro; 3-fluoro-2-methyl; 6-fluoro-2-methyl; 2,6-dimethyl; and 3-fluoro-2,6-dimethyl. In one embodiment, each R3 is the same. In another embodiment, each R3 is different.

[0159] In one implementation, A is a group (Ab):

[0160]

[0161] In one implementation, R4 is H. In a second implementation, R4 is C. 1-4 Alkyl, such as methyl. In the third embodiment, R4 is C. 1-4 Alkylene (aryl), such as benzyl. In a preferred embodiment, R4 is H, methyl, or benzyl, particularly methyl or benzyl. Suitably, the aryl group is substituted with one, two, or three substituents, for example, one or two substituents, such as one substituent, each of which is independently selected from C10. 1-4 Alkyl, such as methyl; C 3-6 Cycloalkyl, such as cyclopropyl; C 1-4 Alkoxy groups, such as OMe; C 1-4 Haloalkyl, such as CF3; halogenated, such as chlorine or fluorine; CN; OH; NR 4a R 4b SO2R 4c ; and NHSO2R 4c Suitablely, the aryl group is substituted by one, two, or three substituents, for example, one or two substituents, such as one substituent, each of which is independently selected from C.1-4 Alkyl, such as methyl; C 3-6 Cycloalkyl, such as cyclopropyl; C 1-4 Alkoxy groups, such as OMe; C 1-4 Halogenated alkyl groups, such as CF3; halogenated groups, such as chlorine or fluorine; and CN. Suitably, the aryl group is substituted with one, two, or three substituents, such as one or two substituents, each of which is independently selected from OH; NR 4a R 4b SO2R 4c ; and NHSO2R 4c Suitably, the aryl group is substituted with one, two, or three substituents, for example, one or two substituents, each independently selected from methyl, chlorine, and fluorine. In one embodiment, the aryl group is substituted with one, two, or three, for example, one or two, for example, one methyl group. In one embodiment, the aryl group is substituted with one, two, or three, for example, one or two, for example, one chlorine group. In one embodiment, the aryl group is substituted with one, two, or three, for example, one or two, for example, one fluorine group. Suitably, the aryl group is unsubstituted.

[0162] In one implementation, R 4a It is H. In the second implementation scheme, R 4a It is C 1-4 Alkyl groups, such as methyl, ethyl, or propyl, especially methyl. In the third embodiment, R 4a It is H or methyl.

[0163] In one implementation, R 4b It is H. In the second implementation scheme, R 4b It is C 1-4 Alkyl groups, such as methyl, ethyl, or propyl, especially methyl. In the third embodiment, R 4b It is C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, and cyclopentyl, especially cyclopropyl. In the fourth embodiment, R 4b It is C 1-4 Alkyl groups, such as OMe or OEt, especially OMe. In the fifth embodiment, R 4b It is C 1-4 Halogenated alkyl groups, such as CF3. In the sixth embodiment, R 4b It is an aryl group, such as a phenyl group. In the seventh embodiment, R 4b It is a 4-7 membered heterocyclic alkyl group, such as an azirmonobutylene or an oxobutylene. In the eighth embodiment, R 4b It is H or methyl.

[0164] In one implementation, R 4c It is C 1-4Alkyl groups, such as methyl, ethyl, or propyl, especially methyl. In the second embodiment, R 4c It is C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, and cyclopentyl, especially cyclopropyl. In the third embodiment, R 4c It is C 1-4 Alkyl groups, such as OMe or OEt, especially OMe. In the fourth embodiment, R 4c It is C 1-4 Halogenated alkyl groups, such as CF3. In the fifth embodiment, R 4c It is an aryl group, such as a phenyl group. In the sixth embodiment, R 4c It is a 4-7 membered heterocyclic alkyl group, such as an azirrobutane or an oxacyclobutane. In the seventh embodiment, R 4c It is H or methyl.

[0165] In one implementation, R 5 It is H.

[0166] In one embodiment, each R6, when present, is independently fluorine or methyl. Suitably, n is 1, 2, or 3, for example, 1 or 2, for example, 1.

[0167] In one implementation, n is 0.

[0168] In one implementation, group A is group (Ac):

[0169]

[0170] In one embodiment, R7 is methyl, CH2OH, or CH2OMe.

[0171] In one implementation, o is 2.

[0172] Suitablely, R is relative to the bond that links the (Ac) group to the amide moiety. 7 The stereochemistry is trans, for example, having one of the following two stereochemical arrangements:

[0173]

[0174] In a preferred embodiment, A is a group (Ad):

[0175]

[0176] In one embodiment, X is a bond or O. Suitably, X is a bond. Suitably, X is O. In a second embodiment, X is CH2.

[0177] In one embodiment, R8 is halogenated. In another embodiment, R8 is C.1-4 Alkyl group. In one embodiment, R8 is C6. 1-4 Alkyl group. In one embodiment, R8 is OH.

[0178] In one embodiment, when present, each R8 is independently methyl, OMe, or fluorine. In one embodiment, each R8 is independently OCH2-cyclopropyl, OCH2-oxetane, OCH2CH2F, methyl, OMe, OEt, or fluorine, such as OCH2CH2F, OMe, or OEt, especially OMe. In another embodiment, each R8 is independently OCH2-cyclopropyl, OCH2-oxetane, OCH2CH2F, or OEt, such as OCH2-cyclopropyl, OCH2-oxetane, or OCH2CH2F.

[0179] Suitably, the cycloalkyl and heterocycloalkyl groups present in R8 are each independently substituted by one, two, or three substituents, for example, one or two substituents, for example, one substituent, each of which is independently selected from C10. 1-4 Alkyl, such as methyl; C 3-6 Cycloalkyl, such as cyclopropyl; C 1-4 Alkoxy groups, such as OMe; C 1-4 Haloalkyl, such as CF3; halogenated, such as chlorine or fluorine; CN; OH; NR 8a R 8b SO2R 8c ; and NHSO2R 8c Suitably, the cycloalkyl and heterocycloalkyl groups are each independently substituted by one, two, or three substituents, for example, one or two substituents, for example, one substituent, each substituent being independently selected from C10. 1-4 Alkyl, such as methyl; C 3-6 Cycloalkyl, such as cyclopropyl; C 1-4 Alkoxy groups, such as OMe; C 1-4 Halogenated alkyl groups, such as CF3; halogenated, such as chlorine or fluorine; and CN. Suitably, the cycloalkyl and heterocycloalkyl groups are each independently substituted by one, two, or three substituents, such as one or two substituents, such as one substituent, each substituent being independently selected from OH; NR 8a R 8b SO2R 8c ; and NHSO2R 8c .

[0180] In one implementation, R 8a It is H. In the second implementation scheme, R 8a It is C 1-4 Alkyl groups, such as methyl, ethyl, or propyl, especially methyl. In the third embodiment, R 8aIt is H or methyl.

[0181] In one implementation, R 8b It is H. In the second implementation scheme, R 8b It is C 1-4 Alkyl groups, such as methyl, ethyl, or propyl, especially methyl. In the third embodiment, R 8b It is C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, and cyclopentyl, especially cyclopropyl. In the fourth embodiment, R 8b It is C 1-4 Alkyl groups, such as OMe or OEt, especially OMe. In the fifth embodiment, R 8b It is C 1-4 Halogenated alkyl groups, such as CF3. In the sixth embodiment, R 8b It is an aryl group, such as a phenyl group. In the seventh embodiment, R 8b It is a 4-7 membered heterocyclic alkyl group, such as an azirmonobutylene or an oxobutylene. In the eighth embodiment, R 8b It is H or methyl.

[0182] In one implementation, R 8c It is C 1-4 Alkyl groups, such as methyl, ethyl, or propyl, especially methyl. In the second embodiment, R 8c It is C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, and cyclopentyl, especially cyclopropyl. In the third embodiment, R 8c It is C 1-4 Alkyl groups, such as OMe or OEt, especially OMe. In the fourth embodiment, R 8c It is C 1-4 Halogenated alkyl groups, such as CF3. In the fifth embodiment, R 8c It is an aryl group, such as a phenyl group. In the sixth embodiment, R 8c It is a 4-7 membered heterocyclic alkyl group, such as an azirrobutane or an oxacyclobutane. In the seventh embodiment, R 8c It is a methyl group.

[0183] Suitably, the cycloalkyl group (e.g., cyclopropyl) present in R8 is surrounded by 1, 2, or 3 carbon atoms. 1-4 Alkyl substituents, such as 1 or 2, for example, 1 C 1-4 Alkyl substituents, such as methyl, ethyl, and propyl, especially methyl-substituted. In one embodiment, the cycloalkyl group is unsubstituted.

[0184] Suitably, the heterocyclic alkyl group (e.g., oxetane) present in R8 is substituted with one, two, or three substituents, for example, one or two substituents, for example, one substituent, each of which is independently selected from fluorine and C. 1-4 Alkyl groups, such as methyl, ethyl, and propyl, especially methyl. In one embodiment, the heterocyclic alkyl group is unsubstituted.

[0185] Suitably, when the heterocyclic alkyl group is an oxetane, the oxygen atom is located at the 2 or 3 position relative to the connection point with the remainder of the R8 group (i.e., 2-oxetane or 3-oxetane), for example:

[0186]

[0187] Suitable, when R8 is OC 1-4 When alkylene (4-7 membered heterocyclic alkyl), such as OCH2-oxetane, the oxetane is 3-oxetane, for example:

[0188]

[0189] When p is 1 or 2, R8 can be located in 2 and / or 3 bits. In one embodiment, p is 1 and R8 is in 2 bits. In a second embodiment, p is 1 and R8 is in 3 bits. In a third embodiment, p is 2, one R8 is in 2 bits and another R8 is in 3 bits. For example:

[0190]

[0191] Examples of suitable R8 substituents include 2-methyl, 2-methoxy, 2-ethoxy, 2-OCH2CH2F, 2-OCH2-cyclopropyl, and 2-OCH2-oxetane, such as 2-methyl and 2-methoxy.

[0192] Ideally, when X is the key, R8 is not in bit 3. Ideally, when X is the key, R8 is in bit 2.

[0193] Suitable examples of substituents are 2-methyl, 2-methoxy, and 3-fluoro.

[0194] In one implementation, p is 0 or 1.

[0195] Suitably, when X is a bond and p is 0, the compound has an (R) stereochemical configuration. Suitably, when X is as defined above and p is 1, R is the stereochemical configuration relative to the bond that links the (Ad) group to the amide substituent. 8 The stereochemistry is trans, for example, having one of the following stereochemical arrangements:

[0196]

[0197] In one implementation, each R9 is fluorine independently of the others when present.

[0198] Suitablely, when q is 1, 2, 3, or 4, R9 can be 5, 6, 7, and / or 8 bits. In one embodiment, q is 1 and R9 is 5 bits. In a second embodiment, q is 1 and R9 is 6 bits. For example:

[0199]

[0200] Ideally, R9 should not be in bit 8. Ideally, R9 should be in bit 7. Ideally, R9 should be in bit 6. Ideally, R9 should be in bit 5.

[0201] In embodiments where X is a bond, it should be understood that the substituent position numbering will change accordingly with the total number of atoms in the bicyclic system, for example:

[0202]

[0203] When X is a bond, suitable examples of R9 substituents are 4-fluoro and 5-fluoro.

[0204] In one implementation, q is 1 or 2.

[0205] In one implementation, D, E, and F are C(R) 10 In the second implementation, D is N, and E and F are C(R). 10 In the third implementation, E is N, and D and F are C(R). 10 In the fourth implementation, F is N, and D and E are C(R). 10 ).

[0206] Suitablely, when D and F are C(R) 10 When E is N, E cannot be N.

[0207] In one implementation, R 10 It is H. In the second implementation scheme, R 10 It is halogenated, for example, fluorine or chlorine, especially chlorine. In the third embodiment, R 10 It is C 1-4 Alkyl groups, such as methyl groups. Suitably, each R 10 They are H, fluorine, chlorine or methyl, which are independent of each other.

[0208] In a preferred embodiment, the compound of the present invention has formula (Ia):

[0209]

[0210] Where A is a group (Aa'), (AdI'), or (AdII');

[0211] R 10a It is H, fluorine, chlorine, or methyl;

[0212] The group (Aa') is:

[0213]

[0214] in:

[0215] R 2d It is methyl, CH2OMe or CH2OCH2C≡CH;

[0216] Each R 3a Each is independently H, methyl, or fluorine; and

[0217] The group (AdI') is:

[0218]

[0219] in:

[0220] R 8d It is H, methyl, or OMe;

[0221] R 9a It is H or F;

[0222] The group (AdII') is:

[0223]

[0224] in:

[0225] X is O; and

[0226] R 8a’ It is methyl;

[0227] The condition is that A is a group (AdI') and R 10a When one of them is fluorine or chlorine, the remaining two R 10a The group is H independently;

[0228] Or its pharmaceutically acceptable salts and / or solvates.

[0229] In one embodiment, the compound of formula (I) is selected from:

[0230] (E)-N-(3-fluoro-2-methylphenyl)-3-(7-methyl-1H-indazol-6-yl)acrylamide;

[0231] (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide;

[0232] (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide;

[0233] (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide (racemic mixture);

[0234] (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide (enantiomer 1);

[0235] (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide (enantiomer 2);

[0236] (E)-N-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide;

[0237] (E)-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide;

[0238] (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide;

[0239] (E)-N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide;

[0240] (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-indazol-6-yl)acrylamide;

[0241] (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-indazol-6-yl)acrylamide;

[0242] (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-indazol-6-yl)acrylamide;

[0243] (E)-3-(5-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide;

[0244] (E)-3-(4-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide;

[0245] (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (a mixture of stereoisomers);

[0246] (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 1);

[0247] (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 2);

[0248] (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 3);

[0249] (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 4);

[0250] (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (a mixture of stereoisomers);

[0251] (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (stereoisomer 1);

[0252] (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (stereoisomer 2);

[0253] (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (stereoisomer 3);

[0254] (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (stereoisomer 4);

[0255] (E)-N-(2-(benzyloxy)phenyl)-3-(1H-indazol-6-yl)acrylamide;

[0256] (E)-3-(1H-indazol-6-yl)-N-(2-(phenoxymethyl)phenyl)acrylamide;

[0257] (E)-N-(2-(cyclobutoxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide;

[0258] (E)-N-(1-benzyl-1H-indazol-7-yl)-3-(1H-indazol-6-yl)acrylamide;

[0259] (E)-3-(1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide;

[0260] (E)-3-(1H-indazol-6-yl)-N-(m-tolyl)acrylamide;

[0261] (E)-N-(3-chlorophenyl)-3-(1H-indazol-6-yl)acrylamide;

[0262] (E)-N-(3-fluorophenyl)-3-(1H-indazol-6-yl)acrylamide;

[0263] (E)-N-(2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide;

[0264] (E)-N-((1R,3R)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide (a mixture of stereoisomers);

[0265] (E)-N-((1R,3R)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide (stereoisomer 1);

[0266] (E)-N-((1R,3S)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide (stereoisomer 2);

[0267] (E)-N-(2-(hydroxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide;

[0268] (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide;

[0269] (E)-3-(1H-indazol-6-yl)-N-(2-(methoxymethyl)phenyl)acrylamide;

[0270] (E)-N-(2-(((1-(2-fluoroethyl)azacyclobutane-3-yl)oxy)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide hydrochloride;

[0271] (E)-N-(2-((3-fluorozacricyclobutan-1-yl)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide;

[0272] (E)-N-(2-(2-(3-fluorozacricyclobutan-1-yl)ethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide;

[0273] (E)-N-(2-fluoro-6-methylphenyl)-3-(1H-indazol-6-yl)acrylamide;

[0274] (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-pyrazolo[4,3-b]pyridin-6-yl)acrylamide;

[0275] (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[4,3-c]pyridin-6-yl)acrylamide;

[0276] (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide;

[0277] (E)-3-(1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-yl)acrylamide;

[0278] (E)-3-(1H-indazol-6-yl)-N-(7-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide;

[0279] (E)-3-(1H-indazol-6-yl)-N-(3-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; and

[0280] (E)-3-(1H-indazol-6-yl)-N-(2-((prop-2-yn-1-yloxy)methyl)phenyl)acrylamide;

[0281] Or a pharmaceutically acceptable salt and / or solvate of any of them.

[0282] The definition of a compound of formula (I) includes all tautomers of the compound.

[0283] 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 pharmaceutically acceptable salts and / or solvates, such as pharmaceutically acceptable salts.

[0284] It should be understood that, for use in pharmaceuticals, salts of compounds of formula (I) must be pharmaceutically acceptable. Non-pharmaceutically acceptable salts of compounds of formula (I) may be used in other situations, such as in 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 by Berge et al. (1977). These pharmaceutically acceptable salts include acid and base addition salts. Pharmaceutically acceptable acid addition salts can form 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, to isolate compounds of formula (I) and are included within the scope of this invention.

[0285] Some compounds of formula (I) can form acid or base addition salts with one or more equivalents of an acid or base. The invention encompasses all possible stoichiometric and non-stoichiometric forms within its scope.

[0286] Compounds of formula (I) can be prepared in crystalline or amorphous form, and if crystalline, can optionally be solvated, for example, as hydrates. The invention encompasses stoichiometric solvates (e.g., hydrates) and compounds containing variable solvents (e.g., water).

[0287] It should be understood that this invention includes all isomers of formula (I) and pharmaceutically acceptable derivatives thereof, including all geometric, tautomeric, and optical forms, and mixtures thereof (e.g., racemic mixtures). When an additional chiral center is present in a compound of formula (I), this invention includes all possible diastereomers, including mixtures thereof, within its scope. Different isomeric forms can be separated or split from each other by conventional methods, or any given isomer can be obtained by conventional synthetic methods or by stereospecific or asymmetric synthesis.

[0288] This disclosure includes all isotopic forms of the compounds of the invention provided herein, whether (i) forms in which all atoms of a given atomic number have a mass number (or a mixture of mass numbers) that is dominant in nature (referred to herein as "natural isotopic forms") or (ii) forms in which one or more atoms are replaced by atoms having the same atomic number but a mass number different from that of the dominant atom in nature (referred to herein as "non-natural variant isotopic forms"). It should be understood that atoms can exist naturally as mixtures of mass numbers. The term "non-natural variant isotopic form" also includes embodiments in which the proportion of atoms of a given atomic number having a less common mass number in nature (referred to herein as "uncommon isotopes") is increased relative to the proportion of naturally occurring isotopes, for example, reaching levels of >20%, >50%, >75%, >90%, >95%, or >99% based on the number of atoms of that atomic number (the latter embodiment is referred to as "isotope-enriched variant form"). The term "non-natural variant isotopic form" also includes embodiments in which the proportion of uncommon isotopes is reduced relative to the proportion of naturally occurring isotopes. Isotopic forms can include radioactive forms (i.e., they are doped with radioactive isotopes) and non-radioactive forms. Radioactive forms are typically isotope-enriched variant forms.

[0289] Therefore, the non-natural variant isotopic form of a compound may contain one or more artificial or uncommon isotopes in one or more atoms, such as 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 I), or may contain an increased proportion of the isotope in one or more atoms compared to the dominant proportion in nature.

[0290] Non-natural variants of radioactive isotopes can be used, for example, for studies of drug and / or substrate tissue distribution. Radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14C), given their ease of incorporation and readily available detection methods, are particularly suitable for this purpose. Incorporation of deuterium... 2 Non-natural variant isotopic forms of H or D can offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, and may therefore be preferred in some cases. Furthermore, isotopes incorporating positron-emitting elements, such as... 11 C 18 F, 15 O and 13 Non-natural variant isotopic forms of N can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy.

[0291] In one embodiment, the compounds of the present invention are provided in the form of natural isotopes.

[0292] In one embodiment, the compounds of the present invention are provided in a non-natural variant isotopic form. In a specific embodiment, the non-natural variant isotopic form is one in which deuterium (i.e.,...) is incorporated. 2 The form is H or D), wherein hydrogen is specified in the chemical structure of one or more atoms of the compound of the invention. In one embodiment, the atoms of the compound of the invention are in a non-radioactive isotopic form. In one embodiment, one or more atoms of the compound of the invention are in a radioactive isotopic form. Suitable radioactive isotopes are stable isotopes. Suitably, non-natural variant isotopic forms are pharmaceutically acceptable forms.

[0293] In one embodiment, a compound of the present invention is provided, wherein a single atom of said compound is present in a non-natural variant isotopic form. In another embodiment, a compound of the present invention is provided, wherein two or more atoms are present in a non-natural variant isotopic form.

[0294] Non-natural isotopic variants can generally be prepared by conventional techniques known to those skilled in the art or by methods described herein, such as those similar to those described in the appended examples for preparing natural isotopic forms. Therefore, non-natural isotopic variants can be prepared by using a suitable isotopic variant (or labeled) reagent instead of the conventional reagents used in the examples. Since the compounds of formula (I) are for use in pharmaceutical compositions, it is readily understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, preferably at least 85%, and especially at least 98% pure (% based on weight / weight). Impure formulations of the compounds can be used to prepare purer forms for use in pharmaceutical compositions.

[0295] Typically, compounds of formula (I) can be prepared according to organic synthesis techniques known to those skilled in the art, as well as by the representative methods listed below, those in the examples, and their modifications. In the following schemes, reactive groups may be protected with protecting groups and deprotected according to established techniques well known to those skilled in the art.

[0296] General route

[0297] A general route for conveniently preparing the compound examples of the present invention is summarized below. In the following description, unless otherwise stated, group R... 1a R 1b A and B are as defined in compound (I) above.

[0298] Option 1

[0299]

[0300] Compound (I) can be synthesized by combining compound (II) with compound (III) under palladium-catalyzed cross-coupling conditions using a palladium precatalyst, such as [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (Pd(dppf)Cl2) with dichloromethane. . CH2Cl2 is prepared by reacting a base, such as triethylamine, with a suitable solvent, such as dimethylformamide (DMF).

[0301] Option 2

[0302]

[0303] In addition, the compound of formula (I) can also be prepared by reacting the compound of formula (IV) with the compound of formula (V) under amidation conditions with an amide coupling agent such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxyhexafluorophosphate (HATU) in a suitable solvent such as DMF in the presence of a base such as N,N-diisopropylethylamine (DIPEA, also known as Hünig's base).

[0304] Option 3

[0305]

[0306] Compound (I) can also be prepared by reacting compound (VI) with compound (V) under alkaline conditions with a base such as lithium bis(trimethylsilyl)amino (LiHMDS) in a suitable solvent such as tetrahydrofuran (THF).

[0307] Option 4

[0308]

[0309] Compound (II) is commercially available. Compound (II) can also be prepared by reacting compound (VII) with compound (VIII) in a suitable solvent, such as dichloromethane (DCM), in the presence of a base, such as N,N-diisopropylethylamine.

[0310] Option 5

[0311]

[0312] Compound (VI) can be obtained by reacting compound (IX) with compound (III) under palladium-catalyzed cross-coupling conditions using a palladium precatalyst, such as [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (II) (Pd(dppf)Cl2·CH2Cl2) in combination with dichloromethane, in the presence of a base such as triethylamine and a suitable solvent such as dimethylformamide (DMF).

[0313] Option 6

[0314]

[0315] Compound (IV) can be obtained by reacting compound (VI) under hydrolytic conditions with a base such as sodium hydroxide (NaOH) in a suitable solvent system such as a mixture of methanol and water.

[0316] Option 7

[0317]

[0318] R 1a H and A are functional groups (Aa), and R2 is C. 1-4 Alkyl group, m is 2 and R3 is C 1-4 Alkyl or halogenated compounds of formula (VII) can be prepared in two steps. The nitro compound of formula (XVI) is reacted under palladium-catalyzed cross-coupling conditions in the presence of a palladium precatalyst, such as [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (Pd(dppf)Cl2·CH2Cl2) complexed with dichloromethane, an organoboron compound such as trimethylcyclotriboroxane, a base such as cesium carbonate (Cs2CO3), and a suitable solvent system such as a mixture of water / 1,4-dioxane, to obtain compound (XVII). Compound (XVII) is further reacted with a metal such as iron in the presence of an acid such as acetic acid to obtain compound (VII).

[0319] Option 8

[0320]

[0321] Where A is a group (Ad), X is a bond, q is 0, p is 1, and R8 is OC. 1-4 Halogenated alkyl, OC 1- Alkylene (4-7 membered heterocyclic alkyl) or C 1-4 Alkoxy compounds of formula (V) can be obtained by combining a compound of formula (XXI) (where PG is a nitrogen protecting group, such as tert-butoxycarbonyl (BOC)) with a compound of formula (XXII) (where C is C 1-4 Alkyl, C 1-4 Halogenated alkyl or C 1-4 Alkylenes (4-7 membered heterocyclic alkyl groups) are reacted in the presence of a base, such as NaH, in a suitable solvent, such as THF, to prepare a compound of formula (XXIII). The compound of formula (XXIII) is then deprotected, for example, with an aqueous solution of an acid, such as 2M HCl, in a suitable solvent, such as methanol, to obtain a compound of formula (V).

[0322] Option 9

[0323]

[0324] Where 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) with cycloalkyl groups can be prepared by reacting a compound of formula (XXIV) (where PG is a nitrogen-protecting group, such as tert-butoxycarbonyl (BOC)) with a suitable reagent, such as diiodomethane, in the presence of an organometallic reagent, such as ZnEt2, in a suitable solvent, such as dichloromethane, to give compound (XXV). Deprotection of compound (XXV) is then performed, for example, with an aqueous solution of an acid, such as 2M HCl, in a suitable solvent, such as methanol, to give compound (V).

[0325] Therefore, in one embodiment, the present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, the method comprising: […].

[0326]

[0327] Among them, A and R 1a and R 1b As defined with respect to compounds of formula (I);

[0328] Reaction with compounds of formula (III) or their salts:

[0329]

[0330] Where X is a halogen, such as bromine or iodine, and B is as defined with respect to compounds of formula (I);

[0331] The condition is that the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazole-6-yl)acrylamide.

[0332] The present invention also provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, the method comprising: […].

[0333]

[0334] Where R 1b And B is as defined with respect to compound (I);

[0335] Reaction with compound of formula (V) or its salt

[0336]

[0337] Among them, A and R 1a As defined with respect to compounds of formula (I);

[0338] The condition is that the compound of formula (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazole-6-yl)acrylamide.

[0339] The present invention also provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, the method comprising: […].

[0340]

[0341] Where R 1b And B is as defined with respect to compound (I);

[0342] Reaction with compounds of formula (V) or their salts:

[0343]

[0344] Among them, A and R 1a As defined with respect to compound (I); provided that compound (I) is not (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-indazol-6-yl)acrylamide.

[0345] Treatment

[0346] The compound of formula (I) of the present invention has the use as an mPTP inhibitor.

[0347] Therefore, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof, which are used as medicines, particularly for the treatment or prevention of diseases or conditions in which inhibition of mPTP provides therapeutic or preventive effects, such as those diseases and conditions mentioned below.

[0348] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof, which are used as medicines, particularly for treating diseases or conditions in which inhibition of mPTP provides a therapeutic effect, such as those mentioned below.

[0349] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof, which are used as medicines, particularly for the prevention of diseases or conditions in which inhibition of mPTP provides a preventive effect, such as those diseases and conditions mentioned below.

[0350] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for use in the preparation of medicaments for treating or preventing diseases or conditions in which inhibition of mPTP provides therapeutic or preventive effects, such as those diseases and conditions mentioned below.

[0351] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for use in the preparation of medicaments for treating diseases or conditions in which inhibition of mPTP provides a therapeutic effect, such as those diseases and conditions mentioned below.

[0352] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for use in the preparation of medicaments for preventing diseases or conditions in which inhibition of mPTP provides a preventive effect, such as those diseases and conditions mentioned below.

[0353] The present invention also provides a method for preventing or treating diseases or conditions in which inhibition of mPTP provides a therapeutic or preventive effect in an individual, such as those mentioned below, the method comprising administering to the individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0354] The present invention also provides a method for treating diseases or conditions in which inhibition of mPTP provides a therapeutic effect in an individual, such as those mentioned below, the method comprising administering to the individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0355] The present invention also provides a method for preventing diseases or conditions in which the inhibition of mPTP provides a preventive effect in an individual, such as those mentioned below, the method comprising administering to the individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0356] The term “treatment” as used in this article includes controlling, alleviating, reducing or regulating a disease state or its symptoms.

[0357] The term “prevention” or “avoidance” as used in this article refers to the prevention of symptoms of a disease or condition in an individual or the prevention of recurrence of symptoms of a disease or condition in an individual with a disease or condition, and is not limited to the complete prevention of illness.

[0358] In one embodiment, the disease or condition is selected from degenerative or neurodegenerative diseases, central nervous system diseases, ischemia or reperfusion injury, metabolic diseases, inflammatory or autoimmune diseases, aging diseases, and kidney diseases.

[0359] In one specific embodiment, the disease or condition is a degenerative or neurodegenerative disease, such as Parkinson's disease, Lewy body dementia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), 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 ataxia. In a preferred embodiment, the disease or condition is Parkinson's disease. In a preferred embodiment, the disease or condition is Alzheimer's disease. In a preferred embodiment, the disease or condition is amyotrophic lateral sclerosis (ALS).

[0360] In another specific implementation, the disease or condition is a central nervous system disease, such as AIDS dementia syndrome, depression, schizophrenia, and epilepsy.

[0361] In another embodiment, the disease or condition is local ischemia or reperfusion injury, such as acute myocardial infarction, stroke, renal ischemia-reperfusion injury, and organ injury during transplantation.

[0362] In another embodiment, the disease or condition is a metabolic disease, such as hepatic steatosis, diabetes, diabetic retinopathy, cognitive decline and other diabetes-related conditions, obesity and eating behavior, and non-alcoholic fatty liver disease.

[0363] In another embodiment, the disease or condition is an inflammatory or autoimmune disease, such as acute pancreatitis, systemic lupus erythematosus, organ failure in sepsis, and hepatitis.

[0364] In another implementation, the disease or condition is an age-related disease, such as bone repair, age-related bone fragility in osteoporosis, and sarcopenia.

[0365] In another embodiment, the disease or condition is a kidney disease, such as chronic kidney disease and chronic kidney disease associated with APOL1 gene mutations.

[0366] Compound (I) is expected to be used to treat or prevent mitochondrial diseases.

[0367] Therefore, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for the treatment or prevention of mitochondrial diseases, such as those diseases and conditions mentioned below.

[0368] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for the treatment of mitochondrial diseases, such as those diseases and conditions mentioned below.

[0369] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for the prevention of mitochondrial diseases, such as those diseases and conditions mentioned below.

[0370] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for use in the preparation of medicaments for the treatment or prevention of mitochondrial diseases such as those mentioned below.

[0371] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for use in the preparation of medicaments for treating mitochondrial diseases such as those mentioned below.

[0372] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for use in the preparation of medicaments for the prevention of mitochondrial diseases such as those mentioned below.

[0373] The present invention also provides a method for treating or preventing mitochondrial diseases in an individual, such as those diseases and conditions mentioned below, comprising administering to the individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0374] The present invention also provides a method for treating an individual with mitochondrial diseases such as those mentioned below, comprising administering to the individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0375] The present invention also provides a method for preventing mitochondrial diseases in an individual, such as those diseases and conditions mentioned below, comprising administering to the individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0376] Suitablely, the mitochondrial disease is selected from Reye syndrome, Leber hereditary optic neuropathy and related conditions, and those disclosed in CA2884607A1 (Stealth Peptides International Inc).

[0377] Compound (I) is intended to be used to treat or prevent diseases or conditions associated with TDP-43 protein disorders, such as TDP-43-related neurodegeneration.

[0378] Therefore, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for the treatment or prevention of diseases or conditions associated with TDP-43 protein disorders, such as TDP-43-associated neurodegeneration, such as those mentioned below.

[0379] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for the treatment of diseases or conditions associated with TDP-43 protein disorders, such as TDP-43-associated neurodegeneration, as mentioned below.

[0380] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for the prevention of diseases or conditions associated with TDP-43 protein disorders, such as TDP-43-associated neurodegeneration, such as those mentioned below.

[0381] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for the preparation of medicaments for the treatment or prevention of diseases or conditions associated with TDP-43 protein disorders, such as TDP-43-associated neurodegeneration, such as those mentioned below.

[0382] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for use in the preparation of medicaments for treating diseases or conditions associated with TDP-43 protein disorders, such as TDP-43-associated neurodegeneration, such as those mentioned below.

[0383] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for the preparation of medicaments for the prevention of diseases or conditions associated with TDP-43 protein disorders, such as TDP-43-associated neurodegeneration, such as those mentioned below.

[0384] The present invention also provides a method for treating or preventing diseases or conditions associated with TDP-43 protein disorders, such as TDP-43-associated neurodegeneration, such as those mentioned below, comprising administering to an individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0385] The present invention also provides a method for treating diseases or conditions associated with TDP-43 protein disorders, such as TDP-43-associated neurodegeneration, such as those mentioned below, comprising administering to an individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0386] The present invention also provides a method for preventing diseases or conditions associated with TDP-43 protein disorders, such as TDP-43-associated neurodegeneration, such as those mentioned below, comprising administering to an individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0387] Suitably, the diseases or conditions associated with TDP-43 protein disorders, such as TDP-43-related neurodegeneration, are selected from amyotrophic lateral sclerosis (ALS), frontotemporal dementia, facial-onset sensory and motor neuron diseases, primary lateral sclerosis, progressive muscular atrophy, inclusion body myopathy associated with early-onset Paget's disease of bone and frontotemporal degenerative dementia, Perry disease, chronic traumatic encephalopathy, severe traumatic brain injury, Alzheimer's disease, hippocampal sclerosis dementia, limbic-dominant age-related TDP-43 encephalopathy, and age-related TDP-43 with sclerosis.

[0388] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for the treatment or prevention of diseases or conditions associated with fibrosis.

[0389] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for the treatment of diseases or conditions associated with fibrosis.

[0390] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for the prevention of diseases or conditions associated with fibrosis.

[0391] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for use in the preparation of medicaments for the treatment or prevention of diseases or conditions associated with fibrosis.

[0392] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for use in the preparation of medicaments for treating diseases or conditions associated with fibrosis.

[0393] The present invention also provides compounds of formula (I) or pharmaceutically acceptable salts and / or solvates thereof for use in the preparation of medicaments for the prevention of diseases or conditions associated with fibrosis.

[0394] The present invention also provides a method for treating or preventing diseases or conditions associated with fibrosis, comprising administering to an individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0395] The present invention also provides a method for treating diseases or conditions associated with fibrosis, comprising administering to an individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0396] The present invention also provides a method for preventing diseases or conditions associated with fibrosis, comprising administering to an individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0397] Suitablely, the fibrosis-related diseases or conditions are selected from chronic kidney disease, idiopathic pulmonary fibrosis, non-alcoholic steatohepatitis, primary cholangitis, and systemic sclerosis.

[0398] Suitablely, the individual is a mammal, and in particular, the individual is a human.

[0399] Pharmaceutical Composition

[0400] For therapeutic use, the compounds of the present invention are typically administered as pharmaceutical compositions. The present invention also provides a pharmaceutical composition 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. The pharmaceutical compositions of the present invention may be in the form of pharmaceutical formulations as described below.

[0401] In one embodiment, a pharmaceutical composition is provided for treating or preventing the disease or condition described herein, comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvation (e.g., a salt) thereof. In another embodiment, a pharmaceutical composition is provided for treating the disease or condition described herein, comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvation (e.g., a salt) thereof. In yet another embodiment, a pharmaceutical composition is provided for preventing the disease or condition described herein, comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvation (e.g., a salt) thereof.

[0402] In another embodiment, a method for treating or preventing the disease or condition described herein is provided, comprising administering to an individual in need an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvation (e.g., a salt). In another embodiment, a method for treating the disease or condition described herein is provided, comprising administering to an individual in need an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvation (e.g., a salt). In another embodiment, a method for preventing the disease or condition described herein is provided, comprising administering to an individual in need an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvation (e.g., a salt).

[0403] The present invention also provides the use of pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvation (e.g., a salt) thereof in the preparation of medicaments for treating or preventing the diseases or conditions described herein. The present invention also provides the use of pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvation (e.g., a salt) thereof in the preparation of medicaments for treating the diseases or conditions described herein. The present invention also provides the use of pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvation (e.g., a salt) thereof in the preparation of medicaments for preventing the diseases or conditions described herein.

[0404] Of course, the amount of active ingredient required to achieve a therapeutic effect will vary depending on the specific compound, route of administration, and the individual being treated or prevented from taking action. This includes the individual's type, species, age, weight, sex, and medical condition, as well as their kidney and liver function, the specific condition or disease being treated or prevented, and its severity. Physicians, veterinarians, or clinicians with general skills can easily determine and prescribe the effective amount of medication needed to prevent, counteract, or halt the progression of a disease.

[0405] When used for a specified effect, the oral dosage of the present invention for adults will range from about 0.01 mg / kg body weight / day (mg / kg / day) to about 100 mg / kg / day, suitably from 0.01 mg / kg body weight / 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 composition is suitable to be provided in tablet form or other forms provided in discrete units containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, and 500 mg of active ingredient, for symptomatic dose adjustment in the patient to be treated. The drug typically contains about 0.01 mg to about 500 mg of active ingredient, suitably from about 1 mg to about 100 mg of active ingredient. When administered intravenously, the most suitable dose range during a constant-rate infusion is about 0.1 to about 10 mg / kg / minute. Advantageously, the compounds of the present invention can be administered in a single daily dose, or the total daily dose can be administered in divided doses twice, three, or four times daily. Furthermore, the compounds of the present invention can be suitably administered intranasally via a suitable intranasal carrier, or via a transdermal route using transdermal skin patches of those forms well known to those skilled in the art. Of course, for administration via a transdermal delivery system, the dosage is continuous rather than intermittent throughout the dosing regimen.

[0406] The pharmaceutical formulations of the present invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous [rapid concentration or infusion] and intra-articular), intranasal (also known as nasal administration), inhalation (including fine particulate powder or mist, which can be produced by various types of metered-dose pressurized aerosols, nebulizers or inhalers), inhalation, rectal, intraperitoneal, local (including skin, mouth, sublingual and intraocular), and intrathecal administration, although the most suitable route may depend, for example, on the recipient's condition and impairment.

[0407] Suitable pharmaceutical formulations according to the invention are those suitable for oral, intrathecal, and parenteral administration; more suitable are those suitable for oral or intrathecal administration.

[0408] In a suitable embodiment, the compound of formula (I) is administered via intrathecal administration. This method of administration involves injecting the compound of the invention into the spinal canal or subarachnoid space so that it reaches the cerebrospinal fluid. This is advantageous for compounds that may not cross the blood-brain barrier when administered via other routes of administration, such as oral administration.

[0409] Suitable pharmaceutical formulations can be administered via continuous infusion, such as through a catheter or pump insufflation, or via a single rapid infusion or intermittent rapid infusion insufflation. For intrathecal administration, the pharmaceutical composition can be administered continuously or intermittently. Intermittent administration can be, for example, every thirty minutes, every hour, every few hours, every 24 hours, every two days (e.g., every 48 or 72 hours), or any combination thereof.

[0410] When the pharmaceutical formulation of the present invention is administered continuously, an implantable delivery device, such as an implantable pump, can be used. Examples of such delivery devices include those that can be implanted subcutaneously in the body or skull and provide access ports for delivering the pharmaceutical formulation to nerves or the brain.

[0411] When used for the specified effects, when administered to adults in a single dose or intermittently, the intrathecal dose of the present invention is typically less than 1 mg per kilogram of body weight, for example less than 500 μg, for example less than 250 μg. When administered continuously, the intrathecal dose of the present invention for adults is typically less than 250 μg / kg body weight / hour, for example less than 125 μg / kg body weight / hour.

[0412] In another suitable embodiment, the compound of formula (I) is administered via intranasal, inhalation (including fine particulate dust or mist, which can be produced by various types of metered-dose pressurized aerosols, nebulizers, or blowpipes), or inhalation. This method of administration allows for the delivery of low doses of the compound of the invention, which can result in a reduction of side effects. For example, daily doses of 10 to 0.01 μg can be used, suitably 1 to 0.01 μg, and more suitably in the range down to 0.1 μg (100 ng) of the compound of the invention.

[0413] Formulations can be conveniently present in unit dosage forms and can be prepared by any method known in the pharmaceutical field. All methods involve the step of binding the active ingredient with a carrier constituting one or more auxiliary ingredients. Typically, formulations are prepared by uniformly and tightly binding the active ingredient with a liquid carrier or a finely chopped solid carrier, or both, and then, if desired, shaping the product into the desired formulation.

[0414] The formulations of the present invention suitable for oral administration can be in the form of discrete units, such as capsules, pouches, pills, or tablets, each containing a predetermined amount of the active ingredient; in the form of powders or granules; in the form of solutions or suspensions in aqueous or non-aqueous liquids, such as elixirs, tinctures, suspensions, or syrups; or in the form of oil-in-water or water-in-oil liquid emulsions. The active ingredient may also be present in the form of large pills, saccharin, or pastes.

[0415] Tablets can be prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as powder or granules, in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored and can be formulated to provide a slow or controlled release of the active ingredient therein. Compounds of formula (I) can be administered, for example, in a form suitable for immediate or prolonged release. Immediate or prolonged release can be achieved by using a suitable pharmaceutical composition comprising the compounds of the present invention, or particularly in the case of prolonged release, by using a device such as a subcutaneous implant or an osmotic pump. The compounds of the present invention can also be administered via liposomes.

[0416] Exemplary compositions for oral administration include suspensions that may contain, for example, microcrystalline cellulose for volume impartation, alginate or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents, such as those known in the art; and immediate-release tablets that may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and / or lactose and / or other excipients, binders, expanders, disintegrants, diluents, and lubricants, such as those 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, tragacanth, or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. Compounds of formula (I) may also be delivered orally via sublingual and / oral administration. Molded tablets, compressed tablets, or lyophilized tablets are exemplary forms that may be used. Exemplary compositions include those formulated with readily soluble diluents such as mannitol, lactose, sucrose, and / or cyclodextrin. These formulations may also include high molecular weight excipients such as cellulose (Avicel) or polyethylene glycol (PEG). Such formulations may also include excipients that promote mucosal adhesion, such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymers (e.g., Gantrez), and controlled-release agents such as polyacrylic acid copolymers (e.g., Carbopol 934). For ease of manufacture and use, lubricants, flow aids, flavoring agents, colorants, and stabilizers may also be added. 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 pharmaceutical component may be combined with any orally available, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerin, water, etc.

[0417] Compounds of formula (I) can also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from various phospholipids, 1,2-dipalmitoylphosphatidylcholine, phosphatidylethanolamine (cephalin), or phosphatidylcholine (lecithin).

[0418] Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners. Formulations may be available in single-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as saline or water for injection, just before use. Immediate-use injectable solutions and suspensions may be prepared from sterile powders, granules, and tablets of the aforementioned types. Exemplary compositions for parenteral administration include injectable solutions or suspensions that may contain, for example, suitable non-toxic, parenteral-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersants, wetting agents, and suspending agents, including synthetic monoglycerides or diglycerides, and fatty acids, including oleic acid or cremaphores.

[0419] Exemplary compositions for intranasal, aerosol, or inhaled administration include saline solutions that may contain, for example, benzyl alcohol or other suitable preservatives, bioavailability enhancers, and / or other solubilizers or dispersants, such as those known in the art.

[0420] Rectal administration can be via suppositories containing commonly used carriers such as cocoa butter, synthetic glycerides, or polyethylene glycol. Such carriers are typically solid at room temperature but liquefy and / or dissolve in the rectal lumen to release the drug.

[0421] Formulations for oral administration, such as oral cavity or sublingual administration, include lozenges containing the active ingredient in a flavoring matrix such as sucrose and gum arabic or tragacanth gum, and soft lozenges containing the active ingredient in a matrix such as gelatin and glycerin or sucrose and gum arabic. Exemplary compositions for topical administration include topical carriers such as Plastibase (mineral oil gelled with polyethylene).

[0422] Suitable unit-dose formulations are those containing the active ingredient at the effective dose or an appropriate portion thereof as described above.

[0423] It should be understood that, in addition to the ingredients specifically mentioned above, the formulations of the present invention may include other agents conventional in the art and relevant to the type of formulation discussed, such as flavoring agents, those suitable for oral administration.

[0424] Compounds of formula (I) are expected to possess one or more of the following advantageous properties:

[0425] -Inhibitory activity of mPTP as demonstrated in the experiments of Biological Example 1; and

[0426] - Improved solubility and / or improved intrinsic clearance (CL) as demonstrated in the assays of biological Examples 2 and 3. int This leads to, for example, improved oral bioavailability and / or improved systemic exposure.

[0427] The present invention is further illustrated by the following non-limiting embodiments. Example

[0428] This invention is illustrated by the following compounds. The following examples describe the laboratory synthesis of specific compounds of this invention and are not intended to limit the scope of the compounds or methods of this invention in any way. It should be understood that, despite the use of specified reagents, solvents, temperatures, and times, many possible equivalent alternatives exist that can be used to produce similar results. This invention is intended to include these equivalents.

[0429] General experimental details

[0430] Unless otherwise stated, starting materials, reagents, and solvents are obtained from commercial suppliers and used without further purification. Unless otherwise stated, all compounds with chiral centers are racemic. When the reaction is described as proceeding in a manner similar to the previously more fully described reaction, the general reaction conditions used are substantially the same. The post-treatment conditions used are of the standard type in the art, but can be adjusted between different reactions. The starting materials do not necessarily need to be prepared from the batches mentioned. The synthesized compounds can have a variety of purities, for example, 85%–99%. For this reason, the calculation of molar numbers and yields needs to be adjusted in some cases.

[0431] The purity of the final compound was confirmed by HPLC / MS analysis, and determined to be at least ≥90%, and in most cases ≥95%. LC-MS analysis was performed using the instruments shown in Table 1. Recordings were taken at 300 K using Bruker 300MHz instruments (ADVANCE III and ADVANCE III HD). 1 ¹H NMR. Preliminary 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 x 150 mm x 5 μm. SFC purification was performed using the following columns: (a) CHIRALPAK AS-H, 3 x 25 cm, 5 μm; (b) SFC-YMC Cellulose-SB, 4.6 x 100 mm, 3 μm.

[0432] Table 1: LC-MS Analysis Conditions

[0433]

[0434] abbreviations

[0435] CH3CN Acetonitrile

[0436] Cs2CO3 (cesium carbonate)

[0437] DCM dichloromethane

[0438] DIPEA (Diisopropylethylamine)

[0439] DMF (dimethylformamide)

[0440] DMT-MM 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride

[0441] Et Ethyl

[0442] Et3N Triethylamine

[0443] EtOAc (ethyl acetate)

[0444] EtOH (ethanol)

[0445] HATU 1-[di(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-hexafluorophosphate oxide

[0446] HCl hydrochloric acid

[0447] hepatocellular carcinoma (HPC)

[0448] K2CO3 (potassium carbonate)

[0449] K3PO4 Potassium phosphate

[0450] LiHMDS bis(trimethylsilyl)aminolithium

[0451] Me methyl

[0452] MeOH (methanol)

[0453] NaHCO3 (Sodium bicarbonate)

[0454] NaOAc (sodium acetate)

[0455] NaOH (sodium hydroxide)

[0456] NBS N-bromosuccinimide

[0457] NCS N-chlorosuccinimide

[0458] NH4Cl ammonium chloride

[0459] PE petroleum ether

[0460] Pd(OAc)₂ Palladium(II) acetate

[0461] Pd(dppf)Cl2.CH2Cl2-bis(diphenylphosphine)ferrocene]palladium(II) dichloride, complexed with dichloromethane

[0462] Pd(dppf)Cl2- [bis(diphenylphosphine)ferrocene]palladium(II) dichloride

[0463] RT room temperature

[0464] o / n Overnight (16h)

[0465] TFA (trifluoroacetic acid)

[0466] THF Tetrahydrofuran

[0467] THP Tetrahydropyran

[0468] T3P Propionic Anhydride

[0469] uL microliter

[0470] uM micromolar

[0471] Preparation of Comparative Example 1

[0472] Comparative Example 1: (E)-N-(2-methyl-3-fluorophenyl)-3-(1H-indazol-6-yl)acrylamide

[0473]

[0474] Comparative Example 1 was prepared according to the method described by Chen et al. (Assay and Drug Development Technologies, 2018, 16, 445-455). Comparative Example 1 can also be prepared using synthetic methods similar to those described in Examples 1 to 40 herein.

[0475] Preparation of Examples 1 to 40

[0476] Intermediate 1: N-(3-fluoro-2-methylphenyl)acrylamide

[0477]

[0478] Acrylamide chloride (0.7 mL, 8.790 mmol, 1.10 eq.) was added dropwise to a stirred solution of 3-fluoro-2-methylaniline (1.0 g, 7.991 mmol, 1.00 eq.) and N,N-diisopropylethylamine (3.1 g, 23.972 mmol, 3.00 eq.) in DCM (40 mL) at 0 °C under an inert nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 3 h under an inert nitrogen atmosphere. The mixture was washed with 2 x 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 yielded 1.04 g (73%) of N-(3-fluoro-2-methylphenyl)acrylamide as a white solid.

[0479] LC-MS(ES,m / z):[M+H] + =180.

[0480] Intermediate 2: N-(3-chloro-2-methylphenyl)acrylamide

[0481]

[0482] 3-Chloro-2-methylaniline (300 mg, 2.12 mmol, 1.00 eq.), DCM (15 mL), and Et3N (1.0 mL, 7.19 mmol, 3.00 eq.) were added dropwise to a 50 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Acryloyl chloride (260 mg, 2.88 mmol, 1.20 eq.) was then added dropwise at 25 °C with stirring. The resulting solution was stirred at 25 °C for 5 h. The resulting mixture was washed with 2 x 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 yielded 300 mg (74%) of pale yellow solid N-(3-chloro-2-methylphenyl)prop-2-enamide. LC-MS (ES, m / z): [M+H] + =196.

[0483] Intermediate 3: (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)acrylic acid

[0484]

[0485] Step 1: Add a 200 mL solution of DCM containing 6-bromo-1H-indazole (19.6 g, 100.00 mmol, 1.00 eq), 3,4-dihydro-2H-pyran (12.6 g, 150.00 mmol, 1.50 eq), and TsOH (1.7 g, 10.00 mmol, 0.10 eq) to a 500 mL 3-necked round-bottom flask purified with nitrogen and maintained under a nitrogen inert atmosphere. Stir the resulting solution overnight at room temperature. Concentrate the solution. Load the residue onto a silica gel column using PE / EtOAc (1:0–3:1). This yields 23.9 g (85%) of solid methyl 3-(1H-indazole-6-yl)acrylate.

[0486] LC-MS(ES,m / z):[M+H] + =281.

[0487]

[0488] Step 2: Add a 200 mL solution of methyl 3-(1H-indazole-6-yl)acrylate (23.9 g, 85.00 mmol, 1.00 eq), methyl acrylate (10.98 g, 127.50 mmol, 1.50 eq), Et3N (23.7 mL, 170.00 mmol, 2.00 eq), and Pd(dppf)Cl2 (1.87 g, 2.55 mmol, 0.03 eq) in DMF to a 500 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution at 110 °C for 2 h. Cool the resulting solution to room temperature and dilute with 300 mL H2O. Extract the mixture with 3 x 500 mL EtOAc. Concentrate the organic layer and load the residue onto a silica gel column using PE / EtOAc (1:0–3:1). Thus, 20.20 g (83%) of solid (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)methyl acrylate was obtained.

[0489] LC-MS(ES,m / z):[M+H] + =287.

[0490]

[0491] Step 3: Add a MeOH / H₂O (80:40 mL) solution of (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)methyl acrylate (11.44 g, 40.00 mmol, 1.00 eq) to a 500 mL 3-necked round-bottom flask purified with nitrogen and maintained under a nitrogen inert atmosphere. Add NaOH (3.20 g, 80.00 mmol, 2.00 equiv). Stir the resulting solution at 50 °C for 6 h. Concentrate the resulting solution to remove MeOH. Adjust the pH of the aqueous phase to 4 with AcOH. Collect the solid by filtration. This yields 8.16 g (75%) of yellow solid 3-(1H-indazole-6-yl)methyl acrylate. LC-MS (ES, m / z): [M+H] + =273.

[0492] Example 1: (E)-N-(3-fluoro-2-methylphenyl)-3-(7-methyl-1H-indazol-6-yl)acrylamide

[0493]

[0494] N-(3-fluoro-2-methylphenyl)acrylamide (intermediate 1, 40.00 mg, 0.22 mmol, 1.00 equiv), DMF (2 mL), 6-bromo-7-methyl-1H-indazole (47.1 mg, 0.22 mmol, 1.00 equiv), Et3N (0.09 mL, 0.67 mmol, 3.00 equiv), and Pd(dppf)Cl2.CH2Cl2 (9.11 mg, 0.011 mmol, 0.05 equiv) were added to an 8-mL vial purified with nitrogen and kept under an inert nitrogen atmosphere. The resulting solution was stirred at 120 °C for 12 h. The crude product was purified by preparative HPLC. This yielded 13 mg (19%) of a white solid (2E)-N-(3-fluoro-2-methylphenyl)-3-(7-methyl-1H-indazole-6-yl)prop-2-enamide.

[0495] LC-MS(ES,m / z):[M+H] + =310.

[0496] 1H NMR (300MHz, DMSO-d6, ppm): δ13.33(s,1H),9.65(s,1H),8.09(s,1H),7.99(d,J=15.6Hz,1H),7.66( d,J=8.4Hz,1H),7.51-7.40(m,2H),7.25-7.23(m,1H),7.04-6.96(m,2H),2.65(s,3H),2.18(s,3H).

[0497] Example 2: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide

[0498]

[0499] Add (2E)-3-(1H-indazol-6-yl)prop-2-enoic acid (40 mg, 0.21 mmol, 1.00 equiv), DMF (3 mL), T3P (88 mg, 0.28 mmol, 1.30 equiv), DIPEA (55 mg, 0.43 mmol, 2.00 equiv), and 1-aminoindenman (31 mg, 0.23 mmol, 1.10 equiv) to an 8-mL vial purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution at 25 °C for 3 h. Purify the mixture by preparative HPLC. This yields 12 mg (19%) of a white solid (2E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)prop-2-enoamide. LC-MS (ES, m / z): [M+H] + =304.

[0500] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.19(brs,1H),8.49(d,J=9.0Hz,1H),8.09(s,1H),7.79(d,J=8.7Hz,1H),7.71-7.65(m,2H),7.39-7 .29(m,1H),7.29-7.19(m,4H),6.75(d,J=15.6Hz,1H),5.44-5.42(m,1H),3.05-2.91(m,2H),2.45-2.44(m,1H),1.86-1.83(m,1H).

[0501] Example 3: (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide

[0502]

[0503] Methyl 3-(1H-indazol-6-yl)prop-2-enoate (110 mg, 0.54 mmol, 1.00 eq), (1R)-2,3-dihydro-1H-indene-1-amine hydrochloride (92 mg, 0.54 mmol, 1.00 eq), and THF (2 mL) were added to an 8 mL sealed tube. LiHMDS (3.2 mL, 3.26 mmol, 6.00 eq) was then added at 0 °C. The resulting solution was stirred at room temperature for 3 hours. The resulting solution was diluted with 10 mL of EtOAc. The reaction was then terminated by adding 15 mL of saturated NH4Cl. The organic layer was washed with 15 mL of water and concentrated under reduced pressure in an oven. The crude product was purified by rapid preparative HPLC. This yielded 72 mg (43%) of N-[(1R)-2,3-dihydro-1H-indene-1-yl]-3-(1H-indazol-6-yl)prop-2-enoamide as a white solid. LC-MS(ES,m / z):[M+H] + =304.

[0504] 1 H NMR (300MHz, DMSO-d6, ppm): δ8.52(d,J=8.1Hz,1H),8.08(s,1H),7.77-7.62(m,3H),7.35-7.19(m,5H ), 6.75 (d, J = 15.9Hz, 1H), 5.47-5.39 (m, 1H), 2.98-2.79 (m, 2H), 2.46-2.41 (m, 1H), 1.89-1.81 (m, 1H).

[0505] Example 4: (racemic) (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide

[0506]

[0507] Add (2E)-3-(1H-indazol-6-yl)prop-2-enoic acid (30 mg, 0.16 mmol, 1.00 equiv), DCM (4 mL), HATU (79 mg, 0.21 mmol, 1.30 equiv), 2-methylcyclohexane-1-amine (20 mg, 0.18 mmol, 1.10 equiv), and DIPEA (41 mg, 0.32 mmol, 2.00 equiv) to an 8-mL vial purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution at 25 °C for 5 h. Then terminate the reaction by adding 4 mL of water. Extract the resulting solution with 5 mL of dichloromethane, dry with anhydrous sodium sulfate, and concentrate. Purify the crude product by preparative HPLC. Thus, 10 mg (22%) of off-white solid (E)-3-(1H-indazole-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide (trans isomer) and 10 mg (22%) of off-white solid (E)-3-(1H-indazole-6-yl)-N-((1S,2R)-2-methylcyclohexyl)acrylamide (cis isomer) were obtained.

[0508] (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide (trans isomer)

[0509] LC-MS(ES,m / z):[M+H] + =284.

[0510] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.19(brs,1H),8.08(s,1H),7.90(d,J=9.0Hz,1H),7.78(d,J=8.4Hz,1H),7.68(s,1H),7.55(d,J=15.7Hz, 1H),7.34(dd,J=8.5,1.5Hz,1H),6.71(d,J=15.6Hz,1H),3.48-3.34(m,1H),1.83-1.62(m,4H),1.37-1.06(m,5H),0.87(d,J=6.6Hz,3H).

[0511] (E)-3-(1H-indazol-6-yl)-N-((1S,2R)-2-methylcyclohexyl)acrylamide (cis isomer)

[0512] LC-MS(ES,m / z):[M+H] + =284.

[0513] 1H NMR (300MHz, DMSO-d6, ppm): δ13.26(brs,1H),8.08(s,1H),7.80-7.74(m,2H),7.56(s,1H),7.36-7.33(m,1H),7.26- 7.09(m,1H),6.92(d,J=15.9Hz,1H),4.15-4.02(m,1H),1.91-1.85(m,1H),1.79-1.30(m,8H),0.85(d,J=6.6Hz,3H).

[0514]

[0515] 550 mg of (E)-3-(1H-indazole-6-yl)-N-(2-methylcyclohexyl)acrylamide from Example 4 was purified by SFC (column: CHIRALPAK IG-3, 100*4.6 mm, 3 μm IG30CS-UL011, eluted with hexane (0.1% DEA), EtOH / MeOH). This yielded 60 mg (11%) of trans-(2E)-3-(1H-indazole-6-yl)-N-[(1S,2S)-2-methylcyclohexyl]prop-2-enamide and 80 mg (15%) of white solid trans-(2E)-3-(1H-indazole-6-yl)-N-[(1R,2R)-2-methylcyclohexyl]prop-2-enamide.

[0516] Example 4a: Enantiomer 1; LC-MS (ES, m / z): [M+H]+=284.

[0517] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.19(brs,1H),8.07(s,1H),7.90(d,J=9.0Hz,1H),7.77(d,J=8.1Hz,1H),7.69(s,1H),7.54(d,J=1 5.9Hz,1H),7.35-7.32(m,1H),6.70(d,J=15.9Hz,1H),3.44-3.32(m,1H),1.83-1.62(m,4H),1.42-0.99(m,5H),0.90-0.80(m,3H).

[0518] Example 4b: Enantiomer 2; LC-MS (ES, m / z): [M+H]+=284.

[0519] 1H NMR (300MHz, DMSO-d6, ppm): δ13.19(brs,1H),8.07(s,1H),7.90(d,J=9.0Hz,1H),7.77(d,J=8.1Hz,1H),7.69(s,1H),7.54(d,J=1 5.9Hz,1H),7.35-7.32(m,1H),6.70(d,J=15.9Hz,1H),3.44-3.32(m,1H),1.83-1.62(m,4H),1.42-0.99(m,5H),0.90-0.80(m,3H).

[0520] Example 5: (E)-N-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide

[0521]

[0522] Step 1: Add a 50 mL solution of 6-bromo-1H-indazole (3.1 g, 15.80 mmol, 1.00 eq), methyl acrylate (1.5 g, 17.40 mmol, 1.10 eq), Et3N (19.6 mL, 140.80 mmol, 2.00 eq), and Pd(dppf)Cl2 (345 mg, 4.70 mmol, 0.03 eq) in DMF to a 100 mL sealed tube. Stir the resulting solution at 110 °C for 2 h. Concentrate the solution. Load the residue onto a silica gel column using THF / hexane (35 / 65). This yields 2.3 g (70%) of a yellow solid, 3-(1H-indazole-6-yl)methyl acrylate.

[0523] LC-MS(ES,m / z):[M+H] + =203.

[0524]

[0525] Step 2: 7-fluoro-2,3-dihydroindene-1-one (800.0 mg, 5.33 mmol, 1.00 eq), NaOAc (874.1 mg, 10.66 mmol, 2.00 eq), MeOH (15.00 mL), and hydroxylamine hydrochloride (1.1 g, 15.98 mmol, 3.00 eq) were added to a 40 mL sealed tube. The resulting solution was stirred at 60 °C for 16 h. The resulting mixture was concentrated. The crude product was diluted with EtOAc (30.00 mL) and H₂O (15.00 mL). The organic layer was separated, washed with 20 mL of H₂O, and concentrated. This yielded 810 mg (92%) of a grayish-white solid, 7-fluoro-2,3-dihydroindene-1-one oxime. LC-MS (ES, m / z): [M+H] + =166.

[0526]

[0527] Step 3: 7-fluoro-2,3-dihydroindene-1-one oxime (810.0 mg, 4.90 mmol, 1.00 eq) and MeOH (20.0 mL) were added to a 50 mL round-bottom flask. Then Pd / C (104.4 mg) was added. The resulting solution was stirred at room temperature under ambient pressure and H₂ for 16 h. The solid was filtered off and washed with 10 mL of MeOH. The combined solutions were concentrated. This yielded 530 mg (71%) of a grayish-white solid, 7-fluoro-2,3-dihydro-1H-indene-1-amine. LC-MS (ES, m / z): [M+H] + =152.

[0528]

[0529] Step 4: 7-fluoro-2,3-dihydro-1H-indene-1-amine (55.0 mg, 0.36 mmol, 1.00 eq), methyl 3-(1H-indazole-6-yl)prop-2-enoate (73.6 mg, 0.36 mmol, 1.00 eq), and THF (3.00 mL) were added to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. Then, LiHMDS (1.5 mL, 1.45 mmol, 4.00 eq) was added at 0 °C. The resulting solution was stirred at room temperature for 30 min. The reaction was then terminated by adding 15 mL of saturated NH4Cl. The organic layer was washed with 15 mL of water and dried under reduced pressure in an oven. The crude product was purified by rapid preparative HPLC. This yielded 18 mg (15%) of a white solid (7-fluoro-2,3-dihydro-1H-indene-1-yl)-3-(1H-indazole-6-yl)acrylamide. LC-MS(ES,m / z):[M+H] + =322.

[0530] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.30 (brs, 1H), 8.50 (d, J = 8.4Hz, 1H), 8.08 (s, 1H), 7.80-7.62 (m, 3H), 7.35-7.27 (m, 2H) ,7.15-6.97(m,2H),6.67(d,J=15.9Hz,1H),5.64-5.57(m,1H),3.10-2.88(m,2H),2.49-2.42(m,1H),1.95-1.88(m,1H).

[0531] Example 6: (E)-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide

[0532]

[0533] Step 1: 6-fluoro-2,3-dihydroindene-1-one (800.0 mg, 5.33 mmol, 1.00 eq), NaOAc (874.1 mg, 10.656 mmol, 2.00 eq), MeOH (15.0 mL), and hydroxylamine hydrochloride (1.1 g, 15.98 mmol, 3.00 eq) were added to a 40 mL sealed tube. 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 H₂O (15.0 mL). The organic phase was washed with 20 mL of H₂O. The solid was dried under reduced pressure in an oven. This yielded 810 mg (92%) of a grayish-white solid N-[6-fluoro-2,3-dihydroindene-1-ide]hydroxylamine. LC-MS (ES, m / z): [M+H] + =166.

[0534]

[0535] Step 2: N-[6-fluoro-2,3-dihydroindene-1-yl]hydroxylamine (810.0 mg, 4.90 mmol, 1.00 eq) and MeOH (20.0 mL) were added to a 50 mL round-bottom flask. Then Pd / C (104.4 mg, 0.98 mmol, 0.20 eq) was added. The resulting solution was stirred at room temperature under normal pressure (H₂) for 16 h. The solid was filtered off and washed with 10 mL of MeOH. The combined solutions were concentrated. This yielded 530 mg (71%) of a grayish-white solid, 6-fluoro-2,3-dihydro-1H-indene-1-amine. LC-MS (ES, m / z): [M+H] + =152.

[0536]

[0537] Step 3: Add 6-fluoro-2,3-dihydro-1H-indene-1-amine (55.0 mg, 0.36 mmol, 1.00 eq), methyl 3-(1H-indazol-6-yl)prop-2-enoate (Example 5, Step 1, 73.6 mg, 0.36 mmol, 1.00 eq), and THF (3.0 mL) to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. Then add LiHMDS (1.5 mL, 1.45 mmol, 4.00 eq) at 0°C. Stir the resulting solution at room temperature for 30 min. Then terminate the reaction by adding 15 mL of saturated NH4Cl. Wash the organic layer with 15 mL of water and dry under reduced pressure in an oven. Purify the crude product by rapid preparative HPLC. This yielded 15 mg (13%) of a white solid (6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide. LC MS: (ES, m / z): [M+H] + =322.

[0538] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.21(brs,1H),8.53(d,J=8.1Hz,1H),8.08(s,1H),7.80-7.63(m,3H),7.36-7.27(m,2H) ,7.08-7.01(m,2H),6.74(d,J=15.6Hz,1H),5.45-5.37(m,1H),2.98-2.76(m,2H),2.55-2.44(m,1H),1.95-1.87(m,1H).

[0539] Example 7: (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide

[0540]

[0541] Step 1: 5-fluoro-2,3-dihydroindene-1-one (800.0 mg, 5.33 mmol, 1.00 eq), NaOAc (874.1 mg, 10.66 mmol, 2.00 eq), MeOH (15.0 mL), and hydroxylamine hydrochloride (1.11 g, 15.98 mmol, 3.00 eq) were added to a 40 mL sealed tube. 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 H₂O (15.0 mL). The organic layer was separated, washed with 20 mL of H₂O, and concentrated. This yielded 810 mg (92%) of a grayish-white solid, 5-fluoro-2,3-dihydroindene-1-one oxime. LC-MS (ES, m / z): [M+H] + =166.

[0542]

[0543] Step 2: Add 810.0 mg (4.90 mmol, 1.00 eq) of 5-fluoro-2,3-dihydroindene-1-one oxime and 20.0 mL of MeOH to a 50 mL round-bottom flask. Then add Pd / C (104.38 mg). Stir the resulting solution at room temperature under H2 for 16 h. Filter the solid and wash with 10 mL of MeOH. Concentrate the combined solutions. This yields 530 mg (71%) of a grayish-white solid, 5-fluoro-2,3-dihydro-1H-indene-1-amine.

[0544] LC-MS(ES,m / z):[M+H] + =152.

[0545]

[0546] Step 3: Add 5-fluoro-2,3-dihydro-1H-indene-1-amine (55.0 mg, 0.36 mmol, 1.00 eq), methyl 3-(1H-indazole-6-yl)prop-2-enoate (73.6 mg, 0.36 mmol, 1.00 eq), and THF (3.00 mL) to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. Then add LiHMDS (1.5 mL, 1.45 mmol, 4.00 eq) at 0 °C. Stir the resulting solution at room temperature for 30 min. Then terminate the reaction by adding 15 mL of saturated NH4Cl. Wash the organic layer with 15 mL of water and dry under reduced pressure in an oven. Purify the crude product by rapid preparative HPLC. This yields 13 mg (12%) of a white solid (5-fluoro-2,3-dihydro-1H-indene-1-yl)-3-(1H-indazole-6-yl)acrylamide. LC-MS:(ES,m / z):[M+H] +=322.

[0547] 1 H NMR: (300MHz, DMSO-d6, ppm): δ13.21 (s, 1H), 8.50 (d, J = 8.1Hz, 1H), 8.08 (s, 1H), 7.80-7.62 (m, 3H), 7.35-7.24 (m, 2H), 7.12-6.98(m,2H),6.74(d,J=15.6Hz,1H),5.39-5.37(m,1H),2.98-2.85(m,2H),2.54-2.46(m,1H),1.92-1.81(m,1H).

[0548] Example 8: (E)-N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide

[0549]

[0550] Step 1: Add 4-fluoro-2,3-dihydroindene-1-one (800.0 mg, 5.33 mmol, 1.00 eq), NaOAc (874.1 mg, 10.66 mmol, 2.00 eq), MeOH (15.0 mL), and hydroxylamine hydrochloride (1.11 g, 15.98 mmol, 3.00 eq) to a 40 mL sealed tube. Stir the resulting solution at 60 °C for 16 h. Concentrate the resulting mixture. Dilute the crude product with EtOAc (30.00 mL) and H₂O (15.00 mL). Separate the organic layer and wash with 20 mL of H₂O and concentrate. This yields 810 mg (92%) of a grayish-white solid, 4-fluoro-2,3-dihydroindene-1-one oxime. LC-MS (ES, m / z): [M+H] + =166.

[0551]

[0552] Step 2: Add 4-fluoro-2,3-dihydroindene-1-one oxime (810.0 mg, 4.90 mmol, 1.00 eq) and MeOH (20.0 mL) to a 50 mL round-bottom flask. Then add Pd / C (104.38 mg). Stir the resulting solution at room temperature under H2 for 16 h. Filter the solid and wash with 10 mL of MeOH. Concentrate the combined solutions. This yields 530 mg (71%) of a grayish-white solid, 4-fluoro-2,3-dihydro-1H-indene-1-amine. LC-MS (ES, m / z): [M+H] + =152.

[0553]

[0554] Step 3: Add 4-fluoro-2,3-dihydro-1H-indene-1-amine (55.0 mg, 0.36 mmol, 1.00 eq), methyl 3-(1H-indazole-6-yl)prop-2-enoate (73.6 mg, 0.36 mmol, 1.00 eq), and THF (3.00 mL) to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. Then add LiHMDS (1.5 mL, 1.45 mmol, 4.00 eq) at 0 °C. Stir the resulting solution at room temperature for 30 min. Then terminate the reaction by adding 15 mL of saturated NH4Cl. Wash the organic layer with 15 mL of water and dry under reduced pressure in an oven. Purify the crude product by rapid preparative HPLC. This yields 19 mg (16%) of a white solid (4-fluoro-2,3-dihydro-1H-indene-1-yl)-3-(1H-indazole-6-yl)acrylamide. LC-MS:(ES,m / z):[M+H] + =322.

[0555] 1 H NMR: (300MHz, DMSO-d6, ppm): δ13.21 (s, 1H), 8.54 (d, J = 8.1Hz, 1H), 8.08 (s, 1H), 7.80-7.62 (m, 3H), 7.35-7.24 (m, 2H), 7.12-6.98(m,2H),6.74(d,J=15.9Hz,1H),5.39-5.37(m,1H),2.98-2.85(m,2H),2.54-2.46(m,1H),1.92-1.81(m,1H).

[0556] Example 9: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-indazol-6-yl)acrylamide

[0557]

[0558] Step 1: A solution of acryloyl chloride (6.80 g, 75.08 mmol, 1.0 equiv), 1-aminoindendrone (10.0 g, 75.08 mmol, 1.0 equiv), and Et3N (20.9 mL, 150.16 mmol, 2.0 equiv) in DCM (200.0 mL) was added to a 500 mL 3-necked round-bottom flask at 0 °C. The resulting solution was stirred at 25 °C for 15 h. The reaction was then terminated by adding 100 mL of water / ice. The resulting solution was extracted with 2 x 100 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 (10 / 1). 7.3 g (52%) of white solid N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide was obtained. LC-MS (ES, m / z): [M+H] + =188.

[0559]

[0560] Step 2: Add N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (100.0 mg, 0.53 mmol, 1.00 equiv), 6-bromo-7-fluoro-1H-indazole (137.8 mg, 0.64 mmol, 1.2 equiv), Pd(dppf)Cl2.CH2Cl2 (43.61 mg, 0.05 mmol, 0.10 equiv), DMF (4 mL), and Et3N (0.22 mL, 1.60 mmol, 3.00 equiv) to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution overnight at 120 °C. Cool the reaction mixture to room temperature. Purify the crude mixture by rapid preparative HPLC. Thus, 67 mg (39%) of a grayish-white solid (2E)-N-(2,3-dihydro-1H-indene-1-yl)-3-(7-fluoro-1H-indazole-6-yl)prop-2-enamide was obtained.

[0561] LC-MS(ES,m / z):[M+H] + =322.

[0562] 1H NMR (300MHz, DMSO-d6, ppm): δ13.80(brs,1H),8.61(d,J=8.1Hz,1H),8.20(s,1H),7.75(d,J=15.9Hz,1H),7.62(d,J=8.4Hz,1H),7.34 -7.18(m,5H),6.85(d,J=15.9Hz,1H),5.47-5.39(m,1H),3.03-2.94(m,1H),2.90-2.80(m,1H),2.47-2.41(m,1H),1.91-1.79(m,1H).

[0563] Example 10: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-indazol-6-yl)acrylamide

[0564]

[0565] Add 6-bromo-5-fluoro-1H-indazole (100.00 mg, 0.46 mmol, 1.00 equiv), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 9, Step 1, 87.08 mg, 0.46 mmol, 1.00 equiv), Pd(dppf)Cl2 (34.03 mg, 0.046 mmol, 0.1 equiv), Et3N (141.2 mg, 1.39 mmol, 3.00 equiv), and DMF (3.00 mL) to an 8-mL round-bottom flask. Stir the resulting solution in an oil bath at 120 °C for 15 h. Cool the mixture to room temperature and load it onto a silica gel column using THF / PE (1 / 1). This yielded 80 mg (54%) of a white solid (2E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-indazol-6-yl)prop-2-enamide. LC-MS (ES, m / z): [M+H] + =322.

[0566] 1 H-NMR (300MHz, DMSO-d6, ppm): δ13.32(s,1H),8.61(d,J=8.1Hz,1H),8.09(s,1H),7.80(d,J=6.0Hz,1H),7.71-7.62(m,2H ),7.30-7.21(m,4H),6.86(d,J=15.9Hz,1H),5.45-5.42(m,1H),2.98-2.85(m,2H),2.52-2.46(m,1H),1.89-1.82(m,1H).

[0567] Example 11: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-indazol-6-yl)acrylamide

[0568]

[0569] N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 9, Step 1, 100.0 mg, 0.53 mmol, 1.00 equiv), 6-bromo-4-fluoro-1H-indazole (137.8 mg, 0.64 mmol, 1.20 equiv), Pd(dppf)Cl2.CH2Cl2 (87.2 mg, 0.11 mmol, 0.2 equiv), DMF (4.0 mL), and Et3N (0.22 mL, 1.60 mmol, 3.00 equiv) were added to an 8-mL sealed tube purified with nitrogen and maintained under a nitrogen inert atmosphere. The resulting solution was stirred overnight at 120 °C. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This yielded 63.6 mg (37%) of a grayish-white solid, (2E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-indazol-6-yl)prop-2-enamide. LC-MS (ES, m / z): [M+H] + =322.

[0570] 1 H-NMR (300MHz, DMSO-d6, ppm): δ13.57(brs,1H),8.50(d,J=8.1Hz,1H),8.19(s,1H),7.67-7.60(m,2H),7.30-7.20(m,4H),7.09(d,J =11.7Hz,1H),6.75(d,J=15.9Hz,1H),5.46-5.38(m,1H),3.03-2.94(m,1H),2.90-2.82(m,1H),2.53-2.40(m,1H),1.91-1.78(m,1H).

[0571] Example 12: (E)-3-(5-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide

[0572]

[0573] N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 9, Step 1, 100.0 mg, 0.53 mmol, 1.00 equiv), 6-bromo-5-chloro-1H-indazole (148.4 mg, 0.64 mmol, 1.20 equiv), Pd(dppf)Cl2.CH2Cl2 (43.6 mg, 0.05 mmol, 0.10 equiv), DMF (4.0 mL), and Et3N (0.22 mL, 1.60 mmol, 3.00 equiv) were added to an 8-mL sealed tube purified with nitrogen and maintained under a nitrogen inert atmosphere. The resulting solution was stirred overnight at 120 °C. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This yielded 38.4 mg (21%) of a grayish-white solid, (2E)-3-(5-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide. LC-MS (ES, m / z): [M+H] + =338.

[0574] 1 H-NMR (300MHz, DMSO-d6, ppm): δ13.37 (brs, 1H), 8.60 (d, J = 8.4Hz, 1H), 8.10 (s, 1H), 7.98 (s, 1H), 7.94-7.83 (m, 2H), 7.30-7.19 (m,4H),6.78(d,J=15.6Hz,1H),5.47-5.39(m,1H),3.04-2.94(m,1H),2.91-2.80(m,1H),2.46-2.42(m,1H),1.92-1.79(m,1H).

[0575] Example 13: (E)-3-(4-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide

[0576]

[0577] Add N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (100.0 mg, 0.53 mmol, 1.00 equiv), 6-bromo-4-chloro-1H-indazole (148.4 mg, 0.64 mmol, 1.20 equiv), Pd(dppf)Cl2.CH2Cl2 (43.6 mg, 0.053 mmol, 0.10 equiv), DMF (4.0 mL), and Et3N (0.22 mL, 1.60 mmol, 3.00 equiv) to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution overnight at 120 °C. Cool the reaction mixture to room temperature. Purify the crude mixture by preparative HPLC. This yielded 57.2 mg (32%) of a grayish-white solid, (2E)-3-(4-chloro-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide. LC-MS (ES, m / z): [M+H] + =338.

[0578] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.53(brs,1H),8.47(d,J=8.1Hz,1H),8.14(s,1H),7.73(s,1H),7.64(d,J=15.9Hz,1H),7.41(s,1H),7. 30-7.18(m,4H),6.79(d,J=15.6Hz,1H),5.46-5.38(m,1H),3.03-2.94(m,1H),2.90-2.79(m,1H),2.47-2.41(m,1H),1.90-1.79(m,1H).

[0579] Example 14: (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (a mixture of stereoisomers)

[0580]

[0581] Step 1: Add 2-methyl-2,3-dihydroindene-1-one (2.00 g, 13.68 mmol, 1.00 equivalent), NH₂OH·HCl (0.95 g, 13.68 mmol, 1.00 equivalent), Et₃N (5.7 mL, 41.04 mmol, 3.00 equivalent), and MeOH (30.00 mL) to a 100-mL round-bottom flask. Stir the resulting solution in an oil bath at 70 °C for 15 h. Cool the reaction mixture to room temperature. Concentrate the resulting mixture. Load the residue onto a silica gel column using EtOAc / hexane (1 / 1). This yields 1.8 g (82%) of solid N-[(1Z)-2-methyl-2,3-dihydroindene-1-ide]hydroxylamine. LC-MS (ES, m / z): [M+H] + =162.

[0582]

[0583] Step 2: Add N-[(1Z)-2-methyl-2,3-dihydroindene-1-yl]hydroxylamine (1.8 g, 11.166 mmol, 1.00 equiv) and Pd / C (0.59 g) in 20.00 mL of 4 M HCl / MeOH solution and 50.00 mL of MeOH to a 100 mL round-bottom flask. Stir the resulting solution at 20 °C under H₂ (30 Psi) for 15 h. Filter the solution and concentrate the organic layer. This yields 1.5 g (73.14%) of solid 2-methyl-2,3-dihydro-1H-indene-1-amine hydrochloride. LC-MS-PH-NRG0310-2 (ES, m / z): [M+H] + =148.

[0584]

[0585] Step 3: Add (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide (Example 5, Step 1, 100.0 mg, 0.35 mmol, 1.00 equiv), 2-methyl-2,3-dihydro-1H-inden-1-amine (51.42 mg, 0.35 mmol, 1.00 equiv), and THF (2.0 mL) to an 8-mL round-bottom flask. Add LiHMDS (1.1 mL, 1.05 mmol, 3.00 equiv) and stir the resulting solution at 0°C for 1 h in a water / ice bath. Terminate the reaction with 1 mL NH4Cl and extract with 2 x 5 mL EtOAc, then concentrate the organic layer. This yielded 100 mg (crude product) of solid (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =402.

[0586]

[0587] Step 4: Add a solution of (2E)-N-(2-methyl-2,3-dihydro-1H-indene-1-yl)-3-[1-(oxacyclohexan-2-yl)indazole-6-yl]prop-2-enamide (100.0 mg, crude) in 4M HCl / MeOH solution (1.0 mL) and MeOH (1.0 mL) to an 8-mL vial. Stir the mixture at 20°C for 15 h. Concentrate the mixture and purify the crude mixture by rapid preparative HPLC. This yields 6.5 mg of a white solid (2E)-3-(1H-indazole-6-yl)-N-(2-methyl-2,3-dihydro-1H-indene-1-yl)prop-2-enamide. LC-MS (ES, m / z): [M+H] + =318.

[0588] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.22(brs,1H),8.47-8.25(m,1H),8.08(s,1H),7.86-7.56(m,3H),7.40-7.14(m,5H) ,6.89-6.75(m,1H),5.47-4.98(m,1H),3.13-2.95(m,1H),2.78-2.54(m,1H),2.34-2.24(m,1H),1.22-0.92(m,3H).

[0589] Examples 14a, 14b, 14c, and 14d: (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-indene-1-yl)acrylamide was separated into four separate isomers by SFC (column; IG 100x4.6mm 3.0um; solvent: MeOH (20mM NH3)).

[0590]

[0591] Example 14a: (E)-3-(1H-indazol-6-yl)-N-((1S,2S)-2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 1)

[0592] LC-MS(ES,m / z):[M+H] + =318

[0593] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.21 (s, 1H), 8.27 (d, J = 9.0Hz, 1H), 8.16 (s, 1H), 7.80-7.45 (m, 3H), 7.45-7.24 (m,5H),6.84(d,J=15.9Hz,1H),5.45-5.39(m,1H),3.06-2.99(m,1H),2.75-2.60(m,2H),0.93(d,J=6.6Hz,3H)

[0594] Example 14b: (E)-3-(1H-indazol-6-yl)-N-((1R,2R)-2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 2)

[0595] LC-MS(ES,m / z):[M+H] + =318

[0596] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.21 (s, 1H), 8.27 (d, J = 9.0Hz, 1H), 8.16 (s, 1H), 7.80-7.45 (m, 3H), 7.45-7.24 (m,5H),6.84(d,J=15.9Hz,1H),5.45-5.39(m,1H),3.06-2.99(m,1H),2.75-2.60(m,2H),0.93(d,J=6.6Hz,3H)

[0597] Example 14c: (E)-3-(1H-indazol-6-yl)-N-((1R,2S)-2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 3)

[0598] LC-MS(ES,m / z):[M+H] + =318

[0599] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.22(s,1H),8.45(d,J=8.7Hz,1H),8.09(s,1H),7.81-7.65(m,3H),7.36(d,J=8.4Hz,1H),7.22-7.1 6(m,4H),6.79(d,J=15.6Hz,1H),5.07-5.02(m,1H),3.18-3.08(m,1H),2.56-2.51(m,1H),2.34-2.29(m,1H),1.21(d,J=6.6Hz,3H)

[0600] Example 14d: (E)-3-(1H-indazol-6-yl)-N-((1S,2R)-2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide (stereoisomer 4)

[0601] LC-MS(ES,m / z):[M+H] + =318

[0602] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.22(s,1H),8.45(d,J=8.7Hz,1H),8.09(s,1H),7.81-7.65(m,3H),7.36(d,J=8.4Hz,1H),7.22-7.1 6(m,4H),6.79(d,J=15.6Hz,1H),5.07-5.02(m,1H),3.18-3.08(m,1H),2.56-2.51(m,1H),2.34-2.29(m,1H),1.21(d,J=6.6Hz,3H)

[0603] Example 15: (E)-3-(1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide (a mixture of stereoisomers)

[0604]

[0605] Step 1: Add 15.0 g (101.24 mmol, 1.00 equiv) and 200.0 mL THF to a 500 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Then, add 121.5 mL (121.48 mmol, 1.20 equiv) of LiHMDS dropwise at -78 °C with stirring. Stir the resulting solution at -78 °C for 40 min. Add 10 mL of THF solution containing MeI (17.2 g, 121.49 mmol, 1.20 equiv) dropwise at -78 °C with stirring. Continue the reaction at 25 °C for 1 h with stirring. Then terminate the reaction by adding 150 mL of saturated NH4Cl. Extract the resulting solution with 2 x 150 mL EtOAc, dry with anhydrous sodium sulfate, and concentrate. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (1 / 10). This yielded 5 g (30%) of a pale yellow oily 3-methyl-2,3-dihydro-1-benzopyran-4-one.

[0606]

[0607] Step 2: Add 1.1 g (6.78 mmol, 1.00 equiv) of 3-methyl-2,3-dihydro-1-benzopyran-4-one, 20.0 mL of MeOH, 1.4 g (20.35 mmol, 3.00 equiv) of NH₂OH·HCl, and 2.8 mL (20.35 mmol, 3.00 equiv) of Et₃N to a 40 mL vial purified with nitrogen and kept under an inert nitrogen atmosphere. Stir the resulting solution at 70 °C for 15 h. Concentrate the resulting mixture. Dilute the residue with 10 mL of water. Extract the resulting solution with 2 x 10 mL of ethyl acetate and dry the organic layer with anhydrous sodium sulfate. Concentrate the resulting mixture. This yields 1 g (83%) of white solid N-[(4E)-3-methyl-2,3-dihydro-1-benzopyran-4-ide]hydroxyamine.

[0608]

[0609] Step 3: Add N-[(4E)-3-methyl-2,3-dihydro-1-benzopyran-4-ide]hydroxylamine (0.70 g, 3.95 mmol, 1.00 equiv), MeOH (20.00 mL), and Pd / C (0.06 g) to a 100-mL vial purified with hydrogen and kept under an inert hydrogen atmosphere. Stir the resulting solution at 40 °C for 12 h. Filter off the solid. Concentrate the resulting mixture. This yields 530 mg (82%) of a pale yellow oily 3-methyl-3,4-dihydro-2H-1-benzopyran-4-amine.

[0610]

[0611] Step 4: Add methyl 3-[1-(oxacyclohexan-2-yl)indazol-6-yl]prop-2-enoate (Example 5, Step 1, 150 mg, 0.52 mmol, 1.00 eq), 7-methyl-2,3-dihydro-1H-indene-1-amine (154.3 mg, 1.04 mmol, 2.00 eq), and THF (3.0 mL) to an 8-mL sealed tube. Then add LiHMDS (2.1 mL, 2.09 mmol, 4.00 eq) at 0°C. Stir the resulting solution at room temperature for 0.5 hours. Then terminate the reaction by adding 2 mL of saturated NH4Cl. Extract the resulting solution with 2 x 15 mL of LEtOAc. Dry the organic phase with sodium sulfate and concentrate. This yielded 130 mg (crude product) of a grayish-white solid, N-(7-methyl-2,3-dihydro-1H-inden-1-yl)-3-[1-(oxacyclohexan-2-yl)indazole-6-yl]prop-2-enamide. LC-MS (ES, m / z): [M+H] + =418.

[0612]

[0613] Step 5: Add N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)-3-[1-(oxacyclohexane-2-yl)indazole-6-yl]prop-2-enamide (130 mg, crude product), MeOH (4.0 mL), and 4M HCl / MeOH (4.00 mL) to a 40-mL sealed tube. Stir the resulting solution at room temperature for 5 hours. Concentrate the mixture. Purify the crude product by rapid preparative HPLC. This yields 19 mg of a grayish-white solid, 3-(1H-indazole-6-yl)-N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)prop-2-enamide.

[0614] LC-MS(ES,m / z):[M+H] + =334.

[0615] 1 H NMR (300MHz, CD3OD, ppm): δ8.07(s,1H),7.81-7.70(m,3H),7.47-7.43(m,1H),7.22-7.14(m,2H),6.93-6. 74(m,3H),5.32-4.92(m,1H),4.28-4.14(m,1H),4.00-3.31(m,1H),2.38-2.19(m,1H),1.10-1.03(m,3H).

[0616] Examples 15a, 15b, 15c, and 15d: (E)-3-(1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-indene-1-yl)acrylamide was separated into four separate isomers by SFC (column; SB 100x4.6mm 3.0um; solvent: MeOH (20mM NH3)).

[0617]

[0618] Example 15a (stereoisomer 1): LC-MS (ES, m / z): [M+H] + =334

[0619] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.21 (s, 1H), 8.36 (d, J = 9.3Hz, 1H), 8.07 (s, 1H),7.78(d,J=8.4Hz,1H),7.70-7.63(m,2H),7.33(d,J=8.4Hz,1H),7.20- 7.16(m,2H),6.92-6.87(m,1H),6.84-6.77(m,2H),5.25-5.20(m,1H),4.15 -4.10(m,1H),3.95-3.88(m,1H),2.29-2.28(m,1H),0.91(d,J=6.9Hz,3H).

[0620] Example 15b (stereoisomer 2): (ES, m / z): [M+H] + =334

[0621] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.21 (s, 1H), 8.36 (d, J = 9.3Hz, 1H), 8.07 (s, 1H),7.78(d,J=8.4Hz,1H),7.70-7.63(m,2H),7.33(d,J=8.4Hz,1H),7.20- 7.16(m,2H),6.92-6.87(m,1H),6.84-6.77(m,2H),5.25-5.20(m,1H),4.15 -4.10(m,1H),3.95-3.88(m,1H),2.29-2.28(m,1H),0.91(d,J=6.9Hz,3H).

[0622] Example 15c (stereoisomer 3): LC-MS: [M+H] + =334

[0623] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.22 (s, 1H), 8.52 (d, J = 8.7Hz, 1H), 8.09 (s, 1H),7.79(d,J=8.4Hz,1H),7.72-7.66(m,2H),7.36(d,J=8.7Hz,1H),7.19- 7.13(m,2H),6.92-6.87(m,1H),6.82-6.74(m,2H),4.87-4.82(m,1H),4.25 -4.20(m,1H),3.99-3.92(m,1H),2.51-2.50(m,1H),0.95(d,J=6.9Hz,3H).

[0624] Example 15d (stereoisomer 4): LC-MS-PH-NRG0375-0 (ES, m / z): [M+H] + =334

[0625] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.22 (s, 1H), 8.52 (d, J = 8.7Hz, 1H), 8.09 (s, 1H),7.79(d,J=8.4Hz,1H),7.72-7.66(m,2H),7.36(d,J=8.7Hz,1H),7.19- 7.13(m,2H),6.92-6.87(m,1H),6.82-6.74(m,2H),4.87-4.82(m,1H),4.25 -4.20(m,1H),3.99-3.92(m,1H),2.51-2.50(m,1H),0.95(d,J=6.9Hz,3H).

[0626] Example 16: (E)-N-(2-(benzyloxy)phenyl)-3-(1H-indazol-6-yl)acrylamide

[0627]

[0628] Step 1: To a 50-mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere, add methyl (2E)-3-[1-(oxacyclohexane-2-yl)indazol-6-yl]prop-2-enoate (Example 5, Step 1, 330.0 mg, 1.15 mmol, 1.00 equiv), THF (20.0 mL), and 2-(benzyloxy)aniline (298.5 mg, 1.50 mmol, 1.30 equiv). Then, with stirring, add LiHMDS (3.5 mL, 1 M THF solution, 3.00 equiv) dropwise at 0°C. Stir the resulting solution at 25°C for 2 h. Then terminate the reaction by adding 10 mL of NH4Cl. Extract the resulting solution with 2 x 30 mL EtOAc. Dry the organic layer with anhydrous sodium sulfate and concentrate. Thus, 310 mg (crude product) of pale yellow solid (2E)-N-[2-(benzyloxy)phenyl]-3-[1-(oxacyclohexane-2-yl)indazole-6-yl]prop-2-enamide was obtained.

[0629]

[0630] Step 2: Add (2E)-N-[2-(benzyloxy)phenyl]-3-[1-(oxacyclohexan-2-yl)indazole-6-yl]prop-2-enamide (100.0 mg, crude product) to a 50-mL 3-necked round-bottom flask. Add HCl in MeOH solution (4M, 10.00 mL) at 25°C. Stir the resulting solution at 40°C for 30 min. Concentrate the mixture. Purify the crude product by preparative HPLC. This yields 20 mg of a grayish-white solid (2E)-N-[2-(benzyloxy)phenyl]-3-(1H-indazole-6-yl)prop-2-enamide. LC-MS (ES, m / z): [M+H] + =370.

[0631] 1 H NMR(300MHz,DMSO-d6,ppm):13.26(s,1H),9.36(s,1H),7.13-7.10(m,2H),7.83-7.70(m,3H),7.54-7 .52(m,2H),7.46-7.42(m,3H),7.39-7.24(m,2H),7.11-7.05(m,2H),6.97-6.94(m,1H),5.28(s,2H).

[0632] Example 17: (E)-3-(1H-indazol-6-yl)-N-(2-(phenoxymethyl)phenyl)acrylamide

[0633]

[0634] Step 1: Add methyl 3-(1H-indazole-6-yl)acrylate (intermediate 3) to a 20-mL sealed tube. , 150.0 mg (0.55 mmol, 1.00 eq), 2-(phenoxymethyl)aniline (109.8 mg, 0.55 mmol, 1.00 eq), MeOH (5.0 mL), and DMT-MM (228.7 mg, 0.83 mmol, 1.50 eq) were added. The resulting solution was stirred at room temperature for 16 h. Water (6.00 mL) was added dropwise with stirring. The solid was collected by filtration. This yielded 130 mg (52%) of a white solid, 3-[1-(oxacyclohexane-2-yl)indazole-6-yl]-N-[2-(phenoxymethyl)phenyl]prop-2-enamide. LC-MS (ES, m / z): [M+H] + =454.

[0635]

[0636] Step 2: Add (E)-N-(2-(phenoxymethyl)phenyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)acrylamide (50.0 mg, 0.11 mmol, 1.00 eq), MeOH (4.0 mL), and HCl / MeOH (4.0 mL, 4 M) to a 20 mL sealed tube. Stir the resulting solution at room temperature for 5 hours and concentrate. Purify the crude product by rapid preparative HPLC. This yields 29 mg (71%) of a white solid, 3-(1H-indazole-6-yl)-N-[2-(phenoxymethyl)phenyl]prop-2-enamide. LC-MS (ES, m / z): [M+H] + =370.

[0637] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.26(s,1H),9.72(s,1H),8.10(s,1H),7.83-7.50(m,4H),7.41-7.21(m,10H),5.16(s,2H).

[0638] Example 18: (E)-N-(2-(cyclobutoxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide

[0639]

[0640] Step 1: Cyclobutanol (1.0 g, 13.86 mmol, 1.00 eq), 3,3,3-trichloropropionitrile (2.2 g, 13.86 mmol, 1.00 eq), and DCM (20.0 mL) were added to a 50 mL 3-necked round-bottom flask purified with nitrogen and maintained under a nitrogen inert atmosphere. Then, DBU (0.21 g, 1.38 mmol, 0.10 eq) was added at 0 °C. The resulting solution was stirred at 0–5 °C for 1 h. The mixture was concentrated at low temperature. The residue was loaded onto a silica gel column using EtOAc / PE (5:95). This yielded 1.3 g (43%) of a light pink, oily cyclobutyl 2,2,2-trichloroethyleneimine. LC-MS (ES, m / z): [M+H] + =216.

[0641]

[0642] Step 2: Add 2-nitrobenzyl alcohol (679.1 mg, 3.69 mmol, 1.20 eq) and DCM (20.01 mL) to a 50 mL 3-necked round-bottom flask. Then add 2,2,2-trichloroethyleneimine cyclobutyl ester (800.0 mg, 3.69 mmol, 1.00 eq) at 0 °C. After stirring at 0 °C for 10 min, add BF3·Et2O (472.0 mg, 3.33 mmol, 0.90 eq). Stir the resulting solution at 0 °C for 1 h. Concentrate the mixture at low temperature. Load the residue onto a silica gel column using THF:PE = 5:95. This yields 530 mg (69%) of a light pink solid, 1-(cyclobutoxymethyl)-2-nitrobenzene.

[0643]

[0644] Step 3: Add 1-(cyclobutoxymethyl)-2-nitrobenzene (500.0 mg, 2.41 mmol, 1.00 eq), MeOH (10.0 mL), H₂O (2.0 mL), Zn (789.1 mg, 2.06 mmol, 5.00 eq), and NH₄Cl (1.3 g, 24.13 mmol, 10.00 eq) to a 40 mL sealed tube. Stir the resulting solution at room temperature for 3 hours. Filter off the solid. Concentrate the filtrate. Dilute the residue with 50 mL of EtOAc. Wash the resulting mixture with 20 mL of H₂O. Concentrate the organic phase. Purify the crude product by rapid preparative HPLC. This yields 160 mg (37%) of off-white solid 2-(cyclobutoxymethyl)aniline. LC-MS (ES, m / z): [M+H] + =178.

[0645]

[0646] Step 4: Add (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)methyl acrylate (60.0 mg, 0.21 mmol, 1.00 eq), 2-(cyclobutoxymethyl)aniline (37.1 mg, 0.21 mmol, 1.00 eq), and THF (4.00 mL) to an 8-mL sealed tube. Then add LiHMDS (0.63 mL, 0.63 mmol, 3.00 eq, 1 M THF solution) at 0 °C. Stir the resulting solution at room temperature for 0.5 hours. Terminate the reaction mixture by adding 10 mL of saturated NH4Cl. Extract the resulting solution with 2 x 15 mL EtOAc. Dry the organic phase with sodium sulfate and concentrate. This yielded 83 mg (crude product) of a grayish-white solid, N-[2-(cyclobutoxymethyl)phenyl]-3-[1-(oxacyclohexane-2-yl)indazol-6-yl]prop-2-enamide. LC-MS (ES, m / z): [M+H] + =432.

[0647]

[0648] Step 5: Add (E)-N-(2-(cyclobutoxymethyl)phenyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)acrylamide (83.00 mg, crude), DCM (2.00 mL), and TFA (2.00 mL) to an 8-mL sealed tube. Stir the resulting solution at room temperature for 1 hour. Concentrate the mixture at low temperature. Purify the crude product by rapid preparative HPLC. This yields 18 mg of N-[2-(cyclobutoxymethyl)phenyl]-3-(1H-indazole-6-yl)prop-2-enamide as a white solid. LC-MS (ES, m / z): [M+H] + =348.

[0649] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.27(s,1H),9.51(s,1H),8.11(s,1H),7.84-7.64(m,4H),7.46-7.40(m,2H),7.34-7.17(m,2H),6. 98(d,J=15.6Hz,1H),4.44(s,2H),4.02-3.97(m,1H),2.18-2.10(m,2H),1.92-1.86(m,2H),1.65-1.61(m,1H),1.49-1.43(m,1H).

[0650] Example 19: (E)-N-(1-benzyl-1H-indazole-7-yl)-3-(1H-indazole-6-yl)acrylamide

[0651]

[0652] Step 1: Add 7-nitroindazole (3.0 g, 18.39 mmol, 1.00 eq), K₂CO₃ (7.6 g, 55.17 mmol, 3.00 eq), CH₃CN (50.0 mL), and PhCH₂Br (4.7 g, 27.58 mmol, 1.50 eq) to a 100 mL round-bottom flask. Stir the resulting solution at room temperature for 16 h. Pour the resulting solution into 150 mL of water. Collect the solid by filtration. Load the residue onto a silica gel column. This yields 1.60 g (34%) of red solid 1-benzyl-7-nitroindazole and 1.40 g (30%) of red solid 2-benzyl-7-nitroindazole.

[0653]

[0654] Step 2: Add 1-benzyl-7-nitroindazole (820.0 mg, 3.24 mmol, 1.00 eq), Zn (1.1 g, 16.19 mmol, 5.00 eq), NH4Cl (1.7 g, 32.38 mmol, 10.00 eq), MeOH (30.0 mL), and H2O (5.0 mL) to a 50 mL round-bottom flask. Stir the resulting solution at room temperature for 3 hours. Filter off the solid. Concentrate the resulting solution. Dilute the residue with 50 mL of EtOAc. Wash the resulting mixture with 20 mL of H2O and 20 mL of brine. Concentrate the organic phase. This yields 650 mg (89%) of a grayish-white solid, 1-benzylindazole-7-amine. LC-MS (ES, m / z): [M+H] + =224.

[0655]

[0656] Step 3: Add (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)methyl acrylate (Example 5, Step 1, 150.0 mg, 0.52 mmol, 1.00 equiv), THF (3.00 mL), and 1-benzylindazole-7-amine (175.5 mg, 0.78 mmol, 1.50 equiv) to an 8-mL sealed tube. Then add LiHMDS (2.10 mL, 2.10 mmol, 4.00 eq) at 0 °C. Stir the resulting solution at room temperature for 0.5 hours. Then terminate the reaction by adding 5 mL of saturated NH4Cl. Extract the resulting solution with 2 x 15 mL EtOAc. Dry the organic phase with sodium sulfate and concentrate. This yielded 120 mg (crude product) of a grayish-white solid, N-(1-benzylindazole-7-yl)-3-[1-(oxacyclohexane-2-yl)indazole-6-yl]prop-2-enamide. LC-MS (ES, m / z): [M+H] + =478.

[0657]

[0658] Step 4: Add (E)-N-(1-benzyl-1H-indazole-7-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)acrylamide (120.0 mg, crude product), MeOH (4.0 mL), and 4M HCl / MeOH (4.0 mL) to a 20-mL sealed tube. Stir the resulting solution at room temperature for 5 hours and concentrate the mixture. Purify the crude product by rapid preparative HPLC. This yields 17 mg of a grayish-white solid, N-(1-benzylindazole-7-yl)-3-(1H-indazole-6-yl)prop-2-enamide. LC-MS (ES, m / z): [M+H] + =394.

[0659] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.27(brs,1H),10.15(brs,1H),8.20(s,1H),8.11(s,1H), 7.85-7.63(m,4H),7.56-7.43(m,1H),7.34-7.11(m,5H),6.97-6.56(m,3H),5.81(s,2H).

[0660] Example 20: (E)-3-(1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide

[0661]

[0662] Step 1: Add (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)acrylate (220.0 mg, 0.77 mmol, 1.00 equiv), THF (20.0 mL), 1-methylindazole-7-amine (147.0 mg, 1.00 mmol, 1.30 equiv), and LiHMDS (2.3 mL, 2.31 mmol, 3.00 equiv) to a 50 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution at 25 °C for 2 h. Then terminate the reaction by adding 20 mL of water. Extract the resulting solution with 100 mL of EtOAc, dry it with anhydrous sodium sulfate, and concentrate it. Thus, 220 mg (crude product) of solid (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-(1H-indazole-6-yl)-N-(1-methyl-1H-indazole-7-yl)acrylamide was obtained.

[0663]

[0664] Step 2: Add (2E)-(1-(tetrahydro-2H-pyran-2-yl)-N-(1-methylindazole-7-yl)-3-[1-(oxacyclohexane-2-yl)indazole-6-yl]prop-2-enamide (80.00 mg, crude product) to a 50-mL 3-necked round-bottom flask. Introduce 10.00 mL of 4M HCl / MeOH at 25°C. Stir the resulting solution at 40°C for 30 min. Concentrate the mixture. Purify the crude product by preparative HPLC. This yields 20 mg of a grayish-white solid (2E)-3-(1H-indazole-6-yl)-N-(1-methylindazole-7-yl)prop-2-enamide. LC-MS (ES, m / z): [M+H] + =318.

[0665] 1 H-NMR(300MHz,DMSO-d6,ppm):13.27(s,1H),10.16(s,1H),8.12-8.08(m,2H),7.85-7.77(m,3H),7.70-7 .68(m,1H),7.48-7.45(m,1H),7.26-7.24(m,1H),7.16-7.11(m,1H),7.02(d,J=15.9Hz,1H),4.12(s,3H).

[0666] Example 21: (E)-3-(1H-indazol-6-yl)-N-(m-tolyl)acrylamide

[0667]

[0668] Step 1: Add (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)methyl acrylate (Example 5, Step 1, 150.0 mg, 0.52 mmol, 1.00 eq), m-toluidine (84.2 mg, 0.78 mmol, 1.50 eq), THF (3.00 mL), and LiHMDS (2.1 mL, 2.09 mmol, 4.00 eq, 1 M THF solution) to an 8-mL sealed tube. Stir the resulting solution at room temperature for 1 hour. Then terminate the reaction by adding 5 mL of saturated NH4Cl. Extract the resulting solution with 2 x 15 mL of ethyl acetate. Dry the organic phase with sodium sulfate and concentrate. This yields 130 mg (crude) of a grayish-white solid (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)-N-(m-toluyl)acrylamide. LC-MS(ES,m / z):[M+H] + =362.

[0669]

[0670] Step 2: Add (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)-N-(m-tolyl)acrylamide (130.00 mg, crude), MeOH (2.00 mL), and HCl / MeOH (2.00 mL, 4 M) to an 8-mL sealed tube. Stir the resulting solution at room temperature for 5 hours. Concentrate the mixture at low temperature. Purify the crude product by rapid preparative HPLC. This yields 35 mg of a grayish-white solid (E)-3-(1H-indazole-6-yl)-N-(m-tolyl)acrylamide. LC-MS (ES, m / z): [M+H] + =278. 1 H-NMR (300MHz, DMSO-d6, ppm): δ10.12(s,1H),8.11(s,1H),7.83-7.70(m, 3H),7.50-7.39(m,3H),7.26-7.20(m,1H),7.09-6.88(m,2H),2.27(s,3H).

[0671] Example 22: (E)-N-(3-chlorophenyl)-3-(1H-indazole-6-yl)acrylamide

[0672]

[0673] Step 1: Add (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)methyl acrylate (Example 5, Step 1, 130.0 mg, 0.45 mmol, 1.00 eq), 3-chloroaniline (86.9 mg, 0.68 mmol, 1.50 eq), THF (3.0 mL), and LiHMDS (1.8 mL, 1.82 mmol, 4.00 eq, 1 M THF solution) to an 8-mL sealed tube. Stir the resulting solution at room temperature for 1 hour. Then terminate the reaction by adding 5 mL of saturated NH4Cl. Extract the resulting solution with 2 x 15 mL EtOAc. Dry the organic phase with sodium sulfate and concentrate. This yields 135 mg (crude) of a grayish-white solid N-(3-chlorophenyl)-3-[1-(oxacyclohexane-2-yl)indazole-6-yl]prop-2-enamide. LC-MS-PH-NRG0319-1(ES,m / z):[M+H] + =382.

[0674]

[0675] Step 2: Add (N-(3-chlorophenyl)-3-[1-(oxacyclohexane-2-yl)indazole-6-yl]prop-2-enamide (130 mg, crude), MeOH (2.00 mL), and 4M HCl / MeOH (2.00 mL) to an 8-mL sealed tube. Stir the resulting solution at room temperature for 5 hours. Concentrate the mixture at low temperature. Purify the crude product by rapid preparative HPLC. This yields 42 mg of a grayish-white solid (E)-N-(3-chlorophenyl)-3-(1H-indazole-6-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =298.

[0676] 1 HNMR(300MHz,DMSO-d6,ppm): δ13.35(brs,1H),10.4(s,1H),8.11(s,1H),7.97-7.74(m ,4H),7.56-7.53(m,1H),7.43-7.35(m,2H),7.15-7.12(m,1H),6.90(d,J=15.9Hz,1H).

[0677] Example 23: (E)-N-(3-fluorophenyl)-3-(1H-indazol-6-yl)acrylamide

[0678]

[0679] Step 1: Add (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)methyl acrylate (150.0 mg, 0.52 mmol, 1.00 eq), 3-fluoroaniline (87.3 mg, 0.78 mmol, 1.50 eq), THF (3.0 mL), and LiHMDS (2.1 mL, 2.10 mmol, 4.00 eq) to an 8-mL sealed tube. Stir the resulting solution at room temperature for 1 hour. Then terminate the reaction by adding 5 mL of saturated NH4Cl. Extract the resulting solution with 2 x 15 mL EtOAc. Dry the organic phase with sodium sulfate and concentrate. This yields 128 mg (crude) of a grayish-white solid N-(3-fluorophenyl)-3-[1-(oxacyclohexane-2-yl)indazole-6-yl]prop-2-enamide.

[0680] LC-MS(ES,m / z):[M+H] + =366.

[0681]

[0682] Step 2: Add N-(3-fluorophenyl)-3-[1-(oxacyclohexane-2-yl)indazole-6-yl]prop-2-enamide (120.0 mg, crude), MeOH (2.0 mL), and 4M HCl / MeOH (2.0 mL) to an 8-mL sealed tube. Stir the resulting solution at room temperature for 5 hours. Concentrate the mixture at low temperature. Purify the crude product by rapid preparative HPLC. This yields 33 mg of a grayish-white solid (E)-N-(3-fluorophenyl)-3-(1H-indazole-6-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =282.

[0683] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.30(brs,1H),10.43(s,1H),8.11(s,1H),7.84-7.73(m,4H),7.47-7.10(m,3H),6.96-6.87(m,2H).

[0684] Example 24: (E)-N-(2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide

[0685]

[0686] Step 1: Add 2,6-dimethylaniline (160.0 mg, 1.32 mmol, 1.00 equiv), DCM (10.0 mL), and triethylamine (0.55 mL, 3.96 mmol, 3.00 equiv) to a 50 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Then, add acryloyl chloride (143.40 mg, 1.58 mmol, 1.20 equiv) dropwise at 0 °C with stirring. Stir the resulting solution at 25 °C for 3 h. Then terminate the reaction by adding 15 mL of water. Extract the resulting solution with 2 x 10 mL of dichloromethane. Dry the organic layer with anhydrous sodium sulfate and concentrate. Load the residue onto a silica gel column using EtOAc / PE (1 / 3). This yields 150 mg (65%) of white solid N-(2,6-dimethylphenyl)prop-2-enamide. LC-MS (ES, m / z): [M+H] + =176.

[0687]

[0688] Step 2: N-(2,6-dimethylphenyl)prop-2-acrylamide (50.0 mg, 0.29 mmol, 1.00 equiv), DMF (4.0 mL), 6-bromo-1H-indazole (61.8 mg, 0.31 mmol, 1.10 equiv), Et3N (0.12 mL, 0.86 mmol, 3.00 equiv), and Pd(dppf)Cl2.CH2Cl2 (11.7 mg, 0.014 mmol, 0.05 equiv) were added to an 8-mL vial purified with nitrogen and kept under an inert nitrogen atmosphere. The resulting solution was stirred at 120 °C for 5 h. The reaction mixture was cooled to 25 °C in a water bath. The crude mixture was purified by rapid preparative HPLC. This yielded 30 mg (36%) of a grayish-white solid (E)-N-(2,6-dimethylphenyl)-3-(1H-indazole-6-yl)acrylamide. LC-MS(ES,m / z):[M+H] + =292.

[0689] 1 H NMR(300MHz,DMSO-d6,ppm):13.24(s,1H),9.50(s,1H),8.10(s,1H),7.84-7.6 8(m,3H),7.45-7.41(m,1H),7.11(s,3H),6.97(d,J=15.9Hz,1H),2.19(s,6H).

[0690] Examples 25 and 26: (E)-N-((1R,3R)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide, isomer 1; (E)-N-((1R,3S)-3-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide, isomer 2

[0691]

[0692] Step 1: Add benzaldehyde (5.5 g, 51.83 mmol, 1.00 equiv), EtOH (30.0 mL), NH4OAc (8.0 g, 103.65 mmol, 2.00 equiv), and malonic acid (5.4 g, 51.83 mmol, 1.00 equiv) to a 100-mL round-bottom flask. Stir the resulting solution at 80°C for 12 h. Collect the solid by filtration. This yields 5 g (58%) of white solid 3-amino-3-phenylpropionic acid.

[0693]

[0694] Step 2: Add 4.9 g (29.66 mmol, 1.00 equiv) of 3-amino-3-phenylpropionic acid and 40.0 mL of DCM to a 100 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Then, add 6.9 g (32.63 mmol, 1.10 equiv) of trifluoroacetic anhydride dropwise at 0 °C with stirring. Stir the resulting solution at 0 °C for 30 min. Collect the solid by filtration. This yields 4 g (52%) of white solid 3-phenyl-3-(2,2,2-trifluoroacetamido)propionic acid.

[0695]

[0696] Step 3: Add 5.0 g (19.14 mmol, 1.00 equiv) of 3-phenyl-3-(2,2,2-trifluoroacetamido)propionic acid and 30 mL of thionyl chloride to a 100 mL round-bottom flask. Stir the resulting solution at 70 °C for 3 h. Concentrate the mixture. This yields 4.5 g (84%) of a white solid, 3-phenyl-3-(2,2,2-trifluoroacetamido)propionyl chloride.

[0697]

[0698] Step 4: Add AlCl3 (4.29 g, 32.18 mmol, 2.00 equiv) and DCM (30.00 mL) to a 100 mL 3-necked round-bottom flask. Then, with stirring, add a solution of 3-phenyl-3-(2,2,2-trifluoroacetamido)propionyl chloride (4.5 g, 16.09 mmol, 1.00 equiv) in 20 mL of DCM at 0 °C. Stir the resulting solution at 40 °C for 12 h. Cool the reaction mixture to 25 °C. Filter off the solid. Dry the mixture with anhydrous sodium sulfate and concentrate. Load the residue onto a silica gel column using EtOAc / PE (1 / 2). This yields 3.4 g (87%) of a white solid, 2,2,2-trifluoro-N-(3-oxo-1,2-dihydroindene-1-yl)acetamide. LC-MS (ES, m / z): [M+H] + =244.

[0699]

[0700] Step 5: Add 3.0 g (12.34 mmol, 1.00 equiv) of 2,2,2-trifluoro-N-(3-oxo-1,2-dihydro-1H-indene-1-yl)acetamide and 30.00 mL of MeOH to a 100 mL 3-necked round-bottom flask purified with nitrogen and maintained under a nitrogen inert atmosphere. Then, add NaBH4 (1.40 g, 37.01 mmol, 3.00 equiv) in portions at 0 °C. Stir the resulting solution at room temperature for 3 h. Then terminate the reaction by adding 30 mL of water. Extract the resulting solution with 2 x 40 mL DCM. Dry the mixture with anhydrous sodium sulfate and concentrate. This yields 2 g (66%) of white solid 2,2,2-trifluoro-N-(3-hydroxy-2,3-dihydro-1H-indene-1-yl)acetamide.

[0701]

[0702] Step 6: Add 2,2,2-trifluoro-N-(3-hydroxy-2,3-dihydro-1H-indene-1-yl)acetamide (2.0 g, 8.16 mmol, 1.00 equiv) and DCM (30.00 mL) to a 100 mL 3-necked round-bottom flask purified with nitrogen and maintained under a nitrogen inert atmosphere. Then, add diethylsulfur trifluoride (1.71 g, 10.60 mmol, 1.30 equiv) dropwise at 0 °C with stirring. Stir the resulting solution at 0 °C for 2 h. Then terminate the reaction by adding 50 mL of NaHCO3 aqueous solution. Extract the resulting solution with 2 x 50 mL of dichloromethane, dry with anhydrous sodium sulfate and concentrate. Load the residue onto a silica gel column using EtOAc / PE (1 / 5). This yielded 810 mg (40%) of pale yellow solid 2,2,2-trifluoro-N-(3-fluoro-2,3-dihydro-1H-indene-1-yl)acetamide.

[0703]

[0704] Step 7: Add 2,2,2-trifluoro-N-(3-fluoro-2,3-dihydro-1H-indene-1-yl)acetamide (800.0 mg, 3.24 mmol, 1.00 equiv), MeOH / H₂O (10.0 mL / 5.0 mL), and NaOH (258.9 mg, 6.472 mmol, 2.00 equiv) to a 40 mL vial. Stir the resulting solution at room temperature for 5 h. Extract the solution with 2 x 20 mL EtOAc and dry the organic layer with anhydrous sodium sulfate and concentrate. This yields 450 mg (92%) of pale yellow solid 3-fluoro-2,3-dihydro-1H-indene-1-amine.

[0705]

[0706] Step 8: Add 3-fluoro-2,3-dihydro-1H-indene-1-amine (410.0 mg, 2.71 mmol, 1.00 equiv), DCM (15.00 mL), and Et3N (0.76 mL, 5.42 mmol, 2.00 equiv) to a 50 mL 3-necked round-bottom flask purified with nitrogen and maintained under a nitrogen inert atmosphere. Then, add acryloyl chloride (294.55 mg, 3.25 mmol, 1.20 equiv) dropwise at 0 °C with stirring. Stir the resulting solution at room temperature for 2 h. Then terminate the reaction by adding 5 mL of water. Extract the resulting solution with 2 x 10 mL of dichloromethane, dry with anhydrous sodium sulfate, and concentrate. Purify the crude product by preparative HPLC. This yields 230 mg (41%) of pale yellow solid N-(3-fluoro-2,3-dihydro-1H-indene-1-yl)prop-2-enamide.

[0707]

[0708] Step 9: Add N-(3-fluoro-2,3-dihydro-1H-inden-1-yl)prop-2-enamide (80.0 mg, 0.39 mmol, 1.00 equiv), DMF (8.0 mL), 6-bromo-1H-indazole (84.5 mg, 0.43 mmol, 1.10 equiv), Et3N (0.14 mL, 0.98 mmol, 2.50 equiv), and Pd(dppf)Cl2.CH2Cl2 (25.40 mg, 0.03 mmol, 0.08 equiv) to a 20-mL vial purified with nitrogen and kept under an inert nitrogen atmosphere. Stir the resulting solution at 120 °C for 12 h. Cool the reaction mixture to 25 °C. Dilute the resulting solution with 8 mL of water. Extract the resulting solution with 2 x 10 mL EtOAc. Wash the resulting mixture with 2 x 15 mL brine. Concentrate the resulting mixture. Purify the crude product by SFC. Thus, 11 mg (9%) of grayish-white solid trans-(2E)-N-[(1R,3R)-3-fluoro-2,3-dihydro-1H-indene-1-yl]-3-(1H-indazole-6-yl)prop-2-enamide (isomer 1) and 13 mg (10%) of grayish-white solid cis-(2E)-N-[(1R,3S)-3-fluoro-2,3-dihydro-1H-indene-1-yl]-3-(1H-indazole-6-yl)prop-2-enamide (isomer 2) were obtained.

[0709] Stereochemistry can be arbitrarily specified:

[0710] Isomer 1: LC-MS (ES, m / z): [M+H] + =322.

[0711] 1 H NMR (300MHz, DMSO-d6, ppm): 13.15 (s, 1H), 8.57 (d, J = 8.1Hz, 1H), 8.09 (s, 1H), 7.77-7.56 (m, 4H), 7.50-7.34 (m,4H),6.73(d,J=15.9Hz,1H),6.26-6.06(m,1H),5.69-5.66(m,1H),2.76-2.61(m,1H),2.31-2.17(m,1H).

[0712] Isomer 2: LC-MS (ES, m / z): [M+H] + =322.

[0713] 1H NMR (300MHz, DMSO-d6, ppm): 13.16 (brs, 1H), 8.67 (d, J = 8.1Hz, 1H), 8.09 (s, 1H), 7.81-7.65 (m, 4H), 7.54-7.3 0(m,4H),6.77(d,J=15.6Hz,1H),6.15-5.92(m,1H),5.42-5.35(m,1H),3.10-2.97(m,1H),2.10-2.01(m,1H).

[0714] Example 27: (E)-N-(2-(hydroxymethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide

[0715]

[0716] Step 1: Add (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)methyl acrylate (Example 5, Step 1, 150.0 mg, 0.52 mmol, 1.00 eq), THF (3.00 mL), 2-(phenoxymethyl)aniline (125.2 mg, 0.62 mmol, 1.20 eq), and LiHMDS (2.62 mL, 2.62 mmol, 5.00 eq) to an 8-mL sealed tube. Stir the resulting solution at room temperature for 1 hour. Then terminate the reaction by adding 5 mL of saturated NH4Cl. Extract the resulting solution with 2 x 15 mL EtOAc. Dry the organic phase with sodium sulfate and concentrate. This yields 78 mg (crude) of a grayish-white solid N-[2-(hydroxymethyl)phenyl]-3-[1-(oxacyclohexane-2-yl)indazole-6-yl]prop-2-enamide. LC-MS-PH-NRG0347-1(ES,m / z):[M+H] + =378.

[0717]

[0718] Step 2: Add (N-[2-(hydroxymethyl)phenyl]-3-[1-(oxacyclohexane-2-yl)indazole-6-yl]prop-2-enamide (75 mg, crude), THF (2 mL), and TFA (2 mL) to an 8-mL sealed tube. Stir the resulting solution at room temperature for 3 hours. Concentrate the mixture at low temperature. Purify the crude product by rapid preparative HPLC. This yields 38 mg of a grayish-white solid (E)-N-(2-(hydroxymethyl)phenyl)-3-(1H-indazole-6-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =294.

[0719] 1H NMR (300MHz, DMSO-d6, ppm): δ13.26(brs,1H),9.57(s,1H),8.11(s,1H),7.83-7.70(m,4H) ,7.53-7.44(m,2H),7.30-7.08(m,2H),7.00(d,J=15.9Hz,1H),5.33(brs,1H),4.57(s,2H).

[0720] Example 28: (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide

[0721]

[0722] Add a solution of 6-bromo-1H-indazole (100.0 mg, 0.51 mmol, 1.00 equiv), N-(3-fluoro-2,6-dimethylphenyl)prop-2-enamide (prepared according to the method described for intermediate 1 using 3-fluoro-2,6-dimethylaniline and acryloyl chloride, 98.1 mg, 0.51 mmol, 1.00 equiv), Pd(dppf)Cl2 (37.1 mg, 0.051 mmol, 0.10 equiv), and Et3N (0.21 mL, 1.52 mmol, 3.00 equiv) in DMF (4.0 mL) to an 8-mL vial. Stir the resulting solution in an oil bath at 120 °C for 2 h. Cool the reaction mixture. Load the residue onto a silica gel column using THF / PE (1 / 1) solution. This yielded 20 mg (13%) of a grayish-white solid (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1H-indazol-6-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =310.

[0723] 1 H NMR(300MHz,DMSO-d6,ppm)δ13.26(s,1H),9.66(s,1H),8.11(s,1H),7.84-7. 71(m,3H),7.44(d,J=9.3Hz,1H),7.16-6.95(m,3H),2.17(s,3H),2.09(s,3H).

[0724] Example 29: (E)-3-(1H-indazol-6-yl)-N-(2-(methoxymethyl)phenyl)acrylamide

[0725]

[0726] Step 1: Add 2-nitrobenzyl alcohol (500.00 mg, 3.26 mmol, 1.00 eq), MeCN (20.00 mL), and K₂CO₃ (676.80 mg, 4.89 mmol, 1.50 eq) to a 40-mL sealed tube. Then add methyl iodine (1.40 g, 9.79 mmol, 3.00 eq) at 0 °C. Stir the resulting solution at room temperature for 3 hours. Then terminate the reaction by adding 50 mL of water. Extract the resulting solution with 2 x 30 mL EtOAc. Wash the organic phase with 2 x 20 mL brine. Dry the organic layer with anhydrous sodium sulfate and concentrate under vacuum. This yields 510 mg (93%) of a pale yellow oily 1-(methoxymethyl)-2-nitrobenzene.

[0727]

[0728] Step 2: Add 1-(methoxymethyl)-2-nitrobenzene (510.0 mg, 3.05 mmol, 1.00 eq), EtOH (10.0 mL), H₂O (2.0 mL), NH₄Cl (1.3 mg, 24.50 mmol, 8.03 eq), and Zn (997.8 mg, 15.25 mmol, 5.00 eq) to a 40 mL sealed tube. Stir the resulting solution at room temperature for 1 hour. Dilute the resulting solution with 50 mL of DCM. Filter off the solid. Dry the filtrate with anhydrous sodium sulfate and concentrate under vacuum. This yields 380 mg (90%) of pale yellow solid 2-(methoxymethyl)aniline. LC-MS (ES, m / z): [M+H] + =138.

[0729]

[0730] Step 3: Add (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)methyl acrylate (50.0 mg, 0.17 mmol, 1.00 eq), 2-(methoxymethyl)aniline (23.3 mg, 0.17 mmol, 1.00 eq), and THF (3.00 mL) to an 8-mL sealed tube. Then add LiHMDS (0.70 mL, 0.70 mmol, 4.00 eq) at 0 °C. Stir the resulting solution at room temperature for 0.5 hours. Then terminate the reaction by adding 5 mL of saturated NH4Cl. Extract the resulting solution with 2 x 10 mL EtOAc. Dry the organic phase with sodium sulfate and concentrate. This yields 51 mg (crude) of a white solid (2E)-N-[2-(methoxymethyl)phenyl]-3-[1-(oxacyclohexane-2-yl)indazole-6-yl]prop-2-enamide. LC-MS(ES,m / z):[M+H] + =392.

[0731]

[0732] Step 4: Add (2E)-N-[2-(methoxymethyl)phenyl]-3-[1-(oxacyclohexane-2-yl)indazole-6-yl]prop-2-enamide (51.0 mg, 0.13 mmol, 1.00 eq), MeOH (2.0 mL), and 4 M HCl / MeOH (2.0 mL) to an 8-mL sealed tube. Stir the resulting solution at room temperature for 5 hours. Concentrate the mixture at low temperature. Purify the crude product by rapid preparative HPLC. This yields 38 mg of a white solid (E)-3-(1H-indazole-6-yl)-N-(2-(methoxymethyl)phenyl)acrylamide. LC-MS (ES, m / z): [M+H] + =308.

[0733] 1 H NMR (300MHz, DMSO-d6, ppm): δ9.49 (s, 1H), 8.11 (s, 1H), 7.84-7.69 (m, 4H), 7.47-7.18 (m, 4H), 7.04 (d, J = 15.9Hz, 1H), 4.49 (s, 2H), 3.33 (s, 3H).

[0734] Example 30: (E)-N-(2-(((1-(2-fluoroethyl)azacyclobutane-3-yl)oxy)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide hydrochloride

[0735]

[0736] Step 1: Add tert-butyl 3-hydroxyazacyclobutane-1-carboxylate (4.0 g, 23.09 mmol, 1.00 eq), DMF (50.0 mL), K₂CO₃ (4.8 g, 34.64 mmol, 1.50 eq), and 1-(bromomethyl)-2-nitrobenzene (4.99 g, 23.09 mmol, 1.00 eq) to a 100-mL three-necked round-bottom flask. Stir the resulting solution at 50 °C for 3 h. Dilute the resulting solution with 150 mL of EtOAc. Filter the solid. Dry the filtrate with anhydrous sodium sulfate and concentrate. Load the residue onto a silica gel column using EtOAc / PE (20:80). This yields 3.5 g (49%) of colorless solid tert-butyl 3-[(2-nitrophenyl)methoxy]azacyclobutane-1-carboxylate.

[0737]

[0738] Step 2: Add 3-[(2-nitrophenyl)methoxy]azacyclobutane-1-carboxylic acid tert-butyl ester (3.0 g, 9.73 mmol, 1.00 eq), DCM (10.0 mL), and TFA (10.0 mL) to a 50-mL round-bottom flask. Stir the resulting solution at room temperature for 3 hours. Concentrate the mixture. Purify the crude product by recrystallization from Et₂O. This yields 2.7 g (91%) of a white solid, 3-((2-nitrobenzyl)oxy)azacyclobutane trifluoroacetate. LC-MS (ES, m / z): [M+H] + =209.

[0739]

[0740] Step 3: Add 3-((2-nitrobenzyl)oxy)azacyclobutane trifluoroacetate (1.00 g, 3.28 mmol, 1.00 eq), MeCN (20.00 mL), K₂CO₃ (0.91 g, 6.57 mmol, 2.00 eq), KI (0.55 g, 3.31 mmol, 1.01 eq), and 1-bromo-2-fluoroethane (0.63 g, 4.93 mmol, 1.50 eq) to a 40-mL sealed tube. Stir the resulting solution at 50°C for 3 h. Dilute the resulting solution with 50 mL of EA. Filter out the solid. Concentrate the filtrate. Load the residue onto a silica gel column using THF:PE = 32:68. This yields 0.75 g (89%) of a pale yellow solid, 1-(2-fluoroethyl)-3-[(2-nitrophenyl)methoxy]azacyclobutane.

[0741]

[0742] Step 4: Add 1-(2-fluoroethyl)-3-[(2-nitrophenyl)methoxy]azacyclobutane (500.0 mg, 1.96 mmol, 1.00 eq), MeOH (10.0 mL), H₂O (2.0 mL), NH₄Cl (841.5 mg, 15.72 mmol, 8.00 eq), and Zn (643.1 mg, 9.80 mmol, 5.00 eq) to a 40 mL sealed tube. Stir the resulting solution at room temperature for 3 hours. Dilute the resulting solution with 50 mL of DCM. Filter off the solid. Concentrate the filtrate. This yields 300 mg (68%) of a grayish-white solid, 2-([[1-(2-fluoroethyl)azacyclobutane-3-yl]oxy]methyl)aniline.

[0743] LC-MS(ES,m / z):[M+H] + =225.

[0744]

[0745] Step 5: Add (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)methyl acrylate (100.0 mg, 0.35 mmol, 1.00 eq), 2-([[1-(2-fluoroethyl)azacyclobutane-3-yl]oxy]methyl)aniline (78.3 mg, 0.35 mmol, 1.00 eq), and THF (3.00 mL) to an 8-mL sealed tube. Then add LiHMDS (1.7 mL, 1.75 mmol, 5.00 eq) at 0 °C. Stir the resulting solution at room temperature for 1 hour. Then terminate the reaction by adding 5 mL of saturated NH4Cl. Extract the resulting solution with 2 x 10 mL of ethyl acetate. Dry the organic phase with sodium sulfate and concentrate. This yielded 105 mg (crude product) of a grayish-white solid, (2E)-N-[2-([[1-(2-fluoroethyl)azacyclobutane-3-yl]oxy]methyl)phenyl]-3-[1-(oxacyclohexane-2-yl)indazol-6-yl]prop-2-enamide. LC-MS (ES, m / z): [M+H] + =479.

[0746]

[0747] Step 6: Add (2E)-N-[2-([[1-(2-fluoroethyl)azacyclobutane-3-yl]oxy]methyl)phenyl]-3-[1-(oxacyclohexane-2-yl)indazole-6-yl]prop-2-enamide (100.0 mg, crude), DCM (5.0 mL), and TFA (119.13 mg, 1.05 mmol, 5.00 eq) to an 8-mL sealed tube. Stir the resulting solution at room temperature for 3 hours. Concentrate the resulting mixture. Purify the crude product by rapid preparative HPLC. This yields 73 mg of a grayish-white solid (E)-N-(2-(((1-(2-fluoroethyl)azacyclobutane-3-yl)oxy)methyl)phenyl)-3-(1H-indazole-6-yl)acrylamide hydrochloride).

[0748] LC-MS(ES,m / z):[M+H] + =395.

[0749] 1 H NMR (300MHz, DMSO-d6, ppm): δ11.40-10.90(m,1H),9.77-9.73(m,1H),8.11(s,1H),7.84- 7.62(m,4H),7.47-7.11(m,5H),4.79-4.58(m,4H),4.45-3.96(m,5H),3.65-3.52(m,2H).

[0750] Example 31: (E)-N-(2-((3-fluorozacricyclobutan-1-yl)methyl)phenyl)-3-(1H-indazol-6-yl)acrylamide

[0751]

[0752] Step 1: 1-(bromomethyl)-2-nitrobenzene (500.0 mg, 2.31 mmol, 1.00 equiv), CH3CN (10.0 mL), Et3N (0.64 mL, 4.63 mmol, 2.00 eq), and 3-fluoroazacyclobutane hydrochloride (309.8 mg, 2.77 mmol, 1.20 eq) were added to a 40-mL sealed tube. The resulting solution was stirred at room temperature for 16 h. The reaction was then terminated by adding 10 mL of water. The resulting solution was extracted with 2 x 20 mL EtOAc. The organic phase was washed with 20 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was loaded onto a silica gel column using EtOAc / PE (20:80). This yielded 380 mg (78%) of a grayish-white solid, 3-fluoro-1-[(2-nitrophenyl)methyl]azacyclobutane.

[0753]

[0754] Step 2: Add 3-fluoro-1-[(2-nitrophenyl)methyl]azacyclobutane (380.0 mg, 1.81 mmol, 1.00 eq), MeOH (8.0 mL), H₂O (1.0 mL), NH₄Cl (773.6 mg, 14.46 mmol, 8.00 eq), and Zn (591.2 mg, 9.04 mmol, 5.00 eq) to a 40 mL vial. Stir the resulting solution at room temperature for 2 hours and dilute with 30 mL of DCM. Filter off the solid. Dry the filtrate with anhydrous sodium sulfate and concentrate under vacuum. This yields 310 mg (95%) of a grayish-white solid, 2-[(3-fluoroazacyclobutane-1-yl)methyl]aniline. LC-MS (ES, m / z): [M+H] + =181.

[0755]

[0756] Step 3: Add methyl (2E)-3-[1-(oxacyclohexan-2-yl)indazol-6-yl]prop-2-enoate (Example 5, Step 1, 70.0 mg, 0.244 mmol, 1.00 eq), THF (2.0 mL), and 2-[(3-fluorozazecyclobutan-1-yl)methyl]aniline (52.9 mg, 0.29 mmol, 1.20 eq) to an 8-mL sealed tube. Then add LiHMDS (1.2 mL, 1.22 mmol, 5.00 eq) at 0°C. Stir the resulting solution at room temperature for 1 hour. Then terminate the reaction by adding 5 mL of saturated NH4Cl. Extract the resulting solution with 2 x 10 mL EtOAc. Dry the organic phase with sodium sulfate and concentrate. This yielded 55 mg (crude product) of a grayish-white solid (2E)-N-[2-[(3-fluorozacricyclobutan-1-yl)methyl]phenyl]-3-[1-(oxacyclohexan-2-yl)indazole-6-yl]prop-2-enamide.

[0757] LC-MS(ES,m / z):[M+H] + =435.

[0758]

[0759] Step 4: Add (2E)-N-[2-[(3-fluorozacricyclobutan-1-yl)methyl]phenyl]-3-[1-(oxacyclohexane-2-yl)indazole-6-yl]prop-2-enamide (55.0 mg, crude), DCM (2.0 mL), and TFA (2.0 mL) to an 8-mL sealed tube. Stir the resulting solution at room temperature for 2 hours. Concentrate the mixture at low temperature. Purify the crude product by rapid preparative HPLC. This yields 18 mg of a grayish-white solid (E)-N-(2-((3-fluorozacricyclobutan-1-yl)methyl)phenyl)-3-(1H-indazole-6-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =351.

[0760] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.26(s,1H),10.22(s,1H),8.11(s,1H),8.00(d,J=8.7Hz,,1H),7.84-7.71(m,3H),7.52-7.49(m,1H) ,7.32-7.27(m,2H),7.12-7.07(m,1H),6.95(d,J=15.6Hz,1H),5.36-5.17(m,1H),3.77(s,2H),3.69-3.58(m,2H),3.27-3.16(m,2H).

[0761] Example 32: (E)-N-(2-(2-(3-fluorozacricyclobutan-1-yl)ethyl)phenyl)-3-(1H-indazol-6-yl)acrylamide

[0762]

[0763] Step 1: 2-Nitrobenzaldehyde (0.90 g, 5.95 mmol, 1.00 eq), bromo(methyl)triphenyl-λ5-phosphine (3.20 g, 8.93 mmol, 1.50 eq), and THF (30.0 mL) were added to a 50-mL round-bottom flask. Then, t-BuOK (1.0 g, 8.93 mmol, 1.50 eq) was added at 0 °C. The resulting solution was stirred at room temperature for 16 h. The reaction was then terminated by adding 30 mL of 2M HCl. The resulting solution was extracted with 50 mL of EtOAc. The organic phase was washed with 20 mL of brine. The resulting solution was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate / petroleum ether (5:95). This yielded 270 mg (30%) of a pale yellow solid, 1-vinyl-2-nitrobenzene.

[0764]

[0765] Step 2: Add 1-vinyl-2-nitrobenzene (270.0 mg, 1.81 mmol, 1.00 eq), MeOH (4.0 mL), Et3N (0.5 mL, 3.62 mmol, 2.00 eq), and 3-fluoroazacyclobutane (149.5 mg, 1.99 mmol, 1.10 eq) to an 8-mL sealed tube. Stir the resulting solution at room temperature for 20 h. Concentrate the resulting mixture at low temperature. Load the residue onto a silica gel column using EtOAc / PE (20:80). This yields 190 mg (46%) of pale yellow solid 3-fluoro-1-[2-(2-nitrophenyl)ethyl]azacyclobutane.

[0766]

[0767] Step 3: Add 3-fluoro-1-[2-(2-nitrophenyl)ethyl]azacyclobutane (190.0 mg, 0.85 mmol, 1.00 eq), MeOH (6.0 mL), H₂O (1.0 mL), NH₄Cl (362.6 mg, 6.77 mmol, 8.00 eq), and Zn (277.1 mg, 4.24 mmol, 5.00 eq) to a 40 mL sealed tube. Stir the resulting solution at room temperature for 2 hours. Dilute the resulting solution with 20 mL of LCM. Filter off the solid. Dry the filtrate with anhydrous sodium sulfate and concentrate. This yields 150 mg (91%) of a grayish-white solid, 2-[2-(3-fluoroazacyclobutane-1-yl)ethyl]aniline.

[0768] LC-MS(ES,m / z):[M+H] + =195.

[0769]

[0770] Step 4: Add (E)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)methyl acrylate (60.0 mg, 0.21 mmol, 1.00 eq), 2-[2-(3-fluorozacricyclobutan-1-yl)ethyl]aniline (40.7 mg, 0.21 mmol, 1.00 eq), and THF (2.0 mL) to an 8-mL sealed tube. Then add LiHMDS (0.84 mL, 0.84 mmol, 4.00 eq) at 0 °C. Stir the resulting solution at room temperature for 0.5 hours. Then terminate the reaction by adding 5 mL of saturated NH4Cl. Extract the resulting solution with 2 x 10 mL EtOAc. Dry the organic phase with Na2SO4 and concentrate. Thus, 51 mg (crude product) of solid N-[2-[2-(3-fluorozacricyclobutan-1-yl)ethyl]phenyl]-3-[1-(oxacyclohexan-2-yl)indazole-6-yl]prop-2-enamide was obtained.

[0771] LC-MS(ES,m / z):[M+H] + =449.

[0772]

[0773] Step 5: Add N-[2-[2-(3-fluorozacricyclobutan-1-yl)ethyl]phenyl]-3-[1-(oxacyclohexane-2-yl)indazole-6-yl]prop-2-enamide (51.00 mg, crude), DCM (1.00 mL), and TFA (1.00 mL) to an 8-mL sealed tube. Stir the resulting solution at room temperature for 2 hours. Concentrate the mixture at low temperature. Purify the crude product by rapid preparative HPLC. This yields 18 mg of a white solid (E)-N-(2-(2-(3-fluorozacricyclobutan-1-yl)ethyl)phenyl)-3-(1H-indazole-6-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =365.

[0774] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.25(brs,1H),10.02(s,1H),8.11(s,1H),7.83-7.72(m,3H),7.63-7.60(m,1H),7.46-7.4 3(m,1H),7.26-7.12(m,3H),7.01(d,J=15.9Hz,1H),5.25-5.06(m,1H),3.61-3.50(m,2H),3.21-3.09(m,2H),2.65(s,4H).

[0775] Example 33: (E)-N-(2-fluoro-6-methylphenyl)-3-(1H-indazol-6-yl)acrylamide

[0776]

[0777] Step 1: 2-fluoro-6-methylaniline (160.0 mg, 1.28 mmol, 1.00 equiv), DCM (6.0 mL), and Et3N (0.45 mL, 3.20 mmol, 2.50 equiv) were added dropwise to a 25 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Acryloyl chloride (138.86 mg, 1.54 mmol, 1.20 equiv) was then added dropwise at 0 °C with stirring. The resulting solution was stirred at 0 °C for 2 h. The reaction was then terminated by adding 10 mL of water. The resulting solution was extracted with 2 x 10 mL dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column using EtOAc / PE (1 / 6). This yielded 120 mg (52%) of pale yellow solid N-(2-fluoro-6-methylphenyl)prop-2-enamide.

[0778] LC-MS-PH-NRG0405-1(ES,m / z):[

[0779]

[0780] Step 2: Add N-(2-fluoro-6-methylphenyl)prop-2-enamide (120.0 mg, 0.67 mmol, 1.00 equiv), DMF (5.0 mL), 6-bromo-1H-indazole (145.1 mg, 0.74 mmol, 1.10 equiv), Et3N (0.28 mL, 2.01 mmol, 3.00 equiv), and Pd(dppf)Cl2.CH2Cl2 (27.28 mg, 0.034 mmol, 0.05 equiv) to an 8-mL vial purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution at 120 °C for 12 h. Cool the reaction mixture to room temperature. Purify the crude mixture by preparative HPLC.

[0781] This yielded 30 mg (15%) of a grayish-white solid (E)-N-(2-fluoro-6-methylphenyl)-3-(1H-indazol-6-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =296.

[0782] 1 H NMR(300MHz,DMSO-d6,ppm):9.70(s,1H),8.11(s,1H),7.84-7.70(m,3H),7.43(d,J=8 .1Hz,1H),7.27-7.20(m,1H),7.14-7.08(m,2H),6.97(d,J=15.9Hz,1H),2.24(s,3H).

[0783] Example 34: (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-pyrazolo[4,3-b]pyridin-6-yl)acrylamide

[0784]

[0785] A 1.5 mL solution of DMF containing N-(3-fluoro-2-methylphenyl)acrylamide (intermediate 1, 100.00 mg, 0.558 mmol, 1.00 equiv), 6-bromo-1H-pyrazolo[4,3b]pyridine (110 mg, 0.558 mmol, 1.00 equiv), Pd(OAc)₂ (19 mg, 0.084 mmol, 0.15 equiv), tris(2-methylphenyl)phosphine (34 mg, 0.112 mmol, 0.20 equiv), and tetrabutylammonium chloride (155 mg, 0.558 mmol, 1.00 equiv) was added to a microwave-safe vial. The resulting solution was stirred at 115 °C for 12 h. The resulting mixture was diluted with 20 mL of EtOAc, washed with 2 x 10 mL of 1 M K₂CO₃ aqueous solution, and the organic layer was concentrated, dried over anhydrous sodium sulfate, and concentrated again. The residue was loaded onto a silica gel column. The crude product was purified by rapid preparative HPLC. This yielded 23 mg (14%) of a white solid (E)-N-(3-fluoro-2-methylphenyl)-3-(1H-pyrazolo[4,3-b]pyridin-6-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =297.

[0786] 1 H NMR (400MHz, DMSO-d6, ppm): δ13.55(s,1H),9.71(s,1H),8.84(d,J=1.8Hz,1H),8.34(d,J=1.0Hz,1H),8.25(d,J =1.7Hz,1H)7.82(d,J=15.9Hz,1H),7.49(d,J=8.1Hz,1H),7.30-7.16(m,2H),7.03(t,J=9.1Hz,1H),2.18(s,3H).

[0787] Example 35: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[4,3-c]pyridin-6-yl)acrylamide

[0788]

[0789] A solution of 6-bromo-1H-pyrazolo[4,3-c]pyridine (Example 9, Step 1, 200.0 mg, 1.01 mmol, 1.00 equivalent), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (189.1 mg, 1.01 mmol, 1.00 equivalent), Pd(dppf)Cl2 (73.9 mg, 0.10 mmol, 0.10 equivalent), and Et3N (0.42 mL, 3.03 mmol, 3.00 equivalent) in DMF (5.00 mL) was added to an 8-mL vial. The resulting solution was stirred in an oil bath at 120 °C for 15 h. The reaction mixture was cooled. The crude mixture was purified by rapid preparative HPLC. This yielded 15 mg (5%) of a white solid (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[4,3-c]pyridin-6-yl)acrylamide. LC MS (ES, m / z): [M+H] + =305.

[0790] 1 H NMR (300MHz, DMSO-d6, ppm): δ9.05(s,1H),8.58(d,J=8.1Hz,1H),8.26(s,1H),7.71(s,1H),7.64(d,J=15 .0Hz,1H),7.33-7.16(m,5H),5.49-5.40(m,1H),3.02-2.81(m,2H),2.46-2.40(m,1H),1.90-1.81(m,1H).

[0791] Example 36: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide

[0792]

[0793] To an 8-mL round-bottom flask, add 6-bromo-1H-pyrazolo[3,4-b]pyridine (Example 9, Step 1, 200.0 mg, 1.01 mmol, 1.00 equivalent), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (189.1 mg, 1.01 mmol, 1.00 equivalent), Pd(dppf)Cl2CH2Cl2 (82.5 mg, 0.10 mmol, 0.10 equivalent), Et3N (0.42 mL, 3.03 mmol, 3.00 equivalent), and DMF (4.00 mL). Stir the resulting solution in an oil bath at 120 °C for 15 h. Cool the reaction mixture. Purify the crude mixture by rapid preparative HPLC. This yielded 15 mg (5%) of solid (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-pyrazolo[3,4-b]pyridin-6-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =305.

[0794] 1 H NMR (300MHz, DMSO-d6, ppm): δ8.75(d,J=8.4Hz,1H),8.27(d,J=8.1Hz,1H),8.16(s,1H),7.63(d,J=15.3Hz,1H),7. 45(d,J=8.4Hz,1H),7.39-6.99(m,6H),5.50-5.40(m,1H),3.07-2.77(m,2H),2.48-2.37(m,1H),1.94-1.74(m,1H).

[0795] Example 37: (E)-3-(1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide

[0796]

[0797] Step 1: Add (1S,2S)-1-amino-2,3-dihydro-1H-indene-2-ol (2.6 g, 17.43 mmol, 1.00 equivalent), DMF (50.0 mL), Et3N (4.9 mL, 34.85 mmol, 2.00 equivalent), and phthalic anhydride (3.9 g, 26.14 mmol, 1.50 equivalent) to a 250 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution overnight at room temperature. Then terminate the reaction by adding 200 mL of water. Adjust the pH of the solution to 5-6 with 2N HCl. Extract the resulting solution with 3 x 100 mL EtOAc. Wash the resulting mixture with 1 x 100 mL of brine. Dry the mixture with anhydrous sodium sulfate and concentrate. Load the residue onto a silica gel column using EtOAc-PE (1:5-1:3). Thus, 3.60 g (74%) of a grayish-white solid 2-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-indene-1-yl]isoindole-1,3-dione was obtained.

[0798]

[0799] Step 2: Add 2-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-indene-1-yl]isoindole-1,3-dione (2.0 g, 7.16 mmol, 1.00 equivalent), DMF (30.0 mL), BaO (13.2 g, 85.93 mmol, 12.00 equivalent), Ba(OH)₂ (7.4 g, 42.97 mmol, 6.00 equivalent), and CH₃I (6.1 g, 42.98 mmol, 6.00 equivalent) to a 100 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution overnight at room temperature. Filter off the solids. Concentrate the resulting mixture. Load the residue onto a silica gel column using THF:PE (1:6–1:4). This yielded 1.60 g (76%) of a grayish-white solid 2-[(1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-yl]isoindole-1,3-dione.

[0800]

[0801] Step 3: Add 2-[(1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-yl]isoindole-1,3-dione (1.60 g, 5.46 mmol, 1.00 equiv), EtOH (50.0 mL), and NH₂NH₂·H₂O (80%, 15 mL) to a 250 mL round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Heat the resulting solution under reflux overnight. Cool the reaction mixture to room temperature. Filter off the solids. Concentrate the resulting mixture. Dilute the resulting solution with 200 mL of EtOAc. Wash the resulting mixture with 2 x 100 H₂O and 100 mL of brine. Dry the organic layer with anhydrous sodium sulfate and concentrate. Load the residue onto a silica gel column using THF:PE (1:3–1:1). This yielded 250 mg (28%) of a grayish-white solid (1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-amine.

[0802]

[0803] Step 4: Add (1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-amine (250.0 mg, 1.53 mmol, 1.00 equiv), (2E)-3-(1H-indazole-6-yl)methyl acrylate (intermediate 3,458.8 mg, 1.69 mmol, 1.10 equiv), HATU (873.6 mg, 2.30 mmol, 1.50 equiv), DMF (10 mL), and DIPEA (593.88 mg, 4.60 mmol, 3.00 equiv) to a 40-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution at room temperature for 4 h. Then terminate the reaction by adding 100 mL of water. Extract the resulting solution with 3 x 60 mL EtOAc. Wash the organic layer with 1 x 50 mL brine, dry with anhydrous sodium sulfate, and concentrate. The residue was loaded onto a silica gel column using THF:PE (1:3-1:1). This yielded 200 mg (31%) of a grayish-white solid (2E)-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-yl]-3-[1-(oxacyclohexane-2-yl)indazole-6-yl]prop-2-enamide.

[0804]

[0805] Step 5: Add a solution of (2E)-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-yl]-3-[1-(oxacyclohexane-2-yl)indazole-6-yl]prop-2-enamide (200.0 mg, 0.48 mmol, 1.00 equiv), 4 M HCl, and EtOAc (10.00 mL) to a 50 mL round-bottom flask purified with nitrogen and maintained under a nitrogen inert atmosphere. Stir the resulting solution overnight at room temperature. Concentrate the mixture. Purify the crude product by preparative HPLC. This yields 27 mg (17%) of a grayish-white solid (E)-3-(1H-indazole-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =334.

[0806] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.21(brs,1H),8.58(d,J=8.7Hz,1H),8.09(s,1H),7.79(d,J=8.4Hz,1H),7.71-7.65(m,2H),7.37-7.34(m ,1H),7.27-7.18(m,4H),6.75(d,J=15.6Hz,1H),5.35-5.30(m,1H),4.07-4.01(m,1H),3.38(s,3H),3.35-3.27(m,1H),2.84-2.76(m,1H).

[0807] Example 38: (E)-3-(1H-indazol-6-yl)-N-(7-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide

[0808]

[0809] Step 1: Methyl 3-[1-(oxacyclohexan-2-yl)indazol-6-yl]prop-2-enoate (150.0 mg, 0.52 mmol, 1.00 eq), 7-methyl-2,3-dihydro-1H-indene-1-amine (154.3 mg, 1.05 mmol, 2.00 eq), and THF (3.00 mL) were added to an 8-mL sealed tube. Then, LiHMDS (2.1 mL, 2.09 mmol, 4.00 eq) was added at room temperature. The resulting solution was stirred at room temperature for 0.5 hours. The reaction was then terminated by adding 20 mL of saturated NH4Cl. The resulting solution was extracted with 2 x 15 mL EtOAc. The organic phase was dried over sodium sulfate and concentrated. This yielded 130 mg (crude product) of grayish-white solid N-(7-methyl-2,3-dihydro-1H-indene-1-yl)-3-[1-(oxacyclohexan-2-yl)indazole-6-yl]prop-2-enamide.

[0810]

[0811] Step 2: Add N-(7-methyl-2,3-dihydro-1H-indene-1-yl)-3-[1-(oxacyclohexan-2-yl)indazole-6-yl]prop-2-enamide (130.0 mg, crude product), MeOH (4.00 mL), and a 4M HCl solution in dioxane (4.00 mL) to a 20-mL round-bottom flask. Stir the resulting solution at room temperature for 5 hours. Concentrate the mixture. Purify the crude product by rapid preparative HPLC. This yields 21 mg of a grayish-white solid (E)-3-(1H-indazole-6-yl)-N-(7-methyl-2,3-dihydro-1H-indene-1-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =318.

[0812] 1 H NMR (300MHz, DMSO-d6, ppm): δ13.21 (s, 1H), 8.39 (d, J = 8.7Hz, 1H), 8.07 (s, 1H), 7.78-7.59 (m, 3H), 7.32-6.99 (m, 4H ), 6.70 (d, J = 15.6Hz, 1H), 5.52-5.45 (m, 1H), 3.09-2.78 (m, 2H), 2.49-2.34 (m, 1H), 2.22 (s, 3H), 1.92-1.85 (m, 1H).

[0813] Example 39: (E)-3-(1H-indazol-6-yl)-N-(3-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide

[0814]

[0815] Step 1: Add a solution of 3-methyl-2,3-dihydroindene-1-one (500.0 mg, 3.42 mmol, 1.00 equiv), NH2OH·HCl (237.7 mg, 3.42 mmol, 1.00 equiv), Et3N (1.4 mL, 10.26 mmol, 3.00 equiv) in MeOH (12.00 mL) to a 40 mL vial. Stir the resulting solution in an oil bath at 70 °C for 10 h. Cool and concentrate the reaction mixture. Load the residue onto a silica gel column using EtOAc / PE (1 / 1). This yields 400 mg (72%) of white solid N-[(1Z)-3-methyl-2,3-dihydroindene-1-ide]hydroxylamine.

[0816]

[0817] Step 2: To a 50-mL round-bottom flask, add a solution of N-[(1Z)-3-methyl-2,3-dihydroindene-1-yl]hydroxylamine (400.0 mg, 2.481 mmol, 1.00 equiv) in 2.0 mL of 4 M HCl / MeOH solution and 10.0 mL of MeOH, and add Pd / C (264 mg). Stir the resulting solution at 20 °C under H2 (30 Psi) for 10 h. Collect the solution by filtration. Concentrate the resulting mixture. This yields 350 mg (77%) of a white solid, 3-methyl-2,3-dihydro-1H-indene-1-amine hydrochloride.

[0818]

[0819] Step 3: Add a 2.0 mL solution of 3-methyl-2,3-dihydro-1H-indene-1-amine hydrochloride (100.0 mg, 0.54 mmol, 1.00 equiv), methyl 3-(1H-indazole-6-yl)acrylate (intermediate 3, 148.3 mg, 0.54 mmol, 1.00 equiv), HATU (310.5 mg, 0.82 mmol, 1.50 equiv), and Et3N (0.23 mL, 1.63 mmol, 3.00 equiv) in DMF to an 8 mL round-bottom flask. Stir the resulting solution at 20 °C for 2 h. Load the residue onto a silica gel column using THF / PE (1 / 1) solution. Thus, 110 mg (50%) of a white solid (2E)-N-(3-methyl-2,3-dihydro-1H-indene-1-yl)-3-[1-(oxacyclohexan-2-yl)indazole-6-yl]prop-2-enamide was obtained.

[0820]

[0821] Step 4: Add (2E)-N-(3-methyl-2,3-dihydro-1H-indene-1-yl)-3-[1-(oxacyclohexan-2-yl)indazole-6-yl]prop-2-enamide (100.00 mg, 0.25 mmol, 1.00 equiv), 4M HCl / MeOH (2.00 mL), and MeOH (2.00 mL) to an 8-mL vial. Stir the resulting solution at 20 °C for 2 h. Purify the mixture with HCl by rapid preparative HPLC. This yields 20 mg (25%) of solid (E)-3-(1H-indazole-6-yl)-N-(3-methyl-2,3-dihydro-1H-indene-1-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =318.

[0822] 1 H-NMR (300MHz, DMSO-d6, ppm) δ8.52-8.48(m,1H),8.08(s,1H),7.79(d,J=8.4Hz,1H),7.72-7.61(m,2H),7.35(d,J=8.4,1 H),7.34-7.20(m,4H),6.78(d,J=15.6Hz,1H),5.41-5.35(m,1H),3.12-3.00(m,1H),2.70-2.60(m,1H),1.50-1.33(m,4H).

[0823] Example 40: (E)-3-(1H-indazol-6-yl)-N-(2-((prop-2-yn-1-yloxy)methyl)phenyl)acrylamide

[0824]

[0825] Step 1: Add (2E)-N-[2-(hydroxymethyl)phenyl]-3-[1-(oxacyclohexane-2-yl)indazol-6-yl]prop-2-enamide (Example 27, 200.0 mg, 0.53 mmol, 1.00 equiv) and THF (5.00 mL) to a 25 mL 3-necked round-bottom flask purified with nitrogen and maintained under a nitrogen inert atmosphere. Then add NaH (19.1 mg, 0.80 mmol, 1.50 equiv) at 0 °C. Stir the resulting solution at 0 °C for 10 min. Add propargyl bromide (63.0 mg, 0.53 mmol, 1.00 equiv) to the solution at 0 °C. Heat the resulting solution to room temperature and stir for 2 h. Then terminate the reaction by adding 5 mL of water. Extract the resulting solution with 2 x 8 mL EtOAc and dry it with anhydrous sodium sulfate. Concentrate the resulting mixture. Purify the residue by preparative HPLC. This yielded 55 mg (25%) of a pale yellow solid (2E)-3-[1-(oxacyclohexane-2-yl)indazol-6-yl]-N-[2-[(prop-2-yn-1-yloxy)methyl]phenyl]prop-2-enamide.

[0826]

[0827] Step 2: Add (2E)-3-[1-(oxacyclohexan-2-yl)indazole-6-yl]-N-[2-[(prop-2-yn-1-yloxy)methyl]phenyl]prop-2-enamide (55.00 mg, 0.13 mmol, 1.00 equiv) and 4M HCl / dioxane (5.00 mL) to a 20-mL vial. Stir the resulting solution at room temperature for 3 hours. Adjust the pH of the solution to 8 using 2M Na₂CO₃. Extract the resulting solution with 2 x 10 mL EtOAc. Dry the organic layer with anhydrous sodium sulfate and concentrate. Purify the crude product by preparative HPLC. This yields 5.1 mg (12%) of a grayish-white solid (E)-3-(1H-indazole-6-yl)-N-(2-((prop-2-yn-1-yloxy)methyl)phenyl)acrylamide. LC-MS (ES, m / z): [M+H] + =332.

[0828] 1 H NMR(300MHz,DMSO-d6,ppm):13.28(brs,1H),9.54(brs,1H),8.11(s,1H),7.84-7.66(m,3H),7.46- 7.30(m,3H),7.21(s,1H),7.12-6.95(m,2H),4.60(s,2H),4.23(d,J=2.1Hz,2H),3.55-3.50(m,1H).

[0829] Biological Examples

[0830] Biological Example 1 - Isolated rat liver mitochondria, human platelet mitochondria, and isolated rat brain mitochondria mPTP activity was determined in the middle.

[0831] Rat liver mitochondrial assay

[0832] Pharmacological inhibition or regulation of mPTP can be performed in well-characterized "Ca" mitochondria isolated from the body. 2+ Measurements were taken during the "preservation" assay. In vitro, isolated mitochondria rapidly isolated exogenous calcium. 2+ Until Ca in the mitochondria 2+ The concentration reaches the threshold for mPTP activation. Once the pores are activated, mitochondrial integrity is disrupted and stored Ca2+ is released. 2+ Membrane impermeability Ca can be used. 2 + Real-time measurement of Ca by sensitive fluorescent dyes 2+ Distribution between the extramitochondrial and intramitochondrial regions. Depending on the formulation, inhibition or regulation of mPTP may delay pore opening or increase the Ca required to induce mPTP opening. 2+ concentration.

[0833] mPTP activity in mitochondria of freshly isolated female Sprague Dawley (250–300 g) rat livers was measured using the following method. The rats were subjected to cervical dislocation. Prior to dissection, the liver was perfused in situ with approximately 40 ml of cold Dulbecco's phosphate-buffered saline (DPBS) and transferred to 30 ml of separation buffer (250 mM sucrose, 10 mM KCl, 1 mM EGTA, 1 mM EDTA, 25 mM HEPES, adjusted to pH 7.5 with 1 M NaOH). Each liver lobe was then removed from the buffer and cut into approximately 5 mm pieces using forceps and a scalpel. The pieces were then transferred to 50 ml Potterton Dounce homogenizing tubes placed 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, adjusted to pH 7.5 with 1 M NaOH, and supplemented with 0.1% bovine serum albumin (BSA) and a complete protease inhibitor mixture (one inhibitor tablet per 50 ml buffer). Homogenization was performed using a polytetrafluoroethylene pestle at 1800 rpm. The homogenate was centrifuged at 800 g for 10 minutes at 4°C, and the supernatant was then centrifuged at 10,000 g for 10 minutes. The precipitate was determined using FLIPR assay buffer (75 mM mannitol, 25 mM sucrose, 5 mM potassium dihydrogen phosphate, 20 mM Tris base, 100 mM KCl, 0.1% BSA, adjusted to pH 7.5 with 1 M NaOH, and supplemented with 0.1% bovine serum albumin (BSA) and a complete protease inhibitor mixture (one inhibitor tablet per 50 ml buffer).). Wash once with HCl (adjust pH to 7.4), centrifuge again, and then resuspend in FLIPR assay buffer to a protein concentration of 8.8 mg / ml.

[0834] The test compound (10 mM DMSO stock solution) was serially diluted in DMSO in a semi-logarithmic manner to produce 10 test concentrations (final concentrations in the assay ranged from 30 μM to 1 nM). First, 5 μl of the DMSO sample was diluted to 247 μl of FLIPR assay buffer, and then 5 μl was transferred to duplicate wells of a 384-well polypropylene assay plate. The control wells contained 0.5% (v / v) DMSO and 5 μM cyclosporine A.

[0835] A mitochondrial / Fluo5N assay stock solution was prepared in 5.6 ml of FLIPR assay buffer (room temperature) supplemented with disodium succinate (10 mM), rotenone (1 μM), Fluo5N pentapotassium salt (2 μM), and 1 ml of mitochondrial suspension. This stock solution was then transferred (15 μl) to an assay plate containing the test compound and incubated at room temperature for 10 minutes. The assay plate was then transferred to a FLIPR Tetra reader (Molecular Devices). Dye fluorescence was measured every 3 seconds for 10 minutes. After 12 seconds, a large dose of CaCl2 (75 μM) was added from the source plate containing 675 μM CaCl2 in the FLIPR assay buffer. The IC50 value of the test compound was calculated using the fluorescence values ​​collected at the 10-minute time point, with % inhibition calculated using DMSO control and cyclosporine A values ​​representing 100% and 0%, respectively.

[0836] Human platelet mitochondrial assay

[0837] The mPTP-based assay was performed using mitochondrial membrane potential flow cytometry on stimulated human platelets. Platelet stimulation leads to Ca2+... 2+ It flows in rapidly across the platelet membrane. Ca 2+ The mitochondria then isolate the cells until the threshold for mPTP opening is reached, at which point the pores open and the mitochondrial membrane potential disappears. Using a standard mitochondrial membrane potential dye, such as iodinated 3,3'-dihexyloxycarbonylcyanine DIOC6(3), the changes in mitochondrial membrane potential due to mPTP opening can be quantified in active platelets, enabling pharmacological characterization of mPTP inhibitors.

[0838] Fresh human blood (20 ml) was collected from an informed consenting donor and diluted in 3.2% sodium citrate. Platelets were separated by centrifugation at 200 g for 20 minutes at room temperature, and the platelet-rich plasma layer was 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 precipitate was resuspended in 4 ml of HEPES assay buffer (137 mM NaCl, 2.7 mM KCl, 11.9 mM NaHO3, 0.42 mM NaH2PO4, 1 mM MgCl2, 5.5 mM glucose, 0.1% bovine serum albumin, 10 mM HEPES, adjusted to pH 7.4) and stored on ice.

[0839] The test compound was prepared from a 10 mM DMSO stock solution and serially diluted in assay buffer containing 0.4% DMSO, with 25 μl transferred to 96-well plates. Platelets were loaded with 200 nM mitochondrial membrane potential dye DiOC6(3) (iodo-3,3'-dihexyloxycarbonylcyanine; Invitrogen) for 30 min, and then 50 μl was plated into each well of the 96-well plate containing the diluted test compound and incubated for 15 min. Control wells contained only DMSO (0.1% final concentration) or 5 μM cyclosporine A. Platelets were then stimulated by adding assay buffer (25 μl) containing CaCl2, α-thrombin, and Convulxin to final concentrations of 2 mM, 0.017 U / ml, and 0.167 μg / ml, respectively, and incubated for 14 min. The reaction was terminated by adding 25 μl of a 15 mM EDTA solution in assay buffer. The mitochondrial membrane potential of platelet populations in each well was then quantified by flow cytometry using a Guava easyCyte5 Benchtop flow cytometer, 3000 times per well. The percentage of platelets with depolarized mitochondrial membrane potential in each well was calculated. The pIC50 of each compound was then calculated using a standard four-parameter curve fitting model (GraphPad Prism).

[0840] The reaction was terminated by adding 25 μl of 15 mM EDTA to the assay buffer. The mitochondrial membrane potential of the 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 in each well was calculated. The pIC50 for each compound was then calculated using a standard four-parameter curve fitting model (GraphPad Prism).

[0841] Rat brain mitochondrial assay

[0842] mPTP activity was measured in mitochondria of the brain freshly isolated from female Sprague Dawley (250–300 g) rats. Anesthetized rats were perfused in situ with approximately 40 ml of cold Dulbecco's phosphate-buffered saline (DPBS), and the brain was then dissected and transferred to 30 ml of separation buffer (225 mM mannitol, 75 mM sucrose, 1 mM EGTA, adjusted to pH 7.4 with 1 M NaOH). The brain was fragmented into pieces approximately 5 mm in size using forceps and a scalpel, and then transferred to 50 ml Potterton Dounce homogenizing tubes placed on ice, containing 10 ml of ice-cold separation buffer (with complete protease inhibitor added as described above; one tablet per 50 ml buffer). Homogenization was performed using a polytetrafluoroethylene pestle at 1800 rpm. The homogenate was centrifuged at 2000 g for 10 minutes at 4 °C, and the supernatant was then centrifuged at 12,000 g for 9 minutes. The precipitate was resuspended in the above separation buffer using a Dounce homogenizer, but 0.02% digitalis saponin was added. The mixture was centrifuged at 12,000g for 11 minutes and finally resuspended in 5 ml of a modified separation buffer (as described above, but with EGTA reduced to 0.1 mM).

[0843] As described above regarding the liver mitochondrial assay, the test compound was prepared in a 384-well polypropylene assay plate. A mitochondrial / Fluo5N assay stock 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, adjusted to pH 7.4) supplemented with 2 μM Fluo5N pentapotassium salt and 1 ml of mitochondrial suspension. This stock solution was then transferred (15 μl) to the assay plate containing the test compound and incubated at room temperature for 10 minutes. The assay plate was then transferred to a FLIPR Tetra reader (Molecular Devices). Dye fluorescence was measured every 3 seconds for a total of 10 minutes. After 12 seconds, a large dose of Ca2+ (75 μM) was added to the source plate containing 675 μM CaCl2 in FLIPR assay buffer. The IC50 value of the test compound was calculated using the fluorescence values ​​collected at the 10-minute time point, and the % inhibition calculated using the DMSO control and cyclosporine A values ​​were 100% and 0%, respectively.

[0844] General cytotoxicity was evaluated in HEK293 and SHSY5Y cells using standard cell survival methods (Cell Titre Glo; Promega), followed by incubation of the test compound for 24 to 96 hours.

[0845] Results: Table 2 below provides the mPTP pIC values ​​of some of the example compounds in a series of mPTP assays. 50 Values. Table 2 also provides the pIC values ​​for Comparative Example 1. 50 Value. The results show that the tested compounds of the present invention exhibit mPTP inhibition, with many example compounds showing a pIC value of 6.0 or greater. 50 Values. Examples 28 and 14c showed the highest activity in rat liver mitochondrial assays, and Example 14c showed the highest activity in rat brain mitochondrial assays. Table 2 also provides mPTP human platelet pIC values ​​for some of the example compounds and Comparative Example 1. 50 Values. Table 2 also provides pIC values ​​of some of the compounds from the examples and the mPTP rat brain mitochondria of Comparative Example 1. 50 These results indicate that the tested compounds are active against isolated rat liver mitochondria, isolated rat brain mitochondria, and human platelet mitochondria.

[0846] Biological Example 2 – Solubility of PBS and FaSSIF

[0847] Prepare a 10 mM DMSO stock solution of the test compound and transfer two 15 μl samples to 1.5 mL glass vials (BioTech Solutions). Add fasted simulated intestinal fluid (FaSSIF) or PBS (pH 7.4) to each vial to a final volume of 500 μl. Before sealing with a PTFE / SIL stopper (BioTech Solutions), place a PTFE-encapsulated stir bar (V&P Scientific) in each vial. Shake the vials at 1100 rpm for 2 hours at 25 °C. Then filter the sample through a MultiScreen Solvinert filter plate (Millipore) under vacuum. Dilute an aliquot (5 μl) of the filtrate with 5 μl of DMSO in 490 μl of 50% acetonitrile aqueous solution containing the internal standard. Analyze and quantify the filtrate relative to a known concentration of standard using LC-MS / MS. Calculate the solubility values ​​of the test compound and control compound as follows:

[0848] [Sample] = (Area Ratio) 样品 *INJ VOL STD*DF 样品 *[STD]) / (Area ratio STD*INJ VOL) 样品 ).

[0849] Results: Solubility values ​​for certain compounds of the present invention are provided in Table 2 below. Table 2 also shows the results for Comparative Example 1. The results indicate that the compounds of some examples have higher solubility in PBS and / or FaSSIF than those of Comparative Example 1. Some compounds of the present invention show high solubility values ​​in either PBS or FaSSIF, while some compounds of the present invention show high solubility values ​​in both PBS and FaSSIF. Therefore, it is expected that some compounds of the present invention will exhibit improved bioavailability and / or improved systemic exposure compared to Comparative Example 1, particularly when the compounds are administered orally.

[0850] Table 2: Summary of the results of biological examples 1 and 2

[0851]

[0852]

[0853] *The average value of multiple experiments (n≥2).

[0854] Biological Example 3 - Assay of Liver Microsomes and Intrinsic Clearance by Hepatocytes

[0855] Hepatocyte clearance assay

[0856] In vitro clearance studies were conducted in primary rat hepatocytes 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' E medium containing 30% Percoll, 1×GlutaMAX-1, 15 mM HEPES, 5% fetal bovine serum (FBS), 4 μg / mL insulin, and 1 μM dexamethasone), centrifuged at 100 g for 10 minutes, and then centrifuged at 0.5 × 10⁻⁶ cells / mL. 6Live cells / mL (the number of live cells was assessed using AO / PI staining) were resuspended in culture medium (Leibovitz's L-15 medium). Hepatocytes (198 μL) were transferred to the wells of a 96-well uncoated plate and incubated at 37°C for 10 min. A test compound solution was prepared from 10 mM DMSO stock solution and diluted to 100 μM in 50% (v / v) acetonitrile. A test compound sample (2 μL) was added to each well of the hepatocytes and incubated at 37°C. Samples (25 μL) were collected at t = 0, 15, 30, 60, and 120 min, 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. Aliquots (100 μL) of the supernatant were 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 the extracted ion chromatograms. The slope value k was determined by linear regression of the natural logarithm of the residual percentage of the parent drug relative to the incubation time curve. The in vitro half-life (in vitro t1 / 2) was determined by the slope value: in vitro t1 / 2 = 0.693 / k. The in vitro t1 / 2 (in minutes) was converted to the in vitro intrinsic clearance (in vitro CL) using the following equation (mean of repeated determinations). int At μL / min / 1×10 6 (Cellular count):

[0857] In vitro CL int =kV / N

[0858] V = Incubation volume (0.2 mL)

[0859] N = number of hepatocytes per well (0.1 × 10⁻⁶) 6 cell).

[0860] Microsomal clearance assay

[0861] The microsomal stability of the test compounds was evaluated using rat liver microsomes (BioIVT) with and without the cofactors nicotinamide adenine dinucleotide phosphate (NADPH) and uridine diphosphate-glucuronic acid (UDPGA). The reaction was carried out in a final volume of 250 μl of preheated (37°C) 100 mM phosphate buffer containing 5 mM MgCl2, 0.025 mg / ml propyl methylglutathione, and 0.5 mg / ml rat liver microsomes. If appropriate, 1 mM and 2 mM NADPH and UDPGA were added, respectively. The reaction was initiated by adding 1 μM (final concentration) of the test compound. Verapamil was used as a positive control. The solution was incubated in a 37°C water bath, and aliquots were collected at 0.5, 5, 15, 30, and 60 minutes. The reaction was terminated by adding 5 volumes of cold acetonitrile containing internal standards (200 nM caffeine and 100 nM tolbutamide). The samples were centrifuged at 3220 g for 40 minutes. Aliquots of the supernatant were diluted 1:1 in ultrapure H2O and then analyzed by LC-MS / MS. Peak areas were determined from the extracted ion chromatograms. The slope value k was determined by linear regression of the natural logarithm of the residual percentage of the parent drug relative to the incubation time curve. The in vitro half-life (in vitro t1 / 2) was determined by the slope value: in vitro t1 / 2 = 0.693 / k. The in vitro t1 / 2 (minutes) was converted to the in vitro intrinsic clearance (in vitro CL) using the following equation (mean of repeated determinations). int (in μL / min / mg protein):

[0862] In vitro Clint = (0.693 / t1 / 2) * (incubation volume (μl) / amount of protein (mg)).

[0863] Results: The intrinsic clearance values ​​of some of the example compounds are listed in Table 3. Table 3 also shows the intrinsic clearance value of Comparative Example 1. These results indicate that some of the example compounds are expected to have improved oral bioavailability and / or improved systemic exposure compared to Comparative Example 1, i.e., they exhibit lower intrinsic clearance (CL) in at least the human or rat species. int The intrinsic clearance (CL) values ​​of some of the compound examples were lower in both human and rat species than those of Comparative Example 1. int )value.

[0864] Table 3: Results of Biological Example 3

[0865]

[0866]

[0867] *The average of the two experiments.

[0868] Conclusion: The results of biological Examples 1 to 3 demonstrate that the tested compounds of the present invention are inhibitors of mPTP in a series of mPTP assays. Compared with Comparative Example 1, some of the tested compounds of the present invention also showed improved solubility and / or lower intrinsic clearance. Therefore, certain compounds of the present invention are expected to have improved pharmacokinetic characteristics, such as improved oral bioavailability and / or improved systemic exposure, compared with Comparative Example 1, and are expected to be useful medicines, particularly for the treatment or prevention of diseases and conditions in which inhibition of mPTP provides therapeutic or preventive effects.

[0869] Throughout the specification and the subsequent claims, unless the context otherwise requires, the word “comprising” and its variations such as “including” and “containing” shall be understood to imply inclusion of the said integer, step, group of integers or set of steps, but not to exclude any other integer, step, group of integers or set of steps.

[0870] An application to which this specification and claims form a part may serve as the basis for priority in any subsequent application. The claims of such subsequent applications may relate to any feature or combination of features described herein. They may take the form of product, composition, method, or use claims and may include, for example, but not limited to, the following claims.

[0871] All publications cited in this specification, including but not limited to patents and patent applications, are incorporated herein by reference as if each individual publication were specifically and individually indicated to be incorporated herein by reference.

[0872] References

[0873] Yu et al., TDP-43 Triggers Mitochondrial DNA Release via mPTP to ActivatecGAS / STING in ALS, Cell, Volume 183, Issue 3, 2020, p 636-649.e18.

[0874] Jang et al., Proximal tubule cyclophilin D mediates kidney fibrogenesis in obstructive nephropathy, 2021, American Journal of Physiology: Renalphysiology, doi:10.1152 / ajprenal.00171.2021. Published online prior to print, PMID:34396791.

[0875] Plyte et al., Cinnamic Anilides as New Mitochondrial Permeability Transition Pore Inhibitors Endowed with Ischemia-Reperfusion Injury Protective Effect in Vivo, J. Med Chem. 2014, 57, 5333-47

[0876] Chen et al., Probing Mitochondrial Permeability Transition Pore Activity in Nucleated Cells and Platelets by High-Throughput Screening Assays Suggests Involvement of Protein Phosphatase 2B in Mitochondrial Dynamics, Assay and Drug Development Technologies, 2018, 16, 445-45

Claims

1. Compound of formula (I): (I) in: R 1a is H or methyl; R 1b is H or fluoro; A is a group (Ab), (Ac), or (Ad): The group (Ab) is: (Ab); in: R4is H, C 1-4 alkyl or benzyl; R5is H or C 1-4 alkyl; each R6is independently C 1-4 alkyl or halo; n is 0, 1, 2, or 3; The group (Ac) is: (And); in: R7is C 1-4 alkyl, C 1-4 alkylene(OH) or C 1-4 alkyleneOC 1-4 alkyl; o is 1 or 2; The group (Ad) is: (Ad); in: X is a bond, O, or CH2; each R8is independently halo, C 1-4 alkyl, C 1-4 alkoxy, OC 1-4 haloalkyl, or OH; each R9is independently halo or C 1-4 alkyl; p is 0, 1, or 2; q is 0, 1, 2, 3, or 4; Where B is: ； in: R 10 is H, halo or C 1-4 alkyl; D, E and F are defined as follows: (i) D, E and F are C(R 10 ) or (ii) D is N and E and F are C(R 10 ) or (iii) E is N and D and F are C(R 10 ) or (iv) F is N and D and E are C(R 10 ). Or its pharmaceutically acceptable salt.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I): (I) in: R 1a is H or methyl; R 1b is H or fluoro; A is a group (Ab), (Ac), or (Ad): The group (Ab) is: (Ab); in: R4is H, C 1-4 alkyl or benzyl; R5is H or C 1-4 alkyl; each R6is independently C 1-4 alkyl or halo; n is 0, 1, 2, or 3; The group (Ac) is: (And); in: R7is C 1-4 alkyl, C 1-4 alkylene(OH) or C 1-4 alkyleneOC 1-4 alkyl; o is 1 or 2; The group (Ad) is: (Ad); in: X is a bond, O, or CH2; each R8is independently halo, C 1-4 alkyl, C 1-4 alkoxy or OH; each R9is independently halo or C 1-4 alkyl; p is 0, 1, or 2; q is 0, 1, 2, 3, or 4; Where B is: ； in: R 10 is H, halo or C 1-4 alkyl; and D, E and F are defined as follows: (i) D, E and F are C(R 10 ) or (ii) D is N and E and F are C(R 10 ) or (iii) E is N and D and F are C(R 10 ) or (iv) F is N and D and E are C(R 10 ); Or its pharmaceutically acceptable salt.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A is a group (Ab): (Ab).

4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein R4 is H, methyl or benzyl, R 5 is H and n is 0.

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein A is a group (Ac): (Ac).

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R7 is methyl, CH2OH or CH2OMe and o is 2.

7. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein A is a group (Ad): (Ad).

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein X is a bond or O, p is 1 and R8 is selected from methyl, OMe or fluorine.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein each R9 is independently fluorine and q is 1 or 2.

10. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein D, E and F are C(R 10 ) and each R 10 is, independently of the others, H, fluoro, chloro or methyl.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (Ia): (Ia), Where A is a group (AdI') or (AdII'); R 10a is H, fluorine, chlorine or methyl; The group (AdI') is: (AdI’); in: R 8d is H, methyl or OMe; R 9a is H or F; The group (AdII') is: (AdII’), in: X is O; and R 8a’ is methyl; provided that when A is a group (Ad') and R 10a is fluoro or chloro, the remaining two R 10a groups are independently H; Or its pharmaceutically acceptable salt.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; and racemic mixture of ； ； (E)-N-(7-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(4-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-lH-inden-l-yl)-3-(7-fluoro-lH-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-lH-inden-l-yl)-3-(5-fluoro-lH-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-lH-inden-l-yl)-3-(4-fluoro-lH-indazol-6-yl)acrylamide; (E)-3-(5-chloro-lH-indazol-6-yl)-N-(2,3-dihydro-lH-inden-l-yl)acrylamide; (E)-3-(4-chloro-lH-indazol-6-yl)-N-(2,3-dihydro-lH-inden-l-yl)acrylamide; , , and a mixture of stereoisomers of ； ； ； ； , , and a mixture of stereoisomers of ； ； ； ； (E)-N-(l-benzyl-lH-indazol-7-yl)-3-(lH-indazol-6-yl)acrylamide; (E)-3-(lH-indazol-6-yl)-N-(l-methyl-lH-indazol-7-yl)acrylamide; and a stereoisomeric mixture of ； ； (E)-N-(2,3-dihydro-lH-inden-l-yl)-3-(lH-pyrazolo[4,3-c]pyridin-6-yl)acrylamide; (E)-N-(2,3-dihydro-lH-inden-l-yl)-3-(lH-pyrazolo[3,4-b]pyridin-6-yl)acrylamide; (E)-3-(lH-indazol-6-yl)-N-((lS,2S)-2-methoxy-2,3-dihydro-lH-inden-l-yl)acrylamide; (E)-3-(lH-indazol-6-yl)-N-(7-methyl-2,3-dihydro-lH-inden-l-yl)acrylamide; and (E)-3-(lH-indazol-6-yl)-N-(3-methyl-2,3-dihydro-lH-inden-l-yl)acrylamide; or a pharmaceutically acceptable salt of any one thereof.

13. Use of a compound according to any one of claims 1, 2, 11 and 12, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with inhibition of mPTP activity, wherein the disease or disorder is a neurodegenerative disease selected from the group consisting of Parkinson's disease, Lewy body dementia, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease, spinocerebellar ataxia, progressive supranuclear palsy, hereditary spastic paraplegia and Friedreich's ataxia.

14. A pharmaceutical composition comprising a compound according to any one of claims 1, 2, 11 and 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

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