New compounds

Abstract

This 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+ efflux 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 more readily absorbed by mitochondria at lower 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] CYP2D6 is a key member of the cytochrome P450 enzyme system, a system of enzymes that metabolize drugs in the human body. It is involved in the hepatic metabolism of a large proportion of clinically used drugs. Inhibition of CYP2D6 can drive interactions between co-formulated drugs metabolized by the same enzyme, leading to increased plasma concentrations that may cause adverse reactions. CYP2D6 is primarily expressed in the liver, but also to a lesser extent in the central nervous system (CNS). In the CNS, it is involved in the synthesis of various neurotransmitters, such as dopamine. Therefore, inhibition of CYP2D6, particularly at the CNS level, may have adverse effects by impairing pathways such as dopamine production. In Parkinson's disease, characterized by the loss of dopaminergic neurons in the substantia nigra, further reductions in dopamine levels through CYP2D6 inhibition may be intolerable.

[0013] When administered orally, the oral bioavailability and systemic exposure of a drug depend to a large extent on the degree 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 / or systemic exposure.

[0014] 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. CA2884607A1 relates to acrylamide and maleimide compounds, which are claimed to be useful for the treatment of mitochondrial diseases.

[0015] More mPTP inhibitor compounds still need to be found, especially those that combine mPTP inhibition with low CYP2D6 inhibition. Such compounds may also exhibit other desired pharmacological properties, such as improved oral bioavailability and / or improved systemic exposure. Invention Overview

[0017] This invention relates to compounds of formula (I):

[0018]

[0019] in:

[0020] R1a It is H or methyl;

[0021] R 1b It is H or F;

[0022] A is a group (Aa), (Ab), (Ac), or (Ad):

[0023] The group (Aa) is:

[0024]

[0025] in:

[0026] 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 alkenyl 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;

[0027] R 2a Selected from H and C 1-4 alkyl;

[0028] 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;

[0029] R2c 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;

[0030] Each R3 is independently of the other: halo, methyl, ethyl, or n-propyl.

[0031] m is 0, 1, 2, 3 or 4;

[0032] The group (Ab) is:

[0033]

[0034] in:

[0035] 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;

[0036] R 4a Selected from H and C 1-4 alkyl;

[0037] 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;

[0038] 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;

[0039] R5 is H or C 1-4 alkyl;

[0040] Each R6 is independently C 1-4 Alkyl or halogenated;

[0041] n is 0, 1, 2, or 3;

[0042] The group (Ac) is:

[0043]

[0044] in:

[0045] R7 is C 1-4 Alkyl, C 1-4 alkylene (OH) or C 1-4 Alkylene OC 1-4 alkyl;

[0046] o is 1 or 2;

[0047] The group (Ad) is:

[0048]

[0049] in:

[0050] X is a bond, O, or CH2;

[0051] 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;

[0052] R 8a Selected from H and C 1-4 alkyl;

[0053] 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;

[0054] R 8c Selected from C 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C1-4 Halogenated alkyl groups, aryl groups, and 4-7 membered heterocyclic alkyl groups;

[0055] Each R9 is independently halogenated or C-substituted. 1-4 alkyl;

[0056] p is 0, 1, or 2;

[0057] q is 0, 1, 2, 3, or 4;

[0058] Where B is a group (Ba), (Bb), or (Bc):

[0059] The group (Ba) is:

[0060]

[0061] in:

[0062] Y is C(R) 11 (R) 12 ), N(R 13 ), O or S;

[0063] Each R 10 They are halogenated or C-type independently of each other. 1-4 alkyl;

[0064] r is 0, 1, 2, or 3;

[0065] R 11 Is it H or C? 1-4 alkyl;

[0066] R 12 Is it H or C? 1-4 Alkyl; or R 11 and R 12 Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl;

[0067] R 13 It is H, C 1-4 Alkyl or C 3-6 cycloalkyl;

[0068] The cycloalkyl group thereon is optionally composed of one, two, or three independently selected from C10. 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, halogenated, CN, OH, NR 13a R 13b SO2R 13c and NHSO2R 13c Substituents of the substituents;

[0069] R 13aSelected from H and C 1-4 alkyl;

[0070] R 13b 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;

[0071] R 13c 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;

[0072] The group (Bb) is:

[0073]

[0074] in:

[0075] Each R 14 They are halogenated or C-type independently of each other. 1-4 alkyl;

[0076] s is 0, 1, 2, or 3;

[0077] The group (Bc) is:

[0078]

[0079] in:

[0080] R 15 It is C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 1-4 Halogenated alkyl, halogenated or CN;

[0081] The cycloalkyl group thereon is optionally composed of one, two, or three independently selected from C10. 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, halogenated, CN, OH, NR 15a R 15b SO2R 15c and NHSO2R 15c Substituents of the substituents;

[0082] R 15a Selected from H and C 1-4 alkyl;

[0083] R15b 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;

[0084] R 15c 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;

[0085] R 16 Is it H, halogenated, or C? 1-4 Alkyl; and

[0086] D, E, and F are each independently C(R) 16 ); or one of D, E, and F is N and the remaining two of the D, E, and F groups are independently C(R) 16 );

[0087] Or its pharmaceutically acceptable salts and / or solvates.

[0088] Suitablely, the present invention provides a compound of formula (I):

[0089]

[0090] in:

[0091] R 1a It is H or methyl;

[0092] R 1b It is H or F;

[0093] A is a group (Aa), (Ab), (Ac), or (Ad):

[0094] The group (Aa) is:

[0095]

[0096] in:

[0097] 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) such as C 1- Alkylene (4-7 membered heterocyclic alkyl), C 1-4 Alkoxy, OC1-4 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 group, or C 1-4 Alkylene O(C) 3-6 (alkynyl); wherein the aryl, heterocyclic alkyl, and cycloalkyl groups may optionally be selected from up to three independently selected from C10. 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, halogenated and CN substituents;

[0098] Each R3 is independently of the other: halo, methyl, ethyl, or n-propyl.

[0099] m is 0, 1, 2, 3 or 4;

[0100] The group (Ab) is:

[0101]

[0102] in:

[0103] 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;

[0104] R5 is H or C 1-4 alkyl;

[0105] Each R6 is independently C 1-4 Alkyl or halogenated;

[0106] n is 0, 1, 2, or 3;

[0107] The group (Ac) is:

[0108]

[0109] in:

[0110] R7 is C 1-4 Alkyl, C 1-4 alkylene (OH) or C1-4 Alkylene OC 1-4 alkyl;

[0111] o is 1 or 2;

[0112] The group (Ad) is:

[0113]

[0114] in:

[0115] X is a bond, O, or CH2;

[0116] Each R8 is independently halogenated, C 1-4 Alkyl, C 1-4 alkoxy or OH;

[0117] Each R9 is independently halogenated or C-substituted. 1-4 alkyl;

[0118] p is 0, 1, or 2;

[0119] q is 0, 1, 2, 3, or 4;

[0120] Where B is a group (Ba), (Bb), or (Bc):

[0121] The group (Ba) is:

[0122]

[0123] in:

[0124] Y is C(R) 11 (R) 12 ), N(R 13 ), O or S;

[0125] Each R 10 They are halogenated or C-type independently of each other. 1-4 alkyl;

[0126] r is 0, 1, 2, or 3;

[0127] R 11 Is it H or C? 1-4 alkyl;

[0128] R 12 Is it H or C? 1-4 Alkyl; or R 11 and R 12 Together with the carbon atoms they are attached to, they form C 3-6 cycloalkyl;

[0129] R 13 It is H, C 1-4 Alkyl or C 3-6cycloalkyl;

[0130] The group (Bb) is:

[0131]

[0132] in:

[0133] Each R 14 They are halogenated or C-type independently of each other. 1-4 alkyl;

[0134] s is 0, 1, 2, or 3;

[0135] The group (Bc) is:

[0136]

[0137] in:

[0138] R 15 It is C 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Halogenated alkyl or CN;

[0139] R 16 Is it H, halogenated, or C? 1-4 Alkyl; and

[0140] D, E, and F are each independently C(R) 16 ); or one of D, E, and F is N and the remaining two of the D, E, and F groups are independently C(R) 16 );

[0141] Or its pharmaceutically acceptable salts and / or solvates.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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 pathology, such as TDP-43-associated neurodegeneration.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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

[0158] 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.

[0159] 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-).

[0160] Term C 1-4 Alkylene (OH) refers to C atoms that have been substituted with OH radicals. 1-4 Alkyl groups, such as CH2OH.

[0161] 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.

[0162] 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.

[0163] 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).

[0164] 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.

[0165] 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 O (4-7 membered heterocyclic alkyl) is a fully saturated hydrocarbon ring containing a specified number of carbon 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] In one implementation, A is a group (Aa):

[0173]

[0174] 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 1-4 Alkylene (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.

[0175] 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 .

[0176] 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.

[0177] 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, R2b 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.

[0178] 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 azirmonobutylene or an oxobutylene. In the seventh embodiment, R 2c It is a methyl group.

[0179] 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.

[0180] 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.

[0181] 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:

[0182]

[0183] Suitablely, when R2 is C 1-4When R2 is an alkylene group (4-7-membered heterocyclic alkyl group), such as CH2-azacyclic butyl or CH2CH2-azacyclic butyl, the azacyclic butyl group is 1-azacyclic butyl. 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:

[0184]

[0185] 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.

[0186] When one or more (e.g., one) 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)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 1-4When 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.

[0187] Suitably, the cycloalkyl group is formed by 1, 2, or 3 C atoms. 1-4 Alkyl substituents, such as one or two, for example, one C 1-4 Alkyl substituents, such as methyl, ethyl, and propyl, especially methyl-substituted. In one embodiment, the cycloalkyl group is unsubstituted.

[0188] Suitable, unless R2 is H, C 1-4 Alkyl or C 1-4 Alkylene OC 1-4 Alkyl, otherwise m is 0. More preferably, m is 0 unless R2 is H, methyl, or CH2OMe.

[0189] In one implementation, when present, each R3 is independently fluorine or methyl, particularly fluorine.

[0190] In one implementation, m is 1 or 2.

[0191] 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, m is 3, one R3 is in 3 bits, one R3 is in 4 bits and one R3 is in 6 bits. In one embodiment, m is 3, one R3 is in 3 bits, one R3 is in 5 bits and one R3 is in 6 bits.

[0192] Suitablely, when R2 is methyl, m is 1, and R3 is chlorine, R3 is not at position 5. Suitablely, when R2 is methyl, m is 1, and R3 is chlorine, R3 is at position 3, 4, or 6. Suitablely, when R2 is H, m is 1, and R3 is C. 1-4 In the case of an alkyl group, R3 is not at the 3- or 5-position. Suitably, this occurs when R2 is H, m is 1, and R3 is C. 1-4 In the case of alkyl groups, R3 is at the 4 or 6 position. Suitably, when m is 2, the two R3 groups are not at the 3 and 5 positions. Suitably, when m is 2, the two R3 groups are at the 4 and 6 positions.

[0193] The positions of the substituents mentioned are relative to their connection positions with the amide moiety, for example:

[0194]

[0195] Examples of suitable substituents include 3-fluoro-2-methyl; 3-fluoro-2-CH₂OCH₃; 3-chloro-2-methyl-; 4,5-difluoro-2-methyl; 5-chloro-2-isopropyl; 5-fluoro-2-methyl; 2-isopropyl-6-methyl; 2,6-dimethyl; 2-methyl; 2-isopropyl; 4-fluoro-3-methyl; 3-fluoro-4-methyl; 3,4-difluoro-2,6-dimethyl; 3,5-difluoro-2,6-dimethyl; and 3-fluoro-2,6-dimethyl. In one embodiment, each R3 is the same. In another embodiment, each R3 is different.

[0196] In one implementation, A is a group (Ab):

[0197]

[0198] 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 present in R4 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 present in R4 is replaced by one, two, or three substituents, for example, one or two substituents, for example, 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 4cSuitably, the aryl group present in R4 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 methyl, chlorine, and fluorine. In one embodiment, the aryl group is substituted with one, two, or three, for example, one or two, such as one methyl group. In one embodiment, the aryl group is substituted with one, two, or three, for example, one or two, such as one chlorine group. In one embodiment, the aryl group is substituted with one, two, or three, for example, one or two, such as one fluorine group. Suitably, the aryl group is unsubstituted.

[0199] 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.

[0200] 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.

[0201] In one implementation, R 4c It is C 1-4 Alkyl 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 4cIt 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 azirmonobutylene or an oxobutylene. In the seventh embodiment, R 4c It is a methyl group.

[0202] In one implementation, R 5 It's H.

[0203] In one embodiment, each R6, when present, is independently fluorine or methyl. Suitably, n can be 1, 2, or 3, for example, 1 or 2, for example, 1.

[0204] In one implementation, n is 0.

[0205] In one implementation, group A is group (Ac):

[0206]

[0207] In one embodiment, R7 is methyl, CH2OH, or CH2OMe.

[0208] In one implementation, o is 2. Suitably, when o is 2, B is not a group (Ba).

[0209] 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:

[0210]

[0211] In one implementation, A is a group (Ad):

[0212]

[0213] In one embodiment, X is a bond or O. Suitably, X is a bond. Alternatively, X is O. In a second embodiment, X is CH2.

[0214] In one embodiment, R8 is halogenated. In a second embodiment, R8 is C. 1-4 Alkyl group. In the third embodiment, R8 is C6. 1-4 Alkyl group. In the fourth embodiment, R8 is OH.

[0215] 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.

[0216] 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 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 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 present in R8 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 present in R8 are each independently substituted by one, two, or three substituents, such as one or two substituents, such as one substituent, each of which is independently selected from OH; NR 8a R 8b SO2R 8c ; and NHSO2R 8c .

[0217] 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 8a It is H or methyl.

[0218] In one implementation, R 8b It is H. In the second implementation scheme, R8b 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.

[0219] 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 azirmonobutylene or an oxobutylene. In the seventh embodiment, R 8c It is a methyl group.

[0220] Suitably, the cycloalkyl group (e.g., cyclopropyl) present in R8 is substituted with one, two, or three substituents, such as one or two substituents, or 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 cycloalkyl group is unsubstituted.

[0221] 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.

[0222] 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:

[0223]

[0224] 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:

[0225]

[0226] 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:

[0227]

[0228] 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.

[0229] In one implementation, p is 0 or 1.

[0230] Suitably, when X is O, p is 1 or 2. Suitably, when X is a bond and group B is (Ba), Y is C(R) 11 (R) 12 ), R 11 and R 12 Both are H, and p is 1 or 2. Suitablely, when X is CH2, B is not (Ba).

[0231] 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:

[0232]

[0233] In one implementation, each R9 is fluorine independently of the others when present.

[0234] 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:

[0235]

[0236] 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:

[0237]

[0238] When X is a bond, suitable examples of R9 substituents are 4-fluoro and 5-fluoro.

[0239] In one implementation, q is 1 or 2.

[0240] In one embodiment, group B is (Ba):

[0241]

[0242] When Y is C(R) 11 (R) 12 In one implementation, R 11 It is H. In the second implementation scheme, R 11 It is C 1-4 Alkyl groups, such as methyl groups.

[0243] When Y is C(R) 11 (R) 12 In one implementation, R 12 It is H. In the second implementation scheme, R 12 It is C 1-4 Alkyl groups, such as methyl groups.

[0244] In a preferred embodiment, when Y is C(R) 11 (R) 12 When R 11 It is H or methyl and R 12 It is H. In the second preferred embodiment, R 11 and R 12 Both are H. In the third implementation scheme, R 11 and R 12 Together with the carbon atoms to which they are attached, they form a cyclopropyl ring. Suitably, the cyclopropyl ring is surrounded by one, two, or three carbon atoms. 1-4 Alkyl substituents, such as one or two, for example, one C 1-4 Alkyl substituents, such as methyl substituents. In one embodiment, the cyclopropyl ring is unsubstituted.

[0245] Suitablely, when Y is C(R) 11 (R) 12 ), R 11 It is methyl and R 12 When it is H, A is not a group (Aa).

[0246] In one implementation, Y is N(R) 13 Suitablely, R 13 It is C 1-4 Alkyl groups, such as methyl, ethyl, propyl, or butyl, especially methyl. In the second embodiment, R 13 It is C 3-6 Cycloalkyl groups, such as cyclopropyl groups. Suitably, R 13 The C present in 3-6 The cycloalkyl group, such as the cyclopropyl group, is substituted by one, two, or three, for example, one or two, for example, one substituent, which are independently selected from C14. 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, halogenated, CN, OH, NR 13a R 13b SO2R 13c and NHSO2R 13c Appropriately, R 13 The C present in 3-6 The cycloalkyl ring, such as cyclopropyl, is substituted by one, two, or three, for example one or two, for example one, substituent, which are independently selected from C14. 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl groups, halogenated groups, and CN groups. Suitablely, R... 13 The C present in 3-6 The cycloalkyl group, such as the cyclopropyl group, is substituted by one, two, or three, for example, one or two, for example, one substituent, which is independently selected from OH, NR. 13a R 13b SO2R 13c and NHSO2R 13c Suitablely, the C 3-6 Cycloalkyl groups, such as cyclopropyl groups, are cyclic with 1, 2, or 3 carbon atoms. 1-4 Alkyl substituents, such as one or two, for example, one C 1-4 Alkyl substituents, such as methyl substituents. In one embodiment, C 3-6 Cycloalkyl groups, such as cyclopropyl groups, are unsubstituted.

[0247] In one implementation, R 13a It is H. In the second implementation scheme, R13a It is C 1-4 Alkyl groups, such as methyl, ethyl, or propyl, especially methyl. In the third embodiment, R 13a It is H or methyl.

[0248] In one implementation, R 13b It is H. In the second implementation scheme, R 13b It is C 1-4 Alkyl groups, such as methyl, ethyl, or propyl, especially methyl. In the third embodiment, R 13b It is C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, and cyclopentyl, especially cyclopropyl. In the fourth embodiment, R 13b It is C 1-4 Alkyl groups, such as OMe or OEt, especially OMe. In the fifth embodiment, R 13b It is C 1-4 Halogenated alkyl groups, such as CF3. In the sixth embodiment, R 13b It is an aryl group, such as a phenyl group. In the seventh embodiment, R 13b It is a 4-7 membered heterocyclic alkyl group, such as an azirmonobutylene or an oxobutylene. In the eighth embodiment, R 13b It is H or methyl.

[0249] In one implementation, R 13c It is C 1-4 Alkyl groups, such as methyl, ethyl, or propyl, especially methyl. In the second embodiment, R 13c It is C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, and cyclopentyl, especially cyclopropyl. In the third embodiment, R 13c It is C 1-4 Alkyl groups, such as OMe or OEt, especially OMe. In the fourth embodiment, R 13c It is C 1-4 Halogenated alkyl groups, such as CF3. In the fifth embodiment, R 13c It is an aryl group, such as a phenyl group. In the sixth embodiment, R 13c It is a 4-7 membered heterocyclic alkyl group, such as an azirmonobutylene or an oxobutylene. In the seventh embodiment, R 13c It is H or methyl.

[0250] In one implementation, Y is O or S.

[0251] In one implementation, when present, each R 10 They are fluorine, chlorine, or methyl, each independent of the other.

[0252] In one implementation, r is 0 or 1, especially 0.

[0253] When r is 1, 2, or 3, R 10 It can be 7 bits, 5 bits, and / or 4 bits. In one implementation, r is 1 and R 10 In 7 bits. In the second implementation, r is 1 and R 10 In 5 bits. In one implementation, r is 1 and R 10 In 4 digits. For example:

[0254]

[0255] Suitable R 10 Examples of substituents include 4-fluoro and 7-fluoro.

[0256] In one implementation, group B is (Bb):

[0257]

[0258] In one implementation, when present, each R 14 They are either fluorine or methyl, which are independent of each other.

[0259] In one implementation, s is 0 or 1, especially 0.

[0260] Suitablely, when s is 1, 2 or 3, R 14 It can be 7 bits, 5 bits, and / or 4 bits. In one implementation, s is 1 and R 14 In 5 positions. In the second implementation, s is 2, an R 14 In 7 bits and one R 14 In 4 digits, for example:

[0261]

[0262] Appropriately, R 14 Not in the 7th position. Appropriately, R 14 Not in the 4th position.

[0263] Suitable R 14 An example of a substituent is 5-fluoro.

[0264] In one implementation, group B is (Bc):

[0265]

[0266] R 15 It is C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 1-4Halogenated alkyl, halogenated, or CN; wherein the cycloalkyl group is optionally selected from C1, 2, or 3 independently. 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, halogenated, CN, OH, NR 15a R 15b SO2R 15c and NHSO2R 15c Substituents are substituted.

[0267] In one implementation, R 15 It is methyl, ethyl, cyclopropyl, CF3, or CN, such as methyl or CN, especially methyl. In the second embodiment, R 15 It is methyl, ethyl, cyclopropyl, CF3, CN, OMe, chlorine, or fluorine, such as methyl, CN, chlorine, or fluorine, especially chlorine or fluorine. In the third embodiment, R 15 It is OMe, chlorine, or fluorine. In the fourth embodiment, R 15 It is methyl, CN, chlorine or fluorine.

[0268] Appropriately, R 15 The C present in 3-6 The cycloalkyl ring, such as cyclopropyl, is substituted by one, two, or three, for example one or two, for example one, substituent, which are independently selected from C14. 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, halogenated, CN, OH, NR 15a R 15b SO2R 15c and NHSO2R 15c Appropriately, R 15 The C present in 3-6 The cycloalkyl ring, such as cyclopropyl, is substituted by one, two, or three, for example one or two, for example one, substituent, which are independently selected from C14. 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl groups, halogenated groups, and CN groups. Suitablely, R... 15 The C present in 3-6 The cycloalkyl group, such as the cyclopropyl group, is substituted by one, two, or three, for example, one or two, for example, one substituent, which is independently selected from OH, NR. 15a R 15b SO2R 15c and NHSO2R 15c Suitablely, the C 3-6Cycloalkyl groups, such as cyclopropyl groups, are cyclic with 1, 2, or 3 carbon atoms. 1-4 Alkyl substituents, such as one or two, for example, one C 1-4 Alkyl substituents, such as methyl substituents. In one embodiment, C 3-6 Cycloalkyl groups, such as cyclopropyl groups, are unsubstituted.

[0269] In one implementation, R 15a It is H. In the second implementation scheme, R 15a It is C 1-4 Alkyl groups, such as methyl, ethyl, or propyl, especially methyl. In the third embodiment, R 15a It is H or methyl.

[0270] In one implementation, R 15b It is H. In the second implementation scheme, R 15b It is C 1-4 Alkyl groups, such as methyl, ethyl, or propyl, especially methyl. In the third embodiment, R 15b It is C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, and cyclopentyl, especially cyclopropyl. In the fourth embodiment, R 15b It is C 1-4 Alkyl groups, such as OMe or OEt, especially OMe. In the fifth embodiment, R 15b It is C 1-4 Halogenated alkyl groups, such as CF3. In the sixth embodiment, R 15b It is an aryl group, such as a phenyl group. In the seventh embodiment, R 15b It is a 4-7 membered heterocyclic alkyl group, such as an azirmonobutylene or an oxobutylene. In the eighth embodiment, R 15b It is H or methyl.

[0271] In one implementation, R 15c It is C 1-4 Alkyl groups, such as methyl, ethyl, or propyl, especially methyl. In the second embodiment, R 15c It is C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, and cyclopentyl, especially cyclopropyl. In the third embodiment, R 15c It is C 1-4 Alkyl groups, such as OMe or OEt, especially OMe. In the fourth embodiment, R 15c It is C 1-4 Halogenated alkyl groups, such as CF3. In the fifth embodiment, R 15c It is an aryl group, such as a phenyl group. In the sixth embodiment, R 15cIt is a 4-7 membered heterocyclic alkyl group, such as an azirmonobutylene or an oxobutylene. In the seventh embodiment, R 15c It is a methyl group.

[0272] In one implementation, D, E, and F are C(R) 16 In the second implementation, D is N and E and F are C(R). 16 In the third implementation, E is N and D and F are C(R). 16 In the fourth embodiment, F is N and D and E are C(R). 16 ).

[0273] In one implementation, R 16 It is H. In the second implementation scheme, R 16 It is halogenated, for example, fluorine or chlorine, especially chlorine. In the third embodiment, R 16 It is C 1-4 Alkyl groups, such as methyl groups. Suitably, each R... 16 They are H, fluorine, chlorine or methyl, which are independent of each other.

[0274] In a preferred embodiment of the invention, the compound of the invention has formula (Ia'):

[0275]

[0276] in:

[0277] A is a group (Aa'), a group (Ab'), a group (Ad'), or a group (Ad”);

[0278] R 15d It is methyl, ethyl, cyclopropyl, CN, CF3, OMe, chlorine or fluorine;

[0279] The group (Aa') is:

[0280]

[0281] in:

[0282] R 2d It is H, methyl, or CH2OMe;

[0283] Each R 3a Each is independently H, fluorine, or methyl; and

[0284] The group (Ab') is:

[0285]

[0286] in:

[0287] R4d It is methyl;

[0288] The group (Ad') is:

[0289]

[0290] in:

[0291] R 8d It is H, methyl, OCH2-cyclopropyl, OCH2-oxetane, OCH2CH2F, OMe or OEt;

[0292] Each R 9a They are H or fluorine, which are independent of each other;

[0293] The group (Ad”) is:

[0294]

[0295] in:

[0296] R 8d It is methyl; and

[0297] Each R 9a They are H or fluorine, which are independent of each other;

[0298] Or its pharmaceutically acceptable salts and / or solvates.

[0299] In a preferred embodiment of the invention, the compound of the invention has formula (Ia):

[0300]

[0301] in:

[0302] A is a group (Aa'), a group (Ab'), or a group (Ad').

[0303] The group (Aa') is:

[0304]

[0305] in:

[0306] R 2d It is H, methyl, or CH2OMe;

[0307] Each R 3a Each is independently H, fluorine, or methyl; and

[0308] R 15d It is methyl or CN;

[0309] The group (Ab') is:

[0310]

[0311] in:

[0312] R 4d It is methyl;

[0313] The group (Ad') is:

[0314]

[0315] in:

[0316] R 8d It is H or methyl; and

[0317] Each R 9a They are H or fluorine, which are independent of each other;

[0318] Or its pharmaceutically acceptable salts and / or solvates.

[0319] In a preferred embodiment, A is a group (Aa) and B is a group (Ba). In a second preferred embodiment, A is a group (Aa) and B is a group (Bb). In a third preferred embodiment, A is a group (Ad) and B is a group (Bc).

[0320] In one embodiment, the compound of formula (I) is selected from:

[0321] (E)-3-(1H-benzo[d][1,2,3]triazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide;

[0322] (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]thiazo-5-yl)acrylamide;

[0323] (E)-3-(3,3-dimethyl-2-oxoindoline-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide;

[0324] (E)-N-(3-fluoro-2-methylphenyl)-3-(2'-oxospiro[cyclopropane-1,3'-indoline]-6'-yl)acrylamide;

[0325] (E)-N-(3-fluoro-2-methylphenyl)-3-(7-fluoro-2-oxoindoline-6-yl)acrylamide;

[0326] (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide;

[0327] (E)-N-(3-fluoro-2-methylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide;

[0328] (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-2-oxoindoline-6-yl)acrylamide;

[0329] (E)-N-(3-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide;

[0330] (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindoline-6-yl)acrylamide;

[0331] (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide;

[0332] (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(o-tolyl)acrylamide;

[0333] (E)-N-(2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide;

[0334] (E)-N-(2-isopropyl-6-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide;

[0335] (E)-N-(5-chloro-2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide;

[0336] (E)-N-(4,5-difluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide;

[0337] (E)-N-(5-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide;

[0338] (E)-N-(3-fluoro-2-methylphenyl)-3-(4-fluoro-2-oxoindoline-6-yl)acrylamide;

[0339] (E)-N-(2,6-dimethylphenyl)-3-(2-oxoindoline-6-yl)acrylamide;

[0340] (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(2-oxoindoline-6-yl)acrylamide;

[0341] (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindololin-6-yl)acrylamide;

[0342] (E)-3-(1-Ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide;

[0343] (E)-3-(1-Cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide;

[0344] (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide;

[0345] (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide;

[0346] (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide;

[0347] (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide;

[0348] (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-(trifluoromethyl)-1H-indazol-6-yl)acrylamide;

[0349] (E)-N-(2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide;

[0350] (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide;

[0351] (E)-N-(2,6-dimethylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide;

[0352] (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-ethyl-1H-indazol-6-yl)acrylamide;

[0353] (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide;

[0354] (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-3-methyl-1H-indazol-6-yl)acrylamide;

[0355] (E)-N-(3,5-difluoro-2,6-dimethylphenyl)-3-(2-oxoindoline-6-yl)acrylamide;

[0356] (E)-N-(3,4-difluoro-2,6-dimethylphenyl)-3-(2-oxoindololin-6-yl)acrylamide;

[0357] (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide;

[0358] (E)-3-(3-methyl-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide;

[0359] (E)-3-(3-methyl-1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide;

[0360] (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide;

[0361] (E)-N-(4-fluoro-3-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide;

[0362] (E)-N-(3-fluoro-4-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide;

[0363] Racemic-(E)-3-(3-methyl-1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide;

[0364] (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide;

[0365] (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide;

[0366] (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide;

[0367] (Z)-2-fluoro-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindoline-6-yl)acrylamide;

[0368] (E)-N-(3-chloro-2-methylphenyl)-N-methyl-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide;

[0369] (E)-N-(2-methylcyclopentyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide;

[0370] (E)-N-(3-fluoro-2-(methoxymethyl)phenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide;

[0371] (E)-3-(3-cyano-1H-indazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide;

[0372] (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methyl-som-4-yl)acrylamide;

[0373] (E)-N-(2-methyl-1,2,3,4-tetrahydronaphth-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide;

[0374] (E)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide;

[0375] (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide;

[0376] (E)-N-(chroman-4-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide;

[0377] (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(1,2,3,4-tetrahydronaphth-1-yl)acrylamide;

[0378] (E)-N-(2-methyl-1,2,3,4-tetrahydronaphth-1-yl)-3-(2-oxoindololin-6-yl)acrylamide;

[0379] (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindololin-6-yl)acrylamide;

[0380] (E)-N-(3,5-difluoro-2-methylphenyl)-3-(2-oxoindoline-6-yl)acrylamide;

[0381] (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide;

[0382] (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide;

[0383] (E)-N-(5-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; and

[0384] (E)-N-(2-methylcyclohexyl)-3-(2-oxoindoline-6-yl)acrylamide;

[0385] Or a pharmaceutically acceptable salt and / or solvate of any of them.

[0386] In one embodiment, the compound of formula (I) is selected from:

[0387] (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methyl-som-4-yl)acrylamide;

[0388] (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4S)-3-methyl-4-yl)acrylamide;

[0389] (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4R)-3-methyl-4-yl)acrylamide;

[0390] (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4R)-3-methyl-4-yl)acrylamide;

[0391] (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4S)-3-methyl-4-yl)acrylamide;

[0392] (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1S,2S)-2-(oxecyclobutane-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl)acrylamide;

[0393] (E)-N-((1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide;

[0394] (E)-N-((1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide;

[0395] (E)-N-((1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide;

[0396] (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide;

[0397] (E)-3-(3-methoxy-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-yl)acrylamide;

[0398] (E)-3-(3-chloro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-yl)acrylamide;

[0399] (E)-3-(3-fluoro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; and

[0400] (E)-3-(3-cyano-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide;

[0401] Or a pharmaceutically acceptable salt and / or solvate of any of them.

[0402] The definition of a compound of formula (I) includes all tautomers of the compound.

[0403] 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.

[0404] 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.

[0405] 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.

[0406] 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).

[0407] 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.

[0408] 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.

[0409] 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.

[0410] 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.

[0411] In one embodiment, the compounds of the present invention are provided in the form of natural isotopes.

[0412] 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.

[0413] 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.

[0414] 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.

[0415] 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.

[0416] General route

[0417] 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 R2, R3, R 13 A and B are as defined in compound (I) above.

[0418] Option 1

[0419]

[0420] Compound (I) can be prepared by reacting compound (II) 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).

[0421] Option 2

[0422]

[0423] 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).

[0424] Option 3

[0425]

[0426] 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).

[0427] Option 4

[0428]

[0429] Compound (II) is commercially available. Compound (II) can also be prepared by reacting compound (VII) with compound (VIII) in the presence of a base, such as N,N-diisopropylethylamine, in a suitable solvent, such as dichloromethane (DCM).

[0430] Option 5

[0431]

[0432] 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).

[0433] Option 6

[0434]

[0435] Compound (IV) can be obtained by reacting compound (VI) with a base, such as sodium hydroxide (NaOH), under hydrolytic conditions in a suitable solvent system, such as a mixture of methanol and water.

[0436] Option 7

[0437]

[0438] R 1a H and A are functional groups (Aa), and R2 is C. 1-4 Alkyl group, m is 3 and R3 is C 1-4 The alkyl or halogenated compound of formula (VII) can be prepared in two steps. First, the compound of formula (X) is reacted with a brominating agent such as N-bromosuccinimide (NBS) in a solvent such as acetonitrile to give the dibromo compound of formula (XI). The compound of formula (VII) is further reacted under palladium-catalyzed cross-coupling conditions with a palladium precatalyst such as [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (II) (Pd(dppf)Cl2.CH2Cl2) complexed with dichloromethane, an organoboron compound such as trimethylcyclotriboroxane, a base such as cesium carbonate (Cs2CO3), and a suitable solvent such as 1,4-dioxane to give the compound of formula (VII).

[0439] Option 8

[0440]

[0441] R1a H and A are functional groups (Aa), and R2 is C. 1-4 Alkyl group, m is 3 and R3 is C 1-4 The alkyl or halogenated compound of formula (VII) can be prepared in four steps. First, the compound of formula (XII) is reacted with a chlorinating agent such as N-chlorosuccinimide (NCS) in a solvent such as acetonitrile to obtain the compound of formula (XIII). The compound of formula (XIII) is further reacted with a brominating agent such as N-bromosuccinimide (NBS) in a solvent such as acetonitrile to obtain the trihalogenated compound of formula (XIV). The compound of formula (XIV) is further reacted under palladium-catalyzed cross-coupling conditions using 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 such as 1,4-dioxane to obtain the compound of formula (XV). Compound (XV) is reacted under reducing dehalogenation conditions using a hydrogen atmosphere, such as hydrogen at 30 atm, a palladium catalyst, such as palladium on carbon (Pd / C), an acid, such as hydrochloric acid, and a solvent, such as ethanol (EtOH), to give compound (VII).

[0442] Option 9

[0443]

[0444] 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 using 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 and 1,4-dioxane, to give compound (XVII). Compound (XVII) can be further reacted with a metal such as iron in the presence of an acid such as acetic acid to give compound (VII).

[0445] Option 10

[0446]

[0447] Where B is a group (Ba) and Y is N (R) 13Compound (III) with r = 0 can be prepared in three steps. First, compound (XVIII) is reacted with an amine in a suitable solvent, such as ethanol, to obtain compound (XIX). Then, compound (XIX) is reduced with a metal, such as zinc, and an inorganic salt, such as ammonium chloride (NH4Cl), in a suitable solvent, such as acetone, to obtain compound (XX). Finally, compound (XX) is reacted with a carbonylating agent, such as triphosgene, in a suitable solvent, such as dichloromethane (DCM), to obtain compound (III).

[0448] Option 11

[0449]

[0450] 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 1-4 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 give compound (XXIII). Compound (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 give compound (V).

[0451] Option 12

[0452]

[0453] 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 obtained by treating 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 obtain compound (XXV). Compound (XXV) can be deprotected, for example, with an aqueous solution of an acid, such as 2M HCl, in a suitable solvent, such as methanol, to obtain compound (V).

[0454] 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: […].

[0455]

[0456] Among them, A and R 1a and R 1b As defined with respect to compounds of formula (I);

[0457] Reaction with compounds of formula (III) or their salts:

[0458]

[0459] Where X is halogenated, such as bromine or iodine, and B is as defined with respect to compounds of formula (I).

[0460] 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: […].

[0461]

[0462] Where R 1b And B is as defined with respect to compound (I);

[0463] Reaction with compounds of formula (V) or their salts:

[0464]

[0465] Among them, A and R 1a As defined with respect to compound (I).

[0466] 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: […].

[0467]

[0468] Where R 1b And B is as defined with respect to compound (I);

[0469] Reaction with compounds of formula (V) or their salts:

[0470]

[0471] Among them, A and R 1a As defined with respect to compound (I).

[0472] Treatment

[0473] The compound of formula (I) of the present invention has the use as an mPTP inhibitor.

[0474] 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.

[0475] 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.

[0476] 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.

[0477] 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.

[0478] 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.

[0479] 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.

[0480] 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.

[0481] 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.

[0482] 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.

[0483] The term “treatment” as used in this article includes controlling, alleviating, reducing or regulating a disease state or its symptoms.

[0484] 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.

[0485] 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.

[0486] 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).

[0487] In another specific implementation, the disease or condition is a central nervous system disease, such as AIDS dementia syndrome, depression, schizophrenia, and epilepsy.

[0488] 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.

[0489] 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.

[0490] 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.

[0491] In another implementation, the disease or condition is an age-related disease, such as bone repair, age-related bone fragility in osteoporosis, and sarcopenia.

[0492] 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.

[0493] Compound (I) is expected to be used to treat or prevent mitochondrial diseases.

[0494] 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.

[0495] 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.

[0496] 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.

[0497] 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.

[0498] 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.

[0499] 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.

[0500] 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.

[0501] 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.

[0502] 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.

[0503] Suitablely, the mitochondrial disease is selected from Reye syndrome, Leber hereditary optic neuropathy and related conditions, as well as those disclosed, for example, in CA2884607A1 (Stealth Peptides International Inc).

[0504] 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.

[0505] 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.

[0506] 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.

[0507] 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.

[0508] 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.

[0509] 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.

[0510] 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.

[0511] 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.

[0512] 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.

[0513] 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.

[0514] 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.

[0515] 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.

[0516] 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.

[0517] 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.

[0518] 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.

[0519] 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.

[0520] 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.

[0521] 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.

[0522] 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.

[0523] 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.

[0524] Suitablely, the fibrosis-related diseases or conditions are selected from chronic kidney disease, idiopathic pulmonary fibrosis, non-alcoholic steatohepatitis, primary cholangitis, and systemic sclerosis.

[0525] Suitablely, the individual is a mammal, and in particular, the individual is a human.

[0526] Pharmaceutical Composition

[0527] 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.

[0528] 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.

[0529] 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). The pharmaceutical compositions of the present invention may be in the form of pharmaceutical formulations as described below.

[0530] 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.

[0531] 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.

[0532] 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.

[0533] 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.

[0534] 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.

[0535] 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.

[0536] 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.

[0537] 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.

[0538] 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.

[0539] 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.

[0540] 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.

[0541] 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.

[0542] 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.

[0543] 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.

[0544] 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).

[0545] 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.

[0546] 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.

[0547] 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.

[0548] 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).

[0549] Suitable unit-dose formulations are those containing the active ingredient at the effective dose or an appropriate portion thereof as described above.

[0550] 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.

[0551] Compounds of formula (I) are expected to possess one or more of the following advantageous properties:

[0552] -Inhibitory activity of mPTP as demonstrated in the assays of Biological Example 1 (preferably with a pIC value of 6.0 or higher). 50 (value); and

[0553] - Low inhibition of CYP2D6, as demonstrated in the assays of Biological Example 2.

[0554] In addition to the properties described above, some compounds of formula (I) may also exhibit one or more of the following advantageous properties:

[0555] - Improved solubility and / or improved intrinsic clearance (CL) as demonstrated in the assays of biological Examples 3 and 4. int This leads to, for example, improved oral bioavailability and / or improved systemic exposure.

[0556] The present invention is further illustrated by the following non-limiting embodiments. Example

[0557] 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.

[0558] General experimental details

[0559] 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.

[0560] 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). 1¹H 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.

[0561] Table 1: LC-MS Analysis Conditions

[0562]

[0563]

[0564] abbreviations

[0565] CH3CN Acetonitrile

[0566] Cs2CO3 (cesium carbonate)

[0567] DCM dichloromethane

[0568] DIPEA (Diisopropylethylamine)

[0569] DMF (dimethylformamide)

[0570] Et Ethyl

[0571] Et3N Triethylamine

[0572] EtOAc (ethyl acetate)

[0573] EtOH (ethanol)

[0574] HATU 1-[di(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0575] hepatocellular carcinoma (HPC)

[0576] HCl hydrochloric acid

[0577] K2CO3 (potassium carbonate)

[0578] K3PO4 Potassium phosphate

[0579] LiHMDS Lithium di(trimethylsilyl)ammonium oxide

[0580] Me methyl

[0581] MeOH (methanol)

[0582] NaHCO3 (Sodium bicarbonate)

[0583] NaOAc (sodium acetate)

[0584] NaOH (sodium hydroxide)

[0585] NBS N-bromosuccinimide

[0586] NCS N-chlorosuccinimide

[0587] NH4Cl ammonium chloride

[0588] PE petroleum ether

[0589] Pd(OAc)₂ Palladium(II) acetate

[0590] Pd(dppf)Cl2.CH2Cl2 [bis(diphenylphosphine)ferrocene]palladium(II) dichloride, complexed with dichloromethane

[0591] Pd(dppf)Cl2 [bis(diphenylphosphine)ferrocene]palladium(II) dichloride

[0592] RT room temperature

[0593] o / n Overnight (16h)

[0594] TFA (trifluoroacetic acid)

[0595] THF Tetrahydrofuran

[0596] THP Tetrahydropyranyl

[0597] T3P propane phosphoric anhydride

[0598] uL microliter

[0599] uM micromolar

[0600] Preparation of Comparative Example 1

[0601] Comparative Example 1: (E)-N-(2-methyl-3-fluorophenyl)-3-(1H-indazol-6-yl)acrylamide

[0602]

[0603] 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 a synthetic method similar to that described in Examples 1 to 64 of this document.

[0604] Preparation of Examples 1 to 74

[0605] Intermediate 1: N-(3-fluoro-2-methylphenyl)acrylamide

[0606]

[0607] Acrylyl chloride (0.71 mL, 8.8 mmol, 1.1 eq.) was added dropwise to a stirred solution of 3-fluoro-2-methylaniline (1.0 g, 8.0 mmol, 1.0 eq.) and DIPEA (3.1 g, 23.9 mmol, 3.0 eq.) in 40 mL of DCM at 0 °C under nitrogen. The resulting mixture was stirred at 25 °C under an inert nitrogen atmosphere for 3 h. 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. LC-MS (ES, m / z): [M+H] + =180.

[0608] Intermediate 2: N-(3-chloro-2-methylphenyl)acrylamide

[0609]

[0610] 3-Chloro-2-methylaniline (300 mg, 2.12 mmol, 1.0 eq.), DCM (15 mL), and Et3N (1 mL, 7.19 mmol, 3.0 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, 2.9 mmol, 1.2 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)acrylamide. LC-MS (ES, m / z): [M+H] + =196.

[0611] Example 1: (E)-3-(1H-benzo[d][1,2,3]triazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide

[0612]

[0613] DMF (1.5 mL) was added to N-(3-fluoro-2-methylphenyl)acrylamide (intermediate 1,100 mg, 0.56 mmol, 1.0 eq.), 5-bromo-3H-1,2,3-benzotriazole (110 mg, 0.56 mmol, 1.0 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, 1.0 equiv). 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. The solution was then dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column. The resulting crude product was purified by rapid preparative HPLC. This yielded 9 mg (5%) of a light gray solid, (E)-3-(1H-benzo[d][1,2,3]triazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide. LC-MS (ES, m / z): [M+H] + =297;

[0614] 1 H NMR (400MHz, DMSO-d6, ppm): δ9.65(s,1H),8.15(s,1H),7.96-7.92(m,1H),7.79(d,J=16.0 Hz,1H),7.71-7.66(m,1H),7.49(s,1H)7.27-7.20(m,1H),7.10-6.96(m,2H),2.18(s,3H).

[0615] Intermediate 3: (E)-3-(3-methyl-1H-indazole-6-yl)acrylic acid

[0616]

[0617] Step 1: Add 6-bromo-3-methyl-1H-indazole (2.50 g, 11.84 mmol, 1.00 equivalent), methyl acrylate (1.53 g, 17.76 mmol, 1.50 equivalent), Et3N (3.60 g, 35.53 mmol, 3.00 equivalent), Pd(dppf)Cl2 (0.87 g, 1.18 mmol, 0.10 equivalent), and DMF (100.00 mL) to a 250 mL 3-necked round-bottom flask. Stir the resulting solution at 120 °C for 10 h. Concentrate the mixture and load the residue onto a silica gel column using THF / PE (1 / 1). This yields 0.9 g (35% yield) of a pale yellow solid, (2E)-3-(3-methyl-1H-indazole-6-yl)prop-2-enoic acid methyl ester.

[0618]

[0619] Step 2: Add methyl (2E)-3-(3-methyl-1H-indazole-6-yl)prop-2-enoate (890.00 mg, 4.12 mmol, 1.00 equiv), NaOH (329.24 mg, 8.23 ​​mmol, 2.00 equiv), H₂O (10.00 mL), and MeOH (10.00 mL) to a 40 mL vial. Stir the resulting solution at 20 °C for 2 h. Adjust the pH of the solution to 3 with HCl (1 mol / L). Collect the solid by filtration. This yields 500 mg (60% yield) of off-white solid (E)-3-(3-methyl-1H-indazole-6-yl)acrylic acid.

[0620] Example 2: (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]thiazolyl-5-yl)acrylamide

[0621]

[0622] DMF (2.8 mL) was added to a microwave-safe vial containing N-(3-fluoro-2-methylphenyl)acrylamide (intermediate 1,180 mg, 1.0 mmol, 1.0 equiv), 5-bromo-3H-1,3-benzothiazol-2-one (231 mg, 1.0 mmol, 1.0 equiv), Pd(OAc)₂ (34 mg, 0.151 mmol, 0.15 equiv), tris(2-methylphenyl)phosphine (62 mg, 0.201 mmol, 0.20 equiv), and tetrabutylammonium chloride (279 mg, 1.0 mmol, 1.0 equiv). The resulting solution was stirred at 115 °C for 12 h. The resulting mixture was diluted with 30 mL of EtOAc, washed with 2 x 15 mL of 1 M K₂CO₃ aqueous solution, and then the organic layer was concentrated, dried over anhydrous sodium sulfate, and concentrated again. The residue was loaded onto a silica gel column. The resulting crude product was purified by rapid preparative HPLC. This yielded 6 mg (2%) of a white solid (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]thiazo-5-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =329.

[0623] 1 H NMR (400MHz, DMSO-d6, ppm): δ12.12(s,1H),9.66(s,1H),7.66-7.56(m,2H),7.48(d ,J=8.0Hz,1H),7.39-7.30(m,2H),7.29-7.21(m,1H)7.06-6.92(m,2H),2.17(s,3H).

[0624] Example 3: (E)-3-(3,3-dimethyl-2-oxoindoline-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide

[0625]

[0626] DMF (2.9 mL) was added to a microwave-safe vial containing N-(3-fluoro-2-methylphenyl)acrylamide (intermediate 1,185 mg, 1.03 mmol, 1.0 equiv), 6-bromo-3,3-dimethyl-1H-indol-2-one (240 mg, 1.03 mmol, 1.0 equiv), Pd(OAc)₂ (35 mg, 0.155 mmol, 0.15 equiv), tris(2-methylphenyl)phosphine (63 mg, 0.206 mmol, 0.20 equiv), and tetrabutylammonium chloride (286 mg, 1.03 mmol, 1.0 equiv). The resulting solution was stirred at 115 °C for 12 h. The resulting mixture was diluted with 30 mL of EtOAc, washed with 2 x 15 mL of 1 M K₂CO₃ aqueous solution, and then the organic layer was concentrated, dried over anhydrous sodium sulfate, and concentrated again. The residue was loaded onto a silica gel column. The resulting crude product was purified by rapid preparative HPLC. This yielded 76 mg (22%) of a white solid (E)-3-(3,3-dimethyl-2-oxoindoline-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide. LC-MS (ES, m / z): [M+H] + =339.

[0627] 1 H NMR (400MHz, DMSO-d6, ppm): δ10.54(s,1H),9.63(s,1H),7.75(d,J=15.7Hz,1H),7.48(d,J=8.1Hz,1H),7.37(d,J=7.6 Hz,1H)7.28-7.17(m,2H),7.09(d,J=1.5Hz,1H),7.05-6.97(m,1H),6.93(d,J=15.7Hz,1H),2.16(s,3H),1.27(s,6H).

[0628] Example 4: (E)-N-(3-fluoro-2-methylphenyl)-3-(2'-oxospiro[cyclopropane-1,3'-indoline]-6'-yl)acrylamide

[0629]

[0630] DMF (2 mL) was added to a microwave-safe vial containing N-(3-fluoro-2-methylphenyl)acrylamide (intermediate 1,130 mg, 0.725 mmol, 1.0 equiv), 6'-bromo-1'H-spiro[cyclopropane-1,3'-indole]-2'-one (172 mg, 0.725 mmol, 1.0 equiv), Pd(OAc)₂ (24 mg, 0.109 mmol, 0.15 equiv), tris(2-methylphenyl)phosphine (44 mg, 0.145 mmol, 0.20 equiv), and tetrabutylammonium chloride (278 mg, 0.725 mmol, 1.0 equiv). The resulting solution was stirred at 115 °C for 12 h. The resulting mixture was diluted with 30 mL of EtOAc, washed with 2 x 15 mL of 1 M K₂CO₃ aqueous solution, and then 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 10 mg (4%) of a white solid (E)-N-(3-fluoro-2-methylphenyl)-3-(2'-oxospiro[cyclopropane-1,3'-indoline]-6'-yl)acrylamide.

[0631] LC-MS(ES,m / z):[M+H] + =337.

[0632] 1 H NMR (400MHz, DMSO-d6, ppm): δ10.77(s,1H),9.62(s,1H),7.57(d,J=15.7Hz,1H),7.49(d,J=8.1Hz,1H),7.29-7.18(m,2H),7.16(s,1 H), 7.06 (d, J = 7.7Hz, 1H), 7.01 (t, J = 9.0Hz, 1H), 6.95 (d, J = 15.7Hz, 1H), 2.17 (d, J = 2.0Hz, 3H), 1.66-1.60 (m, 2H), 1.55-1.50 (m, 2H).

[0633] Example 5: (E)-N-(3-fluoro-2-methylphenyl)-3-(7-fluoro-2-oxoindoline-6-yl)acrylamide

[0634]

[0635] Prepared using intermediate 1 and 6-bromo-7-fluoro-1,3-dihydro-2H-indol-2-one according to the method described above. LC-MS (ES, m / z): 327 [MH] + .

[0636] 1H NMR (300MHz, DMSO-d6, ppm): δ10.59 (s, 1H), 9.72 (s, 1H), 7.64 (d, J = 15.9Hz, 1H), 7.45-7.19 (m, 3H), 7.04-6.98 (m, 3H), 3.56 (s, 2H), 2.16 (s, 3H).

[0637] Example 6: (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0638]

[0639] N-(3-fluoro-2-methylphenyl)acrylamide (intermediate 1, 50 mg, 0.28 mmol, 1.0 equiv), DMF (4 mL), 5-bromo-2-benzoxazolinone (66 mg, 0.31 mmol, 1.10 equiv), Et3N (0.12 mL, 0.84 mmol, 3.0 equiv), and Pd(dppf)Cl2.CH2Cl2 (11 mg, 0.014 mmol, 0.05 equiv) were added to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 120 °C for 12 h. The reaction was then terminated by adding 3 mL of water. The resulting solution was then distilled into 5 mL of water. DCM extraction was performed, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by rapid preparative HPLC. This yielded 21 mg (24%) of a white solid (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide. LC MS (ES, m / z): [M+H] + =313.

[0640] 1 H NMR (300MHz, DMSO-d6, ppm): δ11.89(brs,1H),9.59(s,1H),7.62(d,J=15.6Hz,1H),7.48 (d,J=8.1Hz,1H),7.44-7.31(m,3H),7.26-7.19(m,1H),7.07-6.95(m,2H),2.16(s,3H).

[0641] Example 7: (E)-N-(3-fluoro-2-methylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide

[0642]

[0643] N-(3-fluoro-2-methylphenyl)acrylamide (intermediate 1, 90 mg, 0.50 mmol, 1.0 equiv), DMF (5 mL), 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (137 mg, 0.60 mmol, 1.20 equiv), Et3N (0.21 mL, 1.51 mmol, 3.0 equiv), and Pd(dppf)Cl2.CH2Cl2 (20 mg, 0.025 mmol, 0.05 equiv) were added to an 8-mL vial purified with nitrogen and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 120 °C for 12 h and then cooled to 25 °C. The mixture was purified by preparative HPLC. This yielded 7 mg (4%) of a grayish-white solid (E)-N-(3-fluoro-2-methylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide. LC MS (ES, m / z): [M+H] + =326.

[0644] 1 H NMR (300MHz, DMSO-d6, ppm): δ11.03(s,1H),9.51(s,1H),7.60(d,J=15.6Hz,1H),7.49(d,J=8.1Hz,1H) ,7.33(dd,J=8.1,1.5Hz,1H),7.29-7.16(m,3H),7.0-6.98(m,1H),6.88(d,J=15.6Hz,1H),2.16(s,3H).

[0645] Example 8: (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-2-oxoindoline-6-yl)acrylamide

[0646]

[0647] Step 1: Add 3.5 g (15.48 mmol, 1.0 eq) of 6-bromo-1H-indole-2,3-dione and 70 mL of THF to a 100 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Add 5.2 mL (15.48 mmol, 1.0 eq) of 3M methyl magnesium bromide dropwise over 0.5 h at -78 °C. Continue the reaction at -78 °C for 5 h with stirring, then raise the temperature to 25 °C. The reaction is then terminated by adding 10 mL of 0.2 M HCl. Extract the resulting solution with 2 x 50 mL EtOAc, dry the organic liquid with anhydrous sodium sulfate, and concentrate. Load the residue onto a silica gel column using EtOAc / PE (35 / 65). This yields 3 g (80%) of a grayish-white solid, 6-bromo-3-hydroxy-3-methyl-1H-indole-2-one. LC-MS(ES,m / z):[MH] + =240.

[0648]

[0649] Step 2: 6-Bromo-3-hydroxy-3-methyl-1H-indol-2-one (2.0 g, 8.26 mmol, 1.0 eq) and THF (30 mL) were added to a 100 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Then, diethylaminosulfur trifluoride (DAST) (2.0 g, 12.39 mmol, 1.50 eq) was added at -78 °C. The resulting solution was stirred at -78 °C for 1 h, then heated to 25 °C. The reaction was then terminated by adding 10 mL of saturated NaHCO3. The resulting solution was extracted with 2 x 50 mL EtOAc, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column using EtOAc / PE (25 / 75). This yielded 1.65 g (82%) of a white solid, 6-bromo-3-fluoro-3-methyl-1H-indol-2-one. LC-MS(ES,m / z):[MH] + =242.

[0650]

[0651] Step 3: Add 6-bromo-3-fluoro-3-methyl-1H-indol-2-one (200 mg, 0.82 mmol, 1.0 eq), N-(3-fluoro-2-methylphenyl)acrylamide (intermediate 1,147 mg, 0.82 mmol, 1.0 eq), Pd(dppf)Cl2.CH2Cl2 (13 mg, 0.02 mmol, 0.02 eq), DMF (4 mL), and Et3N (0.23 mL, 1.64 mmol, 2.0 eq) to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution at 110 °C for 2 h. Filter out the solid. Concentrate the filtrate. Purify the crude product by rapid preparative HPLC. Thus, 13 mg (4.5%) (E)-N-(3-fluoro-2-methylphenyl)-3-(3-fluoro-3-methyl-2-oxoindoline-6-yl)acrylamide and 12 mg (4%) (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-2-oxoindoline-6-yl)acrylamide were obtained.

[0652] (E)-N-(3-fluoro-2-methylphenyl)-3-(3-fluoro-3-methyl-2-oxoindoline-6-yl)acrylamide LC-MS (ES, m / z): [M+H + =343.

[0653] 1 H NMR (300MHz, DMSO-d6, ppm): δ10.87(s,1H),9.68(s,1H),7.60-7.46(m,3H),7.34- 7.19(m,2H),7.12(s,1H),7.04-6.97(m,2H),2.16(s,3H),1.70(d,J=22.5Hz,3H).

[0654] (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-2-oxoindoline-6-yl)acrylamide LC-MS (ES, m / z): [M+H + =325.

[0655] 1 H NMR (300MHz, DMSO-d6, ppm): δ10.53(s,1H),9.62(s,1H),7.58-7.46(m,2H),7.34-7. 21(m,3H),7.06-6.90(m,3H),3.48-3.45(m,1H),2.16(s,3H),1.34(d,J=7.8Hz,3H).

[0656] Example 9: (E)-N-(3-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0657]

[0658] N-(3-chloro-2-methylphenyl)prop-2-enamide (intermediate 2.55 mg, 0.28 mmol, 1.0 equiv), DMF (4 mL), 2-benzoxazolinone, 5-bromo- (66 mg, 0.31 mmol, 1.10 equiv), Et3N (0.12 mL, 0.84 mmol, 3.0 equiv), and Pd(dppf)Cl2.CH2Cl2 (11 mg, 0.014 mmol, 0.05 equiv) were added to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 120 °C for 12 h. The reaction was then terminated by adding 3 mL of water. The resulting solution was extracted with 5 mL of DCM, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by rapid preparative HPLC. This yielded 21 mg (24%) of a white solid (E)-N-(3-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide. LC MS (ES, m / z): [M+H] + =329.

[0659] 1 H NMR (300MHz, DMSO-d6, ppm): δ11.83 (s, 1H), 9.68 (s, 1H), 7.61 (d, J = 15.6Hz, 1 H),7.53-7.51(m,1H),7.43-7.30(m,5H),6.91(d,J=15.6Hz,1H),2.28(s,3H).

[0660] Example 10: (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindoline-6-yl)acrylamide

[0661]

[0662] N-(3-fluoro-2-methylphenyl)prop-2-enamide (intermediate 1 (500 mg, 2.79 mmol, 1.0 eq), 6-bromo-1,3-dihydroindol-2-one (592 mg, 2.79 mmol, 1.0 eq), DMF (20 mL), Et3N (1.2 mL, 8.37 mmol, 3.0 eq), and Pd(dppf)Cl2 (41 mg, 0.05 mmol, 0.02 eq) were added to a 40-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. The reaction mixture was stirred at 110 °C for 2 h. The resulting mixture was concentrated. The crude product was purified by rapid preparative HPLC. This yielded 102 mg (11%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindololin-6-yl)acrylamide as a white solid. LC-MS (ES, m / z): [MH] + =309.

[0663] 1 H NMR (300MHz, DMSO-d6, ppm): δ10.57(s,1H),9.62(s,1H),7.55(d,J=15.9Hz,1H),7 .48-7.45(m,1H),7.29-7.18(m,3H),7.05-6.89(m,3H),3.52(s,2H),2.26(s,3H).

[0664] Example 11: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0665]

[0666] Step 1: Add a solution of 5-bromobenzo[d]oxazol-2(3H)-one (10.0 g, 46.96 mmol, 1.0 equiv), methyl acrylate (12.1 g, 140.8 mmol, 3.0 equiv), Et3N (19.6 mL, 140.8 mmol, 3.0 equiv), and Pd(dppf)Cl2 (350 mg, 4.7 mmol, 0.01 equiv) in DMF (200 mL) to a 500 mL sealed tube. Stir the resulting solution at 120 °C for 2 h. Concentrate the solution. Load the residue onto a silica gel column and elute with THF / hexane (20 / 80). This yields 11 g (82%) of a yellow solid (E)-3-(3-(3-methoxy-3-oxopropyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)methyl acrylate.

[0667]

[0668] Step 2: Add THF (300 mL), (E)-3-(3-(3-methoxy-3-oxopropyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)methyl acrylate (11.0 g, 36.1 mmol, 1.0 equiv), and t-BuOK (13.2 g, 108.2 mmol, 3.0 equiv) to a 500 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution at 60 °C for 2 h. Then terminate the reaction by adding 600 mL of saturated NH4Cl. Extract the resulting solution with 2 x 300 mL EtOAc. Wash the organic layer with 2 x 400 mL of water. Dry the organic layer with anhydrous sodium sulfate and concentrate. Concentrate the resulting solution. Load the residue onto a silica gel column using EtOAc / hexane (40 / 60). This yielded 5.5 g (69%) of light red solid (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)methyl acrylate.

[0669]

[0670] Step 3: Add THF (20 mL), (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)methyl acrylate (2.5 g, 11.4 mmol, 1.0 equiv), and 2M NaOH (17.1 mL, 34.2 mmol, 3.0 equiv) to a purified 100 mL 3-necked round-bottom flask. Stir the resulting solution at 25 °C for 2 h. Concentrate the reaction mixture at low temperature (<30 °C). Dissolve the residue in water (30 mL) and adjust the pH to 2-3 with 2M HCl. Collect the solid. This yields 2.5 g (65%) of off-white solid (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylic acid.

[0671]

[0672] Step 4: Add a 2 mL solution of (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylic acid (30 mg, 0.146 mmol, 1.0 equiv) in DMF to a vial. Then add T3P (70 mg, 0.22 mmol, 1.50 equiv), DIPEA (28 mg, 0.22 mmol, 1.50 equiv), and 1-aminoindenhydride (0.161 mmol, 1.1 equiv). Stir the reaction mixture at room temperature for 2 h. Terminate the reaction mixture with water and extract with EtOAc. Concentrate the organic layer under vacuum to obtain the crude product. Then purify the crude product directly by preparative HPLC. Freeze-dry the collected fractions to obtain the final compound. LC-MS (ES, m / z): 321 [M+H] + .

[0673] 1 H NMR: (300MHz, DMSO-d6, ppm): δ11.77(s,1H),8.44(d,J=8.4Hz,1H),7.51(d,J=15.6Hz,1H),7.34-7.18(m ,7H),6.65(d,J=15.9Hz,1H),5.42-5.33(m,1H),2.96-2.81(m,2H),2.48-2.42(m,1H),1.85-1.81(m,1H).

[0674] General Method A:

[0675]

[0676] A solution of (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)methyl acrylate (Example 11, step 2, 30 mg, 0.14 mmol, 1.0 equiv) in THF (2 mL) was added to a vial. An amine (0.18 mmol, 1.30 equiv) was added, and the reaction mixture was cooled to 0 °C. Then, 1 M LiHMDS (0.68 mL, 0.68 mmol, 5.0 equiv) was added. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was terminated with water and extracted with EtOAc. The organic liquid was concentrated under vacuum to give a crude product, which was then purified by preparative HPLC. The collected fraction was freeze-dried to give the final compound.

[0677] Example 12: (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(o-tolyl)acrylamide

[0678]

[0679] (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate was synthesized using general method A from 2-methylaniline to obtain solid (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(o-tolyl)acrylamide. LC-MS (ES, m / z): 295 [M+H] + .

[0680] 1 H NMR: (300MHz, DMSO-d6, ppm): δ9.40(brs,1H),7.63-7.57(m,2H),7.38-7.32(m,3H),7.25-6.91(m,4H),2.26(s,3H).

[0681] Example 13: (E)-N-(2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0682]

[0683] (E)-N-(2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide was synthesized using general method A from 2-isopropylaniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide to obtain solid (E)-N-(2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide. LC-MS (ES, m / z): 323 [M+H] + .

[0684] 1 H NMR (300MHz, DMSO-d6, ppm): δ11.83 (brs, 1H), 9.48 (brs, 1H), 7.59 (d, J = 15.6Hz, 1H), 7.40-7. 34(m,5H),7.24-7.18(m,2H),6.93(d,J=15.3Hz,1H),3.23-.319(m,1H),1.17(d,J=6.6Hz,6H).

[0685] Example 14: (E)-N-(2-isopropyl-6-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0686]

[0687] (E)-N-(2-isopropyl-6-methylaniline)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide was synthesized using general method A from 2-isopropyl-6-methylaniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide to obtain solid (E)-N-(2-isopropyl-6-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide. LC-MS (ES, m / z): 337 [M+H] + .

[0688] 1 H NMR (300MHz, DMSO-d6, ppm): δ11.82(brs,1H),9.43(brs,1H),7.57(d,J=15.6Hz,1H),7.40-7.33(m,3H ),7.27-7.09(m,3H),6.85(d,J=15.6Hz,1H),3.15-.3.06(m,1H),2.18(s,3H),1.173(d,J=6.9Hz,6H).

[0689] Example 15: (E)-N-(5-chloro-2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0690]

[0691] (E)-N-(5-chloro-2-isopropylaniline)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide was synthesized using general method A from 5-chloro-2-isopropylaniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide to obtain solid (E)-N-(5-chloro-2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide. LC-MS (ES, m / z): 357 [M+H] + .

[0692] 1 H NMR (300MHz, DMSO-d6, ppm): δ11.79(brs,1H),9.56(brs,1H),7.64-7.58(m,2H),7. 37-7.23(m,5H),6.95(d,J=15.6Hz,1H),3.25-.3.20(m,1H),1.16(d,J=6.9Hz,6H).

[0693] Example 16: (E)-N-(4,5-difluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0694]

[0695] (E)-N-(4,5-difluoro-2-methylaniline)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide was synthesized using general method A from 4,5-difluoro-2-methylaniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide to obtain solid (E)-N-(4,5-difluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide. LC-MS (ES, m / z): 331 [M+H] + ,373[M+CH3CN] + .

[0696] Example 17: (E)-N-(5-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0697]

[0698] (E)-N-(5-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide was synthesized using general method A from 5-fluoro-2-methylaniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide to obtain solid (E)-N-(5-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide. LC-MS (ES, m / z): 311 [M+H] +

[0699] Example 18: (E)-N-(3-fluoro-2-methylphenyl)-3-(4-fluoro-2-oxoindoline-6-yl)acrylamide

[0700]

[0701] N-(3-fluoro-2-methylphenyl)acrylamide (60.0 mg, 0.34 mmol, 1.0 eq), 6-bromo-4-fluoroindoline-2-one (78 mg, 0.34 mmol, 1.0 eq), Et3N (0.14 mL, 1.0 mmol, 3.0 eq), DMF (4.0 mL), and Pd(dppf)Cl2 (25.2 mg, 0.034 mmol, 0.10 eq) were added to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 120 °C for 2 h. The crude mixture was purified by rapid preparative HPLC. This yielded 11.8 mg (11%) of a grayish-white solid (E)-N-(3-fluoro-2-methylphenyl)-3-(4-fluoro-2-oxoindoline-6-yl)acrylamide.

[0702] LC-MS(ES,m / z):[M+H] + =329.

[0703] 1H NMR (300MHz, DMSO-d6, ppm): δ10.80 (brs, 1H), 9.66 (s, 1H), 7.55 (d, J = 15.9Hz, 1H), 7 .47(d,J=8.4Hz,1H),7.24-7.22(m,1H),7.10-6.93(m,4H),3.60(s,2H),2.15(s,3H).

[0704] Example 19: (E)-N-(2,6-dimethylphenyl)-3-(2-oxoindoline-6-yl)acrylamide

[0705]

[0706] Step 1: Add 20.0 g (94.32 mmol, 1.0 equiv) of 6-bromo-1,3-dihydroindole-2-one, 350 mL of DMF, 6.50 g (75.50 mmol, 0.80 equiv) of methyl acrylate, 26.3 mL (188.64 mmol, 2.0 equiv) of Et3N, and 0.77 g (0.94 mmol, 0.01 equiv) of Pd(dppf)Cl2.CH2Cl2 to a 500 mL 3-necked round-bottom flask purified with nitrogen and kept under an inert nitrogen atmosphere. Stir the resulting solution at 120 °C for 2 h. Cool the reaction mixture to room temperature. Load the mixture onto a silica gel column using THF / PE (2 / 1) solution. This yielded 7.4 g (36%) of pale yellow solid (2E)-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2-enoic acid methyl ester.

[0707]

[0708] Step 2: Add methyl (2E)-3-(2-oxo-1,3-dihydroindole-6-yl)prop-2-enoic acid (3.0 g, 13.81 mmol, 1.0 equiv), MeOH / H₂O (80 / 40 mL), and NaOH (1.7 g, 41.43 mmol, 3.0 equiv) to a 250-mL round-bottom flask. Stir the resulting solution at 25°C for 12 h. Concentrate the resulting mixture. Dilute the resulting solution with 40 mL of water. Extract the resulting solution with 2 x 50 mL DCM. Adjust the pH of the aqueous phase to 5 with 2 M HCl. Collect the solid by filtration. This yields 1.8 g (64%) of pale yellow solid (2E)-3-(2-oxo-1,3-dihydroindole-6-yl)prop-2-enoic acid.

[0709]

[0710] Step 3: A 4.0 mL solution of (E)-3-(2-oxoindoline-6-yl)acrylic acid (60.0 mg, 0.30 mmol, 1.0 equiv) in DMF was added to an 8 mL vial purified with nitrogen and kept under an inert nitrogen atmosphere. Then, HATU (167.6 mg, 0.44 mmol, 1.50 equiv), DIPEA (56.8 mg, 0.44 mmol, 1.50 equiv), and 2,6-dimethylaniline (39.5 mg, 0.33 mmol, 1.10 equiv) were added. The reaction mixture was stirred at room temperature for 2 h. The crude mixture was then purified by preparative HPLC. This yielded 12 mg (13%) of (E)-N-(2,6-dimethylphenyl)-3-(2-oxoindoline-6-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =307.

[0711] 1 HNMR(300MHz,DMSO-d6,ppm)δ10.53(brs,1H),9.47(brs,1H),7.51(d,J=15.9Hz,1H),7 .29-7.18(m,2H),7.10-7.05(m,4H),6.83(d,J=15.9Hz,1H),3.52(s,2H),2.18(s,6H).

[0712] Example 20: (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(2-oxoindoline-6-yl)acrylamide

[0713]

[0714] Add 6-bromoindololin-2-one (100 mg, 0.47 mmol, 1.0 equiv), N-(3-fluoro-2,6-dimethylphenyl)prop-2-enamide (prepared from 2,6-dimethyl-3-fluoroaniline and acryloyl chloride according to the method described in Intermediate 1; 90.7 mg, 0.47 mmol, 1.0 equiv), Pd(dppf)Cl2 (34.4 mg, 0.047 mmol, 0.10 equiv), Et3N (0.2 mL, 1.41 mmol, 3.0 equiv), and DMF (4.0 mL) to an 8-mL round-bottom flask. Stir the resulting solution in an oil bath at 120 °C for 2 h. Load the mixture onto a silica gel column using PE / THF (1 / 1). Thus, 11 mg (7%) of solid (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(2-oxoindoline-6-yl)acrylamide was obtained.

[0715] LC-MS(ES,m / z):[M+H] + =325.

[0716] 1 H NMR (300MHz, DMSO-d6, ppm): δ10.55(s,1H),9.63(s,1H),7.55(d,J=15.6Hz,1H), 7.29-7.03(m,5H),6.84(d,J=15.9Hz,1H),3.53(s,2H),2.14(s,3H),2.07(s,3H).

[0717] Example 21: (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindoline-6-yl)acrylamide

[0718]

[0719] Add a 2.0 mL solution of (E)-3-(2-oxoindoline-6-yl)acrylic acid (50.0 mg, 0.25 mmol, 1.0 equiv), 2-methyl-2,3-dihydro-1H-indene-1-amine hydrochloride (45.20 mg, 0.25 mmol, 1.0 equiv), HATU (141.38 mg, 0.37 mmol, 1.50 equiv), and DIPEA (95.41 mg, 0.74 mmol, 3.0 equiv) in DMF to an 8 mL vial. Stir the resulting solution at 20 °C for 2 h. Purify the mixture by preparative HPLC. This yielded 27 mg (33%) of a grayish-white solid ((E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindoline-6-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =333.

[0720] 1 H NMR(300MHz,DMSO-d6,ppm)δ10.51(brs,1H),8.45-8.20(m,1H),7.50-7.45(m,1H),7.26-7.13(m,6H),7.05-6.96 (m,1H),6.68-6.63(m,1H),5.45-5.0(m,1H),3.51(s,2H),3.10-3.0(m,1H),2.70-2.20(m,2H),1.20-0.90(m,3H).

[0721] Example 22: (E)-3-(1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide

[0722]

[0723] Step 1: Add 2.0 g (9.09 mmol, 1.0 eq) of 4-bromo-1-fluoro-2-nitrobenzene, 8.0 mL (1.0 eq) of EtOH, and 22.73 mL (45.45 mmol, 5.0 eq) of ethylamine (2 M ethanol solution) to a 100 mL sealed tube. Stir the resulting solution at 50 °C for 4 h. Concentrate the mixture. Dilute the residue with 15 mL of H₂O and stir for 15 min. Collect the solid by filtration. This yields 2.2 g (98%) of red solid 4-bromo-N-ethyl-2-nitrobenzene. LC-MS (ES, m / z): [M+H] + =245.

[0724]

[0725] Step 2: Add 4-bromo-N-ethyl-2-nitroaniline (2.0 g, 8.16 mmol, 1.0 eq), acetone (16.0 mL), H₂O (2.0 mL), NH₄Cl (4.37 g, 81.61 mmol, 10.0 eq), and Zn (2.67 g, 40.80 mmol, 5.0 eq) to a 50 mL round-bottom flask. Stir the resulting solution at room temperature for 3 hours. Filter off the solid. Concentrate the filtrate. Dilute the residue with 20 mL of H₂O and stir for 15 min. Collect the solid by filtration. This yields 1.1 g (63%) of pale yellow solid 4-bromo-N-ethyl-2-nitroaniline. 1 1,2-Ethylphenyl-1,2-diamine. LC-MS (ES, m / z): [M+H] + =215.

[0726]

[0727] Step 3: Add 4-bromo-N to a 50-mL 3-necked round-bottom flask purified with nitrogen and kept under a nitrogen inert atmosphere. 15-Ethylphenyl-1,2-diamine (400.0 mg, 1.86 mmol, 1.0 eq), DCM (8.0 mL), and triphosgene (441.5 mg, 1.48 mmol, 0.80 eq) were added. Then, Et3N (0.8 mL, 5.58 mmol, 3.0 eq) was added at 0 °C. The resulting solution was stirred at room temperature for 3 hours. The reaction was then terminated by adding 5 mL of water. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was loaded onto a silica gel column using THF / PE = 18 / 82. This yielded 210 mg (47%) of a light brown solid, 5-bromo-1-ethyl-3H-1,3-benzodiazol-2-one.

[0728] LC-MS(ES,m / z):[M+H] + =240.

[0729]

[0730] Step 4: Add N-(3-fluoro-2-methylphenyl)acrylamide (120.0 mg, 0.67 mmol, 1.0 eq), 5-bromo-1-ethyl-3H-1,3-benzodiazol-2-one (161.5 mg, 0.67 mmol, 1.0 eq), Et3N (0.28 mL, 2.01 mmol, 3.0 eq), DMF (5.0 mL), and Pd(dppf)Cl2 (9.8 mg, 0.01 mmol, 0.02 eq) to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution at 120 °C for 2 h. Purify the crude mixture by rapid preparative HPLC. This yielded 25 mg (11%) of a grayish-white solid, (E)-3-(1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide. LC-MS (ES, m / z): [M+H] + =340.

[0731] 1 H NMR (300MHz, DMSO-d6, ppm): δ11.05(brs,1H),9.52(s,1H),7.62-7.48(m,2H),7.33 -7.19(m,4H),7.11-6.85(m,2H),3.88-3.81(m,2H),2.27(s,3H),1.31-1.19(m,3H).

[0732] Example 23: (E)-3-(1-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide

[0733]

[0734] Step 1: Add 2.0 g (9.09 mmol, 1.0 eq) of 4-bromo-1-fluoro-2-nitrobenzene, 2.60 g (45.45 mmol, 5.0 eq) of aminocyclopropane, and 20.0 mL of EtOH to a 40 mL sealed tube. Stir the resulting solution at 50 °C for 4 h. Concentrate the mixture. Dilute the remaining compound with 15 mL of H₂O and stir for 15 min. Collect the solid by filtration. Dry the solid under reduced pressure in an oven. This yields 2.4 g (96%) of red solid 4-bromo-N-cyclopropyl-2-nitrobenzylamine. LC-MS (ES, m / z): [M+H] + =257.

[0735]

[0736] Step 2: Add 2.0 g (7.8 mmol, 1.0 eq), 16.0 mL (acetone), 2.0 mL (H₂O), 2.54 g (38.89 mmol, 5.0 eq), and 4.16 g (77.8 mmol, 10.0 eq) of 4-bromo-N-cyclopropyl-2-nitroaniline to a 40 mL sealed tube. Stir the resulting solution at 25 °C for 3 h. Filter off the solid. Concentrate the filtrate. Dilute the residue with 20 mL (H₂O) and stir for 15 min. Collect the solid by filtration. This yields 1 g (56%) of light brown solid 4-bromo-N-cyclopropyl-2-nitroaniline. 1 -Cyclopropylphenyl-1,2-diamine.

[0737] LC-MS(ES,m / z):[M+H] + =227.

[0738]

[0739] Step 3: Add 4-bromo-N to a 50-mL 3-necked round-bottom flask purified with nitrogen and kept under a nitrogen inert atmosphere. 1 Cyclopropylphenyl-1,2-diamine (300.0 mg, 1.32 mmol, 1.0 eq), triphosgene (313.60 mg, 1.06 mmol, 0.80 eq), and DCM (6.0 mL) were added. Et3N (0.6 mL, 3.96 mmol, 3.0 eq) was then added at 0 °C. The resulting solution was stirred at room temperature for 3 hours. The reaction was then terminated by adding 5 mL of water. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. This yielded 180 mg (53%) of a light brown solid, 5-bromo-1-cyclopropyl-3H-1,3-benzodiazol-2-one. LC-MS (ES, m / z): [M+H]+ =253.

[0740]

[0741] Step 4: Add N-(3-fluoro-2-methylphenyl)acrylamide (120.0 mg, 0.67 mmol, 1.0 eq), 5-bromo-1-cyclopropyl-3H-1,3-benzodiazol-2-one (169.5 mg, 0.67 mmol, 1.0 eq), Et3N (0.2 mL, 1.34 mmol, 2.0 eq), DMF (5.0 mL), and Pd(dppf)Cl2 (9.80 mg, 0.013 mmol, 0.02 equiv) to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution at 120 °C for 2 h. Filter off the solids. Purify the crude mixture by rapid preparative HPLC. Thus, 21 mg (9%) of grayish-white solid (E)-3-(1-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide was obtained.

[0742] LC-MS(ES,m / z):[M+H] + =352.

[0743] 1 H-NMR (300MHz, DMSO-d6, ppm): δ10.96(brs,1H),9.54(brs,1H),7.61-7.47(m,2H),7. 33-7.18(m,4H),7.02-6.85(m,2H),2.95-2.87(m,1H),2.28(s,3H),1.04-0.88(m,4H).

[0744] Example 24: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide

[0745]

[0746] 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.

[0747]

[0748] A solution of N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (100.0 mg, 0.53 mmol, 1.0 equivalent), 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (121.27 mg, 0.53 mmol, 1.0 equivalent), Pd(dppf)Cl2 (39.08 mg, 0.05 mmol, 0.10 equivalent), and Et3N (0.22 mL, 1.60 mmol, 3.0 equivalent) in DMF (4.0 mL, 25.844 mmol) 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 7.8 mg (4%) of a white solid (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =334. 1 H-NMR (300MHz, DMSO-d6, ppm): δ10.98(brs,1H),8.37(d,J=8.4Hz,1H),7.50(d,J=15.9Hz,1H),7.34-7.03(m,7H) ,6.56(d,J=15.6Hz,1H),5.42-5.39(m,1H),3.29(s,3H),3.02-2.77(m,2H),2.47-2.37(m,1H),1.93-1.72(m,1H).

[0749] Example 25: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0750]

[0751] N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv), 6-bromo-3-methyl-1H-indazole (135.27 mg, 0.64 mmol, 1.20 equiv), Pd(dppf)Cl2.CH2Cl2 (87.23 mg, 0.11 mmol, 0.20 equiv), DMF (4.0 mL), and Et3N (0.22 mL, 1.60 mmol, 3.0 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 64 mg (38%) of a grayish-white solid (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =318.

[0752] 1 H NMR (300MHz, DMSO-d6, ppm): δ12.77(brs,1H),8.46(d,J=8.4Hz,1H),7.73-7.60(m,3H),7.31-7.17(m,5H),6.74(d,J=1 5.9Hz,1H),5.46-5.38(m,1H),3.02-2.93(m,1H),2.89-2.79(m,1H),2.51(s,3H),2.48-2.41(m,1H),1.90-1.77(m,1H).

[0753] Example 26: (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide

[0754]

[0755] N-(2,3-dihydro-1H-indene-1-yl)prop-2-enamide (Example 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv), 6-bromo-1H-indazole-3-carboxylonitrile (142.30 mg, 0.64 mmol, 1.20 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, 3.0 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 24 mg (14%) of a grayish-white solid (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2,3-dihydro-1H-indene-1-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =329.

[0756] 1 H-NMR (300MHz, DMSO-d6, ppm): δ14.33(brs,1H),8.55(d,J=8.1Hz,1H),7.93-7.91(m,2H),7.70(d,J=15.9Hz,1H),7.62-7.59(m,1H),7. 30-7.17(m,4H),6.84(d,J=15.6Hz,1H),5.47-5.39(m,1H),3.03-2.94(m,1H),2.90-2.80(m,1H),2.47-2.42(m,1H),1.91-1.76(m,1H).

[0757] Example 27: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide

[0758]

[0759] N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv), 5-bromo-6-fluoro-3H-1,2,3-benzotriazole (138.44 mg, 0.64 mmol, 1.20 equiv), Pd(dppf)Cl2.CH2Cl2 (43.61 mg, 0.05 mmol, 0.10 equiv), DMF (4.0 mL), and Et3N (0.22 mL, 1.60 mmol, 3.0 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 140 °C. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This yielded 6.3 mg (4%) of a grayish-white solid (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =323.

[0760] 1 H NMR (300MHz, DMSO-d6, ppm): δ8.63(d,J=8.1Hz,1H),8.27(d,J=6.6Hz,1H),7.82(d,J=10.8Hz,1H),7.68(d,J=16.2Hz,1H),7.29-7 .18(m,4H),6.88(d,J=15.9Hz,1H),5.47-5.40(m,1H),3.01-2.94(m,1H),2.90-2.79(m,1H),2.49-2.44(m,1H),1.92-1.79(m,1H).

[0761] Example 28: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-(trifluoromethyl)-1H-indazol-6-yl)acrylamide

[0762]

[0763] N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv), 6-bromo-3-(trifluoromethyl)-1H-indazole (169.9 mg, 0.64 mmol, 1.20 equiv), Pd(dppf)Cl2.CH2Cl2 (43.61 mg, 0.05 mmol, 0.10 equiv), DMF (4.0 mL), and Et3N (0.22 mL, 1.60 mmol, 3.0 equiv) were added to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen 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 80 mg (40%) of a grayish-white solid (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-(trifluoromethyl)-1H-indazol-6-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =372.

[0764] 1 H NMR (300MHz, DMSO-d6, ppm): δ14.16(brs,1H),8.55(d,J=8.1Hz,1H),7.89-7.83(m,2H),7.70(d,J=15.9Hz,1H),7.58-7.54(m,1H),7.3 0-7.17(m,4H),6.83(d,J=15.6Hz,1H),5.47-5.39(m,1H),3.03-2.94(m,1H),2.90-2.80(m,1H),2.47-2.42(m,1H),1.91-1.78(m,1H).

[0765] Example 29: (E)-N-(2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide

[0766]

[0767] Add N-(2,6-dimethylphenyl)prop-2-enamide (prepared from acryloyl chloride and 2,6-dimethylaniline according to the method described in Intermediate 1) 50.0 mg, 0.29 mmol, 1.0 equiv, DMF (4.0 mL), 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (71.3 mg, 0.31 mmol, 1.10 equiv), Et3N (0.12 mL, 0.86 mmol, 3.0 equiv), and Pd(dppf)Cl2.CH2Cl2 (11.65 mg, 0.014 mmol, 0.05 equiv) to an 8-mL vial purified with nitrogen and kept under an inert nitrogen atmosphere. Stir the resulting solution at 120 °C for 5 h. Cool the reaction mixture to room temperature. Load the crude mixture onto a silica gel column using EtOAc / PE (1 / 1). This yielded 20 mg (22%) of off-white solid (E)-N-(2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide.

[0768] LC-MS(ES,m / z):[M+H] + =322.

[0769] 1 H NMR (300MHz, DMSO-d6, ppm): 11.02 (s, 1H), 9.38 (s, 1H), 7.56 (d, J = 15.6Hz, 1H), 7.33-7.31 (m,1H),7.24(s,1H),7.16-7.09(m,4H),6.78(d,J=15.6Hz,1H),3.32(s,1H),2.17(s,6H).

[0770] Example 30: (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide

[0771]

[0772] Step 1: Add a solution of 1-bromo-4-fluoro-3-methyl-2-nitrobenzene (500.0 mg, 2.14 mmol, 1.0 equiv), trimethylcycloboroxane (268.20 mg, 2.13 mmol, 1.0 equiv), K₂CO₃ (590.6 mg, 4.27 mmol, 2.0 equiv), and Pd(dppf)Cl₂ (156.3 mg, 0.21 mmol, 0.10 equiv) in dioxane (10.0 mL) and H₂O (2.0 mL) to a 40 mL vial. Stir the resulting solution in an oil bath at 110 °C for 1 h. Load the crude mixture onto a silica gel column using EtOAc / PE (1 / 10). This yields 250 mg (69%) of solid 1-fluoro-2,4-dimethyl-3-nitrobenzene.

[0773]

[0774] Step 2: Add a solution of 1-bromo-4-fluoro-3-methyl-2-nitrobenzene (0.50 g, 2.14 mmol, 1.0 equiv) in AcOH (10.0 mL) and Fe (596.6 mg, 10.68 mmol, 5.0 equiv) to a 40 mL vial. Stir the resulting solution at room temperature for 1 h. Filter off the solid. Dilute the resulting solution with 20 mL of water and extract with 40 mL of EtOAc. Dry the organic phase and concentrate. This yields 250 mg (84%) of 3-fluoro-2,6-dimethylaniline in solid form. LC-MS (ES, m / z): [M+H] + =140.

[0775]

[0776] Step 3: Add a 4 mL solution of DCM containing 6-bromo-3-fluoro-2-methylaniline (100.0 mg, 0.49 mmol, 1.0 equiv) and Et3N (0.2 mL, 1.47 mmol, 3.0 equiv) and acryloyl chloride (53.2 mg, 0.59 mmol, 1.20 equiv) to an 8 mL vial. Stir the resulting solution at 0 °C for 1 h. Concentrate the mixture under vacuum. Purify the residue by rapid chromatography (PE / EA = 10 / 1). This yields 120 mg (126.72%) of N-(3-fluoro-2,6-dimethylphenyl)prop-2-enamide as a white solid. LC-MS (ES, m / z): [M+H] + =194.

[0777]

[0778] Step 4: Add 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (100 mg, 0.44 mmol, 1.0 equivalent), N-(3-fluoro-2,6-dimethylphenyl)prop-2-enamide (85.1 mg, 0.44 mmol, 1.0 equivalent), Pd(dppf)Cl2 (32.2 mg, 0.044 mmol, 0.10 equivalent), Et3N (0.18 mL, 1.32 mmol, 3.0 equivalent), and DMF (4.0 mL) to an 8-mL round-bottom flask. Stir the resulting solution in an oil bath at 120°C for 2 h. Load the mixture onto a silica gel column using PE / THF (1 / 1). This yielded 45 mg (30%) of solid (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =340.

[0779] 1 H NMR (300MHz, DMSO-d6, ppm): δ11.04(s,1H),9.53(s,1H),7.58(d,J=15.3Hz,1H),7.33(d,J=8.4Hz, 1H),7.24(s,1H),7.17-7.01(m,3H),6.79(d,J=15.6Hz,1H),3.31(s,3H),2.15(s,3H),2.07(s,3H).

[0780] Example 31: (E)-N-(2,6-dimethylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0781]

[0782] 2,6-Dimethylaniline (160.0 mg, 1.32 mmol, 1.0 equiv), DCM (10.0 mL), and Et3N (0.55 mL, 3.96 mmol, 3.0 equiv) were added dropwise to a 50 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Acryloyl chloride (143.40 mg, 1.58 mmol, 1.20 equiv) was then added dropwise at 0 °C with stirring. The resulting solution was stirred at 25 °C for 3 h. The reaction was then terminated by adding 15 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 / 3). This yielded 150 mg (65%) of N-(2,6-dimethylphenyl)prop-2-enamide as a white solid. LC-MS (ES, m / z): [M+H] + =176.

[0783]

[0784] N-(2,6-dimethylphenyl)prop-2-enamide (50.0 mg, 0.29 mmol, 1.0 equiv), DMF (5.0 mL), 6-bromo-3-methyl-1H-indazole (66.3 mg, 0.31 mmol, 1.10 equiv), Et3N (0.12 mL, 0.86 mmol, 3.0 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. The crude mixture was purified by rapid preparative HPLC. This yielded 30 mg (34%) of a grayish-white solid (E)-N-(2,6-dimethylphenyl)-3-(3-methyl-1H-indazole-6-yl)acrylamide. LC-MS(ES,m / z):[M+H] + =306.

[0785] 1 H NMR(300MHz,DMSO-d6,ppm):12.81(s,1H),9.49(s,1H),7.77-7.67(m,3H),7.40 (d,J=8.4Hz,1H),7.11(s,3H),6.97(d,J=15.6Hz,1H),2.51(s,3H),2.19(s,6H).

[0786] Example 32: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-ethyl-1H-indazol-6-yl)acrylamide

[0787]

[0788] N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv), 6-bromo-3-ethyl-1H-indazole (144.3 mg, 0.64 mmol, 1.20 equiv), Pd(dppf)Cl2.CH2Cl2 (43.6 mg, 0.05 mmol, 0.10 equiv), DMF (4.0 mL), and Et3N (0.22 mL, 1.60 mmol, 3.0 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 product was purified by preparative HPLC. This yielded 86 mg (49%) of a grayish-white solid (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-ethyl-1H-indazol-6-yl)acrylamide. LC MS (ES, m / z): [M+H] + =332.

[0789] 1 H NMR (300MHz, DMSO-d6, ppm): δ12.77(brs,1H),8.47(d,J=8.1Hz,1H),7.75(d,J=8.4Hz,1H),7.63-7.61(m,2H),7.31-7.17(m ,5H),6.75(d,J=15.9Hz,1H),5.45-5.39(m,1H),3.03-2.79(m,4H),2.47-2.41(m,1H),1.90-1.78(m,1H),1.34-1.29(m,3H).

[0790] Example 33: (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide

[0791]

[0792] Add N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equivalent), 6-bromo-3-cyclopropyl-1H-indazole (126.6 mg, 0.53 mmol, 1.0 equivalent), Pd(dppf)Cl2 (39.1 mg, 0.05 mmol, 0.10 equivalent), Et3N (0.22 mL, 1.60 mmol, 3.0 equivalent), and DMF (4 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 mixture onto a silica gel column using PE / THF (1 / 1). Thus, 15 mg (8%) of solid (E)-3-(3-cyclopropyl-1H-indazole-6-yl)-N-(2,3-dihydro-1H-indene-1-yl)acrylamide was obtained.

[0793] LC MS(ES,m / z):[M+H] + =344.

[0794] 1 H NMR (300MHz, DMSO-d6, ppm): δ12.70(s,1H),8.48(d,J=8.4Hz,1H),7.78(d,J=8.4Hz,1H),7.63(m,2H),7.37-7.16(m,5H),6.74(d, J=15.6Hz,1H),5.49-5.37(m,1H),3.10-2.75(m,2H),2.48-2.39(m,1H),2.33-2.20(m,1H),1.91-1.77(m,1H),1.06-0.89(m,4H).

[0795] Example 34: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-3-methyl-1H-indazol-6-yl)acrylamide

[0796]

[0797] Add 6-bromo-4-fluoro-3-methyl-1H-indazole (100.0 mg, 0.44 mmol, 1.0 equiv), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 24, Step 1, 81.8 mg, 0.44 mmol, 1.0 equiv), Pd(dppf)Cl2 (31.9 mg, 0.04 mmol, 0.10 equiv), Et3N (0.18 mL, 1.31 mmol, 3.0 equiv), and 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 PE / THF (1 / 1). This yielded 17 mg (12%) of solid (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-3-methyl-1H-indazol-6-yl)acrylamide. LC MS (ES, m / z): [M+H] + =336.

[0798] 1 H-NMR(300MHz,DMSO-d6,ppm)δ13.09(s,1H),8.47(d,J=8.1Hz,1H),7.61(d,J=15.6Hz,1H),7.48(s,1H),7.35-7.15(m,4H),7.01( d,J=12.0Hz,1H),6.73(d,J=15.6Hz,1H),5.49-5.36(m,1H),3.06-2.76(m,2H),2.56(s,3H),2.47-2.38(m,1H),1.92-1.76(m,1H).

[0799] Example 35: (E)-N-(3,5-difluoro-2,6-dimethylphenyl)-3-(2-oxoindololin-6-yl)acrylamide

[0800]

[0801] Step 1: Add 3,5-difluoroaniline (1.0 g, 7.8 mmol, 1.0 equiv), CH3CN (30 mL), and NCS (1.1 g, 8.16 mmol, 1.05 equiv) to a 100 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution at 80 °C for 5 h. Cool the reaction mixture to room temperature. Concentrate the resulting mixture. Load the residue onto a silica gel column using THF:PE (1:4–1:1). This yields 500 mg (39%) of 4-chloro-3,5-difluoroaniline as a gray solid.

[0802]

[0803] Step 2: Add 50 mL of 3-necked round-bottom flasks purified with nitrogen and kept under an inert nitrogen atmosphere to a container containing 4-bromo-3,5-difluoroaniline (500.0 mg, 2.40 mmol, 1.0 equiv), CH3CN (20.0 mL), and NBS (1.3 g, 7.21 mmol, 3.0 equiv). Stir the resulting solution at room temperature for 1 hour. Concentrate the mixture. Load the residue onto a silica gel column using THF:PE (1:5–1:3). This yields 700 mg (91%) of a yellow solid, 2,6-dibromo-4-chloro-3,5-difluoroaniline.

[0804]

[0805] Step 3: Add 2,6-dibromo-4-chloro-3,5-difluoroaniline (3.0 g, 9.36 mmol, 1.0 equiv), Pd(dppf)Cl2.CH2Cl2 (0.76 g, 0.94 mmol, 0.10 equiv), dioxane (60.0 mL), Cs2CO3 (12.20 g, 37.46 mmol, 4.0 equiv), and trimethylcycloborane (8.23 g, 32.77 mmol, 3.50 equiv, 50%) to a 250-mL round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution overnight at 100 °C. Cool the reaction mixture to room temperature. Concentrate the resulting mixture. Purify the crude mixture by preparative HPLC. This yields 600 mg (33%) of a grayish-white solid, 4-chloro-3,5-difluoro-2,6-dimethylaniline.

[0806]

[0807] Step 4: Add 280.0 mg (1.46 mmol, 1.0 equiv) of 4-chloro-3,5-difluoro-2,6-dimethylaniline, 20.0 mL of EtOH, 1.0 mL of HCl, and 77.76 mg of Pd / C to a 100 mL autoclave. Evacuate the flask and rinse it three times with nitrogen, then rinse it with hydrogen. Stir the resulting solution overnight at 70 °C under a hydrogen atmosphere (30 atm). Cool the reaction mixture to room temperature. Filter off the solid and concentrate the resulting mixture. This yields 220 mg (crude) of a grayish-white solid, 3,5-difluoro-2,6-dimethylaniline hydrochloride.

[0808]

[0809] Step 5: Add 3,5-difluoro-2,6-dimethylaniline hydrochloride (220.0 mg, 1.14 mmol, 1.0 equiv), DCM (20.0 mL), and Et3N (0.48 mL, 3.41 mmol, 3.0 equiv) to a 100 mL 3-necked round-bottom flask purified with nitrogen and maintained under a nitrogen inert atmosphere. Then, add acryloyl chloride (123.4 mg, 1.36 mmol, 1.20 equiv) dropwise at 0 °C with stirring. Stir the resulting solution overnight at room temperature. Concentrate the mixture. Load the residue onto a silica gel column using THF:PE (1:5–1:3). This yields 160 mg (67%) of a grayish-white solid N-(3,5-difluoro-2,6-dimethylphenyl)prop-2-enamide.

[0810]

[0811] Step 6: Add N-(3,5-difluoro-2,6-dimethylphenyl)prop-2-enamide (160.0 mg, 0.76 mmol, 1.0 equiv), 6-bromo-1,3-dihydroindole-2-one (192.8 mg, 0.91 mmol, 1.20 equiv), Pd(dppf)Cl2.CH2Cl2 (61.7 mg, 0.076 mmol, 0.10 equiv), DMF (5.0 mL), and Et3N (0.32 mL, 2.27 mmol, 3.0 equiv) to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution at 100 °C for 2 h, and then cool the reaction mixture to room temperature. Purify the crude mixture by preparative HPLC. Thus, 14.8 mg (6%) of solid (E)-N-(3,5-difluoro-2,6-dimethylphenyl)-3-(2-oxoindoline-6-yl)acrylamide was obtained.

[0812] LC MS(ES,m / z):[M+H] + =343.

[0813] 1 H NMR (300MHz, DMSO-d6, ppm): δ10.56 (s, 1H), 9.77 (s, 1H), 7.56 (d, J = 15.6Hz, 1H), 7.29-7.06 (m, 4H), 6.85 (d, J = 15.9Hz, 1H), 3.53 (s, 2H), 2.05 (s, 6H).

[0814] Example 36: (E)-N-(3,4-difluoro-2,6-dimethylphenyl)-3-(2-oxoindoline-6-yl)acrylamide

[0815]

[0816] Step 1: Add 3,4-difluoroaniline (1.0 g, 7.75 mmol, 1.0 equiv), CH3CN (30.0 mL), and NBS (2.9 g, 16.27 mmol, 2.10 equiv) 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. Concentrate the mixture. Load the residue onto a silica gel column using THF:PE (1:5–1:3). This yields 1.4 g (63%) of dark brown solid 2,6-dibromo-3,4-difluoroaniline.

[0817]

[0818] Step 2: Add 2,6-dibromo-3,4-difluoroaniline (1.20 g, 4.18 mmol, 1.0 equiv), Pd(dppf)Cl2.CH2Cl2 (340.7 mg, 0.42 mmol, 0.10 equiv), Cs2CO3 (4.8 g, 14.64 mmol, 3.50 equiv), dioxane (50.0 mL), and trimethylcycloborane (3.2 g, 12.55 mmol, 3.0 equiv, 50%) to a 100 mL round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution overnight at 100 °C. Cool the reaction mixture to room temperature. Concentrate the resulting mixture. Purify the crude mixture by preparative HPLC. This yields 350 mg (53%) of a grayish-white solid, 3,4-difluoro-2,6-dimethylaniline.

[0819]

[0820] Step 3: Add 210.0 mg of 3,4-difluoro-2,6-dimethylaniline, 20 mL of DCM, and 0.28 mL of Et3N (2.0 mmol, 1.50 equiv) to a 100 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Then, add 145.13 mg of acryloyl chloride (1.60 mmol, 1.20 equiv) dropwise at 0 °C with stirring. Stir the resulting solution at room temperature for 2 h. Concentrate the mixture. Load the residue onto a silica gel column using THF:PE (1:5–1:3). This yields 180 mg (64%) of a grayish-white solid N-(3,4-difluoro-2,6-dimethylphenyl)prop-2-enamide.

[0821]

[0822] Step 4: Add N-(3,4-difluoro-2,6-dimethylphenyl)prop-2-enamide (100.0 mg, 0.47 mmol, 1.0 equiv), 6-bromo-1,3-dihydroindole-2-one (120.47 mg, 0.57 mmol, 1.20 equiv), Pd(dppf)Cl2.CH2Cl2 (38.57 mg, 0.05 mmol, 0.10 equiv), DMF (4.0 mL), and Et3N (0.2 mL, 1.42 mmol, 3.0 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. Thus, 11.3 mg (7%) of off-white solid (E)-N-(3,4-difluoro-2,6-dimethylphenyl)-3-(2-oxoindoline-6-yl)acrylamide was obtained.

[0823] LCMS(ES,m / z):[M+H] + =343.

[0824] 1 H NMR (300MHz, DMSO-d6, ppm): δ10.55(s,1H),9.63(s,1H),7.53(d,J=15.9Hz,1H),7.29-7 .18(m,3H),7.06(s,1H),6.82(d,J=15.9Hz,1H),3.53(s,2H),2.05(s,3H),2.10(s,3H).

[0825] Example 37: (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0826]

[0827] N-(3-fluoro-2-methylphenyl)acrylamide (intermediate 1, 110.0 mg, 0.61 mmol, 1.0 equiv), 6-bromo-3-methyl-1H-indazole (155.47 mg, 0.74 mmol, 1.20 equiv), Pd(dppf)Cl2.CH2Cl2 (100.01 mg, 0.12 mmol, 0.20 equiv), DMF (4.0 mL), and Et3N (0.26 mL, 1.84 mmol, 3.0 equiv) were added to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen 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 26 mg (14%) of a grayish-white solid (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-1H-indazole-6-yl)acrylamide. LC MS(ES,m / z):[M+H] + =310.

[0828] 1 H NMR 300MHz, DMSO-d6, ppm): δ12.83(brs,1H),9.62(brs,1H),7.78-7.69(m,3H),7.49(d,J=7.8Hz ,1H),7.39(d,J=8.4Hz,1H),7.27-7.20(m,1H),7.09-6.98(m,2H),2.51(s,3H),2.17(s,3H).

[0829] Example 38: (E)-3-(3-methyl-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide

[0830]

[0831] A solution of 6-bromo-3-methyl-1H-indazole (40.0 mg, 0.19 mmol, 1.0 equiv), N-(2-methyl-2,3-dihydro-1H-indene-1-yl)prop-2-enamide (prepared using 2-methylaminoindene according to the method described in step 1 of Example 24, 38.14 mg, 0.19 mmol, 1.0 equiv), Pd(dppf)Cl2 (13.87 mg, 0.02 mmol, 0.10 equiv), and Et3N (0.8 mL, 0.57 mmol, 3.0 equiv) in DMF (2.0 mL) was added to an 8-mL vial. The resulting solution was stirred in an oil bath at 120 °C for 2 h. The reaction solution was cooled to room temperature. The crude mixture was purified by rapid preparative HPLC. Thus, 29 mg (44%) of off-white solid (E)-3-(3-methyl-1H-indazole-6-yl)-N-(2-methyl-2,3-dihydro-1H-indene-1-yl)acrylamide was obtained.

[0832] LC MS(ES,m / z):[M+H] + =332.

[0833] 1 H-NMR(300MHz,DMSO-d6,ppm)δ12.78(brs,1H),8.45-8.21(m,1H),7.82-7.57(m,3H),7.42-7.11(m,5H),6.88-6.74 (m,1H),5.40-5.0(m,1H),3.12-2.95(m,1H),2.75-2.58(m,2H),2.49(s,3H),2.38-2.24(m,1H),1.24-0.88(m,3H).

[0834] Example 39: (E)-3-(3-methyl-1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide

[0835]

[0836] Step 1: 1-Methylindazole-7-amine (400.0 mg, 2.71 mmol, 1.0 eq), DCM (10.0 mL), and Et3N (0.6 mL, 4.07 mmol, 1.50 eq) were added to a 50 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Acryloyl chloride (246 mg, 2.71 mmol, 1.0 eq) was then added at -30 °C. The resulting solution was stirred at -30 °C for 10 min. The reaction was then terminated by adding 8 mL of water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was loaded onto a silica gel column using EtOAc / PE (15:85). This yielded 120 mg (21%) of a grayish-white solid N-(1-methylindazole-7-yl)prop-2-enamide. LC MS (ES, m / z): [M+H] + =202.

[0837]

[0838] Step 2: N-(1-methylindazole-7-yl)prop-2-enamide (100.0 mg, 0.49 mmol, 1.0 eq), 6-bromo-3-methyl-1H-indazole (104.8 mg, 0.49 mmol, 1.0 eq), DMF (4.0 mL), Et3N (0.14 mL, 0.99 mmol, 2.0 eq), and Pd(dppf)Cl2.CH2Cl2 (41 mg, 0.05 mmol, 0.10 eq) were added to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 120 °C for 2 h. The crude mixture was purified by rapid preparative HPLC. This yielded 33 mg (20%) of a grayish-white solid (E)-3-(3-methyl-1H-indazole-6-yl)-N-(1-methyl-1H-indazole-7-yl)acrylamide.

[0839] LC MS(ES,m / z):[M+H] + =332.

[0840] 1 H NMR(300MHz,DMSO-d6,ppm):12.83(brs,1H),10.14(brs,1H),8.07(s,1H),7.81-7.67(m,4 H),7.44-7.41(m,1H),7.25-7.11(m,2H),7.01(d,J=15.9Hz,1H),4.12(s,3H),2.50(s,3H).

[0841] Example 40: (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0842]

[0843] Step 1: Add 5-fluoro-2,3-dihydroindene-1-one (800.0 mg, 5.33 mmol, 1.0 eq), NaOAc (874.14 mg, 10.66 mmol, 2.0 eq), MeOH (15.0 mL), and hydroxylamine hydrochloride (1.10 g, 15.98 mmol, 3.0 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 (30.0 mL) and H₂O (15.0 mL). Wash the organic phase with 20 mL of H₂O. Concentrate the organic layer. This yields 810 mg (92%) of a grayish-white solid N-[5-fluoro-2,3-dihydroindene-1-ide]hydroxylamine. LC MS (ES, m / z): [M+H] + =166.

[0844]

[0845] Step 2: N-[5-fluoro-2,3-dihydroindene-1-yl]hydroxylamine (810.0 mg, 4.90 mmol, 1.0 eq) and MeOH (20.0 mL) were added to a 50 mL round-bottom flask. Then, Pd / C (104.38 mg) was added under H₂. The resulting solution was stirred at room temperature 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, 5-fluoro-2,3-dihydro-1H-indene-1-amine. LC MS (ES, m / z): [M+H] + =152.

[0846]

[0847] Step 3: Add 5-fluoro-2,3-dihydro-1H-indene-1-amine (210.0 mg, 1.38 mmol, 1.0 eq), DCM (5.0 mL), and Et3N (0.4 mL, 2.77 mmol, 2.0 eq) to a 25 mL 3-necked round-bottom flask purified with nitrogen and maintained under a nitrogen inert atmosphere. Then add acryloyl chloride (188.58 mg, 2.08 mmol, 1.50 eq) at -30 °C. Stir the resulting solution at -30 °C for 10 min. Then terminate the reaction by adding 5 mL of water. Separate and concentrate the organic layer. Load the residue onto a silica gel column using EtOAc / PE (80:20). This yields 200 mg (70%) of a grayish-white solid N-(5-fluoro-2,3-dihydro-1H-indene-1-yl)prop-2-enamide. LC MS(ES,m / z):[M+H] + =206.

[0848]

[0849] Step 4: Add N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)acrylamide (100.0 mg, 0.48 mmol, 1.0 eq), 6-bromo-3-methyl-1H-indazole (102.8 mg, 0.48 mmol, 1.0 eq), Et3N (0.14 mL, 0.97 mmol, 2.0 eq), DMF (5.0 mL), and Pd(dppf)Cl2.CH2Cl2 (39.69 mg, 0.05 mmol, 0.10 eq) to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution at 120 °C for 2 h. Cool the reaction solution to room temperature. Purify the crude mixture by rapid preparative HPLC. This yielded 34 mg (20%) of a white solid (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide. LC MS (ES, m / z): [M+H] + =336.

[0850] 1 H NMR (300MHz, DMSO-d6, ppm): 12.78 (s, 1H), 8.48 (d, J = 8.1Hz, 1H), 7.74-7.61 (m, 3H), 7.32-7.24 (m, 2H), 7.13 -7.09(m,2H),6.73(d,J=15.9Hz,1H),5.40-5.37(m,1H),3.16-2.73(m,2H),2.52(s,3H),2.50-1.83(m,2H).

[0851] Example 41: (E)-N-(4-fluoro-3-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0852]

[0853] Step 1: Add 4-fluoro-3-methylaniline (600.0 mg, 4.79 mmol, 1.0 equiv), DCM (20.0 mL), and Et3N (2.0 mL, 14.38 mmol, 3.0 equiv) to a 100 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Then, add acryloyl chloride (520.73 mg, 5.75 mmol, 1.20 equiv) dropwise at 0 °C with stirring. Stir the resulting solution at room temperature for 1 hour. Concentrate the mixture. Load the residue onto a silica gel column using THF:PE (1:5–1:3). This yields 400 mg (56%) of pale yellow solid N-(4-fluoro-3-methylphenyl)prop-2-enamide.

[0854]

[0855] Step 2: N-(4-fluoro-3-methylphenyl)prop-2-eneamide (110.0 mg, 0.61 mmol, 1.0 equiv), 6-bromo-3-methyl-1H-indazole (155.47 mg, 0.74 mmol, 1.20 equiv), Pd(dppf)Cl2.CH2Cl2 (100.01 mg, 0.12 mmol, 0.20 equiv), DMF (4.0 mL), and Et3N (0.26 mL, 1.84 mmol, 3.0 equiv) were added to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen 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 20.4 mg (11%) of a grayish-white solid (E)-N-(4-fluoro-3-methylphenyl)-3-(3-methyl-1H-indazole-6-yl)acrylamide.

[0856] LC MS(ES,m / z):[M+H] + =310.

[0857] 1H NMR (300MHz, DMSO-d6, ppm): δ12.82(brs,1H),10.16(brs,1H),7.77-7.67(m,3H),7.62-7.59(m,1H),7.56 -7.51(m,1H),7.36(d,J=8.4Hz,1H),7.14-7.08(m,1H),6.88(d,J=15.6Hz,1H),2.51(s,3H),2.24(s,3H).

[0858] Example 42: (E)-N-(3-fluoro-4-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0859]

[0860] Step 1: Add 3-fluoro-4-methylaniline (550.0 mg, 4.40 mmol, 1.0 equiv), DCM (20.0 mL), and Et3N (1.2 mL, 8.79 mmol, 2.0 equiv) to a 100 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Then, add acryloyl chloride (477.34 mg, 5.27 mmol, 1.20 equiv) dropwise at 0 °C with stirring. Stir the resulting solution at room temperature for 1 hour. Concentrate the mixture. Load the residue onto a silica gel column using THF:PE (1:5–1:3). This yields 450 mg (57%) of a grayish-white solid, N-(3-fluoro-4-methylphenyl)prop-2-enamide.

[0861]

[0862] Step 2: N-(3-fluoro-4-methylphenyl)prop-2-eneamide (110.0 mg, 0.61 mmol, 1.0 equiv), 6-bromo-3-methyl-1H-indazole (155.5 mg, 0.74 mmol, 1.20 equiv), Pd(dppf)Cl2.CH2Cl2 (100.0 mg, 0.12 mmol, 0.20 equiv), DMF (4.0 mL), and Et3N (0.26 mL, 1.84 mmol, 3.0 equiv) were added to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen 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 35.8 mg (19%) of a grayish-white solid (E)-N-(3-fluoro-4-methylphenyl)-3-(3-methyl-1H-indazole-6-yl)acrylamide. LC MS(ES,m / z):[M+H] +=310.

[0863] 1 H NMR (300MHz, DMSO-d6, ppm): δ12.83(brs,1H),10.30(brs,1H),7.77-7.67(m,4H),7. 39-7.35(m,1H),7.30-7.20(m,2H),6.87(d,J=15.6Hz,1H),2.51(s,3H),2.20(s,3H).

[0864] Example 43: Racemic-(E)-3-(3-methyl-1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide

[0865]

[0866] Step 1: Add racemic trans-(1R,2R)-2-methylcyclohexane-1-amine hydrochloride (300.0 mg, 2.0 mmol, 1.0 eq), DCM (6.0 mL), and Et3N (0.84 mL, 6.01 mmol, 3.0 eq) to a 25 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Then add acryloyl chloride (181.43 mg, 2.0 mmol, 1.0 eq) at 0 °C. Stir the resulting solution at room temperature for 40 min. Then terminate the reaction by adding 5 mL of water. Dilute the resulting solution with 10 mL of DCM. Wash the resulting mixture with 10 mL of brine. Dry the organic layer with anhydrous sodium sulfate and concentrate. Load the residue onto a silica gel column with ethyl acetate / petroleum ether (22:78). This yielded 200 mg (60%) of a grayish-white solid N-[(1R,2R)-2-methylcyclohexyl]prop-2-enamide.

[0867] LC-MS(ES,m / z):[M+H] + =168.

[0868]

[0869] Step 2: DMF (4.0 mL), N-[(1R,2R)-2-methylcyclohexyl]prop-2-enamide (100.0 mg, 0.60 mmol, 1.0 eq), 6-bromo-3-methyl-1H-indazole (126 mg, 0.60 mmol, 1.0 eq), Et3N (0.25 mL, 1.79 mmol, 3.0 eq), and Pd(dppf)Cl2.CH2Cl2 (48.71 mg, 0.06 mmol, 0.10 eq) were added to an 8-mL sealed tube purified with nitrogen and kept under an inert nitrogen atmosphere. The resulting solution was stirred at 120 °C for 2 h. The crude mixture was purified by rapid preparative HPLC. This yielded 41 mg (23%) of a grayish-white solid racemic (E)-3-(3-methyl-1H-indazole-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide. LC MS(ES,m / z):[M+H] + =298.

[0870] 1 H NMR(300MHz,CD3OD-d4,ppm):7.75-7.60(m,3H),7.43-7.40(m,1H),6.70(d,J=15.6Hz,1H), 3.54-3.50(m,1H),2.57(s,3H),1.96-1.71(m,4H),1.48-1.37(m,5H),1.30(d,J=9.3Hz,3H).

[0871] Example 44: (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide

[0872]

[0873] A solution of 6-bromo-1H-indazole-3-carboxynitrile (40.0 mg, 0.18 mmol, 1.0 equiv), N-(2-methyl-2,3-dihydro-1H-indene-1-yl)prop-2-enamide (prepared according to Example 24, step 1 using 2-methylaminoindene, 36.26 mg, 0.18 mmol, 1.0 equiv), Pd(dppf)Cl2 (13.18 mg, 0.018 mmol, 0.10 equiv), and Et3N (0.075 mL, 0.54 mmol, 3.0 equiv) in DMF (2.0 mL) was added to an 8-mL vial. The resulting solution was stirred in an oil bath at 120 °C for 2 h. The mixture was cooled to room temperature. The crude mixture was purified by rapid preparative HPLC. This yielded 16 mg (26%) of a grayish-white solid, (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide. LC MS (ES, m / z): [M+H] + =343.

[0874] 1 H NMR(300MHz,DMSO-d6,ppm)δ8.59-8.30(m,1H),8.05-7.87(m,2H),7.77-7.55(m,2H),7.34-7.08(m,4H),6.97 -6.79(m,1H),5.50-4.98(m,1H),3.06-2.95(m,1H),2.84-2.62(m,1H),2.39-2.19(m,1H),1.25-0.88(m,3H).

[0875] Example 45: (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide

[0876]

[0877] A solution of 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (50.0 mg, 0.22 mmol, 1.0 equiv), N-(2-methyl-2,3-dihydro-1H-inden-1-yl)prop-2-enamide (prepared according to Example 24, step 1 using 2-methylaminoindenyl, 44.3 mg, 0.22 mmol, 1.0 equiv), Pd(dppf)Cl2 (16.1 mg, 0.022 mmol, 0.10 equiv), and Et3N (0.092 mL, 0.66 mmol, 3.0 equiv) in DMF (2.0 mL) was added to an 8-mL vial. The resulting solution was stirred in an oil bath at 120 °C for 2 h. The reaction solution was cooled to room temperature. The crude mixture was purified by rapid preparative HPLC. This yielded 29 mg (38%) of a grayish-white solid (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide. LC MS (ES, m / z): [M+H] + =348.

[0878] 1 H NMR(300MHz,DMSO-d6,ppm)δ10.99(s,1H),8.32-8.12(m,1H),7.54-7.46(m,1H),7.28-7.10(m,7H),6.69-6.57(m ,1H),5.40-5.02(m,1H),3.30(s,3H),3.07-3.0(m,1H),2.69-2.50(m,1H),2.27-2.20(m,1H),1.21-0.90(m,3H).

[0879] Example 46: (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0880]

[0881] A solution of 2-benzoxazolinone, 5-bromo-(50.0 mg, 0.23 mmol, 1.0 equiv), N-(2-methyl-2,3-dihydro-1H-inden-1-yl)prop-2-enamide (prepared according to Example 24, step 1 using 2-methylaminoindenamide, 47.0 mg, 0.23 mmol, 1.0 equiv), Pd(dppf)Cl2 (17.1 mg, 0.023 mmol, 0.10 equiv), and Et3N (0.098 mL, 0.70 mmol, 3.0 equiv) in DMF (2.0 mL) was added to an 8-mL vial. The resulting solution was stirred in an oil bath at 120 °C for 2 h. The reaction solution was cooled to room temperature. The crude mixture was purified by rapid preparative HPLC. This yielded 29 mg (37%) of a grayish-white solid (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide. LCMS (ES, m / z): [M+H] + =335.

[0882] 1 H NMR(300MHz,DMSO-d6,ppm)δ11.76(brs,1H),8.40-8.19(m,1H),7.56-7.48(m,1H),7.33-7.12(m,6 H),6.74-6.63(m,1H),5.39-4.99(m,1H),3.10-2.94(m,1H),2.69-2.20(m,2H),1.21-0.91(m,3H).

[0883] Example 47: (Z)-2-fluoro-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindoline-6-yl)acrylamide

[0884]

[0885] Step 1: DMF (20.0 mL), 6-bromo-1,3-dihydroindol-2-one (1.0 g, 4.72 mmol, 1.0 eq), methyl 2-fluoroacrylate (0.59 g, 5.66 mmol, 1.20 eq), Pd(dppf)Cl2.CH2Cl2 (77.0 mg, 0.094 mmol, 0.02 eq), and Et3N (1.3 mL, 9.43 mmol, 2.0 eq) were added to a 40-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 110 °C for 2 h. The resulting mixture was concentrated. The residue was loaded onto a silica gel column with a (25 / 75) flow rate. This yielded 420 mg (37%) of methyl 2-fluoro-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2-enoate as a yellow solid. LC-MS-PH-NRG0255-1(ES,m / z):[MH] + =234.

[0886]

[0887] Step 2: Methyl 2-fluoro-3-(2-oxo-1,3-dihydroindolin-6-yl)prop-2-enoate (150.0 mg, 0.64 mmol, 1.0 eq), 3-fluoro-2-methylaniline (239.42 mg, 1.91 mmol, 3.0 eq), and THF (3.0 mL) were added to an 8-mL sealed tube. Then, LiHMDS (1.92 mL, 1.92 mmol, 3.0 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 H₂O. The resulting solution was extracted with 2 x 10 mL EtOAc. The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by rapid preparative HPLC. This yielded 28 mg (13%) of a white solid (Z)-2-fluoro-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide. LC MS(ES,m / z):[M+H] + =329.

[0888] 1 H NMR (300MHz, DMSO-d6, ppm): δ10.50(s,1H),10.16(s,1H),7.31-6.93(m,7H),3.53(s,2H),2.12(s,3H).

[0889] Example 48: (E)-N-(3-chloro-2-methylphenyl)-N-methyl-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0890]

[0891] A solution of (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)methyl acrylate (prepared according to Example 11, step 2, 30.0 mg, 0.14 mmol, 1.0 equiv) in THF (2.0 mL) was added to an 8-mL sealed tube purified with nitrogen and maintained under a nitrogen inert atmosphere. Then, 3-chloro-N,2-dimethylaniline (27.60 mg, 0.18 mmol, 1.30 equiv) was added. The reaction mixture was cooled to 0 °C. Then, 1 M LiHMDS (0.68 mL, 0.68 mmol, 5.0 equiv) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was terminated by passing 1 mL of water and extracted with 2 x 5 mL EtOAc. The organic layer was concentrated under vacuum to obtain the crude product. The crude product was then purified by preparative HPLC. This yielded 9.6 mg (21%) of a white solid, (E)-N-(3-chloro-2-methylphenyl)-N-methyl-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =343.

[0892] Example 49: (E)-N-(2-methylcyclopentyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0893]

[0894] A solution of (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)methyl acrylate (prepared according to Example 11, step 2, 30.0 mg, 0.14 mmol, 1.0 equiv) in THF (2.0 mL) was added to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. Then, 2-methylcyclopentanamine (17.6 mg, 0.18 mmol, 1.30 equiv) was added. The reaction mixture was cooled to 0 °C. Then, 1 M LiHMDS (0.68 mL, 0.68 mmol, 5.0 equiv) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was terminated by passing 1 mL of water and extracted with 2 x 5 mL EtOAc. The organic layer was concentrated under vacuum to obtain the crude product. The crude product was then purified by preparative HPLC. This yielded 19 mg (48%) of a white solid (E)-N-(2-methylcyclopentyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =287.

[0895] Example 50: (E)-N-(3-fluoro-2-(methoxymethyl)phenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0896]

[0897] Step 1: THF (50.0 mL) and 2-fluoro-6-nitrobenzoic acid (2.0 g, 10.80 mmol, 1.0 eq) were added to a 250-mL round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Borane (32.41 mL, 32.41 mmol, 3.0 eq, 1 M / THF) was then added at 0 °C. The resulting solution was stirred at 50 °C for 10 h. The reaction was then terminated by adding 20 mL of 3 M HCl. The resulting solution was diluted with 50 mL of EtOAc. The organic layer was washed with 2 x 30 mL of brine. The solution was dried over sodium sulfate and evaporated under reduced pressure. This yielded 1.3 g (70%) of a light brown solid (2-fluoro-6-nitrophenyl)methanol.

[0898]

[0899] Step 2: Add (2-fluoro-6-nitrophenyl)methanol (1.30 g, 7.59 mmol, 1.0 eq), DMF (20.0 mL), and methyl iodine (5.39 g, 37.98 mmol, 5.0 eq) to a 40-mL sealed tube. Then add Cs₂CO₃ (3.71 g, 11.39 mmol, 1.50 eq) at 0 °C. Stir the resulting solution at 50 °C for 5 h. Filter off the solid. Dilute the filtrate with 100 mL of EtOAc. Wash the resulting mixture with 3 x 50 mL H₂O and 50 mL of brine. Dry the organic layer with sodium sulfate and evaporate. Purify the crude product by rapid preparative HPLC. This yields 0.91 g (64%) of a yellow oily 1-fluoro-2-(methoxymethyl)-3-nitrobenzene.

[0900]

[0901] Step 3: Add 1-fluoro-2-(methoxymethyl)-3-nitrobenzene (0.70 g, 3.78 mmol, 1.0 eq), MeOH (20.0 mL), H₂O (3.0 mL), and NH₄Cl (1.21 g, 22.68 mmol, 6.0 eq) to a 40-mL sealed tube. Then add Zn (1.24 g, 18.90 mmol, 5.0 eq) at 10°C. Stir the resulting solution at 25°C for 1 h. Filter off the solid. Dilute the resulting solution with 20 mL of DCM. Dry the mixture with anhydrous sodium sulfate and concentrate (at low temperature). This yields 0.21 g (35%) of a light brown, oily 3-fluoro-2-(methoxymethyl)aniline (this amine is unstable and is used directly and rapidly in the next step). LC-MS (ES, m / z): [M+H] + =156.

[0902]

[0903] Step 4: 3-fluoro-2-(methoxymethyl)aniline (200.0 mg, 1.28 mmol, 1.0 eq), DCM (4.0 mL), and Et3N (0.36 mL, 2.57 mmol, 2.0 eq) were added to an 8-mL sealed tube. Acryloyl chloride (116.6 mg, 1.28 mmol, 1.0 eq) was then added at 0°C. The resulting solution was stirred at 0°C for 0.5 h. The reaction was then terminated by adding 2 mL of water. The resulting mixture was washed with 2 mL of brine. The organic layer was dried over sodium sulfate and concentrated. This yielded 160 mg (59%) of a grayish-white solid, N-[3-fluoro-2-(methoxymethyl)phenyl]prop-2-enamide. LC-MS (ES, m / z): [M+H] + =210.

[0904]

[0905] Step 5: Add N-[3-fluoro-2-(methoxymethyl)phenyl]prop-2-enamide (100.0 mg, 0.47 mmol, 1.0 eq), DMF (4.0 mL), 6-bromo-3-methyl-1H-indazole (100.88 mg, 0.47 mmol, 1.0 eq), Et3N (0.2 mL, 1.43 mmol, 3.0 eq), and Pd(dppf)Cl2.CH2Cl2 (38.94 mg, 0.048 mmol, 0.10 eq) to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution at 120 °C for 2 h. Purify the crude mixture by rapid preparative HPLC. This yields 71 ​​mg (43%) of a white solid (E)-N-(3-fluoro-2-(methoxymethyl)phenyl)-3-(3-methyl-1H-indazole-6-yl)acrylamide. LC-MS(ES,m / z):[M+H] + =340.

[0906] 1 H NMR (300MHz, DMSO-d6, ppm): δ12.84(s,1H),9.55(s,1H),7.78-7.69(m,4H), 7.44-7.38(m,2H),7.11-7.02(m,2H),4.56(s,2H),3.32(s,3H),2.51(s,3H).

[0907] Example 51: (E)-3-(3-cyano-1H-indazole-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide

[0908]

[0909] Step 1: Add 220.0 mg of 6-bromo-1H-indazole-3-carboxylon (0.99 mmol, 1.0 equiv), 416.7 mg of dihydropyran (4.95 mmol, 5.0 equiv), 10.0 mL of DCM, and 34.1 mg of TsOH (0.20 mmol, 0.20 equiv) to a sealed 40 mL tube purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution overnight at room temperature. Concentrate the mixture. Load the residue onto a silica gel column using THF:PE (1:20–1:8). This yields 300 mg (99%) of a grayish-white solid, 6-bromo-1-(oxacyclohexane-2-yl)indazole-3-carboxylon.

[0910]

[0911] Step 2: Add N-(3-fluoro-2-methylphenyl)acrylamide (150.0 mg, 0.84 mmol, 1.0 equiv), 6-bromo-1-(oxacyclohexane-2-yl)indazole-3-carboxylonitrile (307.5 mg, 1.0 mmol, 1.20 equiv), Pd(dppf)Cl2.CH2Cl2 (68.2 mg, 0.08 mmol, 0.10 equiv), DMF (4.0 mL), and Et3N (0.35 mL, 2.51 mmol, 3.0 equiv) to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution at 120 °C for 3 h. Cool the reaction mixture to room temperature. Load the mixture onto a silica gel column using THF:PE (1:4–1:1). This yielded 150 mg (44%) of light brown solid (2E)-3-[3-cyano-1-(oxacyclohexane-2-yl)indazole-6-yl]-N-(3-fluoro-2-methylphenyl)acrylamide.

[0912]

[0913] Step 3: Add (2E)-3-[3-cyano-1-(oxacyclohexan-2-yl)indazole-6-yl]-N-(3-fluoro-2-methylphenyl)acrylamide (150.0 mg, 0.37 mmol, 1.0 equiv) and 4M HCl / dioxane (10 mL) to a 40-mL sealed tube. Stir the resulting solution overnight at room temperature. Concentrate the mixture. Purify the crude product by preparative HPLC. This yields 12.5 mg (11%) of a grayish-white solid (E)-3-(3-cyano-1H-indazole-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide.

[0914] LC-MS(ES,m / z):[M+H] + =321.

[0915] 1 H NMR (300MHz, DMSO-d6, ppm): δ14.55(brs,1H),9.68(s,1H),8.0-7.95(m,2H),7.80(d,J=15.9Hz,1H),7.68(d,J =9.0Hz,1H),7.49(d,J=9.6Hz,1H),7.28-7.20(m,1H),7.15(d,J=15.9Hz,1H),7.05-6.99(m,1H),2.17(s,3H).

[0916] Example 52: (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide

[0917]

[0918] Step 1: Add 3-methyl-3,4-dihydro-2H-1-benzopyran-4-amine (110.0 mg, 0.67 mmol, 1.0 equiv), DCM (10.0 mL), and Et3N (0.19 mL, 1.35 mmol, 2.0 equiv) to a 25 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Then, add acryloyl chloride (67.10 mg, 0.74 mmol, 1.10 equiv) dropwise at 0 °C with stirring. Stir the resulting solution at room temperature for 2 hours. Then terminate the reaction by adding 10 mL of water. Extract the resulting solution with 2 x 15 mL dichloromethane, dry with anhydrous sodium sulfate, and concentrate. Load the residue onto a silica gel column using EtOAc / PE (1 / 5). This yielded 110 mg (75%) of pale yellow solid N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)prop-2-enamide.

[0919] LC-MS(ES,m / z):[M+H] + =218.

[0920]

[0921] Step 2: Add N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)prop-2-enamide (120.0 mg, 0.55 mmol, 1.0 equiv), DMF (5.0 mL), 6-bromo-3-methyl-1H-indazole (116.6 mg, 0.55 mmol, 1.0 equiv), Et3N (0.23 mL, 1.66 mmol, 3.0 equiv), and Pd(dppf)Cl2.CH2Cl2 (22.50 mg, 0.028 mmol, 0.05 equiv) to an 8-mL vial purified with nitrogen and kept under an inert nitrogen atmosphere. Stir the resulting solution at 120 °C for 5 h. Cool the reaction mixture to room temperature. Load the residue onto a silica gel column using EtOAc (1 / 3). This yielded 55 mg (29%) of a grayish-white solid (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =348.

[0922] 1H NMR(300MHz,DMSO-d6,ppm):12.80(brs,1H),8.52-8.33(m,1H),7.74-7.62(m,3H),7.33-7.28(m,1H),7.18-7.13(m,2H),6.92- 6.73(m,3H),5.24-4.81(m,1H),4.24-4.10(m,1H),3.98-3.88(m,1H),2.50-2.49(m,3H),2.28-2.04(m,1H),0.98-0.90(m,3H).

[0923] Example 53: (E)-N-(2-methyl-1,2,3,4-tetrahydronaphth-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0924]

[0925] Step 1: 2-Methyl-1,2,3,4-tetrahydronaphthyl-1-amine (160.0 mg, 0.99 mmol, 1.0 equiv), DCM (10.0 mL), and Et3N (0.28 mL, 1.98 mmol, 2.0 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 (98.79 mg, 1.09 mmol, 1.10 equiv) was then added dropwise at 0 °C with stirring. The resulting solution was stirred at room temperature for 2 hours. The reaction was then terminated by adding 5 mL of water. The resulting solution was extracted with 2 x 10 mL DCM, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column using EtOAc / PE (1 / 5). This yielded 140 mg (66%) of pale yellow solid N-(2-methyl-1,2,3,4-tetrahydronaphthyl-1-yl)prop-2-enamide.

[0926] LC-MS(ES,m / z):[M+H] + =216.

[0927]

[0928] Step 2: Add N-(2-methyl-1,2,3,4-tetrahydronaphthyl-1-yl)prop-2-enamide (140.0 mg, 0.65 mmol, 1.0 equiv), DMF (5.0 mL), 6-bromo-3-methyl-1H-indazole (137.3 mg, 0.65 mmol, 1.0 equiv), Et3N (0.27 mL, 1.95 mmol, 3.0 equiv), and Pd(dppf)Cl2.CH2Cl2 (26.5 mg, 0.033 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 5 h. Cool the reaction mixture to room temperature. Purify the crude mixture by preparative HPLC. This yielded 30 mg (13%) of a grayish-white solid (E)-N-(2-methyl-1,2,3,4-tetrahydronaphthyl-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide. LC-MS (ES, m / z): [M+H]+=346.

[0929] 1 H NMR(300MHz,DMSO-d6,ppm):12.77(brs,1H),8.39-8.15(m,1H),7.74-7.59(m,3H),7.34-7.11(m,5H),6.84-6.76(m,1 H),5.23-4.76(m,1H),2.84-2.77(m,2H),2.51-2.48(m,3H),2.08-1.98(m,1H),1.97-1.52(m,2H),1.10-0.90(m,3H).

[0930] Example 54: (E)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0931]

[0932] Step 1: Add (1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-amine hydrochloride (300.0 mg, 1.50 mmol, 1.0 equiv), DCM (20.0 mL), and Et3N (0.31 mL, 2.25 mmol, 1.50 equiv) to a 100 mL 3-necked round-bottom flask purified with nitrogen and maintained under a nitrogen inert atmosphere. Then, add acryloyl chloride (163.2 mg, 1.80 mmol, 1.20 equiv) dropwise at 0 °C with stirring. Stir the resulting solution at room temperature for 2 hours. Concentrate the resulting mixture. Load the residue onto a silica gel column using THF:PE (1:5–1:3). This yields 200 mg (61%) of a grayish-white solid N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-yl]prop-2-enamide.

[0933]

[0934] Step 2: Add N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (140.0 mg, 0.64 mmol, 1.0 equiv), 6-bromo-3-methyl-1H-indazole (163.2 mg, 0.77 mmol, 1.20 equiv), Pd(dppf)Cl2.CH2Cl2 (52.5 mg, 0.064 mmol, 0.10 equiv), DMF (4 mL), and Et3N (0.27 mL, 1.93 mmol, 3.0 equiv) to an 8-mL sealed tube purified with nitrogen and maintained under a nitrogen inert atmosphere. Stir the resulting solution at 120 °C for 1 h. Cool the reaction mixture to room temperature. Purify the crude mixture by rapid preparative HPLC. This yielded 28.6 mg (13%) of a grayish-white solid (E)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =348.

[0935] 1¹H NMR (300MHz, DMSO-d6, ppm): δ 12.78 (brs, 1H), 8.58 (d, J = 8.7Hz, 1H), 7.74–7.62 (m, 3H), 7.33–7.18 (m, 5H), 6.75 (d, J = 15.6Hz, 1H), 5.34–5.30 (m, 1H), 4.07–4.01 (m, 1H), 3.38 (s, 3H), 3.35–3.27 (m, 1H), 2.84–2.76 (m, 1H), 2.49 (s, 3H). Example 55: (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[0936] Step 1: Add (1R)-2,3-dihydro-1H-indene-1-amine (100.0 mg, 0.75 mmol, 1.0 equiv), DCM (5.0 mL), and Et3N (0.21 mL, 1.50 mmol, 2.0 equiv) to an 8-mL sealed tube. Then add acryloyl chloride (81.54 mg, 0.90 mmol, 1.20 equiv) at -30°C. Stir the resulting solution at -30°C for 10 min. Then terminate the reaction by adding 5 mL of water. Dry the organic phase with Na2SO4 and concentrate. Load the residue onto a silica gel column with ethyl acetate / petroleum ether (15:75). This yields 93 mg (66%) of white solid N-[(1R)-2,3-dihydro-1H-indene-1-yl]prop-2-enamide.

[0937] LC-MS-PH-NRG0457-1(ES,m / z):[M+H] + =188.

[0938]

[0939] Step 2: Add N-[(1R)-2,3-dihydro-1H-indene-1-yl]prop-2-enamide (60.0 mg, 0.32 mmol, 1.0 equiv), 6-bromo-3-methyl-1H-indazole (67.63 mg, 0.32 mmol, 1.0 equiv), DMF (2.0 mL), Et3N (0.09 mL, 0.64 mmol, 2.0 equiv), and Pd(dppf)Cl2.CH2Cl2 (5.2 mg, 0.06 mmol, 0.02 equiv) to an 8-mL sealed tube purified with nitrogen and maintained under a nitrogen inert atmosphere. Stir the resulting solution at 120 °C for 2 h. Purify the crude mixture by rapid preparative HPLC. This yielded 41 mg (40%) of a white solid (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =318.

[0940] 1 H NMR (300MHz, DMSO-d6, ppm): 12.78 (s, 1H), 8.47 (d, J = 8.4Hz, 1H), 7.73-7.62 (m, 3H), 7.32-7.17 (m, 5H ), 6.74 (d, J = 15.9 Hz, 1H), 5.47-5.39 (m, 1H), 3.03-2.79 (m, 2H), 2.51-2.41 (m, 4H), 1.90-1.81 (m, 1H).

[0941] Example 56: (E)-N-(chroman-4-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0942]

[0943] According to Example 11, step 4 involved preparing a white solid (E)-N-(chroman-4-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylic acid and chroman-4-amine. LC-MS (ES, m / z): [M+H] + =337.

[0944] Example 57: (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(1,2,3,4-tetrahydronaphth-1-yl)acrylamide

[0945]

[0946] According to Example 11, step 4 uses (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylic acid and 1,2,3,4-tetrahydronaphthyl-1-amine to prepare a white solid (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(1,2,3,4-tetrahydronaphthyl-1-yl)acrylamide.

[0947] LC-MS(ES,m / z):[M+H] + =335.

[0948] Example 58: (E)-N-(2-methyl-1,2,3,4-tetrahydronaphth-1-yl)-3-(2-oxoindololin-6-yl)acrylamide

[0949]

[0950] A solution of (E)-3-(2-oxoindoline-6-yl)acrylic acid (50.0 mg, 0.25 mmol, 1.00 equiv), 2-methyl-1,2,3,4-tetrahydronaphthyl-1-amine (40.3 mg, 0.25 mmol, 1.00 equiv), HATU (141.4 mg, 0.37 mmol, 1.50 equiv), and DIPEA (95.4 mg, 0.74 mmol, 3.00 equiv) in DMF (2.00 mL) was added to an 8 mL vial. The solution was stirred at 20 °C for 2 h. The mixture was purified by rapid preparative HPLC. This yielded 19 mg (22%) of a grayish-white solid (E)-N-(2-methyl-1,2,3,4-tetrahydronaphthyl-1-yl)-3-(2-oxoindoline-6-yl)acrylamide. LC-MS(ES,m / z):[M+H]+=347.

[0951] 1 H NMR(300MHz,DMSO-d6,ppm)δ10.51(brs,1H),8.40-8.20(m,1H),7.50-7.45(m,1H),7.27-7.14(m,6H),7.05-6.96( m,1H),6.68-6.63(m,1H),5.45-5.00(m,1H),3.51(s,2H),3.10-3.00(m,1H),2.70-2.20(m,4H),1.20-0.91(m,3H).

[0952] Example 59: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindoline-6-yl)acrylamide

[0953]

[0954] A solution of (E)-3-(2-oxoindoline-6-yl)acrylic acid (50.0 mg, 0.25 mmol, 1.00 equivalent), 2,3-dihydro-1H-indole-1-amine (33.3 mg, 0.25 mmol, 1.00 equivalent), HATU (141.4 mg, 0.37 mmol, 1.50 equivalent), and DIPEA (95.4 mg, 0.74 mmol, 3.00 equivalent) in DMF (2.00 mL) was added to an 8 mL vial. The solution was stirred at 20 °C for 2 h. The mixture was purified by rapid preparative HPLC. This yielded 15 mg (19%) of a grayish-white solid (E)-N-(2,3-dihydro-1H-indole-1-yl)-3-(2-oxoindoline-6-yl)acrylamide. LC-MS (ES, m / z): [M+H]+ = 319.

[0955] 1 H NMR (300MHz, DMSO-d6, ppm) δ10.50(brs,1H),8.46(d,J=8.1Hz,1H),7.45(d,J=15.6Hz,1H),7.29-7.12(m,6H),6.98(s ,1H),6.62(d,J=15.9Hz,1H),5.45-5.37(m,1H),3.51(s,2H),3.02-2.79(m,2H),2.50-2.40(m,1H),1.89-1.82(m,1H).

[0956] Example 60: (E)-N-(3,5-difluoro-2-methylphenyl)-3-(2-oxoindoline-6-yl)acrylamide

[0957]

[0958] Step 1: Add 4-chloro-3,5-difluoro-2-methylaniline (160.00 mg, 0.90 mmol, 1.00 equiv), EtOH (30.00 mL), 4M HCl / EtOH (1.00 mL), and Pd / C (47.94 mg) to a 100-mL pressure vessel reactor. Evacuate the flask and purge it three times with nitrogen, then purge with hydrogen. Stir the resulting solution overnight at 70°C under a hydrogen atmosphere (30 atm). Cool the reaction mixture to room temperature. Filter off the solids. Concentrate the resulting mixture. This yields 120 mg (crude) of 3,5-difluoro-2-methylaniline hydrochloride.

[0959]

[0960] Step 2: Add 3,5-difluoro-2-methylaniline hydrochloride (120.00 mg, 0.67 mmol, 1.00 equiv), DCM (20 mL), and Et3N (0.28 mL, 2.01 mmol, 3.00 equiv) to a 100 mL 3-necked round-bottom flask purified with nitrogen and maintained under a nitrogen inert atmosphere. Then, add acryloyl chloride (90.7 mg, 1.00 mmol, 1.50 equiv) dropwise at 0 °C with stirring. Stir the resulting solution overnight at room temperature. Concentrate the mixture. Load the residue onto a silica gel column using THF:PE (1:5–1:3). This yields 120 mg (91%) of a grayish-white solid N-(3,5-difluoro-2-methylphenyl)prop-2-enamide.

[0961]

[0962] Step 3: Add N-(3,5-difluoro-2-methylphenyl)prop-2-enamide (120.00 mg, 0.61 mmol, 1.00 equivalent), 6-bromo-1,3-dihydroindole-2-one (154.9 mg, 0.73 mmol, 1.20 equivalent), Pd(dppf)Cl2.CH2Cl2 (49.6 mg, 0.06 mmol, 0.10 equivalent), DMF (4.00 mL), and Et3N (0.25 mL, 1.83 mmol, 3.00 equivalent) to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. Stir the resulting solution at 100 °C for 2 h. Cool the reaction mixture to room temperature. Purify the crude mixture by preparative HPLC. Thus, 11.3 mg (6%) of a grayish-white solid (E)-N-(2,3-dihydro-1H-indene-1-yl)-3-(2-oxoindoline-6-yl)acrylamide was obtained.

[0963] LC-MS(ES,m / z):[M+H] + =329.

[0964] 1 H NMR (300MHz, DMSO-d6, ppm): δ10.57 (s, 1H), 9.88 (s, 1H), 7.95-7.90 (m, 1H), 7.54 (d, J = 15. 6Hz,1H),7.31-7.17(m,3H),7.04(s,1H),6.96(d,J=15.3Hz,1H),3.52(s,2H),2.22(s,3H).

[0965] Example 61: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide

[0966]

[0967] Add 5-bromo-4-fluoro-3H-1,2,3-benzotriazole (50.0 mg, 0.23 mmol, 1.00 equivalent), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (43.3 mg, 0.23 mmol, 1.00 equivalent), Pd(dppf)Cl2 (16.9 mg, 0.023 mmol, 0.10 equivalent), Et3N (0.096 mL, 0.70 mmol, 3.00 equivalent), and DMF (3.00 mL) to an 8-mL round-bottom flask. 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 PE / THF (1 / 1). This yielded 19 mg (25%) of solid (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =323.

[0968] 1 H NMR (300MHz, DMSO-d6, ppm): δ8.63 (d, J=8.1Hz, 1H), 7.93-7.63 (m, 3H), 7.32-7.15 (m, 4H), 6.85 (d,J=15.9Hz,1H),5.47-5.35(m,1H),3.06-2.81(m,2H),2.47-2.39(m,1H),1.90-1.78(m,1H).

[0969] Example 62: (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide

[0970]

[0971] Add a solution of 6-bromo-4-fluoro-1H-1,2,3-benzotriazole (40.00 mg, 0.18 mmol, 1.00 equivalent), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (34.7 mg, 0.18 mmol, 1.00 equivalent), Pd(dppf)Cl2 (13.6 mg, 0.019 mmol, 0.10 equivalent), and Et3N (0.077 mL, 0.55 mmol, 3.00 equivalent) in DMF (2.00 mL) to an 8-mL round-bottom flask. Stir the resulting solution in an oil bath at 120 °C for 1 h. Cool the reaction mixture. Load the mixture onto a silica gel column using PE / THF (1 / 1). This yielded 17.8 mg (30%) of a white solid (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide. LC MS (ES, m / z): [M+H] + =323.

[0972] 1 H NMR (300MHz, DMSO-d6, ppm): δ8.51(d,J=8.1Hz,1H),7.90(s,1H),7.68(d,J=15.6Hz,1H),7.41(d,J=12.0Hz,1H),7. 28-7.15(m,4H),6.77(d,J=15.6Hz,1H),5.47-5.34(m,1H),3.03-2.81(m,2H),2.44-2.35(m,1H),1.93-1.78(m,1H).

[0973] Example 63: (E)-N-(5-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide

[0974]

[0975] A solution of (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)methyl acrylate (30.0 mg, 0.14 mmol, 1.00 equiv) in THF (2.00 mL) was added to an 8-mL sealed tube purified with nitrogen and maintained under an inert nitrogen atmosphere. Then, 5-chloro-2-methylaniline (25.4 mg, 0.18 mmol, 1.30 equiv) was added. The reaction mixture was cooled to 0 °C. Then, 1 M LiHMDS (0.68 mL, 0.68 mmol, 5.00 equiv) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was terminated by adding 1 mL of water and extracted with 2 x 5 mL ETOAc. The organic layer was concentrated under vacuum to obtain the crude product. The crude product was then purified by preparative HPLC. This yielded 5 mg (11%) of a white solid (E)-N-(5-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =329.

[0976] 1 H NMR (300MHz, DMSO-d6, ppm) δ9.42 (s, 1H), 7.85 (s, 1H), 7.60 (d, J = 15.9Hz, 1H), 7.36-7.11 (m, 5H), 6.97 (d, J = 15.6Hz, 1H), 2.26 (s, 3H).

[0977] Example 64: (E)-N-(2-methylcyclohexyl)-3-(2-oxoindoline-6-yl)acrylamide

[0978]

[0979] A solution of (E)-3-(2-oxoindoline-6-yl)acrylic acid (50.00 mg, 0.25 mmol, 1.00 equivalent), 2-methylcyclohexaneamine (28.25 mg, 0.25 mmol, 1.00 equivalent), HATU (141.38 mg, 0.37 mmol, 1.50 equivalent), and DIPEA (95.41 mg, 0.74 mmol, 3.00 equivalent) in DMF (2.00 mL) was added to an 8-mL vial. The solution was stirred at 20 °C for 2 h. The mixture was purified by rapid preparative HPLC. This yielded 8.3 mg (11%) of a grayish-white solid (E)-N-(2-methylcyclohexyl)-3-(2-oxoindoline-6-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =299.

[0980] Example 65: (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide

[0981]

[0982] Step 1: Add 2,3-dihydro-1-benzopyran-4-one (15.00 g, 101.24 mmol, 1.00 equiv) and THF (200 mL) to a 500 mL 3-necked round-bottom flask purified with nitrogen and maintained under an inert nitrogen atmosphere. Then, add LiHMDS (1 M THF solution, 1.20 equiv) dropwise at -78 °C with stirring. Stir the resulting solution at -78 °C for 40 min. Add MeI (17.24 g, 121.49 mmol, 1.20 equiv) in THF (10 mL) dropwise at -78 °C with stirring. Continue reacting the resulting solution at -78 °C for 40 min with stirring. Then, continue stirring at 25 °C for 1 h. Finally, terminate the reaction by adding 150 mL of NH4Cl. Extract the resulting solution with 2 x 150 mL ethyl acetate, dry the organic layer 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% yield) of a pale yellow oily 3-methyl-2,3-dihydro-1-benzopyran-4-one.

[0983]

[0984] Step 2: Add 1.10 g (6.78 mmol, 1.00 equiv), 20.00 mL MeOH, 1.41 g (20.35 mmol, 3.00 equiv), and 2.06 g (20.35 mmol, 3.00 equiv) 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 resulting solution with 10 mL of water. Extract the resulting solution with 2 x 10 mL ethyl acetate and dry the organic layer with anhydrous sodium sulfate. Concentrate the resulting mixture. This yields 1 g (83% yield) of white solid N-[(4E)-3-methyl-2,3-dihydro-1-benzopyran-4-ide]hydroxyamine.

[0985]

[0986] Step 3: 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) were added to a 100 mL 1-necked round-bottom flask purified with hydrogen and maintained under an inert hydrogen atmosphere. The resulting solution was stirred at 40 °C for 12 h. The solid was filtered off. The resulting mixture was concentrated. This yielded 530 mg (82% yield) of a pale yellow oily 3-methyl-3,4-dihydro-2H-1-benzopyran-4-amine.

[0987]

[0988] Step 4: Add 3-methyl-3,4-dihydro-2H-1-benzopyran-4-amine (300.00 mg, 1.838 mmol, 1.00 equiv), DCM (10.00 mL), and Et3N (371.98 mg, 3.676 mmol, 2.00 equiv) to a 40 mL vial. Then, with stirring, add a 2 mL solution of acryloyl chloride (182.99 mg, 2.022 mmol, 1.10 equiv) in DCM at 0 °C. Stir the resulting solution at 0 °C for 5 h. Then terminate the reaction by adding 8 mL of water. Extract the resulting solution with 2 x 15 mL dichloromethane and dry the organic layer with anhydrous sodium sulfate and concentrate. Load the residue onto a silica gel column with ethyl acetate / petroleum ether (1 / 2). This yielded 280 mg (70% yield) of a grayish-white solid N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)prop-2-enamide.

[0989]

[0990] Step 5: Add N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)prop-2-enamide (150.00 mg, 0.690 mmol, 1.00 equivalent), DMF (6.00 mL), 6-bromo-3-methyl-1H-indazole (145.72 mg, 0.690 mmol, 1.00 equivalent), Et3N (174.65 mg, 1.725 mmol, 2.50 equivalent), and Pd(dppf)Cl2.CH2Cl2 (33.74 mg, 0.041 mmol, 0.06 equivalent) to a 20-mL vial purified with nitrogen and kept under an inert nitrogen atmosphere. Stir the resulting solution overnight at 120°C. Cool the reaction mixture to room temperature. Load the residue onto a silica gel column using ethyl acetate / petroleum ether (1 / 1). This yielded 110 mg of a pale yellow solid racemic mixture of cis / trans isomers. The mixture was purified by chiral preparative HPLC to obtain four isolated stereoisomers, including (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4R)-3-methylchroman-4-yl)acrylamide (Example 65c). The cis-trans isomers were designated using NOESY NMR. The stereochemistry of each enantiomer pair was arbitrarily assigned.

[0991] Example 65a: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4S)-3-methylchroman-4-yl)acrylamide LC-MS (ES, m / z): [M+H] + =348.

[0992] 1 H-NMR (300MHz, DMSO-d6, ppm): δ12.77 (s, 1H), 8.33 (d, J = 6.6Hz, 1H), 7.73-7.61 (m, 3H),7.30-7.16(m,3H),6.91-6.77(m,3H),5.23-5.20(m,1H),4.13(d,J=8.1Hz,1H).

[0993] Example 65b: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4R)-3-methylchroman-4-yl)acrylamide

[0994] LC-MS1(ES,m / z):[M+H] + =348.

[0995] 1H-NMR (300MHz, DMSO-d6, ppm): δ12.77(s,1H),8.33(d,J=6.9Hz,1H),7.73-7.61(m,3H),7.30-7.16(m,3H),6.91-6.77(m,3H) ),5.23-5.20(m,1H),4.13(d,J=8.1Hz,1H),3.94-3.89(m,1H),2.55-2.50(m,3H),2.29-2.33(m,1H),0.91(d,J=4.5Hz,3H).

[0996] Example 65c: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4R)-3-methylchroman-4-yl)acrylamide

[0997] LC-MS(ES,m / z):[M+H] + =348.

[0998] 1 H-NMR (300MHz, DMSO-d6, ppm): δ12.77 (s, 1H), 8.49 (d, J = 6.3Hz, 1H), 7.73-7.62 (m, 3H), 7.32-7.30 (m, 1H), 7.18-7.13 (m, 2H), 6.91-6.87 (m, 1H),6.81-6.74(m,2H),4.86-4.82(m,1H),4.23-4.21(m,1H),3.97-3. 95(m,1H),2.55-2.50(m,3H),2.08-2.05(m,1H),0.97(d,J=5.1Hz,3H).

[0999] Example 65d: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4S)-3-methylchroman-4-yl)acrylamide LC-MS (ES, m / z): [M+H] + =348.

[1000] 1H-NMR (300MHz, DMSO-d6, ppm): δ12.77 (s, 1H), 8.49 (d, J = 6.3Hz, 1H), 7.73-7.62 (m, 3H), 7.32-7.30 (m, 1H), 7.18-7.13 (m, 2H), 6.91-6.87 (m, 1H),6.81-6.74(m,2H),4.86-4.82(m,1H),4.23-4.21(m,1H),3.97-3. 95(m,1H),2.55-2.50(m,3H),2.08-2.05(m,1H),0.97(d,J=5.1Hz,3H).

[1001] Example 66: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1S,2S)-2-(oxecyclobutane-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl)acrylamide

[1002]

[1003] Step 1: Add oxetane-3-ylmethanol (2.00 g, 22.70 mmol, 1.00 equiv), trifluoromethanesulfonic anhydride (9.61 g, 34.050 mmol, 1.50 equiv), Et3N (4.59 g, 45.40 mmol, 2.00 equiv), and DCM (50.00 mL) to a 100 mL three-necked round-bottom flask. Stir the resulting solution at 20 °C for 10 h. Wash the resulting mixture with 2 x 50 mL NaCO3 aqueous solution and 1 x 50 mL NaCl aqueous solution. Dry the organic layer with anhydrous sodium sulfate and concentrate it, then use it directly in the next step without purification.

[1004]

[1005] Step 2: Add a 20.00 mL solution of N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (1.00 g, 4.01 mmol, 1.00 equiv), oxetane-3-ylmethyltrifluoromethanesulfonate (0.88 g, 4.01 mmol, 1.00 equiv), and NaH (0.14 g, 6.01 mmol, 1.50 equiv) in THF to a 100 mL 3-necked round-bottom flask. Stir the resulting solution at 20 °C for 10 h. Then terminate the reaction by adding 5 mL of water. Extract the resulting solution with 2 x 20 mL ethyl acetate and combine the organic layers. Concentrate the organic layers and load the residue onto a silica gel column using ethyl acetate / petroleum ether (1 / 1). Thus, 150 mg of solid N-[(1S,2S)-2-(oxocyclobutane-3-ylmethoxy)-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester was obtained.

[1006]

[1007] Step 3: Add a solution of N-[(1S,2S)-2-(oxetane-3-ylmethoxy)-2,3-dihydro-1H-indene-1-yl]tert-butyl carbamate (140.00 mg, 0.438 mmol, 1.00 equiv) in 2M HCl (g) / MeOH solution (2.00 mL) and MeOH (2.00 mL) to an 8-mL vial. Stir the resulting solution at 10°C for 2 h. Concentrate the resulting mixture. This yields 35 mg of solid (1S,2S)-2-(oxetane-3-ylmethoxy)-2,3-dihydro-1H-indene-1-amine.

[1008]

[1009] Step 4: Add a 3.00 mL solution of (1S,2S)-2-(oxetane-3-ylmethoxy)-2,3-dihydro-1H-indene-1-amine (25.00 mg, 0.114 mmol, 1.00 equiv), (E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid (intermediate 3, 22.83 mg, 0.114 mmol, 1.00 equiv), HATU (65.02 mg, 0.171 mmol, 1.50 equiv), and Et3N (34.61 mg, 0.342 mmol, 3.00 equiv) in DMF to an 8 mL vial. Stir the resulting solution at 20 °C for 2 h. Purify the crude mixture by preparative HPLC. This yielded 15 mg of a grayish-white solid (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1S,2S)-2-(oxecyclobutane-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =404. 1 H-NMR (300MHz, DMSO-d6, ppm) δ12.78 (s, 1H), 8.58 (d, J = 8.4Hz, 1H), 7.74-7.63 (m,3H),7.33-7.22(m,5H),6.75(d,J=15.9Hz,1H),5.34-5.29(m,1H),4.65-4. 60(m,2H),4.32-4.28(m,2H),4.17-4.14(m,1H),3.89-3.86(m,1H),3.84-3.74 (m,1H),3.36-3.34(m,1H),3.32-3.31(m,1H),2.86-2.78(m,1H),2.50(s,3H).

[1010] Example 67: (E)-N-((1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[1011]

[1012] Step 1: Add a solution of N-(2-hydroxy-octahydro-1H-indene-1-yl)carbamate tert-butyl ester (200.00 mg, 0.783 mmol, 1.00 equiv), allyl bromide (94.75 mg, 0.783 mmol, 1.00 equiv), and NaH (5.00 mg, 0.783 mmol, 60%) in THF (3.00 mL) to an 8 mL vial. Stir the resulting solution at 20 °C for 10 h. Then terminate the reaction by adding 0.5 mL of water. Concentrate the mixture and load the residue onto a silica gel column with ethyl acetate / petroleum ether (1 / 1). This yields 150 mg (66% yield) of pale yellow solid N-[(1S,2S)-2-(prop-2-en-1-yloxy)-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester.

[1013]

[1014] Step 2: Add a solution of N-[2-(prop-2-en-1-yloxy)-octahydro-1H-indene-1-yl]carbamate tert-butyl ester (140.00 mg, 0.474 mmol, 1.00 equivalent), 1M ZnEt2 (4.74 mL, 4.739 mmol, 10.00 equivalent), CH2I2 (1015.41 mg, 3.791 mmol, 8.00 equivalent), and TFA (432.28 mg, 3.791 mmol, 8.00 equivalent) in DCM (5.00 mL) to a 40 mL vial. Stir the resulting solution at 20 °C for 10 h. Concentrate the mixture and load the residue onto a silica gel column using ethyl acetate / petroleum ether (10 / 1). This yielded 70 mg (48% yield) of solid N-[(1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester.

[1015]

[1016] Step 3: Add a solution of N-[2-(cyclopropylmethoxy)-octahydro-1H-indene-1-yl]tert-butyl carbamate (50.00 mg, 1.00 equiv) in 2M HCl (g) / MeOH solution (3.00 mL) and MeOH (3.00 mL) to an 8-mL vial. Stir the resulting solution at 20°C for 2 h. Concentrate the mixture. This yields 30 mg of a grayish-white solid (1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-indene-1-amine.

[1017]

[1018] Step 4: Add a 2.00 mL solution of (1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-indene-1-amine (20.00 mg, 0.098 mmol, 1.00 equivalent), (E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid (19.70 mg, 0.098 mmol, 1.00 equivalent), HATU (56.11 mg, 0.148 mmol, 1.50 equivalent), and Et3N (29.87 mg, 0.295 mmol, 3.00 equivalent) in DMF to an 8 mL vial. Stir the resulting solution at 20 °C for 2 h. Purify the mixture by preparative HPLC. This yielded 20 mg (52% yield) of a grayish-white solid, (E)-N-((1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =388.

[1019] 1 H-NMR (300MHz, DMSO-d6, ppm) δ8.57(d,J=8.7Hz,1H),7.74-7.62(m,3H),7.31(d,J=7.8Hz,1H),7.25-7.19(m,4H),6.74(d,J=15.6Hz,1H),5.31- 5.27(m,1H),4.19-4.12(m,1H),3.48-3.44(m,1H),3.38-3.32(m,2H),2. 84-2.73(m,1H),1.04-1.00(m,1H),0.53-0.42(m,2H),0.24-0.12(m,2H)

[1020] Example 68: (E)-N-((1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[1021]

[1022] Step 1: Add a 60.00 mL solution of 2-fluoroethanol (3.20 g, 49.95 mmol, 1.00 equiv), trifluoromethanesulfonic anhydride (14.09 g, 49.95 mmol, 1.00 equiv), and Et3N (10.11 g, 99.91 mmol, 2.00 equiv) in DCM to a 100 mL 3-necked round-bottom flask. Stir the resulting solution in a liquid nitrogen bath at -78 °C for 10 h. Wash the resulting mixture with 2 x 50 mL NaCO3 aqueous solution and 1 x 50 mL NaCl aqueous solution. Dry the organic layer with anhydrous sodium sulfate and concentrate to obtain 9.7 g, which is used directly in the next step without purification.

[1023]

[1024] Step 2: Add a solution of N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (400.00 mg, 1.60 mmol, 1.00 equiv), 2-fluoroethyl trifluoromethanesulfonate (629.32 mg, 3.21 mmol, 2.00 equiv), and NaH (77.01 mg, 3.21 mmol, 2.00 equiv) in THF (10.00 mL) to a 20 mL vial. Stir the resulting solution at 20 °C for 10 h. Then terminate the reaction by adding 5 mL of water. Extract the resulting solution with 2 x 20 mL ethyl acetate and combine the organic layers. Concentrate the organic layers and load the residue onto a silica gel column using ethyl acetate / petroleum ether (1 / 1). This yielded 300 mg (63% yield) of pale yellow solid N-[(1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester.

[1025]

[1026] Step 3: Add a solution of N-[(1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (300.00 mg) in 2M HCl (g) / MeOH solution (5.00 mL) and MeOH (5.00 mL) to a 20 mL vial and stir at 20 °C for 10 h. Concentrate the resulting mixture. This yields 120 mg of a pale yellow solid (1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-indene-1-amine.

[1027]

[1028] Step 4: Add (1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-indene-1-amine (40.00 mg, 0.205 mmol, 1.00 equiv), ((E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid (intermediate 3, 41.03 mg, 0.205 mmol, 1.00 equiv), HATU (116.85 mg, 0.307 mmol, 1.50 equiv), and DIP to an 8-mL vial. EA (79.44 mg, 0.615 mmol, 3.00 equiv) and DMF (2.00 mL) were added. The resulting solution was stirred at 20 °C for 10 h. The mixture was purified by rapid preparative HPLC. 21 mg of a grayish-white solid (E)-N-((1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide was obtained. LC-MS (ES, m / z): [M+H] + =380.

[1029] 1 H-NMR1(300MHz,DMSO-d6,ppm)δ12.78(s,1H),8.58(d,J=8.1Hz,1H),7.74-7.62(m,3H),7.33-7.22(m,5H),6.75(d,J=15.6Hz,1H),5.34-5 .29(m,1H),4.65-4.62(m,1H),4.49-4.46(m,1H),4.20-4.16(m,1H), 3.97-3.71(m,2H),3.37-3.35(m,1H),2.88-2.80(m,1H),2.50(s,3H).

[1030] Example 69: (E)-N-((1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide

[1031]

[1032] Step 1: Add a 10.00 mL solution of N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (400.00 mg, 1.604 mmol, 1.00 equiv), ethyl iodine (500.47 mg, 3.209 mmol, 2.00 equiv), and NaH (128.36 mg, 3.209 mmol, 2.00 equiv, 60%) in THF to a 20 mL vial. Stir the resulting solution at 20 °C for 10 h. Terminate the reaction with 5 mL of H₂O and extract with 30 mL of ethyl acetate. Combine the organic layers, dry with anhydrous sodium sulfate, and concentrate. Load the residue onto a silica gel column using ethyl acetate / petroleum ether (1 / 1). This yielded 200 mg (45% yield) of pale yellow solid N-[(1S,2S)-2-ethoxy-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester.

[1033]

[1034] Step 2: Add a solution of N-[(1S,2S)-2-ethoxy-2,3-dihydro-1H-indene-1-yl]carbamate tert-butyl ester (170.00 mg) in 2M HCl (g) / MeOH solution (5.00 mL) and MeOH (5.00 mL) to a 20 mL vial and stir at 20 °C for 10 h. Concentrate the resulting mixture. This yields 80 mg of pale yellow solid (1S,2S)-2-ethoxy-2,3-dihydro-1H-indene-1-amine.

[1035]

[1036] Step 3: Add a 2.00 mL solution of (1S,2S)-2-ethoxy-2,3-dihydro-1H-indene-1-amine (40.00 mg, 0.226 mmol, 1.00 equiv), (E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid (intermediate 3, 45.19 mg, 0.226 mmol, 1.00 equiv), HATU (128.71 mg, 0.339 mmol, 1.50 equiv), and DIPEA (87.50 mg, 0.677 mmol, 3.00 equiv) in DMF to an 8 mL vial. Stir the resulting solution at 20 °C for 2 h. Purify the mixture by preparative HPLC. Thus, 25 mg of grayish-white solid (E)-N-((1S,2S)-2-ethoxy-2,3-dihydro-1H-indene-1-yl)-3-(3-methyl-1H-indazole-6-yl)acrylamide was obtained.

[1037] LC-MS(ES,m / z):[M+H]+ =362.

[1038] 1 H-NMR (300MHz, DMSO-d6, ppm) δ8.57 (d, J = 8.4Hz, 1H), 7.74-7.63 (m, 3H), 7.33-7.17 (m, 5H), 6.75 (d, J = 15.6Hz, 1H), 5.32-5. 28(m,1H),4.14-4.10(m,1H),3.69-3.55(m,2H),3.34-3.26(m,1H).2.83-2.73(m,1H),2.78-2.76(m,3H).1.16-1.12(m,3H).

[1039] Example 70: (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide

[1040]

[1041] A solution of N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-yl]prop-2-enamide (see Example 54, Step 1, 60.00 mg, 0.276 mmol, 1.00 equivalent), 6-bromo-3-cyclopropyl-1H-indazole (65.48 mg, 0.276 mmol, 1.00 equivalent), Pd(dppf)Cl2 (20.21 mg, 0.028 mmol, 0.10 equivalent), and Et3N (83.83 mg, 0.828 mmol, 3.00 equivalent) in DMF (2.00 mL) was added to an 8-mL vial. The resulting solution was stirred at 120 °C for 3 h. The mixture was purified by preparative HPLC. This yielded 31 mg of a grayish-white solid (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =374.

[1042] 1H-NMR-(300MHz, DMSO-d6, ppm) δ8.61-8.58(d,J=8.7Hz,1H),7.87-7.78(d,J=8.7Hz,1H),7.68-7.62(m,2H),7.32-7.20(m,5H),6.77-6.72(d, J=15.9Hz,1H),5.34-5.32(m,1H),4.08-4.07(m,1H),3.38(s,3H).3.35 -3.27(m,1H),2.84-2.77(m,1H).2.29-2.24(m,1H),1.01-0.94(m,4H).

[1043] Example 71: (E)-3-(3-methoxy-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-yl)acrylamide

[1044]

[1045] A solution of N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (see Example 54, Step 1, 60.00 mg, 0.276 mmol, 1.00 equivalent), 6-bromo-3-methoxy-1H-indazole (62.70 mg, 0.276 mmol, 1.00 equivalent), Pd(dppf)Cl2 (20.21 mg, 0.028 mmol, 0.10 equivalent), and Et3N (83.83 mg, 0.828 mmol, 3.00 equivalent) in DMF (2.00 mL) was added to an 8-mL vial. The resulting solution was stirred at 120 °C for 3 h. The mixture was purified by preparative HPLC. This yielded 33 mg of a grayish-white solid (E)-3-(3-methoxy-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-yl)acrylamide. The compound was converted to an HCl salt. LC-MS (ES, m / z): [M+H] + =364.

[1046] 1H-NMR (300MHz, DMSO-d6, ppm) δ12.09 (s, 1H), 8.59 (d, J = 8.4Hz, 1H), 7.67-7.54 (m, 3H), 7.26-7.17 (m, 5H), 6.7 4(d,J=15.9Hz,1H),5.34-5.30(m,1H),4.07-4.01(m,4H),3.38(s,3H),3.37-3.29(m,1H),2.84-2.78(m,1H).

[1047] Example 72: (E)-3-(3-chloro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide

[1048]

[1049] A solution of N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (60.00 mg, 0.276 mmol, 1.00 equivalent), 6-bromo-3-chloro-1H-indazole (63.92 mg, 0.276 mmol, 1.00 equivalent), Pd(dppf)Cl2 (20.21 mg, 0.028 mmol, 0.10 equivalent), and Et3N (83.83 mg, 0.828 mmol, 3.00 equivalent) in DMF (4.00 mL) was added to an 8 mL vial. The resulting solution was stirred at 120 °C for 3 h. The mixture was then purified by preparative HPLC. This yielded 32 mg of a grayish-white solid (E)-3-(3-chloro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide. LC-MS (ES, m / z): [M+H] + =368.

[1050] 1 H-NMR (300MHz, DMSO-d6, ppm) δ13.45 (s, 1H), 8.62 (d, J = 8.7Hz, 1H), 7.75-7.67 (m, 3H), 7.46 (d, J = 9.6Hz, 1H), 7.28-7.17 (m,4H),6.80(d,J=15.9Hz,1H),5.35-5.30(m,1H),4.08-4.01(m,1H),3.38(s,3H),3.35-3.27(m,1H),2.84-2.77(m,1H).

[1051] Example 73: (E)-3-(3-fluoro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide

[1052]

[1053] Step 1: Add a solution of 6-bromo-1H-indazole (500.00 mg, 2.54 mmol, 1.00 equiv), Selectfluor (1797.95 mg, 5.075 mmol, 2.00 equiv) in CH3CN (10.00 mL) and AcOH (1.00 mL) to a 40 mL vial. Stir the resulting solution at 95 °C for 15 h. Load the mixture onto a silica gel column with ethyl acetate / petroleum ether (1 / 1). This yields 110 mg (20% yield) of a pale yellow solid, 6-bromo-3-fluoro-1H-indazole.

[1054]

[1055] Step 2: Add a solution of N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-yl]prop-2-enamide (see Example 54, Step 1, 60.00 mg, 0.276 mmol, 1.00 equivalent), 6-bromo-3-fluoro-1H-indazole (59.38 mg, 0.276 mmol, 1.00 equivalent), Pd(dppf)Cl2 (20.21 mg, 0.028 mmol, 0.10 equivalent), and Et3N (83.83 mg, 0.828 mmol, 3.00 equivalent) in DMF (2.00 mL) to an 8-mL vial. Stir the resulting solution at 120 °C for 14 h. Purify the mixture by preparative HPLC. This yielded 34 mg of a grayish-white solid (E)-3-(3-fluoro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide. LC-MS1 (ES, m / z): [M+H] + =352.

[1056] 1H-NMR (300MHz, DMSO-d6, ppm) δ12.72 (s, 1H), 8.62 (d, J = 8.7Hz, 1H), 7.75-7.66 (m, 3H), 7.41 (d, J = 8.7Hz, 1H), 7.27-7.18 (m,4H),6.79(d,J=15.9Hz,1H),5.35-5.30(m,1H),4.08-4.01(m,1H),3.39(s,3H),3.35-3.27(m,1H),2.84-2.78(m,1H).

[1057] Example 74: (E)-3-(3-cyano-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide

[1058]

[1059] Step 1: Add a solution of N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-yl]prop-2-enamide (see Example 54, Step 1, 70.0 mg, 0.322 mmol, 1.00 equiv), 6-bromo-1-(oxacyclohexan-2-yl)indazole-3-carboxynitrile (98.64 mg, 0.322 mmol, 1.00 equiv), Pd(dppf)Cl2 (23.57 mg, 0.032 mmol, 0.10 equiv), and Et3N (97.81 mg, 0.967 mmol, 3.00 equiv) in DMF (4.00 mL) to an 8-mL vial. Stir the resulting solution at 120 °C for 3 h. Load the mixture onto a silica gel column and elute with ethyl acetate / petroleum ether (1 / 1). This yielded 60 mg (42% yield) of pale yellow solid (E)-3-(3-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-yl)acrylamide.

[1060]

[1061] Step 2: Add a solution of (E)-3-(3-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-indazole-1-yl)acrylamide (60.00 mg, 0.136 mmol, 1.00 equiv) in 2 M HCl (g) / MeOH solution (2.00 mL) and MeOH (2.00 mL) to an 8-mL vial. Stir the resulting solution at 10 °C for 2 h. Concentrate the resulting mixture. Purify the residue by preparative HPLC. This yields 31 mg of a grayish-white solid (E)-3-(3-cyano-1H-indazole-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-indazole-1-yl)acrylamide. LC-MS(ES,m / z):[M+H] + =359.

[1062] 1 H-NMR (300MHz, DMSO-d6, ppm) δ14.52 (s, 1H), 8.64 (d, J = 8.4Hz, 1H), 7.94-7.91 (m, 2H), 7.73 (d, J = 15.9Hz, 1H), 7.62 (d, J = 8.7Hz, 1H) ,7.26-7.18(m,4H),6.83(d,J=15.6Hz,1H),5.34-5.30(m,1H),4.07-4.01(m,1H),3.38(s,3H),3.35-3.27(m,1H),2.84-2.73(m,1H).

[1063] Biological Examples Biological Example 1 - In isolated rat liver mitochondria, human platelet mitochondria and isolated... Measurement of mPTP activity in rat brain mitochondria

[1064] Rat liver mitochondrial assay

[1065] 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.

[1066] 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.

[1067] 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.

[1068] 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.

[1069] Human platelet mitochondrial assay

[1070] 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.

[1071] 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.

[1072] 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).

[1073] Rat brain mitochondrial assay

[1074] 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).

[1075] 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.

[1076] 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.

[1077] Results: Table 3 below provides the mPTP pIC values ​​of the compounds of certain embodiments of the present invention in a series of mPTP assays. 50 Values. Table 3 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 37 and 51 showed the highest activity in rat liver mitochondrial assays, and Example 51 also showed the highest activity in rat brain mitochondrial assays. Table 3 also shows the mPTP human platelet pIC values ​​of some of the example compounds and Comparative Example 1. 50 Values. Table 3 also shows the pIC values ​​of mPTP rat brain mitochondria in some of the compounds of the examples and 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.

[1078] Biological Example 2 - Cytochrome P450 Determination

[1079] Studies evaluating the inhibition of the cytochrome P450 enzyme isotype CYP2D6 mediated by the test compounds were performed using human liver microsomes (BD Gentest), with single concentrations (1 μM) of the test compound or concentration responses (0.1, 0.3, 1, 3, 10, and 30 μM) to obtain the IC50. The test compound solution was prepared from a 10 mM stock solution in DMSO and diluted to 200 μM in DMSO. The reaction mixture was prepared in 96-well deep-well plates by mixing 1 μL of the test compound with 179 μL of the reaction mixture (100 mM phosphate-buffered saline (PBS), 0.2 mg / mL microsomes, and 2 μM dextromethorphan, prepared from the stock solution detailed below).

[1080] Table 2: Summary of the culture mixture

[1081] microparticles 20mg / mL 2μL 0.2 mg / mL Phosphate buffer 100mM 176μL 100mM Substrate - 1μL -

[1082] When used at a single concentration, the positive control inhibitor quinidine was used at a final concentration of 0.5 μM. Final concentrations of quinidine used to obtain the IC50 were 0, 0.1, 0.3, 1, 3, 10, and 30 μM. The plate was first incubated at 37°C for 15 min, then the reaction was initiated with 20 μL of 10 mM NADPH in PBS and incubated at 37°C for 20 min. The assay was performed in duplicate. The reaction was quenched with 200 μL of cold acetonitrile containing internal standards (200 nM labetalol, 200 nM alprazolam, and 100 nM tolbutamide). The plate was centrifuged at 4000 rpm for 30 min, placed on ice for 20 min, and then centrifuged again at 4000 rpm for 30 min to precipitate the protein. 100 μL of the supernatant was transferred to a fresh plate, diluted with 100 μL of pure water, and then analyzed using UPLC / MS / MS. The conversion of dextromethorphan to nordextromethorphan was monitored by UPLC-MS / MS. The inhibitory effect of CYP2D6 in human liver microsomes was measured as the percentage decrease in nordextromethorphan formation activity compared to the uninhibited control (=100% activity). IC50 was calculated using ExcelXLfit. 50 Value (concentration of the test compound that produces 50% inhibition).

[1083] Results: The CYP2D6% inhibition values ​​of certain compounds of the present invention are shown in Table 3. Table 3 also shows the CYP2D6% inhibition value of Comparative Example 1. The results indicate that the test compounds showed significantly reduced CYP2D6 inhibition compared to Comparative Example 1. Negative values ​​indicate no effective CYP2D6 inhibition at a concentration of 1 μM of the test compound. Table 3 also shows the CYP2D6 IC50 values ​​of certain example compounds and Comparative Example 1. 50The results showed that Comparative Example 1 was a highly effective inhibitor of CYP2D6 and significantly more effective than the tested compound. This is consistent with the effective CYP2D6% inhibition value shown by Comparative Example 1. Therefore, the tested compounds of the present invention are expected to exhibit improved in vivo properties, such as a reduction in harmful drug-drug interactions and a reduction in the inhibition of neurotransmitter production in the central nervous system, particularly dopamine.

[1084] Table 3: Summary of the results of biological examples 1 and 2

[1085]

[1086]

[1087]

[1088] *Average value of multiple experiments (n≥2)

[1089] **The average of the two experiments.

[1090] Biological Example 3 – Solubility of PBS and FaSSIF

[1091] 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:

[1092] [Sample] = (Area Ratio) 样品 *INJ VOL STD*DF 样品 *[STD]) / (Area ratio STD*INJ VOL) 样品 ).

[1093] Results: Solubility values ​​for certain compounds of the present invention are provided in Table 4 below. Table 4 also provides the results for Comparative Example 1. The results show that certain compounds of the present invention have higher solubility in PBS and / or FaSSIF than those in Comparative Example 1. Some compounds of the present invention are soluble in either PBS or FaSSIF, while some compounds show high solubility values ​​in both PBS and FaSSIF. Therefore, it is expected that certain 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.

[1094] Biological Example 4 - Assay of Liver Microsomes and Intrinsic Clearance by Hepatocytes

[1095] Hepatocyte clearance assay

[1096] 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. 6 Live 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):

[1097] In vitro CL int =kV / N

[1098] V = Incubation volume (0.2 mL)

[1099] N = number of hepatocytes per well (0.1 × 10⁻⁶) 6 cell).

[1100] Microsomal clearance assay

[1101] 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):

[1102] In vitro Clint = (0.693 / t1 / 2) * (incubation volume (μl) / amount of protein (mg)).

[1103] Results: The intrinsic clearance values ​​of certain compounds of the present invention are listed in Table 4. Table 4 also provides the intrinsic clearance values ​​of Comparative Example 1. These results indicate that certain compounds of the present invention 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 human or rat species. int The intrinsic clearance (CL) values ​​of some compounds were lower in both human and rat species than in Comparative Example 1.int )value.

[1104] Table 4: Summary of the results of biological examples 3 and 4

[1105]

[1106]

[1107]

[1108] *The average of the two experiments.

[1109] Conclusions: The results of biological Examples 1 and 2 demonstrate that the tested compounds of the present invention are inhibitors of mPTP in a series of mPTP assays. Compared with Comparative Example 1, the tested compounds of the present invention also showed reduced inhibition of CYP2D6. The results of biological Examples 3 and 4 demonstrate that certain compounds of the present invention exhibit improved solubility and / or lower intrinsic clearance compared with Comparative Example 1, and therefore are expected to show improved oral bioavailability and / or improved systemic exposure compared with Comparative Example 1.

[1110] Therefore, the compounds of the present invention are believed to be useful medicines, particularly for treating or preventing diseases and conditions in which the inhibition of mPTP provides therapeutic or preventative effects.

[1111] 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.

[1112] 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.

[1113] 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.

[1114] References

[1115] Yu et al., TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS / STING in ALS, Cell, Volume 183, Issue 3, 2020, p 636-649.e18.

[1116] Jang et al., Proximal tubule cyclophilin D mediates kidney fibrogenesis in obstructive nephropathy, 2021, American Journal of Physiology: Renal physiology, doi: 10.1152 / ajprenal.00171.2021. Published online ahead of print PMID: 34396791.

[1117] 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, 5333-5347

[1118] 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, 445-454.

Claims

1. Compound of formula (I): (I)； in: R 1a It is H or methyl; R 1b It is H or F; A is a group (Aa), (Ab), (Ac), or (Ad): The group (Aa) is: (Aa); in: R2 is H, C 1-4 Alkyl, C 1-4 Alkylene (OH), C 1-4 Alkoxy or C 1-4 Alkylene OC 1-4 alkyl; Each R3 is independently of the other: halo, methyl, ethyl, or n-propyl. m is 0, 1, 2, 3 or 4; The group (Ab) is: (Ab); in: R4 is H or C. 1-4 alkyl; R5 is H or C 1-4 alkyl; Each R6 is independently C 1-4 Alkyl or halogenated; n is 0, 1, 2, or 3; The group (Ac) is: (And); in: R7 is C 1-4 Alkyl, C 1-4 alkylene (OH) or C 1-4 Alkylene OC 1-4 alkyl; o is 1 or 2; The group (Ad) is: (Ad); in: X is a bond, O, or CH2; 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; Each R9 is independently halogenated or C-substituted. 1-4 alkyl; p is 0, 1, or 2; q is 0, 1, 2, 3, or 4; Where B is a functional group (Bc): (Bc); in: R 15 It is methyl, ethyl, cyclopropyl, CF3, CN, OMe, chlorine or fluorine; R 16 Is it H, halogenated, or C? 1-4 Alkyl; and D, E, and F are C(R) 16 ); 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 It is H or methyl; R 1b It is H or F; A is a group (Aa), (Ab), (Ac), or (Ad): The group (Aa) is: (Aa); in: R2 is H, C 1-4 Alkyl, C 1-4 Alkylene (OH), C 1-4 Alkoxy or C 1-4 Alkylene OC 1-4 alkyl; Each R3 is independently of the other: halo, methyl, ethyl, or n-propyl. m is 0, 1, 2, 3 or 4; The group (Ab) is: (Ab); in: R4 is H or C. 1-4 alkyl; R5 is H or C 1-4 alkyl; Each R6 is independently C 1-4 Alkyl or halogenated; n is 0, 1, 2, or 3; The group (Ac) is: (And); in: R7 is C 1-4 Alkyl, C 1-4 alkylene (OH) or C 1-4 Alkylene OC 1-4 alkyl; o is 1 or 2; The group (Ad) is: (Ad); in: X is a bond, O, or CH2; Each R8 is independently halogenated, C 1-4 Alkyl, C 1-4 alkoxy or OH; Each R9 is independently halogenated or C-substituted. 1-4 alkyl; p is 0, 1, or 2; q is 0, 1, 2, 3, or 4; Where B is a functional group (Bc): (Bc); in: R 15 It is methyl, ethyl, cyclopropyl, CF3, or CN; R 16 Is it H, halogenated, or C? 1-4 Alkyl; and D, E, and F are C(R) 16 ); 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 (Aa): (Aa)。 4. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R2 is C 1-4 Alkyl, C 1-4 alkylene (OH) or C 1-4 Alkylene OC 1-4 alkyl.

5. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein each R3 is independently fluorine or methyl.

6. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.

7. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein m is 1 and R3 is at position 3; or, wherein m is 1 and R3 is at position 6; or, wherein m is 2, one R3 is at position 3 and the other R3 is at position 6.

8. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each R 16 They are H, fluorine, chlorine or methyl, which are independent of each other.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (Ia'): ； in: A is a group (Aa'), a group (Ab'), a group (Ad'), or a group (Ad''); R 15d It is methyl, ethyl, cyclopropyl, CN, CF3, OMe, chlorine or fluorine; The group (Aa') is: (Aa’); in: R 2d It is H, methyl, or CH2OMe; Each R 3a Each is independently H, fluorine, or methyl; and The group (Ab') is: ； in: R 4d It is methyl; The group (Ad') is: (Ad’); in: R 8d It is H, methyl, OCH2-cyclopropyl, OCH2-oxetane, OCH2CH2F, OMe or OEt; Each R 9a They are H or fluorine, which are independent of each other; The group (Ad'') is: (Ad’’); in: R 8d It is methyl; and Each R 9a They are H or fluorine, which are independent of each other; Or its pharmaceutically acceptable salt.

10. 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-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-(trifluoromethyl)-1H-indazol-6-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-ethyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide; (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(4-fluoro-3-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(3-fluoro-4-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; Racemic-(E)-3-(3-methyl-1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-(3-fluoro-2-(methoxymethyl)phenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methyl-som-4-yl)acrylamide; (E)-N-(2-methyl-1,2,3,4-tetrahydronaphth-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(-3-methyl-chroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4S)-3-methyl-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4R)-3-methyl-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4R)-3-methyl-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4S)-3-methyl-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1S,2S)-2-(oxecyclobutane-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-((1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-((1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-((1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-methoxy-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-yl)acrylamide; (E)-3-(3-chloro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-indene-1-yl)acrylamide; (E)-3-(3-fluoro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; and (E)-3-(3-cyano-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; Or any of its pharmaceutically acceptable salts.

11. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 9 or 10 in the preparation of a medicament for treating or preventing a disease or condition in which inhibition of mPTP provides a therapeutic or preventive effect.

12. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 9 or 10 in the preparation of a medicament for the prevention or treatment of diseases or conditions selected from the following: degenerative diseases, central nervous system disorders, ischemia and reperfusion injury, metabolic diseases, inflammatory or autoimmune diseases, aging diseases and kidney diseases.

13. The use according to claim 12, wherein the disease is selected from the following degenerative diseases: Parkinson's disease, Lewy body dementia, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal dementia, chemotherapy-induced neurosis, Huntington's disease, spinocerebellar ataxia, progressive supranuclear palsy, hereditary spastic paraplegia, Duchenne muscular dystrophy, congenital muscular dystrophy, traumatic brain injury, and Friedreich ataxia.

14. A pharmaceutical composition comprising a compound according to any one of claims 1, 2, 9 or 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

15. A compound selected from: -A compound of formula (IV) or a salt thereof: ； Where R 1b And B as defined in claim 1 with respect to compound (I); and Compounds of formula (VI) or their salts: ； Where R 1b B is as defined in claim 1 with respect to compound (I).

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