Acrylamide Compounds

Abstract

The present invention relates to compounds of formula (I): [Formula 1] TIFF2025508898000385.tif18170 and related aspects.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to novel compounds that are inhibitors of the mitochondrial permeability transition pore (mPTP), and in particular to such compounds for use as pharmaceuticals, especially for the treatment or prevention of degenerative, neurodegenerative, or mitochondrial diseases, or other diseases or disorders in which inhibition of mPTP provides a therapeutic or prophylactic effect. [Background technology]

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

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

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

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

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

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

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

[0009] Yu et al. (2020, Cell, 183, 1-14) reported a link between mPTP activation and the mechanisms of TDP-43 proteinopathies, such as TDP-43-associated neurodegeneration. Cytoplasmic neuronal accumulation of TDP-43, a normally nuclear protein, characterizes almost all ALS cases and 40-50% of frontotemporal lobar degeneration (FTLD), with some familial cases caused by mutant forms of the protein. Both diseases are associated with a neuroinflammatory cytokine profile associated with upregulation of the NF-κB and type I IFN pathways, directly suggesting a role for TDP-43 in neuroinflammation. Mutant or overexpressed wild-type TDP-43 in neurons mislocalizes to mitochondria and induces the release of mitochondrial DNA (mtDNA) into the cytoplasm. This mtDNA then activates cGAS-STING, an immune sensor that triggers the induction of innate immune genes such as IL-6, TNFα, and interferon-β. Inhibition of mPTP with cyclosporine A or by CypD knockout prevents TDP-43-induced release of mtDNA and the subsequent induction of innate immune response genes. Furthermore, inhibition of cGAS-STING extends the survival of mutant mice expressing mutant TDP-43. This data implicates mPTP activation in mediating the toxic effects of TDP-43 in ALS and other diseases in which either mutations in the TDP-43 gene cause the disease or TDP-43 proteinopathy is present.

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

[0011] CYP2D6 is one of the major members of the human drug-metabolizing cytochrome P450 enzyme system. It is responsible for the hepatic metabolism of a significant proportion of clinically used drugs. Inhibition of CYP2D6 can promote drug-drug interactions with co-prescribed drugs metabolized by the same enzyme, potentially resulting in increased plasma concentrations to levels that can cause adverse effects. CYP2D6 is primarily expressed in the liver and, to a lesser extent, in the central nervous system (CNS). In the CNS, it is involved in the synthesis of various neurotransmitters, including dopamine. Consequently, inhibition of CYP2D6, particularly at the CNS level, can potentially have adverse effects through impaired pathways such as dopamine production. In Parkinson's disease, characterized by loss of dopaminergic neurons in the substantia nigra, further depletion of dopamine levels through CYP2D6 inhibition may not be tolerated.

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

[0013] WO2010 / 049768 relates to acrylamide derivatives and their use as therapeutic agents, particularly for the prevention and / or treatment of diseases associated with mPTP activity (see also Plyte et al., J. Med Chem. 2014, 57, 5333-47). Chen et al. (Assay and Drug Development Technologies, 2018, 16, 445-455) relates to phenotypic screening of mPTP modulators using platelets and discloses additional acrylamide derivatives. CA2884607A1 relates to acrylamide and maleimide compounds said to be useful in the treatment of mitochondrial diseases.

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

[0015] (Summary of the Invention) In a first aspect, the present invention provides a compound of formula (I): [ka] (In the formula: R 1a is H or methyl; R1b is H or F; A is a group (Aa), (Ab), (Ac), (Ad), or (Ae): wherein the group (Aa) is: [ka] (In the formula: R2 is H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene (C 3-6 cycloalkyl), C 1-4 Alkylene (4-10 membered heterocycloalkyl), 4-10 membered heterocycloalkyl, C 1-4 Alkoxy, OC 1-4 Alkylene (aryl), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 AlkyleneO(4-10 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), C 3-6 Alkynyl, C 1-4 Alkenyl O(C 3-6 alkynyl), C 1-4 Alkylene (CO2H);OC 1-4 Alkylene (COH), C 1-4 Alkylene OC 1-4 Alkylene (COH), N(R 2aa )C 1-4 Alkylene (COH), C 1-4 Alkylene (NR 2ab R 2ac ), O.C. 1-4 Alkylene (NR 2ab R 2ac ), or N(R 2aa )C 1-4 Alkylene (NR 2ab R 2ac wherein the aryl, heterocycloalkyl, and cycloalkyl are C 1-4 Alkyl, C3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 2a R 2b , SO2R 2c , and NHSO2R 2c optionally substituted by 1, 2, or 3 substituents each independently selected from R 2a is H and C 1-4 alkyl; R 2b is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 10-membered heterocycloalkyl; R 2c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 10-membered heterocycloalkyl; Each R 2aa are independently H and C 1-4 alkyl; Each R 2ab are independently H and C 1-4 alkyl; Each R 2ac are independently H and C 1-4 alkyl; or R 2ab and R 2ac together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl; R 2x H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy; Each R3 independently represents a halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy; m is 0, 1, 2, or 3; Or; R 2x is C 1-4 Alkylene (4-10 membered heterocycloalkyl), 4-10 membered heterocycloalkyl, C 1-4 AlkyleneO(4-10 membered heterocycloalkyl), C 1-4 Alkylene (COH), OC 1-4 Alkylene (COH), C 1-4 Alkylene OC 1-4 Alkylene (COH), N(R 2xaa )C 1-4 Alkylene (COH), C 1-4 Alkylene (NR 2xab R 2xac ), O.C. 1-4 Alkylene (NR 2xab R 2xac ), or N(R 2xaa )C 1-4 Alkylene (NR 2xab R 2xac ) wherein the heterocycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 2xa R 2xb , SO2R 2xc , and NHSO2R 2xc optionally substituted by 1, 2, or 3 substituents each independently selected from R 2xa is H and C 1-4 alkyl; R 2xb is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 10-membered heterocycloalkyl; R 2xc is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4selected from haloalkyl, aryl, and 4- to 10-membered heterocycloalkyl; Each R 2xaa are independently H and C 1-4 alkyl; Each R 2xab are independently H and C 1-4 alkyl; Each R 2xac are independently H and C 1-4 alkyl; or R 2xab and R 2xac together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl; R2 is H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, or C 1-4 alkyleneO(4-10 membered heterocycloalkyl); Each R3 independently represents a halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy; m is 0, 1, 2, or 3. and; The group (Ab) is: [ka] (In the formula: R4 is H, C 1-4 Alkyl, or C 1-4 alkylene(aryl); wherein the aryl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 4a R 4b , SO2R 4c , and NHSO2R 4coptionally substituted by 1, 2, or 3 substituents each independently selected from R 4a is H and C 1-4 alkyl; R 4b is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 10-membered heterocycloalkyl; R 4c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 10-membered heterocycloalkyl; R5 is H or C 1-4 is alkyl; Each R6 is independently 1-4 alkyl or halo; n is 0, 1, 2, or 3) and; The group (Ac) is: [ka] (In the formula: R7 is C 1-4 Alkyl, C 1-4 Alkylene (OH) or C 1-4 Alkylene OC 1-4 is alkyl; o is 1 or 2) and; The group (Ad) is: [ka] (In the formula: X is a bond, O, or CH; Each R8 is independently halo, C 1-4 Alkyl, C 1-4 Alkoxy, OC 1-4 Haloalkyl, OC 1-4 Alkylene (C 3-6cycloalkyl), OC 1-4 alkylene (4-10 membered heterocycloalkyl), or OH; wherein the heterocycloalkyl and cycloalkyl are C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 8a R 8b , SO2R 8c , and NHSO2R 8c optionally substituted by 1, 2, or 3 substituents independently selected from R 8a is H and C 1-4 alkyl; R 8b is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 10-membered heterocycloalkyl; R 8c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 10-membered heterocycloalkyl; Each R9 is independently halo or C 1-4 is alkyl; p is 0, 1, or 2; q is 0, 1, 2, 3, or 4 and; The group (Ae) is: [ka] (In the formula: R 17 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene (C 3-6 cycloalkyl), C1-4 Alkylene (4-10 membered heterocycloalkyl), 4-10 membered heterocycloalkyl, C 1-4 Alkoxy, OC 1-4 Alkylene (aryl), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 AlkyleneO(4-10 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), C 3-6 Alkynyl, C 1-4 Alkenyl O(C 3-6 alkynyl), C 1-4 Alkylene (COH), OC 1-4 Alkylene (COH), C 1-4 Alkylene OC 1-4 Alkylene (COH), N(R 17aa )C 1-4 Alkylene (COH), C 1-4 Alkylene (NR 17ab R 17ac ), O.C. 1-4 Alkylene (NR 17ab R 17ac ), or N(R 17aa )C 1-4 Alkylene (NR 17ab R 17ac wherein the aryl, cycloalkyl, or heterocycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 17a R 17b , SO2R 17c , NHSO2R 17c optionally substituted by 1, 2, or 3 substituents each independently selected from R 17a is H and C 1-4 alkyl; R 17b is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 10-membered heterocycloalkyl; R 17c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 10-membered heterocycloalkyl; Each R 17aa are independently H and C 1-4 alkyl; Each R 17ab are independently H and C 1-4 alkyl; Each R 17ac are independently H and C 1-4 alkyl; or R 17ab and R 17ac together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl; R 18 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, or C 1-4 alkyleneO(4-10 membered heterocycloalkyl); R 20 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy; R 21 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy; Or; R 17 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, or C 1-4 alkyleneO(4-10 membered heterocycloalkyl); R 18 is C 1-4 Haloalkyl, C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene (C 3-6 cycloalkyl), C 1-4 Alkylene (4-10 membered heterocycloalkyl), 4-10 membered heterocycloalkyl, OC 1-4 Alkylene (aryl), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 AlkyleneO(4-10 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), C 3-6 Alkynyl, C 1-4 Alkenyl O(C 3-6 alkynyl), C 1-4 Alkylene (COH), OC 1-4 Alkylene (COH), C 1-4 Alkylene OC 1-4 Alkylene (COH), N(R 18aa )C 1-4 Alkylene (COH), C 1-4 Alkylene (NR 18ab R 18ac ), O.C. 1-4 Alkylene (NR 18ab R 18ac ), or N(R 18aa )C 1-4 Alkylene (NR 18ab R 18ac wherein the aryl, cycloalkyl, or heterocycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR18a R 18b , SO2R 18c , NHSO2R 18c optionally substituted by 1, 2, or 3 substituents each independently selected from R 18a is H and C 1-4 alkyl; R 18b is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 10-membered heterocycloalkyl; R 18c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 10-membered heterocycloalkyl; Each R 18aa are independently H and C 1-4 alkyl; Each R 18ab are independently H and C 1-4 alkyl; Each R 18ac are independently H and C 1-4 alkyl; or R 18ab and R 18ac together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl; R 20 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy; R 21 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy; Or; R 17 H, halo, C 1-4 Alkyl, C 1-4Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, or C 1-4 alkyleneO(4-10 membered heterocycloalkyl); R 18 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylene OC 1-4 Alkyl C 1-4 Alkylene OC 3-6 Cycloalkyl, or C 1-4 alkyleneO(4-10 membered heterocycloalkyl); R 20 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy; R 21 is C 1-4 Haloalkyl, C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene (C 3-6 cycloalkyl), C 1-4 Alkylene (4-10 membered heterocycloalkyl), 4-10 membered heterocycloalkyl, OC 1-4 Alkylene (aryl), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 AlkyleneO(4-10 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), C 3-6 Alkynyl, C 1-4 Alkenyl O(C 3-6 alkynyl), C 1-4 Alkylene (COH), OC 1-4 Alkylene (COH), C 1-4 Alkylene OC 1-4 Alkylene (COH), N(R21aa )C 1-4 Alkylene (COH), C 1-4 Alkylene (NR 21ab R 21ac ), O.C. 1-4 Alkylene (NR 21ab R 21ac ), or N(R 21aa )C 1-4 Alkylene (NR 21ab R 21ac wherein the aryl, cycloalkyl, or heterocycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 21a R 21b , SO2R 21c , NHSO2R 21c optionally substituted by 1, 2, or 3 substituents each independently selected from R 21a is H and C 1-4 alkyl; R 21b is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 10-membered heterocycloalkyl; R 21c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 10-membered heterocycloalkyl; Each R 21aa are independently H and C 1-4 alkyl; Each R 21ab are independently H and C 1-4 alkyl; Each R 21ac are independently H and C 1-4 alkyl; or R 21aband R 21ac together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl) and; B is a group (Ba), (Bb), or (Bc); where the group (Ba) is: [ka] (In the formula: Y is C(R 11 )(R 12 ), N(R 13 ), O, or S; Each R 10 are independently halo or C 1-4 is alkyl; r is 0, 1, 2, or 3; R 11 is H or C 1-4 is alkyl; R 12 is H or C 1-4 alkyl; or R 11 and R 12 together with the carbon atoms to which they are attached, form C 3-6 Forming a cycloalkyl; R 13 is H, C 1-4 Alkyl, or C 3-6 is cycloalkyl; wherein the cycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 13a R 13b , SO2R 13c , and NHSO2R 13c optionally substituted by 1, 2, or 3 substituents independently selected from R 13a is H and C 1-4 alkyl; R 13b is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 10-membered heterocycloalkyl; R 13c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 10-membered heterocycloalkyl and; The group (Bb) is: [ka] (In the formula: Each R 14 are independently halo or C 1-4 is alkyl; s is 0, 1, 2, or 3) and; The group (Bc) is: [ka] (In the formula: R 15 is C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 1-4 haloalkyl, halo, or CN; wherein the cycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 15a R 15b , SO2R 15c , and NHSO2R 15c optionally substituted by 1, 2, or 3 substituents independently selected from R 15a is H and C 1-4 alkyl; R 15b is H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C1-4 selected from haloalkyl, aryl, and 4- to 10-membered heterocycloalkyl; R 15c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4- to 10-membered heterocycloalkyl; R 16 is H, halo or C 1-4 is alkyl; and D, E, and F each independently represent C(R 16 ) or one of D, E, and F is N and the remaining two of D, E, and F groups are independently C(R 16 ) is) is); or a pharmaceutically acceptable salt and / or solvate thereof.

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

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

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

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

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

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

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

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

[0024] The present invention also provides a method for preventing or treating a mitochondrial disease in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof.

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

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

[0027] The present invention also provides a method for treating or preventing a disease or disorder associated with TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, comprising administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof.

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

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

[0030] The present invention also provides a method for treating or preventing a disease or disorder associated with fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof.

[0031] Also provided are novel intermediate compounds of formula (II) through formula (XXXVII), including compounds of formula (II), formula (IV), and formula (VI), and salts thereof, which are useful in the preparation of compounds of formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0032] (Detailed Description of the Invention) C 1-4 The term "alkyl," as used herein, whether alone or forming part of a larger group, refers to a linear or branched, fully saturated hydrocarbon chain containing the specified number of carbon atoms. 1-4Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl. Reference to "propyl" includes n-propyl and isopropyl. Reference to "butyl" includes n-butyl, isobutyl, tert-butyl, and sec-butyl.

[0033] Me means methyl. Et means ethyl. Pr means propyl. Bu means butyl.

[0034] C 1-4 The term "alkylene" as used herein, such as alkylene, whether alone, can be used to form a larger group, e.g., C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene (C 3-6 cycloalkyl), OC 1-4 Alkylene (C 3-6 cycloalkyl), C 1-4 Alkylene (4-10 membered heterocycloalkyl), OC 1-4 Alkylene (4-10 membered heterocycloalkyl), C 1-4 Alkoxy, OC 1-4 Alkylene (aryl), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 AlkyleneO(4-10 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), or C 1-4 Alkylene O(C 3-6 alkynyl), e.g., C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene (C 3-6 cycloalkyl), C 1-4 Alkylene (4-10 membered heterocycloalkyl), C 1-4 Alkoxy, OC 1-4 Alkylene (aryl), C 1-4 Alkylene OC1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 AlkyleneO(4-10 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), or C 1-4 Alkylene O(C 3-6 C is a difunctional linear or branched, fully saturated hydrocarbon group containing the specified number of carbon atoms, whether forming part of a cyclic alkyl group (alkynyl). 1-4 Examples of alkylene groups include methylene (i.e., -CH2-), ethylene (i.e., -CH2CH2-), n-propylene (i.e., (-CH2)3-), and n-butylene (i.e., (-CH2)4-). 1-4 An example of a branched alkylene group is i-propylene (ie, -CH(Me)CH2-).

[0035] C 1-4 The term alkylene (OH) refers to a C group substituted by OH, such as CHOH. 1-4 It means an alkyl group.

[0036] C 1-4 The term "alkoxy" as used herein, such as in alkoxy, refers to an alkyl group as defined above, single-bonded to an oxygen atom (e.g., C 1-4 C 1-4 Examples of alkoxy groups include methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy, and 3-butoxy, especially methoxy.

[0037] The term "halo" or "halogen" as used herein means fluorine, chlorine, bromine, or iodine. Particular examples of halo are bromine, fluorine, and chlorine, especially fluorine.

[0038] C 1-4 The term "haloalkyl" as used herein, such as in haloalkyl, whether alone or as O-C 1-4A linear or branched alkyl group containing the specified number of carbon atoms substituted by one or more halo atoms, whether forming part of a larger group such as haloalkyl, for example, fluoromethyl (CHF), di-fluoromethyl (CHF), tri-fluoromethyl (CF), 1-fluoroethyl (CHFCH), and 2-fluoroethyl (CHCHF).

[0039] C 3-6 The term "cycloalkyl" as used herein, such as in cycloalkyl, whether alone, refers to a C 1-4 Alkylene (C 3-6 cycloalkyl) or C 1-4 Alkylene OC 3-6 A fully saturated hydrocarbon ring containing the specified number of carbon atoms, whether it forms part of a larger group such as cycloalkyl. 3-6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, especially cyclopropyl. Cycloalkyl may be optionally substituted as defined herein.

[0040] The term "heterocycloalkyl" as used herein, such as in 4- to 10-membered heterocycloalkyl (e.g., 4- to 7-membered heterocycloalkyl), whether alone or in combination, includes C 1-4 Alkylene (4-10 membered heterocycloalkyl) and C 1-4A fully saturated hydrocarbon ring containing the specified number of carbon atoms, whether forming part of a larger group such as alkyleneO (4-10 membered heterocycloalkyl), wherein at least one of the carbon atoms is replaced by a heteroatom such as N, S, or O. Optionally, the heterocycloalkyl may be substituted as defined herein. A heterocycloalkyl group may be monocyclic. Alternatively, a heterocycloalkyl group may be polycyclic, such as a fused bicyclic or bridged bicyclic ring system. In some instances, a heterocycloalkyl group may incorporate a fused ring. In some instances, a heterocycloalkyl group may incorporate a bridged ring. In some instances, a bicyclic heterocycloalkyl group is spirocyclic, i.e., a bicyclic cycloalkyl group in which the two rings are connected by only one atom. The rings may be different or the same.

[0041] Examples of 4- to 10-membered heterocycloalkyl groups include those containing one heteroatom, such as 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- to 10-membered heterocycloalkyl groups containing one nitrogen atom include azetidinyl, pyrrolidinyl, piperidinyl, and azepanyl. Examples of 4- to 10-membered heterocycloalkyl groups containing two nitrogen atoms include diazetidinyl, imidazolidinyl, pyrazolidinyl, diazinanyl, and diazepanyl.

[0042] Further examples of 4 to 10 membered heterocycloalkyl groups include oxetanyl, thietanyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, triazinanyl, trioxanyl, trithianyl, oxepanyl, and thiepanyl.

[0043] An example of a 4-10 membered heterocycloalkyl group incorporating a bridged ring is 1,4-diazabicyclo[3.2.1]octane or 1-azabicyclo[3.2.1]octane.

[0044] An example of a bicyclic spirocyclic heterocycloalkyl group is 2,6-diazaspiro[3.3]heptane.

[0045] The term "aryl" as used herein refers to a group, whether alone or in combination with a larger group, e.g., C 1-4 Alkylene (aryl), OC 1-4 Alkylene (aryl), or C 1-4 It refers to a phenyl ring whether it forms part of an alkylene O (aryl), which may optionally be substituted as defined herein.

[0046] C 3-6 The term "alkynyl" as used herein, whether alone or as in alkynyl, 1-4 Alkylene O(C 3-6 A linear or branched divalent hydrocarbon chain containing at least one carbon-carbon triple bond, whether it forms part of a larger group such as alkynyl. 3-6 Examples of alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, pentynyl, and hexynyl.

[0047] C 1-4An example of alkylene(aryl) is CHPh (where Ph means phenyl). 1-4 Alkylene OC 1-4 Examples of alkyl include CHOMe, CHOEt, and CHOPr. 1-4 Alkylene OC 3-6 Examples of cycloalkyl include CHO-Ccycloalkyl and CHO-Ccycloalkyl, such as CHO-cyclopropyl or CHO-cyclobutyl. 1-4 Examples of alkylene(4-10 membered heterocycloalkyl) include CH2(4 membered heterocycloalkyl), such as CH2-azetidinyl, CH2CH2-azetidinyl. 1-4 Examples of alkyleneO(4-10 membered heterocycloalkyl) include C 2 O-azetidinyl, etc. 1-4 Examples of alkylOC4 heterocycloalkyl include C 1-4 Alkylene O(C 3-6 An example of an alkynyl is CH2OCH2C≡CH.

[0048] In the embodiments and options described below, when a substituent is shown as being optionally substituted in Formula (I), the optional substituent may be attached to a carbon atom that is bonded to a hydrogen atom, i.e., an available carbon atom, which refers to a CH group, or the optional substituent may be attached to a nitrogen atom that is bonded to a hydrogen atom, i.e., an available nitrogen atom, which refers to an NH group. The optional substituent replaces a hydrogen atom that is bonded to a carbon atom or a hydrogen atom that is bonded to a nitrogen atom.

[0049] In one embodiment, R 1a is methyl. In one embodiment, R 1a is H.

[0050] In one embodiment, R 1b is H. In one embodiment, R 1b is F.

[0051] In one embodiment, R 1a is H and R 1b is H. In one embodiment, R 1a is H and R 1b is F. In one embodiment, R 1a is methyl and R 1b is H.

[0052] In one embodiment, A is a group (Aa): [ka] is.

[0053] In one embodiment, R2 is H. In one embodiment, R2 is halo. In one embodiment, R2 is C 1 , such as methyl, ethyl, propyl, or butyl. 1-4 In one embodiment, R2 is C, such as CF3. 1-4 In one embodiment, R2 is C haloalkyl, such as benzyl. 1-4 In one embodiment, R is C, such as CHOH. 1-4 In one embodiment, R is a C alkylene (OH), such as CHOMe, CHOEt, or CHOPr. 1-4 Alkylene OC 1-4 In one embodiment, R is a C alkyl, such as CHO-C cycloalkyl or CHO-C cycloalkyl. 1-4 Alkylene OC 3-6 In one embodiment, R is a C alkyl group such as CH2O-cyclopropyl or CH2O-cyclobutyl. 1-4 In one embodiment, R2 is a C alkylene O(aryl), such as CH2(4-membered heterocycloalkyl), for example CH2-azetidinyl, or CH2CH2(4-membered heterocycloalkyl), for example CH2CH2-azetidinyl. 1-4 In one embodiment, R2 is C 1-4C alkyl OC heterocycloalkyl etc. 1-4 In one embodiment, R is C, such as CHOCHC≡CH. 1-4 Alkylene O(C 3-6 In one embodiment, R2 is a 4- to 10-membered heterocycloalkyl, such as 1-methylpiperazinyl. In one embodiment, R2 is a C alkyl, such as CH2CH2(CO2H). 1-4 In one embodiment, R is alkylene (COH). 1-4 In one embodiment, R is C 1-4 Alkylene OC 1-4 In one embodiment, R is N(R 2aa )C 1-4 In one embodiment, R is C 1-4 Alkylene (NR 2ab R 2ac In one embodiment, R2 is OC 1-4 Alkylene (NR 2ab R 2ac In one embodiment, R2 is N(R 2aa )C 1-4 Alkylene (NR 2ab R 2ac )

[0054] In one embodiment, R2 is H, C 1-4 Alkyl, C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene (C 3-6 cycloalkyl), C 1-4 Alkylene (4-7 membered heterocycloalkyl), C 1-4 Alkoxy, OC 1-4 Alkylene (aryl), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4AlkyleneO(4-7 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), C 3-6 Alkynyl, or C 1-4 Alkenyl O(C 3-6 alkynyl).

[0055] In one embodiment, R2 is halo, C 1-4 Haloalkyl, C 1-4 Alkylene (8-10 membered heterocycloalkyl), C 1-4 AlkyleneO(8-10 membered heterocycloalkyl), 4-10 membered heterocycloalkyl such as 1-methylpiperazinyl, C such as CH2CH2(CO2H) 1-4 Alkylene (COH), OC 1-4 Alkylene (COH), C 1-4 Alkylene OC 1-4 Alkylene (COH), N(R 2aa )C 1-4 Alkylene (COH), C 1-4 Alkylene (NR 2ab R 2ac ), O.C. 1-4 Alkylene (NR 2ab R 2ac ), or N(R 2aa )C 1-4 Alkylene (NR 2ab R 2ac )

[0056] Aryl, heterocycloalkyl, and cycloalkyl groups present in R2 are C 1-4 Alkyl; C such as cyclopropyl 3-6 Cycloalkyl; C such as OMe 1-4 Alkoxy; C such as CF3 1-4 Haloalkyl; halo such as chloro or fluoro; CN; OH; NR 2a R 2b ;SO2R 2c ; and NHSO2R 2cSuitably, the aryl, heterocycloalkyl, and cycloalkyl groups present in R2 are selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 40 , C 41 , C 1-4 Alkyl; C such as cyclopropyl 3-6 Cycloalkyl; C such as OMe 1-4 Alkoxy; C such as CF3 1-4 and CN. Suitably, the aryl, heterocycloalkyl, and cycloalkyl groups present in R2 are optionally substituted by up to three substituents, for example, one, two, or three, for example, one or two, for example, one, each independently selected from haloalkyl; halo, such as chloro or fluoro; and CN. Suitably, the aryl, heterocycloalkyl, and cycloalkyl groups present in R2 are selected from the group consisting of OH; NR 2a R 2b ;SO2R 2c ; and NHSO2R 2c and optionally substituted by up to three substituents each independently selected from, for example, one, two, or three, for example, one or two, for example, one, substituent.

[0057] In one embodiment, R 2a is H. In a second embodiment, R 2a is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 2a is H or methyl.

[0058] In one embodiment, R 2b is H. In a second embodiment, R 2b is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 2b C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a fourth embodiment, R 2b C such as OMe or OEt 1-4In a fifth embodiment, R 2b is C such as CF3 1-4 In a sixth embodiment, R 2b is aryl, such as phenyl. In a seventh embodiment, R 2b is a 4-10 membered heterocycloalkyl such as azetidinyl or oxetanyl. In an eighth embodiment, R 2b is H or methyl.

[0059] In one embodiment, R 2c is C such as methyl, ethyl, or propyl 1-4 In a second embodiment, R 2c C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a third embodiment, R 2c C such as OMe or OEt 1-4 In a fourth embodiment, R 2c is C such as CF3 1-4 In a fifth embodiment, R 2c is aryl, such as phenyl. In a sixth embodiment, R 2c is a 4-10 membered heterocycloalkyl such as azetidinyl or oxetanyl. In a seventh embodiment, R 2c is methyl.

[0060] In one embodiment, R 2aa is H. In one embodiment, R 2aa is C such as methyl, ethyl, or propyl 1-4 Alkyl, especially methyl.

[0061] In one embodiment, R 2ab is H. In one embodiment, R 2aa is C such as methyl, ethyl, or propyl 1-4 alkyl, in particular methyl. In one embodiment, R 2acis H. In one embodiment, R 2ac is C 1-4 Alternatively, in one embodiment, R 2ab and R 2ac taken together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl such as azetidinyl or oxetanyl.

[0062] In one embodiment, R 2x is H. In one embodiment, R 2x is halo, such as chloro or fluoro. In one embodiment, R 2x is C such as methyl, ethyl, or propyl 1-4 alkyl, in particular methyl. In one embodiment, R 2x is C such as CF3 1-4 In one embodiment, R 2x C such as OMe or OEt 1-4 Alkoxy, especially OMe.

[0063] Alternatively, R 2x is C 1-4 Alkylene (4-10 membered heterocycloalkyl), 4-10 membered heterocycloalkyl such as 1-methylpiperazinyl, C 1-4 C such as alkyleneO(4-10 membered heterocycloalkyl), CH2CH2(CO2H) 1-4 Alkylene (COH), OC 1-4 Alkylene (COH), C 1-4 Alkylene OC 1-4 Alkylene (COH), N(R 2xaa )C 1-4 Alkylene (COH), C 1-4 Alkylene (NR 2xab R 2xac ), O.C. 1-4 Alkylene (NR 2xab R 2xac ), or N(R 2xaa )C 1-4 Alkylene (NR 2xab R 2xac In one embodiment, R 2x is C1-4 alkylene(4-10 membered heterocycloalkyl). In one embodiment, R 2x is a 4-10 membered heterocycloalkyl, such as 1-methylpiperazinyl. In one embodiment, R 2x is C 1-4 alkyleneO(4-10 membered heterocycloalkyl). In one embodiment, R 2x is C such as CH2CH2(CO2H) 1-4 alkylene (COH). In one embodiment, R 2x is O.C. 1-4 alkylene (COH). In one embodiment, R 2x is C 1-4 Alkylene OC 1-4 alkylene (COH). In one embodiment, R 2x is N(R 2xaa )C 1-4 alkylene (COH). In one embodiment, R 2x is C 1-4 Alkylene (NR 2xab R 2xac In one embodiment, R 2x is O.C. 1-4 Alkylene (NR 2xab R 2xac In one embodiment, R 2x is N(R 2xaa )C 1-4 Alkylene (NR 2xab R 2xac )

[0064] Within such embodiments, R2 is selected from the group consisting of H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl C 1-4 Alkoxy, C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, or C 1-4In one embodiment, R2 is alkyleneO(4-10 membered heterocycloalkyl). In one embodiment, R2 is H. In one embodiment, R2 is halo, such as chloro or fluoro. In one embodiment, R2 is C, such as methyl, ethyl, or propyl. 1-4 In one embodiment, R2 is C, such as CF3. 1-4 In one embodiment, R2 is a C alkyl group such as OMe or OEt. 1-4 In one embodiment, R2 is C 1-4 Alkylene OC 1-4 In one embodiment, R2 is C 1-4 Alkylene OC 3-6 In one embodiment, R2 is C 1-4 alkyleneO(4-10 membered heterocycloalkyl).

[0065] R 2x The heterocycloalkyl groups present in may be optionally substituted by up to three substituents, for example, one, two, or three, for example, one or two, for example, one substituent, and the aryl, heterocycloalkyl, and cycloalkyl are C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 2xa R 2xb , SO2R 2xc , and NHSO2R 2xc and optionally substituted with 1, 2, or 3 substituents each independently selected from 2x Heterocycloalkyl groups present in C, such as methyl 1-4 Alkyl; C such as cyclopropyl 3-6 Cycloalkyl; C such as OMe 1-4 Alkoxy; C such as CF3 1-4Optionally, R is optionally substituted by up to three substituents, for example, one, two, or three, for example, one or two, for example, one, each independently selected from haloalkyl; halo, such as chloro or fluoro; and CN. Suitably, R 2x The heterocycloalkyl groups present in 2xa R 2xb ;SO 2x R 2xc ; and NHSO2R 2xc and optionally substituted by up to three substituents each independently selected from, for example, one, two, or three, for example, one or two, for example, one, substituent.

[0066] In one embodiment, R 2xa is H. In a second embodiment, R 2xa is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 2xa is H or methyl.

[0067] In one embodiment, R 2xb is H. In a second embodiment, R 2xb is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 2xb C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a fourth embodiment, R 2xb C such as OMe or OEt 1-4 In a fifth embodiment, R 2xb is C such as CF3 1-4 In a sixth embodiment, R 2xb is aryl, such as phenyl. In a seventh embodiment, R 2xb is a 4-10 membered heterocycloalkyl such as azetidinyl or oxetanyl. In an eighth embodiment, R 2xb is H or methyl.

[0068] In one embodiment, R 2xc is C such as methyl, ethyl, or propyl 1-4 In a second embodiment, R 2xc C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a third embodiment, R 2xc C such as OMe or OEt 1-4 In a fourth embodiment, R 2xc is C such as CF3 1-4 In a fifth embodiment, R 2xc is aryl, such as phenyl. In a sixth embodiment, R 2xc is a 4-10 membered heterocycloalkyl such as azetidinyl or oxetanyl. In a seventh embodiment, R 2xc is methyl.

[0069] In one embodiment, R 2xaa is H. In one embodiment, R 2xaa is C such as methyl, ethyl, or propyl 1-4 Alkyl, especially methyl.

[0070] In one embodiment, R 2xab is H. In one embodiment, R 2xab is C such as methyl, ethyl, or propyl 1-4 alkyl, in particular methyl. In one embodiment, R 2xac is H. In one embodiment, R 2xac is C 1-4 Alternatively, in one embodiment, R 2xab and R 2xac taken together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl such as azetidinyl or oxetanyl.

[0071] Suitably, in any of the above embodiments, aryl is substituted with one, two, or three substituents, for example, one or two, for example, one, each independently selected from methyl, chloro, and fluoro. In one embodiment, aryl is unsubstituted.

[0072] Suitably, in any of the above embodiments, heterocycloalkyl is substituted with one, two, or three substituents, e.g., one or two, e.g., one, each independently selected from CH2CH2F (particularly as a substituent on a nitrogen atom) and fluoro (particularly as a substituent on a carbon atom). In one embodiment, heterocycloalkyl is unsubstituted.

[0073] Suitably, when the heterocycloalkyl is azetidinyl, the nitrogen atom is in the 1- or 3-position relative to the point of attachment to the remainder of the R2 group (i.e., 1-azetidinyl or 3-azetidinyl), for example: [ka] is.

[0074] Suitably, R2 is C such as CH2-azetidinyl or CH2CH2-azetidinyl. 1-4 When R is alkylene (4-10 membered heterocycloalkyl), the azetidinyl is 1-azetidinyl. Suitably, R is C 2 O-azetidinyl, such as C 1-4 When alkyleneO(4-10 membered heterocycloalkyl), the azetidinyl is 3-azetidinyl. For example: [ka] is.

[0075] Suitably, in any of the above embodiments, when heterocycloalkyl contains one or more nitrogen atoms, the nitrogen atom(s) may be bonded to a hydrogen atom to form an NH group, where valence requires. Alternatively, the nitrogen atom(s) may be a C hydroxyl group, such as methyl. 1-4 C alkyl, such as CH2CH2F 1-4 Haloalkyl, C(O)H, C(O)C 1-4 C(O)OC such as alkyl, C(O)OtBu 1-4 C(O)OC such as alkyl, C(O)Obz 1-4 Alkylene (aryl), C(O)NHC 1-4 Alkyl, C(O)NHC such as C(O)NHBz 1-4 Alkylene (aryl), Fmoc group, C(O)C 1-4 Haloalkyl, C(O)OC 1-4 Haloalkyl, or C(O)NHC 1-4 It may be substituted with haloalkyl (e.g., one nitrogen atom is substituted). Preferably, when the heterocycloalkyl contains one or more S atoms, the S atom(s) are substituted with one or two oxygen atoms (i.e., S(O) or S(O)2) (e.g., one S atom is substituted). Alternatively, none of the sulfur atoms in the heterocycloalkyl ring are substituted.

[0076] One or more (e.g., one) nitrogen atoms are C, such as methyl 1-4 C alkyl, such as CH2CH2F 1-4 Haloalkyl, C(O)H, C(O)C 1-4 C(O)OC such as alkyl, C(O)OtBu 1-4 C(O)OC such as alkyl, C(O)Obz 1-4 Alkylene (aryl), C(O)NHC 1-4 Alkyl, C(O)NHC such as C(O)NHBz 1-4 Alkylene (aryl), Fmoc group, C(O)C 1-4 Haloalkyl, C(O)OC 1-4 Haloalkyl, or C(O)NHC 1-4When substituted by haloalkyl, these substituents may be present in addition to the optional substituents described above in connection with heterocycloalkyl. Such substituents on a nitrogen atom may also be referred to as or function as protecting groups, which may be added and removed by methods known to those skilled in the art.

[0077] Suitably, in any of the above embodiments, cycloalkyl is selected from the group consisting of 1, 2, or 3 C 1-4 Alkyl substituents, e.g., one or two, e.g., one C 1-4 It is substituted with alkyl substituents (such as methyl, ethyl, and propyl, especially methyl). In one embodiment, the cycloalkyl is unsubstituted.

[0078] Preferably, R2 is H, C 1-4 Alkyl, or C 1-4 Alkylene OC 1-4 Except when R2 is alkyl, m is 0. More preferably, m is 0 except when R2 is H, methyl, or CHOMe.

[0079] In one embodiment, when present, each R is independently selected from halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 In one embodiment, at least one R is alkoxy, such as chloro or fluoro. In one embodiment, at least one R is C alkoxy, such as methyl, ethyl, or propyl. 1-4 In one embodiment, at least one R is a C alkyl, such as CF. 1-4 In one embodiment, at least one R is a C haloalkyl, such as OMe or OEt. 1-4 In one embodiment, each R3 is independently fluoro or methyl. In one embodiment, each R3 is independently halo, C 1-4 Alkyl (other than methyl, ethyl, or n-propyl), C 1-4 Haloalkyl, or C 1-4It is an alkoxy.

[0080] In one embodiment, m is 0, 1, or 2. In one embodiment, m is 1 or 2. In one embodiment, m is 1. In one embodiment, m is 2. In one embodiment, m is 2, one R3 is fluoro, and one R3 is methyl.

[0081] As used herein, R 2x’ is R except that it is not H 2x As defined in terms of

[0082] In one preferred embodiment, m is 0 and R 2x is R 2x’ In another preferred embodiment, R 2x is H, m is 1, and R is in the 6 position. In another preferred embodiment, m is 1 and R 2x is R 2x and R3 is at position 6. In one embodiment, m is 2 and one R 2x is R 2x’ and one R3 is at the 4-position and the other R3 is at the 6-position. In one embodiment, m is 2 and R 2x is R 2x’ where one R3 is at position 5 and the other R3 is at position 6.

[0083] Suitably, when R2 is methyl, m is 1 and R3 is chloro, R 2x is H and R3 is not in the 5-position. Preferably, when R2 is methyl, m is 1 and R3 is chloro, R3 is in the 4- or 6-position and R 2x is R 2x’ Preferably, R2 is H, m is 1, and R3 is C 1-4 If it is alkyl, R 2x is H and R3 is not at the 5-position. Preferably, R2 is H, m is 1 and R 2xis H and R3 is C 1-4 When it is alkyl, R3 is in the 4- or 6-position. Preferably, when m is 1, R 2x is R 2x’ and no R group is at the 5-position. Preferably, when m is 2, R 2x is H, and the two R groups are in the 4 and 6 positions.

[0084] References to substituent positions are with respect to the bond to the amide moiety, for example: [ka] is.

[0085] Examples of suitable substituents include 3-fluoro-2-methyl; 3-fluoro-2-CHOCH; 3-chloro-2-methyl-; 4,5-difluoro-2-methyl; 5-chloro-2-isopropyl; 5-fluoro-2-methyl; 2-isopropyl-6-methyl; 2,6-dimethyl; 2-methyl; 2-isopropyl; 4-fluoro-3-methyl; 3-fluoro-4-methyl; 3,4-difluoro-2,6-dimethyl; 3,5-difluoro-2,6-dimethyl; and 3-fluoro-2,6-dimethyl.In one embodiment, each R is the same.In one embodiment, each R is different.

[0086] Preferably, R and R 2x One of the groups (i.e., the 2- or 3-position substituent) may be a 4- to 10-membered heterocycloalkyl such as 1-methylpiperazinyl, a C alkyl group such as CHCH(COH), 1-4 Alkylene (COH), OC 1-4 Alkylene (COH), C 1-4 Alkylene OC 1-4 Alkylene (COH), N(R 2aa )C 1-4 Alkylene (COH), C 1-4 Alkylene (NR 2ab R 2ac ), O.C. 1-4 Alkylene (NR 2ab R 2ac), or N(R 2aa )C 1-4 Alkylene (NR 2ab R 2ac and R3 is halo such as chloro and fluoro or C such as methyl 1-4 alkyl, for example, R3 at position 5 is halo such as fluoro and R3 at position 6 is C such as methyl 1-4 It is alkyl.

[0087] In one embodiment, (Aa) is a group (Aa′): [ka] (In the formula: R2 is a 4- to 10-membered heterocycloalkyl such as 1-methylpiperazinyl, C such as CH2CH2(CO2H) 1-4 Alkylene (COH), OC 1-4 Alkylene (COH), C 1-4 Alkylene OC 1-4 Alkylene (COH), N(R 2aa )C 1-4 Alkylene (COH), C 1-4 Alkylene (NR 2ab R 2ac ), O.C. 1-4 Alkylene (NR 2ab R 2ac ), or N(R 2aa )C 1-4 Alkylene (NR 2ab R 2ac ) and; R 2x is H or C 1-4 is alkyl, R 2v is H or C 1-4 is alkyl; R 2y is H, halo, or C 1-4 is alkyl; R 2z is H, halo, or C 1-4 is alkyl; Each R 2aa are independently H and C 1-4 alkyl; Each R2ab are independently H and C 1-4 alkyl; Each R 2ac are independently H and C 1-4 alkyl; or R 2ab and R 2ac together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl; or R2 is H or C 1-4 is alkyl; R 2x is a 4- to 10-membered heterocycloalkyl such as 1-methylpiperazinyl, C such as CH2CH2(CO2H) 1-4 Alkylene (COH), OC 1-4 Alkylene (COH), C 1-4 Alkylene OC 1-4 Alkylene (COH), N(R 2xaa )C 1-4 Alkylene (COH), C 1-4 Alkylene (NR 2xab R 2xac ), O.C. 1-4 Alkylene (NR 2xab R 2xac ), or N(R 2xaa )C 1-4 Alkylene (NR 2xab R 2xac ) and; R 2v is H or C 1-4 is alkyl; R 2y is H, halo, or C 1-4 is alkyl; R 2z is H, halo, or C 1-4 is alkyl; Each R 2xaa are independently H and C 1-4 alkyl; Each R 2xab are independently H and C 1-4 alkyl; Each R 2xac are independently H and C 1-4 alkyl; or R 2xab and R 2xac together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl is.

[0088] In one embodiment, R2 is CH2CH2(CO2H), and R 2x is H and R 2v is H and R 2y is fluoro and R 2z In one embodiment, R2 is 1-methylpiperazinyl and R 2x is H and R 2v is H and R 2y is fluoro and R 2z is methyl.

[0089] In one embodiment, R2 is H and R 2x is CH2CH2(CO2H), and R 2v is H and R 2y is fluoro and R 2z is methyl.

[0090] In one embodiment, A is a group (Ab): [ka] is.

[0091] In one embodiment, R4 is H. In a second embodiment, R4 is C, such as methyl. 1-4 In a third embodiment, R4 is C alkyl, such as benzyl. 1-4 In a preferred embodiment, R4 is H, methyl, or benzyl, in particular methyl or benzyl. Suitably, the aryl present in R4 is C aryl, such as methyl. 1-4 Alkyl; C such as cyclopropyl 3-6 Cycloalkyl; C such as OMe 1-4 Alkoxy; C such as CF3 1-4Haloalkyl; halo such as chloro or fluoro; CN; OH; NR 4a R 4b ;SO2R 4c ; and NHSO2R 4c Preferably, the aryl present in R4 is substituted by one, two, or three substituents, for example one or two, for example one, each independently selected from 1-4 Alkyl; C such as cyclopropyl 3-6 Cycloalkyl; C such as OMe 1-4 Alkoxy; C such as CF3 1-4 and CN. Preferably, the aryl present in R4 is substituted by one, two, or three substituents, for example one or two, for example one, each independently selected from haloalkyl; halo, such as chloro or fluoro; and CN. Suitably ..., for example one, independently selected from haloalkyl; halo, such as chloro or fluoro; and CN. Suitably, the aryl present in R4 is substituted by one, two, or three, for example one, independently selected from haloalkyl; halo, such as chloro or fluoro; and CN. Suitably, the aryl present in R4 is substituted by one, two, or three, for example one, independently selected from haloalkyl; halo, such as chloro or fluoro; and CN 4a R 4b ;SO2R 4c ; and NHSO2R 4c The aryl is substituted by one, two, or three substituents, for example, one or two, for example, one, each independently selected from the following:

[0092] In one embodiment, R 4a is H. In a second embodiment, R 4a is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 4a is H or methyl.

[0093] In one embodiment, R 4b is H. In a second embodiment, R 4b is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 4b C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a fourth embodiment, R 4b C such as OMe or OEt 1-4 In a fifth embodiment, R 4b is C such as CF3 1-4 In a sixth embodiment, R 4b is aryl, such as phenyl. In a seventh embodiment, R 4b is a 4-10 membered heterocycloalkyl such as azetidinyl or oxetanyl. In an eighth embodiment, R 4b is H or methyl.

[0094] In one embodiment, R 4c is C such as methyl, ethyl, or propyl 1-4 In a second embodiment, R 4c C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a third embodiment, R 4c C such as OMe or OEt 1-4 In a fourth embodiment, R 4c is C such as CF3 1-4 In a fifth embodiment, R 4c is aryl, such as phenyl. In a sixth embodiment, R 4c is a 4-10 membered heterocycloalkyl such as azetidinyl or oxetanyl. In a seventh embodiment, R 4c is methyl.

[0095] In one embodiment, R 5 is H.

[0096] When present, in one embodiment, each R6 is independently fluoro or methyl. Suitably, n may be 1, 2 or 3, such as 1 or 2, for example 1.

[0097] In one embodiment, n is 0.

[0098] In one embodiment, the group A is the group (Ac): [ka] is.

[0099] In one embodiment, R7 is C 1-4 In one embodiment, R7 is methyl, CH2OH or CHOMe, particularly methyl.

[0100] In one embodiment, o is 2. Suitably, when o is 2, B is not a group (Ba).

[0101] Suitably, the stereochemistry of R7 is trans with respect to the bond connecting the (Ac) group to the amide moiety, for example, the following two stereochemical configurations: [ka] The ion implantation device has one of the following:

[0102] In one embodiment, A is a group (Ad): [ka] is.

[0103] 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.

[0104] In one embodiment, R8 is halo. In a second embodiment, R8 is C 1-4 In a third embodiment, R8 is C 1-4 In a fourth embodiment, R8 is OH.

[0105] When present, in one embodiment, each R is independently methyl, OMe, or fluoro. In one embodiment, each R is independently OCH-cyclopropyl, OCH-oxetanyl, OCHCHF, methyl, OMe, OEt, or fluoro, e.g., OCHCHF, OMe, or OEt, particularly OMe. In another embodiment, each R is independently OCH-cyclopropyl, OCH-oxetanyl, OCHCHF, or OEt, e.g., OCH-cyclopropyl, OCH-oxetanyl, or OCHCHF.

[0106] Suitably, each cycloalkyl and heterocycloalkyl present in R is independently selected from C methyl, 1-4 Alkyl; C such as cyclopropyl 3-6 Cycloalkyl; C such as OMe 1-4 Alkoxy; C such as CF3 1-4 Haloalkyl; halo such as chloro or fluoro; CN; OH; NR 8a R 8b ;SO2R 8c ; and NHSO2R 8c Preferably, the cycloalkyl and heterocycloalkyl present in R8 are each independently selected from C methyl, such as methyl. 1-4 Alkyl; C such as cyclopropyl 3-6 Cycloalkyl; C such as OMe 1-4 Alkoxy; C such as CF3 1-4Preferably, the cycloalkyl and heterocycloalkyl present in R8 are each independently selected from OH; NR8; NR8; and NR8. 8a R 8b ;SO2R 8c ; and NHSO2R 8c Substituted by 1, 2, or 3 substituents, eg, 1 or 2, eg, 1, each independently selected from

[0107] In one embodiment, R 8a is H. In a second embodiment, R 8a is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 8a is H or methyl.

[0108] In one embodiment, R 8b is H. In a second embodiment, R 8b is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 8b C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a fourth embodiment, R 8b C such as OMe or OEt 1-4 In a fifth embodiment, R 8b is C such as CF3 1-4 In a sixth embodiment, R 8b is aryl, such as phenyl. In a seventh embodiment, R 8b is a 4-10 membered heterocycloalkyl such as azetidinyl or oxetanyl. In an eighth embodiment, R 8b is H or methyl.

[0109] In one embodiment, R 8c is C such as methyl, ethyl, or propyl 1-4 In a second embodiment, R 8c C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a third embodiment, R 8c C such as OMe or OEt 1-4 In a fourth embodiment, R 8c is C such as CF3 1-4 In a fifth embodiment, R 8c is aryl, such as phenyl. In a sixth embodiment, R 8c is a 4-10 membered heterocycloalkyl such as azetidinyl or oxetanyl. In a seventh embodiment, R 8c is methyl.

[0110] Suitably, cycloalkyl (e.g., cyclopropyl) present in R8 is selected from C 11 alkyl, C 21 alkyl, C 31 alkyl, C 41 alkyl, C 51 alkyl, C 61 alkyl, C 71 alkyl, C 81 alkyl, C 91 alkyl, C 101 alkyl, C 111 alkyl, C 121 alkyl, C 131 alkyl, C 141 alkyl, C 151 alkyl, C 161 alkyl, C 1-4 In one embodiment, the cycloalkyl is substituted with one, two, or three substituents, e.g., one or two, e.g., one, each independently selected from alkyl. In one embodiment, the cycloalkyl is unsubstituted.

[0111] Suitably, heterocycloalkyl present in R (e.g., oxetanyl) is selected from C 11 alkyl, C 21 alkyl, C 31 alkyl, C 41 alkyl, C 51 alkyl, C 61 alkyl, C 71 alkyl, C 81 alkyl, C 91 alkyl, C 101 alkyl, C 111 alkyl, C 121 alkyl, C 131 alkyl, C 141 alkyl, C 151 alkyl, C 161 alkyl, 1-4 In one embodiment, the heterocycloalkyl is substituted with one, two, or three substituents, e.g., one or two, e.g., one, each independently selected from alkyl. In one embodiment, the heterocycloalkyl is unsubstituted.

[0112] Suitably, when the heterocycloalkyl is oxetanyl, the oxygen atom is in the 2- or 3-position relative to the point of attachment to the remainder of the R group (i.e., 2-oxetanyl or 3-oxetanyl), for example: [ka] is.

[0113] Preferably, R8 is OC such as OCH2-oxetanyl. 1-4 When alkylene(4-10 membered heterocycloalkyl), the oxetanyl may be 3-oxetanyl, for example: [ka] is.

[0114] When p is 1 or 2, R8 may be in the 2-position and / or the 3-position. In one embodiment, p is 1 and R8 is in the 2-position. In a second embodiment, p is 1 and R8 is in the 3-position. In a third embodiment, p is 2, one R8 is in the 2-position and one R8 is in the 3-position. For example: [ka] is.

[0115] Examples of suitable R8 substituents include 2-methyl, 2-methoxy, 2-ethoxy, 2-OCH2CH2F, 2-OCH2-cyclopropyl, and 2-OCH2-oxetanyl, such as 2-methyl and 2-methoxy.

[0116] In one embodiment, p is 0 or 1.

[0117] Preferably, when X is O, p is 1 or 2. Preferably, when X is a bond and the group B is (Ba), Y is C(R 11 )(R 12 ) and R 11 and R 12 are both H and p is 1 or 2. Preferably, when X is CH2, B is not (Ba).

[0118] Preferably, when X is a bond and p is 0, the compound has the R stereochemical configuration. Preferably, when X is as defined above and p is 1, the stereochemistry of R is trans with respect to the bond connecting the (Ad) group to the amide substituent, for example, the following stereochemical configuration: [ka] The ion implantation device has one of the following:

[0119] When present, in one embodiment, each R9 is independently fluoro.

[0120] Suitably, when q is 1, 2, 3, or 4, R9 may be in the 5, 6, 7, and / or 8 positions. In one embodiment, q is 1 and R9 is in the 5 position. In a second embodiment, q is 1 and R9 is in the 6 position. For example: [ka] is.

[0121] In embodiments where X is a bond, it will be understood that the substituent position numbering will scale with the total number of atoms in the bicyclic ring system. For example: [ka] is.

[0122] Suitable examples of R9 substituents when X is a bond are 4-fluoro and 5-fluoro.

[0123] In one embodiment, q is 1 or 2.

[0124] In one embodiment, the group A is (Ae): [ka] is.

[0125] In one embodiment, R 17 is H. In one embodiment, R 17 is halo. In one embodiment, R 17 C such as methyl, ethyl, propyl, or butyl 1-4 alkyl, in particular methyl. In one embodiment, R 17 is C such as CF3 1-4 In one embodiment, R 17 C such as benzyl 1-4 In one embodiment, R 17 is C such as CH2OH 1-4 In one embodiment, R 17 C such as CH2OMe, CH2OEt, or CH2OPr 1-4 Alkylene OC 1-4 alkyl, in particular CHOMe. In one embodiment, R 17 is C, such as CHO-Ccycloalkyl or CHO-Ccycloalkyl 1-4 Alkylene OC 3-6 cycloalkyl, for example, CHO-cyclopropyl or CHO-cyclobutyl. In one embodiment, R 17 is C such as CH2OPh 1-4 alkylene O(aryl). In one embodiment, R 17 is CH2(4-membered heterocycloalkyl), e.g., CH2-azetidinyl, or CH2CH2(4-membered heterocycloalkyl), e.g., CH2CH2-azetidinyl, 1-4 alkylene(4-10 membered heterocycloalkyl). In one embodiment, R 17 is C 1-4 C alkyl OC heterocycloalkyl etc. 1-4 alkyleneO(4-10 membered heterocycloalkyl), in particular, CHO-azetidinyl. In one embodiment, R 17 is C, such as CH2OCH2C≡CH 1-4 Alkylene O(C 3-6 alkynyl). In one embodiment, R 17is a 4-10 membered heterocycloalkyl, such as 1-methylpiperazinyl. In one embodiment, R 17 is C such as CH2CH2(CO2H) 1-4 alkylene (COH). In one embodiment, R 17 is O.C. 1-4 alkylene (COH). In one embodiment, R 17 is C 1-4 Alkylene OC 1-4 alkylene (COH). In one embodiment, R 17 is N(R 2aa )C 1-4 alkylene (COH). In one embodiment, R 17 is C 1-4 Alkylene (NR 17ab R 17ac In one embodiment, R 17 is O.C. 1-4 Alkylene (NR 17ab R 17ac In one embodiment, R 17 is N(R 17aa )C 1-4 Alkylene (NR 17ab R 17ac )

[0126] In one embodiment, R 17 is a 4- to 10-membered heterocycloalkyl such as 1-methylpiperazinyl, C such as CH2CH2(CO2H) 1-4 Alkylene (COH), OC 1-4 Alkylene (COH), C 1-4 Alkylene OC 1-4 Alkylene (COH), N(R 17aa )C 1-4 Alkylene (COH), C 1-4 Alkylene (NR 17ab R 17ac ), O.C. 1-4 Alkylene (NR 17ab R 17ac ), or N(R 17aa )C 1-4 Alkylene (NR 17ab R 17ac )

[0127] R 17 The aryl, cycloalkyl, or heterocycloalkyl group present in 1-4 Alkyl; C such as cyclopropyl 3-6 Cycloalkyl; C such as OMe 1-4 Alkoxy; C such as CF3 1-4 Haloalkyl; halo such as chloro or fluoro; CN; OH; NR 17a R 17b ;SO2R 17c ; and NHSO2R 17c and optionally substituted by up to three substituents, for example one, two or three, for example one or two, for example one, each independently selected from 17 The aryl, heterocycloalkyl, and cycloalkyl groups present in 1-4 Alkyl; C such as cyclopropyl 3-6 Cycloalkyl; C such as OMe 1-4 Alkoxy; C such as CF3 1-4 and CN. Suitably, the aryl, heterocycloalkyl, and cycloalkyl groups present in R2 are optionally substituted by up to three substituents, for example, one, two, or three, for example, one or two, for example, one, each independently selected from haloalkyl; halo, such as chloro or fluoro; and CN. Suitably, the aryl, heterocycloalkyl, and cycloalkyl groups present in R2 are selected from the group consisting of OH; NR 17a R 17b ;SO2R 17c ; and NHSO2R 17c and optionally substituted by up to three substituents each independently selected from, for example, one, two, or three, for example, one or two, for example, one, substituent.

[0128] In one embodiment, R 17a is H. In a second embodiment, R 17a is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 17a is H or methyl.

[0129] In one embodiment, R 17b is H. In a second embodiment, R 17b is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 17b C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a fourth embodiment, R 17b C such as OMe or OEt 1-4 In a fifth embodiment, R 17b is C such as CF3 1-4 In a sixth embodiment, R 17b is aryl, such as phenyl. In a seventh embodiment, R 17b is a 4-10 membered heterocycloalkyl such as azetidinyl or oxetanyl. In an eighth embodiment, R 17b is H or methyl.

[0130] In one embodiment, R 17c is C such as methyl, ethyl, or propyl 1-4 In a second embodiment, R 17c C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a third embodiment, R 17c C such as OMe or OEt 1-4 In a fourth embodiment, R 17c is C such as CF3 1-4 In a fifth embodiment, R 17c is aryl, such as phenyl. In a sixth embodiment, R 17c is a 4-10 membered heterocycloalkyl such as azetidinyl or oxetanyl. In a seventh embodiment, R 17c is methyl.

[0131] In one embodiment, R 17aa is H. In one embodiment, R 17aa is C such as methyl, ethyl, or propyl 1-4 Alkyl, especially methyl.

[0132] In one embodiment, R 17ab is H. In one embodiment, R 17ab is C such as methyl, ethyl, or propyl 1-4 alkyl, in particular methyl. In one embodiment, R 17ac is H. In one embodiment, R 17ac is C 1-4 Alternatively, in one embodiment, R 17ab and R 17ac taken together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl such as azetidinyl or oxetanyl.

[0133] Within such embodiments, R 18 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, or C 1-4 alkyleneO(4-10 membered heterocycloalkyl). In one embodiment, R 18 is H. In one embodiment, R 18 is halo, such as chloro or fluoro. In one embodiment, R 18 is C such as methyl, ethyl, or propyl 1-4 alkyl, in particular methyl. In one embodiment, R 18 is C such as CF3 1-4 In one embodiment, R 18 C such as OMe or OEt 1-4 Alkoxy, in particular OMe. In one embodiment, R 18 is C1-4 Alkylene OC 1-4 In one embodiment, R 18 is C 1-4 Alkylene OC 3-6 In one embodiment, R 18 is C 1-4 alkyleneO(4-10 membered heterocycloalkyl).

[0134] Within such embodiments, R 20 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 In one embodiment, R 20 is H. In one embodiment, R 20 is halo, such as chloro or fluoro. In one embodiment, R 20 is C such as methyl, ethyl, or propyl 1-4 alkyl, in particular methyl. In one embodiment, R 20 is C such as CF3 1-4 In one embodiment, R 20 C such as OMe or OEt 1-4 Alkoxy, especially OMe.

[0135] Within such embodiments, R 21 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 In one embodiment, R 21 is H. In one embodiment, R 21 is halo, such as chloro or fluoro. In one embodiment, R 21 is C such as methyl, ethyl, or propyl 1-4 alkyl, in particular methyl. In one embodiment, R 21 is C such as CF3 1-4 In one embodiment, R 21 C such as OMe or OEt 1-4 Alkoxy, especially OMe.

[0136] Alternatively, R 18 is C 1-4 Haloalkyl, C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene (C 3-6 cycloalkyl), C 1-4 Alkylene (4-10 membered heterocycloalkyl), 4-10 membered heterocycloalkyl such as 1-methylpiperazinyl, OC 1-4 Alkylene (aryl), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 AlkyleneO(4-10 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), C 3-6 Alkynyl, C 1-4 Alkenyl O(C 3-6 C such as alkynyl, CH2CH2(CO2H) 1-4 Alkylene (COH), OC 1-4 Alkylene (COH), C 1-4 Alkylene OC 1-4 Alkylene (COH), N(R 18aa )C 1-4 Alkylene (COH), C 1-4 Alkylene (NR 18ab R 18ac ), O.C. 1-4 Alkylene (NR 18ab R 18ac ), or N(R 18aa )C 1-4 Alkylene (NR 18ab R 18ac )

[0137] In one embodiment, R 18 is a 4- to 10-membered heterocycloalkyl such as 1-methylpiperazinyl, C such as CH2CH2(CO2H) 1-4 Alkylene (COH), OC 1-4 Alkylene (COH), C 1-4 Alkylene OC1-4 Alkylene (COH), N(R 18aa )C 1-4 Alkylene (COH), C 1-4 Alkylene (NR 18ab R 18ac ), O.C. 1-4 Alkylene (NR 18ab R 18ac ), or N(R 18aa )C 1-4 Alkylene (NR 18ab R 18ac )

[0138] In one embodiment, R 18 is C such as CF3 1-4 In one embodiment, R 18 C such as benzyl 1-4 In one embodiment, R is C, such as CHOH. 1-4 In one embodiment, R 18 C such as CH2OMe, CH2OEt, or CH2OPr 1-4 Alkylene OC 1-4 alkyl, in particular CHOMe. In one embodiment, R 18 is C, such as CHO-Ccycloalkyl or CHO-Ccycloalkyl 1-4 Alkylene OC 3-6 cycloalkyl, for example, CHO-cyclopropyl or CHO-cyclobutyl. In one embodiment, R 18 is C such as CH2OPh 1-4 alkylene O(aryl). In one embodiment, R 18 is CH2(4-membered heterocycloalkyl), e.g., CH2-azetidinyl, or CH2CH2(4-membered heterocycloalkyl), e.g., CH2CH2-azetidinyl, 1-4 alkylene(4-10 membered heterocycloalkyl). In one embodiment, R 18 is C 1-4 C alkyl OC heterocycloalkyl etc. 1-4alkyleneO(4-10 membered heterocycloalkyl), in particular, CHO-azetidinyl. In one embodiment, R 18 is C, such as CH2OCH2C≡CH 1-4 Alkylene O(C 3-6 alkynyl). In one embodiment, R 18 is a 4-10 membered heterocycloalkyl, such as 1-methylpiperazinyl. In one embodiment, R 18 is C such as CH2CH2(CO2H) 1-4 alkylene (COH). In one embodiment, R 18 is O.C. 1-4 alkylene (COH). In one embodiment, R 18 is C 1-4 Alkylene OC 1-4 alkylene (COH). In one embodiment, R 18 is N(R 18aa )C 1-4 alkylene (COH). In one embodiment, R 18 is C 1-4 Alkylene (NR 18ab R 18ac In one embodiment, R 18 is O.C. 1-4 Alkylene (NR 18ab R 18ac In one embodiment, R 18 is N(R 18aa )C 1-4 Alkylene (NR 18ab R 18ac )

[0139] R 18 The aryl, cycloalkyl, or heterocycloalkyl group present in 1-4 Alkyl; C such as cyclopropyl 3-6 Cycloalkyl; C such as OMe 1-4 Alkoxy; C such as CF3 1-4 Haloalkyl; halo such as chloro or fluoro; CN; OH; NR 18a R 18b ;SO2R 18c ; and NHSO2R 18cand optionally substituted by up to three substituents, for example one, two or three, for example one or two, for example one, each independently selected from 18 Heterocycloalkyl groups present in C, such as methyl 1-4 Alkyl; C such as cyclopropyl 3-6 Cycloalkyl; C such as OMe 1-4 Alkoxy; C such as CF3 1-4 Optionally, R is optionally substituted by up to three substituents, for example, one, two, or three, for example, one or two, for example, one, each independently selected from haloalkyl; halo, such as chloro or fluoro; and CN. Suitably, R 18 The heterocycloalkyl groups present in 18a R 18b ;SO2R 18c ; and NHSO2R 18c and optionally substituted by up to three substituents each independently selected from, for example, one, two, or three, for example, one or two, for example, one, substituent.

[0140] In one embodiment, R 18a is H. In a second embodiment, R 18a is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 18a is H or methyl.

[0141] In one embodiment, R 18b is H. In a second embodiment, R 18b is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 18b C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a fourth embodiment, R 18b C such as OMe or OEt 1-4In a fifth embodiment, R 18b is C such as CF3 1-4 In a sixth embodiment, R 18b is aryl, such as phenyl. In a seventh embodiment, R 18b is a 4-10 membered heterocycloalkyl such as azetidinyl or oxetanyl. In an eighth embodiment, R 18b is H or methyl.

[0142] In one embodiment, R 18c is C such as methyl, ethyl, or propyl 1-4 In a second embodiment, R 18c C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a third embodiment, R 18c C such as OMe or OEt 1-4 In a fourth embodiment, R 18c is C such as CF3 1-4 In a fifth embodiment, R 18c is aryl, such as phenyl. In a sixth embodiment, R 18c is a 4-10 membered heterocycloalkyl such as azetidinyl or oxetanyl. In a seventh embodiment, R 18c is methyl.

[0143] In one embodiment, R 18aa is H. In one embodiment, R 18aa is C such as methyl, ethyl, or propyl 1-4 Alkyl, especially methyl.

[0144] In one embodiment, R 18ab is H. In one embodiment, R 18aa is C such as methyl, ethyl, or propyl 1-4 alkyl, in particular methyl. In one embodiment, R 18acis H. In one embodiment, R 18ac is C 1-4 Alternatively, in one embodiment, R 18ab and R 18ac taken together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl such as azetidinyl or oxetanyl.

[0145] Within such embodiments, R 17 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl C 1-4 Alkoxy, C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, or C 1-4 alkyleneO(4-10 membered heterocycloalkyl). In one embodiment, R 17 is H. In one embodiment, R 18 is halo, such as chloro or fluoro. In one embodiment, R 17 is C such as methyl, ethyl, or propyl 1-4 alkyl, in particular methyl. In one embodiment, R 17 is C such as CF3 1-4 In one embodiment, R 17 C such as OMe or OEt 1-4 Alkoxy, in particular OMe. In one embodiment, R 17 is C 1-4 Alkylene OC 1-4 In one embodiment, R 17 is C 1-4 Alkylene OC 3-6 In one embodiment, R 17 is C 1-4 alkyleneO(4-10 membered heterocycloalkyl).

[0146] Within such embodiments, R 20 H, halo, C 1-4 Alkyl, C1-4 Haloalkyl, or C 1-4 In one embodiment, R 20 is H. In one embodiment, R 20 is halo, such as chloro or fluoro. In one embodiment, R 20 is C such as methyl, ethyl, or propyl 1-4 alkyl, in particular methyl. In one embodiment, R 20 is C such as CF3 1-4 In one embodiment, R 20 C such as OMe or OEt 1-4 Alkoxy, especially OMe.

[0147] Within such embodiments, R 21 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 In one embodiment, R 21 is H. In one embodiment, R 21 is halo, such as chloro or fluoro. In one embodiment, R 21 is C such as methyl, ethyl, or propyl 1-4 alkyl, in particular methyl. In one embodiment, R 21 is C such as CF3 1-4 In one embodiment, R 21 C such as OMe or OEt 1-4 Alkoxy, especially OMe.

[0148] Alternatively, R 21 is C 1-4 Haloalkyl, C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene (C 3-6 cycloalkyl), C 1-4 Alkylene (4-10 membered heterocycloalkyl), 4-10 membered heterocycloalkyl such as 1-methylpiperazinyl, OC 1-4 Alkylene (aryl), C1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 AlkyleneO(4-10 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), C 3-6 Alkynyl, C 1-4 Alkenyl O(C 3-6 C such as alkynyl, CH2CH2(CO2H) 1-4 Alkylene (COH), OC 1-4 Alkylene (COH), C 1-4 Alkylene OC 1-4 Alkylene (COH), N(R 21aa )C 1-4 Alkylene (COH), C 1-4 Alkylene (NR 21ab R 21ac ), O.C. 1-4 Alkylene (NR 21ab R 21ac ), or N(R 21aa )C 1-4 Alkylene (NR 21ab R 21ac )

[0149] In one embodiment, R 21 is a 4- to 10-membered heterocycloalkyl such as 1-methylpiperazinyl, C such as CH2CH2(CO2H) 1-4 Alkylene (CO2H), OC 1-4 Alkylene (COH), C 1-4 Alkylene OC 1-4 Alkylene (COH), N(R 21aa )C 1-4 Alkylene (COH), C 1-4 Alkylene (NR 21ab R 21ac ), O.C. 1-4 Alkylene (NR 21ab R 21ac ), or N(R 21aa )C 1-4 Alkylene (NR 21ab R 21ac )

[0150] In one embodiment, R 21 is C such as CF3 1-4 In one embodiment, R 21 C such as benzyl 1-4 In one embodiment, R 21 is C such as CH2OH 1-4 In one embodiment, R 21 C such as CH2OMe, CH2OEt, or CH2OPr 1-4 Alkylene OC 1-4 alkyl, in particular CHOMe. In one embodiment, R 21 is C, such as CHO-Ccycloalkyl or CHO-Ccycloalkyl 1-4 Alkylene OC 3-6 cycloalkyl, for example, CHO-cyclopropyl or CHO-cyclobutyl. In one embodiment, R 21 is C such as CH2OPh 1-4 alkylene O(aryl). In one embodiment, R 21 is CH2(4-membered heterocycloalkyl), e.g., CH2-azetidinyl, or CH2CH2(4-membered heterocycloalkyl), e.g., CH2CH2-azetidinyl, 1-4 alkylene(4-10 membered heterocycloalkyl). In one embodiment, R 21 is C 1-4 C alkyl OC heterocycloalkyl etc. 1-4 alkyleneO(4-10 membered heterocycloalkyl), in particular, CHO-azetidinyl. In one embodiment, R 21 is C, such as CH2OCH2C≡CH 1-4 Alkylene O(C 3-6 alkynyl). In one embodiment, R 21 is a 4-10 membered heterocycloalkyl, such as 1-methylpiperazinyl. In one embodiment, R 21 is C such as CH2CH2(CO2H) 1-4 In one embodiment, R is alkylene (COH). 1-4alkylene (COH). In one embodiment, R 21 is C 1-4 Alkylene OC 1-4 alkylene (COH). In one embodiment, R 21 is N(R 21aa )C 1-4 alkylene (COH). In one embodiment, R 21 is C 1-4 Alkylene (NR 21ab R 21ac In one embodiment, R 21 is O.C. 1-4 Alkylene (NR 21ab R 21ac In one embodiment, R 21 is N(R 21aa )C 1-4 Alkylene (NR 21ab R 21ac )

[0151] R 21 The aryl, cycloalkyl, or heterocycloalkyl group present in 1-4 Alkyl; C such as cyclopropyl 3-6 Cycloalkyl; C such as OMe 1-4 Alkoxy; C such as CF3 1-4 Haloalkyl; halo such as chloro or fluoro; CN; OH; NR 21a R 21b ;SO2R 21c ; and NHSO2R 21c and optionally substituted by up to three substituents, for example one, two or three, for example one or two, for example one, each independently selected from 21 Heterocycloalkyl groups present in C, such as methyl 1-4 Alkyl; C such as cyclopropyl 3-6 Cycloalkyl; C such as OMe 1-4 Alkoxy; C such as CF3 1-4Optionally, R is optionally substituted by up to three substituents, for example, one, two, or three, for example, one or two, for example, one, each independently selected from haloalkyl; halo, such as chloro or fluoro; and CN. Suitably, R 18 The heterocycloalkyl groups present in 21a R 21b ;SO2R 21c ; and NHSO2R 21c and optionally substituted by up to three substituents each independently selected from, for example, one, two, or three, for example, one or two, for example, one, substituent.

[0152] In one embodiment, R 21a is H. In a second embodiment, R 21a is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 21a is H or methyl.

[0153] In one embodiment, R 21b is H. In a second embodiment, R 21b is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 21b C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a fourth embodiment, R 21b C such as OMe or OEt 1-4 In a fifth embodiment, R 21b is C such as CF3 1-4 In a sixth embodiment, R 21b is aryl, such as phenyl. In a seventh embodiment, R 21b is a 4-10 membered heterocycloalkyl such as azetidinyl or oxetanyl. In an eighth embodiment, R 21b is H or methyl.

[0154] In one embodiment, R 21c is C such as methyl, ethyl, or propyl 1-4 In a second embodiment, R 21c C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a third embodiment, R 21c C such as OMe or OEt 1-4 In a fourth embodiment, R 21c is C such as CF3 1-4 In a fifth embodiment, R 21c is aryl, such as phenyl. In a sixth embodiment, R 21c is a 4-10 membered heterocycloalkyl such as azetidinyl or oxetanyl. In a seventh embodiment, R 21c is methyl.

[0155] In one embodiment, R 21aa is H. In one embodiment, R 21aa is C such as methyl, ethyl, or propyl 1-4 Alkyl, especially methyl.

[0156] In one embodiment, R 21ab is H. In one embodiment, R 21aa is C such as methyl, ethyl, or propyl 1-4 alkyl, in particular methyl. In one embodiment, R 21ac is H. In one embodiment, R 21ac is C 1-4 Alternatively, in one embodiment, R 21ab and R 21ac taken together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl such as azetidinyl or oxetanyl.

[0157] Within such embodiments, R 17H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl C 1-4 Alkoxy, C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, or C 1-4 alkyleneO(4-10 membered heterocycloalkyl). In one embodiment, R 17 is H. In one embodiment, R 17 is halo, such as chloro or fluoro. In one embodiment, R 17 is C such as methyl, ethyl, or propyl 1-4 alkyl, in particular methyl. In one embodiment, R 17 is C such as CF3 1-4 In one embodiment, R 17 C such as OMe or OEt 1-4 Alkoxy, in particular OMe. In one embodiment, R 17 is C 1-4 Alkylene OC 1-4 In one embodiment, R 17 is C 1-4 Alkylene OC 3-6 In one embodiment, R 17 is C 1-4 alkyleneO(4-10 membered heterocycloalkyl).

[0158] Within such embodiments, R 18 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, or C 1-4 alkyleneO(4-10 membered heterocycloalkyl). In one embodiment, R 18 is H. In one embodiment, R 18is halo, such as chloro or fluoro. In one embodiment, R 18 is C such as methyl, ethyl, or propyl 1-4 alkyl, in particular methyl. In one embodiment, R 18 is C such as CF3 1-4 In one embodiment, R 18 C such as OMe or OEt 1-4 Alkoxy, in particular OMe. In one embodiment, R 18 is C 1-4 Alkylene OC 3-6 In one embodiment, R 18 is C 1-4 alkyleneO(4-10 membered heterocycloalkyl).

[0159] Within such embodiments, R 20 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 In one embodiment, R 20 is H. In one embodiment, R 21 is halo, such as chloro or fluoro. In one embodiment, R 20 is C such as methyl, ethyl, or propyl 1-4 alkyl, in particular methyl. In one embodiment, R 20 is C such as CF3 1-4 In one embodiment, R 20 C such as OMe or OEt 1-4 Alkoxy, especially OMe.

[0160] It is believed that compounds of the invention having functional groups that can carry a charge at or near neutral or physiological pH (i.e., at or near pH 7.0 or 7.4) can enhance the solubility of the compounds. Thus, in one embodiment, R and R 2x At least one of R2 is a heterocycloalkyl or a group containing a carboxylic acid (e.g., R2 is a 4- to 10-membered heterocycloalkyl, C1-4 Alkylene (4-10 membered heterocycloalkyl), C 1-4 AlkyleneO(4-10 membered heterocycloalkyl), C 1-4 Alkylene (NR 2xab R 2xac ), O.C. 1-4 Alkylene (NR 2xab R 2xac ), N(R 2xaa )C 1-4 Alkylene (NR 2xab R 2xac ), CH2CH2(CO2H) etc. 1-4 Alkylene (COH), OC 1-4 Alkylene (COH), C 1-4 Alkylene OC 1-4 Alkylene (COH), or N(R 2aa )C 1-4 alkylene (COH); R 2x is a heterocycloalkyl or carboxylic acid-containing group, the corresponding R 2x It will be understood that groups are selected. 17 , R 18 , or R 21 At least one of the groups is a heterocycloalkyl or a carboxylic acid-containing group (e.g., R 17 is a 4- to 10-membered heterocycloalkyl, C 1-4 Alkylene (4-10 membered heterocycloalkyl), C 1-4 AlkyleneO(4-10 membered heterocycloalkyl), C 1-4 Alkylene (NR 17ab R 17ac ), O.C. 1-4 Alkylene (NR 17ab R 17ac ), N(R 17aa )C 1-4 Alkylene (NR 17ab R 17ac ), CH2CH2(CO2H) etc. 1-4 Alkylene (COH), OC 1-4 Alkylene (COH), C 1-4 Alkylene OC 1-4 Alkylene (COH), or N(R 17a )C1-4 alkylene (COH); R 18 or R 21 is a heterocycloalkyl or carboxylic acid-containing group, the corresponding R 18 or R 21 It will be understood that the group is selected.

[0161] Preferably, R2, R 2x , R 17 , R 18 , or R 21 When either of the groups is a 4- to 10-membered heterocycle (whether alone or with a larger group, e.g., C 1-4 Whether forming part of an alkylene(4-10 membered heterocycloalkyl), the 4-10 membered heterocycloalkyl is: [ka] (In the formula: Za is CH or N; Each R c1 are independently H and C such as methyl 1-4 alkyl; R c2 are independently H and C such as methyl 1-4 alkyl; R c3 are independently H or C such as methyl 1-4 alkyl; x1 is 0, 1, or 2; x2 is 0, 1, or 2; x3 is 0, 1, or 2; and x4 is 0, 1, or 2) may be selected from:

[0162] Suitably, the 4- to 10-membered heterocycle contains at least one N atom, for example, one or two N atoms.

[0163] In one embodiment, the 4- to 10-membered heterocycle is (Ca). In one embodiment, the 4- to 10-membered heterocycle is (Cb). In one embodiment, the 4- to 10-membered heterocycle is (Cc). In one embodiment, the 4- to 10-membered heterocycle is (Cd).

[0164] In one embodiment, R 17 is C such as methyl 1-4 alkyl, and R 20 C such as OMe 1-4 is alkoxy, and R 21 is H and R 18 is C such as methyl 1-4 It is alkyl.

[0165] In one embodiment, the group B is (Ba): [ka] is.

[0166] Y is C(R 11 )(R 12 ), in one embodiment, R 11 is H. In a second embodiment, R 11 is C such as methyl 1-4 It is alkyl.

[0167] Y is C(R 11 )(R 12 ), in one embodiment, R 12 is H. In a second embodiment, R 12 is C such as methyl 1-4 It is alkyl.

[0168] In a preferred embodiment, Y is C(R 11 )(R 12 ), then R 11 is H or methyl, and R 12 is H. In a second preferred embodiment, R 11 and R 12 are both H. In a third embodiment, R11 and R 12 together with the carbon atoms to which they are attached form a cyclopropyl ring. Preferably, the cyclopropyl ring contains one, two, or three C 1-4 Alkyl substituents, e.g., one or two, e.g., one C 1-4 It is substituted with an alkyl substituent (such as methyl). In one embodiment, the cyclopropyl ring is unsubstituted.

[0169] Preferably, Y is C(R 11 )(R 12 ), then R 11 is methyl and R 12 is H and A is not a group (Aa).

[0170] In one embodiment, Y is N(R 13 ). Preferably, R 13 C such as methyl, ethyl, propyl, or butyl 1-4 In a second embodiment, R 13 is C such as cyclopropyl 3-6 Preferably, R 13 C present in 3-6 Cycloalkyl, e.g., cyclopropyl rings, are C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 13a R 13b , SO2R 13c , and NHSO2R 13c and R is substituted by 1, 2, or 3, for example 1 or 2, for example 1, substituents independently selected from 13 C present in 3-6 Cycloalkyl, e.g., cyclopropyl rings, are C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4Substituted by 1, 2, or 3, e.g., 1 or 2, e.g., 1, substituents independently selected from haloalkyl, halo, and CN. Suitably, R 13 C present in 3-6 Cycloalkyl, e.g., cyclopropyl rings, can be OH, NR 13a R 13b , SO2R 13c , and NHSO2R 13c and is substituted by one, two or three, for example one or two, for example one, substituent independently selected from: 3-6 A cycloalkyl, e.g., cyclopropyl, ring may contain one, two, or three C 1-4 Alkyl substituents, e.g., one or two, e.g., one C 1-4 Substituted by alkyl substituents (such as methyl). In one embodiment, C 3-6 Cycloalkyl groups, such as cyclopropyl rings, are unsubstituted.

[0171] In one embodiment, R 13a is H. In a second embodiment, R 13a is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 13a is H or methyl.

[0172] In one embodiment, R 13b is H. In a second embodiment, R 13b is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 13b C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a fourth embodiment, R 13b C such as OMe or OEt 1-4 In a fifth embodiment, R 13b is C such as CF3 1-4 In a sixth embodiment, R13b is aryl, such as phenyl. In a seventh embodiment, R 13b is a 4-10 membered heterocycloalkyl such as azetidinyl or oxetanyl. In an eighth embodiment, R 13b is H or methyl.

[0173] In one embodiment, R 13c is C such as methyl, ethyl, or propyl 1-4 In a second embodiment, R 13c C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a third embodiment, R 13c C such as OMe or OEt 1-4 In a fourth embodiment, R 13c is C such as CF3 1-4 In a fifth embodiment, R 13c is aryl, such as phenyl. In a sixth embodiment, R 13c is a 4-10 membered heterocycloalkyl such as azetidinyl or oxetanyl. In a seventh embodiment, R 13c is H or methyl.

[0174] In one embodiment, Y is O or S.

[0175] When present, in one embodiment, each R 10 is independently fluoro, chloro, or methyl.

[0176] In one embodiment, r is 0 or 1, in particular 0.

[0177] When r is 1, 2, or 3, R 10 may be at position 7, 5, and / or 4. In one embodiment, r is 1 and R 10 is at position 7. In a second embodiment, r is 1 and R 10is at position 5. In one embodiment, r is 1 and R 10 is in fourth place. For example: [ka] is.

[0178] Suitable R 10 Examples of substituents include 4-fluoro and 7-fluoro.

[0179] In one embodiment, the group B is (Bb): [ka] is.

[0180] When present, in one embodiment, each R 14 is independently fluoro or methyl.

[0181] In one embodiment, s is 0 or 1, in particular 0.

[0182] Preferably, when s is 1, 2, or 3, R 14 may be at positions 7, 5, and / or 4. In one embodiment, s is 1 and R 14 is at position 5. In a second embodiment, s is 2 and one R 14 is in 7th place and has one R 14 is in 4th place. For example: [ka] is.

[0183] Preferably, R 14 is not at position 7. Preferably, R 14 is not in fourth place.

[0184] Suitable R 14 An example of a substituent is 5-fluoro.

[0185] In one embodiment, the group B is (Bc): [ka] is.

[0186] R 15 is C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 1-4 haloalkyl, halo, or CN; wherein the cycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 15a R 15b , SO2R 15c , and NHSO2R 15c and optionally substituted with 1, 2, or 3 substituents independently selected from:

[0187] In one embodiment, R 15 is methyl, ethyl, cyclopropyl, CF3, or CN, for example methyl or CN, especially methyl. In a second embodiment, R 15 is methyl, ethyl, cyclopropyl, CF3, CN, OMe, chloro, or fluoro, for example methyl, CN, chloro, or fluoro, in particular chloro or fluoro. In a third embodiment, R 15 is OMe, chloro, or fluoro. In a fourth embodiment, R 15 is methyl, CN, chloro, or fluoro.

[0188] Preferably, R 15 C present in 3-6 Cycloalkyl, e.g., cyclopropyl rings, are C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 15a R 15b , SO2R 15c, and NHSO2R 15c and R is substituted by 1, 2, or 3, for example 1 or 2, for example 1, substituents independently selected from 15 C present in 3-6 Cycloalkyl, e.g., cyclopropyl rings, are C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Substituted by 1, 2, or 3, e.g., 1 or 2, e.g., 1, substituents independently selected from haloalkyl, halo, and CN. Suitably, R 15 C present in 3-6 Cycloalkyl, e.g., cyclopropyl rings, can be OH, NR 15a R 15b , SO2R 15c , and NHSO2R 15c and is substituted by one, two or three, for example one or two, for example one, substituent independently selected from: 3-6 A cycloalkyl, e.g., cyclopropyl, ring may contain one, two, or three C 1-4 Alkyl substituents, e.g., one or two, e.g., one C 1-4 Substituted by alkyl substituents (such as methyl). In one embodiment, C 3-6 Cycloalkyl groups, such as cyclopropyl rings, are unsubstituted.

[0189] In one embodiment, R 15a is H. In a second embodiment, R 15a is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R 15a is H or methyl.

[0190] In one embodiment, R 15b is H. In a second embodiment, R 15b is C such as methyl, ethyl, or propyl 1-4 In a third embodiment, R15b C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a fourth embodiment, R 15b C such as OMe or OEt 1-4 In a fifth embodiment, R 15b is C such as CF3 1-4 In a sixth embodiment, R 15b is aryl, such as phenyl. In a seventh embodiment, R 15b is a 4-10 membered heterocycloalkyl such as azetidinyl or oxetanyl. In an eighth embodiment, R 15b is H or methyl.

[0191] In one embodiment, R 15c is C such as methyl, ethyl, or propyl 1-4 In a second embodiment, R 15c C such as cyclopropyl, cyclobutyl, and cyclopentyl 3-6 In a third embodiment, R 15c C such as OMe or OEt 1-4 In a fourth embodiment, R 15c is C such as CF3 1-4 In a fifth embodiment, R 15c is aryl, such as phenyl. In a sixth embodiment, R 15c is a 4-10 membered heterocycloalkyl such as azetidinyl or oxetanyl. In a seventh embodiment, R 15c is methyl.

[0192] In one embodiment, D, E, and F are C(R 16 In a second embodiment, D is N and E and F are C(R 16 In a third embodiment, E is N and D and F are C(R 16In a fourth embodiment, F is N and D and E are C(R 16 )

[0193] In one embodiment, R 16 is H. In a second embodiment, R 16 is halo, such as fluoro or chloro, and in particular chloro. In a third embodiment, R 16 is C such as methyl 1-4 Preferably, each R 16 is independently H, fluoro, chloro, or methyl.

[0194] In one preferred embodiment, A is group (Aa) and B is group (Ba). In a second preferred embodiment, A is group (Aa) and B is group (Bb). In a third preferred embodiment, A is group (Ad) and B is group (Bc). In a fourth preferred embodiment, A is group (Ae) and B is group (Ba). In a fifth preferred embodiment, A is group (Ae) and B is group (Bb). In a sixth preferred embodiment, A is group (Ae) and B is group (Bc).

[0195] In one embodiment, the compound of formula (I) is: (E)-3-(1H-benzo[d][1,2,3]triazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)acrylamide; (E)-3-(3,3-dimethyl-2-oxoindolin-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2'-oxospiro[cyclopropane-1,3'-indoline]-6'-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(7-fluoro-2-oxoindolin-6-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-2-oxoindolin-6-yl)acrylamide; (E)-N-(3-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(o-tolyl)acrylamide; (E)-N-(2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(2-isopropyl-6-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(5-chloro-2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(4,5-difluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(5-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(4-fluoro-2-oxoindolin-6-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-3-(1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-3-(1-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-(trifluoromethyl)-1H-indazol-6-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(2,6-dimethylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-ethyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(3,5-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3,4-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide; (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(4-fluoro-3-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(3-fluoro-4-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; Racemic -(E)-3-(3-methyl-1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide; (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (Z)-2-fluoro-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3-chloro-2-methylphenyl)-N-methyl-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(2-methylcyclopentyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-N-(3-fluoro-2-(methoxymethyl)phenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide; (E)-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-(chroman-4-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)acrylamide; (E)-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(3,5-difluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide; (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide; (E)-N-(5-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide; and (E)-N-(2-methylcyclohexyl)-3-(2-oxoindolin-6-yl)acrylamide; or a pharmaceutically acceptable salt and / or solvate of any one of these.

[0196] In one embodiment, the compound of formula (I) is: (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4S)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4R)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4R)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4S)-3-methylchroman-4-yl)acrylamide; (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-N-((1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-((1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-N-((1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-methoxy-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-chloro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; (E)-3-(3-fluoro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; and (E)-3-(3-cyano-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide; or a pharmaceutically acceptable salt and / or solvate of any one of these.

[0197] In one embodiment, the compound of formula (I) is: (E)-3-(3-fluoro-4-methyl-5-(3-(3-methyl-1H-indazol-6-yl)acrylamido)phenyl)propanoic acid; (E)-3-(3-(3-(3-chloro-1H-indazol-6-yl)acrylamido)-5-fluoro-4-methylphenyl)propanoic acid; (E)-3-(3-fluoro-5-(3-(3-fluoro-1H-indazol-6-yl)acrylamido)-4-methylphenyl)propanoic acid; (E)-3-(3-(3-(3-cyano-1H-indazol-6-yl)acrylamido)-5-fluoro-4-methylphenyl)propanoic acid; (E)-3-(3-fluoro-5-(3-(5-fluoro-3-methyl-1H-indazol-6-yl)acrylamido)-4-methylphenyl)propanoic acid; (E)-3-(3-(3-(3-chloro-5-fluoro-1H-indazol-6-yl)acrylamido)-5-fluoro-4-methylphenyl)propanoic acid; (E)-3-(3-(3-(3,5-difluoro-1H-indazol-6-yl)acrylamido)-5-fluoro-4-methylphenyl)propanoic acid; (E)-3-(3-(3-(3-cyano-5-fluoro-1H-indazol-6-yl)acrylamido)-5-fluoro-4-methylphenyl)propanoic acid; (E)-3-(4-fluoro-3-methyl-2-(3-(3-methyl-1H-indazol-6-yl)acrylamido)phenyl)propanoic acid; (E)-3-(2-(3-(3-chloro-1H-indazol-6-yl)acrylamido)-4-fluoro-3-methylphenyl)propanoic acid; (E)-3-(4-fluoro-2-(3-(3-fluoro-1H-indazol-6-yl)acrylamido)-3-methylphenyl)propanoic acid; (E)-3-(2-(3-(3-cyano-1H-indazol-6-yl)acrylamido)-4-fluoro-3-methylphenyl)propanoic acid; (E)-3-(4-fluoro-2-(3-(5-fluoro-3-methyl-1H-indazol-6-yl)acrylamido)-3-methylphenyl)propanoic acid; (E)-3-(2-(3-(3-chloro-5-fluoro-1H-indazol-6-yl)acrylamido)-4-fluoro-3-methylphenyl)propanoic acid; (E)-3-(2-(3-(3,5-difluoro-1H-indazol-6-yl)acrylamido)-4-fluoro-3-methylphenyl)propanoic acid; (E)-3-(2-(3-(3-cyano-5-fluoro-1H-indazol-6-yl)acrylamido)-4-fluoro-3-methylphenyl)propanoic acid; (E)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-chloro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (E)-3-(3-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (E)-3-(5-fluoro-3-methyl-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (E)-3-(3-chloro-5-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (E)-3-(3,5-difluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (E)-3-(3-cyano-5-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (E)-N-(3-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)phenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-chloro-1H-indazol-6-yl)-N-(3-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)phenyl)acrylamide; (E)-3-(3-fluoro-1H-indazol-6-yl)-N-(3-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)phenyl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(3-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)phenyl)acrylamide; (E)-N-(3-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)phenyl)-3-(5-fluoro-3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-chloro-5-fluoro-1H-indazol-6-yl)-N-(3-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)phenyl)acrylamide; (E)-3-(3,5-difluoro-1H-indazol-6-yl)-N-(3-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)phenyl)acrylamide; and (E)-3-(3-cyano-5-fluoro-1H-indazol-6-yl)-N-(3-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)phenyl)acrylamide; or a pharmaceutically acceptable salt and / or solvate of any one of these.

[0198] In one embodiment, the compound of formula (I) is: (2E)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2E)-3-(3-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-3-(3-cyano-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-3-(5-fluoro-3-methyl-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-3-(3-chloro-5-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-3-(3,5-difluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-3-(3-cyano-5-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(5-fluoro-3-methyl-1H-indazol-6-yl)prop-2-enamide; (2E)-3-(3-fluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-3-(3-chloro-5-fluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-N-(5-fluoro-4-methylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2E)-3-(3,5-difluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-3-(3-chloro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2E)-N-[5-fluoro-4-(methoxymethyl)pyridin-3-yl]-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2E)-3-(3-methyl-1H-indazol-6-yl)-N-(2-methylpyridin-3-yl)prop-2-enamide; (2E)-N-(2,4-dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2E)-N-[5-fluoro-4-(methoxymethyl)-2-methylpyridin-3-yl]-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; or a pharmaceutically acceptable salt and / or solvate of any one of these.

[0199] The definition of a compound of formula (I) is intended to include all tautomers of the compound.

[0200] The compounds of the present invention may be provided in the form of their pharmaceutically acceptable salts and / or solvates. In particular, the compounds of formula (I) may be provided in the form of their pharmaceutically acceptable salts and / or solvates, e.g., pharmaceutically acceptable salts.

[0201] It will be recognized that for use in medicine, salts of compounds of formula (I) should be pharmaceutically acceptable. Non-pharmaceutically acceptable salts of compounds of formula (I) may be useful in other contexts, such as during the preparation of compounds of formula (I). Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described in Berge et al. (1977). Such pharmaceutically acceptable salts include acid and base addition salts. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, and organic acids, such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, or naphthalenesulfonic acid. Other salts, such as oxalates or formates, may be used, for example, in the isolation of compounds of formula (I) and are within the scope of the present invention. Pharmaceutically acceptable salts may also be formed with organic bases such as basic amines, for example, ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine, or lysine. Pharmaceutically acceptable salts may also be formed with inorganic bases, such as Group 1 or 2 metal ions, for example, lithium, sodium, potassium, magnesium, or calcium.

[0202] Certain compounds of formula (I) can form acid or base addition salts with one or more equivalents of acid or base. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms. In one embodiment, the compound of formula (I) is in free base form. Alternatively, a compound of formula (I) in the form of a free acid is provided. If the compound contains a basic group in addition to the free acid, it may be a zwitterion.

[0203] The compounds of formula (I) may be prepared in crystalline or non-crystalline form. If crystalline, the compounds of formula (I) may optionally be solvated, for example as hydrates. The present invention includes within its scope stoichiometric solvates (e.g., hydrates) as well as compounds containing variable amounts of solvent (e.g., water).

[0204] The present invention should be understood to encompass all isomers of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric, and optical forms, and mixtures thereof (e.g., racemic mixtures). When additional chiral centers are present in compounds of formula (I), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods. Alternatively, any isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

[0205] The present disclosure includes all isotopic forms of the compounds of the present invention provided herein, whether (i) in a form in which all atoms of a given atomic number have a mass number (or mixture of mass numbers) that is predominant in nature (referred to herein as a "natural isotopic form") or (ii) in a form in which one or more atoms are replaced by an atom having the same atomic number but a mass number that is different from the mass number of the atom that is predominant in nature (referred to herein as a "non-natural variant isotopic form"). It is understood that atoms may naturally occur as a mixture of mass numbers. The term "non-natural variant isotopic form" also includes embodiments in which the proportion of atoms of a given atomic number that have mass numbers that are less common in nature (referred to herein as "rare isotopes") is increased compared to the proportion occurring in nature, for example, to a level of >20%, >50%, >75%, >90%, >95%, or >99% of the number of atoms of that atomic number (the latter embodiment being referred to as an "isotopically enriched variant form"). The term "non-natural variant isotopic form" also includes embodiments in which the proportion of a rare isotope is reduced compared to the proportion occurring in nature. Isotopic forms can include radioactive forms (i.e., which incorporate a radioactive isotope) and non-radioactive forms. Radioactive forms are typically isotopically enriched variant forms.

[0206] Thus, non-naturally occurring variant isotopic forms of the compounds may contain deuterium ( 2 H or D), carbon-11 ( 11 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-15( 15 N), oxygen-15( 15 O), oxygen-17( 17 O), oxygen-18( 18 O), phosphorus-32( 32 P), sulfur-35( 35 S), chlorine-36( 36 Cl), chlorine-37( 37 Cl), fluorine-18( 18 F), iodine-123(123 I), iodine-125( 125 It may contain one or more artificial or rare isotopes, such as I), or may contain an increased proportion of such isotopes at one or more atoms compared to the proportion that predominates in nature.

[0207] Non-natural variant isotopic forms containing radioactive isotopes may be used, for example, for drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. 2 Non-natural variant isotopic forms incorporating H or D may offer certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in certain circumstances. 11 C. 18 F, 15 O, and 13 Non-natural variant isotopic forms can be prepared incorporating positron emitting isotopes, such as N, which can be useful in positron emission tissue distribution (PET) studies to examine substrate receptor occupancy.

[0208] In one embodiment, the compounds of the invention are provided in natural isotopic form.

[0209] In one embodiment, the compounds of the present invention are provided in non-natural variant isotopic forms. In a specific embodiment, non-natural variant isotopic forms are those in which deuterium (i.e., 2In one embodiment, the atoms of the compounds of the present invention are in a non-radioactive isotopic form. In one embodiment, one or more atoms of the compounds of the present invention are in a radioactive isotopic form. Preferably, the radioisotope is a stable isotope. Preferably, the non-natural variant isotopic form is a pharmaceutically acceptable form.

[0210] In one embodiment, compounds of the present invention are provided in which a single atom of the compound exists in a non-natural variant isotopic form. In another embodiment, compounds of the present invention are provided in which two or more atoms exist in a non-natural variant isotopic form.

[0211] Non-natural isotopically variant forms can generally be prepared by conventional techniques known to those skilled in the art or by methods described herein, for example, by methods similar to those described in the Examples below for preparing natural isotopically variant forms. Thus, non-natural isotopically variant forms could be prepared by substituting appropriate isotopically variant (or labeled) reagents for the conventional reagents employed in the Examples. Because the compounds of formula (I) are intended for use in pharmaceutical compositions, it will be readily understood that they are each preferably provided in substantially pure form, e.g., at least 60% pure, more preferably at least 75% pure, and preferably at least 85%, especially at least 98% pure (percentages weight by weight). Impure preparations of the compounds may be used to prepare purer forms for use in pharmaceutical compositions.

[0212] In general, compounds of formula (I) can be made by organic synthesis techniques known to those skilled in the art, as well as by the representative methods described below, those in the Examples, and modifications thereof. In the following schemes, reactive groups can be protected with protecting groups and deprotected by established techniques well known to those skilled in the art.

[0213] (General route) General routes by which examples of compounds of the invention can be conveniently prepared are outlined below. In the following description, the group R 1a , R 1b , R2, R3, R 13 , A, and B are as defined above in relation to compounds of formula (I) unless otherwise specified.

[0214] (Scheme 1) [ka] Compounds of formula (I) may be prepared by reacting compounds of formula (II) with compounds of formula (III) under palladium-catalyzed cross-coupling conditions using a palladium catalyst precursor such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane complex (Pd(dppf)Cl2·CH2Cl2) in the presence of a base such as triethylamine and a suitable solvent such as dimethylformamide (DMF).

[0215] (Scheme 2) [ka] Alternatively, compounds of formula (I) may be prepared by reacting a compound of formula (IV) with a compound of formula (V) under amidation conditions using an amide coupling reagent such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) in the presence of a base such as N,N-diisopropylethylamine (DIPEA, also known as Hunig's base) in a suitable solvent such as DMF.

[0216] (Scheme 3) [ka] Compounds of formula (I) may also be prepared by reacting compounds of formula (VI) with compounds of formula (V) under basic conditions using a base such as lithium bis(trimethylsilyl)amide (LiHMDS) in a suitable solvent such as tetrahydrofuran (THF).

[0217] (Scheme 4) [ka] Compounds of formula (II) are commercially available. Compounds of formula (II) can also be prepared by reacting compounds of formula (VII) with compounds of formula (VIII) in the presence of a base such as N,N-diisopropylethylamine in a suitable solvent such as dichloromethane (DCM).

[0218] (Scheme 5) [ka] Compounds of formula (VI) can be obtained by reacting compounds of formula (IX) with compounds of formula (III) under palladium-catalyzed cross-coupling conditions using a palladium catalyst precursor such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane complex (Pd(dppf)Cl2·CH2Cl2) in the presence of a base such as triethylamine and a suitable solvent such as dimethylformamide (DMF).

[0219] (Scheme 6) [ka] Compounds of formula (IV) can be obtained by reacting compounds of formula (VI) under hydrolysis conditions with a base such as sodium hydroxide (NaOH) in a suitable solvent system such as a mixture of methanol and water.

[0220] (Scheme 7) [ka] R1a is H, A is a group (Aa), and R2 is C 1-4 alkyl, m is 3, and R3 is C 1-4 Compounds of formula (VII), which are alkyl or halo, can be prepared in two steps. First, compounds of formula (X) are reacted with a brominating agent such as N-bromosuccinimide (NBS) in a solvent such as acetonitrile to give dibrominated compounds of formula (XI). Compounds of formula (VII) can be further reacted under palladium-catalyzed cross-coupling conditions using a palladium catalyst precursor such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane complex (Pd(dppf)Cl2·CHCl2), an organoboron compound such as trimethyl-1,3,5,2,4,6-trioxatriborinane, a base such as cesium carbonate (Cs2CO3), and a suitable solvent such as 1,4-dioxane to give compounds of formula (VII).

[0221] (Scheme 8) [ka] R 1a is H, A is a group (Aa), and R2 is C 1-4 alkyl, m is 3, and R3 is C 1-4The alkyl or halo compound of formula (VII) can be prepared in four steps. First, a compound of formula (XII) is reacted with a chlorinating agent such as N-chlorosuccinimide (NCS) in a solvent such as acetonitrile to give a compound of formula (XIII). Then, a compound of formula (XIII) is reacted with a brominating agent such as N-bromosuccinimide (NBS) in a solvent such as acetonitrile to give a trihalogenated compound of formula (XIV). Compounds of formula (XIV) can be further reacted under palladium-catalyzed cross-coupling conditions using a palladium catalyst precursor such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane complex (Pd(dppf)Cl2·CHCl2), an organoboron compound such as trimethyl-1,3,5,2,4,6-trioxatriborinane, a base such as cesium carbonate (Cs2CO3), and a suitable solvent such as 1,4-dioxane to give compounds of formula (XV). Compounds of formula (XV) can be further reacted under reductive dehalogenation conditions using a hydrogen atmosphere such as 30 atmospheres of hydrogen, a palladium catalyst such as palladium on carbon (Pd / C), an acid such as hydrochloric acid, and a solvent such as ethanol (EtOH) to give compounds of formula (VII).

[0222] (Scheme 9) [ka] R 1a is H, A is a group (Aa), and R2 is C 1-4 alkyl, m is 2, and R3 is C 1-4Compounds of formula (VII), which are alkyl or halo, can be prepared in two steps. A nitro compound of formula (XVI) can be reacted under palladium-catalyzed cross-coupling conditions using a palladium catalyst precursor such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane complex (Pd(dppf)Cl2·CHCl2), an organoboron compound such as trimethyl-1,3,5,2,4,6-trioxatriborinane, a base such as cesium carbonate (Cs2CO3), and a suitable solvent system such as a mixture of water and 1,4-dioxane to give compounds of formula (XVII). Compounds of formula (XVII) can then be reacted with a metal such as iron in the presence of an acid such as acetic acid to give compounds of formula (VII).

[0223] (Scheme 10) [ka] B is a group (Ba) and Y is N(R 13 Compounds of formula (III), wherein r is 0, can be prepared in three steps. First, compounds of formula (XVIII) can be reacted with an amine in a suitable solvent, such as ethanol, to give compounds of formula (XIX). Subsequently, compounds of formula (XIX) can be subjected to reducing conditions using a metal, such as zinc, and an inorganic salt, such as ammonium chloride (NH4Cl), in a suitable solvent, such as acetone, to give compounds of formula (XX). Finally, compounds of formula (XX) can be reacted with a carbonylating agent, such as triphosgene, in a suitable solvent, such as dichloromethane (DCM), to give compounds of formula (III).

[0224] (Scheme 11) [ka] A is a group (Ad), X is a bond, q is 0, p is 1, and R8 is OC 1-4 Haloalkyl, OC 1- Alkylene (4-10 membered heterocycloalkyl), or C 1-4A compound of formula (V) where PG is a nitrogen protecting group such as tert-butoxycarbonyl (BOC) can be prepared by reacting a compound of formula (XXI) where C is C in the presence of a base such as NaH in a suitable solvent such as THF. 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 The compound of formula (V) can be prepared by reacting a compound of formula (XXII) with a compound of formula (XXII) which is alkylene(4-10 membered heterocycloalkyl) to give a compound of formula (XXIII). Deprotection of the compound of formula (XXIII) with an aqueous acid, such as 2M HCl, in a suitable solvent, such as methanol, gives a compound of formula (V).

[0225] (Scheme 12) [ka] A is a group (Ad), X is a bond, q is 0, p is 1, and R8 is OC 1-4 Alkylene (C 3-6 Compounds of formula (V), where PG is a nitrogen protecting group such as tert-butoxycarbonyl (BOC), can be prepared by treating a compound of formula (XXIV), where PG is a nitrogen protecting group such as tert-butoxycarbonyl (BOC), with a suitable reagent, for example, diiodomethane, in the presence of an organometallic reagent, for example, ZnEt, in a suitable solvent, such as dichloromethane, to give compounds of formula (XXV). Deprotection of compound of formula (XXV) with an aqueous acid, for example, 2 M HCl, in a suitable solvent, such as methanol, gives compounds of formula (V).

[0226] (Scheme 13) [ka] R2 or R 2x One of them is C 1-4 alkylene (COH) (e.g., R 2x But C 1-4Compounds of formula (II), where R is an alkylene, can be prepared by reacting a compound of formula (XXX) with a compound of formula (XXXI) under palladium-catalyzed cross-coupling conditions using a palladium catalyst precursor such as Pd(OAc) 2 , a phosphine ligand such as triphenylphosphonic acid, an inorganic base such as NaHCO 3 , and an organic base such as triethylamine in a solvent such as DMF to give a compound of formula (XXXII). Treatment of the nitro compound (XXXII) under hydrogenation conditions using a palladium catalyst such as palladium on carbon (Pd / C) and a solvent such as ethanol gives a compound of formula (XXXIII). Compounds of formula (XXXIII) can be reacted with a compound of formula (XXXIV) in the presence of an organic base, for example, triethylamine, to give a compound of formula (II). Compounds of formula (I) can be prepared from compounds of formula (II) using methods known to those skilled in the art and / or methods disclosed herein. The tert-butyl esters of compounds of Formula (XXX), Formula (XXXII), Formula (XXXIII), and Formula (II) can be removed by methods known to those skilled in the art, such as treatment with trifluoroacetic acid in dichloromethane to give the corresponding carboxylic acid.

[0227] (Scheme 14) [ka] R2 or R 2xCompounds of formula (II) in which one of R is a 4- to 7-membered heterocycloalkyl (e.g., as shown in Scheme 14, R is a 4- to 7-membered heterocycloalkyl) can be prepared by reacting a compound of formula (XXXV) with a compound of formula (XXXVI) under palladium-catalyzed cross-coupling conditions using a palladium catalyst precursor such as Pd(OAc), a phosphine ligand such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), an inorganic base such as sodium butoxide, and a solvent such as toluene. Subsequent reduction of the nitro group under reducing conditions, for example, treatment with tin chloride in a solvent such as ethanol, provides a compound of formula (XXXVII). Compounds of formula (XXXVII) can be reacted with a compound of formula (XXXIV) in the presence of an organic base, for example, triethylamine, to produce compounds of formula (II). Compounds of formula (I) may be prepared from compounds of formula (II) using methods known to those skilled in the art and / or methods disclosed herein.

[0228] Thus, in one embodiment, the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, comprising: Compounds of formula (II): [ka] (In the formula, A, R 1a and R 1b is as defined in relation to compounds of formula (I); or a salt thereof; Compounds of formula (III): [ka] wherein X is halo, such as bromo or iodo, and B is as defined in relation to compounds of formula (I); or a salt thereof.

[0229] The present invention also provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, comprising the steps of: Compounds of formula (IV): [ka] (In the formula, R 1b and B are as defined in relation to the compounds of formula (I); or a salt thereof; Compounds of formula (V): [ka] (Wherein, A and R 1a is as defined in relation to the compounds of formula (I); or a salt thereof The method also provides the method, comprising reacting

[0230] The present invention also provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, comprising the steps of: Compounds of formula (VI): [ka] (In the formula, R 1b and B are as defined in relation to the compounds of formula (I); or a salt thereof; Compounds of formula (V): [ka] (Wherein, A and R 1a is as defined in relation to the compounds of formula (I); or a salt thereof The method also provides the method, comprising reacting

[0231] In one embodiment, a compound of formula (II): [ka] (In the formula, A, R 1a , and R 1b is as defined elsewhere herein) or a salt thereof.

[0232] In one embodiment, a compound of formula (IV): [ka] (Wherein, B and R 1b is as defined elsewhere herein) or a salt thereof.

[0233] In one embodiment, a compound of formula (VI): [ka] (Wherein, B and R 1b is as defined elsewhere herein) or a salt thereof.

[0234] The novel compounds of formula (II) to formula (XXXVII) and salts thereof are also provided as aspects of the invention.

[0235] (Treatment method) The compounds of formula (I) of the present invention are useful as inhibitors of mPTP.

[0236] Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, as a medicament, in particular for use in the treatment or prevention of diseases or disorders in which inhibition of mPTP provides a therapeutic or prophylactic effect, such as the diseases and disorders mentioned herein below.

[0237] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, as a medicament, in particular for use in the treatment of diseases or disorders in which inhibition of mPTP provides a therapeutic effect, such as the diseases and disorders mentioned herein below.

[0238] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use as a medicament, in particular in the prevention of diseases or disorders in which inhibition of mPTP provides a preventive effect, such as the diseases and disorders mentioned herein below.

[0239] The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect, such as the diseases and disorders mentioned herein below.

[0240] The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder in which inhibition of mPTP provides a therapeutic effect, such as the diseases and disorders mentioned herein below.

[0241] The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the prevention of diseases or disorders in which inhibition of mPTP provides a preventive effect, such as the diseases and disorders mentioned herein below.

[0242] The present invention also provides a method for preventing or treating a disease or disorder in a subject in which inhibition of mPTP provides a therapeutic or prophylactic effect, such as the diseases and disorders mentioned herein below, which method comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof.

[0243] The present invention also provides a method for treating a disease or disorder in a subject in which inhibition of mPTP provides a therapeutic effect, such as the diseases and disorders mentioned herein below, comprising administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof.

[0244] The present invention also provides a method for preventing in a subject a disease or disorder in which inhibition of mPTP provides a preventive effect, such as the diseases and disorders mentioned herein below, which method comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof.

[0245] As used herein, the term "treatment" or "treating" includes controlling, alleviating, reducing, or modulating a disease state or its symptoms.

[0246] The term "prevention" or "preventing" as used herein shall mean preventing the symptoms of a disease or disorder in a subject or preventing the recurrence of symptoms of a disease or disorder in an affected subject, and is not limited to complete prevention of disease.

[0247] In one embodiment, the disease or disorder is selected from a degenerative or neurodegenerative disease, a disorder of the central nervous system, an ischemia or reperfusion injury, a metabolic disease, an inflammatory or autoimmune disease, an age-related disease, and a renal disease.

[0248] In a particular embodiment, the disease or disorder is degenerative or neurodegenerative disease, such as Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal dementia, chemotherapy-induced neuropathy, Huntington's disease, spinocerebellar ataxia, progressive supranuclear palsy, hereditary spastic paraplegia, Duchenne muscular dystrophy, congenital muscular dystrophy, traumatic brain injury, and Friedreich's ataxia.In a preferred embodiment, the disease or disorder is Parkinson's disease.In a preferred embodiment, the disease or disorder is Alzheimer's disease.In a preferred embodiment, the disease or disorder is amyotrophic lateral sclerosis.

[0249] In another particular embodiment, the disease or disorder is a disease of the central nervous system, such as AIDS dementia complex, depressive disorders, schizophrenia, and epilepsy.

[0250] In another embodiment, the disease or disorder is ischemia or reperfusion injury, such as acute myocardial infarction, stroke, renal ischemia-reperfusion injury, and organ damage during transplantation.

[0251] In another embodiment, the disease or disorder is a metabolic disease such as fatty liver, diabetes, diabetic retinopathy, cognitive decline and other diabetes-related conditions, obesity and eating behavior, and non-alcoholic fatty liver disease.

[0252] In another embodiment, the disease or disorder is an inflammatory or autoimmune disease such as acute pancreatitis, systemic lupus, organ failure in sepsis, and hepatitis. In another embodiment, the disease or disorder is a disease associated with mtDNA release and innate immune activation, such as macular degeneration.

[0253] In another embodiment, the disease or disorder is a disease of aging, such as bone repair, bone frailty in aging in osteoporosis, and sarcopenia.

[0254] In another embodiment, the disease or disorder is a kidney disease, such as chronic kidney disease and chronic kidney disease associated with APOL1 gene variants.

[0255] In another embodiment, the disease or disorder is pulmonary dysfunction or multiple organ failure associated with a severe respiratory viral infection, e.g., COVID 19 infection. In another embodiment, the disease or disorder is adrenoleukodystrophy, particularly X-linked adrenoleukodystrophy.

[0256] The compounds of formula (I) are expected to be useful in the treatment or prevention of mitochondrial diseases.

[0257] Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of mitochondrial diseases, such as the diseases and disorders mentioned herein below.

[0258] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of mitochondrial diseases, such as the diseases and disorders mentioned herein below.

[0259] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the prevention of mitochondrial diseases, such as the diseases and disorders mentioned herein below.

[0260] The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the treatment or prevention of mitochondrial diseases, such as the diseases and disorders mentioned herein below.

[0261] The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the treatment of mitochondrial diseases, such as the diseases and disorders mentioned herein below.

[0262] The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the prevention of mitochondrial diseases, such as the diseases and disorders mentioned herein below.

[0263] The present invention also provides a method for treating or preventing a mitochondrial disease, such as the diseases and disorders mentioned herein below, in a subject, said method comprising administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof.

[0264] The present invention also provides a method of treating a mitochondrial disease in a subject, such as the diseases and disorders mentioned herein below, comprising administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof.

[0265] The present invention also provides a method for preventing a mitochondrial disease in a subject, such as the diseases and disorders mentioned herein below, which method comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof.

[0266] Suitably, the mitochondrial disease is selected from disorders such as Reye's syndrome, Leber's hereditary optic neuropathy and related disorders, and diseases and disorders disclosed in CA2884607A1 (Stealth Peptides International).

[0267] The compounds of formula (I) are expected to be useful in the treatment or prevention of diseases or disorders associated with TDP-43 proteinopathies, such as TDP-43 associated neurodegeneration.

[0268] Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, for example the diseases and disorders mentioned herein below.

[0269] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, for example the diseases and disorders mentioned herein below.

[0270] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the prevention of a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, for example the diseases and disorders mentioned herein below.

[0271] The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, such as the diseases and disorders mentioned herein below.

[0272] The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, for example the diseases and disorders mentioned herein below.

[0273] The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the prevention of a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, such as the diseases and disorders mentioned herein below.

[0274] The present invention also provides a method for treating or preventing a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, such as the diseases and disorders mentioned herein below, which method comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof.

[0275] The present invention also provides a method for treating a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, for example the diseases and disorders mentioned herein below, comprising administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof.

[0276] The present invention also provides a method for preventing a disease or disorder associated with a TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, such as the diseases and disorders mentioned herein below, comprising administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof.

[0277] Suitably, the disease or disorder associated with TDP-43 proteinopathy, such as TDP-43-associated neurodegeneration, is selected from amyotrophic lateral sclerosis, frontotemporal dementia, facial-onset sensorimotor neuropathy, primary lateral sclerosis, progressive muscular atrophy, early-onset Paget's disease of bone and inclusion body myopathy associated with frontotemporal lobar degeneration dementia, Perry's disease, chronic traumatic brain injury, severe traumatic brain injury, Alzheimer's disease, hippocampal sclerosis dementia, limbic-predominant age-related TDP-43 encephalopathy, and cerebral age-related TDP-43 with sclerosis.

[0278] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment or prevention of a disease or disorder associated with fibrosis.

[0279] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the treatment of a disease or disorder associated with fibrosis.

[0280] The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, for use in the prevention of a disease or disorder associated with fibrosis.

[0281] The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with fibrosis.

[0282] The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with fibrosis.

[0283] The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the prevention of a disease or disorder associated with fibrosis.

[0284] The present invention also provides a method for treating or preventing a disease or disorder associated with fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof.

[0285] The present invention also provides a method of treating a disease or disorder associated with fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof.

[0286] The present invention also provides a method for preventing a disease or disorder associated with fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof.

[0287] Suitably, the fibrosis-related disease or disorder is selected from chronic kidney disease, idiopathic pulmonary fibrosis, non-alcoholic steatohepatitis, primary biliary cholangitis, and systemic sclerosis.

[0288] Preferably, the subject is a mammal, and in particular, the subject is a human.

[0289] (Pharmaceutical composition) For use in therapy, the compounds of the invention are typically administered as pharmaceutical compositions. The invention also provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g., a salt) thereof, and a pharmaceutically acceptable carrier or excipient.

[0290] In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof, for use in the treatment or prevention of a disease or disorder as described herein. In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof, for use in the treatment of a disease or disorder as described herein. In one embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof, for use in the prevention of a disease or disorder as described herein.

[0291] In a further embodiment, there is provided a method for the treatment or prevention of a disease or disorder as described herein, comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., a salt) thereof. In a further embodiment, there is provided a method for the treatment of a disease or disorder as described herein, comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., a salt) thereof. In a further embodiment, there is provided a method for the prevention of a disease or disorder as described herein, comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., a salt) thereof. The pharmaceutical compositions of the present invention may take the form of pharmaceutical formulations as described below.

[0292] The present invention also provides the use of a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof, in the manufacture of a medicament for the treatment or prevention of a disease or disorder as described herein. The present invention also provides the use of a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof, in the manufacture of a medicament for the treatment of a disease or disorder as described herein. The present invention also provides the use of a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g., salt) thereof, in the manufacture of a medicament for the prevention of a disease or disorder as described herein.

[0293] Of course, the amount of active ingredient required to achieve a therapeutic effect will vary depending on the subject being treated or prevented, including the particular compound, the route of administration, the type, species, age, weight, sex, and medical condition of the subject, and the particular disorder or disease being treated or prevented, and its severity, including the renal and hepatic function of the subject. A physician, veterinarian, or clinician of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, or halt the progress of the disease.

[0294] Oral dosages of the present invention, when used for the indicated effects, will range from about 0.01 mg / kg body weight per day (mg / kg / day) to about 100 mg / kg / day for adult humans, preferably from 0.01 mg / kg body weight per day (mg / kg / day) to 10 mg / kg / day, and most preferably from 0.1 to 5.0 mg / kg / day. For oral administration, the compositions are preferably provided in the form of tablets or other presentations provided as individually discrete units containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, and 500 milligrams of active ingredient for symptomatic adjustment of dosage to the patient being treated. Pharmaceutical preparations typically contain from about 0.01 mg to about 500 mg of active ingredient, preferably from about 1 mg to about 100 mg. Intravenously, the most preferred dosages will be in the range of about 0.1 to about 10 mg / kg / minute during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times per day. Furthermore, compounds of the present invention can be preferably administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patch forms well known to those skilled in the art. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

[0295] Although the most suitable route will depend, for example, on the condition and disorder of the recipient, pharmaceutical formulations according to the present invention include those suitable for oral administration, parenteral administration (including subcutaneous, intradermal, intramuscular, intravenous (bolus or infusion), and intraarticular), intranasal (also known as intranasal), inhalation administration (including fine particle dusts or mists that may be generated by various types of pressurized metered dose aerosols, nebulizers, or inhalers), insufflation, rectal, intraperitoneal, topical administration (including cutaneous, buccal, sublingual, and intraocular), and intrathecal administration.

[0296] Preferred pharmaceutical formulations according to the present invention are those suitable for oral, intrathecal, and parenteral administration; more preferably, those suitable for oral or intrathecal administration.

[0297] In a preferred embodiment, the compound according to formula (I) is administered by intrathecal administration.This method of administration involves injecting the compound of the present invention into the spinal canal or intrathecal space, so that it reaches the cerebrospinal fluid.This is advantageous for administering compounds that may not be able to cross the blood-brain barrier by other routes of administration, such as oral administration.

[0298] Suitable pharmaceutical formulations can be administered intrathecally by continuous infusion, such as with a catheter or pump, or by single bolus injection or intermittent bolus injection. For intrathecal administration, the pharmaceutical composition can be administered continuously or intermittently. Intermittent administration can be, for example, every 30 minutes, every hour, every few hours, every 24 hours, every few days (e.g., every 48 hours or 72 hours), or any combination thereof.

[0299] When the pharmaceutical formulations of the present invention are administered continuously, an implantable delivery device, such as an implantable pump, can be employed. Examples of such delivery devices include devices that can be implanted subcutaneously in the body or skull and provide an access port through which the pharmaceutical formulation can be delivered to a nerve or the brain.

[0300] When used for the indicated effects, the intrathecal dosage of the present invention will typically be less than 1 mg, such as less than 500 μg / kg body weight, for example, less than 250 μg / kg, when administered in a single dose or intermittently to an adult human. When administered continuously, the intrathecal dosage of the present invention will typically be less than 250 μg / kg body weight per hour, such as less than 125 μg / kg body weight per hour, for an adult human.

[0301] In another preferred embodiment, the compounds according to Formula (I) are administered intranasally, by inhalation (including fine particle dusts or mists that can be generated by various types of pressurized metered-dose aerosols, nebulizers, or inhalers), or by insufflation. Such methods of administration allow lower doses of the compounds of the invention to be administered, which may lead to fewer side effects. For example, daily doses of the compounds of the invention ranging from 10 to 0.01 μg may be used, preferably from 1 to 0.01 μg, and more preferably as low as 0.1 μg (100 ng).

[0302] The formulations can be conveniently provided in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy.All methods include the step of combining the active ingredient with the carrier, which constitutes one or more accessory ingredients.In general, the formulations are prepared by uniformly and intimately combining the active ingredient with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation.

[0303] Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, pills, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or non-aqueous liquid, for example, an elixir, tincture, suspension, or syrup; or as an oil-in-water or water-in-oil emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0304] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricant, surfactant, or dispersant, in a suitable machine. Molded tablets may be made by molding a mixture of powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored, and may be formulated to provide slow or controlled release of the active ingredient therein. The compounds of formula (I) can be administered, for example, in a form suitable for immediate release or sustained release. Immediate release or sustained release can be achieved by using a suitable pharmaceutical composition containing the compound of the present invention, or, particularly in the case of sustained release, by using devices such as subcutaneous implants or osmotic pumps. The compounds of the present invention may also be administered liposomally.

[0305] Exemplary compositions for oral administration include suspensions, which may contain, for example, microcrystalline cellulose to provide bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents known in the art; and immediate-release tablets, which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose, and / or lactose, and / or other excipients, binders, extenders, disintegrants, diluents, and lubricants known in the art. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as gum arabic and tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. The compound of Formula (I) can also be delivered through the oral cavity by sublingual and / or buccal administration. Molded tablets, compressed tablets, or freeze-dried tablets are exemplary forms that can be used. Exemplary compositions include those in which the compound of the present invention is formulated with a fast-dissolving diluent such as mannitol, lactose, sucrose, and / or cyclodextrin. Such formulations can also include high molecular weight excipients such as cellulose (avicel) or polyethylene glycol (PEG). Such formulations can also include excipients that aid adhesion to the mucosa, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymers (e.g., Gantrez), and release-controlling agents such as polyacrylic acid copolymers (e.g., Carbopol 934). Lubricants, glidants, flavors, colors, and stabilizers can also be added for ease of production and use.Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. For oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc.

[0306] The compounds of formula (I) can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from various phospholipids, 1,2-dipalmitoylphosphatidylcholine, phosphatidylethanolamine (cephalin), or phosphatidylcholine (lecithin).

[0307] Preparations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. The preparations may be presented in single-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, saline or water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described. Exemplary compositions for parenteral administration include, for example, suitable non-toxic parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents such as synthetic mono- or diglycerides, and injectable solvents or suspensions which may contain fatty acids such as oleic acid or Cremaphor.

[0308] Exemplary compositions for intranasal, aerosol, or inhalation administration include solutions in saline, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, and / or other solubilizing or dispersing agents such as those known in the art.

[0309] Formulations for rectal administration can be presented as suppositories using conventional carriers such as cocoa butter, synthetic glyceride esters, or polyethylene glycols. Such carriers are usually solid at room temperature but liquefy and / or melt in the rectal cavity to release the drug.

[0310] Formulations for topical administration in the mouth, e.g., buccal or sublingual administration, include lozenges comprising the active ingredient in a base such as flavored sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a base such as gelatin and glycerin or sucrose and acacia. Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).

[0311] Suitable unit dosage formulations are those containing an effective dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0312] It should be understood that the formulations of the present invention, in addition to the ingredients particularly mentioned above, may contain other agents conventionally used in the art, taking into account the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0313] The compounds of formula (I) have the following advantageous properties: - inhibitory activity of mPTP (preferably pIC) as demonstrated in the assay of Biological Example 1 50 value is 6.0 or greater); and - Low inhibition of CYP2D6 as demonstrated in the assay of Biological Example 2 It is expected that you will demonstrate one or more of the following:

[0314] In addition to the properties mentioned above, certain compounds of formula (I) have the following advantageous properties: - improved (i.e., higher) solubility and / or improved (i.e., lower) intrinsic clearance (CL) resulting in, for example, improved (i.e., higher) oral bioavailability and / or improved (i.e., higher) systemic exposure, as demonstrated in the assays of Biological Examples 3 and 4. int ) may also indicate one or more of:

[0315] The present invention is further illustrated by the following non-limiting examples. [Example]

[0316] (Example) The present invention is exemplified by the compounds described below. The following examples describe the laboratory synthesis of specific compounds of the present invention and are in no way intended to limit the scope of the present invention with respect to the compounds or methods. Although specific reagents, solvents, temperatures, and time periods are used, it is understood that there are many possible equivalent alternatives that can be used to produce similar results. The present invention is intended to encompass such equivalents.

[0317] (General experimental details) Starting materials, reagents, and solvents were obtained from commercial suppliers and used without further purification unless otherwise noted. All compounds containing a chiral center were racemic unless otherwise noted. Where reactions are described as being carried out in a manner similar to earlier, more fully described reactions, the general reaction conditions used were essentially the same. Workup conditions used were of a type standard in the art but may have varied from one reaction to another. Starting materials may not necessarily have been prepared from the batch described. Synthesized compounds may have varying purities, for example, ranging from 85% to 99%. In some cases, mole and yield calculations have been adjusted for this.

[0318] The purity of the final compounds was confirmed by HPLC / MS analysis and determined to be at least ≥90%, and frequently ≥95%. Analytical LCMS was performed using the instrumentation shown in Table 1. 1 H NMR was recorded at 300 K on a Bruker 300 MHz instrument (ADVANCE III and ADVANCE III HD). Flash preparative HPLC was performed using the following columns: XBridge Prep C18 OBD column, 5 μm, 19 × 150 mm; XBridge Prep C18 OBD column, 5 μm, 30 × 150 mm; Welch Xtimate C18, 21.2 × 250 mm, 5 μm; and SunFire Prep C18 OBD 19 × 150 mm × 5 μm. SFC purification was performed using the following columns: (a) CHIRALPAK AS-H, 3 × 25 cm, 5 μm; (b) SFC-YMC Cellulose-SB, 4.6 × 100 mm, 3 μm. (Table 1: LC-MS conditions for analysis) [Table 1]

[0319] (abbreviation) [Table 2] TIFF2025508898000058.tif16170

[0320] (Preparation of Comparative Example 1) (Comparative Example 1: (E)-N-(2-methyl-3-fluorophenyl)-3-(1H-indazol-6-yl)acrylamide) [ka] Comparative Example 1 was prepared according to the method described in Chen et al. (Assay and Drug Development Technologies, 2018, 16, 445-455) and may also be prepared using synthetic methods similar to those described herein for Examples 1-64.

[0321] (Preparation of Examples 1 to 117) (Intermediate 1: N-(3-fluoro-2-methylphenyl)acrylamide) [ka] To a stirred solution of 3-fluoro-2-methylaniline (1.0 g, 8.0 mmol, 1.0 equiv.) and DIPEA (3.1 g, 23.9 mmol, 3.0 equiv.) in DCM (40 mL) under nitrogen at 0° C., acryloyl chloride (0.71 mL, 8.8 mmol, 1.1 equiv.) was added dropwise. The resulting mixture was stirred at 25° C. under an inert atmosphere of nitrogen for 3 h. The resulting mixture was washed with 2×30 mL of water, and the organic layer was concentrated. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (1:5). This afforded 1.04 g (73%) of N-(3-fluoro-2-methylphenyl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =180

[0322] (Intermediate 2: N-(3-chloro-2-methylphenyl)acrylamide) [ka] Into a 50 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, 3-chloro-2-methyl-aniline (300 mg, 2.12 mmol, 1.0 equiv.), DCM (15 mL), and EtN (1 mL, 7.19 mmol, 3.4 equiv.) were placed. Subsequently, acryloyl chloride (260 mg, 2.9 mmol, 1.4 equiv.) was added dropwise with stirring at 25 °C. The resulting solution was stirred for 5 h at 25 °C. The resulting mixture was washed with 2 × 10 mL of water, and the organic layer was concentrated. The residue was purified by silica gel chromatography eluting with EtOAc / PE (1:5). This afforded 300 mg (74%) of N-(3-chloro-2-methylphenyl)acrylamide as a pale yellow solid. LC-MS (ES, m / z): [M+H] + =196

[0323] (Intermediate 3: (E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid) [ka] (Process 1) A 250 mL three-necked round-bottom flask was charged with 6-bromo-3-methyl-1H-indazole (2.50 g, 11.84 mmol, 1.00 equiv.), methyl acrylate (1.53 g, 17.76 mmol, 1.50 equiv.), EtN (3.60 g, 35.53 mmol, 3.00 equiv.), Pd(dppf)Cl (0.87 g, 1.18 mmol, 0.10 equiv.), and DMF (100.00 mL). The resulting solution was stirred at 120 °C for 10 h. The mixture was concentrated, and the residue was applied to a silica gel column using THF / PE (1 / 1). This afforded 0.9 g (35% yield) of methyl (2E)-3-(3-methyl-1H-indazol-6-yl)prop-2-enoate as a pale yellow solid.

[0324] [ka] (Process 2) A 40 mL vial was charged with methyl (2E)-3-(3-methyl-1H-indazol-6-yl)prop-2-enoate (890.00 mg, 4.12 mmol, 1.00 equiv.), NaOH (329.24 mg, 8.23 ​​mmol, 2.00 equiv.) in HO (10.00 mL), and MeOH (10.00 mL). The resulting solution was stirred for 2 hours at 20 °C. The pH of the solution was adjusted to 3 with HCl (1 mol / L). The solid was collected by filtration. This afforded 500 mg (60% yield) of (E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid as an off-white solid.

[0325] (Intermediate 4: N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide) [ka] (Process 1) To a stirred solution of 2-hydroxy-4,6-dimethylpyridine-3-carbonitrile (70 g, 472 mmol) in AcO (278 mL) was added c.HNO (43 mL) dropwise in portions at 0 °C. The ice bath was removed, and the reaction was allowed to warm to room temperature and stirred for 10 h. The resulting mixture was cooled and diluted with H2O (200 mL). The precipitated solid was collected by filtration, washed with H2O (2 x 20 mL), and then dried under reduced pressure to give 2-hydroxy-4,6-dimethyl-5-nitronicotinonitrile (56 g, 70% yield) as a yellow solid. LC MS (ES, m / z): [M+H] + = 194

[0326] [ka] (Process 2) c. A solution of 2-hydroxy-4,6-dimethyl-5-nitronicotinonitrile (55 g, 327 mmol) and HO (55 mL) in HSO (275 mL) was stirred at 150 °C for 4 h. The mixture was cooled and diluted with HO (300 mL). The precipitated solid was collected by filtration, washed with HO (2 × 20 mL), and then dried under reduced pressure to give 4,6-dimethyl-5-nitropyridin-2-ol (24 g, 44% yield) as a pale yellow solid. LCMS (ES, m / z): [M+H] + = 169

[0327] [ka] (Step 3) To a stirred solution of 4,6-dimethyl-5-nitropyridin-2-ol (10 g, 58 mmol) and dimethyl sulfate (15 g, 116 mmol, 2.0 equiv.) in DMF (200 mL) was added 60% NaH in oil (2.86 g, 116 mmol, 2.0 equiv.) in portions at 0 °C. The reaction was stirred at 0 °C for 4 h and then quenched by the addition of water (200 mL). The resulting mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic layers were dried over anhydrous NaSO and then concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / AcOEt (3:1) to give 6-methoxy-2,4-dimethyl-3-nitropyridine (2.4 g, 22% yield) as a pale yellow solid. LC MS (ES, m / z): [M+H] + = 183

[0328] [ka] (Step 4) 6-Methoxy-2,4-dimethyl-3-nitropyridine (2.4 g, 14 mmol) and 10% Pd / C (0.40 g) in MeOH (30 mL) were hydrogenated under an atmosphere of hydrogen for 2 hours. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 2 mL). The combined filtrate was concentrated to give 6-methoxy-2,4-dimethylpyridin-3-amine (1.61 g, 81% yield) as a pale yellow oil. LC MS (ES, m / z): [M+H] + = 153

[0329] [ka] (Step 5) To a stirred solution of 6-methoxy-2,4-dimethylpyridin-3-amine (1.5 g, 9.8 mmol), TEA (2.99 g, 30 mmol, 3 equiv.), and DMAP (0.24 g, 1.9 mmol, 0.2 equiv.) in DCM (30 mL) was added acryloyl chloride (2.1 g, 24 mmol, 2.4 equiv.) dropwise over 30 min at 0 °C. The resulting mixture was stirred for 2 h and diluted with ice-water (20 mL). The aqueous layer was extracted with DCM (3 × 20 mL). The combined organic layers were dried over anhydrous NaSO and then concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / AcOEt (1:1) to give N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide (1.4 g, 69% yield) as an off-white solid.

[0330] (Intermediate 5: 6-bromo-5-fluoro-3-methyl-1H-indazole) [ka] (Process 1) To a solution of 1-(4-bromo-2,5-difluorophenyl)ethanone (4.0 g, 17 mmol) in ethylene glycol (100 mL) was added 98% NH2NH2·H2O (2.2 g, 43 mmol, 2.5 equiv.). The mixture was stirred at 160 °C under a N2 atmosphere for 16 h, then cooled and quenched with water (200 mL). The precipitated solid was collected by filtration and washed with water (2 × 50 mL). Drying under reduced pressure gave 6-bromo-5-fluoro-3-methyl-1H-indazole (3.0 g, 77% yield) as an off-white solid. LCMS (ES, m / z): 229, 231 [M+H] +

[0331] (Intermediate 6: (2E)-3-[3-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid) [ka] (Process 1) A solution of 6-bromo-1H-indazole (4.4 g, 22 mmol), Selectfluor (15 g, 42 mmol, 1.9 equiv.), and AcOH (3 mL, 53 mmol, 2.4 equiv.) in MeCN (300 mL) was stirred at reflux for 4 h. The mixture was cooled and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate (5:1) to give 6-bromo-3-fluoro-1H-indazole (1.13 g, 23% yield) as a yellow solid. LC-MS (ES, m / z): 215, 217 [M+H]

[0332] [ka] (Process 2) A solution of 6-bromo-3-fluoro-1H-indazole (1.1 g, 5.1 mmol), DHP (6.0 g, 72 mmol, 14 equiv.), and PPTS (642 mg, 2.5 mmol, 0.5 equiv.) in THF (80 mL) was stirred at 70 °C for 10 h. The mixture was cooled and diluted with saturated brine (100 mL) and saturated aqueous NaHCO (20 mL). The aqueous layer was extracted with EA (2 × 100 mL). The combined mixture was dried over anhydrous NaSO and concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / AcOEt (5:1) to give 6-bromo-3-fluoro-1-(oxan-2-yl)indazole (1.0 g, 65% yield) as a yellow solid. LC-MS (ES, m / z): 299, 301 [M+H] +

[0333] [ka] (Step 3) A solution of 6-bromo-3-fluoro-1-(oxan-2-yl)indazole (700 mg, 2.3 mmol), methyl acrylate (604 mg, 7.0 mmol, 3 equiv.), Pd(dppf)Cl (191 mg, 0.3 mmol, 0.1 equiv.), and TEA (1.06 g, 10.4 mmol, 4.5 equiv.) in DMF (15 mL) was stirred at 110 °C for 4 h. The mixture was cooled, diluted with HO (20 mL), and then extracted with ethyl acetate (4 × 50 mL). The combined organic layers were dried over anhydrous NaSO and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate (3:1) to give methyl (2E)-3-[3-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (300 mg, 42% yield) as a pale yellow solid. LC-MS (ES, m / z): 305 [M+H] +

[0334] [ka] (Step 4) A solution of (2E)-3-[3-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (300 mg, 0.9 mmol), NaOH (107 mg, 2.7 mmol, 3.0 equiv.) in HO (2 mL) and MeOH (2 mL) was stirred at room temperature for 4 hours. The resulting mixture was concentrated and then diluted with HO (3 mL). The mixture was neutralized to pH 6 with 1 M HCl. The precipitated solid was collected by filtration and washed with HO (2 × 2 mL). The solid was dried under vacuum to give (2E)-3-[3-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid (234 mg, 82% yield) as a white solid. LC-MS (ES, m / z): 291 [M+H] +

[0335] (Intermediate 7: 6-bromo-3-chloro-5-fluoro-1H-indazole) [ka] A solution of 6-bromo-5-fluoro-1H-indazole (200 mg, 0.9 mmol) and NCS (248 mg, 1.8 mmol, 2 equiv.) in DMF (4 mL) was stirred at 60 °C for 2 h. The mixture was cooled and diluted with HO (8 mL). The precipitated solid was collected by filtration and washed with HO (2 × 5 mL). The precipitate was purified by silica gel column chromatography eluting with n-hexane / AcOEt (1:1) to give 6-bromo-3-chloro-5-fluoro-1H-indazole (143 mg, 67% yield) as an off-white solid. LCMS (ES, m / z): 249 [M+H] +

[0336] (Intermediate 8: (2E)-3-[3,5-difluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid) [ka] (Process 1) A mixture of 6-bromo-5-fluoro-1H-indazole (2.8 g, 13 mmol), Selectfluor (9.5 g, 27 mmol, 2 equiv.), and AcOH (2 mL, 35 mmol, 2.6 equiv.) in MeCN (40 mL) was stirred at reflux for 2 h. The mixture was cooled and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate (5:1) to give 6-bromo-3,5-difluoro-1H-indazole (490 mg, 16% yield) as a brown solid. LC-MS (ES, m / z): 233 [M+H] +

[0337] [ka] (Process 2) A solution of 6-bromo-3,5-difluoro-1H-indazole (440 mg, 1.9 mmol), DHP (2.22 g, 26 mmol, 14 equiv.), and PPTS (237 mg, 0.9 mmol, 0.5 equiv.) in THF (10 mL) was stirred at 70 °C for 2 h. The reaction was cooled and diluted with saturated brine (20 mL) and saturated aqueous NaHCO (5 mL). The resulting mixture was extracted with CHCl (3 × 20 mL). The combined organic layers were dried over anhydrous NaSO. The residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate (3:1) to afford 6-bromo-3,5-difluoro-1-(oxan-2-yl)indazole (320 mg, 53% yield) as a brown solid. LC-MS (ES, m / z): 317 [M+H] +

[0338] [ka] (Step 3) A solution of 6-bromo-3,5-difluoro-1-(oxan-2-yl)indazole (320 mg, 1.0 mmol), methyl acrylate (344 mg, 4.0 mmol, 4 equiv), Pd(dppf)Cl (163 mg, 0.2 mmol, 0.2 equiv), and TEA (505 mg, 5.0 mmol, 5 equiv) in DMF (10 mL) was stirred at 110 °C under a N atmosphere for 2 h. The mixture was cooled, diluted with HO (20 mL), and then extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried over anhydrous NaSO and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate (5:1) to give methyl (2E)-3-[3,5-difluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (120 mg, 24% yield) as a pale yellow solid. LC-MS (ES, m / z): 323 [M+H] +

[0339] [ka] (Step 4) A solution of methyl (2E)-3-[3,5-difluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (120 mg, 0.3 mmol) and NaOH (36 mg, 0.9 mmol, 3 equiv.) in HO (1 mL) and MeOH (1 mL) was stirred at room temperature for 4 hours. The mixture was acidified to pH 6 with 1 M HCl, and the precipitated solid was collected by filtration and washed with THF (3 × 3 mL). Drying under vacuum afforded (2E)-3-[3,5-difluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid (63 mg, 55% yield) as a white solid. LC-MS (ES, m / z): 309 [M+H] +

[0340] (Intermediate 9: 6-bromo-5-fluoro-1-(oxan-2-yl)indazole-3-carbonitrile) [ka] (Process 1) A mixture of 6-bromo-5-fluoro-1H-indazole (3.0 g, 13 mmol), NaOH (0.56 g, 39 mmol, 3 equiv.), and iodine (7.1 g, 26 mmol, 2 equiv.) in dioxane (60 mL) and HO (10 mL) was stirred for 2 h and then neutralized with 1 M aqueous HCl. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous NaSO and concentrated. The residue was purified by silica gel column chromatography using petroleum ether:EtOAc (2:1) to give 6-bromo-5-fluoro-3-iodo-1H-indazole (2.90 g, 61% yield) as a white solid. LCMS (ES, m / z): 340 [M+H] +

[0341] [ka] (Process 2) A mixture of 6-bromo-5-fluoro-3-iodo-1H-indazole (2.9 g, 8.5 mmol), Zn(CN) (1.2 g, 10 mmol, 1.2 equiv.), Dppf (0.94 g, 1.7 mmol, 0.2 equiv.), Pd(dba) (0.78 g, 0.86 mmol, 0.1 equiv.), and KCO (3.5 g, 26 mmol, 3 equiv.) in DMF (60 mL) was stirred at 60 °C under a nitrogen atmosphere for 2 h. The mixture was cooled, diluted with water (80 mL), and then extracted with EtOAc (3 × 80 mL). The combined organic layer was dried over anhydrous NaSO and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether: EtOAc (1:1) to give 6-bromo-5-fluoro-1H-indazole-3-carbonitrile (1.3 g, 64% yield) as a white solid. LCMS (ES, m / z): 240 [M+H] +

[0342] [ka] (Step 3) A solution of 6-bromo-5-fluoro-1H-indazole-3-carbonitrile (1.3 g, 5.4 mmol), DHP (1.37 g, 16 mmol, 3 equiv.), and TsOH (0.28 g, 1.6 mmol, 0.3 equiv.) in THF (26 mL) was stirred at 65 °C for 13 h. The reaction was cooled and diluted with saturated brine (20 mL) and saturated aqueous NaHCO (5 mL). The mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over anhydrous NaSO and concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / EtOAc (8:1) to give 6-bromo-5-fluoro-1-(oxan-2-yl)indazole-3-carbonitrile (1.6 g, 92% yield) as an off-white solid.

[0343] (Intermediate 10: N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide) [ka] (Process 1) To a solution of 2,4-dibromo-5-fluoro-3-nitropyridine (1.00 g, 3.3 mmol) in 1,4-dioxane (10 mL) and HO (1 mL) was added 50% trimethyl-1,3,5,2,4,6-trioxatriborinane (1.7 g, 6.6 mmol, 2 equiv.) in THF, Pd(dppf)Cl (0.24 g, 0.3 mmol, 0.1 equiv.), and CsCO (2.17 g, 6.6 mmol, 2 equiv.). The mixture was stirred at 100 °C for 16 h under a N atmosphere. The reaction was cooled and diluted with water (20 mL), and the resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / AcOEt (9:1) to give 5-fluoro-2,4-dimethyl-3-nitropyridine (0.46 g, 81% yield) as a pale red oil.

[0344] [ka] (Process 2) To a solution of 5-fluoro-2,4-dimethyl-3-nitropyridine (0.46 g, 1.8 mmol) in MeOH (10 mL) was added 10% Pd / C (120 mg). The mixture was stirred at room temperature under an H atmosphere for 2 hours. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 5 mL). The combined filtrate was concentrated under reduced pressure to give 5-fluoro-2,4-dimethylpyridin-3-amine (0.32 g, 86% yield) as an off-white solid. LCMS (ES, m / z): 141 [M+H] +

[0345] [ka] (Step 3) To a solution of 5-fluoro-2,4-dimethylpyridin-3-amine (0.32 g, 2.2 mmol) in DCM (2 mL) was added TEA (0.69 g, 6.8 mmol, 3 equiv). The reaction was cooled to 0 ° C., and acryloyl chloride (0.31 g, 3.4 mmol, 1.5 equiv) in DCM (1 mL) was added dropwise at 0 ° C. over 2 minutes. The reaction was stirred at 0 ° C. for 2 hours and then concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / AcOEt (1:5) to give N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide (0.16 g, 36% yield) as an off-white solid. LCMS (ES, m / z): 195 [M+H] +

[0346] (Intermediate 11: N-[5-fluoro-4-(methoxymethyl)-2-methylpyridin-3-yl]prop-2-enamide) [ka] (Process 1) To 2-chloro-5-fluoropyridin-4-amine (4.0 g, 27 mmol) in H2SO4 (60 mL) at 0 °C was added HNO3 (3.44 g, 55 mmol, 2 equiv.) dropwise over 5 min. The mixture was stirred at 0 °C for 1 h and then at room temperature for 20 h. The reaction was quenched with water / ice and basified to pH 9 with NH3·H2O. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 3 mL), dried over anhydrous Na2SO4, and concentrated to give 2-chloro-5-fluoro-3-nitropyridin-4-amine (4.8 g, 92% yield) as a pale yellow solid. LCMS (ES, m / z): 192 [M+H] +

[0347] [ka] (Process 2) To a solution of 2-chloro-5-fluoro-3-nitropyridin-4-amine (2.0 g, 10 mmol) in 1,4-dioxane (11 mL) and HO (1 mL) was added 50% trimethyl-1,3,5,2,4,6-trioxatriborinane (7.9 g, 31 mmol, 3 equiv.) in THF, Pd(dppf)Cl (0.76 g, 1 mmol, 0.1 equiv.), and CsCO (6.8 g, 21 mmol, 2 equiv.). The reaction was stirred at 100 °C under a N atmosphere for 16 h, then cooled and diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / AcOEt (1:1) to give 5-fluoro-2-methyl-3-nitropyridin-4-amine (1.2 g, 67% yield) as a pale yellow solid. LCMS (ES, m / z): 172 [M+H] +

[0348] [ka] (Step 3) To 5-fluoro-2-methyl-3-nitropyridin-4-amine (0.90, 5.2 mmol) in CHCN (9 mL) was added CuBr (3.0 g, 21 mmol, 4 equivalents) and t-BuNO (1.1 g, 11 mmol, 2 equivalents) at 0° C. The mixture was stirred at 0° C. for 2 hours and then concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / AcOEt (3:1) to give 4-bromo-5-fluoro-2-methyl-3-nitropyridine (1.0 g, 81% yield) as an off-white solid.

[0349] [ka] (Step 4) To 4-bromo-5-fluoro-2-methyl-3-nitropyridine (0.90 g, 3.9 mmol) in toluene (9 mL) was added tributyl(methoxymethyl)stannane (2.6 g, 7.8 mmol, 2 equiv.) and Pd(PPh3)2Cl2 (273 mg, 0.39 mmol, 0.1 equiv.). The reaction was stirred at 120 °C under a N2 atmosphere for 2 h. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / AcOEt (2:1) to give 5-fluoro-4-(methoxymethyl)-2-methyl-3-nitropyridine (600 mg, 78% yield) as a colorless oil. [ka]

[0350] [ka] (Step 5) To a solution of 5-fluoro-4-(methoxymethyl)-2-methyl-3-nitropyridine (0.90 g, 4.5 mmol) in MeOH (10 mL) was added 10% Pd / C (0.48 g, 0.4 mmol, 0.1 equiv.). The reaction was stirred at room temperature under an H atmosphere for 2 hours. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 3 mL). The filtrate was concentrated to give 5-fluoro-4-(methoxymethyl)-2-methylpyridin-3-amine (600 mg, 78% yield) as an off-white solid. LCMS-6 (ES, m / z): [M+H] + =171

[0351] [ka] (Step 6) To 5-fluoro-4-(methoxymethyl)-2-methylpyridin-3-amine (0.30 g, 1.7 mmol) in DCM (2.0 mL) was added TEA (0.53 g, 5.3 mmol, 3 equivalents). The mixture was cooled to 0° C., and acryloyl chloride (0.16 g, 1.8 mmol) in DCM (1.0 mL) was added dropwise at 0° C. over 2 minutes. The resulting mixture was stirred at 0° C. for 2 hours and then concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / AcOEt (1:1) to give N-[5-fluoro-4-(methoxymethyl)-2-methylpyridin-3-yl]prop-2-enamide (120 mg, 30% yield) as an off-white solid. LCMS (ES, m / z): 225 [M+H] +

[0352] (Intermediate 12: N-[5-fluoro-4-(methoxymethyl)pyridin-3-yl]prop-2-enamide) [ka] (Process 1) To tert-butyl N-(5-fluoropyridin-3-yl)carbamate (0.50 g, 2.3 mmol) in THF (5 mL) was added TMEDA (0.68 g, 5.9 mmol, 2.5 equiv). The reaction mixture was cooled to -30 °C, and 2.5 M n-BuLi in hexanes (2.4 mL, 5.9 mmol, 2.5 equiv) was added while maintaining the internal temperature below -20 °C. Upon complete addition, the reaction mixture was stirred at -30 °C for an additional 50 min. Iodine (0.96 g, 3.7 mmol, 1.6 equiv) was slowly added, and the mixture was then stirred at -30 °C for an additional 45 min. The reaction was quenched by the slow addition of saturated aqueous ammonium chloride (5 mL) and water (5 mL). The resulting mixture was extracted with EtOAc (3 × 7 mL). The combined organic layer was washed with brine (3 × 3 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give tert-butyl N-(5-fluoro-4-iodopyridin-3-yl)carbamate (0.50 g, 63% yield) as an off-white solid. LCMS (ES, m / z): 339 [M+H] +

[0353] [ka] (Process 2) To a solution of tert-butyl N-(5-fluoro-4-iodopyridin-3-yl)carbamate (0.50 g, 1.5 mmol) in toluene (5 mL) was added tributyl(methoxymethyl)stannane (0.99 g, 2.9 mmol, 2 equiv.) and Pd(PPh3)2Cl2 (0.10 g, 0.1 mmol, 0.1 equiv.). The reaction was stirred at 120 °C for 8 h, then cooled and quenched with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1:1) to give tert-butyl N-[5-fluoro-4-(methoxymethyl)pyridin-3-yl]carbamate (0.28 g, 74% yield) as a pale yellow oil. LCMS (ES, m / z): 257 [M+H] +

[0354] [ka] (Step 3) A solution of tert-butyl N-[5-fluoro-4-(methoxymethyl)pyridin-3-yl]carbamate (280 mg, 1.1 mmol) in 4 M HCl in 1,4-dioxane (2 mL) was stirred at 60 ° C. for 10 minutes, and then concentrated to give 5-fluoro-4-(methoxymethyl)pyridin-3-amine (160 mg, crude product) as an off-white solid. The crude product was used directly in the next step without further purification. LCMS (ES, m / z): 157 [M+H] +

[0355] [ka] (Step 4) To a solution of 5-fluoro-4-(methoxymethyl)pyridin-3-amine (150 mg, 0.9 mmol) in DCM (1 mL) was added TEA (97 mg, 2.7 mmol, 3 equiv.). The solution was cooled in an ice bath, and acryloyl chloride (44 mg, 1.3 mmol, 1.5 equiv.) in DCM (0.5 mL) was added dropwise. The reaction was stirred to room temperature for 1 hour and then concentrated. The residue was dissolved in DCM (5 mL) and purified by silica gel column chromatography eluting with n-hexane / AcOEt (1:1) to give N-[5-fluoro-4-(methoxymethyl)-pyridin-3-yl]prop-2-enamide (120 mg, 30% yield) as an off-white solid. LCMS (ES, m / z): 211 [M+H] +

[0356] (Intermediate 13: (2E)-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid) [ka] (Process 1) A solution of 6-bromo-3-methyl-1H-indazole (4.0 g, 19 mmol) in THF (80 mL) was treated with DHP (4.8 g, 57 mmol, 3.0 equiv.) and PPTS (480 mg, 1.9 mmol, 0.1 equiv.). The solution was stirred at 70 °C for 2 h, then cooled and quenched with water. The resulting mixture was extracted with CHCl (4 × 50 mL). The combined organic layers were dried over anhydrous NaSO and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether:THF (5:1) to afford 6-bromo-3-methyl-1-(oxan-2-yl)indazole (4.9 g, 88% yield) as an off-white solid. LC-MS (ES, m / z): 295 [M+H] +

[0357] [ka] (Process 2) A solution of 6-bromo-3-methyl-1-(oxan-2-yl)indazole (4.9 g, 17 mmol), methyl acrylate (5.7 g, 66 mmol, 4.0 equiv.), Pd(dppf)Cl.CHCl (2.7 g, 3.3 mmol, 0.2 equiv.), and TEA (8.4 g, 83 mmol, 5.0 equiv.) in DMF (100 mL) was stirred at 110 °C under a N atmosphere for 2 h. The mixture was allowed to cool and quenched with water. The resulting mixture was extracted with ethyl acetate (4 × 50 mL). The combined organic layers were washed with brine (3 × 5 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give methyl (2E)-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (4.0 g, 80% yield) as a yellow solid. LC-MS (ES, m / z): 301 [M+H] +

[0358] [ka] (Step 3) A solution of methyl (2E)-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (4.0 g, 13 mmol) in HO (27 mL), MeOH (27 mL), and THF (27 mL) was treated with NaOH (1.6 g, 40 mmol, 3 equiv.). The mixture was stirred at room temperature for 4 hours and then acidified to pH 6 with 1 M HCl. The precipitated solid was collected by filtration and washed with THF (3 × 10 mL). Drying under vacuum afforded (2E)-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid (3.2 g, 84% yield) as a white solid. LC-MS (ES, m / z): 287 [M+H] +

[0359] (Intermediate 14: (2E)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid) [ka] (Process 1) To a solution of 6-bromo-1H-indazole (35 g, 178 mmol) and PPTS (4.5 g, 18 mmol, 0.1 equiv.) in THF (400 mL) was added dihydropyran (37.4 g, 444 mmol, 2.5 equiv.). The reaction was stirred at 70 °C for 3 h, then cooled, concentrated, and diluted with water (300 mL). The resulting mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (3 × 200 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / EtOAc (3:1) to give 6-bromo-1-(oxan-2-yl)indazole (30 g, 60% yield) as an off-white solid. LCMS (ES, m / z): 281 [M+H] +

[0360] [ka] (Process 2) To a stirred solution of 6-bromo-1-(oxan-2-yl)indazole (30 g, 107 mmol) in DMF (300 mL) was added methyl acrylate (18.4 g, 213 mmol, 2.0 equiv.), TEA (32.4 g, 320 mmol, 3.0 equiv.), and Pd(dppf)Cl (7.8 g, 11 mmol, 0.1 equiv.) at room temperature under a nitrogen atmosphere. The reaction was stirred at 110 °C for 3 h, then cooled, quenched with water (500 mL), and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / EtOAc (1:1) to give methyl (2E)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (25 g, 82% yield) as a pale yellow oil. LCMS (ES, m / z): 287 [M+H]+

[0361] [ka] (Step 3) To a stirred solution of methyl (2E)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enoate (25 g, 87 mmol) in MeOH (250 mL) and HO (100 mL) was added NaOH (7.0 g, 175 mmol, 2.0 equiv.). The resulting mixture was stirred at room temperature for 3 h and then concentrated. The remaining aqueous layer was washed with EtOAc (2 × 300 mL) and then acidified to pH 4 with 0.1 M HCl (aq.). The resulting mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over anhydrous NaSO, and concentrated to give (2E)-3-[1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid (10 g, 42% yield) as an off-white solid. LCMS (ES, m / z): 273 [M+H] +

[0362] Example 1: (E)-3-(1H-benzo[d][1,2,3]triazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide [ka] To a microwave vial containing N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 100 mg, 0.56 mmol, 1.0 equiv.), 5-bromo-3H-1,2,3-benzotriazole (110 mg, 0.56 mmol, 1.0 equiv.), Pd(OAc) (19 mg, 0.084 mmol, 0.15 equiv.), tris(2-methylphenyl)phosphane (34 mg, 0.112 mmol, 0.20 equiv.), and tetrabutylammonium chloride (155 mg, 0.558 mmol, 1.0 equiv.) was added DMF (1.5 mL). The resulting solution was stirred at 115 °C for 12 h. The resulting mixture was diluted with 20 mL of EtOAc and washed with 2 × 10 mL of 1 M aqueous KCO. The organic layer was concentrated, dried over anhydrous sodium sulfate, and concentrated. The residue was loaded onto a silica gel column. The resulting crude product was purified by flash preparative HPLC to give 9 mg (5%) of (£)-3-(1H-benzo[d][1,2,3]triazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide as a pale gray solid. LC-MS(ES,m / z):[M+H] + =297; [ka]

[0363] Example 2: (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)acrylamide [ka] To a microwave vial containing N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 180 mg, 1.0 mmol, 1.0 equiv.), 5-bromo-3H-1,3-benzothiazol-2-one (231 mg, 1.0 mmol, 1.0 equiv.), Pd(OAc) (34 mg, 0.151 mmol, 0.15 equiv.), tris(2-methylphenyl)phosphane (62 mg, 0.201 mmol, 0.20 equiv.), and tetrabutylammonium chloride (279 mg, 1.0 mmol, 1.0 equiv.) was added DMF (2.8 mL). The resulting solution was stirred at 115 °C for 12 h. The resulting mixture was diluted with 30 mL of EtOAc and washed with 2 × 15 mL of 1 M aqueous KCO. The organic layer was concentrated, dried over anhydrous sodium sulfate, and concentrated. The residue was loaded onto a silica gel column. The resulting crude product was purified by flash preparative HPLC to give 6 mg (2%) of (£)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]thiazol-5-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =329 [ka]

[0364] Example 3: (E)-3-(3,3-dimethyl-2-oxoindolin-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide [ka] To a microwave vial containing N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 185 mg, 1.03 mmol, 1.0 equiv.), 6-bromo-3,3-dimethyl-1H-indol-2-one (240 mg, 1.03 mmol, 1.0 equiv.), Pd(OAc) (35 mg, 0.155 mmol, 0.15 equiv.), tris(2-methylphenyl)phosphane (63 mg, 0.206 mmol, 0.20 equiv.), and tetrabutylammonium chloride (286 mg, 1.03 mmol, 1.0 equiv.) was added DMF (2.9 mL). The resulting solution was stirred at 115 °C for 12 h. The resulting mixture was diluted with 30 mL of EtOAc and washed with 2 × 15 mL of 1 M aqueous KCO. The organic layer was concentrated, dried over anhydrous sodium sulfate, and concentrated. The residue was loaded onto a silica gel column. The resulting crude product was purified by flash preparative HPLC to give 76 mg (22%) of (£)-3-(3,3-dimethyl-2-oxoindolin-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =339 [ka]

[0365] Example 4: (E)-N-(3-fluoro-2-methylphenyl)-3-(2'-oxospiro[cyclopropane-1,3'-indoline]-6'-yl)acrylamide [ka] To a microwave vial containing N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 130 mg, 0.725 mmol, 1.0 equiv.), 6'-bromo-1'H-spiro[cyclopropane-1,3'-indol]-2'-one (172 mg, 0.725 mmol, 1.0 equiv.), Pd(OAc) (24 mg, 0.109 mmol, 0.15 equiv.), tris(2-methylphenyl)phosphane (44 mg, 0.145 mmol, 0.20 equiv.), and tetrabutylammonium chloride (278 mg, 0.725 mmol, 1.0 equiv.) was added DMF (2 mL). The resulting solution was stirred at 115 °C for 12 h. The resulting mixture was diluted with 30 mL of EtOAc, washed with 2 × 15 mL of 1 M aqueous KCO, and the organic layer was concentrated, dried over anhydrous sodium sulfate, and concentrated. The residue was loaded onto a silica gel column. The resulting crude product was purified by flash preparative HPLC. This afforded 10 mg (4%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(2'-oxospiro[cyclopropane-1,3'-indoline]-6'-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =337 [ka]

[0366] Example 5: (E)—N-(3-fluoro-2-methylphenyl)-3-(7-fluoro-2-oxoindolin-6-yl)acrylamide [ka] Prepared by the method described above using intermediate 1 and 6-bromo-7-fluoro-1,3-dihydro-2H-indol-2-one. LC-MS (ES, m / z): 327 [M−H] + [ka]

[0367] Example 6: (E)—N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] Into an 8 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was placed N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 50 mg, 0.28 mmol, 1.0 equiv.), DMF (4 mL), 5-bromo-2-benzoxazolinone (66 mg, 0.31 mmol, 1.10 equiv.), EtN (0.12 mL, 0.84 mmol, 3.0 equiv.), and Pd(dppf)Cl CHCl (11 mg, 0.014 mmol, 0.05 equiv.). The resulting solution was stirred at 120°C for 12 hours. The reaction was then quenched by the addition of 3 mL of water. The resulting solution was extracted with 5 mL of DCM, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash preparative HPLC. This afforded 21 mg (24%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a white solid. LC MS (ES, m / z): [M+H] + =313 [ka]

[0368] Example 7: (E)—N-(3-fluoro-2-methylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide [ka] An 8 mL vial purged and maintained under an inert atmosphere of nitrogen was charged with N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 90 mg, 0.50 mmol, 1.0 equiv.), DMF (5 mL), 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (137 mg, 0.60 mmol, 1.20 equiv.), EtN (0.21 mL, 1.51 mmol, 3.0 equiv.), and Pd(dppf)Cl·CHCl (20 mg, 0.025 mmol, 0.05 equiv.). The resulting solution was stirred at 120 °C for 12 h and cooled to 25 °C. The mixture was purified by preparative HPLC. This gave 7 mg (4%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide as an off-white solid. LC MS (ES, m / z): [M+H] + =326 [ka]

[0369] Example 8: (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-2-oxoindolin-6-yl)acrylamide [ka] (Process 1) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 6-bromo-1H-indole-2,3-dione (3.5 g, 15.48 mmol, 1.0 equiv.) and THF (70 mL). 3 M methylmagnesium bromide (5.2 mL, 15.48 mmol, 1.0 equiv.) was added dropwise over 0.5 h at −78° C. The resulting solution was stirred for an additional 5 h at −78° C., after which the temperature was raised to 25° C. The reaction was then quenched by the addition of 10 mL of 0.2 M HCl. The resulting solution was extracted with 2×50 mL of EtOAc, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column using 35 / 65 EtOAc / PE. This gave 3 g (80%) of 6-bromo-3-hydroxy-3-methyl-1H-indol-2-one as an off-white solid. LC-MS (ES, m / z): [MH] + =240

[0370] [ka] (Process 2) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 6-bromo-3-hydroxy-3-methyl-1H-indol-2-one (2.0 g, 8.26 mmol, 1.0 equiv.) and THF (30 mL). Subsequently, diethylaminosulfur trifluoride (DAST) (2.0 g, 12.39 mmol, 1.50 equiv.) was added at −78° C. The resulting solution was stirred from −78° C. for 1 hour and warmed to 25° C. The reaction was then quenched by the addition of 10 mL of saturated NaHCO3. The resulting solution was extracted with 2×50 mL of EtOAc, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column using 25 / 75 EtOAc / PE. This gave 1.65 g (82%) of 6-bromo-3-fluoro-3-methyl-1H-indol-2-one as a white solid. LC-MS (ES, m / z): [MH] + =242

[0371] [ka] (Step 3) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with 6-bromo-3-fluoro-3-methyl-1H-indol-2-one (200 mg, 0.82 mmol, 1.0 equiv.), N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 147 mg, 0.82 mmol, 1.0 equiv.), Pd(dppf)Cl.CHCl (13 mg, 0.02 mmol, 0.02 equiv.), DMF (4 mL), and EtN (0.23 mL, 1.64 mmol, 2.0 equiv.). The resulting solution was stirred at 110 °C for 2 h. The solids were removed by filtration. The filtrate was concentrated. The crude product was purified by flash preparative HPLC. This gave 13 mg (4.5%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(3-fluoro-3-methyl-2-oxoindolin-6-yl)acrylamide and 12 mg (4%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-2-oxoindolin-6-yl)acrylamide. (E)-N-(3-fluoro-2-methylphenyl)-3-(3-fluoro-3-methyl-2-oxoindolin-6-yl)acrylamide LC-MS (ES, m / z): [M+H] + =343 [ka] E) -N-(3-fluoro-2-methylphenyl)-3-(3-methyl-2-oxoindolin-6-yl)acrylamide LC-MS (ES, m / z): [M+H] + =325 [ka]

[0372] Example 9: (E)—N-(3-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(3-chloro-2-methylphenyl)prop-2-enamide (Intermediate 2, 55 mg, 0.28 mmol, 1.0 equiv.), DMF (4 mL), 2-benzoxazolinone, 5-bromo- (66 mg, 0.31 mmol, 1.10 equiv.), EtN (0.12 mL, 0.84 mmol, 3.0 equiv.), and Pd(dppf)Cl.CHCl (11 mg, 0.014 mmol, 0.05 equiv.). The resulting solution was stirred at 120 °C for 12 h. The reaction was then quenched by the addition of 3 mL of water. The resulting solution was extracted with 5 mL of DCM, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash preparative HPLC. This gave 21 mg (24%) of (E)-N-(3-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a white solid. LC MS (ES, m / z): [M+H] + =329 [ka]

[0373] Example 10: (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide [ka] A 40 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was charged with N-(3-fluoro-2-methylphenyl)prop-2-enamide (Intermediate 1, (500 mg, 2.79 mmol, 1.0 equiv.), 6-bromo-1,3-dihydroindol-2-one (592 mg, 2.79 mmol, 1.0 equiv.), DMF (20 mL), EtN (1.2 mL, 8.37 mmol, 3.0 equiv.), and Pd(dppf)Cl (41 mg, 0.05 mmol, 0.02 equiv.). The reaction mixture was stirred for 2 h at 110 °C. The resulting mixture was concentrated. The crude product was purified by flash preparative HPLC. This afforded 102 mg (11%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M−H] + =309 [ka]

[0374] Example 11: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] (Process 1) A 500 mL sealed tube was charged with 5-bromobenzo[d]oxazol-2(3H)-one (10.0 g, 46.96 mmol, 1.0 equiv.), methyl acrylate (12.1 g, 140.8 mmol, 3.0 equiv.), EtN (19.6 mL, 140.8 mmol, 3.0 equiv.), and Pd(dppf)Cl (350 mg, 4.7 mmol, 0.01 equiv.) in DMF (200 mL). The resulting solution was stirred at 120 °C for 2 h. The resulting solution was concentrated. The residue was loaded onto a silica gel column eluted with THF / hexane (20 / 80). This gave 11 g (82%) of methyl (E)-3-(3-(3-methoxy-3-oxopropyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate as a yellow solid.

[0375] [ka] (Process 2) A 500 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with THF (300 mL), methyl (E)-3-(3-(3-methoxy-3-oxopropyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate (11.0 g, 36.1 mmol, 1.0 equiv.), and t-BuOK (13.2 g, 108.2 mmol, 3.0 equiv.). The resulting solution was stirred for 2 hours at 60°C. The reaction was then quenched by the addition of 600 mL of saturated NH4Cl. The resulting solution was extracted with 2 x 300 mL of EtOAc. The organic layer was washed with 2 x 400 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting solution was concentrated. The residue was loaded onto a silica gel column using 40 / 60 EtOAc / hexanes. This gave 5.5 g (69%) of methyl (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate as a pale red solid.

[0376] [ka] (Step 3) A purged 100 mL three-neck round-bottom flask was charged with THF (20 mL), methyl (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate (2.5 g, 11.4 mmol, 1.0 equiv.), and 2 M NaOH (17.1 mL, 34.2 mmol, 3.0 equiv.). The resulting solution was stirred for 2 h at 25 °C. The reaction mixture was concentrated at low temperature (<30 °C). The residue was dissolved in water (30 mL) and the pH was adjusted to 2-3 with 2 M HCl. The solid was collected. This afforded 2.5 g (65%) of (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylic acid as an off-white solid.

[0377] [ka] (Step 4) Each vial was charged with (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylic acid (30 mg, 0.146 mmol, 1.0 equiv.) in DMF (2 mL). Then, T3P (70 mg, 0.22 mmol, 1.50 equiv.), DIPEA (28 mg, 0.22 mmol, 1.50 equiv.), and 1-indanamine (0.161 mmol, 1.1 equiv.) were added. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with water, extracted with EtOAc, and the organic layer was concentrated in vacuo to give the crude product. The crude product was then directly purified by preparative HPLC. The collected fractions were lyophilized to give the final compound. LC-MS (ES, m / z): 321 [M+H] + [ka]

[0378] (General Procedure A) [ka] To each vial was added methyl (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate (Example 11, Step 2, 30 mg, 0.14 mmol, 1.0 equiv.) in THF (2 mL). The 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 for 1 h at 25° C. The reaction mixture was quenched with water, extracted with EtOAc, and the organic layer was concentrated in vacuo to give the crude product, which was then purified by preparative HPLC. The collected fractions were lyophilized to give the final compound.

[0379] Example 12: (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(o-tolyl)acrylamide [ka] Synthesis using general procedure A using 2-methylaniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate to give (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(o-tolyl)acrylamide as a solid. LC-MS (ES, m / z): 295 [M+H] + [ka]

[0380] Example 13: (E)-N-(2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] Synthesis using general procedure A using 2-isopropylaniline and (£)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate to give (£)-N-(2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a solid. LC-MS (ES, m / z): 323[M+H] + [ka]

[0381] Example 14: (E)-N-(2-isopropyl-6-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] Synthesis using general procedure A using 2-isopropyl-6-methylaniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate to give (E)-N-(2-isopropyl-6-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a solid. LC-MS (ES, m / z): 337[M+H] + [ka]

[0382] Example 15: (E)-N-(5-chloro-2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] Synthesis using general procedure A using 5-chloro-2-isopropylaniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate to give (E)-N-(5-chloro-2-isopropylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a solid. LC-MS (ES, m / z): 357[M+H] + [ka]

[0383] Example 16: (E)—N-(4,5-difluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] Synthesis using 4,5-difluoro-2-methylaniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate according to general procedure A gave (E)-N-(4,5-difluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a solid. LC-MS (ES, m / z): 331 [M+H] + , 373 [M+CH3CN] + .

[0384] Example 17: (E)—N-(5-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] Synthesis using general procedure A with 5-fluoro-2-methylaniline and (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate gave (E)-N-(5-fluoro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a solid. LC-MS (ES, m / z): 311 [M+H] +

[0385] Example 18: (E)—N-(3-fluoro-2-methylphenyl)-3-(4-fluoro-2-oxoindolin-6-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(3-fluoro-2-methylphenyl)acrylamide (60.0 mg, 0.34 mmol, 1.0 equiv.), 6-bromo-4-fluoroindolin-2-one (78 mg, 0.34 mmol, 1.0 equiv.), EtN (0.14 mL, 1.0 mmol, 3.0 equiv.), DMF (4.0 mL), and Pd(dppf)Cl (25.2 mg, 0.034 mmol, 0.10 equiv.). The resulting solution was stirred at 120 °C for 2 h. The crude mixture was purified by flash preparative HPLC. This afforded 11.8 mg (11%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(4-fluoro-2-oxoindolin-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =329 [ka]

[0386] Example 19: (E)—N-(2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide [ka] (Process 1) A 500 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 6-bromo-1,3-dihydroindol-2-one (20.0 g, 94.32 mmol, 1.0 equiv.), DMF (350 mL), methyl acrylate (6.50 g, 75.50 mmol, 0.80 equiv.), EtN (26.3 mL, 188.64 mmol, 2.0 equiv.), and Pd(dppf)Cl.CHCl (0.77 g, 0.94 mmol, 0.01 equiv.). The resulting solution was stirred at 120 °C for 2 h. The reaction mixture was cooled to room temperature. The mixture was loaded onto a silica gel column using THF / PE (2 / 1). This gave 7.4 g (36%) of methyl (2E)-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2-enoate as a pale yellow solid.

[0387] [ka] (Process 2) A 250 mL round-bottom flask was charged with methyl (2E)-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2-enoate (3.0 g, 13.81 mmol, 1.0 equiv.), MeOH / HO (80 / 40 mL), and NaOH (1.7 g, 41.43 mmol, 3.0 equiv.). The resulting solution was stirred for 12 hours at 25 °C. The resulting mixture was concentrated. The resulting solution was diluted with 40 mL of water. The resulting solution was extracted with 2 × 50 mL of DCM. The pH of the aqueous phase was adjusted to 5 with 2 M HCl. The solid was collected by filtration. This afforded 1.8 g (64%) of (2E)-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2-enoic acid as a pale yellow solid.

[0388] [ka] (Step 3) To an 8 mL vial purged and maintained under an inert atmosphere of nitrogen was added (E)-3-(2-oxoindolin-6-yl)acrylic acid (60.0 mg, 0.30 mmol, 1.0 equiv.) in DMF (4.0 mL). HATU (167.6 mg, 0.44 mmol, 1.50 equiv.), DIPEA (56.8 mg, 0.44 mmol, 1.50 equiv.), and 2,6-dimethylbenzenamine (39.5 mg, 0.33 mmol, 1.10 equiv.) were then added. The reaction mixture was stirred at room temperature for 2 hours. The crude mixture was then purified by preparative HPLC. This afforded 12 mg (13%) of (E)-N-(2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =307 [ka]

[0389] Example 20: (E)—N-(3-fluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide [ka] An 8 mL round-bottom flask was charged with 6-bromoindolin-2-one (100 mg, 0.47 mmol, 1.0 equiv.), N-(3-fluoro-2,6-dimethylphenyl)prop-2-enamide (prepared from 2,6-dimethyl-3-fluoroaniline and acryloyl chloride by the procedure described for Intermediate 1; 90.7 mg, 0.47 mmol, 1.0 equiv.), Pd(dppf)Cl (34.4 mg, 0.047 mmol, 0.10 equiv.), EtN (0.2 mL, 1.41 mmol, 3.0 equiv.), and DMF (4.0 mL). The resulting solution was stirred in an oil bath at 120 °C for 2 hours. The mixture was loaded onto a silica gel column using PE / THF (1 / 1). This gave 11 mg (7%) of (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide as a solid. LC-MS (ES, m / z): [M+H] + =325 [ka]

[0390] Example 21: (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide [ka] An 8 mL vial was charged with (£)-3-(2-oxoindolin-6-yl)acrylic acid (50.0 mg, 0.25 mmol, 1.0 equiv.), 2-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride (45.20 mg, 0.25 mmol, 1.0 equiv.), HATU (141.38 mg, 0.37 mmol, 1.50 equiv.), and DIPEA (95.41 mg, 0.74 mmol, 3.0 equiv.) in DMF (2.0 mL). The resulting solution was stirred for 2 hours at 20°C. The mixture was purified by flash preparative HPLC. This gave 27 mg (33%) of ((E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =333 [ka]

[0391] Example 22: (E)-3-(1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide [ka] (Process 1) A 100 mL sealed tube was charged with 4-bromo-1-fluoro-2-nitrobenzene (2.0 g, 9.09 mmol, 1.0 equiv.), EtOH (8.0 mL, 1.0 equiv.), and ethylamine (22.73 mL, 45.45 mmol, 5.0 equiv., 2M in ethanol). The resulting solution was stirred for 4 h at 50 °C. The resulting mixture was concentrated. The residue was diluted with 15 mL of HO and stirred for 15 min. The solid was collected by filtration. This afforded 2.2 g (98%) of 4-bromo-N-ethyl-2-nitroaniline as a red solid. LC-MS (ES, m / z): [M+H] + =245

[0392] [ka] (Process 2) A 50 mL round-bottom flask was charged with 4-bromo-N-ethyl-2-nitroaniline (2.0 g, 8.16 mmol, 1.0 equiv), acetone (16.0 mL), HO (2.0 mL), NHCl (4.37 g, 81.61 mmol, 10.0 equiv), and Zn (2.67 g, 40.80 mmol, 5.0 equiv). The resulting solution was stirred for 3 h at room temperature. The solid was removed by filtration. The filtrate was concentrated. The residue was diluted with 20 mL of HO and stirred for 15 min. The solid was collected by filtration. This afforded 1.1 g (63%) of 4-bromo-N 1 -ethylbenzene-1,2-diamine was obtained as a pale yellow solid. LC-MS (ES, m / z): [M+H] + =215

[0393] [ka] (Step 3) In a 50 mL three-neck round-bottom flask purged and maintained under an inert atmosphere of nitrogen, 4-bromo-N 1A mixture of 1,2-ethylbenzene-1,2-diamine (400.0 mg, 1.86 mmol, 1.0 equiv.), DCM (8.0 mL), and triphosgene (441.5 mg, 1.48 mmol, 0.80 equiv.) was added. Subsequently, EtN (0.8 mL, 5.58 mmol, 3.0 equiv.) was added at 0 °C. The resulting solution was stirred at room temperature for 3 h. The reaction was then quenched by the addition of 5 mL of water. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column using (THF / PE=18 / 82). This afforded 210 mg (47%) of 5-bromo-1-ethyl-3H-1,3-benzodiazol-2-one as a light brown solid. LC-MS (ES, m / z): [M+H] + =240

[0394] [ka] (Step 4) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(3-fluoro-2-methylphenyl)acrylamide (120.0 mg, 0.67 mmol, 1.0 equiv.), 5-bromo-1-ethyl-3H-1,3-benzodiazol-2-one (161.5 mg, 0.67 mmol, 1.0 equiv.), EtN (0.28 mL, 2.01 mmol, 3.0 equiv.), DMF (5.0 mL), and Pd(dppf)Cl (9.8 mg, 0.01 mmol, 0.02 equiv.). The resulting solution was stirred at 120 °C for 2 h. The crude mixture was purified by flash preparative HPLC. This gave 25 mg (11%) of (E)-3-(1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =340 [ka]

[0395] Example 23: (E)-3-(1-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide [ka] (Process 1) A 40 mL sealed tube was charged with 4-bromo-1-fluoro-2-nitrobenzene (2.0 g, 9.09 mmol, 1.0 equiv.), aminocyclopropane (2.60 g, 45.45 mmol, 5.0 equiv.), and EtOH (20.0 mL). The resulting solution was stirred for 4 hours at 50 °C. The resulting mixture was concentrated. The residual compound was diluted with 15 mL of HO and stirred for 15 minutes. The solid was collected by filtration. The solid was dried in an oven under reduced pressure. This afforded 2.4 g (96%) of 4-bromo-N-cyclopropyl-2-nitroaniline as a red solid. LC-MS (ES, m / z): [M+H] + =257

[0396] [ka] (Process 2) A 40 mL sealed tube was charged with 4-bromo-N-cyclopropyl-2-nitroaniline (2.0 g, 7.8 mmol, 1.0 equiv), acetone (16.0 mL), HO (2.0 mL), Zn (2.54 g, 38.89 mmol, 5.0 equiv), and NHCl (4.16 g, 77.8 mmol, 10.0 equiv). The resulting solution was stirred for 3 h at 25 °C. The solid was removed by filtration. The filtrate was concentrated. The residue was diluted with 20 mL of HO and stirred for 15 min. The solid was collected by filtration. This afforded 1 g (56%) of 4-bromo-N 1 -cyclopropylbenzene-1,2-diamine was obtained as a light brown solid. LC-MS (ES, m / z): [M+H] + =227

[0397] [ka] (Step 3) In a 50 mL three-neck round-bottom flask purged and maintained under an inert atmosphere of nitrogen, 4-bromo-N 1 A mixture of 1,2-cyclopropylbenzene-1,2-diamine (300.0 mg, 1.32 mmol, 1.0 equiv.), triphosgene (313.60 mg, 1.06 mmol, 0.80 equiv.), and DCM (6.0 mL) was added. This was followed by the addition of EtN (0.6 mL, 3.96 mmol, 3.0 equiv.) at 0° C. The resulting solution was stirred at room temperature for 3 hours. The reaction was then quenched by the addition of 5 mL of water. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. This afforded 180 mg (53%) of 5-bromo-1-cyclopropyl-3H-1,3-benzodiazol-2-one as a light brown solid. LC-MS (ES, m / z): [M+H] + =253

[0398] [ka] (Step 4) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(3-fluoro-2-methylphenyl)acrylamide (120.0 mg, 0.67 mmol, 1.0 equiv.), 5-bromo-1-cyclopropyl-3H-1,3-benzodiazol-2-one (169.5 mg, 0.67 mmol, 1.0 equiv.), EtN (0.2 mL, 1.34 mmol, 2.0 equiv.), DMF (5.0 mL), and Pd(dppf)Cl (9.80 mg, 0.013 mmol, 0.02 equiv.). The resulting solution was stirred at 120 °C for 2 h. The solids were removed by filtration. The crude mixture was purified by flash preparative HPLC. This gave 21 mg (9%) of (E)-3-(1-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-(3-fluoro-2-methylphenyl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =352 [ka]

[0399] Example 24: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide [ka] (Process 1) In a 500 mL three-necked round-bottom flask, acryloyl chloride (6.80 g, 75.08 mmol, 1.0 equiv.) was added to indanamine (10.0 g, 75.08 mmol, 1.0 equiv.) and EtN (20.9 mL, 150.16 mmol, 2.0 equiv.) in DCM (200.0 mL) at 0 °C. The resulting solution was stirred for 15 h at 25 °C. The reaction was then quenched by the addition of 100 mL of water / ice. The resulting solution was extracted with 2 × 100 mL of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was subjected to a silica gel column using EtOAc / PE (10 / 1) to give 7.3 g (52%) of N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide as a white solid. LC-MS (ES, m / z): [M+H] + =188

[0400] [ka] An 8 mL vial was charged with N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (100.0 mg, 0.53 mmol, 1.0 equiv.), 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (121.27 mg, 0.53 mmol, 1.0 equiv.), Pd(dppf)Cl (39.08 mg, 0.05 mmol, 0.10 equiv.), and EtN (0.22 mL, 1.60 mmol, 3.0 equiv.) in DMF (4.0 mL, 25.844 mmol). The resulting solution was stirred at 120 °C in an oil bath for 15 h. The reaction mixture was cooled. The crude mixture was purified by flash preparative HPLC. This gave 7.8 mg (4%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =334 [ka]

[0401] Example 25: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv.), 6-bromo-3-methyl-1H-indazole (135.27 mg, 0.64 mmol, 1.20 equiv.), Pd(dppf)Cl.CHCl (87.23 mg, 0.11 mmol, 0.20 equiv.), DMF (4.0 mL), and EtN (0.22 mL, 1.60 mmol, 3.0 equiv.). The resulting solution was stirred at 120 °C overnight. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This gave 64 mg (38%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =318 [ka]

[0402] Example 26: (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv.), 6-bromo-1H-indazole-3-carbonitrile (142.30 mg, 0.64 mmol, 1.20 equiv.), Pd(dppf)Cl.CHCl (43.61 mg, 0.05 mmol, 0.10 equiv.), DMF (4 mL), and EtN (0.22 mL, 1.60 mmol, 3.0 equiv.). The resulting solution was stirred at 120 °C overnight. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This gave 24 mg (14%) of (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =329 [ka]

[0403] Example 27: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv.), 5-bromo-6-fluoro-3H-1,2,3-benzotriazole (138.44 mg, 0.64 mmol, 1.20 equiv.), Pd(dppf)Cl·CHCl (43.61 mg, 0.05 mmol, 0.10 equiv.), DMF (4.0 mL), and EtN (0.22 mL, 1.60 mmol, 3.0 equiv.). The resulting solution was stirred at 140 °C overnight. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This gave 6.3 mg (4%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =323 [ka]

[0404] Example 28: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(3-(trifluoromethyl)-1H-indazol-6-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv.), 6-bromo-3-(trifluoromethyl)-1H-indazole (169.9 mg, 0.64 mmol, 1.20 equiv.), Pd(dppf)Cl·CHCl (43.61 mg, 0.05 mmol, 0.10 equiv.), DMF (4.0 mL), and EtN (0.22 mL, 1.60 mmol, 3.0 equiv.). The resulting solution was stirred at 120 °C overnight. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This gave 80 mg (40%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-(trifluoromethyl)-1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =372 [ka]

[0405] Example 29: (E)—N-(2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide [ka] An 8 mL vial purged and maintained under an inert atmosphere of nitrogen was charged with N-(2,6-dimethylphenyl)prop-2-enamide (50.0 mg, 0.29 mmol, 1.0 equiv. (prepared similarly to Intermediate 1 from acroyl chloride and 2,6-dimethylaniline), DMF (4.0 mL), 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (71.3 mg, 0.31 mmol, 1.10 equiv.), EtN (0.12 mL, 0.86 mmol, 3.0 equiv.), and Pd(dppf)Cl.CHCl (11.65 mg, 0.014 mmol, 0.05 equiv.). The resulting solution was stirred at 120 °C for 5 h. The reaction mixture was cooled to room temperature. The crude mixture was loaded onto a silica gel column using 1 / 1 EtOAc / PE. This gave 20 mg (22%) of (E)-N-(2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =322 [ka]

[0406] Example 30: (E)—N-(3-fluoro-2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide [ka] (Process 1) A 40 mL vial was charged with 1-bromo-4-fluoro-3-methyl-2-nitrobenzene (500.0 mg, 2.14 mmol, 1.0 equiv.), trimethyl-1,3,5,2,4,6-trioxatriborinane (268.20 mg, 2.13 mmol, 1.0 equiv.), KCO (590.6 mg, 4.27 mmol, 2.0 equiv.), and Pd(dppf)Cl (156.3 mg, 0.21 mmol, 0.10 equiv.) in dioxane (10.0 mL) and HO (2.0 mL). The resulting solution was stirred at 110 °C in an oil bath for 1 h. The crude mixture was applied to a silica gel column using EtOAc / PE (1 / 10). This afforded 250 mg (69%) of 1-fluoro-2,4-dimethyl-3-nitrobenzene as a solid.

[0407] [ka] (Process 2) A 40 mL vial was charged with 1-bromo-4-fluoro-3-methyl-2-nitrobenzene (0.50 g, 2.14 mmol, 1.0 equiv.) in AcOH (10.0 mL), and Fe (596.6 mg, 10.68 mmol, 5.0 equiv.) was added. The resulting solution was stirred for 1 h at room temperature. The solid was filtered off. The resulting solution was diluted with 20 mL of water and extracted with 40 mL of EtOAc. The organic layer was dried and concentrated. This afforded 250 mg (84%) of 3-fluoro-2,6-dimethylaniline as a solid. LC-MS (ES, m / z): [M+H] + =140

[0408] [ka] (Step 3) In an 8 mL vial, 6-bromo-3-fluoro-2-methylaniline (100.0 mg, 0.49 mmol, 1.0 equiv.) and EtN (0.2 mL, 1.47 mmol, 3.0 equiv.) were placed in DCM (4 mL), and acryloyl chloride (53.2 mg, 0.59 mmol, 1.20 equiv.) was added. The resulting solution was stirred for 1 h at 0 °C. The resulting mixture was concentrated in vacuo. The residue was purified by flash chromatography (PE / EA = 10 / 1). This afforded 120 mg (126.72%) of N-(3-fluoro-2,6-dimethylphenyl)prop-2-enamide as a white solid. LC-MS (ES, m / z): [M+H] + =194

[0409] [ka] (Step 4) An 8 mL round-bottom flask was charged with 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (100 mg, 0.44 mmol, 1.0 equiv.), N-(3-fluoro-2,6-dimethylphenyl)prop-2-enamide (85.1 mg, 0.44 mmol, 1.0 equiv.), Pd(dppf)Cl (32.2 mg, 0.044 mmol, 0.10 equiv.), EtN (0.18 mL, 1.32 mmol, 3.0 equiv.), and DMF (4.0 mL). The resulting solution was stirred in an oil bath at 120 °C for 2 hours. The mixture was loaded onto a silica gel column using PE / THF (1 / 1). This gave 45 mg (30%) of (E)-N-(3-fluoro-2,6-dimethylphenyl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide as a solid. LC-MS (ES, m / z): [M+H] + =340 [ka]

[0410] Example 31: (E)-N-(2,6-dimethylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] A 50 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2,6-dimethylaniline (160.0 mg, 1.32 mmol, 1.0 equiv.), DCM (10.0 mL), and EtN (0.55 mL, 3.96 mmol, 3.0 equiv.). Subsequently, acryloyl chloride (143.40 mg, 1.58 mmol, 1.20 equiv.) was added dropwise at 0°C with stirring. The resulting solution was stirred at 25°C for 3 hours. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 2 × 10 mL of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column using EtOAc / PE (1 / 3). This afforded 150 mg (65%) of N-(2,6-dimethylphenyl)prop-2-enamide as a white solid. LC-MS (ES, m / z): [M+H] + =176

[0411] [ka] An 8 mL vial purged and maintained under an inert atmosphere of nitrogen was charged with N-(2,6-dimethylphenyl)prop-2-enamide (50.0 mg, 0.29 mmol, 1.0 equiv.), DMF (5.0 mL), 6-bromo-3-methyl-1H-indazole (66.3 mg, 0.31 mmol, 1.10 equiv.), EtN (0.12 mL, 0.86 mmol, 3.0 equiv.), and Pd(dppf)Cl·CHCl (11.7 mg, 0.014 mmol, 0.05 equiv.). The resulting solution was stirred at 120 °C for 5 h. The reaction mixture was cooled to 25 °C. The crude mixture was purified by flash preparative HPLC. This gave 30 mg (34%) of (E)-N-(2,6-dimethylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =306 [ka]

[0412] Example 32: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(3-ethyl-1H-indazol-6-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv.), 6-bromo-3-ethyl-1H-indazole (144.3 mg, 0.64 mmol, 1.20 equiv.), Pd(dppf)Cl·CHCl (43.6 mg, 0.05 mmol, 0.10 equiv.), DMF (4.0 mL), and EtN (0.22 mL, 1.60 mmol, 3.0 equiv.). The resulting solution was stirred overnight at 120 °C. The reaction mixture was cooled to room temperature. The crude product was purified by preparative HPLC. This gave 86 mg (49%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-ethyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC MS (ES, m / z): [M+H] + =332 [ka]

[0413] Example 33: (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide [ka] An 8 mL vial was charged with N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (Example 24, Step 1, 100.0 mg, 0.53 mmol, 1.0 equiv), 6-bromo-3-cyclopropyl-1H-indazole (126.6 mg, 0.53 mmol, 1.0 equiv), Pd(dppf)Cl (39.1 mg, 0.05 mmol, 0.10 equiv), EtN (0.22 mL, 1.60 mmol, 3.0 equiv), and DMF (4 mL). The resulting solution was stirred in an oil bath at 120 °C for 2 hours. The reaction mixture was cooled. The mixture was loaded onto a silica gel column using PE / THF (1 / 1). This gave 15 mg (8%) of (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-(2,3-dihydro-1H-inden-1-yl)acrylamide as a solid. LC MS (ES, m / z): [M+H] + =344 [ka]

[0414] Example 34: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-3-methyl-1H-indazol-6-yl)acrylamide [ka] An 8 mL vial was charged with 6-bromo-4-fluoro-3-methyl-1H-indazole (Example 24, Step 1, 100.0 mg, 0.44 mmol, 1.0 equiv.), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (81.8 mg, 0.44 mmol, 1.0 equiv.), Pd(dppf)Cl (31.9 mg, 0.04 mmol, 0.10 equiv.), EtN (0.18 mL, 1.31 mmol, 3.0 equiv.), and DMF (4.0 mL). The resulting solution was stirred in an oil bath at 120° C. for 2 hours. The reaction mixture was cooled. The residue was applied to a silica gel column using PE / THF (1 / 1). This gave 17 mg (12%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-3-methyl-1H-indazol-6-yl)acrylamide as a solid. LC MS (ES, m / z): [M+H] + =336 [ka]

[0415] Example 35: (E)—N-(3,5-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide [ka] (Process 1) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 3,5-difluoroaniline (1.0 g, 7.8 mmol, 1.0 equiv.), CHCN (30 mL), and NCS (1.1 g, 8.16 mmol, 1.05 equiv.). The resulting solution was stirred at 80 °C for 5 h. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The residue was applied to a silica gel column using THF:PE (1:4 to 1:1). This afforded 500 mg (39%) of 4-chloro-3,5-difluoroaniline as a gray solid.

[0416] [ka] (Process 2) A 50 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 4-bromo-3,5-difluoroaniline (500.0 mg, 2.40 mmol, 1.0 equiv.), CHCN (20.0 mL), and NBS (1.3 g, 7.21 mmol, 3.0 equiv.). The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using THF:PE (1:5 to 1:3). This afforded 700 mg (91%) of 2,6-dibromo-4-chloro-3,5-difluoroaniline as a yellow solid.

[0417] [ka] (Step 3) A 250 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2,6-dibromo-4-chloro-3,5-difluoroaniline (3.0 g, 9.36 mmol, 1.0 equiv.), Pd(dppf)Cl.CHCl (0.76 g, 0.94 mmol, 0.10 equiv.), dioxane (60.0 mL), CsCO (12.20 g, 37.46 mmol, 4.0 equiv.), and trimethyl-1,3,5,2,4,6-trioxatriborinane (8.23 g, 32.77 mmol, 3.50 equiv., 50%). The resulting solution was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The crude mixture was purified by preparative HPLC. This gave 600 mg (33%) of 4-chloro-3,5-difluoro-2,6-dimethylaniline as an off-white solid.

[0418] [ka] (Step 4) A 100 mL pressure tank reactor was charged with 4-chloro-3,5-difluoro-2,6-dimethylaniline (280.0 mg, 1.46 mmol, 1.0 equiv), EtOH (20.0 mL), HCl (1.0 mL), and Pd / C (77.76 mg). The flask was evacuated and flushed with nitrogen three times, followed by hydrogen. The resulting solution was stirred at 70 °C under an atmosphere of hydrogen (30 atm) overnight. The reaction mixture was cooled to room temperature. The solids were removed by filtration, and the resulting mixture was concentrated. This yielded 220 mg (crude) of 3,5-difluoro-2,6-dimethylaniline hydrochloride as an off-white solid.

[0419] [ka] (Step 5) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 3,5-difluoro-2,6-dimethylaniline hydrochloride (220.0 mg, 1.14 mmol, 1.0 equiv.), DCM (20.0 mL), and EtN (0.48 mL, 3.41 mmol, 3.0 equiv.). Subsequently, acryloyl chloride (123.4 mg, 1.36 mmol, 1.20 equiv.) was added dropwise with stirring at 0 °C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using THF:PE (1:5 to 1:3). This afforded 160 mg (67%) of N-(3,5-difluoro-2,6-dimethylphenyl)prop-2-enamide as an off-white solid.

[0420] [ka] (Step 6) In an 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen, N-(3,5-difluoro-2,6-dimethylphenyl)prop-2-enamide (160.0 mg, 0.76 mmol, 1.0 equiv.), 6-bromo-1,3-dihydroindol-2-one (192.8 mg, 0.91 mmol, 1.20 equiv.), Pd(dppf)Cl·CHCl (61.7 mg, 0.076 mmol, 0.10 equiv.), DMF (5.0 mL), and EtN (0.32 mL, 2.27 mmol, 3.0 equiv.) were added. The resulting solution was stirred at 100 °C for 2 h, and the reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This gave 14.8 mg (6%) of (E)-N-(3,5-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide as a solid. LC MS (ES, m / z): [M+H] + =343 [ka]

[0421] Example 36: (E)—N-(3,4-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide [ka] (Process 1) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with benzeneamine, 3,4-difluoro- (1.0 g, 7.75 mmol, 1.0 equiv.), CHCN (30.0 mL), and NBS (2.9 g, 16.27 mmol, 2.10 equiv.). The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using THF:PE (1:5 to 1:3). This afforded 1.4 g (63%) of 2,6-dibromo-3,4-difluoroaniline as a dark brown solid.

[0422] [ka] (Process 2) A 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2,6-dibromo-3,4-difluoroaniline (1.20 g, 4.18 mmol, 1.0 equiv.), Pd(dppf)Cl2·CHCl2 (340.7 mg, 0.42 mmol, 0.10 equiv.), CsCO3 (4.8 g, 14.64 mmol, 3.50 equiv.), dioxane (50.0 mL), and trimethyl-1,3,5,2,4,6-trioxatriborinane (3.2 g, 12.55 mmol, 3.0 equiv., 50%). The resulting solution was stirred overnight at 100 °C. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The crude mixture was purified by preparative HPLC. This gave 350 mg (53%) of 3,4-difluoro-2,6-dimethylaniline as an off-white solid.

[0423] [ka] (Step 3) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 3,4-difluoro-2,6-dimethylaniline (210.0 mg, 1.34 mmol, 1.0 equiv.), DCM (20 mL), and EtN (0.28 mL, 2.0 mmol, 1.50 equiv.). Subsequently, acryloyl chloride (145.13 mg, 1.60 mmol, 1.20 equiv.) was added dropwise at 0 °C with stirring. The resulting solution was stirred at room temperature for 2 h. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using THF:PE (1:5 to 1:3). This afforded 180 mg (64%) of N-(3,4-difluoro-2,6-dimethylphenyl)prop-2-enamide as an off-white solid.

[0424] [ka] (Step 4) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(3,4-difluoro-2,6-dimethylphenyl)prop-2-enamide (100.0 mg, 0.47 mmol, 1.0 equiv.), 6-bromo-1,3-dihydroindol-2-one (120.47 mg, 0.57 mmol, 1.20 equiv.), Pd(dppf)Cl·CHCl (38.57 mg, 0.05 mmol, 0.10 equiv.), DMF (4.0 mL), and EtN (0.2 mL, 1.42 mmol, 3.0 equiv.). The resulting solution was stirred at 120 °C overnight. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This gave 11.3 mg (7%) of (E)-N-(3,4-difluoro-2,6-dimethylphenyl)-3-(2-oxoindolin-6-yl)acrylamide as an off-white solid. LCMS (ES, m / z): [M+H] + =343 [ka]

[0425] Example 37: (E)—N-(3-fluoro-2-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(3-fluoro-2-methylphenyl)acrylamide (Intermediate 1, 110.0 mg, 0.61 mmol, 1.0 equiv.), 6-bromo-3-methyl-1H-indazole (155.47 mg, 0.74 mmol, 1.20 equiv.), Pd(dppf)Cl.CHCl (100.01 mg, 0.12 mmol, 0.20 equiv.), DMF (4.0 mL), and EtN (0.26 mL, 1.84 mmol, 3.0 equiv.). The resulting solution was stirred at 120 °C overnight. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This gave 26 mg (14%) of (E)-N-(3-fluoro-2-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC MS (ES, m / z): [M+H] + =310 [ka]

[0426] Example 38: (E)-3-(3-methyl-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide [ka] An 8 mL vial was charged with 6-bromo-3-methyl-1H-indazole (40.0 mg, 0.19 mmol, 1.0 equiv.), N-(2-methyl-2,3-dihydro-1H-inden-1-yl)prop-2-enamide (prepared using 2-methylindanamine according to Example 24, Step 1, 38.14 mg, 0.19 mmol, 1.0 equiv.), Pd(dppf)Cl (13.87 mg, 0.02 mmol, 0.10 equiv.), and EtN (0.8 mL, 0.57 mmol, 3.0 equiv.) in DMF (2.0 mL). The resulting solution was stirred at 120 °C in an oil bath for 2 hours. The reaction solution was cooled to room temperature. The crude mixture was purified by flash preparative HPLC. This gave 29 mg (44%) of (E)-3-(3-methyl-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC MS (ES, m / z): [M+H] + =332 [ka]

[0427] Example 39: (E)-3-(3-methyl-1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide [ka] (Process 1) A 50 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 1-methylindazol-7-amine (400.0 mg, 2.71 mmol, 1.0 equiv.), DCM (10.0 mL), and EtN (0.6 mL, 4.07 mmol, 1.50 equiv.). Subsequently, acryloyl chloride (246 mg, 2.71 mmol, 1.0 equiv.) was added at −30° C. The resulting solution was stirred for 10 minutes at −30° C. The reaction was then quenched by the addition of 8 mL of water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was loaded onto a silica gel column using EtOAc / PE (15:85). This afforded 120 mg (21%) of N-(1-methylindazol-7-yl)prop-2-enamide as an off-white solid. LC MS (ES, m / z): [M+H] + =202

[0428] [ka] (Process 2) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(1-methylindazol-7-yl)prop-2-enamide (100.0 mg, 0.49 mmol, 1.0 equiv.), 6-bromo-3-methyl-1H-indazole (104.8 mg, 0.49 mmol, 1.0 equiv.), DMF (4.0 mL), EtN (0.14 mL, 0.99 mmol, 2.0 equiv.), and Pd(dppf)Cl CHCl (41 mg, 0.05 mmol, 0.10 equiv.). The resulting solution was stirred at 120 °C for 2 h. The crude mixture was purified by flash preparative HPLC. This gave 33 mg (20%) of (E)-3-(3-methyl-1H-indazol-6-yl)-N-(1-methyl-1H-indazol-7-yl)acrylamide as an off-white solid. LC MS (ES, m / z): [M+H] + =332 [ka]

[0429] Example 40: (E)—N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] (Process 1) A 40 mL sealed tube was charged with 5-fluoro-2,3-dihydroinden-1-one (800.0 mg, 5.33 mmol, 1.0 equiv), NaOAc (874.14 mg, 10.66 mmol, 2.0 equiv), MeOH (15.0 mL), and hydroxylamine hydrochloride (1.10 g, 15.98 mmol, 3.0 equiv). The resulting solution was stirred at 60 °C for 16 h. The resulting mixture was concentrated. The crude product was diluted with EtOAc (30.0 mL) and HO (15.0 mL). The organic phase was washed with 20 mL of HO. The organic layer was concentrated. This afforded 810 mg (92%) of N-[5-fluoro-2,3-dihydroinden-1-ylidene]hydroxylamine as an off-white solid. LC MS (ES, m / z): [M+H] + =166

[0430] [ka] (Process 2) A 50 mL round-bottom flask was charged with N-[5-fluoro-2,3-dihydroinden-1-ylidene]hydroxylamine (810.0 mg, 4.90 mmol, 1.0 equiv) and MeOH (20.0 mL). Subsequently, Pd / C (104.38 mg) was added under H2. The resulting solution was stirred at room temperature for 16 hours. The solid was filtered off and washed with 10 mL of MeOH. The combined solution was concentrated. This afforded 530 mg (71%) of 5-fluoro-2,3-dihydro-1H-inden-1-amine as an off-white solid. LC MS (ES, m / z): [M+H] + =152

[0431] [ka] (Step 3) A 25 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 5-fluoro-2,3-dihydro-1H-inden-1-amine (210.0 mg, 1.38 mmol, 1.0 equiv.), DCM (5.0 mL), and EtN (0.4 mL, 2.77 mmol, 2.0 equiv.). Subsequently, acryloyl chloride (188.58 mg, 2.08 mmol, 1.50 equiv.) was added at −30° C. The resulting solution was stirred for 10 minutes at −30° C. The reaction was then quenched by the addition of 5 mL of water. The organic layer was separated and concentrated. The residue was loaded onto a silica gel column using EtOAc / PE (80:20). This gave 200 mg (70%) of N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)prop-2-enamide as an off-white solid. LC MS (ES, m / z): [M+H] + =206

[0432] [ka] (Step 4) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)acrylamide (100.0 mg, 0.48 mmol, 1.0 equiv.), 6-bromo-3-methyl-1H-indazole (102.8 mg, 0.48 mmol, 1.0 equiv.), EtN (0.14 mL, 0.97 mmol, 2.0 equiv.), DMF (5.0 mL), and Pd(dppf)Cl·CHCl (39.69 mg, 0.05 mmol, 0.10 equiv.). The resulting solution was stirred at 120 °C for 2 h. The reaction solution was cooled to room temperature. The crude mixture was purified by flash preparative HPLC. This gave 34 mg (20%) of (E)-N-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as a white solid. LC MS (ES, m / z): [M+H] + =336 [ka]

[0433] Example 41: (E)-N-(4-fluoro-3-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] (Process 1) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 4-fluoro-3-methylaniline (600.0 mg, 4.79 mmol, 1.0 equiv.), DCM (20.0 mL), and EtN (2.0 mL, 14.38 mmol, 3.0 equiv.). Subsequently, acryloyl chloride (520.73 mg, 5.75 mmol, 1.20 equiv.) was added dropwise at 0 °C with stirring. The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using THF:PE (1:5 to 1:3). This afforded 400 mg (56%) of N-(4-fluoro-3-methylphenyl)prop-2-enamide as a pale yellow solid.

[0434] [ka] (Process 2) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(4-fluoro-3-methylphenyl)prop-2-enamide (110.0 mg, 0.61 mmol, 1.0 equiv.), 6-bromo-3-methyl-1H-indazole (155.47 mg, 0.74 mmol, 1.20 equiv.), Pd(dppf)Cl.CHCl (100.01 mg, 0.12 mmol, 0.20 equiv.), DMF (4.0 mL), and EtN (0.26 mL, 1.84 mmol, 3.0 equiv.). The resulting solution was stirred at 120 °C overnight. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This gave 20.4 mg (11%) of (E)-N-(4-fluoro-3-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC MS (ES, m / z): [M+H] + =310 [ka]

[0435] Example 42: (E)—N-(3-fluoro-4-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] (Process 1) A 100 mL three-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with 3-fluoro-4-methylaniline (550.0 mg, 4.40 mmol, 1.0 equiv.), DCM (20.0 mL), and EtN (1.2 mL, 8.79 mmol, 2.0 equiv.). Subsequently, acryloyl chloride (477.34 mg, 5.27 mmol, 1.20 equiv.) was added dropwise at 0 °C with stirring. The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using THF:PE (1:5 to 1:3). This afforded 450 mg (57%) of N-(3-fluoro-4-methylphenyl)prop-2-enamide as an off-white solid.

[0436] [ka] (Process 2) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-(3-fluoro-4-methylphenyl)prop-2-enamide (110.0 mg, 0.61 mmol, 1.0 equiv.), 6-bromo-3-methyl-1H-indazole (155.5 mg, 0.74 mmol, 1.20 equiv.), Pd(dppf)Cl.CHCl (100.0 mg, 0.12 mmol, 0.20 equiv.), DMF (4.0 mL), and EtN (0.26 mL, 1.84 mmol, 3.0 equiv.). The resulting solution was stirred at 120 °C overnight. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This gave 35.8 mg (19%) of (E)-N-(3-fluoro-4-methylphenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC MS (ES, m / z): [M+H] + =310 [ka]

[0437] Example 43: Racemic (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide [ka] (Process 1) A 25 mL three-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen was charged with racemic trans-(1R,2R)-2-methylcyclohexan-1-amine hydrochloride (300.0 mg, 2.0 mmol, 1.0 equiv.), DCM (6.0 mL), and EtN (0.84 mL, 6.01 mmol, 3.0 equiv.). Subsequently, acryloyl chloride (181.43 mg, 2.0 mmol, 1.0 equiv.) was added at 0°C. The resulting solution was stirred at room temperature for 40 minutes. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was diluted with 10 mL of DCM. The resulting mixture was washed with 10 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (22:78). This gave 200 mg (60%) of N-[(1R,2R)-2-methylcyclohexyl]prop-2-enamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =168

[0438] [ka] (Process 2) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with DMF (4.0 mL), N-[(1R,2R)-2-methylcyclohexyl]prop-2-enamide (100.0 mg, 0.60 mmol, 1.0 equiv.), 6-bromo-3-methyl-1H-indazole (126.0 mg, 0.60 mmol, 1.0 equiv.), EtN (0.25 mL, 1.79 mmol, 3.0 equiv.), and Pd(dppf)Cl CHCl (48.71 mg, 0.06 mmol, 0.10 equiv.). The resulting solution was stirred at 120 °C for 2 h. The crude mixture was purified by flash preparative HPLC. This gave 41 mg (23%) of racemic (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1R,2R)-2-methylcyclohexyl)acrylamide as an off-white solid. LC MS (ES, m / z): [M+H] + =298 [ka]

[0439] Example 44: (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide [ka] An 8 mL vial was charged with 6-bromo-1H-indazole-3-carbonitrile (40.0 mg, 0.18 mmol, 1.0 equiv.), N-(2-methyl-2,3-dihydro-1H-inden-1-yl)prop-2-enamide (prepared using 2-methylindanamine according to Example 24, Step 1, 36.26 mg, 0.18 mmol, 1.0 equiv.), Pd(dppf)Cl (13.18 mg, 0.018 mmol, 0.10 equiv.), and EtN (0.075 mL, 0.54 mmol, 3.0 equiv.) in DMF (2.0 mL). The resulting solution was stirred at 120 °C in an oil bath for 2 hours. The mixture was cooled to room temperature. The crude mixture was purified by flash preparative HPLC. This gave 16 mg (26%) of (E)-3-(3-cyano-1H-indazol-6-yl)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC MS (ES, m / z): [M+H] + =343 [ka]

[0440] Example 45: (E)—N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)acrylamide [ka] An 8 mL vial was charged with 5-bromo-1-methyl-3H-1,3-benzodiazol-2-one (50.0 mg, 0.22 mmol, 1.0 equiv.), N-(2-methyl-2,3-dihydro-1H-inden-1-yl)prop-2-enamide (prepared using 2-methylindanamine according to Example 24, Step 1, 44.3 mg, 0.22 mmol, 1.0 equiv.), Pd(dppf)Cl (16.1 mg, 0.022 mmol, 0.10 equiv.), and EtN (0.092 mL, 0.66 mmol, 3.0 equiv.) in DMF (2.0 mL). The resulting solution was stirred at 120 °C in an oil bath for 2 hours. The reaction solution was cooled to room temperature. The crude mixture was purified by flash preparative HPLC. This gave 29 mg (38%) of (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 as an off-white solid. LC MS (ES, m / z): [M+H] + =348 [ka]

[0441] Example 46: (E)—N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] An 8 mL vial was charged with 2-benzoxazolinone, 5-bromo- (50.0 mg, 0.23 mmol, 1.0 equiv.), N-(2-methyl-2,3-dihydro-1H-inden-1-yl)prop-2-enamide (prepared using 2-methylindanamine according to Example 24, Step 1, 47.0 mg, 0.23 mmol, 1.0 equiv.), Pd(dppf)Cl (17.1 mg, 0.023 mmol, 0.10 equiv.), and EtN (0.098 mL, 0.70 mmol, 3.0 equiv.) in DMF (2.0 mL). The resulting solution was stirred in an oil bath at 120 °C for 2 hours. The reaction solution was cooled to room temperature. The crude mixture was purified by flash preparative HPLC. This gave 29 mg (37%) of (E)-N-(2-methyl-2,3-dihydro-1H-inden-1-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as an off-white solid. LCMS (ES, m / z): [M+H] + =335 [ka]

[0442] Example 47: (Z)-2-fluoro-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide [ka] (Process 1) A 40 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with DMF (20.0 mL), 6-bromo-1,3-dihydroindol-2-one (1.0 g, 4.72 mmol, 1.0 equiv), methyl 2-fluoroacrylate (0.59 g, 5.66 mmol, 1.20 equiv), Pd(dppf)Cl.CHCl (77.0 mg, 0.094 mmol, 0.02 equiv), and EtN (1.3 mL, 9.43 mmol, 2.0 equiv). The resulting solution was stirred at 110 °C for 2 h. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using (25 / 75) elution. This gave 420 mg (37%) of methyl 2-fluoro-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2-enoate as a yellow solid. LC-MS (ES, m / z): [MH] + =234

[0443] [ka] (Process 2) An 8 mL sealed tube was charged with methyl 2-fluoro-3-(2-oxo-1,3-dihydroindol-6-yl)prop-2-enoate (150.0 mg, 0.64 mmol, 1.0 equiv.), 3-fluoro-2-methyl-aniline (239.42 mg, 1.91 mmol, 3.0 equiv.), and THF (3.0 mL). Subsequently, LiHMDS (1.92 mL, 1.92 mmol, 3.0 equiv.) was added at 0 °C. The resulting solution was stirred at room temperature for 30 minutes. The reaction was then quenched by the addition of 15 mL of HO. The resulting solution was extracted with 2 × 10 mL of EtOAc. The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash preparative HPLC. This gave 28 mg (13%) of (Z)-2-fluoro-N-(3-fluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide as a white solid. LC MS (ES, m / z): [M+H] + =329 [ka]

[0444] Example 48: (E)-N-(3-chloro-2-methylphenyl)-N-methyl-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was charged with (E)-methyl 3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate (prepared by Example 11, Step 2, 30.0 mg, 0.14 mmol, 1.0 equiv.) in THF (2.0 mL). 3-Chloro-N,2-dimethylbenzenamine (27.60 mg, 0.18 mmol, 1.30 equiv.) was then added. The reaction mixture was cooled to 0° C. 1 M LiHMDS (0.68 mL, 0.68 mmol, 5.0 equiv.) was then added. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was quenched with 1 mL of water, extracted with 2×5 mL of EtOAc, and the organic layer was concentrated in vacuo to give the crude product. The crude product was then purified by preparative HPLC. This gave 9.6 mg (21%) of (£)-N-(3-chloro-2-methylphenyl)-N-methyl-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =343

[0445] Example 49: (E)—N-(2-methylcyclopentyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained with an inert atmosphere of nitrogen was charged with (E)-methyl 3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate (prepared by Example 11, Step 2, 30.0 mg, 0.14 mmol, 1.0 equiv.) in THF (2.0 mL). 2-Methylcyclopentanamine (17.6 mg, 0.18 mmol, 1.30 equiv.) was then added. The reaction mixture was cooled to 0° C. 1 M LiHMDS (0.68 mL, 0.68 mmol, 5.0 equiv.) was then added. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was quenched with 1 mL of water, extracted with 2×5 mL of EtOAc, and the organic layer was concentrated in vacuo to give the crude product. The crude product was then purified by preparative HPLC. This gave 19 mg (48%) of (E)-N-(2-methylcyclopentyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =287

[0446] Example 50: (E)—N-(3-fluoro-2-(methoxymethyl)phenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] (Process 1) A 250 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with THF (50.0 mL) and 2-fluoro-6-nitrobenzoic acid (2.0 g, 10.80 mmol, 1.0 equiv.). Subsequently, borane (32.41 mL, 32.41 mmol, 3.0 equiv., 1 M / THF) was added at 0° C. The resulting solution was stirred for 10 hours at 50° C. The reaction was then quenched by the addition of 20 mL of 3 M HCl. The resulting solution was diluted with 50 mL of EtOAc. The organic layer was washed with 2×30 mL of brine. The solution was dried over sodium sulfate and evaporated under reduced pressure. This afforded 1.3 g (70%) of (2-fluoro-6-nitrophenyl)methanol as a light brown solid.

[0447] [ka] (Process 2) A 40 mL sealed tube was charged with (2-fluoro-6-nitrophenyl)methanol (1.30 g, 7.59 mmol, 1.0 equiv.), DMF (20.0 mL), and methyl iodide (5.39 g, 37.98 mmol, 5.0 equiv.). Subsequently, Cs2CO3 (3.71 g, 11.39 mmol, 1.50 equiv.) was added at 0 °C. The resulting solution was stirred at 50 °C for 5 h. The solid was filtered off. The filtrate solution was diluted with 100 mL of EtOAc. The resulting mixture was washed with 3 × 50 mL of H2O and 50 mL of brine. The organic layer was dried over sodium sulfate and evaporated. The crude product was purified by flash preparative HPLC. This afforded 0.91 g (64%) of 1-fluoro-2-(methoxymethyl)-3-nitrobenzene as a yellow oil.

[0448] [ka] (Step 3) A 40 mL sealed tube was charged with 1-fluoro-2-(methoxymethyl)-3-nitrobenzene (0.70 g, 3.78 mmol, 1.0 equiv.), MeOH (20.0 mL), HO (3.0 mL), and NHCl (1.21 g, 22.68 mmol, 6.0 equiv.). Zn (1.24 g, 18.90 mmol, 5.0 equiv.) was then added at 10 °C. The resulting solution was stirred at 25 °C for 1 h. The solid was filtered off. The resulting solution was diluted with 20 mL of DCM. The mixture was dried over anhydrous sodium sulfate and concentrated (cold). This afforded 0.21 g (35%) of 3-fluoro-2-(methoxymethyl)aniline as a light brown oil (this amine was unstable and was used immediately in the next step). LC-MS (ES, m / z): [M+H] + =156

[0449] [ka] (Step 4) An 8 mL sealed tube was charged with 3-fluoro-2-(methoxymethyl)aniline (200.0 mg, 1.28 mmol, 1.0 equiv.), DCM (4.0 mL), and EtN (0.36 mL, 2.57 mmol, 2.0 equiv.). Subsequently, acryloyl chloride (116.6 mg, 1.28 mmol, 1.0 equiv.) was added at 0° C. The resulting solution was stirred for 0.5 h at 0° C. The reaction was then quenched by the addition of 2 mL of water. The resulting mixture was washed with 2 mL of brine. The organic layer was dried over sodium sulfate and concentrated. This afforded 160 mg (59%) of N-[3-fluoro-2-(methoxymethyl)phenyl]prop-2-enamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =210

[0450] [ka] (Step 5) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-[3-fluoro-2-(methoxymethyl)phenyl]prop-2-enamide (100.0 mg, 0.47 mmol, 1.0 equiv.), DMF (4.0 mL), 6-bromo-3-methyl-1H-indazole (100.88 mg, 0.47 mmol, 1.0 equiv.), EtN (0.2 mL, 1.43 mmol, 3.0 equiv.), and Pd(dppf)Cl·CHCl (38.94 mg, 0.048 mmol, 0.10 equiv.). The resulting solution was stirred at 120 °C for 2 h. The crude mixture was purified by flash preparative HPLC. This gave 71 mg (43%) of (E)-N-(3-fluoro-2-(methoxymethyl)phenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =340 [ka]

[0451] Example 51: (E)-3-(3-cyano-1H-indazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide [ka] (Process 1) A 40 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with 6-bromo-1H-indazole-3-carbonitrile (220.0 mg, 0.99 mmol, 1.0 equiv), dihydropyran (416.7 mg, 4.95 mmol, 5.0 equiv), DCM (10.0 mL), and TsOH (34.1 mg, 0.20 mmol, 0.20 equiv). The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using THF:PE (1:20 to 1:8). This afforded 300 mg (99%) of 6-bromo-1-(oxan-2-yl)indazole-3-carbonitrile as an off-white solid.

[0452] [ka] (Process 2) In an 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen, N-(3-fluoro-2-methylphenyl)acrylamide (150.0 mg, 0.84 mmol, 1.0 equiv.), 6-bromo-1-(oxan-2-yl)indazole-3-carbonitrile (307.5 mg, 1.0 mmol, 1.20 equiv.), Pd(dppf)Cl₂·CHCl₂ (68.2 mg, 0.08 mmol, 0.10 equiv.), DMF (4.0 mL), and EtN (0.35 mL, 2.51 mmol, 3.0 equiv.) were added. The resulting solution was stirred at 120 °C for 3 h. The reaction mixture was cooled to room temperature. The mixture was loaded onto a silica gel column using THF:PE (1:4 to 1:1). This gave 150 mg (44%) of (2E)-3-[3-cyano-1-(oxan-2-yl)indazol-6-yl]-N-(3-fluoro-2-methylphenyl)acrylamide as a light brown solid.

[0453] [ka] (Step 3) A 40 mL sealed tube was charged with (2E)-3-[3-cyano-1-(oxan-2-yl)indazol-6-yl]-N-(3-fluoro-2-methylphenyl)acrylamide (150.0 mg, 0.37 mmol, 1.0 equiv.) and 4 M HCl / dioxane (10 mL). The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated. The crude product was purified by preparative HPLC. This afforded 12.5 mg (11%) of (E)-3-(3-cyano-1H-indazol-6-yl)-N-(3-fluoro-2-methylphenyl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =321 [ka]

[0454] Example 52: (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide [ka] (Process 1) A 25 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 3-methyl-3,4-dihydro-2H-1-benzopyran-4-amine (110.0 mg, 0.67 mmol, 1.0 equiv.), DCM (10.0 mL), and EtN (0.19 mL, 1.35 mmol, 2.0 equiv.). Subsequently, acryloyl chloride (67.10 mg, 0.74 mmol, 1.10 equiv.) was added dropwise at 0° C. with stirring. The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×15 mL of dichloromethane, dried over anhydrous sodium sulfate, and concentrated. The residue was loaded onto a silica gel column using EtOAc / PE (1 / 5). This gave 110 mg (75%) of N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)prop-2-enamide as a pale yellow solid. LC-MS (ES, m / z): [M+H] + =218

[0455] [ka] (Process 2) An 8 mL vial purged and maintained under an inert atmosphere of nitrogen was charged with N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)prop-2-enamide (120.0 mg, 0.55 mmol, 1.0 equiv.), DMF (5.0 mL), 6-bromo-3-methyl-1H-indazole (116.6 mg, 0.55 mmol, 1.0 equiv.), EtN (0.23 mL, 1.66 mmol, 3.0 equiv.), and Pd(dppf)Cl.CHCl (22.50 mg, 0.028 mmol, 0.05 equiv.). The resulting solution was stirred at 120 °C for 5 h. The reaction mixture was cooled to room temperature. The residue was loaded onto a silica gel column using EtOAc (1 / 3). This gave 55 mg (29%) of (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =348 [ka]

[0456] Example 53: (E)—N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] (Process 1) A 25 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (160.0 mg, 0.99 mmol, 1.0 equiv.), DCM (10.0 mL), and EtN (0.28 mL, 1.98 mmol, 2.0 equiv.). Subsequently, acryloyl chloride (98.79 mg, 1.09 mmol, 1.10 equiv.) was added dropwise at 0°C with stirring. The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 2 × 10 mL of DCM, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column using EtOAc / PE (1 / 5). This gave 140 mg (66%) of N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)prop-2-enamide as a pale yellow solid. LC-MS (ES, m / z): [M+H] + =216

[0457] [ka] (Process 2) An 8 mL vial purged and maintained under an inert atmosphere of nitrogen was charged with N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)prop-2-enamide (140.0 mg, 0.65 mmol, 1.0 equiv.), DMF (5.0 mL), 6-bromo-3-methyl-1H-indazole (137.3 mg, 0.65 mmol, 1.0 equiv.), EtN (0.27 mL, 1.95 mmol, 3.0 equiv.), and Pd(dppf)Cl.CHCl (26.5 mg, 0.033 mmol, 0.05 equiv.). The resulting solution was stirred at 120 °C for 5 h. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This gave 30 mg (13%) of (E)-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H]+=346 [ka]

[0458] Example 54: (E)—N-((1S,2S)-2-Methoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] (Process 1) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with (1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-amine hydrochloride (300.0 mg, 1.50 mmol, 1.0 equiv.), DCM (20.0 mL), and EtN (0.31 mL, 2.25 mmol, 1.50 equiv.). Subsequently, acryloyl chloride (163.2 mg, 1.80 mmol, 1.20 equiv.) was added dropwise at 0°C with stirring. The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using THF:PE (1:5 to 1:3). This gave 200 mg (61%) of N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide as an off-white solid.

[0459] [ka] (Process 2) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (140.0 mg, 0.64 mmol, 1.0 equiv.), 6-bromo-3-methyl-1H-indazole (163.2 mg, 0.77 mmol, 1.20 equiv.), Pd(dppf)Cl·CHCl (52.5 mg, 0.064 mmol, 0.10 equiv.), DMF (4 mL), and EtN (0.27 mL, 1.93 mmol, 3.0 equiv.). The resulting solution was stirred at 120 °C for 1 h. The reaction mixture was cooled to room temperature. The crude mixture was purified by flash preparative HPLC. This gave 28.6 mg (13%) of (E)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =348 [ka]

[0460] Example 55: (R,E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] (Process 1) An 8 mL sealed tube was charged with (1R)-2,3-dihydro-1H-inden-1-amine (100.0 mg, 0.75 mmol, 1.0 equiv.), DCM (5.0 mL), and EtN (0.21 mL, 1.50 mmol, 2.0 equiv.). Subsequently, acryloyl chloride (81.54 mg, 0.90 mmol, 1.20 equiv.) was added at −30° C. The resulting solution was stirred for 10 minutes at −30° C. The reaction was then quenched by the addition of 5 mL of water. The organic phase was dried over NaSO and concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (15:75). This afforded 93 mg (66%) of N-[(1R)-2,3-dihydro-1H-inden-1-yl]prop-2-enamide as a white solid. LC-MS (ES, m / z): [M+H] + =188

[0461] [ka] (Process 2) An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with N-[(1R)-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (60.0 mg, 0.32 mmol, 1.0 equiv.), 6-bromo-3-methyl-1H-indazole (67.63 mg, 0.32 mmol, 1.0 equiv.), DMF (2.0 mL), EtN (0.09 mL, 0.64 mmol, 2.0 equiv.), and Pd(dppf)Cl·CHCl (5.2 mg, 0.06 mmol, 0.02 equiv.). The resulting solution was stirred at 120 °C for 2 h. The crude mixture was purified by flash preparative HPLC. This gave 41 mg (40%) of (R,E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =318 [ka]

[0462] Example 56: (E)-N-(chroman-4-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] Prepared according to Example 11, step 4 using (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylic acid and chroman-4-amine to give (E)-N-(chroman-4-yl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =337

[0463] Example 57: (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)acrylamide [ka] Prepared according to example 11, step 4 using (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylic acid and 1,2,3,4-tetrahydronaphthalen-1-amine to give (E)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =335

[0464] Example 58: (E)—N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-oxoindolin-6-yl)acrylamide [ka] An 8 mL vial was charged with (£)-3-(2-oxoindolin-6-yl)acrylic acid (50.0 mg, 0.25 mmol, 1.00 equiv.), 2-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (40.3 mg, 0.25 mmol, 1.00 equiv.), HATU (141.4 mg, 0.37 mmol, 1.50 equiv.), and DIPEA (95.4 mg, 0.74 mmol, 3.00 equiv.) in DMF (2.00 mL). The resulting solution was stirred for 2 hours at 20°C. The mixture was purified by flash preparative HPLC. This gave 19 mg (22%) of (E)-N-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-3-(2-oxoindolin-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H]+=347 [ka]

[0465] Example 59: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide [ka] An 8 mL vial was charged with (E)-3-(2-oxoindolin-6-yl)acrylic acid (50.0 mg, 0.25 mmol, 1.00 equiv.), 2,3-dihydro-1H-inden-1-amine (33.3 mg, 0.25 mmol, 1.00 equiv.), HATU (141.4 mg, 0.37 mmol, 1.50 equiv.), and DIPEA (95.4 mg, 0.74 mmol, 3.00 equiv.) in DMF (2.00 mL). The resulting solution was stirred for 2 hours at 20°C. The mixture was purified by flash preparative HPLC. This afforded 15 mg (19%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H]+=319 [ka]

[0466] Example 60: (E)—N-(3,5-difluoro-2-methylphenyl)-3-(2-oxoindolin-6-yl)acrylamide [ka] (Process 1) A 100 mL pressure tank reactor was charged with 4-chloro-3,5-difluoro-2-methylaniline (160.00 mg, 0.90 mmol, 1.00 equiv), EtOH (30.00 mL), 4 M HCl / EtOH (1.00 mL), and Pd / C (47.94 mg). The flask was evacuated and flushed with nitrogen three times, followed by hydrogen. The resulting solution was stirred at 70 °C under an atmosphere of hydrogen (30 atm) overnight. The reaction mixture was cooled to room temperature. The solids were removed by filtration. The resulting mixture was concentrated. This afforded 120 mg (crude) of 3,5-3,5-difluoro-2-methylaniline hydrochloride.

[0467] [ka] (Process 2) A 100 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 3,5-difluoro-2-methylaniline hydrochloride (120.00 mg, 0.67 mmol, 1.00 equiv.), DCM (20 mL), and EtN (0.28 mL, 2.01 mmol, 3.00 equiv.). Subsequently, acryloyl chloride (90.7 mg, 1.00 mmol, 1.50 equiv.) was added dropwise at 0 °C with stirring. The resulting solution was stirred at room temperature overnight. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using THF:PE (1:5 to 1:3). This afforded 120 mg (91%) of N-(3,5-difluoro-2-methylphenyl)prop-2-enamide as an off-white solid.

[0468] [ka] (Step 3) In an 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen, N-(3,5-difluoro-2-methylphenyl)prop-2-enamide (120.00 mg, 0.61 mmol, 1.00 equiv.), 6-bromo-1,3-dihydroindol-2-one (154.9 mg, 0.73 mmol, 1.20 equiv.), Pd(dppf)Cl.CHCl (49.6 mg, 0.06 mmol, 0.10 equiv.), DMF (4.00 mL), and EtN (0.25 mL, 1.83 mmol, 3.00 equiv.) were added. The resulting solution was stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature. The crude mixture was purified by preparative HPLC. This gave 11.3 mg (6%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(2-oxoindolin-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =329 [ka]

[0469] Example 61: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide [ka] An 8 mL round-bottom flask was charged with 5-bromo-4-fluoro-3H-1,2,3-benzotriazole (50.0 mg, 0.23 mmol, 1.00 equiv.), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (43.3 mg, 0.23 mmol, 1.00 equiv.), Pd(dppf)Cl (16.9 mg, 0.023 mmol, 0.10 equiv.), EtN (0.096 mL, 0.70 mmol, 3.00 equiv.), and DMF (3.00 mL). The resulting solution was stirred in an oil bath at 120 °C for 2 hours. The reaction mixture was cooled. The residue was applied to a silica gel column using PE / THF (1 / 1). This gave 19 mg (25%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(7-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide as a solid. LC-MS (ES, m / z): [M+H] + =323 [ka]

[0470] Example 62: (E)—N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide [ka] An 8 mL round-bottom flask was charged with 6-bromo-4-fluoro-1H-1,2,3-benzotriazole (40.00 mg, 0.18 mmol, 1.00 equiv.), N-(2,3-dihydro-1H-inden-1-yl)prop-2-enamide (34.7 mg, 0.18 mmol, 1.00 equiv.), Pd(dppf)Cl (13.6 mg, 0.019 mmol, 0.10 equiv.), and EtN (0.077 mL, 0.55 mmol, 3.00 equiv.) in DMF (2.00 mL). The resulting solution was stirred in an oil bath at 120 °C for 1 hour. The reaction mixture was cooled. The mixture was loaded onto a silica gel column using PE / THF (1 / 1). This gave 17.8 mg (30%) of (E)-N-(2,3-dihydro-1H-inden-1-yl)-3-(4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)acrylamide as a white solid. LC MS (ES, m / z): [M+H] + =323 [ka]

[0471] Example 63: (E)—N-(5-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide [ka] An 8 mL sealed tube purged and maintained under an inert atmosphere of nitrogen was charged with (E)-methyl 3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylate (30.0 mg, 0.14 mmol, 1.00 equiv.) in THF (2.00 mL). 5-Chloro-2-methylbenzenamine (25.4 mg, 0.18 mmol, 1.30 equiv.) was then added. The reaction mixture was cooled to 0° C. 1 M LiHMDS (0.68 mL, 0.68 mmol, 5.00 equiv.) was then added. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was quenched with 1 mL of water, extracted with 2×5 mL of ETOAc, and the organic layer was concentrated in vacuo to give the crude product. The crude product was then purified by preparative HPLC. This gave 5 mg (11%) of (E)-N-(5-chloro-2-methylphenyl)-3-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)acrylamide as a white solid. LC-MS (ES, m / z): [M+H] + =329 [ka]

[0472] Example 64: (E)-N-(2-methylcyclohexyl)-3-(2-oxoindolin-6-yl)acrylamide [ka] An 8 mL vial was charged with (E)-3-(2-oxoindolin-6-yl)acrylic acid (50.00 mg, 0.25 mmol, 1.00 equiv.), 2-methylcyclohexanamine (28.25 mg, 0.25 mmol, 1.00 equiv.), HATU (141.38 mg, 0.37 mmol, 1.50 equiv.), and DIPEA (95.41 mg, 0.74 mmol, 3.00 equiv.) in DMF (2.00 mL). The resulting solution was stirred for 2 hours at 20°C. The mixture was purified by flash preparative HPLC. This afforded 8.3 mg (11%) of (E)-N-(2-methylcyclohexyl)-3-(2-oxoindolin-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =299

[0473] Example 65: (E)-3-(3-methyl-1H-indazol-6-yl)-N-(3-methylchroman-4-yl)acrylamide [ka] (Process 1) A 500 mL three-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with 2,3-dihydro-1-benzopyran-4-one (15.00 g, 101.24 mmol, 1.00 equiv.) and THF (200 mL). Subsequently, LiHMDS (1 M in THF, 1.20 equiv.) was added dropwise with stirring at −78° C. The resulting solution was stirred at −78° C. for 40 minutes. To this was added a solution of MeI (17.24 g, 121.49 mmol, 1.20 equiv.) in THF (10 mL) dropwise with stirring at −78° C. The resulting solution was allowed to react at −78° C. for an additional 40 minutes with stirring, followed by stirring at 25° C. for an additional hour. The reaction was then quenched by the addition of 150 mL of NH4Cl. The resulting solution was extracted with 2 x 150 mL of ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1 / 10). This afforded 5 g (30% yield) of 3-methyl-2,3-dihydro-1-benzopyran-4-one as a pale yellow oil.

[0474] [ka] (Process 2) A 40 mL vial purged and maintained under an inert atmosphere of nitrogen was charged with 3-methyl-2,3-dihydro-1-benzopyran-4-one (1.10 g, 6.78 mmol, 1.00 equiv.), MeOH (20.00 mL), NHOH.HCl (1.41 g, 20.35 mmol, 3.00 equiv.), and EtN (2.06 g, 20.35 mmol, 3.00 equiv.). The resulting solution was stirred at 70 °C for 15 hours. The resulting mixture was concentrated. The resulting solution was diluted with 10 mL of water. The resulting solution was extracted with 2 × 10 mL of ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The resulting mixture was concentrated. This afforded 1 g (83% yield) of N-[(4E)-3-methyl-2,3-dihydro-1-benzopyran-4-ylidene]hydroxylamine as a white solid.

[0475] [ka] (Step 3) A 100 mL single-neck round-bottom flask purged and maintained with an inert atmosphere of H was charged with N-[(4E)-3-methyl-2,3-dihydro-1-benzopyran-4-ylidene]hydroxylamine (0.70 g, 3.95 mmol, 1.00 equiv), MeOH (20.00 mL), and Pd / C (0.06 g). The resulting solution was stirred for 12 hours at 40 °C. The solids were removed by filtration. The resulting mixture was concentrated. This afforded 530 mg (82% yield) of 3-methyl-3,4-dihydro-2H-1-benzopyran-4-amine as a pale yellow oil.

[0476] [ka] (Step 4) A 40 mL vial was charged with 3-methyl-3,4-dihydro-2H-1-benzopyran-4-amine (300.00 mg, 1.838 mmol, 1.00 equiv.), DCM (10.00 mL), and EtN (371.98 mg, 3.676 mmol, 2.00 equiv.). Subsequently, a solution of acryloyl chloride (182.99 mg, 2.022 mmol, 1.10 equiv.) in DCM (2 mL) was added dropwise with stirring at 0°C. The resulting solution was stirred for 5 hours at 0°C. The reaction was then quenched by the addition of 8 mL of water. The resulting solution was extracted with 2 × 15 mL of dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1 / 2). This gave 280 mg (70% yield) of N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)prop-2-enamide as an off-white solid.

[0477] [ka] (Step 5) A 20 mL vial purged and maintained under an inert atmosphere of nitrogen was charged with N-(3-methyl-3,4-dihydro-2H-1-benzopyran-4-yl)prop-2-enamide (150.00 mg, 0.690 mmol, 1.00 equiv.), DMF (6.00 mL), 6-bromo-3-methyl-1H-indazole (145.72 mg, 0.690 mmol, 1.00 equiv.), EtN (174.65 mg, 1.725 mmol, 2.50 equiv.), and Pd(dppf)Cl.CHCl (33.74 mg, 0.041 mmol, 0.06 equiv.). The resulting solution was stirred overnight at 120 °C. The reaction mixture was cooled to room temperature. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1 / 1). This gave 110 mg of a racemic mixture of cis / trans isomers as a pale yellow solid. This mixture was purified by chiral preparative HPLC to give four separate stereoisomers, including (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4R)-3-methylchroman-4-yl)acrylamide (Example 65c). The cis-trans isomers were assigned using NOESY NMR. The stereochemistry of each enantiomeric pair has been arbitrarily assigned.

[0478] Example 65a: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4S)-3-methylchroman-4-yl)acrylamide LC-MS (ES, m / z): [M+H] + =348 [ka]

[0479] Example 65b: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4R)-3-methylchroman-4-yl)acrylamide LC-MS1 (ES, m / z): [M+H] + =348 [ka]

[0480] Example 65c: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3R,4R)-3-methylchroman-4-yl)acrylamide LC-MS (ES, m / z): [M+H] + =348 [ka]

[0481] Example 65d: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((3S,4S)-3-methylchroman-4-yl)acrylamide LC-MS (ES, m / z): [M+H] + =348 [ka]

[0482] Example 66: (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl)acrylamide [ka] (Process 1) A 100 mL three-necked round-bottom flask was charged with oxetan-3-ylmethanol (2.00 g, 22.70 mmol, 1.00 equiv), trifluoromethanesulfonic anhydride (9.61 g, 34.050 mmol, 1.50 equiv), EtN (4.59 g, 45.40 mmol, 2.00 equiv), and DCM (50.00 mL). The resulting solution was stirred for 10 h at 20 °C. The resulting mixture was washed with 2 × 50 mL of aqueous NaCO and 1 × 50 mL of aqueous NaCl. The organic layer was dried over anhydrous sodium sulfate, concentrated, and used in the next step without purification.

[0483] [ka] (Process 2) A 100 mL three-necked round-bottom flask was charged with tert-butyl N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamate (1.00 g, 4.01 mmol, 1.00 equiv.), oxetan-3-ylmethyl trifluoromethanesulfonate (0.88 g, 4.01 mmol, 1.00 equiv.), and NaH (0.14 g, 6.01 mmol, 1.50 equiv.) in THF (20.00 mL). The resulting solution was stirred for 10 hours at 20 °C. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 2 × 20 mL of ethyl acetate, and the organic layers were combined. The organic layer was concentrated, and the residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1 / 1). This gave 150 mg of tert-butyl N-[(1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl]carbamate as a solid.

[0484] [ka] (Step 3) An 8 mL vial was charged with MeOH (2.00 mL) and tert-butyl N-[(1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl]carbamate (140.00 mg, 0.438 mmol, 1.00 equiv.) in 2 M HCl (g) in MeOH (2.00 mL). The resulting solution was stirred for 2 hours at 10° C. The resulting mixture was concentrated. This afforded 35 mg of (1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-amine as a solid.

[0485] [ka] (Step 4) An 8 mL vial was charged with (1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-amine (25.00 mg, 0.114 mmol, 1.00 equiv.), (E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid (Intermediate 3, 22.83 mg, 0.114 mmol, 1.00 equiv.), HATU (65.02 mg, 0.171 mmol, 1.50 equiv.), and EtN (34.61 mg, 0.342 mmol, 3.00 equiv.) in DMF (3.00 mL). The resulting solution was stirred for 2 hours at 20 °C. The crude mixture was purified by preparative HPLC. This gave 15 mg of (E)-3-(3-methyl-1H-indazol-6-yl)-N-((1S,2S)-2-(oxetan-3-ylmethoxy)-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =404 [ka]

[0486] Example 67: (E)—N-((1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] (Process 1) An 8 mL vial was charged with tert-butyl N-(2-hydroxy-octahydro-1H-inden-1-yl)carbamate (200.00 mg, 0.783 mmol, 1.00 equiv.), allyl bromide (94.75 mg, 0.783 mmol, 1.00 equiv.), and NaH (5.00 mg, 0.783 mmol, 60%) in THF (3.00 mL). The resulting solution was stirred for 10 hours at 20° C. The reaction was then quenched by the addition of 0.5 mL of water. The mixture was concentrated, and the residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1 / 1). This gave 150 mg (66% yield) of tert-butyl N-[(1S,2S)-2-(prop-2-en-1-yloxy)-2,3-dihydro-1H-inden-1-yl]carbamate as a pale yellow solid.

[0487] [ka] (Process 2) A 40 mL vial was charged with tert-butyl N-[2-(prop-2-en-1-yloxy)-octahydro-1H-inden-1-yl]carbamate (140.00 mg, 0.474 mmol, 1.00 equiv.), 1 M ZnEt (4.74 mL, 4.739 mmol, 10.00 equiv.), CHCl (1015.41 mg, 3.791 mmol, 8.00 equiv.), and TFA (432.28 mg, 3.791 mmol, 8.00 equiv.) in DCM (5.00 mL). The resulting solution was stirred for 10 hours at 20 °C. The mixture was concentrated, and the residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (10 / 1). This gave 70 mg (48% yield) of tert-butyl N-[(1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl]carbamate as a solid.

[0488] [ka] (Step 3) An 8 mL vial was charged with MeOH (3.00 mL) and tert-butyl N-[2-(cyclopropylmethoxy)-octahydro-1H-inden-1-yl]carbamate (50.00 mg, 1.00 equiv.) in 2 M HCl (g) in MeOH (3.00 mL). The resulting solution was stirred for 2 hours at 20° C. The resulting mixture was concentrated. This afforded 30 mg of (1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-amine as an off-white solid.

[0489] [ka] (Step 4) An 8 mL vial was charged with (1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-amine (20.00 mg, 0.098 mmol, 1.00 equiv.), (E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid (19.70 mg, 0.098 mmol, 1.00 equiv.), HATU (56.11 mg, 0.148 mmol, 1.50 equiv.), and EtN (29.87 mg, 0.295 mmol, 3.00 equiv.) in DMF (2.00 mL). The resulting solution was stirred for 2 hours at 20 °C. The mixture was purified by flash preparative HPLC. This gave 20 mg (52% yield) of (E)-N-((1S,2S)-2-(cyclopropylmethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =388 [ka]

[0490] Example 68: (E)—N-((1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] (Process 1) A 100 mL three-necked round-bottom flask was charged with 2-fluoroethanol (3.20 g, 49.95 mmol, 1.00 equiv.), trifluoromethanesulfonic anhydride (14.09 g, 49.95 mmol, 1.00 equiv.), and EtN (10.11 g, 99.91 mmol, 2.00 equiv.) in DCM (60.00 mL). The resulting solution was stirred at −78° C. for 10 hours in a liquid nitrogen bath. The resulting mixture was washed with 2×50 mL of aqueous NaCO and 1×50 mL of aqueous NaCl. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 9.7 g, which was used in the next step without purification.

[0491] [ka] (Process 2) A 20 mL vial was charged with tert-butyl N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamate (400.00 mg, 1.60 mmol, 1.00 equiv.), 2-fluoroethyl trifluoromethanesulfonate (629.32 mg, 3.21 mmol, 2.00 equiv.), and NaH (77.01 mg, 3.21 mmol, 2.00 equiv.) in THF (10.00 mL). The resulting solution was stirred for 10 hours at 20°C. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 2 x 20 mL of ethyl acetate, and the organic layers were combined. The organic layer was concentrated, and the residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1 / 1). This gave 300 mg (63% yield) of tert-butyl N-[(1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]carbamate as a pale yellow solid.

[0492] [ka] (Step 3) A 20 mL vial was charged with MeOH (5.00 mL) and tert-butyl N-[(1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl]carbamate (300.00 mg) in 2 M HCl (g) in MeOH (5.00 mL) and stirred for 10 hours at 20° C. The resulting mixture was concentrated to give 120 mg of (1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-amine as a pale yellow solid.

[0493] [ka] (Step 4) In an 8 mL vial, (1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-amine (40.00 mg, 0.205 mmol, 1.00 equiv.), ((E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid (Intermediate 3, 41.03 mg, 0.205 mmol, 1.00 equiv.), HATU (116.85 mg, 0.307 mmol, 1.50 equiv.), DIPEA (79.44 mg , 0.615 mmol, 3.00 equiv) and DMF (2.00 mL) were charged. The resulting solution was stirred for 10 hours at 20°C. The mixture was purified by flash preparative HPLC. This gave 21 mg of (E)-N-((1S,2S)-2-(2-fluoroethoxy)-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =380 [ka]

[0494] Example 69: (E)—N-((1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide [ka] (Process 1) A 20 mL vial was charged with tert-butyl N-[(1S,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamate (400.00 mg, 1.604 mmol, 1.00 equiv.), ethyl iodide (500.47 mg, 3.209 mmol, 2.00 equiv.), and NaH (128.36 mg, 3.209 mmol, 2.00 equiv., 60%) in THF (10.00 mL). The resulting solution was stirred for 10 hours at 20 °C. The mixture was quenched with 5 mL of HO and extracted with 30 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1 / 1). This gave 200 mg (45% yield) of tert-butyl N-[(1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]carbamate as a pale yellow solid.

[0495] [ka] (Process 2) A 20 mL vial was charged with MeOH (5.00 mL) and tert-butyl N-[(1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]carbamate (170.00 mg) in 2 M HCl (g) in MeOH (5.00 mL) and stirred for 10 hours at 20° C. The resulting mixture was concentrated to give 80 mg of (1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-amine as a pale yellow solid.

[0496] [ka] (Step 3) An 8 mL vial was charged with (1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-amine (40.00 mg, 0.226 mmol, 1.00 equiv.), (E)-3-(3-methyl-1H-indazol-6-yl)acrylic acid (Intermediate 3, 45.19 mg, 0.226 mmol, 1.00 equiv.), HATU (128.71 mg, 0.339 mmol, 1.50 equiv.), and DIPEA (87.50 mg, 0.677 mmol, 3.00 equiv.) in DMF (2.00 mL). The resulting solution was stirred at 20° C. for 2 hours. The mixture was purified by preparative HPLC. This gave 25 mg of (E)-N-((1S,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =362 [ka]

[0497] Example 70: (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide [ka] An 8 mL vial was charged with N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (see Example 54, Step 1, 60.00 mg, 0.276 mmol, 1.00 equiv.), 6-bromo-3-cyclopropyl-1H-indazole (65.48 mg, 0.276 mmol, 1.00 equiv.), Pd(dppf)Cl (20.21 mg, 0.028 mmol, 0.10 equiv.), and EtN (83.83 mg, 0.828 mmol, 3.00 equiv.) in DMF (2.00 mL). The resulting solution was stirred at 120° C. for 3 hours. The mixture was purified by preparative HPLC. This gave 31 mg of (E)-3-(3-cyclopropyl-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =374 [ka]

[0498] Example 71: (E)-3-(3-methoxy-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide [ka] An 8 mL vial was charged with N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (see Example 54, Step 1, 60.00 mg, 0.276 mmol, 1.00 equiv.), 6-bromo-3-methoxy-1H-indazole (62.70 mg, 0.276 mmol, 1.00 equiv.), Pd(dppf)Cl (20.21 mg, 0.028 mmol, 0.10 equiv.), and EtN (83.83 mg, 0.828 mmol, 3.00 equiv.) in DMF (2.00 mL). The resulting solution was stirred at 120° C. for 3 hours. The mixture was purified by preparative HPLC. This gave 33 mg of (E)-3-(3-methoxy-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid, which was converted to HCl. LC-MS (ES, m / z): [M+H] + =364 [ka]

[0499] Example 72: (E)-3-(3-chloro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide [ka] An 8 mL vial was charged with N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (60.00 mg, 0.276 mmol, 1.00 equiv.), 6-bromo-3-chloro-1H-indazole (63.92 mg, 0.276 mmol, 1.00 equiv.), Pd(dppf)Cl (20.21 mg, 0.028 mmol, 0.10 equiv.), and EtN (83.83 mg, 0.828 mmol, 3.00 equiv.) in DMF (4.00 mL). The resulting solution was stirred at 120 °C for 3 h. The mixture was purified by preparative HPLC. This gave 32 mg of (E)-3-(3-chloro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =368 [ka]

[0500] Example 73: (E)-3-(3-fluoro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide [ka] (Process 1) A 40 mL vial was charged with 6-bromo-1H-indazole (500.00 mg, 2.54 mmol, 1.00 equiv.) and Selectfluor (1797.95 mg, 5.075 mmol, 2.00 equiv.) in CHCN (10.00 mL) and AcOH (1.00 mL). The resulting solution was stirred at 95 °C for 15 hours. The mixture was applied to a silica gel column using ethyl acetate / petroleum ether (1 / 1). This afforded 110 mg (20% yield) of 6-bromo-3-fluoro-1H-indazole as a pale yellow solid.

[0501] [ka] (Process 2) An 8 mL vial was charged with N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (see Example 54, Step 1, 60.00 mg, 0.276 mmol, 1.00 equiv.), 6-bromo-3-fluoro-1H-indazole (59.38 mg, 0.276 mmol, 1.00 equiv.), Pd(dppf)Cl (20.21 mg, 0.028 mmol, 0.10 equiv.), and EtN (83.83 mg, 0.828 mmol, 3.00 equiv.) in DMF (2.00 mL). The resulting solution was stirred at 120° C. for 14 hours. The mixture was purified by preparative HPLC. This gave 34 mg of (E)-3-(3-fluoro-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC-MS1 (ES, m / z): [M+H] + =352 [ka]

[0502] Example 74: (E)-3-(3-cyano-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide [ka] (Process 1) An 8 mL vial was charged with N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]prop-2-enamide (see Example 54, Step 1, 70.0 mg, 0.322 mmol, 1.00 equiv.), 6-bromo-1-(oxan-2-yl)indazole-3-carbonitrile (98.64 mg, 0.322 mmol, 1.00 equiv.), Pd(dppf)Cl (23.57 mg, 0.032 mmol, 0.10 equiv.), and EtN (97.81 mg, 0.967 mmol, 3.00 equiv.) in DMF (4.00 mL). The resulting solution was stirred at 120 °C for 3 h. The mixture was loaded onto a silica gel column and eluted with ethyl acetate / petroleum ether (1 / 1). This gave 60 mg (42% yield) of (E)-3-(3-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide as a pale yellow solid.

[0503] [ka] (Process 2) An 8 mL vial was charged with MeOH (2.00 mL) and (E)-3-(3-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide (60.00 mg, 0.136 mmol, 1.00 equiv) in 2 M HCl (g) in MeOH (2.00 mL). The resulting solution was stirred for 2 hours at 10° C. The resulting mixture was concentrated. The residue was purified by preparative HPLC. This afforded 31 mg of (E)-3-(3-cyano-1H-indazol-6-yl)-N-((1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl)acrylamide as an off-white solid. LC-MS (ES, m / z): [M+H] + =359 [ka]

[0504] Example compounds 75-106 shown in Table 1a below can be prepared by methods known to those skilled in the art or using the methods disclosed herein: (Table 1a: Example compounds 75 to 106) [Table 3] TIFF2025508898000312.tif226170TIFF2025508898000313.tif243170TIFF2025508898000314.tif235170TIFF2025508898000315.tif248170

[0505] Example 91: (2E)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide [ka] (Process 1) A solution of (2E)-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid (Intermediate 13, 0.22 g, 0.7 mmol), 6-methoxy-2,4-dimethylpyridin-3-amine (0.12 g, 0.9 mmol, 1.2 equiv), HATU (0.58 g, 1.5 mmol, 2 equiv), and DIEA (0.10 g, 1.5 mmol, 2 equiv) in DMF (5 mL) was stirred at 60 °C for 2 h. The mixture was cooled, diluted with water (8 mL), and then extracted with EtOAc (3 × 5 mL). The combined organic layer was washed with water (3 × 5 mL), dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel column chromatography eluting with hexane / AcOEt (1:1) to give (2E)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (0.15 g, 46% yield) as a white solid. LCMS (ES, m / z): 421 [M+H]+

[0506] [ka] (Process 2) A solution of (2E)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-[3-methyl-1-(oxan-2-yl)indazol-6-yl]prop-2-enamide (0.15 g, 0.4 mmol) in 4 M HCl in 1,4-dioxane (2 mL) was stirred at 60 °C for 1 h. The mixture was cooled, concentrated, and then basified with NaHCO solution. The crude product was purified by preparative HPLC: Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase: 24–58% MeCN / water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O) in 10 min; Flow rate: 30 mL / min. Concentration of the appropriate fractions gave (2E)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide (60 mg, 37% yield) as a white solid. LCMS (ES, m / z): 337 [M+H] + [ka]

[0507] Example 93: (2E)-3-(3-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide [ka] (Process 1) A solution of (2E)-3-[3-fluoro-1-(oxan-2-yl)indazol-6-yl]prop-2-enoic acid (Intermediate 6, 150 mg, 0.5 mmol), 6-methoxy-2,4-dimethylpyridin-3-amine (102 mg, 0.6 mmol, 1.3 equiv), HATU (392 mg, 1.0 mmol, 2.0 equiv), and DIEA (133 mg, 1.0 mmol, 2.0 equiv) in DMF (3 mL) was stirred at 60 °C for 1 h. The reaction was cooled and diluted with HO (10 mL). The resulting mixture was extracted with ethyl acetate (3 × 10 mL), and the combined organic layers were dried over anhydrous NaSO and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate (3:1) to give (2E)-3-[3-fluoro-1-(oxan-2-yl)indazol-6-yl]-N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide (164 mg, 75% yield).

[0508] [ka] (Process 2) A solution of (2E)-3-[3-fluoro-1-(oxan-2-yl)indazol-6-yl]-N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide (162 mg, 0.4 mmol) and TFA (3.5 mL) in DCM (11 mL) was stirred at room temperature for 2 hours. The resulting mixture was diluted with HO (5 mL) and basified with NaHCO. The resulting mixture was extracted with CHCl (3 × 5 mL). The combined organic layers were dried over anhydrous NaSO and concentrated. The residue was dissolved in MeOH (3 mL) and purified by preparative HPLC: Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase: 25–57% MeCN / water (10 mmol / L NH4HCO3 + 0.1% NH3 HO) in 9 min; Flow rate: 30 mL / min. Concentration of the appropriate fractions afforded (2E)-3-(3-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide (32 mg, 25% yield) as an off-white solid. LC-MS(ES, m / z): 341 [M+H] + [ka]

[0509] Example 94: (2E)-3-(3-cyano-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide [ka] (Process 1) A solution of 6-bromo-1H-indazole-3-carbonitrile (0.30 g, 1.3 mmol), DHP (0.68 g, 8.1 mmol, 6 equiv.), and PPTS (0.10 g, 0.3 mmol, 0.3 equiv.) in THF (6 mL) was stirred at 70 °C for 10 h. The mixture was cooled and diluted with saturated brine (10 mL) and saturated aqueous NaHCO (2 mL). The aqueous layer was extracted with EtOAc (2 × 8 mL). The combined organic layers were dried over anhydrous NaSO and concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane / AcOEt (5:1) to give 6-bromo-1-(oxan-2-yl)indazole-3-carb...

Claims

1. Formula (I): 【Chemistry 1】 (In the formula: R 1a is H or methyl; R 1b is H or F; A is a group (Aa), (Ab), (Ac), (Ad), or (Ae): wherein the group (Aa) is: 【Chemistry 2】 (In the formula: R 2 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene(C 3-6 Cycloalkyl), C 1-4 Alkylene(4-10 membered heterocycloalkyl), 4-10 membered heterocycloalkyl, C 1-4 Alkoxy, OC 1-4 Alkylene (aryl), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 AlkyleneO(4-10 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), C 3-6 Alkynyl, C 1-4 AlkenylO(C 3-6 alkynyl), C 1-4 Alkylene(CO 2 H);OC 1-4 Alkylene(CO 2 H), C 1-4 Alkylene OC 1-4 Alkylene(CO 2 H), N(R 2aa ) C 1-4 Alkylene(CO 2 H), C 1-4 Alkylene (NR 2ab R 2ac ), O.C. 1-4 Alkylene (NR 2ab R 2ac ), or N(R 2aa ) C 1-4 Alkylene (NR 2ab R 2ac wherein the aryl, heterocycloalkyl, and cycloalkyl are C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 2a R 2b , S.O. 2 R 2c , and NHSO 2 R 2c optionally substituted with 1, 2, or 3 substituents each independently selected from R 2a H and C 1-4 alkyl; R 2b , H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4 to 10 membered heterocycloalkyl; R 2c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4 to 10 membered heterocycloalkyl; Each R 2aa are independently H and C 1-4 alkyl; Each R 2ab are independently H and C 1-4 alkyl; Each R 2ac are independently H and C 1-4 alkyl; or R 2ab and R 2ac together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl; R 2x H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy; Each R 3 are independent, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy; m is 0, 1, 2, or 3; or; R 2x is C 1-4 Alkylene(4-10 membered heterocycloalkyl), 4-10 membered heterocycloalkyl, C 1-4 AlkyleneO(4-10 membered heterocycloalkyl), C 1-4 Alkylene(CO 2 H), O.C. 1-4 Alkylene(CO 2 H), C 1-4 Alkylene OC 1-4 Alkylene(CO 2 H), N(R 2xaa ) C 1-4 Alkylene(CO 2 H), C 1-4 Alkylene (NR 2xab R 2xac ), O.C. 1-4 Alkylene (NR 2xab R 2xac ), or N(R 2xaa ) C 1-4 Alkylene (NR 2xab R 2xac wherein the heterocycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 2xa R 2xb , S.O. 2 R 2xc , and NHSO 2 R 2xc optionally substituted with 1, 2, or 3 substituents each independently selected from R 2xa H and C 1-4 alkyl; R 2xb , H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4 to 10 membered heterocycloalkyl; R 2xc is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4 to 10 membered heterocycloalkyl; Each R 2xaa are independently H and C 1-4 alkyl; Each R 2xab are independently H and C 1-4 alkyl; Each R 2xac are independently H and C 1-4 alkyl; or R 2xab and R 2xac together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl; R 2 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, or C 1-4 alkyleneO(4-10 membered heterocycloalkyl); Each R 3 are independent, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy; m is 0, 1, 2, or 3. and; The group (Ab) is: 【Chemistry 3】 (In the formula: R 4 , H, C 1-4 Alkyl or C 1-4 alkylene(aryl); wherein the aryl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 4a R 4b , S.O. 2 R 4c , and NHSO 2 R 4c optionally substituted with 1, 2, or 3 substituents each independently selected from R 4a H and C 1-4 alkyl; R 4b , H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4 to 10 membered heterocycloalkyl; R 4c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4 to 10 membered heterocycloalkyl; R 5 is H or C 1-4 is alkyl; Each R 6 are independent, C 1-4 alkyl or halo; n is 0, 1, 2, or 3. and; The group (Ac) is: 【Chemistry 4】 (In the formula: R 7 is C 1-4 Alkyl, C 1-4 Alkylene (OH) or C 1-4 Alkylene OC 1-4 is alkyl; o is 1 or 2) and; The group (Ad) is: 【Chemistry 5】 (In the formula: X is a bond, O, or CH 2 and; Each R 8 are independent, halo, C 1-4 Alkyl, C 1-4 Alkoxy, OC 1-4 Haloalkyl, OC 1-4 Alkylene(C 3-6 Cycloalkyl), OC 1-4 alkylene (4-10 membered heterocycloalkyl), or OH; wherein the heterocycloalkyl and cycloalkyl are C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 8a R 8b , S.O. 2 R 8c , and NHSO 2 R 8c is optionally substituted by 1, 2, or 3 substituents independently selected from R 8a H and C 1-4 alkyl; R 8b , H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4 to 10 membered heterocycloalkyl; R 8c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4 to 10 membered heterocycloalkyl; Each R 9 are independently halo or C 1-4 is alkyl; p is 0, 1, or 2; q is 0, 1, 2, 3, or 4. and; The group (Ae) is: 【Chemistry 6】 (In the formula: R 17 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene(C 3-6 Cycloalkyl), C 1-4 Alkylene(4-10 membered heterocycloalkyl), 4-10 membered heterocycloalkyl, C 1-4 Alkoxy, OC 1-4 Alkylene (aryl), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 AlkyleneO(4-10 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), C 3-6 Alkynyl, C 1-4 AlkenylO(C 3-6 alkynyl), C 1-4 Alkylene(CO 2 H), O.C. 1-4 Alkylene(CO 2 H), C 1-4 Alkylene OC 1-4 Alkylene(CO 2 H), N(R 17aa ) C 1-4 Alkylene(CO 2 H), C 1-4 Alkylene (NR 17ab R 17ac ), O.C. 1-4 Alkylene (NR 17ab R 17ac ), or N(R 17aa ) C 1-4 Alkylene (NR 17ab R 17ac wherein the aryl, cycloalkyl, or heterocycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 17a R 17b , S.O. 2 R 17c , N.H.S.O. 2 R 17c optionally substituted with 1, 2, or 3 substituents each independently selected from R 17a H and C 1-4 alkyl; R 17b , H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4 to 10 membered heterocycloalkyl; R 17c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4 to 10 membered heterocycloalkyl; Each R 17aa are independently H and C 1-4 alkyl; Each R 17ab are independently H and C 1-4 alkyl; Each R 17ac are independently H and C 1-4 alkyl; or R 17ab and R 17ac together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl; R 18 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, or C 1-4 alkyleneO(4-10 membered heterocycloalkyl); R 20 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy; R 21 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy; or; R 17 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, or C 1-4 alkyleneO(4-10 membered heterocycloalkyl); R 18 is C 1-4 Haloalkyl, C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene(C 3-6 Cycloalkyl), C 1-4 Alkylene(4-10 membered heterocycloalkyl), 4-10 membered heterocycloalkyl, OC 1-4 Alkylene (aryl), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 AlkyleneO(4-10 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), C 3-6 Alkynyl, C 1-4 AlkenylO(C 3-6 alkynyl), C 1-4 Alkylene(CO 2 H), O.C. 1-4 Alkylene(CO 2 H), C 1-4 Alkylene OC 1-4 Alkylene(CO 2 H), N(R 18aa ) C 1-4 Alkylene(CO 2 H), C 1-4 Alkylene (NR 18ab R 18ac ), O.C. 1-4 Alkylene (NR 18ab R 18ac ), or N(R 18aa ) C 1-4 Alkylene (NR 18ab R 18ac wherein the aryl, cycloalkyl, or heterocycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 18a R 18b , S.O. 2 R 18c , N.H.S.O. 2 R 18c optionally substituted with 1, 2, or 3 substituents each independently selected from R 18a H and C 1-4 alkyl; R 18b , H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4 to 10 membered heterocycloalkyl; R 18c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4 to 10 membered heterocycloalkyl; Each R 18aa are independently H and C 1-4 alkyl; Each R 18ab are independently H and C 1-4 alkyl; Each R 18ac are independently H and C 1-4 alkyl; or R 18ab and R 18ac together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl; R 20 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy; R 21 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy; or; R 17 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, or C 1-4 alkyleneO(4-10 membered heterocycloalkyl); R 18 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylene OC 1-4 Alkyl C 1-4 Alkylene OC 3-6 Cycloalkyl, or C 1-4 alkyleneO(4-10 membered heterocycloalkyl); R 20 H, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy; R 21 is C 1-4 Haloalkyl, C 1-4 Alkylene (aryl), C 1-4 Alkylene (OH), C 1-4 Alkylene(C 3-6 Cycloalkyl), C 1-4 Alkylene(4-10 membered heterocycloalkyl), 4-10 membered heterocycloalkyl, OC 1-4 Alkylene (aryl), C 1-4 Alkylene OC 1-4 Alkyl, C 1-4 Alkylene OC 3-6 Cycloalkyl, C 1-4 AlkyleneO(4-10 membered heterocycloalkyl), C 1-4 Alkylene O (aryl), C 3-6 Alkynyl, C 1-4 AlkenylO(C 3-6 alkynyl), C 1-4 Alkylene(CO 2 H), O.C. 1-4 Alkylene(CO 2 H), C 1-4 Alkylene OC 1-4 Alkylene(CO 2 H), N(R 21aa ) C 1-4 Alkylene(CO 2 H), C 1-4 Alkylene (NR 21ab R 21ac ), O.C. 1-4 Alkylene (NR 21ab R 21ac ), or N(R 21aa ) C 1-4 Alkylene (NR 21ab R 21ac wherein the aryl, cycloalkyl, or heterocycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 21a R 21b , S.O. 2 R 21c , N.H.S.O. 2 R 21c optionally substituted with 1, 2, or 3 substituents each independently selected from R 21a H and C 1-4 alkyl; R 21b , H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4 to 10 membered heterocycloalkyl; R 21c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4 to 10 membered heterocycloalkyl; Each R 21aa are independently H and C 1-4 alkyl; Each R 21ab are independently H and C 1-4 alkyl; Each R 21ac are independently H and C 1-4 alkyl; or R 21ab and R 21ac together with the nitrogen atom to which they are attached form a 4- to 10-membered heterocycloalkyl. and; B is a group (Ba), (Bb) or (Bc): Wherein the group (Ba) is: 【Chemistry 7】 (In the formula: Y is C(R 11 )(R 12 ), N(R 13 ), O, or S; Each R 10 are independently halo or C 1-4 is alkyl; r is 0, 1, 2, or 3; R 11 is H or C 1-4 is alkyl; R 12 is H or C 1-4 alkyl; or R 11 and R 12 together with the carbon atom to which they are attached, C 3-6 Forming a cycloalkyl; R 13 , H, C 1-4 Alkyl or C 3-6 is cycloalkyl; wherein the cycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 13a R 13b , S.O. 2 R 13c , and NHSO 2 R 13c is optionally substituted by 1, 2, or 3 substituents independently selected from R 13a H and C 1-4 alkyl; R 13b , H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4 to 10 membered heterocycloalkyl; R 13c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 haloalkyl, aryl, and 4- to 10-membered heterocycloalkyl. and; The group (Bb) is: 【Chemistry 8】 (In the formula: Each R 14 are independently halo or C 1-4 is alkyl; s is 0, 1, 2, or 3) and; The group (Bc) is: 【Chemistry 9】 (In the formula: R 15 is C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 1-4 haloalkyl, halo, or CN; where the cycloalkyl is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, Halo, CN, OH, NR 15a R 15b , S.O. 2 R 15c , and NHSO 2 R 15c is optionally substituted by 1, 2, or 3 substituents independently selected from R 15a H and C 1-4 alkyl; R 15b , H, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4 to 10 membered heterocycloalkyl; R 15c is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkyl, aryl, and 4 to 10 membered heterocycloalkyl; R 16 is H, halo, or C 1-4 is alkyl; and D, E, and F are each independently selected from C(R 16 or one of D, E, and F is N and the remaining two of D, E, and F groups are independently C(R 16 ) is) is); or a pharma- ceutically acceptable salt and / or solvate thereof.

2. 2. A pharma- ceutical acceptable salt according to claim 1.

3. 2. The compound of claim 1.

4. A is a group (Aa) 【Chemistry 10】 The compound according to any one of claims 1 to 3, or a pharma- ceutical acceptable salt and / or solvate thereof,

5. R 2 But, Halo, C 1-4 Haloalkyl, C 1-4 Alkylene (8-10 membered heterocycloalkyl), C 1-4 AlkyleneO(8-10 membered heterocycloalkyl), 4-10 membered heterocycloalkyl such as 1-methylpiperazinyl, CH 2 CH 2 (CO 2 H) and other C 1-4 Alkylene(CO 2 H), O.C. 1-4 Alkylene(CO 2 H), C 1-4 Alkylene OC 1-4 Alkylene(CO 2 H), N(R 2aa ) C 1-4 Alkylene(CO 2 H), C 1-4 Alkylene (NR 2ab R 2ac ), O.C. 1-4 Alkylene (NR 2ab R 2ac ), or N(R 2aa ) C 1-4 Alkylene (NR 2ab R 2ac 5. The compound according to any one of claims 1 to 4, or a pharma- ceutical acceptable salt and / or solvate thereof, wherein

6. R 2 The compound according to claim 5, wherein is a 4-10 membered heterocycloalkyl, such as 1-methylpiperazinyl, or a pharma- ceutically acceptable salt and / or solvate thereof.

7. R 2 But, CH 2 CH 2 (CO 2 H) and other C 1-4 Alkylene(CO 2 H) or a pharma- ceutical acceptable salt and / or solvate thereof according to claim 5.

8. R 2x The compound according to any one of claims 5 to 7, wherein is H, or a pharma- ceutically acceptable salt and / or solvate thereof.

9. R 2x But, C 1-4 Alkylene (4- to 10-membered heterocycloalkyl), 4- to 10-membered heterocycloalkyl such as 1-methylpiperazinyl, C 1-4 AlkyleneO(4-10 membered heterocycloalkyl), CH 2 CH 2 (CO 2 H) and other C 1-4 Alkylene(CO 2 H), O.C. 1-4 Alkylene(CO 2 H), C 1-4 Alkylene OC 1-4 Alkylene(CO 2 H), N(R 2xaa ) C 1-4 Alkylene(CO 2 H), C 1-4 Alkylene (NR 2xab R 2xac ), O.C. 1-4 Alkylene (NR 2xab R 2xac ), or N(R 2xaa ) C 1-4 Alkylene (NR 2xab R 2xac 5. The compound according to claim 4, or a pharma- ceutical acceptable salt and / or solvate thereof, wherein

10. R 2x The compound according to claim 9, wherein is a 4-10 membered heterocycloalkyl, such as 1-methylpiperazinyl, or a pharma- ceutically acceptable salt and / or solvate thereof.

11. R 2x But, CH 2 CH 2 (CO 2 H) and other C 1-4 Alkylene(CO 2 H) or a pharma- ceutical acceptable salt and / or solvate thereof according to claim 9.

12. R 2 The compound according to any one of claims 9 to 11, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein is H.

13. m is 2 and each R 3 The compound according to any one of claims 4 to 12, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein is independently fluoro and methyl.

14. A is a group (Ae) 【Chemistry 11】 The compound according to any one of claims 1 to 3, or a pharma- ceutical acceptable salt and / or solvate thereof,

15. R 17 C such as methyl, ethyl, or propyl 1-4 15. The compound according to claim 14, wherein alkyl, in particular methyl, or a pharma- ceutically acceptable salt and / or solvate thereof.

16. R 18 C such as methyl, ethyl, or propyl 1-4 16. The compound according to claim 14 or 15, wherein alkyl, in particular methyl, is substituted or unsubstituted, or a pharma- ceutically acceptable salt and / or solvate thereof.

17. R 20 However, C such as OMe or OEt 1-4 The compound according to any one of claims 14 to 16, which is alkoxy, in particular OMe, or a pharma- ceutically acceptable salt and / or solvate thereof.

18. R 21 The compound according to any one of claims 14 to 17, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein is H.

19. B is a group (Bc): 【Chemistry 12】 The compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt and / or solvate thereof,

20. R 15 Methyl, ethyl, cyclopropyl, CF 3 , CN, OMe, chloro, or fluoro, e.g., methyl, ethyl, cyclopropyl, CF 3 20. The compound of claim 19, wherein R is H, or CN, or a pharma- ceutically acceptable salt and / or solvate thereof.

21. D, E, and F are C(R 16 ) and each R 16 21. The compound of claim 19 or 20, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein is independently H, fluoro, chloro, or methyl.

22. (E)-3-(3-fluoro-4-methyl-5-(3-(3-methyl-1H-indazol-6-yl)acrylamido)phenyl)propanoic acid; (E)-3-(3-(3-(3-chloro-1H-indazol-6-yl)acrylamido)-5-fluoro-4-methylphenyl)propanoic acid; (E)-3-(3-fluoro-5-(3-(3-fluoro-1H-indazol-6-yl)acrylamido)-4-methylphenyl)propanoic acid; (E)-3-(3-(3-(3-cyano-1H-indazol-6-yl)acrylamido)-5-fluoro-4-methylphenyl)propanoic acid; (E)-3-(3-fluoro-5-(3-(5-fluoro-3-methyl-1H-indazol-6-yl)acrylamido)-4-methylphenyl)propanoic acid; (E)-3-(3-(3-(3-chloro-5-fluoro-1H-indazol-6-yl)acrylamido)-5-fluoro-4-methylphenyl)propanoic acid; (E)-3-(3-(3-(3,5-difluoro-1H-indazol-6-yl)acrylamido)-5-fluoro-4-methylphenyl)propanoic acid; (E)-3-(3-(3-(3-cyano-5-fluoro-1H-indazol-6-yl)acrylamido)-5-fluoro-4-methylphenyl)propanoic acid; (E)-3-(4-fluoro-3-methyl-2-(3-(3-methyl-1H-indazol-6-yl)acrylamido)phenyl)propanoic acid; (E)-3-(2-(3-(3-chloro-1H-indazol-6-yl)acrylamido)-4-fluoro-3-methylphenyl)propanoic acid; (E)-3-(4-fluoro-2-(3-(3-fluoro-1H-indazol-6-yl)acrylamido)-3-methylphenyl)propanoic acid; (E)-3-(2-(3-(3-cyano-1H-indazol-6-yl)acrylamido)-4-fluoro-3-methylphenyl)propanoic acid; (E)-3-(4-fluoro-2-(3-(5-fluoro-3-methyl-1H-indazol-6-yl)acrylamido)-3-methylphenyl)propanoic acid; (E)-3-(2-(3-(3-chloro-5-fluoro-1H-indazol-6-yl)acrylamido)-4-fluoro-3-methylphenyl)propanoic acid; (E)-3-(2-(3-(3,5-difluoro-1H-indazol-6-yl)acrylamido)-4-fluoro-3-methylphenyl)propanoic acid; (E)-3-(2-(3-(3-cyano-5-fluoro-1H-indazol-6-yl)acrylamido)-4-fluoro-3-methylphenyl)propanoic acid; (E)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-chloro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (E)-3-(3-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (E)-3-(5-fluoro-3-methyl-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (E)-3-(3-chloro-5-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (E)-3-(3,5-difluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (E)-3-(3-cyano-5-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)acrylamide; (E)-N-(3-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)phenyl)-3-(3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-chloro-1H-indazol-6-yl)-N-(3-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)phenyl)acrylamide; (E)-3-(3-fluoro-1H-indazol-6-yl)-N-(3-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)phenyl)acrylamide; (E)-3-(3-cyano-1H-indazol-6-yl)-N-(3-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)phenyl)acrylamide; (E)-N-(3-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)phenyl)-3-(5-fluoro-3-methyl-1H-indazol-6-yl)acrylamide; (E)-3-(3-chloro-5-fluoro-1H-indazol-6-yl)-N-(3-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)phenyl)acrylamide; (E)-3-(3,5-difluoro-1H-indazol-6-yl)-N-(3-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)phenyl)acrylamide; and (E)-3-(3-cyano-5-fluoro-1H-indazol-6-yl)-N-(3-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)phenyl)acrylamide, or a pharma- ceutical acceptable salt and / or solvate thereof, selected from the group consisting of the compound according to claim 1, or a pharma- ceutical acceptable salt and / or solvate thereof.

23. (2E)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2E)-3-(3-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-3-(3-cyano-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-3-(5-fluoro-3-methyl-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-3-(3-chloro-5-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-3-(3,5-difluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-3-(3-cyano-5-fluoro-1H-indazol-6-yl)-N-(6-methoxy-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(5-fluoro-3-methyl-1H-indazol-6-yl)prop-2-enamide; (2E)-3-(3-fluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-3-(3-chloro-5-fluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-N-(5-fluoro-4-methylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2E)-3-(3,5-difluoro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-3-(3-chloro-1H-indazol-6-yl)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)prop-2-enamide; (2E)-N-(5-fluoro-2,4-dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2E)-N-[5-fluoro-4-(methoxymethyl)pyridin-3-yl]-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2E)-3-(3-methyl-1H-indazol-6-yl)-N-(2-methylpyridin-3-yl)prop-2-enamide; (2E)-N-(2,4-dimethylpyridin-3-yl)-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; (2E)-N-[5-fluoro-4-(methoxymethyl)-2-methylpyridin-3-yl]-3-(3-methyl-1H-indazol-6-yl)prop-2-enamide; or a pharma- ceutical acceptable salt and / or solvate thereof, selected from the group consisting of the compound according to claim 1, or a pharma- ceutical acceptable salt and / or solvate thereof.

24. 24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23 and a pharma- ceutically acceptable carrier or excipient.

25. A compound according to any one of claims 1 to 23, a pharma- ceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to claim 24, for use as a medicament.

26. A compound according to any one of claims 1 to 23, a pharma- ceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to claim 24, for use in the treatment or prevention of a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect.

27. Use of a compound according to any one of claims 1 to 23, a pharma- ceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to claim 24, in the manufacture of a medicament for treating or preventing a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect.

28. A method for treating or preventing a disease or disorder in which inhibition of mPTP provides a therapeutic or prophylactic effect, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 23, a pharma- ceutically acceptable salt and / or solvate thereof, or a pharmaceutical composition according to claim 24.

29. The disease or disorder is a degenerative or neurodegenerative disease (Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal dementia, chemotherapy-induced neuropathy, Huntington's disease, spinocerebellar ataxia, progressive supranuclear palsy, hereditary spastic paraplegia, Duchenne muscular dystrophy, congenital muscular dystrophy, traumatic brain injury, and Friedreich's ataxia, in particular Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis). disorders of the central nervous system (such as AIDS dementia complex, depressive disorders, schizophrenia, and epilepsy); ischemia and reperfusion injury (such as acute myocardial infarction, stroke, renal ischemia-reperfusion injury, and organ damage during transplant); metabolic diseases (such as fatty liver, diabetes, diabetic retinopathy, cognitive decline, and other diabetes-related conditions, obesity and eating behavior, and non-alcoholic fatty liver disease); inflammatory or autoimmune diseases (such as acute pancreatitis, systemic lupus, organ failure in sepsis, and hepatitis). ), diseases of aging (such as bone repair, bone frailty in aging in osteoporosis, and sarcopenia), kidney diseases (such as chronic kidney disease and chronic kidney disease associated with APOL1 gene variants), mitochondrial diseases (such as Reye's syndrome, Leber's hereditary optic neuropathy, and related disorders and disorders), and TDP-43 diseases or disorders such as TDP-43-associated neurodegeneration (e.g., amyotrophic lateral sclerosis, frontotemporal dementia, facial onset sensorimotor neuropathy, primary lateral sclerosis, advanced myelopathy, and pulmonary hypertension) 29. The compound for use according to any one of claims 26 to 28, a medicament for treating the disease ...

30. 30. The compound for use, its pharma- ceutically acceptable salt and / or solvate, pharmaceutical composition for use, use, or method according to any one of claims 26 to 29, wherein said compound is for administration to a human subject.

31. A compound for use, a pharma- ceutically acceptable salt and / or solvate thereof, a pharmaceutical composition for use, a use or a method according to any one of claims 26 to 30 for use in combination with a further therapeutic agent.

32. Formula (II): 【Chemistry 13】 (In the formula: A and R 1a is as defined in any one of claims 1 to 24); or a salt thereof.

33. Formula (IV): 【Chemistry 14】 (In the formula: B and R 1b is as defined in any one of claims 1 to 24); or a salt thereof.

34. Formula (VI): 【Chemistry 15】 (In the formula: B and R 1b is as defined in any one of claims 1 to 24); or a salt thereof.

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