Aldehyde dehydrogenase inhibitors and their therapeutic uses

Abstract

The present invention generally relates to the field of therapeutic compounds. More specifically, the present invention relates to certain aldehyde dehydrogenase inhibitor compounds (also referred to herein as "ALDHI compounds") that inhibit, inter alia, the aldehyde dehydrogenase enzyme ALDH1A3. The present invention also relates to pharmaceutical compositions containing such compounds and uses of such compounds and compositions to inhibit the ALDH1A3 enzyme, treat disorders (e.g., diseases) that are ameliorated by the inhibition of the ALDH1A3 enzyme, such as proliferative disorders, cancer, obesity, diabetes, cardiovascular disorders, etc., both in vitro and in vivo.

Description

[Technical Field]

[0001] This application is related to United Kingdom (GB) Patent Application No. 2019475.9, filed December 10, 2020, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention generally relates to the field of therapeutic compounds. More specifically, the present invention relates to certain aldehyde dehydrogenase inhibitor compounds (also referred to herein as "ALDHI compounds") that inhibit, inter alia, the aldehyde dehydrogenase enzyme ALDH1A3. The present invention also relates to pharmaceutical compositions containing such compounds and uses of such compounds and compositions to inhibit the ALDH1A3 enzyme, treat disorders (e.g., diseases) that are ameliorated by the inhibition of the ALDH1A3 enzyme, such as proliferative disorders, cancer, obesity, diabetes, cardiovascular disorders, etc., both in vitro and in vivo. [Background technology]

[0003] Publications are cited herein in order to more fully describe the state of the art to which this invention pertains. Each of these references is herein incorporated by reference in its entirety into the present disclosure to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

[0004] Throughout this specification, including the claims that follow, unless the context otherwise requires, the word "comprise," and variations such as "comprises" and "comprising," will be understood to mean the inclusion of a specified integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps.

[0005] It must be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.

[0006] Ranges are often expressed herein as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by use of the prefix "about," it will be understood that the particular value forms another embodiment.

[0007] This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any information presented herein is prior art or relevant to the invention(s) claimed herein, or that any publication referenced specifically or implicitly is prior art.

[0008] Aldehyde dehydrogenase enzyme Aldehyde dehydrogenase enzymes (ALDHs) (EC 1.2.1.3) are a class of evolutionarily conserved NAD(P)-dependent oxido-reductases (19 human isoforms) that catalyze the oxidation of various exogenous and endogenous aldehydes to their corresponding carboxylic acids.

[0009] ALDH enzymes are involved in a wide range of biological processes, but the biological roles of most isoforms remain unclear. ALDH2, the most studied isoform, plays a key role in alcohol metabolism (oxidizing acetaldehyde to acetate), ischemic cardiac protection, and cancer (see, e.g., Rodriguez-Zavala, 2019). Recent literature has highlighted the importance of members of the ALDH1A subfamily, particularly ALDH1A3, in various pathologies, such as type II diabetes, obesity, cancer, pulmonary arterial hypertension (PAH), and neointimal hyperplasia (NIH). ALDH1A3 is a member of a subfamily of cytoplasmic homotetrameric enzymes that also includes ALDH1A1 and ALDH1A2.

[0010] Overexpression of ALDH1A3 plays an important role in type II diabetes. ALDH1A3 expression is elevated in rodent models of diabetes and in patients with type II diabetes and is associated with reduced insulin production by pancreatic islet cells. ALDH1A3 is a marker of dedifferentiated pancreatic β-cells, which have impaired insulin secretion and mitochondrial function (see, e.g., Kim-Muller, 2016; Cinti et al., 2016; Burke et al., 2018). Treating mice with pharmacological ALDH1A3 inhibitors restores insulin secretion and improves blood glucose control (see, e.g., Esposito et al., 2021).

[0011] ALDH1A3 expression is also elevated in rodent models of obesity, leading to type II diabetes (see, e.g., Burke et al., 2017), and pancreatic islet cells derived from obese diabetic mice express high levels of ALDH1A3 (see, e.g., Esposito et al., 2021).

[0012] In cancer, aberrant expression of ALDH1A3 is associated with progression and poor prognosis in several tumor types and is a hallmark of subpopulations of cancer cells known as cancer stem cells (CSCs) or tumor-initiating cells (TICs) (see, e.g., Marcato, 2011a; Luo, 2012).

[0013] CSCs are a subpopulation of undifferentiated cells within heterogeneous tumors defined by their ability to self-renew and produce differentiated daughter cells during asymmetric division. They are characterized by an increased potential for tumor dissemination, are involved in tumor progression and metastasis, and are associated with chemoresistance and radioresistance. Current therapies target bulk tumor cells, but CSCs escape, leading to tumor recurrence and treatment failure (see, e.g., Pattabiraman, 2014). As a result, tumors may initially appear eradicated but later recur due to the persistence of a small subpopulation of CSCs. This concept is clinically important because it highlights the critical need to target CSCs to achieve durable responses. Therefore, therapeutic targeting of the survival mechanisms used by CSCs could enhance the efficacy of anticancer treatments and reduce the risk of recurrence and progression.

[0014] ALDH activity, measured by the Aldefluor assay, has been used as a marker for CSCs and to isolate these cells from bulk tumors (see, e.g., Ginestier, 2007). In many tumor types, ALDH1A3 has been reported as the predominant isoform and is responsible for Aldefluor activity. ALDH1A3 is a key functional driver of CSC survival, growth, metastasis, and resistance, and is also associated with poor prognosis and poor overall survival in patients with many types of tumors, including melanoma, breast, and glioblastoma (see, e.g., Duan, 2016; Rodriguez-Torres, 2016).

[0015] The underlying mechanism by which ALDH1A3 contributes to the survival and progression of cancer cells and CSCs remains unclear, particularly as two major functions of ALDH1A3 have been suggested to play a key role: detoxification of cytotoxic aldehydes and biosynthesis of retinoic acid (RA) (see, e.g., Duan, 2016).

[0016] Oxidative stress, resulting from chemotherapy or other factors, is a recurrent hallmark of cancer cells and CSCs, leading to an increase in intracellular reactive oxygen species (ROS). This increase in ROS results in phospholipid peroxidation and the generation of reactive aldehydes, such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). The abnormal accumulation of aldehydes can lead to oxidative damage to cells and apoptosis. These apoptotic aldehydes must be metabolized to less toxic carboxylic acids by overexpression of ALDH1A3 to preserve homeostasis in cancer cells and CSCs (see, e.g., Laskar, 2019).

[0017] ALDH1A3, together with other members of the ALDH1A subfamily, also plays an important role in the biosynthesis of RA from the retina and in the expression of numerous RA-inducible genes involved in stemness and proliferation through the interaction of RA with the nuclear RA receptors RAR and RXR (see, e.g., Duan, 2016).

[0018] In ovarian cancer, not only ALDH1A3 but also ALDH1A1 are overexpressed in numerous cell lines according to the Cancer Cell Line Encyclopedia (CCLE), with ALDH1A3 being the predominant isoform in ovarian cancer cell lines derived from several serous adenocarcinomas (see, e.g., https: / / portals.broadinstitute.org / ccle; Chefetz, 2019). Genetic knockdown of ALDH1A3 by siRNA resulted in necroptosis of the CD133+ CSC population of these cells in vitro (Chefetz, 2019). Inhibition of ALDH1A3 reverses resistance and synergizes with chemotherapy (e.g., Taxol) in resistant cell lines and tumor spheroids derived from patients with high-grade serous ovarian cancer (see, e.g., Huddle et al., 2021) and DNA damage checkpoint inhibitors (ATMi / ATRi) in vitro and in vivo (see, e.g., Grimley et al., 2021).

[0019] In melanoma, ALDH1A3 is the most highly expressed isoform in various cell lines, including patient-derived cells (CCLE), whereas its expression is low in nonmalignant human epidermal melanocytes and is regulated by epigenetic mechanisms (see, e.g., Perez-Alea, 2017). ALDH1A3 is associated with CSCs (see, e.g., Luo, 2012; Kozovska, 2016) and plays an important role in melanoma formation, progression, and metastasis. Its role in the clearance of cytotoxic 4-HNE and MDA has been suggested to explain the effect of ALDH1A3 on preserving cellular homeostasis (see, e.g., Perez-Alea, 2017), whereas other studies have reported RA-induced expression of stem cell genes (see, e.g., Luo, 2012). Its inhibition by genetic knockdown (ALDH1A3 shRNA) resulted in a reduction in the number of colonies and spheres formed in vitro and tumor growth in vivo in various cell lines (see, e.g., Perez-Alea, 2017), and sensitized paclitaxel-resistant ALDH+ 1205Lu and A375 cells to drug-induced cell death (see, e.g., Luo, 2012). Notably, genetic knockdown of both ALDH1A1 and ALDH1A3 by shRNA or their inhibition with the pan-ALDH1A inhibitor DIMATE produced potent effects both in vitro and in vivo (see, e.g., Perez-Alea, 2017).

[0020] In breast cancer, ALDH1A3 is a key contributor to Aldefluor activity in most cell lines and in breast CSCs, especially CD44 + CD24 -ALDH1A3 has been reported as a marker of tumor recurrence (see, e.g., Marcato, 2011b). There is evidence that CSCs in breast cancer are responsible for tumor recurrence after targeted therapy (see, e.g., Simoes, 2015). Several studies have focused on ALDH1A3 as a key driver of tumor growth and lung metastasis in several breast cancer cell lines, such as MDA-MB-231 and SUM-159 cells (see, e.g., Marcato, 2015; Croker, 2017). It has been suggested that mechanisms involving RA and the upregulation of RA-induced genes explain the effect of ALDH1A3 on tumor growth (see, e.g., Marcato, 2015). ALDH1A3 is a key driver of tumor growth and lung metastasis in several breast cancer cell lines, such as MDA-MB-231 and SUM-159 cells (see, e.g., Marcato, 2015). It has been suggested that mechanisms involving RA and the upregulation of RA-induced genes explain the effect of ALDH1A3 on tumor growth (see, e.g., Marcato, 2015). It has also been suggested that ALDH1A3 plays a key role in tumor recurrence, particularly in the triple-negative subtype (ER). - / PR - / HER2 - Increased expression of ALDH1A3 in breast cancer patients with ALDH1A3 is associated with poor prognosis and worse clinical outcome, tumor stage and grade, and is also predictive of metastasis (see, e.g., Opdenaker, 2014; Marcato, 2015).

[0021] In glioma patients, abnormal expression of ALDH1A3 is associated with the majority of advanced, high-grade glioblastomas and is a marker of poor prognosis and overall survival (see, e.g., Mao, 2013; Zhang, 2013; Li, 2018; Ni, 2020). At the cellular level, ALDH1A3 is overexpressed in the more advanced, radioresistant mesenchymal subtype of glioma stem cells (Mes-GSCs) (see, e.g., Ni, 2020), is a key driver of proneural to mesenchymal transition (see, e.g., Li, 2018), and is associated with processes such as cell proliferation, ECM organization, cell adhesion, and ECM-receptor interactions (see, e.g., Vasilogiannakopoulou, 2018). The relationship between ALDH1A3 and the transcription factor FOXD1 (see, e.g., Cheng, 2016) or the role of ALDH1A3 in promoting glucose uptake (see, e.g., Ni, 2020) have been suggested to explain the relevance of ALDH1A3 in Mes-GSC maintenance and tumorigenesis.

[0022] ALDH1A3 has also been implicated in poor prognosis and metastasis in patients with pancreatic cancer (see, e.g., Kong, 2016; Nie, 2020), gallbladder cancer (see, e.g., Yang, 2013), prostate cancer (associated with elevated expression of miR-187) (see, e.g., Casanova-Salas, 2015), papillary thyroid cancer (see, e.g., Cai et al., 2021), malignant phenotypes in neuroblastoma (see, e.g., Flahaut, 2016), and chemoresistance and metastasis in colorectal cancer models (see, e.g., Durinikova, 2018). ALDH1A3 has also been associated with testicular germ cell tumors (see, e.g., Schmidtova et al., 2019), gastric cancer (see, e.g., Kawakami et al., 2020), and cholangiocarcinoma (see, e.g., Chen et al., 2016). ALDH1A3 plays an essential role in maintaining the CSC population in non-small cell lung cancer (see, e.g., Shao, 2014) and is associated with resistance to EGFR inhibitors in NSCLC (see, e.g., Aissa et al., 2021). ALDH1A3 is upregulated in cisplatin-resistant hepatoblastoma (see, e.g., Marayati et al., 2021) and sunitinib-resistant renal cell carcinoma (see, e.g., Kamada et al., 2021). ALDH1A3 expression is responsible for the survival and activity of malignant pleural mesothelioma (MPM) chemoresistant cell subpopulations (see, e.g., Cioce et al., 2021). In colorectal cancer (CRC) cells, ALDH1A3 knockdown reduces clonogenicity and proliferation and induces apoptosis. ALDH1A3 has been suggested as a key protein responsible for the efficacy of DSF-Cu complexes in CRC xenografts and for driving increased glycolysis in CRC tumors (see, e.g., Huang et al., 2021).

[0023] ALDH1A3 signaling appears to be important for T regulatory (Treg) cell induction and function through the production of retinoic acid by multiple cell types (e.g., dendritic cells, macrophages, eosinophils, epithelial cells). Inhibition of ALDH1A3 increases the ratio of effector T cells to Treg cells in tumor tissue, resulting in enhanced tumor immunity and tumor rejection (see, e.g., Bazewicz et al., 2019). Genetic knockout of ALDH1A3 (RALDH3) in a fibrosarcoma tumor model resulted in robust T cell infiltration and impaired tumor growth in immunocompetent mice, leading to interaction with immune checkpoint inhibitors, such as anti-PD1 antibodies. Thus, ALDH1A3 inhibitors can enhance anti-tumor responses to immunotherapy, such as anti-PD1, anti-PDL1, anti-CTLA4, and anti-IL3 antibodies (see, e.g., Haldar et al., 2020).

[0024] ALDH1A3 exhibits all the attributes of a promising therapeutic target in cancer. Moreover, its low expression and minor physiological role in non-malignant cells limits the on-target toxicity of potential ALDH1A3 inhibitors.

[0025] Recently, the important role of ALDH1A3 in the proliferation of vascular smooth muscle cells (SMCs) (see, e.g., Xie et al., 2019) and pulmonary artery smooth muscle (see, e.g., Li et al., 2021) and the resulting neointima formation has been reported. This reduction in lumen space leads to lesions such as neointimal hyperplasia (NIH), a major cause of restenosis and pulmonary arterial hypertension (PAH). Genetic inhibition of ALDH1A3 in vitro blocks vascular SMC proliferation and pulmonary artery SMC proliferation. In vivo, perivascular administration of disulfiram reduces NIH in a rat angioplasty model, while ALDH1A3 gene knockout mice do not develop hypoxia-induced PAH.

[0026] Inhibition of ALDH1A3 can result in a reduction in intimal hyperplasia and may therefore be useful for treating restenosis and / or increasing the chances of successful coronary angioplasty / stenting procedures or bypass vein grafting, arteriovenous fistulas for dialysis access, and allograft transplantation (see, e.g., Xie et al., 2019).

[0027] There are currently no ALDH1A3-selective inhibitors approved or in clinical development. Several non-selective, broad-spectrum ALDH inhibitors of ALDH1A1, ALDH2, and / or ALDH3A1 have been reported in the literature to also inhibit ALDH1A3. These inhibitors exhibit poor pharmacokinetic (PK) properties, including off-target toxicity, short half-lives, and lack of oral bioavailability, and / or lack of in vivo efficacy. The earliest non-selective small molecules reported to inhibit ALDH1A3 include citral, dimethylthioampal (DIMATE), N,N-diethylaminobenzaldehyde (DEAB), and disulfiram (DSF) (see, e.g., Koppaka, 2012; Pors, 2014; Morgan, 2015; Yasgar, 2017; Dinavahi, 2019). These compounds demonstrate in vivo reduction of tumor growth and / or metastasis in various models, particularly breast and melanoma (see, e.g., Thomas, 2016; Perez-Alea, 2017; Matsunaga, 2018). All of these compounds have poor PK properties, limiting their use for intravenous or intraperitoneal administration. Some of these compounds inhibit multiple other targets and pathways unrelated to the ALDH1A family, such as DSF, currently in clinical development for patients with advanced lung cancer, but it is unclear which of the metabolites potentially generated in vivo and what pharmacological activity is responsible for their anticancer efficacy.

[0028] Compound 673A, a DEAB analog (see, e.g., Chefetz, 2019), and a series of thiopyrimidinones (see, e.g., Huddle, 2018; Larsen, 2017) demonstrate inhibition of all three ALDH1A isoforms. 673A demonstrated in vivo reduction of tumor growth in several models of ovarian cancer in combination with cisplatin (see, e.g., Chefetz, 2019). These compounds lack oral bioavailability. Recently reported nonselective pan-ALDH1A family pyrazolopyrimidinone inhibitors have shown efficacy in ovarian cancer cell models (see, e.g., Huddle et al., 2021).

[0029] A series of tetrahydroquinoline derivatives that selectively inhibit ALDH1A3 have recently been reported (see, e.g., Esposito, 2020). Compound MBE-1.5, when combined with paclitaxel in a paclitaxel-resistant model of breast cancer, demonstrated in vivo reduction of tumor growth and metastasis in mice. Like other reported compounds, these analogs are not administered orally.

[0030] Additional heterocyclic inhibitors of ALDH1A3 have been described that, when combined with paclitaxel, exhibit anti-metastatic efficacy and restore insulin secretion in diabetic mouse models (see, e.g., Esposito et al., 2021). The imidazopyridine ALDH1A3 inhibitor NR6 (see, e.g., Gelardi et al., 2021) exhibits anti-metastatic activity in wound healing and in invasion assays in glioblastoma and colon cancer cells, but NR6 lacks biochemical efficacy (IC50 approximately 5 μM). Benzyloxybenzaldehyde ALDH1A3 inhibitors have been reported, but lack pharmacokinetic data (see, e.g., Ibrahim et al., 2021). Summary of the Invention [Problem to be solved by the invention]

[0031] There is clearly a need for potent, selective ALDH1A3 inhibitors with good pharmacokinetic properties, which are suitable for oral administration with minimal or no toxicity. [Means for solving the problem]

[0032] The present disclosure provides compounds and compositions that selectively inhibit ALDH1A3 and target cancer and CSC subpopulations, resulting in regression of various tumor types and, when combined with conventional or targeted therapies, appear to result in tumor elimination. The compounds also appear to have therapeutic utility in the treatment of other diseases discussed herein, such as type II diabetes.

[0033] One aspect of the present invention pertains to certain aldehyde dehydrogenase inhibitor compounds (herein referred to as ALDHI compounds), as described herein.

[0034] Another aspect of the present invention pertains to compositions (eg, pharmaceutical compositions) comprising an ALDHI compound described herein and a pharmaceutically acceptable carrier or diluent.

[0035] Another aspect of the present invention relates to a method for preparing a composition (e.g., a pharmaceutical composition) comprising mixing an ALDHI compound described herein and a pharmaceutically acceptable carrier or diluent.

[0036] Another aspect of the present invention relates to a method of inhibiting the ALDH1A3 enzyme (e.g., inhibiting, reducing, or blocking the activity or function of the ALDH1A3 enzyme) in vitro or in vivo, comprising contacting the ALDH1A3 enzyme with an effective amount of an ALDHI compound described herein.

[0037] Another aspect of the invention relates to a method of inhibiting the ALDH1A3 enzyme (e.g., inhibiting, reducing, or blocking the activity or function of the ALDH1A3 enzyme) in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of an ALDH1A3 compound described herein.

[0038] Another aspect of the present invention pertains to the ALDHI compounds described herein for use in methods of treatment of the human or animal body by therapy, e.g., for use in methods of treatment of disorders (e.g., diseases) described herein.

[0039] Another aspect of the present invention relates to the use of the ALDHI compounds described herein in methods of treatment of the human or animal body by therapy, e.g., in methods of treatment of disorders (e.g., diseases) described herein.

[0040] Another aspect of the invention relates to the use of an ALDHI compound as described herein, e.g., in the manufacture of a medicament for use in a method of treatment, e.g., a method of treatment of a disorder (e.g., a disease) as described herein.

[0041] Another aspect of the present invention relates to methods of treatment, e.g., methods of treating a disorder (e.g., a disease) described herein, comprising administering to a subject in need of treatment a therapeutically effective amount of an ALDHI compound described herein, preferably in the form of a pharmaceutical composition.

[0042] In one embodiment, the disorder is one that is ameliorated by inhibition of the ALDH1A3 enzyme (eg, by inhibiting, reducing, or blocking the activity or function of the ALDH1A3 enzyme).

[0043] In one embodiment, the disorder is, for example, a proliferative condition, cancer, diabetes, cardiovascular disorder, etc., as described herein.

[0044] Another aspect of the present invention relates to kits that include (a) an ALDHI compound described herein, preferably supplied as a composition (e.g., a pharmaceutical composition) in a suitable container and / or in suitable packaging, and (b) instructions for use, e.g., written instructions on how to administer the compound, e.g., in a method of treating a disorder (e.g., a disease) described herein.

[0045] Another aspect of the present invention pertains to ALDHI compounds obtainable by the synthetic methods described herein or by methods including the synthetic methods described herein.

[0046] Another aspect of the present invention pertains to ALDHI compounds obtained by the synthetic methods described herein or by a method including the synthetic methods described herein.

[0047] Another aspect of the present invention pertains to novel intermediates, as described herein, that are suitable for use in the methods of synthesis described herein.

[0048] Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.

[0049] As will be appreciated by those skilled in the art, features and preferred embodiments of one aspect of the invention also relate to other aspects of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0050] compound One aspect of the present invention is a compound of the following general formula: 1 , R 3 and R 4 is as defined herein (for convenience, collectively referred to herein as "aldehyde dehydrogenase inhibitor compounds," "ALDH inhibitor compounds," and "ALDHI compounds"):

[0051] [ka] Regarding.

[0052] Some embodiments of the compound include: (1) A compound of the following formula:

[0053] [ka] or a pharmaceutically acceptable salt or solvate thereof: [Wherein -J is

[0054] [ka] and During the ceremony, Ring A is an aromatic monocyclic ring having 5 or 6 ring atoms, one or more substituents -R A and optionally substituted by -R A are each independently -R AA , -R AAX , -OH, -OR AA , -OR AAX , -F, -Cl, -Br, -I, -NH2, -NHR AA , -NR AA 2, -R AAN , -C(=O)R AA , -C(=O)OH, -C(=O)OR AA , -OC(=O)R AA , -NHC(=O)R AA , -C(=O)NH2, -C(=O)NHR AA , -C(=O)NR AA 2. -C(=O)R AAN , -S(=O)2R AA , -S(=O)2NH2, -S(=O)2NHR AA , -S(=O)2NR AA 2. -S(=O)2R AAN , -CN or -NO2, -R AAare each independently a linear or branched saturated C 1~4 Alkyl or saturated C 3~6 is cycloalkyl, -R AAX are each independently a linear or branched saturated C 1~4 is haloalkyl, -R AAN are each independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or 1,1-dioxo-thiomorpholino; -R AA , -OH and -OR AA and optionally substituted with one or more substituents selected from -M 1 teeth,

[0055] [ka] (In the formula, -R M1a and -R M1e are each independently -H or -R M1-オルト and -R M1b and -R M1d are each independently -H or -R M1-メタ and -R M1c are independently -H or -R M1-パラ and However, -R M1a , -R M1b , -R M1c , -R M1d and -R M1e is provided that they are not all -H, Each-R M1-オルト , each -R M1-メタ , -R M1-パラ are independent, -R M11 , -R M11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br, -I, -NH2, -NHR M11 , -NR M11 2, -R M11N , -C(=O)R M11, -C(=O)OH, -C(=O)OR M11 , -OC(=O)R M11 , -NHC(=O)R M11 , -C(=O)NH2, -C(=O)NHR M11 , -C(=O)NR M11 2. -C(=O)R M11N , -S(=O)2R M11 , -S(=O)2NH2, -S(=O)2NHR M11 , -S(=O)2NR M11 2. -S(=O)2R M11N , -CN or -NO2, -M 1 -M 1 and a ring carbon atom of ring A. Or or -M 1 is an aromatic monocyclic heterocycle having 5 or 6 ring atoms, one or more substituents -R M1 and optionally substituted by -R M1 are each independently -R M11 , -R M11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br, -I, -NH2, -NHR M11 , -NR M11 2, -R M11N , -C(=O)R M11 , -C(=O)OH, -C(=O)OR M11 , -OC(=O)R M11 , -NHC(=O)R M11 , -C(=O)NH2, -C(=O)NHR M11 , -C(=O)NR M11 2. -C(=O)R M11N , -S(=O)2R M11 , -S(=O)2NH2, -S(=O)2NHR M11 , -S(=O)2NR M11 2. -S(=O)2R M11N , -CN or -NO2, -R M11 are each independently a linear or branched saturated C1~4 is alkyl, -R M11X are each independently a linear or branched saturated C 1~4 is haloalkyl, -R M11N are each independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or 1,1-dioxo-thiomorpholino; -R M11 , -OH and -OR M11 and optionally substituted with one or more substituents selected from -M 1 -M 1 is connected to ring A by a bond between a ring carbon atom of Either or in which -J is

[0056] [ka] (In the formula, -R J1 are each independently -H or -R JJ and -R J2 are each independently -H or -R JJ and -R J3 are independent, -R JJ , -L JJ -OH, -L JJ -NH2, -L JJ -NHR JJ or -L JJ -NR JJ 2, -R J4 are independently -H, -R JJ , -L JJ -OH, -L JJ -NH2, -L JJ -NHR JJ or -L JJ -NR JJ 2, -R J5 are independently -H, -R JJ , -L JJ -OH, -LJJ -NH2, -L JJ -NHR JJ or -L JJ -NR JJ 2, Or, -R J4 and -R J5 together form =O, -R JJ are each independently a linear or branched saturated C 1~4 is alkyl, -L JJ - each independently represents a linear or branched saturated C 1~4 is alkylene, Ring B is independently ring B1 or ring B2; Ring B1 is a non-aromatic monocyclic heterocycle having 4 to 7 ring atoms, one or more substituents -R B1 and optionally substituted by and / or optionally substituted by =O, -R B1 are each independently -R BB , -R BBX , -OH, -OR BB , -OR BBX , -F, -Cl, -Br, -I, -NH2, -NHR BB , -NR BB 2, -R BBN , -C(=O)R BB , -C(=O)OH, -C(=O)OR BB , -OC(=O)R BB , -NHC(=O)R BB , -C(=O)NH2, -C(=O)NHR BB , -C(=O)NR BB 2. -C(=O)R BBN , -S(=O)2R BB , -S(=O)2NH2, -S(=O)2NHR BB , -S(=O)2NR BB 2. -S(=O)2R BBN , -CN or -NO2, Ring B2 is a heteroaromatic monocyclic ring having 5 or 6 ring atoms, one or more substituents -RB2 and optionally substituted by -R B2 are each independently -R BB , -R BBX , -OH, -OR BB , -OR BBX , -F, -Cl, -Br, -I, -NH2, -NHR BB , -NR BB 2, -R BBN , -C(=O)R BB , -C(=O)OH, -C(=O)OR BB , -OC(=O)R BB , -NHC(=O)R BB , -C(=O)NH2, -C(=O)NHR BB , -C(=O)NR BB 2. -C(=O)R BBN , -S(=O)2R BB , -S(=O)2NH2, -S(=O)2NHR BB , -S(=O)2NR BB 2. -S(=O)2R BBN , -CN or -NO2, -R BB are each independently a linear or branched saturated C 1~4 Alkyl or saturated C 3~6 is cycloalkyl, -R BBX are each independently a linear or branched saturated C 1~4 is haloalkyl, -R BBN are each independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or 1,1-dioxo-thiomorpholino; -R BB , -OH and -OR BB and optionally substituted with one or more substituents selected from -M 2 is independent, Phenyl and one or more substituents -R M2 or an aromatic monocyclic heterocycle having 5 or 6 ring atoms, one or more substituents -R M2 and optionally substituted by -R M2 are each independently -R M22 , -R M22X , -OH, -OR M22 , -OR M22X , -F, -Cl, -Br, -I, -NH2, -NHR M22 , -NR M22 2, -R M22N , -C(=O)R M22 , -C(=O)OH, -C(=O)OR M22 , -OC(=O)R M22 , -NHC(=O)R M22 , -C(=O)NH2, -C(=O)NHR M22 , -C(=O)NR M22 2. -C(=O)R M22N , -S(=O)2R M22 , -S(=O)2NH2, -S(=O)2NHR M22 , -S(=O)2NR M22 2. -S(=O)2R M22N , -CN or -NO2, -R M22 are each independently a linear or branched saturated C 1~4 is alkyl, -R M22X are each independently a linear or branched saturated C 1~4 is haloalkyl, -R M22N are each independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or 1,1-dioxo-thiomorpholino; -R M22 , -OH and -OR M22 and optionally substituted with one or more substituents selected from and -Q- is independently: -CH2-CR Q1 R Q2 -, -O-CR Q1 R Q2 -, -S-CR Q1 RQ2 -, -CH2-CH2-CR Q1 R Q2 -or -CR Q3 =CR Q4 - and -R Q1 are each independently -H or -R QQ and -R Q2 are each independently -H or -R QQ and -R Q3 are independently -H or -R QQ and -R Q4 are independently -H or -R QQ and -R QQ are each independently a linear or branched saturated C 1~4 is alkyl, -R 1 are independently -H or -R 11 and -R 3 are independently -H or -R 33 and -R 4 are independently -H or -R 44 and R 11 are independently -R, -R X , -OH, -OR, -OR X , -F, -Cl, -Br, -I, -NH2, -NHR, -NR2, -R N , -CN or -NO2, R 33 are independently -R, -R X , -OH, -OR, -OR X , -F, -Cl, -Br, -I, -NH2, -NHR, -NR2, -R N , -CN or -NO2, R 44 are independently -R, -R X , -OH, -OR, -OR X , -F, -Cl, -Br, -I, -NH2, -NHR, -NR2, -RN , -CN or -NO2, - R is independently a linear or branched saturated C 1~4 is alkyl, -R X are each independently a linear or branched saturated C 1~4 is haloalkyl, -R N are each independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or 1,1-dioxo-thiomorpholino, and are optionally substituted with one or more substituents selected from -R, -OH, and -OR. And, provided that the compound is not a compound of one of the following formulas, or a pharmaceutically acceptable salt or solvate thereof:

[0057] [Table 1] provided that the compound is not a compound of one of the following formulas, or a pharmaceutically acceptable salt or solvate thereof:

[0058] [Table 2] provided that the compound is not a compound of one of the following formulas, or a pharmaceutically acceptable salt or solvate thereof:

[0059] [Table 3] TIFF0007815250000009.tif130142 with the proviso that the compound is not a compound of one of the following formulas or a pharmaceutically acceptable salt or solvate thereof:

[0060] [Table 4] provided that the compound is not a compound of one of the following formulas, or a pharmaceutically acceptable salt or solvate thereof:

[0061] [Table 5] The compound described above, or a pharmaceutically acceptable salt or solvate thereof.

[0062] For the avoidance of doubt, the group -Q-, written from left to right, is attached to the benzene ring on the left and to the carbonyl group on the right. For example, -Q- is -O-CR Q1 R Q2 -, the O on the left is attached to the benzene ring (marked by an asterisk, below), and the CR on the right Q1 R Q2 is attached to the carbonyl group (marked by a hash, below).

[0063] [ka]

[0064] For the avoidance of doubt, it is not intended that ring atom N in a ring containing -Q- is substituted; instead, it is intended that ring atom N in a ring containing -Q- is unsubstituted.

[0065] To avoid misunderstanding, the groups -Q-, -J, and -R 1 , -R 3 and -R 4 are not intended to be linked other than through the ring atom to which they are attached. For example, -Q- and -R 1 are not intended to form a fused ring structure together; -R 1 and -J are not intended to be taken together to form a fused ring structure; -J and -R 3 are not intended to form a fused ring structure together; -R 3 and -R 4are not intended to be taken together to form a fused ring structure; -Q- and -J are not intended to be taken together to form a fused ring structure; -R 1 and -R 3 are not intended to be taken together to form a fused ring structure;

[0066] Unless otherwise indicated, when a compound is shown or described as having one or more chiral centers, and more than one stereoisomer is possible, all such stereoisomers are disclosed and included, both individually (e.g., isolated from other stereoisomers) and in admixture (e.g., equimolar or non-equimolar mixtures of two or more stereoisomers). For example, unless otherwise indicated, if a compound has one chiral center, each of the (R) and (S) enantiomers is disclosed and included, both individually (e.g., isolated from other enantiomers) and in admixture (e.g., equimolar or non-equimolar mixtures of the two enantiomers).

[0067] For example, -Q- becomes -O-CR Q1 R Q2 - and -R Q1 and -R Q2 If different, -R Q1 and -R Q2 The carbon atom to which is attached is a chiral center, marked by an asterisk (*) in the formula below. Unless otherwise specified, the carbon atom at this position may be in either the (R) or the (S) configuration.

[0068] [ka]

[0069] Unless otherwise indicated, when a compound is shown or described that is prone to tautomers, and two tautomers are possible, both tautomers are disclosed and encompassed, both individually (e.g., isolated from the other tautomer) and as mixtures (e.g., as an equimolar or non-equimolar mixture of the two tautomers).

[0070] The term "linear or branched saturated C 1~4 "Alkyl" means -CH3(methyl), -CH2CH3(ethyl), -CH2CH2CH3(n-propyl), -CH(CH3)2(iso-propyl), -CH2CH2CH2CH3(n-butyl), -CH2CH(CH3)2(iso-butyl), -CH(CH3)CH2CH3(sec-butyl) and -C(CH3)3(tert-butyl).

[0071] The term "linear or branched saturated C 1~4 "Haloalkyl" refers to a linear or branched saturated C alkyl group substituted with one or more halo groups (e.g., -F, -Cl, -Br, -I). 1~4 The alkyl group refers to, for example, a linear or branched saturated C 1~4 "Fluoroalkyl" includes, for example, -CF3, -CHF2, -CH2CF3, -CH2CH2F, -CH2CHF2, -CH(CH3)CF3, -CH2C(CH3)2F, -CH2CF2CH3, -CH2CH2CF2CH3, -CH2CH2CHF2 and -CH2CH2CF3.

[0072] The term “saturated C 3~6 "Cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0073] The term "linear or branched saturated C 1~4 "Alkylene" refers to a divalent linear or branched saturated C 1~4 It refers to alkyl groups and includes, for example, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH(CH3)-, and -CH2CH(CH3)-.

[0074] The term “Non-aromatic C 4~7 "Heterocyclyl" means a non-aromatic cyclic group having 4 to 7 ring atoms, in which exactly 1, exactly 2, or exactly 3 of the ring atoms are ring heteroatoms, each ring heteroatom being selected from O, N, and S (the ring S atoms may optionally be in an oxidized form, e.g., S(=O) or S(=O)2). Such groups may be monocyclic or polycyclic, e.g., bridged or spiro. Examples include, for example, non-aromatic monocyclic C 4~7 Heterocyclyls include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxanyl, dioxanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,4-thiazinan 1,1-dioxide, azepanyl, oxazepanyl, and diazepanyl; non-aromatic bridged C7 heterocyclyls include diazabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane, azabicyclo[2.2.1]heptane, and azabicyclo[4.1.0]heptane; and non-aromatic spiro C7 heterocyclyls include 6-oxa-3-azaspiro[3.3]heptane.

[0075] The term “C 5~6 "Heteroaryl" means an aromatic group having 5 to 6 ring atoms, where exactly 1, exactly 2, or exactly 3 of the aromatic ring atoms are ring heteroatoms, each ring heteroatom being selected from O, N, and S. Examples include, for example, "C5 heteroaryl" groups such as furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and "C6 heteroaryl" groups such as pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0076] Group-Q- (2) -Q- is independently -CH2-CR Q1 R Q2 -, -O-CR Q1 R Q2 -or-S-CR Q1 R Q2- a compound according to (1).

[0077] (3) -Q- is -CH2-CR Q1 R Q2 -,for example:

[0078] [ka] The compound according to (1).

[0079] (4) -Q- is independent, -O-CR Q1 R Q2 -or-S-CR Q1 R Q2 - a compound according to (1).

[0080] (5)-Q- is -O-CR Q1 R Q2 -,for example:

[0081] [ka] The compound according to (1).

[0082] (6)-Q- is -S-CR Q1 R Q2 -,for example:

[0083] [ka] The compound according to (1).

[0084] (7) -Q- is -CH2-CH2-CR Q1 R Q2 -,for example:

[0085] [ka] The compound according to (1).

[0086] (8)-Q- is -CR Q3 =CRQ4 -,for example:

[0087] [ka] The compound according to (1).

[0088] Group-R Q1 (9)-R Q1 A compound according to any one of (1) to (8), wherein each, if present, is —H.

[0089] (10)-R Q1 If each exists, -R QQ A compound according to any one of (1) to (8), wherein

[0090] Group-R Q2 (11)-R Q2 A compound according to any one of (1) to (10), wherein each, if present, is —H.

[0091] (12)-R Q2 If each exists, -R QQ A compound according to any one of (1) to (10), wherein

[0092] Group-R Q3 (13)-R Q3 A compound according to any one of (1) to (12), wherein each, if present, is —H.

[0093] (14)-R Q3 If each exists, -R QQ A compound according to any one of (1) to (12),

[0094] Group-R Q4 (15)-R Q4 A compound according to any one of (1) to (14), wherein each, if present, is —H.

[0095] (16)-R Q4 If each exists, -R QQ A compound according to any one of (1) to (14),

[0096] Group-R QQ (17)-R QQ If present, independently linear or branched saturated C 1~3 A compound according to any one of (1) to (16), wherein the compound is alkyl.

[0097] (18)-R QQ A compound according to any one of (1) to (16), wherein, if present, is independently -Me or -Et.

[0098] (19)-R QQ A compound according to any one of (1) to (16), wherein, if present, is -Me.

[0099] Group-R 1 (20)-R 1 A compound according to any one of (1) to (19), wherein is -H.

[0100] (21)-R 1 Ga-R 11 A compound according to any one of (1) to (19), wherein

[0101] Group-R 3 (22)-R 3 A compound according to any one of (1) to (21), wherein is -H.

[0102] (23)-R 3 Ga-R 33 A compound according to any one of (1) to (21),

[0103] Group-R 4 (24)-R 4 A compound according to any one of (1) to (23), wherein is -H.

[0104] (25)-R 4 Ga-R 44 A compound according to any one of (1) to (23), wherein

[0105] Group-R 11 (26)-R 11 , if present, are independently -R, -R X , -OH, -OR, -OR X , -F, -Cl, -Br or -I.

[0106] (27)-R 11 , if present, are independently -R, -R X , -F, or -Cl.

[0107] (28)-R 11 A compound according to any one of (1) to (25), wherein, if present, is independently -F or -Cl.

[0108] (29)-R 11 A compound according to any one of (1) to (25), wherein, if present, is -F.

[0109] Group-R 33 (30)-R 33 , if present, are independently -R, -R X , -OH, -OR, -OR X , -F, -Cl, -Br or -I.

[0110] (31)-R 33 , if present, are independently -R, -R X , -F, or -Cl.

[0111] (32)-R 33 A compound according to any one of (1) to (29), wherein, if present, is independently —R, —F, or —Cl.

[0112] (33)-R 33 A compound according to any one of (1) to (29), wherein, if present, is independently -F or -Cl.

[0113] Group-R 44 (34)-R 44 , if present, are independently -R, -R X , -OH, -OR, -OR X , -F, -Cl, -Br or -I.

[0114] (35)-R 44 , if present, are independently -R, -R X , -F, or -Cl.

[0115] (36)-R 44 A compound according to any one of (1) to (33), wherein, if present, is independently -F or -Cl.

[0116] (37)-R 44 A compound according to any one of (1) to (33), wherein, if present, is -F.

[0117] Group-R (38)-R, if present, is independently a linear or branched saturated C 1~3 A compound according to any one of (1) to (37), wherein the compound is alkyl.

[0118] (39) The compound according to any one of (1) to (37), wherein each -R, if present, is independently -Me or -Et.

[0119] (40) The compound according to any one of (1) to (37), wherein each —R, if present, is —Me.

[0120] Group-R X (41)-R X each, if present, independently represents a linear or branched saturated C 1~3 A compound according to any one of (1) to (40), which is haloalkyl.

[0121] (42)-R x A compound according to any one of (1) to (40), wherein each, if present, is —CF 3 .

[0122] Group-R N (43)-R N A compound according to any one of (1) to (42), wherein each, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, or morpholino, and is optionally substituted with one or more substituents selected from -R, -OH, and -OR.

[0123] (44)-R N A compound according to any one of (1) to (42), wherein each, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, or morpholino.

[0124] Moto-J (Part 1) (45)-J

[0125] [ka] A compound according to any one of (1) to (44),

[0126] Ring A (heteroaryl) (46) Ring A, if present, is C 5~6 is a heteroaryl group, and is a group having one or more substituents -R AA compound according to any one of (1) to (45), optionally substituted by:

[0127] (47) Ring A, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and is substituted with one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by:

[0128] (48) Ring A, if present, is a C5 heteroaryl group and is substituted with one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by:

[0129] (49) Ring A, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, or thiadiazolyl, and is substituted with one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by:

[0130] (50) Ring A, if present, is independently thienyl, oxazolyl, isoxazolyl, thiazolyl, and pyrazolyl, and is substituted with one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by:

[0131] (51) Ring A, if present, is independently thiazolyl or pyrazolyl and contains one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by:

[0132] (52) Ring A, if present, is thiazolyl and is substituted with -R AA compound according to any one of (1) to (45), optionally substituted by:

[0133] (53) Ring A, when present, is a thiazolyl of the following formula: 1 represents the point of attachment of the group -J to -C(=O)-, and (#) represents the point of attachment of the group -J to -C(=O)-, and the substituent -R A A compound according to any one of (1) to (45), optionally substituted by:

[0134] [ka] For example, in this case, -J is

[0135] [ka] is.

[0136] (54) When ring A is present, it is a thiazolyl of the following formula: 1 represents the point of attachment of the group -J to -C(=O)-, and (#) represents the point of attachment of the group -J to -C(=O)-, and the substituent -R A A compound according to any one of (1) to (45), optionally substituted by:

[0137] [ka]

[0138] (55) A compound according to any one of (1) to (45), wherein ring A, if present, is thiazolyl and is unsubstituted.

[0139] (56) When ring A is present, it is an unsubstituted thiazolyl of the following formula: 1 and (#) represents the point of attachment of the group -J to -C(=O)-:

[0140] [ka]

[0141] (57) When ring A is present, it is an unsubstituted thiazolyl of the following formula: 1 and (#) represents the point of attachment of the group -J to -C(=O)-:

[0142] [ka]

[0143] (58) Ring A, if present, is pyrazolyl and contains one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by:

[0144] (59) Ring A, when present, is pyrazolyl of one of the following formulae: 1 and (#) represents the point of attachment of the group -J to -C(=O)-), and one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by:

[0145] [ka]

[0146] (60) A compound according to any one of (1) to (45), wherein ring A, if present, is pyrazolyl and is unsubstituted.

[0147] (61) Ring A, if present, is thienyl and is substituted with one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by:

[0148] (62) Ring A, when present, is a thienyl of the following formula: 1 and (#) represents the point of attachment of the group -J to -C(=O)-), and one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by:

[0149] [ka]

[0150] (63) A compound according to any one of (1) to (45), wherein ring A, if present, is thienyl and is unsubstituted.

[0151] (64) Ring A, if present, is oxazolyl and the substituent -R A A compound according to any one of (1) to (45), optionally substituted by:

[0152] (65) Ring A, when present, is an oxazolyl of the following formula: 1 represents the point of attachment of the group -J to -C(=O)-, and (#) represents the point of attachment of the group -J to -C(=O)-, and the substituent -R A A compound according to any one of (1) to (45), optionally substituted by:

[0153] [ka]

[0154] (66) A compound according to any one of (1) to (45), wherein ring A, if present, is oxazolyl and is unsubstituted.

[0155] (67) Ring A, if present, is isoxazolyl and the substituent -R A A compound according to any one of (1) to (45), optionally substituted by:

[0156] (68) Ring A, when present, is an isoxazolyl of the following formula: 1 represents the point of attachment of the group -J to -C(=O)-, and (#) represents the point of attachment of the group -J to -C(=O)-, and the substituent -R A A compound according to any one of (1) to (45), optionally substituted by:

[0157] [ka]

[0158] (69) A compound according to any one of (1) to (45), wherein ring A, if present, is isoxazolyl and is unsubstituted.

[0159] (70) Ring A, if present, is a C6 heteroaryl group and is substituted with one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by:

[0160] (71) Ring A, if present, is independently pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and is substituted with one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by:

[0161] (72) Ring A, if present, is independently pyridyl or pyrimidinyl and contains one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by:

[0162] (73) Ring A, if present, is pyridyl and contains one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by:

[0163] (74) Ring A, when present, is a pyridyl of the following formula: 1and (#) represents the point of attachment of the group -J to -C(=O)-), and one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by:

[0164] [ka]

[0165] (75) A compound according to any one of (1) to (45), wherein ring A, if present, is pyridyl and is unsubstituted.

[0166] (76) Ring A, if present, is pyrimidinyl and contains one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by:

[0167] (77) When ring A is present, it is a pyrimidinyl of the following formula (wherein (*) is -M 1 and (#) represents the point of attachment of the group -J to -C(=O)-), and one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by:

[0168] [ka]

[0169] (78) A compound according to any one of (1) to (45), wherein ring A, if present, is pyrimidinyl and unsubstituted.

[0170] Ring A (Carboaryl) (79) Ring A, if present, is phenyl and contains one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by:

[0171] Group-RA (80)-R A are each, if present, independently -R AA , -R AAX , -OH, -OR AA , -OR AAX , -F, -Cl, -Br, -I, -NH2, -NHR AA , -NR AA 2, -R AAN , -C(=O)R AA , -C(=O)OR AA , -OC(=O)R AA , -NHC(=O)R AA , -C(=O)NH2, -C(=O)NHR AA , -C(=O)NR AA 2. -C(=O)R AAN , -S(=O)2R AA , -CN or -NO2.

[0172] (81)-R A are each, if present, independently -R AA , -R AAX , -OH, -OR AA , -OR AAX , -F, -Cl, -Br, -I, -NH2, -NHR AA , -NR AA 2, -R AAN , -CN or -NO2.

[0173] (82)-R A each, when present, independently represents -NH2, -NHR AA , -NR AA 2 or -R AAN A compound according to any one of (1) to (79),

[0174] (83)-R A If each exists, -R AA A compound according to any one of (1) to (79),

[0175] (84)-R A If each exists, -R AAN A compound according to any one of (1) to (79),

[0176] (85)-R A respectively, if present, -NR AA 2. A compound according to any one of (1) to (79).

[0177] Group-R AA (86)-R AA each, if present, independently represents a linear or branched saturated C 1~4 A compound according to any one of (1) to (85), wherein the compound is alkyl.

[0178] (87)-R AA each, if present, independently represents a linear or branched saturated C 1~3 A compound according to any one of (1) to (85), wherein the compound is alkyl.

[0179] (88)-R AA A compound according to any one of (1) to (85), wherein each, if present, is independently -Me or -Et.

[0180] (89)-R AA A compound according to any one of (1) to (85), wherein each, if present, is -Me.

[0181] Group-R AAX (90)-R AAX If present, each of the linear or branched saturated C 1~4 A compound according to any one of (1) to (89), which is fluoroalkyl.

[0182] (91)-R AAX A compound according to any one of (1) to (89), wherein each, if present, is —CF 3 .

[0183] Group-R AAN (92)-R AAN each, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, or morpholino; -R AA , -OH and -OR AA A compound according to any one of (1) to (91), optionally substituted with one or more substituents selected from:

[0184] (93)-R AAN A compound according to any one of (1) to (91), wherein each, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, or morpholino.

[0185] Group-M 1 (Carboaryl) Again, -M 1 -M 1 and a ring carbon atom of Ring A.

[0186] (94)-M 1 But if it exists,

[0187] [ka] A compound according to any one of (1) to (93),

[0188] (95)-M 1 But if it exists,

[0189] [ka] A compound according to any one of (1) to (93),

[0190] (96)-M 1 But if it exists,

[0191] [ka] A compound according to any one of (1) to (93),

[0192] (97)-M 1 But if it exists,

[0193] [ka] A compound according to any one of (1) to (93),

[0194] (98)-M 1 But if it exists,

[0195] [ka] A compound according to any one of (1) to (93),

[0196] (99)-M 1 But if it exists,

[0197] [ka] A compound according to any one of (1) to (93),

[0198] (100)-M 1 But if it exists,

[0199] [ka] A compound according to any one of (1) to (93),

[0200] (101)-M 1 But if it exists,

[0201] [ka] A compound according to any one of (1) to (93),

[0202] (102)-M 1 But if it exists,

[0203] [ka] A compound according to any one of (1) to (93),

[0204] Group-R M1a (103)-R M1a A compound according to any one of (1) to (102), wherein, if present, is —H.

[0205] (104)-R M1a If present, -R M1-オルト A compound according to any one of (1) to (102),

[0206] Group-R M1b (105)-R M1b A compound according to any one of (1) to (104), wherein, if present, is —H.

[0207] (106)-R M1b If present, -R M1-メタ A compound according to any one of (1) to (104),

[0208] Group-R M1c (107)-R M1c A compound according to any one of (1) to (106), wherein, if present, is —H.

[0209] (108)-R M1c If present, -R M1-パラ A compound according to any one of (1) to (106), wherein

[0210] Group-RM1d (109)-R M1d A compound according to any one of (1) to (108), wherein, if present, is —H.

[0211] (110)-R M1d If present, -R M1-メタ A compound according to any one of (1) to (108), wherein

[0212] Group-R M1e (111)-R M1e A compound according to any one of (1) to (110), wherein, if present, is —H.

[0213] (112)-R M1e If present, -R M1-オルト A compound according to any one of (1) to (110), wherein

[0214] Group-R M1-オルト (113)-R M1-オルト are each, if present, independently -R M11 , -R M11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br, -I, -NH2, -NHR M11 , -NR M11 2, -R M11N , -C(=O)R M11 , -C(=O)OR M11 , -OC(=O)R M11 , -NHC(=O)R M11 , -C(=O)NH2, -C(=O)NHR M11 , -C(=O)NR M11 2. -C(=O)R M11N , -S(=O)2R M11 , -CN or -NO2.

[0215] (114)-R M1-オルト are each, if present, independently -RM11 , -R M11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br, -I, -NH2, -NHR M11 , -NR M11 2, -R M11N , -S(=O)2R M11 , -CN or -NO2.

[0216] (115)-R M1-オルト are each, if present, independently -R M11 , -R M11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br, -I, -NH2, -NHR M11 , -NR M11 2 or -R M11N A compound according to any one of (1) to (112), wherein

[0217] (116)-R M1-オルト are each, if present, independently -R M11 , -R M11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br or -I.

[0218] (117)-R M1-オルト are each, if present, independently -R M11 , -OH, -OR M11 , -F, -Cl, -Br or -I.

[0219] (118)-R M1-オルト are each, if present, independently -R M11 , -OH, -OR M11 or -F.

[0220] (119)-R M1-オルトare each, if present, independently -R M11 , -F, -Cl, -Br or -I.

[0221] (120)-R M1-オルト are each, if present, independently -R M11 or -F.

[0222] (121)-R M1-オルト A compound according to any one of (1) to (112), wherein each, if present, is independently -F, -Cl, -Br, or -I.

[0223] (122)-R M1-オルト A compound according to any one of (1) to (112), wherein each, if present, is —F.

[0224] Group-R M1-メタ (123)-R M1-メタ are each, if present, independently -R M11 , -R M11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br, -I, -NH2, -NHR M11 , -NR M11 2, -R M11N , -C(=O)R M11 , -C(=O)OR M11 , -OC(=O)R M11 , -NHC(=O)R M11 , -C(=O)NH2, -C(=O)NHR M11 , -C(=O)NR M11 2. -C(=O)R M11N , -S(=O)2R M11 , -CN or -NO2.

[0225] (124)-R M1-メタ are each, if present, independently -R M11 , -RM11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br, -I, -NH2, -NHR M11 , -NR M11 2, -R M11N , -S(=O)2R M11 , -CN or -NO2.

[0226] (125)-R M1-メタ are each, if present, independently -R M11 , -R M11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br, -I, -NH2, -NHR M11 , -NR M11 2 or -R M11N A compound according to any one of (1) to (122),

[0227] (126)-R M1-メタ are each, if present, independently -R M11 , -R M11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br or -I.

[0228] (127)-R M1-メタ are each, if present, independently -R M11 , -OH, -OR M11 , -F, -Cl, -Br or -I.

[0229] (128)-R M1-メタ are each, if present, independently -R M11 , -F, -Cl, -Br or -I.

[0230] (129)-R M1-メタA compound according to any one of (1) to (122), wherein each, if present, is independently -F, -Cl, -Br, or -I.

[0231] (130)-R M1-メタ A compound according to any one of (1) to (122), wherein each, if present, is independently -F or -Cl.

[0232] (131)-R M1-メタ A compound according to any one of (1) to (122), wherein each, if present, is —F.

[0233] Group-R M1-パラ (132)-R M1-パラ are each, if present, independently -R M11 , -R M11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br, -I, -NH2, -NHR M11 , -NR M11 2, -R M11N , -C(=O)R M11 , -C(=O)OR M11 , -OC(=O)R M11 , -NHC(=O)R M11 , -C(=O)NH2, -C(=O)NHR M11 , -C(=O)NR M11 2. -C(=O)R M11N , -S(=O)2R M11 , -CN or -NO2.

[0234] (133)-R M1-パラ are each, if present, independently -R M11 , -R M11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br, -I, -NH2, -NHR M11 , -NR M11 2, -R M11N , -S(=O)2R M11, -CN or -NO2.

[0235] (134)-R M1-パラ are each, if present, independently -R M11 , -OH, -OR M11 , -F, -Cl, -Br, -I, -NH2, -NHR M11 , -NR M11 2, -R M11N , -S(=O)2R M11 , -CN or -NO2.

[0236] (135)-R M1-パラ are each, if present, independently -R M11 , -R M11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br, -I, -NH2, -NHR M11 , -NR M11 2, -R M11N or -CN.

[0237] (136)-R M1-パラ are each, if present, independently -R M11 , -OH, -F, -Cl, -Br, -I, -NH2, -NHR M11 , -NR M11 2, -R M11N or -CN.

[0238] (137)-R M1-パラ are each, if present, independently -R M11 , -R M11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br or -I.

[0239] (138)-R M1-パラare each, if present, independently -R M11 , -OH, -F, -Cl, -Br or -I.

[0240] (139)-R M1-パラ are each, if present, independently -R M11 , -F, -Cl, -Br or -I.

[0241] (140)-R M1-パラ A compound according to any one of (1) to (131), wherein each, if present, is independently -F, -Cl, -Br, or -I.

[0242] (141)-R M1-パラ A compound according to any one of (1) to (131), wherein each, if present, is independently -F or -Cl.

[0243] (142)-R M1-パラ A compound according to any one of (1) to (131), wherein each, if present, is —F.

[0244] Group-R M1-オルト , -R M1-メタ and -R M1-パラ (143)-R M1-オルト are each, if present, -F, -R M1-メタ are each, if present, -F, -R M1-パラ are -F, if present A compound according to any one of (1) to (112).

[0245] Specific group -M 1 (144)-M 1 But if it exists,

[0246] [ka] A compound according to any one of (1) to (93),

[0247] (145)-M 1 But if it exists,

[0248] [ka] A compound according to any one of (1) to (93),

[0249] (146)-M 1 But if it exists,

[0250] [ka] A compound according to any one of (1) to (93),

[0251] Group-M 1 (heteroaryl) Again, -M 1 -M 1 and a ring carbon atom of Ring A.

[0252] (147)-M 1 is, when present, an aromatic monocyclic heterocycle having 5 or 6 ring atoms and is substituted with one or more substituents -R M1 A compound according to any one of (1) to (93), optionally substituted by:

[0253] (148)-M 1 If exists, C 5~6 is a heteroaryl group, and is a group having one or more substituents -R M1 A compound according to any one of (1) to (93), optionally substituted by:

[0254] (149)-M 1is, if present, independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and one or more substituents -R M1 A compound according to any one of (1) to (93), optionally substituted by:

[0255] (150)-M 1 is, if present, independently thienyl, oxadiazolyl, or pyridyl, and one or more substituents -R M1 A compound according to any one of (1) to (93), optionally substituted by:

[0256] (151)-M 1 is, if present, a C5 heteroaryl group and one or more substituents -R M1 A compound according to any one of (1) to (93), optionally substituted by:

[0257] (152)-M 1 is, if present, independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, or thiadiazolyl, and one or more substituents -R M1 A compound according to any one of (1) to (93), optionally substituted by:

[0258] (153)-M 1 is, if present, independently thienyl or oxadiazolyl, and one or more substituents -R M1 A compound according to any one of (1) to (93), optionally substituted by:

[0259] (154)-M 1 is thienyl, if present, and one or more substituents -R M1A compound according to any one of (1) to (93), optionally substituted by:

[0260] (155)-M 1 is, if present, thien-2-yl and one or more substituents -R M1 A compound according to any one of (1) to (93), optionally substituted by:

[0261] (156)-M 1 is, if present, oxadiazolyl and one or more substituents -R M1 A compound according to any one of (1) to (93), optionally substituted by:

[0262] (157)-M 1 is, if present, 1,2,4-oxadiazol-5-yl and one or more substituents -R M1 A compound according to any one of (1) to (93), optionally substituted by:

[0263] (158)-M 1 is, if present, a C6 heteroaryl group and one or more substituents -R M1 A compound according to any one of (1) to (93), optionally substituted by:

[0264] (159)-M 1 is, if present, independently pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and one or more substituents -R M1 A compound according to any one of (1) to (93), optionally substituted by:

[0265] Group-R M1 (160)-R M1 are each, if present, independently -R M11 , -R M11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br, -I, -NH2, -NHRM11 , -NR M11 2, -R M11N , -C(=O)R M11 , -C(=O)OR M11 , -OC(=O)R M11 , -NHC(=O)R M11 , -C(=O)NH2, -C(=O)NHR M11 , -C(=O)NR M11 2. -C(=O)R M11N , -S(=O)2R M11 , -CN or -NO2.

[0266] (161)-R M1 are each, if present, independently -R M11 , -R M11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br, -I, -NH2, -NHR M11 , -NR M11 2, -R M11N , -S(=O)2R M11 , -CN or -NO2.

[0267] (162)-R M1 are each, if present, independently -R M11 , -R M11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br, -I, -NH2, -NHR M11 , -NR M11 2 or -R M11N A compound according to any one of (1) to (159),

[0268] (163)-R M1 are each, if present, independently -R M11 , -R M11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br or -I.

[0269] (164)-R M1 are each, if present, independently -R M11 , -OH, -OR M11 , -F, -Cl, -Br or -I.

[0270] (165)-R M1 are each, if present, independently -R M11 , -F, -Cl, -Br or -I.

[0271] (166)-R M1 If each exists, -R M11 A compound according to any one of (1) to (159),

[0272] (167)-R M1 A compound according to any one of (1) to (159), wherein each, if present, is independently -F, -Cl, -Br, or -I.

[0273] Group-R M11 (168)-R M11 each, if present, independently represents a linear or branched saturated C 1~3 A compound according to any one of (1) to (167), wherein the compound is alkyl.

[0274] (169)-R M11 A compound according to any one of (1) to (167), wherein each, if present, is independently -Me or -Et.

[0275] (170)-R M11 A compound according to any one of (1) to (167), wherein each, if present, is -Me.

[0276] Group-R M11X (171)-RM11X If present, each of the linear or branched saturated C 1~4 A compound according to any one of (1) to (170), which is fluoroalkyl.

[0277] (172)-R M11X A compound according to any one of (1) to (170), wherein each, if present, is —CF 3 .

[0278] Group-R M11N (173)-R M11N each, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, or morpholino; -R M11 , -OH and -OR M11 A compound according to any one of (1) to (172), optionally substituted with one or more substituents selected from:

[0279] (174)-R M11N A compound according to any one of (1) to (172), wherein each, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, or morpholino.

[0280] Moto-J (Part 2) (175)-J is independently

[0281] [ka] A compound according to any one of (1) to (44),

[0282] (176)-J

[0283] [ka] A compound according to any one of (1) to (44),

[0284] (177)-J

[0285] [ka] A compound according to any one of (1) to (44),

[0286] Ring B (178) A compound according to any one of (1) to (44), (175) and (176), wherein ring B, if present, is ring B1.

[0287] (179) A compound according to any one of (1) to (44), (175) and (176), wherein ring B, if present, is ring B2.

[0288] Ring B1 (180) Ring B1, if present, is a non-aromatic monocyclic C 4~7 a heterocyclyl group, which may be one or more substituents -R B1 and / or optionally substituted by =O.

[0289] (181) Ring B1, if present, is independently azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is not further limited to one or more substituents -R B1 and / or optionally substituted by =O.

[0290] (182) Ring B1, if present, is pyrrolidinyl and has one or more substituents -R B1 and / or optionally substituted by =O.

[0291] Ring B2 (183) Ring B2, if present, is C 5~6is a heteroaryl group, and is a group having one or more substituents -R B2 A compound according to any one of (1) to (44), (175), (176) and (179), optionally substituted by:

[0292] (184) Ring B2, if present, is a heteroaromatic monocyclic ring having 5 ring atoms and is substituted with one or more substituents -R B2 A compound according to any one of (1) to (44), (175), (176) and (179), optionally substituted by:

[0293] (185) Ring B2, if present, is a C5 heteroaryl group and is substituted with one or more substituents -R B2 A compound according to any one of (1) to (44), (175), (176) and (179), optionally substituted by:

[0294] (186) Ring B2, if present, is independently pyrrolyl, imidazolyl, pyrazolyl, triazolyl, or tetrazolyl, and is substituted with one or more substituents -R B2 A compound according to any one of (1) to (44), (175), (176) and (179), optionally substituted by:

[0295] (187) Ring B2, if present, is independently pyrrolyl, imidazolyl, pyrazolyl, or triazolyl, and is substituted with one or more substituents -R B2 A compound according to any one of (1) to (44), (175), (176) and (179), optionally substituted by:

[0296] (188) Ring B2, if present, is independently pyrrolyl, imidazolyl, or pyrazolyl, and is substituted with one or more substituents -R B2 A compound according to any one of (1) to (44), (175), (176) and (179), optionally substituted by:

[0297] (189) Ring B2, if present, is independently imidazolyl or pyrazolyl and contains one or more substituents -R B2 A compound according to any one of (1) to (44), (175), (176) and (179), optionally substituted by:

[0298] (190) Ring B2, if present, is imidazolyl and has one or more substituents -R B2 A compound according to any one of (1) to (44), (175), (176) and (179), optionally substituted by:

[0299] (191) Ring B2, if present, is pyrazolyl and is substituted with one or more substituents -R B2 A compound according to any one of (1) to (44), (175), (176) and (179), optionally substituted by:

[0300] Group-R B1 (192)-R B1 are each, if present, independently -R BB , -R BBX , -OH, -OR BB , -OR BBX , -F, -Cl, -Br, -I, -NH2, -NHR BB , -NR BB 2, -R BBN , -C(=O)R BB , -C(=O)OR BB , -OC(=O)R BB , -NHC(=O)R BB , -C(=O)NH2, -C(=O)NHR BB , -C(=O)NR BB 2. -C(=O)R BBN , -S(=O)2R BB , —CN, or —NO2, according to any one of (1) to (44), (175), (176), (178), and (180) to (182).

[0301] (193)-R B1are each, if present, independently -R BB , -R BBX , -OH, -OR BB , -OR BBX , -F, -NH2, -NHR BB , -NR BB 2, -R BBN , -C(=O)R BB , -C(=O)OR BB , -OC(=O)R BB , -NHC(=O)R BB , -C(=O)NH2, -C(=O)NHR BB , -C(=O)NR BB 2. -C(=O)R BBN , -S(=O)2R BB or -CN.

[0302] (194)-R B1 are each, if present, independently -R BB , -R BBX , -OH, -OR BB , -OR BBX , -F, -NH2, -NHR BB , -NR BB 2, -R BBN or -S(=O)2R BB A compound according to any one of (1) to (44), (175), (176), (178), and (180) to (182), wherein

[0303] (195)-R B1 are each, if present, independently -R BB , -R BBX , -OH, -OR BB , -OR BBX , -F, -Cl, -Br, -I or -S(=O)R BB A compound according to any one of (1) to (44), (175), (176), (178), and (180) to (182), wherein

[0304] (196)-R B1are each, if present, independently -R BB , -R BBX , -OH, -OR BB , -OR BBX , -S(=O)2R BB or -F.

[0305] (197)-R B1 are each, if present, independently -R BB , -OH, -OR BB , -S(=O)2R BB or -F.

[0306] (198)-R B1 are each, if present, independently -R BB , -OH, -S(=O)2R BB or -F.

[0307] Group-R B2 (199)-R B2 are each, if present, independently -R BB , -R BBX , -OH, -OR BB , -OR BBX , -F, -Cl, -Br, -I, -NH2, -NHR BB , -NR BB 2, -R BBN , -C(=O)R BB , -C(=O)OR BB , -OC(=O)R BB , -NHC(=O)R BB , -C(=O)NH2, -C(=O)NHR BB , -C(=O)NR BB 2. -C(=O)R BBN , -S(=O)2R BB, —CN, or —NO2, according to any one of (1) to (44), (175), (176), (179), and (183) to (191).

[0308] (200)-R B2 are each, if present, independently -R BB , -R BBX , -OH, -OR BB , -OR BBX , -F, -Cl, -Br, -I, -NH2, -NHR BB , -NR BB 2, -R BBN , -S(=O)2R BB , —CN, or —NO2, according to any one of (1) to (44), (175), (176), (179), and (183) to (191).

[0309] (201)-R B2 are each, if present, independently -R BB , -R BBX , -OH, -OR BB , -OR BBX , -F, -Cl, -Br, -I, -NH2, -NHR BB , -NR BB 2, -R BBN or -CN.

[0310] (202)-R B2 are each, if present, independently -R BB , -R BBX , -OH, -OR BB , -OR BBX , -F, -Cl, -Br, or -I, according to any one of (1) to (44), (175), (176), (179), and (183) to (191).

[0311] (203)-R B2 are each, if present, independently -R BB , -OH, -OR BB, -F, -Cl, -Br, or -I, according to any one of (1) to (44), (175), (176), (179), and (183) to (191).

[0312] Group-R BB (204)-R BB each, if present, independently represents a linear or branched saturated C 1~4 A compound according to any one of (1) to (44) and (175) to (203), wherein the compound is alkyl.

[0313] (205)-R BB each, if present, independently represents a linear or branched saturated C 1~3 A compound according to any one of (1) to (44) and (175) to (203), wherein the compound is alkyl.

[0314] (206)-R BB A compound according to any one of (1) to (44) and (175) to (203), wherein each, if present, is independently -Me or -Et.

[0315] (207)-R BB A compound according to any one of (1) to (44) and (175) to (203), wherein each, if present, is -Me.

[0316] Group-R BBX (208)-R BBX If present, each of the linear or branched saturated C 1~4 A compound according to any one of (1) to (44) and (175) to (207), which is fluoroalkyl.

[0317] (209)-R BBX A compound according to any one of (1) to (44) and (175) to (207), wherein each, if present, is —CF 3 .

[0318] Group-R BBN (210)-R BBN each, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, or morpholino; -R BB , -OH and -OR BB A compound according to any one of (1) to (44) and (175) to (209), optionally substituted with one or more substituents selected from:

[0319] (211)-R BBN A compound according to any one of (1) to (44) and (175) to (209), wherein each, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, or morpholino.

[0320] Group-M 2 (Carboaryl) (212)-M 2 is, if present, phenyl and one or more substituents -R M2 A compound according to any one of (1) to (44) and (175) to (211), optionally substituted by:

[0321] Group-M 2 (heteroaryl) (213)-M 2 If exists, C 5~6 is a heteroaryl group, and is a group having one or more substituents -R M2 A compound according to any one of (1) to (44) and (175) to (211), optionally substituted by:

[0322] (214)-M 2 is, if present, independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and one or more substituents -R M2 A compound according to any one of (1) to (44) and (175) to (211), optionally substituted by:

[0323] (215)-M 2 is, if present, a C5 heteroaryl group and one or more substituents -R M2 A compound according to any one of (1) to (44) and (175) to (211), optionally substituted by:

[0324] (216)-M 2 is, if present, independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, or thiadiazolyl, and one or more substituents -R M2 A compound according to any one of (1) to (44) and (175) to (211), optionally substituted by:

[0325] (217)-M 2 is, if present, independently thienyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, or thiadiazolyl, and one or more substituents -R M2 A compound according to any one of (1) to (44) and (175) to (211), optionally substituted by:

[0326] (218)-M 2 is, if present, independently thienyl, pyrrolyl, or pyrazolyl, and one or more substituents -R M2 A compound according to any one of (1) to (44) and (175) to (211), optionally substituted by:

[0327] (219)-M 2 is, if present, independently thienyl or pyrrolyl, and one or more substituents -R M2 A compound according to any one of (1) to (44) and (175) to (211), optionally substituted by:

[0328] (220)-M 2is, if present, a C6 heteroaryl group and one or more substituents -R M2 A compound according to any one of (1) to (44) and (175) to (211), optionally substituted by:

[0329] (221)-M 2 is, if present, independently pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and one or more substituents -R M2 A compound according to any one of (1) to (44) and (175) to (211), optionally substituted by:

[0330] (222)-M 2 is, if present, pyridyl and one or more substituents -R M2 A compound according to any one of (1) to (44) and (175) to (211), optionally substituted by:

[0331] Group-R M2 (223)-R M2 are each, if present, independently -R M22 , -R M22X , -OH, -OR M22 , -OR M22X , -F, -Cl, -Br, -I, -NH2, -NHR M22 , -NR M22 2, -R M22N , -C(=O)R M22 , -C(=O)OR M22 , -OC(=O)R M22 , -NHC(=O)R M22 , -C(=O)NH2, -C(=O)NHR M22 , -C(=O)NR M22 2. -C(=O)R M22N , -S(=O)2R M22 , —CN, or —NO2, according to any one of (1) to (44) and (175) to (222).

[0332] (224)-R M2 are each, if present, independently -R M22, -R M22X , -OH, -OR M22 , -OR M22X , -F, -Cl, -Br, -I, -NH2, -NHR M22 , -NR M22 2, -R M22N , -S(=O)2R M22 , —CN, or —NO2, according to any one of (1) to (44) and (175) to (222).

[0333] (225)-R M2 are each, if present, independently -R M22 , -R M22X , -OH, -OR M22 , -OR M22X , -F, -Cl, -Br, -I, -NH2, -NHR M22 , -NR M22 2 or -R M22N A compound according to any one of (1) to (44) and (175) to (222),

[0334] (226)-R M2 are each, if present, independently -R M22 , -R M22X , -OH, -OR M22 , -OR M22X , -F, -Cl, -Br or -I.

[0335] (227)-R M2 are each, if present, independently -R M22 , -OH, -OR M22 , -F, -Cl, -Br or -I.

[0336] (228)-R M2 are each, if present, independently -R M22 , -F, -Cl, -Br or -I.

[0337] (229)-R M2 A compound according to any one of (1) to (44) and (175) to (222), wherein each, if present, is independently —F, —Cl, —Br, or —I.

[0338] Group-R M22 (230)-R M22 each, if present, independently represents a linear or branched saturated C 1~3 A compound according to any one of (1) to (44) and (175) to (229), wherein the compound is alkyl.

[0339] (231)-R M22 A compound according to any one of (1) to (44) and (175) to (229), wherein each, if present, is independently -Me or -Et.

[0340] (232)-R M22 A compound according to any one of (1) to (44) and (175) to (229), wherein each, if present, is -Me.

[0341] Group-R M22X (233)-R M22X If present, each of the linear or branched saturated C 1~4 A compound according to any one of (1) to (44) and (175) to (232), which is fluoroalkyl.

[0342] (234)-R M22X A compound according to any one of (1) to (44) and (175) to (232), wherein each, if present, is —CF 3 .

[0343] Group-R M22N (235)-R M22N each, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, or morpholino; -R M22 , -OH and -OR M22A compound according to any one of (1) to (44) and (175) to (234), optionally substituted with one or more substituents selected from:

[0344] (236)-R M22N A compound according to any one of (1) to (44) and (175) to (234), wherein each, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, or morpholino.

[0345] Group-R J1 (237)-R J1 A compound according to any one of (1) to (44) and (175) to (236), wherein each, if present, is —H.

[0346] (238)-R J1 If each exists, -R JJ A compound according to any one of (1) to (44) and (175) to (236),

[0347] Group-R J2 (239)-R J2 A compound according to any one of (1) to (44) and (175) to (238), wherein each, if present, is —H.

[0348] (240)-R J2 If each exists, -R JJ A compound according to any one of (1) to (44) and (175) to (238),

[0349] Group-R J3 (241)-R J3 If present, -R JJ A compound according to any one of (1) to (44) and (175) to (240),

[0350] Group-R J4 and -R J5 (242)-R J4 , if present, are independently -H, -R JJ or -L JJ -OH, -R J5 , if present, are independently -H, -R JJ or -L JJ is —OH, or -R J4 and -R J5 , when present, combine to form =O, A compound according to any one of (1) to (44) and (175) to (241).

[0351] (243)-R J5 A compound according to any one of (1) to (44) and (175) to (241), wherein, if present, is —H.

[0352] (244)-R J4 , if present, are independently -H, -R JJ or -L JJ -OH, -R J5 is, if present, -H, or -R J4 and -R J5 , when present, combine to form =O, A compound according to any one of (1) to (44) and (175) to (241).

[0353] (245)-R J4 is -H, if present; -R J5 is -H, if present; A compound according to any one of (1) to (44) and (175) to (241).

[0354] Group-R JJ (246)-R JJ each, if present, independently represents a linear or branched saturated C 1~3A compound according to any one of (1) to (44) and (175) to (245), wherein the compound is alkyl.

[0355] (247)-R JJ A compound according to any one of (1) to (44) and (175) to (245), wherein each, if present, is independently -Me or -Et.

[0356] (248)-R JJ A compound according to any one of (1) to (44) and (175) to (245), wherein each, if present, is -Me.

[0357] Group-L JJ - (249)-L JJ - each, if present, independently a linear or branched saturated C 1~3 A compound according to any one of (1) to (44) and (175) to (248), wherein the compound is alkylene.

[0358] (250)-L JJ A compound according to any one of (1) to (44) and (175) to (248), wherein each -, if present, is independently -CH2-, -CH2CH2-, or -CH2CH2CH2-.

[0359] (251)-L JJ A compound according to any one of (1) to (44) and (175) to (248), wherein each -, if present, is independently -CH2- or -CH2CH2-.

[0360] Specific Embodiments (252) A compound according to (1), which is one of the following formulae, or a pharmaceutically acceptable salt or solvate thereof:

[0361] [Table 6] TIFF0007815250000047.tif255139TIFF0007815250000048.tif250137TIFF0007815250000049.tif77139

[0362] (253) A compound according to (1), which is one of the following formulae, or a pharmaceutically acceptable salt or solvate thereof:

[0363] [Table 7] TIFF0007815250000051.tif251152TIFF0007815250000052.tif250152TIFF0007815250000053.tif245153TIFF0007815250000054.tif95154

[0364] (254) A compound according to (1), which is one of the following formulae, or a pharmaceutically acceptable salt or solvate thereof:

[0365] [Table 8] TIFF0007815250000056.tif27155

[0366] combination It is understood that certain features of the compounds that are, for clarity, described in the context of individual embodiments, may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the compounds that are described in the context of a single embodiment may also be provided individually or in any suitable subcombination. Variable groups (e.g., -Q-, -J, R 1 , R 3 , R 4All combinations of embodiments for chemical groups represented by the variables (e.g., ...

[0367] Substantially Purified Form One aspect of the present invention pertains to the ALDHI compounds described herein in substantially purified form and / or substantially free of impurities.

[0368] In one embodiment the substantially purified form is at least 50% by weight, such as at least 60% by weight, for example at least 70% by weight, such as at least 80% by weight, for example at least 90% by weight, such as at least 95% by weight, for example at least 97% by weight, such as at least 98% by weight, for example at least 99% by weight.

[0369] Unless otherwise specified, a substantially purified form refers to a compound in any stereoisomeric or enantiomeric form. For example, in one embodiment, a substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds. In one embodiment, a substantially purified form refers to a single stereoisomer, e.g., an optically pure stereoisomer. In one embodiment, a substantially purified form refers to a mixture of enantiomers. In one embodiment, a substantially purified form refers to an equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, a substantially purified form refers to a single enantiomer, e.g., an optically pure enantiomer.

[0370] In one embodiment, the impurities represent 50% by weight or less, such as 40% by weight or less, for example 30% by weight or less, such as 20% by weight or less, for example 10% by weight or less, such as 5% by weight or less, for example 3% by weight or less, such as 2% by weight or less, for example 1% by weight or less.

[0371] Unless specified, impurities refer to other compounds, i.e., other than stereoisomers or enantiomers. In one embodiment, impurities refer to other compounds and other stereoisomers. In one embodiment, impurities refer to other compounds and other enantiomers.

[0372] In one embodiment, the substantially purified form is at least 60% optically pure (i.e., 60% of the compound is the desired stereoisomer or enantiomer on a molar basis and 40% is the undesired stereoisomer or enantiomer), such as at least 70% optically pure, such as at least 80% optically pure, for example at least 90% optically pure, such as at least 95% optically pure, for example at least 97% optically pure, such as at least 98% optically pure, for example at least 99% optically pure.

[0373] Isomers Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereomeric, epimeric, atropic, stereoisomeric, tautomeric, stereoconfigurative, or anomeric forms, including, but not limited to, cis and trans forms; E and Z forms; c, t and r forms; endo and exo forms; R, S and meso forms; D and L forms; d and l forms; (+) and (-) forms; keto, enol, and enolate forms; syn and anti forms; synclinal and anticlinal forms; α and β forms; axial and equatorial forms; boat, chair, twisted, envelope, and half-chair forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").

[0374] When referring to a structural class, structural isomeric forms that fall within that class can of course be included (e.g., C 1~7 (Alkyl includes n-propyl and isopropyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl. However, when referring to a particular group or substitution pattern, it is not intended to include other structures (or constitutional isomers) that differ with respect to the bonds between atoms rather than by position in space. For example, when referring to a methoxy group, -OCH3 should not be construed as referring to its constitutional isomer, the hydroxymethyl group, i.e., -CH2OH. Similarly, when referring to ortho-chlorophenyl, it should not be construed as referring to its constitutional isomer, meta-chlorophenyl.

[0375] The above exclusion does not relate to tautomers, such as keto, enol, and enolate, as in, for example, the following tautomeric pairs: keto / enol (exemplified below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, N-nitroso / hydroxyazo, and nitro / aci-nitro. When one tautomer is mentioned herein, it is intended to encompass both tautomers.

[0376] [ka]

[0377] For example, 1H-pyridin-2-one-5-yl and 2-hydroxyl-pyridin-5-yl (shown below) are tautomers of each other, and when one is mentioned herein, both are intended to be included.

[0378] [ka]

[0379] It should be noted that the term "isomer" specifically includes compounds with one or more isotopic substitutions. For example, H is 1 H, 2 H(D) and 3 H may be any isotope, including T; C may be 12 C. 13 C and 14 It can be any isotope, including C; O can be 16 O and 18 It may be any isotope containing O;

[0380] Unless otherwise specified, a reference to a particular compound includes all such isomers, including mixtures thereof (e.g., racemic mixtures). Methods for preparing (e.g., asymmetric synthesis) and separating (e.g., fractional crystallization and chromatographic means) such isomers are either known in the art or readily obtained by the methods taught herein or by adapting known methods in a known manner.

[0381] salt It may be convenient or desirable to prepare, purify, and / or handle corresponding salts of the compounds, e.g., pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., 66:1-19.

[0382] For example, if the compound is anionic, or if a functional group that can be anionic (e.g., -COOH can be replaced with -COO - (which may be) salts can be formed with suitable cations. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions, such as Na + and K. + , alkaline earth cations, e.g., Ca 2+ and Mg 2+ , as well as other cations, such as Al 3+ , and ammonium ions (i.e., NH4 +Examples of suitable organic cations include, but are not limited to, substituted ammonium ions (e.g., NHR + , NH2R2 + , NHR3 + , NR4 + ), for example, where each R is independently a linear or branched saturated C 1~18 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl-C 1~6 Alkyl and phenyl-C 1~6 The substituted ammonium ions are alkyl, and the phenyl group is optionally substituted. Some suitable examples of substituted ammonium ions are ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, and those derived from amino acids such as lysine and arginine. One example of a common quaternary ammonium ion is N(CH3)4 + is.

[0383] If a compound is cationic, or if it is protonated, it can become cationic (e.g., -NH2 becomes -NH3 + If the compound has a functional group which can be a salt, salts can be formed with a suitable anion.

[0384] For example, if the parent structure contains a cationic group (e.g., -NMe2 + ), or when protonated, can be cationic (e.g., -NH2 becomes -NH3 + If the compound has a functional group (e.g., -NMe2), salts can be formed with a suitable anion. In the case of quaternary ammonium compounds, a counter anion is generally always present to counteract the positive charge. If the compound has a cationic group (e.g., -NMe2), salts can be formed with a suitable anion. In the case of quaternary ammonium compounds, a counter anion is generally always present to counteract the positive charge. + , -NH3 + ), also contains a group capable of forming an anion (e.g., —COOH), an internal salt (also called a zwitterion) may be formed.

[0385] Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.

[0386] Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyloxybenzoic acid, acetic acid, trifluoroacetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edetic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalenecarboxylic acid, isethionic acid, lactic acid, lactobioic acid, lauric acid, maleic acid, malic acid, methanesulfonic acid, mucic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic acid, phenylacetic acid, phenylsulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, toluenesulfonic acid, and valeric acid. Examples of suitable organic anionic polymers include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

[0387] Unless otherwise specified, a reference to a particular compound also includes its salt forms.

[0388] Solvates and Hydrates It may be convenient or desirable to prepare, purify, and / or handle a corresponding solvate of a compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. When the solvent is water, the solvate may be conveniently referred to as a hydrate, e.g., a monohydrate, a dihydrate, a trihydrate, etc.

[0389] Unless otherwise specified, when a particular compound is mentioned, solvates and hydrate forms thereof are also included.

[0390] chemical protection form It may be convenient or desirable to prepare, purify, and / or handle compounds in chemically protected form. The term "chemically protected form" is used herein in its conventional chemical sense to refer to a compound in which one or more reactive functional groups are protected from undesired chemical reactions under certain conditions (e.g., pH, temperature, radiation, solvents, reactive chemical reagents, etc.). Indeed, well-known chemical methods are used to reversibly render unreactive functional groups that would otherwise be reactive under certain conditions. In chemically protected form, one or more reactive functional groups are in the form of protected or protecting groups (alternatively, as masked or blocked groups). Protecting a reactive functional group allows reactions involving other unprotected reactive functional groups to be carried out without affecting the protected group. Typically, in a subsequent step, the protecting group can be removed or the masking group can be transformed without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th ed.; John Wiley and Sons, 2006).

[0391] A wide variety of such "protecting," "blocking," or "masking" methods are widely used and well known in organic synthesis. For example, a compound having two unequal reactive functional groups (both of which are reactive under certain conditions) can be derivatized to render one of the functional groups "protected," i.e., unreactive under certain conditions; so protected, the compound can be used as a reactant effectively possessing only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group can be "deprotected," returning the protected group to its original functionality.

[0392] For example, a hydroxy group can be protected as an ether (-OR) or ester (-OC(=O)R), such as a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl) or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH, -OAc).

[0393] For example, amine groups may be substituted, for example, as amides (-NRCO-R), such as acetamide (-NHCO-CH); or as carbamates (-NRCO-OR), such as benzyloxycarbamate (-NHCO-OCH2C6H5, -NH-Cbz), t-butoxycarbamate (-NHCO-OC(CH3)3, -NH-Boc); 2-biphenyl-2-propoxycarbamate (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc), 9-fluorenylmethoxycarbamate (-NH-Fmoc), 6-nitro It can be protected as a veratryloxycarbamate (-NH-Nvoc), as a 2-trimethylsilylethyloxycarbamate (-NH-Teoc), as a 2,2,2-trichloroethyloxycarbamate (-NH-Troc), as an allyloxyamide (-NH-Alloc) or as a 2(-phenylsulfonyl)ethyloxycarbamate (-NH-Psec); or, where appropriate (e.g., a cyclic amine), as a nitroxide radical (>NO●); or, where appropriate (e.g., a heterocyclic nitrogen), as a 2-trimethylsilylethoxymethyl (N-SEM).

[0394] Prodrug It may be convenient or desirable to prepare, purify, and / or handle compounds in the form of a prodrug. The term "prodrug," as used herein, refers to a compound that yields the desired active compound in vivo. Typically, prodrugs are inactive or less active than the desired active compound, but may offer advantageous handling, administration, or metabolic properties.

[0395] For example, some prodrugs are esters of the active compound (e.g., physiologically acceptable, metabolically labile esters). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters can be formed, for example, by esterifying any carboxylic acid groups (-C(=O)OH) in the parent compound, optionally before protecting any other reactive groups present in the parent compound, followed by deprotection, if necessary.

[0396] composition Also described herein are compositions (e.g., pharmaceutical compositions) comprising an ALDHI compound described herein and a pharmaceutically acceptable carrier, diluent, or excipient.

[0397] Also described herein are methods for preparing compositions (e.g., pharmaceutical compositions) that include mixing an ALDHI compound described herein and a pharmaceutically acceptable carrier, diluent, or excipient.

[0398] use The ALDH1A3 compounds described herein inhibit the ALDH1A3 enzyme (eg, inhibit, reduce, or block the activity or function of the ALDH1A3 enzyme).

[0399] Thus, the ALDH1A3 compounds described herein are useful, for example, for treating disorders (e.g., diseases) that are ameliorated by inhibition of the ALDH1A3 enzyme (e.g., by inhibiting, reducing, or blocking the activity or function of the ALDH1A3 enzyme).

[0400] Use in methods for inhibiting the ALDH1A3 enzyme Similarly, methods are described herein for inhibiting the ALDH1A3 enzyme (e.g., inhibiting, reducing, or blocking the activity or function of the ALDH1A3 enzyme) in vitro or in vivo, comprising contacting the ALDH1A3 enzyme with an effective amount of an ALDHI compound described herein.

[0401] Similarly, methods are described herein for inhibiting the ALDH1A3 enzyme (e.g., inhibiting, reducing, or blocking the activity or function of the ALDH1A3 enzyme) in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of an ALDH1A3 compound described herein.

[0402] In one embodiment, the method is performed in vitro.

[0403] In one embodiment, the method is performed in vivo.

[0404] In one embodiment, the ALDHI compound is provided in the form of a pharmaceutically acceptable composition.

[0405] One skilled in the art can readily determine whether a candidate compound inhibits the ALDH1A3 enzyme (e.g., inhibits, reduces, or blocks the activity or function of the ALDH1A3 enzyme). For example, suitable assays are described herein and / or known in the art.

[0406] Those skilled in the art can easily determine whether a candidate compound inhibits ALDH1A3 enzyme in cells (e.g., inhibits, reduces, or blocks the activity or function of ALDH1A3 enzyme). For example, a sample of cells can be grown in vitro, a compound can be contacted with the cells, and the effect of the compound on the cells can be observed. As an example of "effect," the morphological state of the cells (e.g., whether alive or dead) can be determined. If the compound is found to affect cells, this can be used as a prognostic or diagnostic marker for the effectiveness of the compound in methods of treating subjects (e.g., patients) with cells of the same cell type. As another example of "effect," the direct interaction of the compound with a target in cells can be measured, for example, using colorimetric, fluorescent, or luminescent readings (e.g., "target engagement assay").

[0407] Use in methods for inhibiting cell proliferation, etc. The ALDHI compounds described herein can, for example, (a) modulate (e.g., inhibit) cell proliferation, (b) inhibit cell cycle progression, (c) promote apoptosis, (d) reduce clonogenicity, (e) reduce tumor growth or self-renewal, or (f) a combination of one or more of these.

[0408] Thus, also described herein are methods for modulating (e.g., inhibiting) cell proliferation (e.g., proliferation of cells), inhibiting cell cycle progression, promoting apoptosis, reducing clonogenicity, reducing tumor growth or self-renewal, in vitro or in vivo, or a combination of one or more thereof, comprising contacting a cell with an effective amount of an ALDHI compound described herein.

[0409] In one embodiment, the method is performed in vitro.

[0410] In one embodiment, the method is performed in vivo.

[0411] In one embodiment, the ALDHI compound is provided in the form of a pharmaceutically acceptable composition.

[0412] For example, any type of cell can be treated or targeted, including blood (including, e.g., neutrophils, eosinophils, basophils, lymphocytes, monocytes, red blood cells, platelets), lung, gastrointestinal tract (including, e.g., intestine, colon), breast (breast), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreatic, brain, and skin cells.

[0413] One of ordinary skill in the art can readily determine whether a candidate compound modulates (e.g., inhibits) cell proliferation, etc. For example, assays that can be conveniently used to evaluate the activity exerted by a particular compound are described herein and / or known in the art.

[0414] The ALDHI compounds described herein can inhibit cell migration and invasion, for example, can inhibit metastasis.

[0415] The ALDHI compounds described herein can restore sensitivity to another drug in a resistant cell population.

[0416] The ALDHI compounds described herein can prevent the emergence of resistance to other drugs in a cell population.

[0417] Use in methods of treatment Also described herein are ALDHI compounds described herein for use in methods of treatment of the human or animal body by therapy, e.g., for use in methods of treatment of disorders (e.g., diseases) described herein.

[0418] Also described herein is the use of the ALDHI compounds described herein in methods of treatment of the human or animal body by therapy, for example, in methods of treatment of disorders (e.g., diseases) described herein.

[0419] Use in the manufacture of medicines Also described herein is the use of the ALDHI compounds described herein, e.g., in the manufacture of a medicament for use in a method of treatment, e.g., for use in a method of treatment of a disorder (e.g., a disease) described herein.

[0420] In one embodiment, the medicament comprises an ALDHI compound.

[0421] Treatment method Similarly, methods of treatment, e.g., methods of treating a disorder (e.g., a disease) described herein, comprising administering to a subject in need of treatment a therapeutically effective amount of an ALDHI compound described herein, preferably in the form of a pharmaceutical composition, are described herein.

[0422] Disorders Treated - Disorders ameliorated by inhibition of the ALDH1A3 enzyme In one embodiment (e.g., compounds for use in methods of treatment, uses in methods of treatment, uses in the manufacture of medicaments, methods of treatment), treatment refers to treatment of a disorder (e.g., a disease) that is ameliorated by inhibition of the ALDH1A3 enzyme (e.g., by inhibiting, reducing, or blocking the activity or function of the ALDH1A3 enzyme).

[0423] Disorders to be treated In one embodiment (e.g., compounds for use in methods of treatment, uses in methods of treatment, uses in the manufacture of medicaments, methods of treatment), treatment refers to treatment of a disorder (e.g., disease) described herein, e.g., proliferative disorder, cancer, diabetes, cardiovascular disorder, etc.

[0424] Proliferative disorders In one embodiment, the disorder is a proliferative disorder.

[0425] The term "proliferative disorder" as used herein relates to unwanted or uncontrolled cell proliferation, such as unwanted excess or abnormal cells, eg, neoplastic or hypertrophic growth.

[0426] In one embodiment, the proliferative disorder is characterized by benign, pre-malignant, malignant, pre-metastatic, metastatic, or non-metastatic cell proliferation, including, for example: neoplasia, hyperplasia, tumor (e.g., histiocytoma, glioma, astrocytoma, osteoma), cancer, psoriasis, bone disease, fibroproliferative disorders (e.g., of connective tissue), pulmonary fibrosis, atherosclerosis, and smooth muscle cell proliferation in blood vessels, e.g., stenosis or restenosis after angioplasty.

[0427] cancer In one embodiment, the disorder is cancer.

[0428] In one embodiment, the cancer is: Sarcomas of the bone or muscle, such as: bone cancer; osteosarcoma; chondrosarcoma; Ewing's sarcoma; cardiac cancer; leiomyosarcoma; malignant fibrous histiocytoma of bone; osteosarcoma; or rhabdomyosarcoma; Brain and nervous system cancers, including: Astrocytoma; brain cancer; brain stem glioma; cerebellar astrocytoma; cerebral astrocytoma; ependymoma; glioblastoma; glioma; medulloblastoma; neuroblastoma; oligodendroglioma; pilocytic astrocytoma; pineal astrocytoma; pituitary adenoma; primitive neuroectodermal tumor; schwannoma; or visual pathway and hypothalamic glioma; Breast cancer, such as: breast cancer; invasive cribriform carcinoma; inflammatory breast cancer; invasive lobular carcinoma; medullary carcinoma; male breast cancer; phyllodes tumor; or tubular carcinoma; Endocrine system cancers, such as: adrenal gland cancer; adrenocortical carcinoma; papillary thyroid cancer; follicular thyroid cancer; islet cell carcinoma; multiple endocrine neoplasia syndrome; parathyroid carcinoma; pheochromocytoma; thyroid cancer; or thyroid carcinoma; Eye cancers, such as: retinoblastoma; or uveal melanoma; Gastrointestinal cancers, including: Anal cancer; appendix cancer; bile duct cancer; intestinal cancer; cholangiocarcinoma; colon adenocarcinoma; colon adenoma; colon cancer; exocrine pancreatic cancer; extrahepatic bile duct cancer; gallbladder cancer; gastric (stomach) cancer; gastrointestinal cancer; gastrointestinal carcinoid tumor; gastrointestinal carcinoid tumor; gastrointestinal stromal tumor (GIST); hepatocellular carcinoma; hepatoblastoma; kidney cancer; colon cancer; liver cancer; ocolorectal cancer; pancreatic cancer; rectal cancer; or small intestine cancer; Genitourinary or gynecological cancers, such as: bladder cancer; cervical cancer; endometrial cancer; extragonadal germ cell tumor; genitourinary cancer; gestational trophoblastic tumor; gynecological cancer; ovarian cancer; ovarian epithelial cancer; ovarian germ cell tumor; penile cancer; prostate cancer; renal cell carcinoma; renal pelvis and ureter, transitional cell carcinoma; seminoma; teratocarcinoma; testicular cancer; transitional cell carcinoma of the ureter and renal pelvis; urethral cancer; uterine sarcoma; vaginal cancer; vulvar cancer; or Wilms' tumor; Head and neck cancers, such as: esophageal cancer; head and neck cancer; head and neck squamous cell carcinoma; hypopharyngeal cancer; nasopharyngeal cancer; oral cancer; oropharynx cancer; paranasal sinus and nasal cavity cancer; pharyngeal cancer; or salivary gland cancer; Cancers of the hematopoietic tissue, such as: Plasma cell neoplasms, such as plasmacytoma or multiple myeloma; Leukemias, for example: acute biphenotypic leukemia; acute eosinophilic leukemia; acute lymphoblastic leukemia; acute myeloid dendritic cell leukemia; acute myeloid leukemia; acute promyelocytic leukemia; B-cell prolymphocytic leukemia; chronic lymphocytic leukemia; chronic myeloid leukemia; hairy cell leukemia; large granular lymphocytic leukemia; mast cell leukemia; precursor B-lymphoblastic leukemia; T-cell prolymphocytic leukemia; Lymphomas, such as: AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic T-cell lymphoma; Burkitt's lymphoma; cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; follicular lymphoma; hepatosplenic T-cell lymphoma; Hodgkin's lymphoma; intravascular large B-cell lymphoma; lymphomatoid granulomatosis; lymphoplasmacytic lymphoma; mantle cell lymphoma; marginal zone B-cell lymphoma; mediastinal large B-cell lymphoma; mucosa-associated lymphoid tissue lymphoma; mycosis fungoides; nodal marginal zone B-cell lymphoma; non-Hodgkin's lymphoma; plasmablastic lymphoma; primary central nervous system lymphoma; primary cutaneous follicular lymphoma; primary cutaneous immunocytoma; primary effusion lymphoma; Sézary syndrome; or splenic marginal zone lymphoma; or myelodysplastic syndrome; Skin cancer, such as: basal cell carcinoma; dermatofibrosarcoma protuberans; fibrosarcoma; keratoacanthoma; malignant melanoma; melanoma; Merkel cell carcinoma; sebaceous gland carcinoma; or squamous cell carcinoma; Thoracic and respiratory cancers, such as: adenocarcinoma; bronchial adenoma; bronchial carcinoid; laryngeal cancer; lung cancer; mediastinal cancer; mesothelioma; non-small cell lung cancer; peritoneal cancer; pleuropulmonary blastoma; small cell lung cancer; thymic carcinoma; or thymoma carcinoma; HIV / AIDS-related cancers, e.g., Kaposi's sarcoma; or other cancers, such as epithelioid hemangioendothelioma; desmoplastic small cell tumor; or liposarcoma.

[0429] In one embodiment, the cancer is: melanoma Fibrosarcoma Breast cancer, e.g., triple-negative subtype breast cancer glioma Glioblastoma Lung cancer, e.g., non-small cell lung cancer mesothelioma thyroid cancer renal cell carcinoma Pancreatic cancer stomach cancer Colorectal cancer Gallbladder cancer Cholangiocellular carcinoma Neuroblastoma Testicular germ cell cancer ovarian cancer or Prostate cancer.

[0430] In one embodiment, the cancer (eg, as described above) is characterized by aberrant expression of ALDH1A3.

[0431] In one embodiment, the cancer (eg, as described above) is characterized by overexpression of ALDH1A3.

[0432] In one embodiment, the cancer (eg, described above) is characterized or further characterized as a chemotherapy-resistant cancer and / or a radiotherapy-resistant cancer.

[0433] In one embodiment, the cancer (e.g., described above) is characterized or further characterized as an immunotherapy-resistant cancer.

[0434] In one embodiment, the cancer (e.g., described above) is characterized or further characterized as an immunotherapy-resistant cancer characterized by the presence or elevated abundance of regulatory T cells.

[0435] In one embodiment, the cancer (eg, described above) is characterized or further characterized as a metastatic cancer.

[0436] obesity In one embodiment, the disorder is obesity or a complication of obesity.

[0437] In one embodiment, the disorder is obesity.

[0438] In one embodiment, the disorder is a complication of obesity, including type II diabetes.

[0439] diabetes In one embodiment, the disorder is diabetes.

[0440] In one embodiment, the disorder is type II diabetes.

[0441] cardiovascular disorders In one embodiment, the disorder is a cardiovascular disorder.

[0442] In one embodiment, the disorder is restenosis.

[0443] In one embodiment, the disorder is intimal hyperplasia.

[0444] In one embodiment, the disorder is intimal hyperplasia after vascular reconstruction.

[0445] In one embodiment, the disorder is intimal hyperplasia after coronary angioplasty / stenting, bypass vein graft, arteriovenous fistula (eg, for dialysis access), or allograft transplantation.

[0446] In one embodiment, the disorder is pulmonary arterial hypertension (PAH).

[0447] treatment The term "treatment," as used herein generally, in the context of treating a disorder (e.g., a disease), relates to the treatment of a human or animal (e.g., in veterinary applications) to achieve a desired therapeutic effect, such as inhibiting the progression of the disorder (e.g., including slowing or stopping the rate of progression), alleviating the symptoms of the disorder, ameliorating the disorder, and curing the disorder. Treatment as a preventative measure (i.e., prophylaxis) is also included. For example, use in subjects (e.g., patients) who have not yet developed the disorder but are at risk of developing the disorder is encompassed by the term "treatment."

[0448] For example, treating cancer includes reducing the progression of cancer, alleviating the symptoms of cancer, reducing the incidence of cancer, preventing cancer, and the like.

[0449] The term "therapeutically effective amount," as used herein, relates to that amount of a compound or agent, composition containing a compound, or dosage form that, when administered in accordance with a desired treatment regimen, is effective to produce some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio.

[0450] Combination therapy The term "treatment," as used herein, includes combination treatments and combination therapies, where two or more treatments or therapies are combined, e.g., sequentially or simultaneously. For example, the ALDHI compounds described herein may also be used in combination therapy, e.g., in conjunction with other agents.

[0451] Thus, also described herein are ALDHI compounds described herein in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents.

[0452] The particular combination is at the discretion of the physician who will select dosages using common general knowledge and dosing regimens known to the skilled physician.

[0453] The agents (e.g., an ALDHI compound described herein and one or more other agents) may be administered simultaneously or sequentially, and may be administered on various individual dosing schedules and by various routes. For example, if the agents are administered sequentially, they may be administered closely spaced apart (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., spaced 1 hour, 2 hours, 3 hours, 4 hours, or more, or even longer if necessary), with the exact dosing regimen being consistent with the properties of the therapeutic agents.

[0454] The agents (e.g., an ALDHI compound described herein and one or more other agents) may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and provided together in the form of a kit, optionally with instructions for their use.

[0455] In one embodiment, the other agent (e.g., additional therapeutic agent) is an immunotherapeutic agent, e.g., an immune checkpoint inhibitor.

[0456] Other uses The ALDH1A3 compounds described herein may also be used as additives for cell culture to inhibit the ALDH1A3 enzyme (e.g., to inhibit, reduce, or block the activity or function of the ALDH1A3 enzyme).

[0457] The ALDHI compounds described herein may also be used as part of an in vitro assay, for example, to determine whether a candidate host is likely to benefit from treatment with the compound of interest.

[0458] The ALDH1A3 compounds described herein may be used as standards in assays, for example, to identify other active compounds, ie, other ALDH1A3 enzyme inhibitors.

[0459] kit Also described herein are kits that include (a) an ALDHI compound described herein, preferably supplied as a composition (e.g., a pharmaceutical composition) in a suitable container and / or in suitable packaging, and (b) instructions for use, e.g., written instructions on how to administer the compound, e.g., in a method of treating a disorder (e.g., a disease) described herein.

[0460] The written instructions may also include a list of indications for which the ALDHI compound is a suitable treatment.

[0461] Administration route The ALDHI compound, or a pharmaceutical composition comprising the ALDHI compound, may be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (i.e., at the desired site of action).

[0462] Routes of administration include, for example, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by mouth or nose, e.g., by aerosol, e.g., by inhalation therapy or inhalation therapy); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral by injection, including, for example, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intrathecal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal;

[0463] subject The subject (e.g., a patient) can be an invertebrate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., a kangaroo, a wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), a murine (e.g., a mouse), a lagomorph (e.g., a rabbit), an avian (e.g., a bird), a canine (e.g., a dog), a feline (e.g., a cat), an equine (e.g., a horse), a porcine (e.g., a pig), an ovine (e.g., a sheep), a bovine (e.g., a cow), a primate, a simian (e.g., a monkey or ape), a monkey (e.g., a marmoset, a baboon), an ape (e.g., a gorilla, a chimpanzee, an orangutan, a gibbon), or a human.

[0464] Furthermore, a subject (eg, a patient) may be in any of its forms of development, for example, a fetus.

[0465] In a preferred embodiment, the subject (eg, patient) is a human.

[0466] formulation While it is possible for an ALDHI compound to be administered alone, it is preferable to provide the compound as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one ALDHI compound described herein together with one or more other pharmaceutically acceptable ingredients known to those of skill in the art (e.g., including pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavoring agents, and sweetening agents). The formulation may further comprise other active agents, e.g., other therapeutic or prophylactic agents.

[0467] Thus, also described herein are pharmaceutical compositions as defined above, and methods of making such compositions comprising mixing at least one ALDHI compound described herein together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, such as carriers, diluents, excipients, etc. When formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.

[0468] The term "pharmaceutically acceptable," as used herein, pertains to compounds, ingredients, substances, compositions, dosage forms, and the like, that are suitable for use in contact with the tissues of the subject in question (e.g., humans) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0469] Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical textbooks, such as Remington: The Science and Practice of Pharmacy, 21st ed., Lippinott Williams and Wilkins, 2005; Remington: The Science and Practice of Pharmacy, 22nd ed., Pharmaceutical Press, 2012; and Handbook of Pharmaceutical Excipients, 7th ed., Pharmaceutical Press, 2012.

[0470] The formulations may be prepared by any method well known in the art of pharmacy. Such methods include the step of combining the compound with a carrier, which constitutes one or more accessory ingredients. Generally, the formulations are prepared by uniformly and intimately bringing the compound into association with a carrier (e.g., a liquid carrier, a finely divided solid carrier, etc.), and then, if necessary, shaping the product.

[0471] The formulations may be prepared to provide fast or slow release; immediate, delayed, time-modified or sustained release, or combinations thereof.

[0472] Formulations may suitably be in the form of a liquid, solution (e.g., aqueous, non-aqueous), suspension (e.g., aqueous, non-aqueous), emulsion (e.g., oil-in-water, water-in-oil), elixir, syrup, electuary, mouthwash, drops, tablet (e.g., including coated tablets), granules, powder, lozenge, pastille, capsule (e.g., including hard and soft gelatin capsules), cachet, pill, ampoule, bolus, suppository, pessary, tincture, gel, paste, ointment, cream, lotion, oil, foam, spray, mist or aerosol.

[0473] The formulations may suitably be presented as patches, adhesive plasters, bandages, dressings, etc., impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients including, for example, penetration enhancers, permeation enhancers and absorption enhancers. The formulations may also suitably be presented in the form of a depot or reservoir.

[0474] The compound may be dissolved, suspended, or mixed with one or more other pharmaceutically acceptable ingredients. The compound may also be delivered in liposomes or other microparticles that are designed to target the compound, for example, to blood components or one or more organs.

[0475] Formulations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, lozenges, tablets, granules, powders, capsules, cachets, pills, ampoules, and boluses.

[0476] Formulations suitable for oral administration include mouthwashes, lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Lozenges typically contain the compound in a flavored base, typically sucrose and acacia or tragacanth. Pastilles typically contain the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically contain the compound in a suitable liquid carrier.

[0477] Formulations suitable for sublingual administration include tablets, lozenges, pastilles, capsules, and pills.

[0478] Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), mouthwashes, lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.

[0479] Formulations suitable for parenteral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.

[0480] Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.

[0481] Tablets can be prepared by conventional means, such as compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the compound in a free-flowing form, such as powder or granules, in a suitable machine, optionally mixed with one or more of the following: binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethylcellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose); surfactants or dispersants or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavors, flavor enhancers, and sweeteners. Molded tablets can also be prepared by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or engraved and may be formulated to provide slow or controlled release of the compound in the tablet, for example, using various percentages of hydroxypropyl methylcellulose to achieve a desired release profile. Tablets may optionally be provided with a release coating, for example, an enteric coating, to provide release in parts of the digestive tract other than the stomach.

[0482] Ointments are typically prepared from the compound and a paraffinic base or a water-miscible ointment base.

[0483] Creams are typically prepared from the compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base can contain, for example, at least about 30% w / w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol, and mixtures thereof. Topical formulations may desirably contain a compound that enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

[0484] Emulsions are usually prepared simply from the compound and an oily phase, which may optionally contain an emulsifier (otherwise known as an emulsifier), or they may contain a mixture of at least one emulsifier with a fat or oil, or both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer.It is also preferred that the hydrophilic emulsifier contains both an oil and a fat.At the same time, the emulsifier, with or without a stabilizer, constitutes the so-called emulsifying wax, and the wax together with the oil and / or fat constitutes the so-called emulsifying ointment base that forms the oily dispersed phase of a cream formulation.

[0485] Suitable emulsifier and emulsion stabilizers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. Because the solubility of the present compounds in most oils likely to be used in pharmaceutical emulsion formulations can be very low, the selection of an oil or fat suitable for the formulation is based on achieving the desired cosmetic properties. Therefore, creams should preferably be non-sticky, non-staining, and washable products with suitable consistency to avoid leakage from tubes or other containers. Linear or branched mono- or dibasic alkyl esters, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of branched esters (known as Crodamol CAP), may also be used, the latter three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white petrolatum and / or liquid paraffin or other mineral oils can be used.

[0486] Suitable formulations for intranasal administration, where the carrier is a liquid, include, for example, nasal spray, nasal drops, or by aerosol administration by nebulizer, include aqueous or oily solutions of the compound.

[0487] Where the carrier is a solid, formulations suitable for nasal administration include those supplied as a coarse powder having a particle size in the range, for example, from about 20 to about 500 microns, which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nose.

[0488] Formulations suitable for pulmonary administration (e.g., by inhalation or inhalation therapy) include those delivered as an aerosol spray from pressurized packs with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.

[0489] Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.

[0490] Formulations suitable for rectal administration may be presented as suppositories with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, such as cocoa butter or salicylates; or as solutions or suspensions for administration by enema.

[0491] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the compound, such carriers as are known in the art to be appropriate.

[0492] Formulations suitable for parenteral administration (e.g., by injection) include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions) in which the compound is dissolved, suspended, or otherwise provided (e.g., in liposomes or other microparticles). Such liquids may further contain other pharmaceutically acceptable ingredients, such as antioxidants, buffers, preservatives, stabilizers, bacteriostats, suspending agents, thickeners, and solutes that render the formulation isotonic with the blood (or other relevant body fluids) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of isotonic carriers suitable for use in such formulations include sodium chloride injection, Ringer's solution, or lactated Ringer's solution. Typically, the concentration of the compound in the liquid is from about 1 ng / mL to about 10 μg / mL, e.g., from about 10 ng / mL to about 1 μg / mL. The formulations may be supplied in unit-dose or multi-dose sealed containers, for example, ampoules and vials and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

[0493] Dosage Those skilled in the art will understand that appropriate dosages of ALDHI compounds and compositions containing ALDHI compounds may vary from subject to subject (e.g., patient to patient). Determining the optimal dosage generally involves balancing the level of therapeutic benefit against any risk or adverse side effects. The selected dosage level will depend on a variety of factors, including the specific ALDHI compound, the route of administration, the time of administration, the rate of excretion of the ALDHI compound, the duration of treatment, other drugs, concomitant compounds and / or substances, the severity of the disorder, and the species, sex, age, weight, condition, general health, and medical history of the subject (e.g., patient). The amount and route of administration of the ALDHI compound are ultimately at the discretion of the physician, veterinarian, or clinician, but generally, the dosage will be selected to achieve a local concentration at the site of action that achieves the desired effect without causing significant harm or adverse side effects.

[0494] Administration can be in one dose, continuously, or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those skilled in the art and will vary depending on the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.

[0495] In general, a suitable dose of the ALDHI compound is in the range of about 0.01 mg to about 5000 mg (more typically, about 0.1 mg to about 1000 mg, eg, about 0.1 mg to about 300 mg) per day.

[0496] Where the compound is a salt, solvate, ester, amide, prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately. [Example]

[0497] chemical synthesis Abbreviation {1H}: proton decoupling. Aq.: Aqueous. BAST: [bis(2-methoxyethyl)amino]sulfur trifluoride (Deoxo-Fluor®). t-Boc: tert-butyloxycarbonyl. DBU: 1,8-diazabicyclo[5.4.0]undeca-7-ene. DCM: dichloromethane (methylene chloride). DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. DIAD: diisopropyl azodicarboxylate. DIPEA: N,N-diisopropylethylamine. DME: 1,2-dimethoxyethane. DMP: Dess-Martin periodinane. DMAP: 4-(dimethylamino)pyridine. DMSO: dimethyl sulfoxide. ES: electrospray ionization. Et2O: Ether (diethyl ether). EtOAc: ethyl acetate. EtOH: Ethanol (ethyl alcohol). HATU: 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate. MeCN: acetonitrile. MeOH: methanol (methyl alcohol). NaBH4: sodium borohydride. NaOtBu: sodium tert-butoxide. NBS: N-bromosuccinimide. NaHCO3: Sodium bicarbonate. NH4Cl: ammonium chloride. Pd / C: Palladium on carbon. pTSA: p-toluenesulfonic acid monohydrate. RT: Room temperature. Na2S2O3: Sodium thiosulfate. Sat.aq: Saturated aqueous. tBuBrettPhos Pd G3: [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate. TBAF: tetrabutylammonium fluoride. TBDMS: tert-butyldimethylsilyl. THF: tetrahydrofuran. UPLC: ultra-performance liquid chromatography.

[0498] General Experiment Flash chromatography was performed using pre-packed silica gel cartridges (RediSep Rf, Isco). Thin-layer chromatography was performed using 5x10 cm plates coated with Merck Type 60 F254 silica gel to a thickness of 0.25 mm. All reagents obtained from suppliers were used without further purification. Anhydrous solvents were obtained from Sigma-Aldrich Chemical Company Ltd. or Fisher Chemicals Ltd. and used without further drying. HPLC-grade solvents were obtained from Fisher Chemicals Ltd.

[0499] All compounds were analyzed by LCMS and 1 The purity was >90% as determined by examination of both H NMR spectra. When Cl or Br was present, the expected isotope distribution pattern was observed. NMR

[0500] proton( 1 H) and carbon ( 13 C NMR spectra were recorded on a 300 MHz Bruker spectrometer. Solutions were typically prepared in either deuterated chloroform (CDCl), deuterated methanol (methanol-d), or deuterated dimethyl sulfoxide (DMSO-d), with chemical shifts referenced to tetramethylsilane (TMS) or the deuterated solvent as an internal standard. 1 H NMR data includes chemical shifts (δ), integrals (e.g., 1 The NMR spectrum (H), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; dd, doublet of doublets), and coupling constants (J) (in Hz) are reported. Deuterated solvents were purchased from Sigma-Aldrich Chemical Company, Goss, or Fluorochem.

[0501] AnalyticalLC-MS LCMS analysis was performed using a BEH C chromatograph equipped with a diode array detector coupled to an SQD mass spectrometer. 18 Waters Acquity UPLC using a 1.7 μM column (2.1 x 50 mm) or BEH C equipped with a diode array detector coupled to a QDa mass spectrometer 18 Analysis was performed on an Acquity I-Class UPLC using a 1.7 μM column (2.1×50 mm). Analysis was performed in either buffered acidic or basic solvents using gradients as described below. Low pH: Solvent A - Water + 10 mM ammonium bicarbonate + 0.1% formic acid. Solvent B - MeCN + 5% water + 0.1% formic acid.

[0502] High pH: Solvent A - Water + 10 mM ammonium bicarbonate + 0.1% ammonia solution. Solvent B - MeCN + 5% water + 0.1% ammonia solution.

[0503] [Table 9]

[0504] Preparative HPLC-MS Some compounds were treated with Phenomonex Gemini NX 5μm C 18 Waters FractionLynx MS automated purification system with a 100 mm x 21.2 mm id column (for low pH runs) or Waters XBridge 5 μm C column with UV diode array detection (210-400 nm) and mass-directed collection (using both positive and negative mass ion detection) operated at a flow rate of 20 mL / min. 18 The product was purified by preparative HPLC on a 100mm x 19mm id column (for high pH runs).

[0505] Purification was performed using buffered acidic or basic solvent systems as appropriate. Compound retention times in the system were routinely assessed using 30-50 μL test injections and standard gradients, and then purified using specialized gradients as described below, appropriately selected based on the observed retention times.

[0506] Low pH: Solvent A - Water + 10 mM ammonium formate + 0.1% formic acid. Solvent B - MeCN + 5% water + 0.1% formic acid.

[0507] High pH: Solvent A - Water + 10 mM ammonium formate + 0.1% ammonia solution. Solvent B- MeCN + 5% water + 0.1% ammonia solution.

[0508] [Table 10]

[0509] [Table 11]

[0510] Synthesis method Several methods for the chemical synthesis of the compounds of the present invention are described herein. These and / or other well-known methods may be modified and / or adapted in known ways to facilitate the synthesis of additional compounds within the scope of the present invention.

[0511] Preparation of alkyl-aryl ethers by alkylation Scheme 1 Alkylation of 2-substituted cyclic amines with 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one

[0512] [ka]

[0513] Synthesis 1 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one

[0514] [ka] To a mixture of 6-hydroxy-3,4-dihydro-2(1H)-quinolinone (1.0 g, 6.13 mmol, 1 equiv.) and K2CO3 (1.69 g, 12.3 mmol, 2 equiv.) in MeCN (30 mL) under nitrogen, 1-bromo-2-chloroethane (2.6 mL, 30.6 mmol, 5 equiv.) was added. The mixture was refluxed for 3 days. The mixture was cooled, filtered, washed with MeCN (3 × 10 mL), and concentrated in vacuo. The resulting solid was stirred in DCM (25 mL) for 0.5 h, filtered, washed with DCM (3 × 25 mL), and concentrated in vacuo. The solid was purified by chromatography (C) using 5-95% MeCN:HO as eluent. 18 ) to give the title compound (766 mg, 3.39 mmol, 55%) as a white powder. MS (ES+) m / z 226.2 / 228.2 (M+H), Cl isotope pattern. 1 H NMR (300 MHz, CDCl3) δ 7.80 (s, 1H), 6.84 - 6.62 (m, 3H), 4.22 (t, J = 5.9 Hz, 2H), 3.82 (t, J = 5.9 Hz, 2H), 3.02 - 2.90 (m, 2H), 2.70 - 2.58 (m, 2H).

[0515] General method A: Alkylation of 2-arylcyclic amines with 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one A mixture of 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (1 equivalent), 2-substituted cyclic amine (1.2–2.4 equivalents), KCO (2–3 equivalents), and KI (0.2–1 equivalent) in MeCN (0.02–0.11 M) was heated to reflux under nitrogen for 3–6 days. If necessary, additional 2-aryl cyclic amine and KI were added to drive the reaction to completion. The mixture was cooled, water was added, followed by DCM or EtOAc, and the phases were separated. The aqueous phase was washed with DCM or EtOAc, and the combined organic extracts were filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by normal-phase chromatography (SiO) using a gradient of MeOH:DCM (optionally containing 1% aqueous NH) or reverse-phase chromatography (C) using a gradient of MeCN:HO. 18 ), and / or preparative HPLC-MS using a gradient of high or low pH aqueous MeCN. Further purification by trituration with EtO or petroleum ether, if necessary.

[0516] Synthesis 2 6-[2-[2-(3-methoxyphenyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2034)

[0517] [ka] Prepared as described in Method A from 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (30 mg, 0.133 mmol, 1 equiv), 2-(3-methoxy-phenyl)-pyrrolidine hydrochloride (43 mg, 0.199 mmol, 1.5 equiv), K2CO3 (55 mg, 0.399 mmol, 3 equiv), KI (22 mg, 0.133 mmol, 1 equiv) in MeCN (2.5 mL) to give the title compound (27 mg, 0.0723 mmol, 54%) as a white powder after preparative HPLC-MS (high pH). MS (ES+) m / z 367.3 (M+H). 1H NMR (300 MHz, methanol-d4) δ 7.22 (t, J = 7.9 Hz, 1H), 7.04 - 6.98 (m, 1H), 6.98 - 6.90 (m, 1H), 6.83 - 6.64 (m, 4H), 3.97 (t, J = 5.8 Hz, 2H), 3.78 (s, 3H), 3.50 - 3.41 (m, 1H), 3.38 - 3.29 (m, 1H), 3.01 - 2.84 (m, 3H), 2.59 - 2.48 (m, 3H), 2.43 (q, J = 9.0 Hz, 1H), 2.28 - 2.10 (m, 1H), 2.06 - 1.64 (m, 3H).

[0518] The following examples were similarly prepared using Method A with the appropriate 2-substituted cyclic amine.

[0519] Synthesis 3 6-[2-(2-phenylpyrrolidin-1-yl)ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2019)

[0520] [ka] MS (ES+) m / z 337.3 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.88 (s, 1H), 7.39 - 7.19 (m, 5H), 6.75 - 6.61 (m, 3H), 3.92 (td, J = 6.1, 2.3 Hz, 2H), 3.40 - 3.28 (m, 2H), 2.85 - 2.71 (m, 3H), 2.45 - 2.28 (m, 4H), 2.19 - 2.04 (m, 1H), 1.89 - 1.70 (m, 2H), 1.62 - 1.41 (m, 1H).

[0521] Synthesis 4 6-[2-[2-(p-tolyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2010)

[0522] [ka] MS (ES+) m / z 351.3 (M+H). 1 H NMR (300 MHz, CDCl3) δ 7.46 (s, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 6.66 - 6.56 (m, 3H), 3.93 (td, J = 6.2, 1.5 Hz, 2H), 3.43 (td, J = 8.7, 2.6 Hz, 1H), 3.36 - 3.24 (m, 1H), 2.99 - 2.84 (m, 3H), 2.63 - 2.55 (m, 2H), 2.55 - 2.35 (m, 2H), 2.33 (s, 3H), 2.20 - 2.07 (m, 1H), 2.02 - 1.78 (m, 2H), 1.78 - 1.62 (m, 1H).

[0523] Synthesis 5 6-[2-[2-(m-tolyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2011)

[0524] [ka] MS (ES+) m / z 351.5 (M+H). 1H NMR (300 MHz, CDCl3) δ 7.38 (s, 1H), 7.24 - 7.11 (m, 3H), 7.07 - 7.01 (m, 1H), 6.67 - 6.55 (m, 3H), 3.94 (t, J = 6.2 Hz, 2H), 3.48 - 3.38 (m, 1H), 3.34 - 3.25 (m, 1H), 3.00 - 2.85 (m, 3H), 2.63 - 2.34 (m, 4H), 2.33 (s, 3H), 2.21 - 2.07 (m, 1H), 2.05 - 1.79 (m, 2H), 1.79 - 1.63 (m, 1H).

[0525] Synthesize 6 6-[2-[2-(o-トリル)ピロリジン-1-イル]エトキシ]-3,4-ジヒドロ-1H-キノリン-2-オン (ALDHI-2012)

[0526]

change

[0527] Synthesis 7 6-[2-[2-(4-pyridyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2004)

[0528] [ka] MS (ES+) m / z 338.3 (M+H). 1 H NMR (300 MHz, CDCl3) δ 8.56 - 8.47 (m, 2H), 7.44 (s, 1H), 7.36 - 7.27 (m, 2H), 6.69 - 6.55 (m, 3H), 3.95 (t, J = 5.9 Hz, 2H), 3.50 - 3.37 (m, 2H), 2.96 - 2.84 (m, 3H), 2.66 - 2.55 (m, 3H), 2.46 (q, J = 8.8 Hz, 1H), 2.28 - 2.13 (m, 1H), 2.04 - 1.79 (m, 3H), 1.74 - 1.53 (m, 1H).

[0529] Synthesis 8 6-[2-[2-(3-pyridyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2005)

[0530] [ka] MS (ES+) m / z 338.3 (M+H). 1H NMR (300 MHz, CDCl3) δ 8.61 (d, J = 2.2 Hz, 1H), 8.51 (dd, J = 4.8, 1.7 Hz, 1H), 7.82 - 7.72 (m, 1H), 7.47 (s, 1H), 7.33 - 7.22 (m, 1H), 6.70 - 6.60 (m, 3H), 3.96 (t, J = 5.9 Hz, 2H), 3.54 - 3.41 (m, 2H), 2.98 - 2.87 (m, 3H), 2.66 - 2.55 (m, 3H), 2.48 (q, J = 8.8 Hz, 1H), 2.30 - 2.16 (m, 1H), 2.10 - 1.83 (m, 3H).

[0531] Synthesis 9 6-[2-[2-(2-ピリジル)ピロリジン-1-イル]エトキシ]-3,4-ジヒドロ-1H-キノリン-2-オン (ALDHI-2006)

[0532]

change

[0533] Synthesis 10 6-[2-[2-(6-methyl-3-pyridyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2030)

[0534] [ka] MS (ES+) m / z 352.3 (M+H). 1 H NMR (300 MHz, methanol-d4) δ 8.42 (d, J = 2.2 Hz, 1H), 7.79 (dd, J = 8.0, 2.3 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.79 - 6.63 (m, 3H), 4.07 - 3.89 (m, 2H), 3.61 - 3.43 (m, 2H), 3.00 - 2.85 (m, 3H), 2.73 - 2.61 (m, 1H), 2.60 - 2.48 (m, 6H), 2.36 - 2.18 (m, 1H), 2.09 - 1.84 (m, 2H), 1.83 - 1.64 (m, 1H).

[0535] Synthesis 11 6-[2-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2007)

[0536] [ka] MS (ES+) m / z 335.3 (M+H). 1H NMR (300 MHz, CDCl3) δ 7.97 (s, 1H), 7.32 - 7.18 (m, 2H), 7.20 (s, 2H), 7.18 - 7.07 (m, 2H), 6.97 - 6.84 (m, 1H), 6.70 - 6.61 (m, 3H), 3.95 (t, J = 6.1 Hz, 2H), 3.49 - 3.32 (m, 2H), 3.01 - 2.85 (m, 3H), 2.65 - 2.49 (m, 3H), 2.41 (q, J = 8.8 Hz, 1H), 2.26 - 2.08 (m, 1H), 2.06 - 1.74 (m, 2H), 1.75 - 1.56 (m, 1H). 19 F { 1 H} NMR (282 MHz, CDCl3) δ -113.48.

[0537] Synthesize 12 6-[2-[(2S)-2-(3-フルオロフェニル)ピロリジン- 1-イル]エトキシ]-3,4-ジヒドロ-1H-キノリン-2-オン (ALDHI-2018)

[0538]

change

[0539] Synthesis 13 6-[2-[2-(2-fluorophenyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2002)

[0540] [ka] MS (ES+) m / z 355.3 (M+H). 1 H NMR (300 MHz, CDCl3) δ 7.59 (td, J = 7.5, 2.0 Hz, 1H), 7.52 (s, 1H), 7.23 - 7.04 (m, 2H), 6.99 (ddd, J = 10.5, 8.0, 1.4 Hz, 1H), 6.71 - 6.57 (m, 3H), 3.98 (t, J = 6.1 Hz, 2H), 3.80 (t, J = 8.1 Hz, 1H), 3.50 - 3.37 (m, 1H), 3.05 - 2.85 (m, 3H), 2.66 - 2.51 (m, 3H), 2.43 (q, J = 8.8 Hz, 1H), 2.34 - 2.16 (m, 1H), 1.95 - 1.80 (m, 2H), 1.73 - 1.60 (m, 1H). 19 F { 1 H} NMR (282 MHz, CDCl3) δ -120.19.

[0541] Synthesis 14 6-[2-[2-(4-fluorophenyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2003)

[0542] [ka] MS (ES+) m / z 355.3 (M+H). 1 H NMR (300 MHz, CDCl3) δ 7.68 (s, 1H), 7.37 - 7.28 (m, 2H), 7.04 - 6.93 (m, 2H), 6.67 - 6.57 (m, 3H), 3.92 (t, J = 6.1 Hz, 2H), 3.42 (td, J=8.4, 2.7 Hz, 1H), 3.38 - 3.27 (m, 1H), 2.97 - 2.82 (m, 3H), 2.65 - 2.56 (m, 2H), 2.51 (dt, J = 12.4, 6.0 Hz, 1H), 2.40 (q, J = 8.8Hz, 1H), 2.22 - 2.06 (m, 1H), 2.06 - 1.75 (m, 2H), 1.73 - 1.61 (m, 1H). 19 F { 1 H} NMR (282 MHz, CDCl3) δ -116.14.

[0543] Synthesis 15 6-[2-[2-(3,4-difluorophenyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2039)

[0544] [ka] MS (ES+) m / z 373.2 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 9.88 (s, 1H), 7.46 - 7.34 (m, 1H), 7.35 - 7.09 (m, 2H), 6.78 - 6.61 (m, 3H), 3.96 (t, J = 5.8 Hz, 2H), 3.77 (t, J = 8.1 Hz, 1H), 3.42 - 3.32 (m, 1H), 2.90 - 2.75 (m, 3H), 2.61 - 2.51 (m, 1H), 2.43 - 2.33 (m, 3H), 2.29 - 2.14 (m, 1H), 1.91 - 1.74 (m, 2H), 1.63 - 1.44 (m, 1H). 19 F { 1 H} NMR (282 MHz, DMSO-d6) δ -140.05, -145.94.

[0545] Synthesis 16 6-[2-[2-(3,5-difluorophenyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2032)

[0546] [ka] MS (ES+) m / z 373.3 (M+H). 1 H NMR (300 MHz, methanol-d4-d4) δ 7.08 - 6.98 (m, 2H), 6.81 - 6.65 (m, 4H), 4.09 - 3.91 (m, 2H), 3.54 - 3.39 (m, 2H), 3.00 - 2.85 (m, 3H), 2.68 - 2.39 (m, 4H), 2.34 - 2.15 (m, 1H), 2.03 - 1.81 (m, 2H), 1.73 - 1.54 (m, 1H). 19 F {1H} NMR (282 MHz, methanol-d4) δ -112.19.

[0547] Synthesis 17 6-[2-[2-(2-thienyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2013)

[0548] [ka] MS (ES+) m / z 343.3 (M+H). 1 H NMR (300 MHz, CDCl3) δ 7.46 (s, 1H), 7.21 (ddd, J = 4.8, 1.5, 0.6 Hz, 1H), 6.96 - 6.90 (m, 2H), 6.70 - 6.57 (m, 3H), 3.99 (td, J = 6.3, 1.9 Hz, 2H), 3.75 (t, J = 7.7 Hz, 1H), 3.41 (td, J = 8.6, 2.6 Hz, 1H), 3.12 - 3.00 (m, 1H), 2.95 - 2.85 (m, 2H), 2.65 - 2.53 (m, 3H), 2.44 (q, J = 8.6 Hz, 1H), 2.29 - 2.15 (m, 1H), 2.08 - 1.74 (m, 3H).

[0549] Synthesis 18 6-[2-[2-(3-thienyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2014)

[0550] [ka] MS (ES+) m / z 343.3 (M+H). 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), 7.29 - 7.26 (m, 1H), 7.16 (dd, J = 2.9, 1.2 Hz, 1H), 7.09 (dd, J = 5.0, 1.3 Hz, 1H), 6.67 - 6.58 (m, 3H), 3.94 (t, J = 6.2 Hz, 2H), 3.49 (t, J = 8.0 Hz, 1H), 3.39 (td, J = 9.0, 2.7 Hz, 1H), 3.04 - 2.94 (m, 1H), 2.94 - 2.85 (m, 2H), 2.63 - 2.47 (m, 3H), 2.38 (q, J = 8.7 Hz, 1H), 2.20 - 2.07 (m, 1H), 2.04 - 1.69 (m, 3H).

[0551] Synthesis 19 6-[2-[2-(2-メチルチアゾール-4-イル)ピロリジン- 1-イル]エトキシ]-3,4-ジヒドロ-1H-キノリン-2-オン (ALDHI-2033)

[0552]

change

[0553] Synthesize 20 6-[2-[2-(1-ethylpyrazol-4-yl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2016)

[0554] [ka] MS (ES+) m / z 355.4 (M+H). 1 H NMR (300 MHz, CDCl3) δ 7.48 (s, 1H), 7.46 (d, J = 0.8 Hz, 1H), 7.34 (s, 1H), 6.70 - 6.58 (m, 3H), 4.12 (q, J = 7.3 Hz, 2H), 3.96 (t, J = 6.1 Hz, 2H), 3.40 - 3.29 (m, 2H), 3.06 (dt, J = 12.5, 6.2 Hz, 1H), 2.95 - 2.85 (m, 2H), 2.64 - 2.55 (m, 2H), 2.49 (dt, J = 12.5, 6.0 Hz, 1H), 2.35 (q, J = 8.6 Hz, 1H), 2.20 - 2.06 (m, 1H), 2.04 - 1.68 (m, 3H), 1.46 (t, J = 7.3 Hz, 3H).

[0555] Synthesis 21 6-[2-[2-(1,3-dimethylpyrazol-4-yl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2015)

[0556] [ka] MS (ES+) m / z 355.4 (M+H). 1H NMR (300 MHz, CDCl3) δ 7.48 (s, 1H), 7.23 (s, 1H), 6.70 - 6.58 (m, 3H), 3.96 (t, J = 6.0 Hz, 2H), 3.78 (s, 3H), 3.42 - 3.32 (m, 1H), 3.32 - 3.22 (m, 1H), 3.09 - 2.98 (m, 1H), 2.94 - 2.87 (m, 2H), 2.64 - 2.55 (m, 2H), 2.51 - 2.40 (m, 1H), 2.30 (q, J = 8.9 Hz, 1H), 2.23 (s, 3H), 2.17 - 2.04 (m, 1H), 1.99 - 1.62 (m, 3H).

[0557] Synthesis 22 6-[2-[2-(1-メチルピロール-2-イル)ピロリジン-1 -イル]エトキシ]-3,4-ジヒドロ-1H-キノリン-2-オン (ALDHI-2017)

[0558]

change

[0559] Synthesis 23 6-[2-[2-(3-fluorophenyl)-4-hydroxy-pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one Mixture of diastereomers (4:1) (ALDHI-2035)

[0560] [ka] MS (ES+) m / z 371.3 (M+H). Major reported isomers: 1 H NMR (300 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.41 - 7.14 (m, 3H), 7.09 - 6.98 (m, 1H), 6.78 - 6.60 (m, 3H), 4.89 (s, 1H), 4.31 - 4.23 (m, 1H), 3.91 (t, J = 5.8 Hz, 2H), 3.73 (dd, J = 9.7, 6.7 Hz, 1H), 3.61 (dd, J = 9.9, 6.1 Hz, 1H), 2.86 - 2.66 (m, 3H), 2.58 - 2.51 (m, 1H), 2.44 - 2.27 (m, 3H), 1.96 (ddd, J = 12.9, 6.8, 2.5 Hz, 1H), 1.71 (ddd, J = 12.8, 9.8, 7.1 Hz, 1H). Both reported isomers: 19 F {1H} NMR (282 MHz, DMSO-d6) δ -113.42 (major isomer), -113.54 (minor isomer).

[0561] Synthesis 24 6-[2-[2-(3-fluorophenyl)azetidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2021)

[0562] [ka] MS (ES+) m / z 341.3 (M+H). 1 H NMR (300 MHz, CDCl3) δ 7.55 (s, 1H), 7.23 - 7.10 (m, 3H), 6.89 (tdd, J = 8.1, 2.7, 1.2 Hz, 1H), 6.61 - 6.56 (m, 3H), 4.11 (t, J = 8.2 Hz, 1H), 3.87 (t, J = 5.7 Hz, 2H), 3.58 - 3.49 (m, 1H), 3.10 - 2.98 (m, 1H), 2.93 - 2.82 (m, 4H), 2.63 - 2.54 (m, 2H), 2.40 - 2.27 (m, 1H), 2.17 - 2.01 (m, 1H). 19 F { 1 H} NMR (282 MHz, CDCl3) δ -113.51.

[0563] Synthesis 25 6-[2-[2-(3-fluorophenyl)-1-piperidyl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2038)

[0564] [ka] MS (ES+) m / z 369.3 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.42 - 7.29 (m, 1H), 7.23 - 7.12 (m, 2H), 7.05 (dddd, J = 9.1, 8.2, 2.7, 1.1 Hz, 1H), 6.76 - 6.57 (m, 3H), 3.95 - 3.84 (m, 2H), 3.25 - 3.15 (m, 2H), 2.79 (t, J = 7.5 Hz, 2H), 2.75 - 2.61 (m, 1H), 2.43 - 2.32 (m, 2H), 2.32 - 2.13 (m, 2H), 1.80 - 1.22 (m, 6H). 19 F { 1 H} NMR (282 MHz, DMSO-d6) δ -113.35.

[0565] Synthesis 26 6-[2-(4-メチルスルホニル-2-フェニル-ピペラジン-1 -イル)エトキシ]-3,4-ジヒドロ-1H-キノリン-2-オン (ALDHI-2046)

[0566]

change

[0567] Synthesis 27 6-[2-[3-(3-fluorophenyl)morpholin-4-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2031)

[0568] [ka] MS (ES+) m / z 371.3 (M+H). 1 H NMR (300 MHz, methanol-d4) δ 7.43 - 7.29 (m, 1H), 7.28 - 7.17 (m, 2H), 7.09 - 6.96 (m, 1H), 6.82 - 6.63 (m, 3H), 4.10 - 3.86 (m, 3H), 3.84 - 3.64 (m, 2H), 3.52 - 3.35 (m, 2H), 3.22 - 3.12 (m, 1H), 2.97 - 2.80 (m, 3H), 2.63 - 2.49 (m, 3H), 2.42 (dt, J = 13.7, 5.1 Hz, 1H). 19 F {1H} NMR (282 MHz, methanol-d4) δ -114.97.

[0569] Synthesis 28 6-[2-(3-methyl-3-phenyl-morpholin-4-yl)ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2040)

[0570] [ka] MS (ES+) m / z 367.3 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.69 - 7.59 (m, 2H), 7.42 - 7.31 (m, 2H), 7.31 - 7.21 (m, 1H), 6.75 - 6.56 (m, 3H), 3.99 - 3.79 (m, 3H), 3.61 (td, J = 11.5, 3.0 Hz, 1H), 3.33 - 3.24 (m, 2H), 2.97 - 2.86 (m, 1H), 2.85 - 2.67 (m, 3H), 2.48 - 2.44 (m, 1H), 2.42 - 2.34 (m, 2H), 2.31 - 2.21 (m, 1H), 1.44 (s, 3H).

[0571] Synthesis 29 6-[2-(2-methyl-5-phenyl-morpholin-4-yl)ethoxy]-3,4-dihydro-1H-quinolin-2-one Mixture of diastereomers (1:4). (ALDHI-2042)

[0572] [ka] MS (ES+) m / z 367.3 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.88 (s, 1H), 7.49 - 7.23 (m, 5H), 6.83 - 6.57 (m, 3H), 4.00 - 3.86 (m, 2H), 3.77 - 3.42 (m, 2H), 3.30 - 3.23 (m, 2H), 3.14 (dd, J = 11.5, 2.2 Hz, 1H), 2.86 - 2.66 (m, 3H), 2.43 - 2.22 (m, 3H), 2.16 - 2.02 (m, 1H), 1.12 (d, J = 6.2 Hz, 2H).

[0573] Synthesis 30 6-[2-(2-phenylpiperazin-1-yl)ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2036)

[0574] [ka] A mixture of 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (60 mg, 0.266 mmol, 1 equiv.), tert-butyl 3-phenylpiperazine-1-carboxylate (105 mg, 0.399 mmol, 1.5 equiv.), KCO (75 mg, 0.532 mmol, 2 equiv.), and KI (44 mg, 0.266 mmol, 1 equiv.) in MeCN (5 mL) was heated to reflux under nitrogen for 6 days. The mixture was cooled, water (10 mL) was added, followed by DCM (10 mL), and the phases were separated. The aqueous phase was washed with DCM (10 mL), and the combined organic extracts were filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was chromatographed (SiO 2 ) using 0–100% EtOAc:petroleum ether as eluent. The residue was dissolved in DCM (5 mL) and trifluoroacetic acid (2.0 mL, 26.0 mmol, 97.6 equiv) was added. The mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with DCM (20 mL) and quenched with saturated aqueous NaHCO3 (50 mL). The phases were separated and the water was extracted with DCM (20 mL). The combined extracts were washed with brine (50 mL), filtered through a hydrophobic frit and concentrated in vacuo. The residue was purified by preparative HPLC-MS (low pH, then high pH). The appropriate fractions were combined, saturated aqueous NaHCO3 (10 mL) was added and extracted with DCM (2 x 10 mL). The combined extracts were washed with brine (20 mL), filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was triturated with Et2O and dried in vacuo at 50 C to give the title compound (15 mg, 0.0435 mmol, 16%) as a white powder. MS (ES+) m / z 352.3 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.40 - 7.19 (m, 5H), 6.74 - 6.56 (m, 3H), 3.97 - 3.81 (m, 2H), 3.19 (dd, J = 10.2, 3.1 Hz, 1H), 3.11 - 3.02 (m, 1H), 2.92 - 2.61 (m, 6H), 2.48 - 2.19 (m, 5H).

[0575] Synthesis 31 6-[2-(2-phenylimidazol-1-yl)ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2041)

[0576] [ka] Prepared as described in Method A from 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (30 mg, 0.133 mmol, 1 equiv), 2-phenyl-1H-imidazole (29 mg, 0.199 mmol, 1.5 equiv), KCO (37 mg, 0.266 mmol, 2 equiv) and KI (22 mg, 0.133 mmol, 1.0 equiv) in MeCN (2.5 mL) to give the title compound (16.2 mg, 0.0486 mmol, 37%) as a white powder after purification by preparative HPLC-MS (high pH). MS (ES+) m / z 334.3 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.91 (s, 1H), 7.70 - 7.59 (m, 2H), 7.56 - 7.38 (m, 4H), 7.02 (d, J = 1.2 Hz, 1H), 6.86 - 6.60 (m, 3H), 4.37 (t, J = 5.2 Hz, 2H), 4.21 (t, J = 5.2 Hz, 2H), 2.80 (dd, J = 8.5, 6.5 Hz, 2H), 2.44 - 2.32 (m, 2H).

[0577] Synthesis 32 6-[2-[5-(3-fluorophenyl)pyrazol-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2023)

[0578] [ka] Prepared as described in Method A from 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (100 mg, 0.400 mmol, 1 equiv.), 3-(3-fluorophenyl)-1H-pyrazole hydrochloride (118.8 mg, 0.600 mmol, 1.5 equiv.), KCO (165.4 mg, 1.2 mmol, 3 equiv.) and KI (66.2 mg, 0.400 mmol, 1 equiv.) in MeCN (8 mL) to give the title compound (10 mg, 0.0296 mmol, 7%) as a white powder after purification by preparative HPLC-MS (high pH). MS (ES+) m / z 352.3 (M+H). 1 H NMR (300 MHz, CDCl3) δ 7.68 (s, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.50 - 7.36 (m, 1H), 7.33 - 7.20 (m, 2H), 7.13 (tdd, J = 8.4, 2.6, 1.1 Hz, 1H), 6.61 (s, 3H), 6.31 (d, J = 1.8 Hz, 1H), 4.53 - 4.40 (m, 2H), 4.40 - 4.32 (m, 2H), 2.95 - 2.83 (m, 2H), 2.65 - 2.52 (m, 2H). 19 F { 1 H} NMR (282 MHz, CDCl3) δ -112.20.

[0579] Synthesis 33 6-[2-[2-(3-fluorophenyl)-2-methyl-pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2037)

[0580] [ka] Step 1: 5-(3-fluorophenyl)-3,4-dihydro-2H-pyrrole To a mixture of tert-butyl 2-oxopyrrolidine-1-carboxylate (1.8 mL, 10.8 mmol, 1 equiv.) in THF (40 mL) under nitrogen at −78° C. was added 3-fluorophenylmagnesium bromide (1 M in THF, 16 mL, 16.2 mmol, 1.5 equiv.) dropwise. The mixture was stirred for 18 h, during which time the temperature slowly warmed to room temperature. The mixture was quenched with MeOH (50 mL) and stirred for 1 h. The solvent was removed in vacuo, then EtOAc (100 mL) and brine (100 mL) were added and the phases were separated by filtration. The organic phase was washed with brine (3×100 mL), saturated aqueous NaHCO (3×100 mL), filtered through a hydrophobic frit, and concentrated in vacuo to give a yellow oil. The oil was dissolved in MeOH (40 mL) and concentrated HCl (3.3 mL, 108 mmol, 10 equiv) was added. The mixture was stirred at 90 °C for 2 h. The mixture was cooled, carefully neutralized with saturated aqueous NaHCO (50 mL), extracted with EtOAc (3 × 100 mL), and the combined extracts were filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was chromatographed (SiO) using 0–25% EtOAc:petroleum ether as eluent to give 5-(3-fluorophenyl)-3,4-dihydro-2H-pyrrole (792 mg, 4.85 mmol, 45%) as a pale yellow oil. MS (ES+) m / z 164.1 (M+H). 1 H NMR (300 MHz, CDCl3) δ 7.65 - 7.49 (m, 2H), 7.42 - 7.32 (m, 1H), 7.12 (tdd, J = 8.3, 2.6, 1.0 Hz, 1H), 4.08 (tt, J = 7.4, 2.1 Hz, 2H), 2.93 (ddt, J = 8.3, 7.3, 2.1 Hz, 2H), 2.14 - 1.94 (m, 2H). 19 F {1H} NMR (282 MHz, CDCl3) δ -113.03.

[0581] Step 2: 2-(3-fluorophenyl)-2-methyl-pyrrolidine To a solution of 5-(3-fluorophenyl)-3,4-dihydro-2H-pyrrole (775 mg, 4.27 mmol, 1 equiv.) in THF (45 mL) was added boron trifluoride diethyl etherate (1.1 mL, 8.55 mmol, 2 equiv.) over approximately 5 minutes at −78° C. The mixture was stirred for 40 minutes, and then methyllithium (6.7 mL, 10.7 mmol, 2.5 equiv.) was added dropwise over 10 minutes. The mixture was stirred for 16 hours and allowed to warm slowly to room temperature. Water (40 mL), then aqueous HCl (2 M, 10 mL), then EtOAc (50 mL) were added, and the phases were separated. The organic phase was washed with aqueous HCl (1 M, 25 mL), and the aqueous phases were combined. The aqueous phase was basified to pH 12 with aqueous NaOH (2 M) and extracted with EtOAc (2 x 50 mL), the extracts washed with brine (100 mL), filtered through a hydrophobic frit and concentrated in vacuo to give 2-(3-fluorophenyl)-2-methyl-pyrrolidine (669 mg, 0.448 mmol, 10%, approx. 12% pure by LCMS) as an orange oil which was used in the next step without further purification. MS (ES+) m / z 180.2 (M+H).

[0582] Step 3: 6-[2-[2-(3-fluorophenyl)-2-methyl-pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one Prepared from 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (30 mg, 0.133 mmol, 1 equiv.), 2-(3-fluorophenyl)-2-methyl-pyrrolidine (300 mg, 0.201 mmol, 1.5 equiv., approx. 12% pure by LCMS), KCO (37 mg, 0.266 mmol, 2 equiv.), and KI (22 mg, 0.133 mmol, 1 equiv.) in MeCN (5 mL) as described in Method A and purified by reversed-phase chromatography (C) using 5-95% MeCN:HO as eluent. 18 ) and subsequent purification by preparative HPLC-MS (high pH) gave the title compound (10.1 mg, 0.0274 mmol, 21%) as a light beige powder. MS (ES+) m / z 369.3 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.45 - 7.27 (m, 3H), 7.10 - 6.93 (m, 1H), 6.80 - 6.64 (m, 3H), 4.01 - 3.92 (m, 2H), 2.82 (t, J = 8.5, 6.5 Hz, 2H), 2.73 - 2.56 (m, 2H), 2.44 - 2.33 (m, 2H), 1.91 - 1.61 (m, 4H), 1.30 (s, 3H). 19 F {1H} NMR (282 MHz, DMSO-d6) δ -113.60.

[0583] Synthesis 34 6-[2-[4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2052)

[0584] [ka]

[0585] Step 1: tert-butyl 2-(3-fluorophenyl)-4-hydroxy-pyrrolidine-1-carboxylate To a suspension of 5-(3-fluorophenyl)pyrrolidin-3-ol hydrochloride (diastereomeric mixture) (250 mg, 1.15 mmol, 1 equiv.) in THF (10 mL) was added triethylamine (0.48 mL, 3.45 mmol, 3 equiv.), DMAP (7 mg, 0.0574 mmol, 0.05 equiv.), and di-tert-butyl dicarbonate (276 mg, 1.26 mmol, 1.1 equiv.). The reaction mixture was stirred at room temperature for 16 h, then quenched with water (20 mL) and extracted with DCM (2 × 25 mL). The extracts were washed with brine (50 mL), filtered through a hydrophobic frit, and concentrated in vacuo. The resulting residue was purified by chromatography (C) using 5–95% MeCN:HO as eluent. 18 ) to afford tert-butyl 2-(3-fluorophenyl)-4-hydroxy-pyrrolidine-1-carboxylate (238 mg, 0.846 mmol, 74%) as an off-white powder, which was used in the next step without further purification. MS (ES+) m / z 262.12 m / z (M+H-tBu).

[0586] Step 2: tert-butyl 4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate To a solution of tert-butyl 2-(3-fluorophenyl)-4-hydroxy-pyrrolidine-1-carboxylate (100 mg, 0.355 mmol, 1 equiv.) in DCM (10 mL) under nitrogen, BAST (50% in toluene, 0.27 mL, 0.533 mmol, 1.5 equiv.) was added via syringe. The mixture was stirred at room temperature for 16 h, then aqueous NaOH (1 M, 5 mL) was added and stirred for 0.5 h. The phases were separated, and the organic layer was washed with brine (3 × 10 mL), dried (MgSO), filtered, and concentrated in vacuo. The residue was chromatographed (SiO 2 ) using 0–20% EtOAc:petroleum ether as eluent to give tert-butyl 4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate (40 mg, 0.141 mmol, 40%) as a colorless oil that solidified upon standing. MS (ES+) m / z 228.1 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 7.35 (td, J = 7.9, 6.1 Hz, 1H), 7.10 - 6.93 (m, 3H), 5.45 - 5.18 (m, 1H), 5.09 - 4.85 (m, 1H), 3.83 - 3.78 (m, 1H), 3.78 - 3.60 (m, 1H), 2.82 - 2.54 (m, 1H), 2.20 - 2.02 (m, 1H), 1.57 - 1.02 (m, 9H). 19 F { 1 H} NMR (282 MHz, DMSO-d6) δ -114.08, -170.17.

[0587] Step 3: 4-Fluoro-2-(3-fluorophenyl)pyrrolidine hydrochloride To a solution of tert-butyl 4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate (33 mg, 0.116 mmol, 1 equiv) in 1,4-dioxane (2 mL) was added HCl (4 M in 1,4-dioxane, 2.0 mL, 8.00 mmol, 69 equiv) and the mixture was heated to 60° C. for 1 h. The mixture was then cooled and concentrated in vacuo, and the resulting solid was triturated with EtO and dried in vacuo at 50° C. to give 4-fluoro-2-(3-fluorophenyl)pyrrolidine hydrochloride (24 mg, 0.109 mmol, 94%) as an off-white powder. MS (ES+) m / z 184.1 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.93 (br.s, 2H), 7.60 - 7.47 (m, 1H), 7.42 - 7.23 (m, 3H), 5.71 - 5.45 (m, 1H), 4.79 (t, J = 8.8 Hz, 1H), 3.74 - 3.41 (m, 2H), 3.05 - 2.82 (m, 1H), 2.46 - 2.23 (m, 1H). 19 F { 1 H} NMR (282 MHz, DMSO-d6) δ -112.23, -170.12.

[0588] Step 4: 6-[2-[4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one Prepared as described in Method A from 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (22 mg, 0.0956 mmol, 0.9 equiv), 4-fluoro-2-(3-fluorophenyl)pyrrolidine hydrochloride (23 mg, 0.105 mmol, 1 equiv), KCO (44 mg, 0.315 mmol, 3 equiv) and KI (17 mg, 0.105 mmol, 1 equiv) in MeCN (2.5 mL) to give, after purification by preparative HPLC-MS (low pH), the title compound (10 mg, 0.0256 mmol, 23%) as a white powder. MS (ES+) m / z 373.3 (M+H). 1 H NMR (300 MHz, methanol-d4) δ 7.39 - 7.28 (m, 1H), 7.26 - 7.18 (m, 2H), 7.03 - 6.94 (m, 1H), 6.82 - 6.64 (m, 3H), 4.00 (t, J = 5.6 Hz, 2H), 3.63 (d, J = 11.8 Hz, 1H), 3.48 (t, J = 8.4 Hz, 2H), 2.92 (dd, J = 9.5, 6.3 Hz, 3H), 2.78 - 2.49 (m, 5H), 1.94 - 1.80 (m, 1H). 19 F { 1 H} NMR (282 MHz, methanol-d4) δ −115.27, −167.41.

[0589] Synthesis 35 6-[2-[4,4-difluoro-2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2053)

[0590] [ka]

[0591] Step 1: tert-butyl 2-(3-fluorophenyl)-4-oxo-pyrrolidine-1-carboxylate To a solution of tert-butyl 2-(3-fluorophenyl)-4-hydroxy-pyrrolidine-1-carboxylate (160 mg, 0.569 mmol, 1 equiv.) in DCM (5 mL) was added DMP (289 mg, 0.682 mmol, 1.2 equiv.). The reaction mixture was stirred at room temperature for 40 h, then aqueous NaOH (1 M, 5 mL) was added and the mixture was stirred for 1 h. The mixture was diluted with DCM (10 mL), the phases were separated, the aqueous phase was extracted with DCM (10 mL), and the extracts were combined. The extract was washed with water (20 mL), brine (25 mL), filtered through a hydrophobic frit, and concentrated in vacuo. The resulting solid was chromatographed (SiO2) using 0-30% EtOAc:petroleum ether as eluent to afford tert-butyl 2-(3-fluorophenyl)-4-oxo-pyrrolidine-1-carboxylate (138 mg, 0.494 mmol, 87%) as a colorless oil, which was used directly in the next step. MS (ES-) m / z 278.2 (MH-tBu). 1 H NMR (300 MHz, DMSO-d6) δ 7.46 - 7.32 (m, 1H), 7.21 - 6.95 (m, 3H), 5.26 (br. s, 1H), 3.97 (s, 2H), 3.31 - 3.20 (m, 1H), 2.40 (dd, J = 18.6, 3.4 Hz, 1H), 1.50 - 1.11 (m, 9H). 19 F NMR { 1 H} (282 MHz, DMSO-d6) δ -111.94 - -113.63 (m).

[0592] Step 2: tert-butyl 4,4-difluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate To a solution of tert-butyl 2-(3-fluorophenyl)-4-oxo-pyrrolidine-1-carboxylate (133 mg, 0.476 mmol, 1 equiv.) in DCM (10 mL) under nitrogen, BAST (50% in toluene, 0.36 mL, 0.714 mmol, 1.5 equiv.) was added via syringe. The mixture was stirred at room temperature for 18 h. Aqueous NaOH (1 M, 5 mL) was added and stirred for 0.5 h. The phases were separated, the aqueous layer was washed with DCM (10 mL), and the extracts were combined. The extract was washed with water (20 mL), brine (20 mL), filtered through a hydrophobic frit, and concentrated in vacuo. The resulting residue was chromatographed (SiO2) using 0-20% EtOAc:petroleum ether to afford tert-butyl 4,4-difluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate (113 mg, 0.375 mmol, 79%) as a colorless oil, which was used directly in the next step. MS (ES+) m / z 246.1 (M+H-tBu). 1 H NMR (300 MHz, DMSO-d6) δ 7.46 - 7.32 (m, 1H), 7.25 - 6.97 (m, 3H), 4.99 (s, 1H), 4.09 - 3.79 (m, 2H), 3.07 - 2.85 (m, 1H), 2.46 - 2.19 (m, 1H), 1.58 - 0.99 (m, 9H). 19 F { 1 H} NMR (282 MHz, DMSO-d6) δ -98.03 - -100.70 (m), -101.00 - -103.61 (m), -112.94 - -114.40 (m).

[0593] Step 3: 4,4-Difluoro-2-(3-fluorophenyl)pyrrolidine hydrochloride To a solution of tert-butyl 4,4-difluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate (110 mg, 0.365 mmol, 1 equiv.) in 1,4-dioxane (2 mL) was added HCl (4 M in 1,4-dioxane, 2.0 mL, 8.00 mmol, 22 equiv.). The mixture was heated to 60° C. for 1 hour, then cooled to room temperature and concentrated in vacuo. The resulting solid was triturated with EtO and dried in vacuo at 50° C. to give 4,4-difluoro-2-(3-fluorophenyl)pyrrolidine hydrochloride (68 mg, 0.286 mmol, 78%) as a pink powder. MS (ES+) m / z 202.1 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 10.29 (br s, 2H), 7.61 - 7.26 (m, 4H), 5.01 (dd, J = 12.5, 6.6 Hz, 1H), 4.02 - 3.68 (m, 2H), 3.14 - 2.95 (m, 1H), 2.95 - 2.68 (m, 1H). 19 F {1H} NMR (282 MHz, DMSO-d6) δ -90.76 (d, J = 233.0 Hz), -96.40 (d, J = 233.0 Hz), -112.16.

[0594] Step 4: 6-[2-[4,4-difluoro-2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one Prepared as described in Method A from 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (25 mg, 0.111 mmol, 1 equiv), 4,4-difluoro-2-(3-fluorophenyl)pyrrolidine hydrochloride (29 mg, 0.122 mmol, 1.1 equiv), KCO (47 mg, 0.332 mmol, 3 equiv) and KI (18 mg, 0.111 mmol, 1 equiv) in MeCN (2.5 mL) to give the title compound (10 mg, 0.0256 mmol, 23%) as a white powder after purification by preparative HPLC-MS (low pH). MS (ES+) m / z 391.3 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.47 - 7.34 (m, 1H), 7.30 - 7.19 (m, 2H), 7.18 - 7.04 (m, 1H), 6.81 - 6.61 (m, 3H), 3.99 - 3.90 (m, 2H), 3.90 - 3.80 (m, 1H), 3.80 - 3.65 (m, 1H), 3.00 - 2.60 (m, 5H), 2.58 - 2.53 (m, 1H), 2.45 - 2.34 (m, 2H), 2.22 - 1.96 (m, 1H). 19 F { 1 H} NMR (282 MHz, DMSO-d6) δ -89.39 (d, J = 226.0 Hz), -93.33 (d, J = 226.0 Hz), -112.97.

[0595] Scheme 2 Alkylation of 2-substituted cyclic amines with 7-(2-chloroethoxy)-4H-1,4-benzoxazin-3-one

[0596] [ka]

[0597] Synthesis 36 7-(2-chloroethoxy)-4H-1,4-benzoxazin-3-one

[0598] [ka] To a mixture of 7-hydroxy-4H-1,4-benzoxazin-3-one (100 mg, 0.606 mmol, 1 equiv.) (prepared as reported in La et al., Journal of Medicinal Chemistry, 2008, vol. 51, pp. 1695-1705) and KCO (167 mg, 1.21 mmol, 2 equiv.) in MeCN (5 mL) under nitrogen was added 1-bromo-2-chloroethane (0.25 mL, 3.03 mmol, 5 equiv.). The mixture was heated to reflux for 3 days, then cooled to room temperature, and water (10 mL) followed by DCM (10 mL) was added. The phases were separated, the aqueous phase washed with DCM (10 mL), and the combined organic extracts were filtered through a hydrophobic frit and concentrated in vacuo. The resulting solid was chromatographed (SiO 2 ) using 0-5% MeOH:DCM (+1% aqueous NH 3 ) as eluent to afford the title compound (41 mg, 0.180 mmol, 30%) as an orange powder. MS (ES-) m / z 226.1 / 228.1 (MH), Cl isotope pattern. 1 H NMR (300 MHz, CDCl3) δ 7.82 (s, 1H), 6.70 (d, J = 8.6 Hz, 1H), 6.63 - 6.49 (m, 2H), 4.60 (s, 2H), 4.18 (t, J = 5.9 Hz, 2H), 3.79 (t, J = 5.8Hz, 2H).

[0599] General method B: Alkylation of 2-substituted cyclic amines with 7-(2-chloroethoxy)-4H-1,4-benzoxazin-3-one A mixture of 7-(2-chloroethoxy)-4H-1,4-benzoxazin-3-one (1 equiv.), 2-substituted cyclic amine (1.5 equiv.), KCO (2 equiv.), and KI (1 equiv.) in MeCN (0.04 M–0.05 M) was heated to reflux under nitrogen for 3 days and then cooled to room temperature. Water, followed by DCM, was added and the phases were separated. The aqueous phase was washed with DCM, and the combined organic extracts were filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by preparative HPLC-MS using a gradient of high or low pH aqueous MeCN.

[0600] Synthesis 37 7-[2-[2-(1-methylpyrazol-4-yl)pyrrolidin-1-yl]ethoxy]-4H-1,4-benzoxazin-3-one (ALDHI-2024)

[0601] [ka] Prepared as described in Method B from 7-(2-chloroethoxy)-4H-1,4-benzoxazin-3-one (20 mg, 0.0879 mmol, 1 equiv), 1-methyl-4-(pyrrolidin-2-yl)-1H-pyrazole (20 mg, 0.132 mmol, 1.5 equiv), KCO (24 mg, 0.176 mmol, 2 equiv) and KI (15 mg, 0.0879 mmol, 1 equiv) in MeCN (2.5 mL) to give the title compound (17 mg, 0.0497 mmol, 57%) as a colorless gum after purification by preparative HPLC-MS (high pH). MS (ES+) m / z 343.3 (M+H). 1H NMR (300 MHz, methanol-d4) δ 8.49 (s, 1H), 7.76 (s, 1H), 7.60 (d, J = 0.8 Hz, 1H), 6.81 (dd, J = 8.3, 0.6 Hz, 1H), 6.61 - 6.49 (m, 2H), 4.53 (s, 2H), 4.24 - 4.04 (m, 3H), 3.87 (s, 3H), 3.75 - 3.61 (m, 1H), 3.42 - 3.32 (m, 1H), 3.20 - 3.01 (m, 2H), 2.48 - 2.29 (m, 1H), 2.25 - 2.03 (m, 3H).

[0602] The following examples were similarly prepared using Method B with the appropriate 2-substituted cyclic amine.

[0603] Synthesis 38 7-[2-[2-(2-pyridyl)pyrrolidin-1-yl]ethoxy]-4H-1,4-benzoxazin-3-one (ALDHI-2025)

[0604] [ka] MS (ES+) m / z 340.3 (M+H). 1H NMR (300 MHz, methanol-d4) δ 8.57 - 8.47 (m, 2H), 7.82 (td, J = 7.7, 1.8 Hz, 1H), 7.58 (dt, J = 7.9, 1.1 Hz, 1H), 7.32 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 6.78 (dt, J = 9.0, 1.4 Hz, 1H), 6.52 - 6.42 (m, 2H), 4.54 (s, 2H), 4.26 (t, J = 8.1 Hz, 1H), 4.16 - 3.98 (m, 2H), 3.79 - 3.65 (m, 1H), 3.31 - 3.22 (m, 1H), 3.21 - 3.11 (m, 1H), 3.06 - 2.92 (m, 1H), 2.57 - 2.39 (m, 1H), 2.17 - 2.03 (m, 2H), 2.03 - 1.83 (m, 1H).

[0605] Scheme 3 Alkylation of 2-substituted cyclic amines with 7-(2-chloroethoxy)-4H-1,4-benzothiazin-3-one

[0606] [ka]

[0607] Synthesis 39 7-(2-chloroethoxy)-4H-1,4-benzothiazin-3-one

[0608] [ka] To a mixture of 7-hydroxy-4H-1,4-benzothiazin-3-one (89 mg, 0.491 mmol, 1 equiv.) (prepared as reported in Zhang et al., Chemical and Pharmaceutical Bulletin, 2010, Vol. 58, pp. 326-331) and KCO (136 mg, 0.982 mmol, 2 equiv.) in MeCN (5 mL) under nitrogen was added 1-bromo-2-chloroethane (0.20 mL, 2.46 mmol, 5 equiv.). The mixture was heated to reflux for 3 days, then cooled to room temperature, and water (10 mL) followed by DCM (10 mL) was added. The phases were separated, the aqueous phase washed with DCM (10 mL), and the combined organic extracts were filtered through a hydrophobic frit and concentrated in vacuo. The resulting solid was chromatographed (SiO 2 ) using 0-5% MeOH:DCM (+1% aqueous NH 3 ) as eluent to afford the title compound (83 mg, 0.341 mmol, 69%) as an off-white powder. MS (ES+) m / z 244.2 / 246.2 (M+H), Cl isotope pattern. 1 H NMR (300 MHz, CDCl3) δ 7.77 (s, 1H), 6.93 - 6.85 (m, 1H), 6.76 (d, J = 1.6 Hz, 2H), 4.19 (t, J = 5.8 Hz, 2H), 3.79 (t, J = 5.8 Hz, 2H), 3.42 (s, 2H).

[0609] General method C: Alkylation of 2-substituted cyclic amines with 7-(2-chloroethoxy)-4H-1,4-benzothiazin-3-one A mixture of 7-(2-chloroethoxy)-4H-1,4-benzothiazin-3-one (1 equiv.), 2-substituted cyclic amine (1.5 equiv.), KCO (2 equiv.), and KI (1 equiv.) in MeCN (0.03-0.05 M) was heated to reflux for 3 days and then cooled to room temperature. Water, followed by DCM, was added, and the phases were separated. The aqueous phase was washed with DCM, and the combined organic extracts were filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by preparative HPLC-MS using a gradient of high or low pH aqueous MeCN.

[0610] Synthesis 40 7-[2-[2-(1-methylpyrazol-4-yl)pyrrolidin-1-yl]ethoxy]-4H-1,4-benzothiazin-3-one (ALDHI-2026)

[0611] [ka] Prepared as described in Method C from 7-(2-chloroethoxy)-4H-1,4-benzothiazin-3-one (20 mg, 0.0821 mmol, 1 equiv), 1-methyl-4-(pyrrolidin-2-yl)-1H-pyrazole (19 mg, 0.123 mmol, 1.5 equiv), KCO (23 mg, 0.164 mmol, 2 equiv), KI (14 mg, 0.0821 mmol, 1 equiv) in MeCN (1.5 mL) to give the title compound (19 mg, 0.053 mmol, 65%) as the formate salt as a colorless gum after preparative HPLC-MS (high pH). MS (ES+) m / z 359.3 (M+H). 1H NMR (300 MHz, CDCl3) δ 8.92 (s, 1H), 7.50 (d, J = 0.8 Hz, 1H), 7.47 (d, J = 0.8 Hz, 1H), 6.83 - 6.74 (m, 2H), 6.66 (dd, J = 8.7, 2.7 Hz, 1H), 4.19 - 3.98 (m, 2H), 3.88 (s, 3H), 3.79 - 3.67 (m, 1H), 3.60 - 3.46 (m, 1H), 3.39 (s, 2H), 3.15 (dt, J = 13.2, 5.4 Hz, 1H), 2.81 - 2.61 (m, 2H), 2.30 - 2.15 (m, 1H), 2.15 - 1.86 (m, 3H).

[0612] The following examples were similarly prepared using Method C with the appropriate 2-substituted cyclic amine.

[0613] Synthesis 41 7-[2-[2-(2-pyridyl)pyrrolidin-1-yl]ethoxy]-4H-1,4-benzothiazin-3-one (ALDHI-2027)

[0614] [ka] MS (ES+) m / z 356.3 (M+H). 1H NMR (300 MHz, CDCl3) δ 8.59 - 8.49 (m, 2H), 7.65 (td, J = 7.7, 1.8 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.21 - 7.10 (m, 1H), 6.79 - 6.70 (m, 2H), 6.63 (dd, J = 8.7, 2.7 Hz, 1H), 3.96 (t, J = 5.9 Hz, 2H), 3.71 (t, J = 7.9 Hz, 1H), 3.52 - 3.20 (m, 3H), 2.97 (dt, J = 12.3, 6.0 Hz, 1H), 2.74 (dt, J = 12.5, 5.8 Hz, 1H), 2.56 (q, J = 8.6 Hz, 1H), 2.37 - 2.21 (m, 1H), 2.08 - 1.73 (m, 3H).

[0615] Synthesis 42 7-[2-[2-(3-ピリジル)ピロリジン-1-イル]エトキシ]-4H-1,4-ベンゾチアジン-3-オン (ALDHI-2028)

[0616]

change

[0617] Synthesis 43 7-[2-[2-(4-pyridyl)pyrrolidin-1-yl]ethoxy]-4H-1,4-benzothiazin-3-one (ALDHI-2029)

[0618] [ka] MS (ES+) m / z 356.2 (M+H). 1H NMR (300 MHz, methanol-d4) δ 8.47 - 8.39 (m, 2H), 7.53 - 7.45 (m, 2H), 6.91 - 6.78 (m, 2H), 6.70 (dd, J = 8.8, 2.7 Hz, 1H), 4.09 - 3.91 (m, 2H), 3.56 (t, J = 8.1 Hz, 1H), 3.47 (ddd, J = 9.6, 7.2, 3.1 Hz, 1H), 3.40 (s, 2H), 2.92 (ddd, J = 13.2, 6.5, 5.0 Hz, 1H), 2.68 (ddd, J = 13.2, 5.8, 4.7Hz, 1H), 2.53 (q, J = 8.8 Hz, 1H), 2.30 (dtd, J = 12.4, 8.4, 6.0 Hz, 1H), 2.07 - 1.83 (m, 2H), 1.75 - 1.57 (m, 1H).

[0619] Alkylation of 2-(3-fluorophenyl)pyrrolidine with 6-(2-chloroethoxy)-1H-quinolin-2-one Synthesis 44 6-[2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-1H-quinolin-2-one (ALDHI-2022)

[0620] [ka]

[0621] Step 1: 6-(2-chloroethoxy)-1H-quinolin-2-one To a solution of 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (150 mg, 0.665 mmol, 1 equiv.) in 1,4-dioxane (15 mL) was added DDQ (226 mg, 0.997 mmol, 1.5 equiv.), and the reaction mixture was heated to reflux for 16 h. It was then cooled to room temperature, diluted with water (25 mL), and extracted with EtOAc (2 × 25 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO), filtered, and the solvent was removed in vacuo. The residue was chromatographed (SiO) using 0–5% MeOH:DCM to give 6-(2-chloroethoxy)-1H-quinolin-2-one (54 mg, 0.241 mmol, 36%) as a beige powder. MS (ES+) 224.1 / 226.1 (M+H), Cl isotope pattern. 1 H NMR (300 MHz, DMSO-d6) δ 11.65 (s, 1H), 7.84 (d, J = 9.6 Hz, 1H), 7.30 - 7.23 (m, 2H), 7.19 (dd, J = 9.0, 2.6 Hz, 1H), 6.50 (d, J = 9.5 Hz, 1H), 4.35 - 4.23 (m, 2H), 4.01 - 3.90 (m, 2H).

[0622] Step 2: 6-[2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]quinolin-2-ol To a solution of 6-(2-chloroethoxy)-1H-quinolin-2-one (54 mg, 0.241 mmol, 1 equiv.), 2-(3-fluorophenyl)pyrrolidine (60 mg, 0.362 mmol, 1.5 equiv.) in MeCN (5 mL) was added K2CO3 (67 mg, 0.483 mmol, 2 equiv.) and KI (4 mg, 0.0241 mmol, 0.1 equiv.), and the mixture was refluxed for 5 days. The mixture was cooled to room temperature, and water (20 mL) was added, followed by EtOAc (25 mL). The phases were separated, the aqueous phase was washed with EtOAc (2 x 25 mL), and the combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by chromatography (C) using 5-95% MeCN:HO as eluent. 18 ) to give the title compound (27.8 mg, 0.0789 mmol, 33%) as a yellow powder. MS (ES+) m / z 353.3 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 11.61 (s, 1H), 7.79 (d, J = 9.5 Hz, 1H), 7.34 (td, J = 8.0, 6.1 Hz, 1H), 7.26 - 7.07 (m, 5H), 7.06 - 6.96 (m, 1H), 6.48 (d, J = 9.5 Hz, 1H), 4.03 (t, J = 5.8 Hz, 2H), 3.50 - 3.34 (m, 2H), 2.84 (dt, J = 12.5, 6.1 Hz, 1H), 2.38 (q, J = 8.8 Hz, 1H), 2.24 - 2.07 (m, 1H), 1.91 - 1.73 (m, 2H), 1.52 (dtd, J = 12.2, 9.8, 6.5 Hz, 1H).

[0623] Scheme 4 Alkylation of 2-substituted alkylamines with 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one

[0624] [ka]

[0625] General method D: Alkylation of 2-substituted alkylamines with 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one A mixture of 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (1 equiv.), 2-substituted alkylamine (1.5 equiv.), KCO (2–3 equiv.), and KI (1 equiv.) in MeCN (0.04–0.05 M) was heated to reflux under nitrogen for 3–7 days. If necessary, additional 2-arylamine was added to drive the reaction to completion. The mixture was cooled to room temperature, and water, followed by DCM or EtOAc, was added, and the phases were separated. The aqueous phase was washed with DCM or EtOAc, and the combined organic extracts were filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified either by normal-phase chromatography (SiO) using a gradient of MeOH:DCM (optionally containing 1% aqueous NH) or by preparative HPLC-MS using a gradient of high- or low-pH aqueous MeCN. If the resulting solid was isolated as a salt, the solid was dissolved in saturated aqueous NaHCO, extracted with DCM, and concentrated in vacuo to give the free base. If necessary, further purification was carried out by trituration with EtO.

[0626] Synthesis 45 6-[2-[methyl(3-pyridylmethyl)amino]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-3010)

[0627] [ka] Prepared as described in Method D from 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (30 mg, 0.133 mmol, 1 equiv), N-methyl-N-(3-pyridylmethyl)amine (24 mg, 0.199 mmol, 1.5 equiv), KCO (37 mg, 0.266 mmol, 2 equiv) and KI (22 mg, 0.133 mmol, 1 equiv) in MeCN (2.5 mL) to give, after purification by preparative HPLC-MS (high pH), the title compound (18 mg, 0.0562 mmol, 42%) as an orange gum. MS (ES+) m / z 312.2 (M+H). 1 H NMR (300 MHz, CDCl3) δ 8.56 (dd, J = 2.2, 0.8 Hz, 1H), 8.51 (dd, J = 4.8, 1.7 Hz, 1H), 8.36 (s, 1H), 7.74 - 7.63 (m, 1H), 7.31 - 7.19 (m, 1H), 6.79 - 6.63 (m, 3H), 4.05 (t, J = 5.7 Hz, 2H), 3.63 (s, 2H), 2.92 (dd, J = 8.5, 6.4 Hz, 2H), 2.82 (t, J = 5.7 Hz, 2H), 2.66 - 2.54 (m, 2H), 2.33 (s, 3H).

[0628] The following examples were similarly prepared using Method D with the appropriate 2-substituted alkylamine starting material.

[0629] Synthesis 46 6-[2-[methyl(2-pyridylmethyl)amino]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-3012)

[0630] [ka] MS (ES+) m / z 312.1 (M+H). 1H NMR (300 MHz, CDCl3) δ 8.55 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.71 - 7.56 (m, 2H), 7.44 (dt, J = 7.8, 1.1 Hz, 1H), 7.16 (ddd, J = 7.5, 4.9, 1.2 Hz, 1H), 6.77 - 6.59 (m, 3H), 4.08 (t, J = 5.9 Hz, 2H), 3.79 (s, 2H), 2.98 - 2.84 (m, 4H), 2.66 - 2.54 (m, 2H), 2.40 (s, 3H).

[0631] Synthesis 47 6-[2-[methyl(4-pyridylmethyl)amino]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-3014)

[0632] [ka] MS (ES+) m / z 312.3 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.54 - 8.46 (m, 2H), 7.38 - 7.30 (m, 2H), 6.83 - 6.67 (m, 3H), 4.05 (t, J = 5.8 Hz, 2H), 3.61 (s, 2H), 2.88 - 2.78 (m, 2H), 2.73 (t, J = 5.8 Hz, 2H), 2.45 - 2.34 (m, 2H), 2.25 (s, 3H).

[0633] Synthesis 48 6-[2-[(3-fluorophenyl)methyl-methyl-amino]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-3001)

[0634] [ka] MS (ES+) m / z 329.3 (M−H). 1 H NMR (300 MHz, CDCl3) δ 7.74 (s, 1H), 7.31 - 7.21 (m, 1H), 7.13 - 7.04 (m, 2H), 6.98 - 6.88 (m, 1H), 6.75 - 6.61 (m, 3H), 4.05 (t, J = 5.8 Hz, 2H), 3.61 (s, 2H), 2.97 - 2.87 (m, 2H), 2.81 (t, J = 5.8 Hz, 2H), 2.65 - 2.56 (m, 2H), 2.34 (s, 3H). 19 F { 1 H} NMR (282 MHz, CDCl3) δ -113.73.

[0635] Synthesis 49 6-[2-[methyl-[(1-methylpyrazol-4-yl)methyl]amino]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-3009)

[0636] [ka] MS (ES+) m / z 315.2 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.56 (s, 1H), 7.33 - 7.27 (m, 1H), 6.82 - 6.66 (m, 3H), 3.99 (t, J = 6.0 Hz, 2H), 3.79 (s, 3H), 3.45 (s, 2H), 2.88 - 2.77 (m, 2H), 2.64 (t, J = 6.0 Hz, 2H), 2.45 - 2.34 (m, 2H), 2.20 (s, 3H).

[0637] Synthesis 50 6-[2-[(3-fluorophenyl)methyl-(2-hydroxyethyl)amino]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-3002)

[0638] [ka] MS (ES+) m / z 359.3 (M+H). 1 H NMR (300 MHz, methanol-d4) δ 7.39 - 7.25 (m, 1H), 7.24 - 7.13 (m, 2H), 7.05 - 6.91 (m, 1H), 6.87 - 6.68 (m, 3H), 4.08 (t, J = 5.6 Hz, 2H), 3.85 (s, 2H), 3.67 (t, J = 6.0 Hz, 2H), 3.04 - 2.86 (m, 4H), 2.81 (t, J = 6.1 Hz, 2H), 2.61 - 2.49 (m, 2H). 19 F { 1 H} NMR (282 MHz, methanol-d4) −115.74.

[0639] Synthesis 51 6-[2-[2-hydroxyethyl(3-pyridylmethyl)amino]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-3005)

[0640] [ka] MS (ES+) m / z 342.3 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.57 - 8.49 (m, 1H), 8.45 (dd, J = 4.8, 1.7 Hz, 1H), 7.75 (dt, J = 7.9, 2.1 Hz, 1H), 7.34 (ddd, J = 7.7, 4.8, 0.9 Hz, 1H), 6.80 - 6.63 (m, 3H), 4.40 (t, J = 5.4 Hz, 1H), 3.99 (t, J = 6.0 Hz, 2H), 3.75 (s, 2H), 3.49 (q, J = 6.1 Hz, 2H), 2.89 - 2.76 (m, 4H), 2.61 (t, J = 6.4 Hz, 2H), 2.45 - 2.34 (m, 2H).

[0641] Synthesis 52 6-[2-[2-hydroxyethyl-[(1R)-1-phenylethyl]amino]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-3006)

[0642] [ka] MS (ES+) m / z 355.2 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.44 - 7.26 (m, 4H), 7.29 - 7.17 (m, 1H), 6.78 - 6.60 (m, 3H), 4.29 (t, J = 5.4 Hz, 1H), 4.01 - 3.84 (m, 3H), 3.42 (q, J = 6.3 Hz, 2H), 2.91 - 2.54 (m, 5H), 2.44 - 2.34 (m, 2H), 1.32 (d, J = 6.7 Hz, 3H).

[0643] Synthesis 53 6-[2-[2-hydroxyethyl-[(1S)-1-phenylethyl]amino]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-3007)

[0644] [ka] MS (ES+) m / z 355.3 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.44 - 7.26 (m, 4H), 7.29 - 7.17 (m, 1H), 6.77 - 6.60 (m, 3H), 4.29 (t, J = 5.4 Hz, 1H), 4.01 - 3.84 (m, 3H), 3.42 (q, J = 6.4 Hz, 2H), 2.91 - 2.55 (m, 5H), 2.44 - 2.33 (m, 2H), 1.32 (d, J = 6.8 Hz, 3H).

[0645] Synthesis 54 6-[2-[benzyl-[2-(diethylamino)ethyl]amino]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-3004)

[0646] [ka] MS (ES+) m / z 396.4 (M+H). 1 H NMR (300 MHz, methanol-d4) δ 7.44 - 7.20 (m, 5H), 6.85 - 6.70 (m, 3H), 4.08 (t, J = 5.5 Hz, 2H), 3.76 (s, 2H), 2.99 - 2.87 (m, 4H), 2.81 - 2.70 (m, 4H), 2.64 (q, J = 7.2 Hz, 4H), 2.58 - 2.49 (m, 2H), 1.04 (t, J = 7.2 Hz, 6H).

[0647] Synthesis 55 6-[2-[[1-(3-fluorophenyl)-2-hydroxy-ethyl]-methyl-amino]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-3003)

[0648] [ka] MS (ES+) m / z 359.3 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.43 - 7.29 (m, 1H), 7.23 - 7.12 (m, 2H), 7.12 - 7.00 (m, 1H), 6.80 - 6.64 (m, 3H), 4.51 (t, J = 5.1 Hz, 1H), 3.97 (t, J = 6.0 Hz, 2H), 3.85 - 3.58 (m, 3H), 2.88 - 2.72 (m, 3H), 2.72 - 2.58 (m, 1H), 2.45 - 2.34 (m, 2H), 2.25 (s, 3H). 19 F { 1 H} NMR (282 MHz, DMSO-d6) δ -114.00.

[0649] Synthesis 56 6-[2-[2-hydroxyethyl-[(1-methylpyrazol-4-yl)methyl]amino]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-3011)

[0650] [ka]

[0651] Step 1: 2-[tert-butyl(dimethyl)silyl]oxy-N-[(1-methylpyrazol-4-yl)methyl]ethanamine To a solution of 4-formyl-1-methyl-1H-pyrazole (100 mg, 0.908 mmol, 1 equiv.) in THF (2.5 mL) and ethanol (2.5 mL) was added 2-(tert-butyldimethylsilyloxy)ethanamine (0.20 mL, 1.14 mmol, 1.25 equiv.). The mixture was stirred at room temperature for 16 h, then NaBH (34 mg, 0.908 mmol, 1 equiv.) was added and stirring continued for 3 h. Additional NaBH (34 mg, 0.908 mmol, 1 equiv.) was added and the mixture was stirred for an additional 18 h, then quenched with saturated aqueous NH Cl (5 mL) and extracted with EtOAc (2 × 10 mL). The combined extracts were washed with brine (10 mL), filtered through a hydrophobic frit, and concentrated in vacuo. The resulting residue was chromatographed (SiO) using 0–5% MeOH:DCM (+1% aqueous NH) as eluent to afford 2-[tert-butyl(dimethyl)silyl]oxy-N-[(1-methylpyrazol-4-yl)methyl]ethanamine (192 mg, 0.713 mmol, 78%) as a colorless oil (approximately 10% w / w of 2-(tert-butyldimethylsilyloxy)ethanamine). 1 H NMR (300 MHz, methanol-d4) δ 7.56 (s, 1H), 7.45 (s, 1H), 3.88 (s, 3H), 3.78 (t, 2H), 3.71 (s, 2H), 2.74 (t, 2H), 0.92 (s, 9H), 0.10 (s, 6H).

[0652] Step 2: 6-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl-[(1-methylpyrazol-4-yl)methyl]amino]ethoxy]-3,4-dihydro-1H-quinolin-2-one 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (50 mg, 0.222 mmol, 1 equiv.), 2-[tert-butyl(dimethyl)silyl]oxy-N-[(1-methylpyrazol-4-yl)methyl]ethanamine (90 mg, 0.332 mmol, 1.5 equiv.), KCO (62 mg, 0.443 mmol, 2 equiv.) and KI (37 mg, 0.222 mmol, 1 equiv.) in MeCN (2.5 mL). Prepared from 2% ethanol (2% ethanol) as described in Method D to give 6-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl-[(1-methylpyrazol-4-yl)methyl]amino]ethoxy]-3,4-dihydro-1H-quinolin-2-one (66 mg, 0.144 mmol, 65%) as a colorless residue after normal phase chromatography (SiO) using 0-5% MeOH:DCM (+1% aqueous NH) as eluent. Used directly in the next step. MS (ES+) m / z 459.3 (M+H).

[0653] Step 3: 6-[2-[2-hydroxyethyl-[(1-methylpyrazol-4-yl)methyl]amino]ethoxy]-3,4-dihydro-1H-quinolin-2-one To a solution of 6-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl-[(1-methylpyrazol-4-yl)methyl]amino]ethoxy]-3,4-dihydro-1H-quinolin-2-one (65 mg, 0.142 mmol, 1 equiv.) in THF (5 mL) was added TBAF (1 M in THF, 0.15 mL, 0.149 mmol, 1.05 equiv.). The mixture was stirred at room temperature for 1 h, then quenched with saturated aqueous NaHCO (10 mL) and extracted with DCM (2 × 10 mL). The combined extracts were washed with brine (20 mL), filtered through a hydrophobic frit, and the solvent was removed under reduced pressure. The resulting residue was chromatographed (SiO2) using 0-5% MeOH:DCM as eluent and then purified by preparative HPLC (high pH) to afford the title compound (7.9 mg, 0.0229 mmol, 16%) as a colorless gum. MS (ES+) m / z 345.1 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.31 (d, J = 0.8 Hz, 1H), 6.81 - 6.65 (m, 3H), 4.32 (t, J = 5.4 Hz, 1H), 3.97 (t, J = 6.1 Hz, 2H), 3.79 (s, 3H), 3.57 (s, 2H), 3.48 (q, J = 6.4, 5.3 Hz, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.74 (t, J = 6.1 Hz, 2H), 2.57 - 2.50 (m, 2H), 2.46 - 2.34 (m, 2H).

[0654] Scheme 5 Preparation of alkyl-aryl ethers by Mitsunobu coupling

[0655] [ka]

[0656] Synthesis 57 2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethanol

[0657] [ka] A mixture of 2-(3-fluorophenyl)pyrrolidine (2.4 mL, 15.7 mmol, 1 equiv.), 2-bromoethanol (2.2 mL, 31.4 mmol, 2 equiv.), and K2CO3 (4.34 g, 31.5 mmol, 2 equiv.) in MeCN (20 mL) was refluxed for 18 h. The mixture was cooled and partitioned between EtOAc (20 mL) and water (20 mL). The phases were separated and the aqueous phase was washed with EtOAc (20 mL). The combined extracts were washed with brine (50 mL), filtered through a hydrophobic frit, and concentrated in vacuo. The residue was chromatographed (SiO2) using 0–5% MeOH:DCM (+1% aqueous NH3) as eluent to give 2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethanol (2.1 g, 10.2 mmol, 65%) as a yellow oil. MS (ES+) m / z 210.2 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 7.41 - 7.28 (m, 1H), 7.23 - 7.11 (m, 2H), 7.09 - 6.97 (m, 1H), 4.43 - 4.33 (m, 1H), 3.51 - 3.22 (m, 4H), 2.61 - 2.51 (m, 1H), 2.24 (q, J = 8.8 Hz, 1H), 2.20 - 2.03 (m, 2H), 1.92 - 1.66 (m, 2H), 1.57 - 1.39 (m, 1H).

[0658] General method E: Mitsunobu Coupling between Substituted Phenols and 2-[2-(3-Fluorophenyl)pyrrolidin-1-yl]ethanol To a suspension of 2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethanol (1-1.05 equiv.) and triphenylphosphine (1.5 equiv.) in THF (0.05-0.1 M) was added DIAD (1.5 equiv.), followed by the appropriately substituted phenol (1-1.1 equiv.). The mixture was stirred under nitrogen at room temperature for 18 h. The mixture was diluted with water, extracted with DCM or EtOAc, and the phases were separated. The aqueous phase was washed with DCM or EtOAc, and the combined organic extracts were washed with brine, filtered through a hydrophobic frit, and concentrated in vacuo. The crude material was purified first by normal-phase chromatography (SiO2) using a gradient of MeOH:DCM (optionally containing 1% aqueous NH3), and then by reverse-phase chromatography (C) using a gradient of MeCN:HO. 18 ), or purified by preparative HPLC-MS using a gradient of high or low pH aqueous MeCN.

[0659] Synthesis 58 7-[2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-1,3,4,5-tetrahydro-1-benzazepin-2-one (ALDHI-2020)

[0660] [ka] 2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethanol (100 mg, 0.480 mmol), triphenylphosphine (188 mg, 0.720 mmol), DIAD (0.14 mL, 0.720 mmol), and 7-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (93.2 mg, 0.530 mmol), prepared as described in Method E, was purified by normal phase chromatography (SiO) using 0-70% EtOAc:petroleum ether as eluent, followed by reverse phase chromatography (C) using 5-95% MeCN:HO as eluent. 18 ) to give the title compound (16 mg, 0.0434 mmol, 9%) as a white solid powder. MS (ES+) m / z 369.3 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.27 (s, 1H), 7.41 - 7.28 (m, 1H), 7.25 - 7.14 (m, 2H), 7.10 - 6.97 (m, 1H), 6.89 - 6.68 (m, 3H), 3.98 (t, J = 5.9 Hz, 2H), 3.53 - 3.34 (m, 2H), 2.87 - 2.75 (m, 1H), 2.67 - 2.57 (m, 2H), 2.47 - 2.30 (m, 2H), 2.24 - 2.01 (m, 5H), 1.91 - 1.73 (m, 2H), 1.60 - 1.42 (m, 1H).

[0661] The following examples were similarly prepared using Method E with the appropriate phenol.

[0662] Synthesis 59 6-[2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2001)

[0663] [ka] MS (ES+) m / z 355.3 (M+H). 1H NMR (300 MHz, CDCl3) δ 7.59 (s, 1H), 7.30 - 7.20 (m, 1H), 7.18 - 7.07 (m, 2H), 6.91 (td, J = 8.6, 2.8 Hz, 1H), 6.70 - 6.56 (m, 3H), 3.96 (t, J = 6.0 Hz, 2H), 3.50 - 3.34 (m, 2H), 3.01 - 2.85 (m, 3H), 2.65 - 2.49 (m, 3H), 2.43 (q, J = 8.8 Hz, 1H), 2.25 - 2.09 (m, 1H), 2.05 - 1.54 (m, 3H). 19 F { 1 H} NMR (282 MHz, CDCl3) δ -113.45.

[0664] Synthesis 60 7-[2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-4H-1,4-benzoxazin-3-one (ALDHI-2009)

[0665] [ka] MS (ES+) m / z 357.3 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 10.51 (s, 1H), 7.41 - 7.27 (m, 1H), 7.24 - 7.14 (m, 2H), 7.04 (dddd, J = 9.1, 8.2, 2.4, 1.4 Hz, 1H), 6.82 - 6.71 (m, 1H), 6.54 - 6.43 (m, 2H), 4.51 (s, 2H), 3.93 (t, J = 5.8 Hz, 2H), 3.43 (t, J = 8.1 Hz, 1H), 3.38 - 3.29 (m, 1H), 2.78 (dt, J = 12.6, 6.2 Hz, 1H), 2.50 - 2.40 (m, 1H), 2.35 (q, J = 8.8 Hz, 1H), 2.23 - 2.06 (m, 1H), 1.90 - 1.69 (m, 2H), 1.60 - 1.41 (m, 1H).

[0666] Synthesis 61 7-[2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-4H-1,4-benzothiazin-3-one (ALDHI-2008)

[0667] [ka] MS (ES+) m / z 373.3 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.41 - 7.28 (m, 1H), 7.24 - 7.13 (m, 2H), 7.10 - 6.97 (m, 1H), 6.91 - 6.80 (m, 2H), 6.71 (dd, J = 8.7, 2.8 Hz, 1H), 3.96 (t, J = 5.8 Hz, 2H), 3.49 - 3.38 (m, 3H), 3.38 - 3.27 (m, 1H), 2.86 - 2.71 (m, 1H), 2.49 - 2.41 (m, 1H), 2.35 (q, J = 8.8 Hz, 1H), 2.23 - 2.06 (m, 1H), 1.90 - 1.72 (m, 2H), 1.60 - 1.41 (m, 1H).

[0668] Scheme 6 Preparation of alkyl-aryl ethers by Pd-catalyzed coupling with aryl halides Palladium-catalyzed coupling of aryl bromides with primary alcohols

[0669] [ka]

[0670] Synthesis of aryl bromides

[0671] Synthesis 62 6-Bromo-3-methyl-3,4-dihydro-1H-quinolin-2-one

[0672] [ka]

[0673] Step 1: 3-methyl-3,4-dihydro-1H-quinolin-2-one To a solution of methyl 2-diethoxyphosphorylpropanoate (408 mg, 1.82 mmol, 1.1 equiv.) in THF (10 mL) was added sodium hydride (60% in mineral oil, 79 mg, 1.99 mmol, 1.2 equiv.) at 0 °C. The mixture was stirred for 0.5 h, then a solution of 2-nitrobenzaldehyde (250 mg, 1.65 mmol, 1 equiv.) in THF (10 mL) was added, and stirring was continued at room temperature overnight. Water (5 mL) was added dropwise, followed by saturated aqueous NaHCO3 (10 mL). The mixture was extracted with EtOAc (3 × 25 mL). The organic phase was separated, washed with brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was chromatographed (SiO2) using 0–20% EtOAc:petroleum ether to give a yellow oil. The oil was dissolved in EtOH (26 mL) and loaded onto a 10% Pd / C H-cube cartridge (1 mL / min, 50 °C, 50 bar). The solvent was removed in vacuo to give 3-methyl-3,4-dihydro-1H-quinolin-2-one (194 mg, 1.20 mmol, 92%) as a colorless oil that solidified on standing to give an off-white powder. 1 H NMR showed approximately 10% unreduced product. Used directly in the next step. MS (ES+) m / z 162.0 (M+H). 1 H NMR (DMSO-d6) δ: 10.03 (s, 1H), 7.22 - 7.07 (m, 2H), 6.96 - 6.67 (m, 2H), 2.93 (dd, J = 15.3, 5.7 Hz, 1H), 2.71 - 2.55 (m, 1H), 1.12 (d, J = 6.8 Hz, 3H).

[0674] Step 2: 6-Bromo-3-methyl-3,4-dihydro-1H-quinolin-2-one To a solution of 3-methyl-3,4-dihydro-1H-quinolin-2-one (194 mg, 1.20 mmol, 1 equiv.) in DMF (5 mL) cooled to 0 °C was added NBS (214 mg, 1.20 mmol, 1 equiv.) in portions. The mixture was warmed to room temperature and stirred for 2 h, then poured into water and extracted with EtOAc (2 × 25 mL). The organic phase was washed with aqueous NaSO (25 mL), brine (25 mL), dried (MgSO), filtered, and concentrated in vacuo. The residue was chromatographed (SiO) using 0–50% EtOAc:petroleum ether to give the title compound (200 mg, 0.833 mmol, 69%) as a white powder. MS (ES+) m / z 240.0 / 242.0 (M+H), Br isotope pattern. 1 H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.31 (dd, J = 8.4, 2.3 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 2.95 (dd, J = 15.6, 5.8 Hz, 1H), 2.71 - 2.58 (m, 1H), 2.57 - 2.42 (m, 1H), 1.11 (d, J = 6.8 Hz, 3H).

[0675] General method F: Cyclization of 2-amino-5-bromophenol with substituted methyl 2-bromoacetates.

[0676] [ka] A mixture of 2-amino-5-bromophenol (1.1-1.2 equiv.), DBU (1.1-1.2 equiv.), substituted methyl 2-bromoacetate (1 equiv.), and NMP (0.22-0.51 M) was heated in a microwave reactor at 180 °C for 3 min. The reaction was partitioned between EtOAc (25 mL) and water (25 mL). The organic phase was separated, washed with water (25 mL), brine (3 × 25 mL), dried (MgSO), filtered, and concentrated in vacuo. The crude material was purified by normal phase chromatography (SiO) using an EtOAc:petroleum ether gradient. If necessary, the material was triturated with water for further purification.

[0677] Synthesis 63 7-Bromo-2-ethyl-4H-1,4-benzoxazin-3-one

[0678] [ka] Prepared as described in Method F from 2-amino-5-bromophenol (249 mg, 1.33 mmol, 1.2 equiv.), DBU (0.18 mL, 1.22 mmol, 1.1 equiv.), and methyl 2-bromobutyrate (0.13 mL, 1.10 mmol, 1 equiv.) in NMP (4 mL), the title compound (235 mg, 0.918 mmol, 83%) was obtained as an orange solid after normal phase chromatography (SiO2) using 0-40% EtOAc:petroleum ether as eluent. MS (ES-) m / z 254.0 / 256.0 (MH), Br isotope pattern. 1 H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.19 (d, J = 2.1 Hz, 1H), 7.13 (dd, J = 8.3, 2.1 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 4.56 (dd, J = 7.6, 4.7 Hz, 1H), 1.93 - 1.64 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).

[0679] The following intermediate compounds were similarly prepared using Method F using the appropriately substituted methyl 2-bromoacetate.

[0680] Synthesis 63 7-Bromo-2-propyl-4H-1,4-benzoxazin-3-one

[0681] [ka] MS (ES+) 270.0 / 272.0 (M+H), Br isotope pattern. 1 H NMR (300 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.18 (d, J = 2.1 Hz, 1H), 7.13 (dd, J = 8.3, 2.1 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 4.66 - 4.56 (m, 1H), 1.85 - 1.61 (m, 2H), 1.61 - 1.34 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H).

[0682] Synthesis 64 7-Bromo-2,2-dimethyl-4H-1,4-benzoxazin-3-one

[0683] [ka] MS (ES+) 254 / 256 (MH), Br isotope pattern. 1 H NMR (DMSO-d6) δ: 10.74 (s, 1H), 7.18 - 7.10 (m, 2H), 6.88 - 6.81 (m, 1H), 1.40 (s, 6H).

[0684] Synthesis 65 7-Bromo-2-isopropyl-4H-1,4-benzoxazin-3-one

[0685] [ka] To a solution of 2-amino-5-bromophenol (500 mg, 2.66 mmol, 1 equiv) in THF (10 mL) was added NaHCO (670 mg, 7.98 mmol, 3 equiv) at 0 °C, and the mixture was stirred for 10 min. A solution of 2-bromo-3-methylbutanoyl chloride (530 mg, 2.66 mmol, 1 equiv) in THF (1 mL) was added dropwise, followed by stirring for 6 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3 × 20 mL). The organic extract was washed with brine, dried (MgSO), filtered, and concentrated in vacuo. The crude amide was dissolved in DMF (5 mL), and KCO (551 mg, 3.99 mmol, 1.5 equiv) was added and stirred at room temperature for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 20 mL). The organic extract was washed with brine (3 x 50 mL), dried (MgSO), filtered, and concentrated in vacuo. The residue was chromatographed (SiO) using 0-30% EtOAc:petroleum ether as eluent to afford the title compound (569 mg, 2.11 mmol, 79%) as a yellow powder. MS (ES+) m / z 268.0 / 270.0 (M+H), Br isotope pattern. 1 H NMR (300 MHz, DMSO-d6) δ 10.79 (s, 1H), 7.18 (d, J = 2.2 Hz, 1H), 7.11 (dd, J = 8.3, 2.1 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 4.40 (d, J = 5.5 Hz, 1H), 2.15 (pd, J = 6.8, 5.5 Hz, 1H), 1.01 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H).

[0686] General method G: Preparation of alkyl-aryl ethers by Pd-catalyzed coupling with aryl halides A mixture of primary alcohol (1-2 equiv.), aryl bromide (1 equiv.), tBuBrettPhos Pd G3 (0.02-0.1 equiv.), and NaOtBu (1-2 equiv.) in 1,4-dioxane (0.1-0.2 M) was purged with nitrogen (x3) and then heated to 80 °C for 16-36 h. If necessary, additional tBuBrettPhos Pd G3 (0.05 equiv.) followed by primary alcohol (0.2 equiv.) was added to drive the reaction to completion. The mixture was cooled and filtered through a pad of Celite, rinsing with EtOAc. The organic phase was washed with water, brine, and either filtered through a hydrophobic frit or dried over MgSO4 and concentrated in vacuo. The crude material was purified by normal-phase chromatography (SiO2) using a gradient of EtOAc:petroleum ether and / or reverse-phase chromatography (C) using a gradient of MeCN:HO. 18 ), and / or by preparative HPLC-MS using a gradient of high or low pH aqueous MeCN.

[0687] Synthesis 66 6-[2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-3-methyl-3,4-dihydro-1H-quinolin-2-one (ALDHI-2048)

[0688] [ka] Prepared from 2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethanol (0.25 g, 1.20 mmol, 2 equiv.), 6-bromo-3-methyl-3,4-dihydro-1H-quinolin-2-one (100 mg, 0.416 mmol, 1 equiv.), tBuBrettPhos Pd G3 (36 mg, 0.0416 mmol, 0.100 equiv.) and NaOtBu (48 mg, 0.500 mmol, 1.2 equiv.) in 1,4-dioxane (2.9 mL) as described in Method G and purified by reversed-phase chromatography (C) using 5–95% MeCN:HO as eluent. 18 ) to give the title compound (8 mg, 0.0217 mmol, 5.2%) as a white powder. MS (ES+) m / z 369.2 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.86 (s, 1H), 7.41 - 7.28 (m, 1H), 7.25 - 7.14 (m, 2H), 7.10 - 6.97 (m, 1H), 6.77 - 6.62 (m, 3H), 3.94 (t, J = 5.9 Hz, 2H), 3.43 (t, J = 8.1 Hz, 1H), 3.35 (ddd, J = 9.1, 7.2, 3.3 Hz, 1H), 2.93 - 2.72 (m, 2H), 2.65 - 2.53 (m, 1H), 2.52 - 2.40 (m, 2H), 2.40 - 2.29 (m, 1H), 2.24 - 2.06 (m, 1H), 1.90 - 1.72 (m, 2H), 1.60 - 1.42 (m, 1H), 1.10 (d, J = 6.8 Hz, 3H).

[0689] The following example compounds were similarly prepared using Method G with appropriately substituted aryl bromides.

[0690] Synthesis 67 7-[2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-2-methyl-4H-1,4-benzoxazin-3-one (ALDHI-2044)

[0691] [ka] MS (ES+) m / z 371.2 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.40 - 7.27 (m, 1H), 7.24 - 7.14 (m, 2H), 7.10 - 6.97 (m, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.54 - 6.43 (m, 2H), 4.60 (q, J = 6.8 Hz, 1H), 3.93 (t, J = 5.8 Hz, 2H), 3.43 (t, J = 8.1 Hz, 1H), 3.39 - 3.28 (m, 1H), 2.85 - 2.71 (m, 1H), 2.49 - 2.40 (m, 1H), 2.35 (q, J = 8.8 Hz, 1H), 2.23 - 2.06 (m, 1H), 1.90 - 1.72 (m, 2H), 1.60 - 1.43 (m, 1H), 1.39 (d, J = 6.8 Hz, 3H).

[0692] Synthesis 68 2-Ethyl-7-[2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-4H-1,4-benzoxazin-3-one (ALDHI-2045)

[0693] [ka] MS (ES+) m / z 385.2 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.40 - 7.27 (m, 1H), 7.24 - 7.14 (m, 2H), 7.09 - 6.96 (m, 1H), 6.75 (d, J = 8.5 Hz, 1H), 6.55 - 6.42 (m, 2H), 4.44 (ddd, J = 7.8, 4.6, 0.9 Hz, 1H), 3.93 (t, J = 5.8 Hz, 2H), 3.43 (t, J = 8.1 Hz, 1H), 3.39 - 3.29 (m, 1H), 2.86 - 2.71 (m, 1H), 2.49 - 2.41 (m, 1H), 2.35 (q, J = 8.7 Hz, 1H), 2.23 - 2.06 (m, 1H), 1.90 - 1.61 (m, 4H), 1.59 - 1.41 (m, 1H), 0.97 (t, J = 7.3 Hz, 3H).

[0694] Synthesis 69 7-[2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-2-propyl-4H-1,4-benzoxazin-3-one (ALDHI-2047)

[0695] [ka] MS (ES+) m / z 399.2 (M+H) 1H NMR (300 MHz, CDCl3) δ 7.97 (s, 1H), 7.29 - 7.20 (m, 1H), 7.17 - 7.09 (m, 2H), 6.91 (tdd, J = 8.3, 2.7, 1.1 Hz, 1H), 6.64 (d, J = 8.6 Hz, 1H), 6.50 (d, J = 2.6 Hz, 1H), 6.43 (ddd, J = 8.6, 2.6, 1.0 Hz, 1H), 4.57 - 4.50 (m, 1H), 3.93 (t, J = 6.0 Hz, 2H), 3.49 - 3.33 (m, 2H), 2.93 (dt, J = 12.5, 6.1 Hz, 1H), 2.55 (dt, J = 12.4, 5.9 Hz, 1H), 2.41 (q, J = 8.8 Hz, 1H), 2.26 - 2.08 (m, 1H), 2.05 - 1.75 (m, 4H), 1.72 - 1.42 (m, 3H), 0.97 (t, J = 7.3 Hz, 3H).

[0696] Synthesis 70 7-[2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-2,2-dimethyl-4H-1,4-benzoxazin-3-one (ALDHI-2043)

[0697] [ka] MS (ES+) m / z 385.2 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 10.41 (s, 1H), 7.40 - 7.27 (m, 1H), 7.24 - 7.14 (m, 2H), 7.09 - 6.96 (m, 1H), 6.80 - 6.70 (m, 1H), 6.52 - 6.42 (m, 2H), 3.93 (t, J = 5.8 Hz, 2H), 3.43 (t, J = 8.1 Hz, 1H), 3.39 - 3.31 (m, 1H), 2.86 - 2.73 (m, 1H), 2.48 - 2.40 (m, 1H), 2.35 (q, J = 8.8 Hz, 1H), 2.23 - 2.06 (m, 1H), 1.90 - 1.72 (m, 2H), 1.59 - 1.41 (m, 1H), 1.37 (s, 6H).

[0698] Synthesis 71 7-[2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-2-isopropyl-4H-1,4-benzoxazin-3-one (ALDHI-2049)

[0699] [ka] MS (ES+) m / z 399.2 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 10.47 (s, 1H), 7.40 - 7.27 (m, 1H), 7.25 - 7.14 (m, 2H), 7.09 - 6.96 (m, 1H), 6.73 (d, J = 8.5 Hz, 1H), 6.54 - 6.39 (m, 2H), 4.27 (dd, J = 5.7, 1.7 Hz, 1H), 3.93 (t, J = 5.8 Hz, 2H), 3.43 (t, J = 8.1 Hz, 1H), 3.35 (ddd, J = 9.1, 7.2, 3.4 Hz, 1H), 2.86 - 2.71 (m, 1H), 2.49 - 2.40 (m, 1H), 2.35 (q, J = 8.8 Hz, 1H), 2.22 - 2.04 (m, 2H), 1.90 - 1.72 (m, 2H), 1.59 - 1.41 (m, 1H), 1.01 (d, J = 6.9 Hz, 3H), 0.92 (dd, J = 6.7, 1.7 Hz, 3H).

[0700] Synthesis 72 7-Fluoro-6-[2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2050)

[0701] [ka] MS (ES+) m / z 373.2 (M+H) 1H NMR (300 MHz, DMSO-d6) δ 9.93 (s, 1H), 7.40 - 7.27 (m, 1H), 7.24 - 7.13 (m, 2H), 7.10 - 6.98 (m, 1H), 6.95 (d, J = 9.0 Hz, 1H), 6.67 (d, J = 12.2 Hz, 1H), 4.10 - 3.93 (m, 2H), 3.44 (t, J = 8.1 Hz, 1H), 3.41 - 3.27 (m, 1H), 2.89 - 2.74 (m, 3H), 2.49 - 2.30 (m, 4H), 2.24 - 2.06 (m, 1H), 1.93 - 1.69 (m, 2H), 1.60 - 1.41 (m, 1H).

[0702] Synthesis 73 6-[2-(2-oxo-5-phenyl-pyrrolidin-1-yl)ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2051)

[0703] [ka]

[0704] Step 1: 1-(2-hydroxyethyl)-5-phenyl-pyrrolidin-2-one To a solution of 7a-phenyl-2,3,6,7-tetrahydropyrrolo[2,1-b]oxazol-5-one (758 mg, 3.73 mmol, 1 equiv.) (prepared as reported in Trapani et al., Journal of Pharmacy and Pharmacology, 1996, vol. 48, pp. 834-840) and triethylsilane (1.8 mL, 11.2 mmol, 3 equiv.) in DCM (40 mL) was added titanium(IV) tetrachloride (1 M in toluene, 7.5 mL, 7.46 mmol, 2 equiv.) at −78° C. under nitrogen. The mixture was allowed to warm to room temperature overnight and then cooled to 0° C. Aqueous saturated NH4Cl (25 mL) and water (25 mL) were added and the phases were separated. The organic phase was washed with brine (50 mL), filtered through a hydrophobic frit, and concentrated in vacuo. The resulting solid was chromatographed (SiO2) using 0-10% MeOH:DCM as eluent to afford 1-(2-hydroxyethyl)-5-phenyl-pyrrolidin-2-one (578 mg, 2.82 mmol, 76%) as an oil that solidified to a white solid. MS (ES+) m / z 206.1 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 7.44 - 7.28 (m, 3H), 7.28 - 7.20 (m, 2H), 4.82 - 4.72 (m, 1H), 4.65 (t, J = 5.6 Hz, 1H), 3.59 - 3.46 (m, 1H), 3.46 - 3.23 (m, 2H), 2.59 - 2.23 (m, 4H), 1.83 - 1.67 (m, 1H).

[0705] Step 2: 6-[2-(2-oxo-5-phenyl-pyrrolidin-1-yl)ethoxy]-3,4-dihydro-1H-quinolin-2-one Prepared from 1-(2-hydroxyethyl)-5-phenyl-pyrrolidin-2-one (200 mg, 0.974 mmol, 1 equiv.), 6-bromo-1,2,3,4-tetrahydro-2-quinolinone (220 mg, 0.974 mmol, 1 equiv.), tBuBrettPhos Pd G3 (83 mg, 0.0974 mmol, 0.1 equiv.) and NaOtBu (187 mg, 1.95 mmol, 2 equiv.) in 1,4-dioxane (10 mL) as described in Method G and purified by reversed-phase chromatography (C) using 5–95% MeCN:HO as eluent. 18 ), and subsequent purification by preparative HPLC-MS (high pH) afforded the title compound (40 mg, 0.114 mmol, 12%) as a white powder. After 16 h, additional tBuBrettPhos Pd G3 (42 mg, 0.0487 mmol, 0.05 equiv) was added, followed by 1-(2-hydroxyethyl)-5-phenyl-pyrrolidin-2-one (40 mg, 0.195 mmol, 0.2 equiv) and stirring at 80 °C for another 16 h to drive the reaction to completion. MS (ES+) mz 351.3 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.46 - 7.24 (m, 5H), 6.78 - 6.61 (m, 3H), 4.85 - 4.75 (m, 1H), 3.99 - 3.80 (m, 2H), 3.83 - 3.69 (m, 1H), 2.87 - 2.74 (m, 3H), 2.47 - 2.25 (m, 5H), 1.89 - 1.68 (m, 1H).

[0706] Synthesis 74 3-Fluoro-N-methyl-N-[2-[(2-oxo-3,4-dihydro-1H-quinolin-6-yl)oxy]ethyl]benzamide (ALDHI-3008)

[0707] [ka]

[0708] Step 1: 3-Fluoro-N-(2-hydroxyethyl)-N-methyl-benzamide To a solution of 3-fluorobenzoyl chloride (0.77 mL, 6.31 mmol, 1 equiv) in DCM (10 mL) was added DIPEA (1.6 mL, 9.46 mmol, 1.5 equiv) followed by 2-(methylamino)ethanol (0.76 mL, 9.46 mmol, 1.5 equiv) under nitrogen at 0° C. The mixture was stirred at room temperature for 19 h, then quenched with water (10 mL) and the phases separated. The organic phase was washed with aqueous HCl (1 M, 10 mL), brine (10 mL), filtered through a hydrophobic frit, and concentrated in vacuo to give 3-fluoro-N-(2-hydroxyethyl)-N-methyl-benzamide (1.04 g, 5.27 mmol, 84%) as a colorless oil, which was used directly in the next step. MS (ES+) m / z 198.1 (M+H). 1 H NMR (300 MHz, CDCl3) δ 7.39 (q, J = 7.4 Hz, 1H), 7.25 - 7.01 (m, 3H), 3.98 - 2.90 (m, 8H).

[0709] Step 2: 3-Fluoro-N-methyl-N-[2-[(2-oxo-3,4-dihydro-1H-quinolin-6-yl)oxy]ethyl]benzamide Prepared as described in Method G from 3-fluoro-N-(2-hydroxyethyl)-N-methyl-benzamide (1.01 g, 5.12 mmol, 1 equiv.), 6-bromo-1,2,3,4-tetrahydro-2-quinolinone (1.16 g, 5.12 mmol, 1 equiv.), NaOtBu (591 mg, 6.15 mmol, 1.2 equiv.), and tBuBrettPhos Pd G3 (438 mg, 0.512 mmol, 0.1 equiv.) in 1,4-dioxane (25 mL), and purified by normal phase chromatography (SiO2) using 0-100% EtOAc:petroleum ether as eluent, followed by reverse phase chromatography (C) using 5-95% MeCN:HO as eluent. 18) to give the title compound (288 mg, 0.842 mmol, 16%) as a white powder. MS (ES+) m / z 343.0 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.91 (s, 1H), 7.56 - 7.40 (m, 1H), 7.35 - 7.15 (m, 3H), 6.90 - 6.59 (m, 3H), 4.17 (br.s, 1H), 4.02 (br.s, 1H), 3.79 (br.s, 1H), 3.56 (br.s, 1H), 3.08 - 2.91 (m, 3H), 2.88 - 2.74 (m, 2H), 2.40 (t, J = 7.5 Hz, 2H). 19 F NMR { 1 H} (282 MHz, DMSO-d6) δ -112.30 - -112.64 (m).

[0710] Synthesis 75 N-methyl-N-[2-[(2-oxo-3,4-dihydro-1H-quinolin-6-yl)oxy]ethyl]pyridine-3-carboxamide (ALDHI-3013)

[0711] [ka]

[0712] Step 1: N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-N-methyl-pyridine-3-carboxamide To a mixture of nicotinic acid (290 mg, 2.36 mmol, 1 equiv.) and HATU (1.75 g, 2.83 mmol, 1.2 equiv.) in DMF (5 mL) (anhydrous) was added DIPEA (0.82 mL, 4.71 mmol, 2 equiv.). The mixture was stirred for 0.25 h, then N-[2-(tert-butyldimethylsilyloxy)ethyl]methylamine (491 mg, 2.59 mmol, 1.1 equiv.) was added and stirring was continued at room temperature for 24 h. Water (20 mL) was added and the mixture was extracted with EtOAc (2 × 10 mL). The combined extracts were washed with brine (25 mL), dried (MgSO), filtered, and concentrated in vacuo. The resulting residue was purified by chromatography (C) using 5–95% MeCN:HO as eluent. 18 ), and the product-containing fractions were combined and extracted with DCM (2 x 100 mL). The organic extracts were filtered through a hydrophobic frit and concentrated in vacuo to give N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-N-methyl-pyridine-3-carboxamide (533 mg, 1.81 mmol, 77%) as an orange oil. MS (ES+) m / z 295.2 (M+H). 1 H NMR (300 MHz, CDCl3) δ 8.74 - 8.60 (m, 2H), 7.85 - 7.71 (m, 1H), 7.38 - 7.29 (m, 1H), 3.99 - 3.83 (m, 1H), 3.78 - 3.58 (m, 2H), 3.49 - 3.33 (m, 1H), 3.19 - 3.03 (m, 3H), 0.99 - 0.80 (m, 9H), 0.07 (dd, J = 12.4, 5.3 Hz, 6H).

[0713] Step 2: N-(2-hydroxyethyl)-N-methyl-pyridine-3-carboxamide To a solution of N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-N-methyl-pyridine-3-carboxamide (532 mg, 1.81 mmol, 1 equiv.) in THF (5 mL) under nitrogen was added TBAF (1 M in THF, 1.9 mL, 1.90 mmol, 1.05 equiv.). The mixture was stirred at room temperature for 1 h, then quenched with saturated aqueous NaHCO3 (10 mL) and extracted with DCM (2 x 20 mL). The combined extracts were washed with brine (20 mL), filtered through a hydrophobic frit, and concentrated in vacuo. The residue was purified by chromatography (C) using 5-95% MeCN:HO as eluent. 18 ) to give N-(2-hydroxyethyl)-N-methyl-pyridine-3-carboxamide (138 mg, 0.766 mmol, 42%) as a colorless gum. MS (ES+) m / z 181.3 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 8.66 - 8.57 (m, 2H), 7.89 - 7.79 (m, 1H), 7.51 - 7.40 (m, 1H), 4.90 - 4.76 (m, 1H), 3.68 - 3.58 (m, 1H), 3.58 - 3.44 (m, 2H), 3.32 - 3.22 (m, 1H), 3.03 - 2.93 (m, 3H).

[0714] Step 3: N-methyl-N-[2-[(2-oxo-3,4-dihydro-1H-quinolin-6-yl)oxy]ethyl]pyridine-3-carboxamide Prepared from N-(2-hydroxyethyl)-N-methyl-pyridine-3-carboxamide (136 mg, 0.755 mmol, 1 equiv.), 6-bromo-1,2,3,4-tetrahydro-2-quinolinone (171 mg, 0.755 mmol, 1 equiv.), tBuBrettPhos Pd G3 (64 mg, 0.0755 mmol, 0.1 equiv.) and NaOtBu (87 mg, 0.906 mmol, 1.2 equiv.) in 1,4-dioxane (5 mL) as described in Method G and purified by reversed-phase chromatography (C) using 5–95% MeCN:HO as eluent.18 ), and subsequent purification by preparative HPLC-MS (low pH) gave the title compound (28 mg, 0.0861 mmol, 11%) as a yellow powder. MS (ES+) m / z 326.1 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.71 - 8.52 (m, 2H), 7.83 (d, J = 7.8 Hz, 1H), 7.51 - 7.40 (m, 1H), 6.89 - 6.58 (m, 3H), 4.26 - 4.11 (m, 1H), 4.07 - 3.97 (m, 1H), 3.87 - 3.76 (m, 1H), 3.63 - 3.53 (m, 1H), 3.07 - 2.97 (m, 3H), 2.89 - 2.75 (m, 2H), 2.40 (t, J = 7.5Hz, 2H).

[0715] Scheme 7 Preparation of amides from amines and carboxylic acids

[0716] [ka] Preparation of alkyl carboxylates

[0717] Synthesis 76 Ethyl 2-bromo-4-(3-fluorophenyl)thiazole-5-carboxylate

[0718] [ka]

[0719] Step 1: Ethyl 2-bromo-3-(3-fluorophenyl)-3-oxo-propanoate To a solution of 3-(3-fluoro-phenyl)-3-oxo-propionic acid ethyl ester (1.4 mL, 7.66 mmol, 1 equiv) in DCM (60 mL) was added pTSA (291 mg, 1.53 mmol, 0.2 equiv), followed by NBS (1.70 g, 9.57 mmol, 1.25 equiv). The mixture was stirred at room temperature for 20 h. The solvent was removed in vacuo, and the resulting residue was dissolved in EtO (25 mL). The precipitate was filtered and washed with EtO (2 × 25 mL). The filtrate was washed with saturated aqueous NaHCO (25 mL) and water (25 mL), filtered through a hydrophobic frit, and concentrated in vacuo. The resulting residue was chromatographed (SiO2) using 0-5% EtOAc:petroleum ether as eluent to give ethyl 2-bromo-3-(3-fluorophenyl)-3-oxo-propanoate (1.91 g, 6.61 mmol, 86%) as a pale yellow oil, which was used directly in the next step. MS (ES-) m / z 287.0 / 289.0 (MH), Br isotope pattern. 1 H NMR (300 MHz, CDCl3) δ 7.82 - 7.73 (m, 1H), 7.74 - 7.64 (m, 1H), 7.54 - 7.43 (m, 1H), 7.33 (tdd, J = 8.2, 2.6, 1.0 Hz, 1H), 5.59 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H). 19 F NMR { 1 H} (282 MHz, CDCl3) δ -110.71.

[0720] Step 2: Ethyl 2-amino-4-(3-fluorophenyl)thiazole-5-carboxylate To a solution of ethyl 2-bromo-3-(3-fluorophenyl)-3-oxopropanoate (1.90 g, 6.57 mmol, 1 equiv.) in EtOH (50 mL) was added thiourea (600 mg, 7.89 mmol, 1.2 equiv.). The mixture was refluxed for 2 h. The solution was cooled and concentrated in vacuo, and the resulting residue was dissolved in DCM (20 mL) and washed with saturated aqueous NaHCO (20 mL). The aqueous layer was extracted with DCM (20 mL), and the combined organic extracts were concentrated in vacuo. The solid was stirred in a minimal amount of EtO, filtered, and washed with EtO (2 × 20 mL) and petroleum ether (2 × 20 mL) to give ethyl 2-amino-4-(3-fluorophenyl)thiazole-5-carboxylate (1.43 g, 5.37 mmol, 82%) as a pale yellow powder. MS (ES+) m / z 267.0 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 7.89 (s, 2H), 7.54 - 7.38 (m, 3H), 7.29 - 7.16 (m, 1H), 4.11 (q, J = 7.1 Hz, 2H), 1.16 (t, J = 7.1 Hz, 3H). 19 F { 1 H} NMR (282 MHz, DMSO-d6) δ -114.52.

[0721] Step 3: Ethyl 2-bromo-4-(3-fluorophenyl)thiazole-5-carboxylate To a mixture of ethyl 2-amino-4-(3-fluorophenyl)thiazole-5-carboxylate (1.40 g, 5.26 mmol, 1 equiv.) and copper(I) bromide (905 mg, 6.31 mmol, 1.2 equiv.) in MeCN (50 mL) under nitrogen was added t-butyl nitrite (0.94 mL, 7.89 mmol, 1.5 equiv.). The mixture was heated to 60° C. for 1 h, then cooled, filtered through Celite, washed with MeCN (4×25 mL), and concentrated in vacuo. The residue was partitioned between DCM (50 mL) and saturated aqueous NaHCO (50 mL), and the phases were separated. The aqueous layer was washed with DCM (2×50 mL), and the combined organic extracts were washed with brine (100 mL), filtered through a hydrophobic frit, and concentrated in vacuo. The resulting solid was chromatographed (SiO2) using 0–10% EtOAc:petroleum ether as the eluent to give ethyl 2-bromo-4-(3-fluorophenyl)thiazole-5-carboxylate (1.22 g, 3.70 mmol, 70%) as a white powder. MS (ES+) m / z 329.9 / 331.9 (M+H), Br isotope pattern. 1 H NMR (300 MHz, DMSO-d6) δ 7.63 - 7.44 (m, 3H), 7.40 - 7.27 (m, 1H), 4.24 (q, J = 7.1 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H). 19 F NMR { 1 H} (282 MHz, DMSO-d6) δ -113.74.

[0722] Synthesis 77 Ethyl 4-(3-fluorophenyl)thiazole-5-carboxylate

[0723] [ka] A solution of ethyl 2-bromo-4-(3-fluorophenyl)thiazole-5-carboxylate (225 mg, 0.681 mmol, 1 equiv) in 0.05 M EtOH (14 mL) was passed through a 10% Pd / CH cube cartridge (1 mL / min, 80 °C, 40 bar). The solvent was removed in vacuo, and the resulting residue was chromatographed (SiO2) using 0-10% EtOAc:petroleum ether as eluent to give ethyl 4-(3-fluorophenyl)thiazole-5-carboxylate (133 mg, 0.529 mmol, 78%) as a white powder. MS (ES+) m / z 252.0 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.36 (s, 1H), 7.63 - 7.55 (m, 2H), 7.55 - 7.46 (m, 1H), 7.35 - 7.26 (m, 1H), 4.25 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H). 19 F NMR { 1 H} (282 MHz, DMSO-d6) δ -113.99.

[0724] General method H: Preparation of carboxylic acids

[0725] [ka] A mixture of ethyl carboxylate (1 equiv.) and lithium hydroxide monohydrate (2 equiv.) or sodium hydroxide (1 equiv.) in water and THF (1:5) was heated to 60°C for 3.5-4 h. The mixture was cooled and concentrated in vacuo, the remaining aqueous layer was acidified with aqueous HCl (2 M), diluted with water, and the precipitate was filtered, washed with water (2 x 25 mL), and dried in vacuo at 50°C to give the desired compound.

[0726] Synthesis 78 2-Bromo-4-(3-fluorophenyl)thiazole-5-carboxylic acid

[0727] [ka] Prepared as described in Method H from ethyl 2-bromo-4-(3-fluorophenyl)thiazole-5-carboxylate (1.18 g, 3.57 mmol, 1 equiv.) and lithium hydroxide monohydrate (307 mg, 7.15 mmol, 2 equiv.) in water (4 mL) and THF (20 mL) to afford the title compound (1.05 g, 3.48 mmol, 97%) as a white powder. MS (ES+) m / z 301.8 / 303.8 (M+H), Br isotope pattern. 1 H NMR (300 MHz, DMSO-d6) δ 13.91 (s, 1H), 7.64 - 7.53 (m, 2H), 7.56 - 7.43 (m, 1H), 7.37 - 7.24 (m, 1H). 19 F { 1 H} NMR (282 MHz, DMSO-d6) δ -113.76.

[0728] The following intermediate compounds were similarly prepared using Method H using the appropriate ester.

[0729] Synthesis 79 4-(3-fluorophenyl)thiazole-5-carboxylic acid

[0730] [ka] MS (ES+) m / z 223.9 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 13.54 (s, 1H), 9.30 (s, 1H), 7.65 - 7.55 (m, 2H), 7.55 - 7.43 (m, 1H), 7.28 (dddd, J = 9.2, 8.3, 2.6, 1.1 Hz, 1H). 19 F { 1H} NMR (282 MHz, DMSO-d6) δ -114.02.

[0731] General method I: Preparation of amides To a mixture of carboxylic acid (1 equiv.), 6-amino-3,4-dihydroquinolin-2(1H)-one (1 equiv.), and HATU (1.1 equiv.) in DMF (0.2 M) was added DIPEA (2 equiv.). The mixture was stirred at room temperature for 2 h, then quenched with brine and stirred for 0.25 h. The resulting precipitate was filtered, washed with water, and dried in vacuo at 50 °C. The crude material was purified by normal phase chromatography (SiO2) using a gradient of EtOAc:petroleum ether or reverse phase chromatography (C) using a gradient of MeCN:HO. 18 ), or purified by preparative HPLC-MS (high pH).

[0732] Synthesis 80 2-Bromo-4-(3-fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)thiazole-5-carboxamide

[0733] [ka] Prepared as described in Method I from 2-bromo-4-(3-fluorophenyl)thiazole-5-carboxylic acid (1.04 g, 3.44 mmol, 1 equiv.), 6-amino-3,4-dihydroquinolin-2(1H)-one (558 mg, 3.44 mmol, 1 equiv.), HATU (1.44 g, 3.79 mmol, 1.1 equiv.), and DIPEA (1.2 mL, 6.88 mmol, 2 equiv.) in DMF (20 mL) to afford the title compound (730 mg, 1.64 mmol, 48%) as a pale orange powder after normal phase chromatography (SiO) using 0-100% EtOAc:petroleum ether as eluent. MS (ES+) m / z 445.8 / 447.8 (M+H), Br isotope pattern. 1H NMR (300 MHz, DMSO-d6) δ 10.56 (s, 1H), 10.08 (s, 1H), 7.59 - 7.44 (m, 3H), 7.44 - 7.40 (m, 1H), 7.34 - 7.21 (m, 2H), 6.81 (d, J = 8.5 Hz, 1H), 2.85 (t, J = 7.5 Hz, 2H), 2.49 - 2.38 (m, 2H). 19 F { 1 H} NMR (282 MHz, DMSO-d6) δ -112.68.

[0734] The following examples were similarly prepared using Method I with the appropriate carboxylic acid.

[0735] Synthesis 81 4-(3-Fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)thiazole-5-carboxamide (ALDHI-1003)

[0736] [ka] MS (ES+) m / z 367.9 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 10.53 (s, 1H), 10.07 (s, 1H), 9.28 (s, 1H), 7.65 - 7.42 (m, 4H), 7.36 - 7.27 (m, 1H), 7.27 - 7.18 (m, 1H), 6.82 (d, J = 8.5 Hz, 1H), 2.86 (t, J = 7.5 Hz, 2H), 2.48 - 2.39 (m, 2H). 19 F { 1 H} NMR (282 MHz, DMSO-d6) δ -112.95.

[0737] Synthesis 82 3-(3-Fluorophenyl)-N-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazole-4-carboxamide (ALDHI-1006)

[0738] [ka] MS (ES+) m / z 349.0 (M−H). 1 H NMR (300 MHz, CDCl3) δ 8.21 (s, 1H), 7.57 - 7.33 (m, 4H), 7.04 (d, J = 10.7 Hz, 1H), 6.66 (d, J = 8.4 Hz, 2H), 3.03 - 2.93 (m, 2H), 2.66 - 2.54 (m, 2H).

[0739] Synthesis 83 3'-Fluoro-N-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-[1,1'-biphenyl]-2-carboxamide (ALDHI-1007)

[0740] [ka] MS (ES+) m / z 361.1 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 10.15 (s, 1H), 10.00 (s, 1H), 7.62-7.35 (m, 6H), 7.29-7.11 (m, 4H), 6.75 (d, J= 8.5 Hz, 1H), 2.81 (t, J= 7.5Hz, 2H), 2.46-2.37 (m, 2H)

[0741] General method J: Amination of 2-bromo-4-aryl-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)thiazole-5-carboxamide

[0742] [ka] A mixture of 2-bromo-4-(3-fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)thiazole-5-carboxamide (1 equivalent), substituted amine (2 equivalents), and CsCO (3 equivalents) or KCO (3 equivalents) in MeCN (0.02–0.04 M) was heated to reflux for 1–3 days. If necessary, additional substituted amine and base were added to drive the reaction to completion. The mixture was cooled, and then water and then DCM were added. If precipitation occurred at this stage, the solid was stirred for 0.5 h, filtered, washed with DCM, water, and dried in vacuo at 50°C. If no precipitate formed, the phases were separated and the aqueous phase was washed with DCM. The combined organic extracts were washed with brine, filtered through a hydrophobic frit, and concentrated in vacuo. The crude material was purified by normal phase chromatography (SiO) using a gradient of MeOH:DCM (optionally containing 1% aqueous NH) or by preparative HPLC-MS using a gradient of high or low pH aqueous MeCN, or by trituration with EtO or petroleum ether, as necessary.

[0743] Synthesis 84 4-(3-Fluorophenyl)-2-(3-hydroxyazetidin-1-yl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)thiazole-5-carboxamide (ALDHI-1004)

[0744] [ka] Prepared as described in Method J from 2-bromo-4-(3-fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)thiazole-5-carboxamide (40 mg, 0.0896 mmol, 1 equiv.), 3-hydroxyazetidine hydrochloride (20 mg, 0.179 mmol, 2 equiv.) and CsCO (88 mg, 0.269 mmol, 3 equiv.) in MeCN (2.5 mL) to give the title compound (16 mg, 0.0358 mmol, 40%) as a pale yellow powder after preparative HPLC-MS (high pH). MS (ES+) m / z 439.0 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.80 (s, 1H), 7.51 - 7.33 (m, 4H), 7.27 - 7.14 (m, 2H), 6.76 (d, J = 8.5 Hz, 1H), 5.92 (d, J = 6.6 Hz, 1H), 4.73 - 4.60 (m, 1H), 4.37 - 4.25 (m, 2H), 3.86 (dd, J = 9.0, 4.5 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.46 - 2.37 (m, 2H). 19 F NMR { 1 H} (282 MHz, DMSO-d6) δ -113.61.

[0745] The following examples were similarly prepared using Method J with the appropriate amine.

[0746] Synthesis 85 2-(Dimethylamino)-4-(3-fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)thiazole-5-carboxamide (ALDHI-1002)

[0747] [ka] MS (ES+) m / z 411.4 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.71 (s, 1H), 7.53 - 7.32 (m, 4H), 7.26 - 7.14 (m, 2H), 6.76 (d, J = 8.5 Hz, 1H), 3.13 (s, 6H), 2.82 (t, J = 7.5 Hz, 2H), 2.46 - 2.37 (m, 2H). 19 F { 1 H} NMR (282 MHz, DMSO-d6) δ -113.68.

[0748] Synthesis 86 4-(3-Fluorophenyl)-2-morpholino-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)thiazole-5-carboxamide (ALDHI-1001)

[0749] [ka] MS (ES+) m / z 453.4 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.87 (s, 1H), 7.53 - 7.34 (m, 4H), 7.27 - 7.14 (m, 2H), 6.77 (d, J = 8.5 Hz, 1H), 3.79 - 3.70 (m, 4H), 3.55 - 3.46 (m, 4H), 2.83 (t, J = 7.5 Hz, 2H), 2.48 - 2.37 (m, 2H). 19 F { 1 H} NMR (282 MHz, DMSO-d6) δ -113.55.

[0750] Synthesis 87 4-(3-Fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-2-piperazin-1-yl-thiazole-5-carboxamide (ALDHI-1005)

[0751] [ka] A mixture of 2-bromo-4-(3-fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)thiazole-5-carboxamide (49 mg, 0.110 mmol, 1 equiv.), CsCO (108 mg, 0.329 mmol, 3 equiv.), and 1-t-Boc-piperazine (41 mg, 0.220 mmol, 2 equiv.) in MeCN (2.5 mL) was refluxed for 5 days. The mixture was cooled, and water (10 mL) was added, followed by DCM (10 mL). The mixture was stirred for 0.5 h. The phases were separated, the aqueous phase washed with DCM (10 mL), and the combined organic extracts were filtered through a hydrophobic frit and concentrated in vacuo. The resulting solid was chromatographed (SiO) using 0–5% MeOH:DCM (+1% aqueous NH) as eluent to afford the t-Boc-protected intermediate (31 mg) as a brown powder. MS (ES+) m / z 552.3 (M+H). The residue was dissolved in DCM (2 mL) and trifluoroacetic acid (0.50 mL, 6.49 mmol, 59.1 equiv) was added. The mixture was stirred for 1.5 h, concentrated in vacuo, and the resulting solid was triturated with EtO and then purified by preparative HPLC-MS (low pH) to afford the title compound (8 mg, 0.0177 mmol, 16%) as a yellow powder. MS (ES+) m / z 452.0 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.81 (s, 1H), 7.54 - 7.33 (m, 4H), 7.26 - 7.13 (m, 2H), 6.77 (d, J = 8.5 Hz, 1H), 3.49 - 3.40 (m, 4H), 2.91 - 2.76 (m, 6H), 2.47 - 2.35 (m, 2H). 19 F NMR { 1 H} (282 MHz, DMSO-d6) δ -113.60.

[0752] Synthesis 88 Methyl 3-(3-fluorophenyl)-5-methylisoxazole-4-carboxylate

[0753] [ka] To a solution of (1Z)-3-fluoro-N-hydroxy-benzimidoyl chloride (90 mg, 0.519 mmol, 1.00 equiv.) and methyl 3-oxobutanoate (120 mg, 1.04 mmol, 2.00 equiv.) in methanol (6.6724 mL) was added sodium methoxide (25% in methanol, 0.36 mL, 1.56 mmol, 3.00 equiv.) at −10° C. The reaction mixture was allowed to warm to room temperature over 2 h and then evaporated to dryness. The resulting residue was dissolved in ethyl acetate, and the organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and evaporated to dryness. The crude mixture was purified by silica (SiO2) gel column chromatography using a 0–10% gradient of ethyl acetate in petroleum ether to give methyl 3-(3-fluorophenyl)-5-methyl-isoxazole-4-carboxylate (30 mg, 0.128 mmol, 25%) as a colorless oil. MS (ES+) m / z 236.2 (M+H). 1H NMR (300, CDCl3) δ 7.49 - 7.35 (m, 3H), 7.25 - 7.15 (m, 1H), 3.82 (s, 3H), 2.76 (s, 3H) ppm.

[0754] Synthesis 89 Ethyl 4-(3-fluorophenyl)-2-methylthiazole-5-carboxylate

[0755] [ka] To a solution of ethyl 2-bromo-3-(3-fluorophenyl)-3-oxo-propanoate (1.23 g, 3.87 mmol, 1 equiv.) in EtOH (20 mL) was added thioacetamide (349 mg, 4.65 mmol, 1.2 equiv.). The mixture was refluxed for 3 h, then cooled and concentrated in vacuo. The resulting residue was dissolved in DCM (30 mL) and washed with saturated aqueous NaHCO3 (30 mL). The organic layer was filtered through a hydrophobic frit and concentrated in vacuo. The crude mixture was purified by flash chromatography (SiO2) using a 0-100% gradient of EtOAc in petroleum ether to give a residue that was used in the next step without further purification. MS (ES+) m / z 266.2 (M+H).

[0756] General method K: Synthesis of thiazoles from β-ketoesters

[0757] [ka]

[0758] Step 1: Bromination of beta-ketoesters To a solution of appropriately substituted phenyl 3-oxo-propionic acid ethyl ester (1 equiv.) in DCM (0.13 M) was added pTSA (0.2 equiv.) and NBS (1.25 equiv.). The mixture was stirred at room temperature for 20 h and then evaporated to dryness. The resulting residue was dissolved in EtO, and the precipitate was filtered and washed with EtO. The filtrate was washed with saturated aqueous NaHCO and water, filtered through a hydrophobic frit, and concentrated in vacuo. The resulting residue was chromatographed (SiO) using a gradient of EtOAc in petroleum ether as eluent to give the appropriately substituted phenylethyl 2-bromo-3-oxo-propanoate.

[0759] Step 2: Thiazole ring formation To a solution of appropriately substituted phenylethyl 2-bromo-3-oxo-propanoate (1 equivalent) in EtOH (0.13 M) was added thiourea (1.2 equivalents). The mixture was refluxed for 2 hours, then cooled and concentrated in vacuo. The resulting residue was dissolved in DCM and washed with saturated aqueous NaHCO. The aqueous layer was extracted with DCM, and the combined organic extracts were concentrated in vacuo. The resulting solid was stirred in a minimum amount of EtO, filtered, and washed with EtO and petroleum ether to give the appropriately substituted phenylethyl 2-amino-thiazole-5-carboxylate.

[0760] Step 3: Conversion of an amine to a bromine substituent To a mixture of appropriately substituted phenylethyl 2-amino-thiazole-5-carboxylate (1 equiv.) and copper(I) bromide (1.2 equiv.) in MeCN (0.1 M) under nitrogen was added t-butyl nitrite (1.5 equiv.). The mixture was heated to 60°C for 1-6 h, then cooled, filtered through Celite, washed with MeCN, and concentrated in vacuo. The residue was partitioned between DCM and saturated aqueous NaHCO3, and the phases were separated. The aqueous layer was washed with DCM, and the combined organic extracts were washed with brine, filtered through a hydrophobic frit, and concentrated in vacuo. The resulting solid was either used directly in the next step without further purification or chromatographed (SiO2) using a gradient of EtOAc in petroleum ether as eluent to give the appropriately substituted ethyl 2-bromo-thiazole-5-carboxylate.

[0761] Step 4: Conversion of bromine atoms and hydrogen atoms A solution of appropriately substituted ethyl 2-bromo-thiazole-5-carboxylate (225 mg, 1 equiv.) in EtOH (0.05 M) was passed through a 10% Pd / CH cube cartridge (1 mL / min, 80 °C, 40 bar). The solvent was removed in vacuo and the resulting residue was chromatographed (SiO2) using a gradient of EtOAc in petroleum ether as eluent to give the desired intermediate.

[0762] The following intermediate compounds were prepared in four steps as described in Method K.

[0763] Synthesis 90 Ethyl 4-(2-chlorophenyl)thiazole-5-carboxylate

[0764] [ka] MS (ES+) m / z 268.1 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 9.39 (s, 1H), 7.61 - 7.54 (m, 1H), 7.54 - 7.41 (m, 3H), 4.15 (q, J = 7.1 Hz, 2H), 1.09 (t, J = 7.1 Hz, 3H).

[0765] Synthesis 91 Ethyl 4-(m-tolyl)thiazole-5-carboxylate

[0766] [ka] MS (ES+) m / z 249.1 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 7.59 - 7.49 (m, 2H), 7.40 - 7.23 (m, 2H), 4.23 (q, J = 7.1 Hz, 2H), 2.36 (d, J = 0.8 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H).

[0767] General method L: Suzuki Coupling of Brominated Heteroaromatic Esters

[0768] [ka] To a solution of brominated ethyl carboxylate (1.00 equiv.) and boronic acid (1.00 equiv.) in DME (0.1 M) was added Pd(PPh3)4 (0.05 equiv.) and K2CO3 (0.4 M in water, 2.00 equiv.). The resulting mixture was degassed for 15 min, stirred at 85 °C for 2 h, cooled to room temperature, then diluted with water, filtered, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered, and evaporated to dryness. The crude material was purified by flash chromatography (SiO2) using a gradient of EtOAc in petroleum ether to give the desired compound.

[0769] Synthesis 92 Ethyl 4-(3-fluorophenyl)oxazole-5-carboxylate

[0770] [ka] Prepared as described in Method L from ethyl 4-bromo-oxazole-5-carboxylate (200 mg, 0.909 mmol, 1.00 equiv), 3-fluorobenzeneboronic acid (127 mg, 0.909 mmol, 1.00 equiv), Pd(PPh3)4 (53 mg, 0.0455 mmol, 0.0500 equiv) and K2CO3 (0.4 M in water, 4.5 mL, 1.82 mmol, 2.00 equiv) in DME (8 mL) to afford the title compound, ethyl 4-(3-fluorophenyl)oxazole-5-carboxylate (48 mg, 0.196 mmol, 22%) as a yellow oil. MS (ES+) m / z 236.2 (M+H). 1 H NMR (DMSO-d6) δ 8.74 (s, 1H), 7.94-7.83 (m, 2H), 7.55 (td, J= 8.2, 6.3 Hz, 1H), 7.33 (tdd, J= 8.6, 2.5 Hz, 1H), 4.35 (q, J= 7.1 Hz, 2H), 1.31 (t, J= 7.1 Hz, 3H) ppm.

[0771] The following intermediate compounds were similarly prepared using Method L using the appropriate brominated ester and boronic acid.

[0772] Synthesis 93 Ethyl 3-(3-fluorophenyl)pyridine-2-carboxylate

[0773] [ka] MS (ES+) m / z 246.2 (M+H). 1H NMR (DMSO-d6) δ 8.67 (dt, J= 4.8, 1.5 Hz, 1H), 7.99 (dt, J= 7.9, 1.5 Hz, 1H), 7.67 (ddd, J= 7.9, 4.7, 1.3 Hz, 1H), 7.58-7.48 (m, 1H), 7.37-7.12 (m, 3H), 4.15 (q, J= 7.1 Hz, 2H), 1.05 (t, J= 7.1 Hz, 3H) ppm.

[0774] Synthesis 94 Ethyl 4-(2-fluorophenyl)thiazole-5-carboxylate

[0775] [ka] MS (ES+) m / z 252.2 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.62-7.48 (m, 2H), 7.36-7.26 (m, 2H), 4.20 (q, J= 7.1 Hz, 2H), 1.16 (t, J= 7.1 Hz, 3H) ppm. 19 F {1H} NMR (282 MHz, DMSO-d6) δ -114.52 ppm.

[0776] Synthesis 95 Ethyl 3-(3-fluorophenyl)thiophene-2-carboxylate

[0777] [ka] MS (ES+) m / z 251.2 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 7.96 (d, J= 5.1 Hz, 1H), 7.45 (dddd, J= 8.2, 7.5, 6.2, 0.6 Hz, 1H), 7.37-7.18 (m, 4H), 4.18 (q, J= 7.1 Hz, 2H), 1.17 (t, J= 7.1 Hz, 3H) ppm. 19 F {1H} NMR (282 MHz, DMSO-d6) δ -114.18 ppm.

[0778] Synthesis 96 Ethyl 4-(thiophen-2-yl)thiazole-5-carboxylate

[0779] [ka] MS (ES+) m / z 240.1 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.31 (dd, J= 3.8, 1.2 Hz, 1H), 7.75 (dd, J= 5.1, 1.2 Hz, 1H), 7.20 (dd, J= 5.1, 3.8 Hz, 1H), 4.34 (q, J= 7.1 Hz, 2H), 1.32 (t, J= 7.1 Hz, 3H) ppm.

[0780] Synthesis 97 Ethyl 4-(3,5-difluorophenyl)thiazole-5-carboxylate

[0781] [ka] MS (ES+) m / z 287.2 (M+NH4). 1H NMR (300 MHz, DMSO-d6) δ 9.37 (s, 1H), 7.55-7.45 (m, 2H), 7.43-7.33 (m, 1H), 4.26 (q, J= 7.1 Hz, 2H), 1.23 (t, J= 7.1 Hz, 3H) ppm. 19 F {1H} NMR (282 MHz, DMSO-d6) δ -110.53 ppm.

[0782] General method M: One-pot Suzuki coupling and ester deprotection to carboxylic acids

[0783] [ka] To a solution of brominated ethyl carboxylate (1.00 equiv.) and boronic acid (1.00 equiv.) in DME (0.1 M) was added Pd(PPh3)4 (0.05 equiv.) and K2CO3 (0.4 M in water, 2.00 equiv.). The resulting mixture was degassed for 20 min, stirred at 110 °C for 24 h, cooled to room temperature, then filtered through a Celite pad and evaporated to dryness. The resulting residue was diluted with aqueous HCl 2 M and extracted with diethyl ether. The combined organic layers were dried over anhydrous MgSO4, filtered, and evaporated to dryness. This residue was used in the next step without further purification.

[0784] Synthesis 98 5-(pyridin-3-yl)thiazole-4-carboxylic acid

[0785] [ka] Prepared as described in Method M from ethyl 5-bromothiazole-4-carboxylate (250 mg, 1.06 mmol, 1.00 equiv), pyridine-3-boronic acid (130 mg, 1.06 mmol, 1.00 equiv), Pd(PPh3)4 (61 mg, 0.05 mmol, 0.05 equiv) and potassium carbonate (0.4 M in water, 5.4 mL, 2.14 mmol, 2.00 equiv) in DME (9.5 mL) to give a residue which was used in the next step without further purification. MS (ES+) m / z 207.1 (M+H).

[0786] The following intermediate compounds were similarly prepared using Method M using the appropriate brominated ester and boronic acid.

[0787] Synthesis 99 5-(Thiophen-3-yl)thiazole-4-carboxylic acid

[0788] [ka] MS (ES+) m / z 212.1 (M+H).

[0789] Synthesis 100 5-(3-fluorophenyl)thiazole-4-carboxylic acid

[0790] [ka] MS (ES+) m / z 224.2 (M+H).

[0791] Synthesis 101 4-(3-(trifluoromethyl)phenyl)thiazole-5-carboxylic acid

[0792] [ka] MS (ES+) m / z 274.1 (M+H).

[0793] Synthesis 102 4-(4-fluorophenyl)thiazole-5-carboxylic acid

[0794] [ka] MS (ES+) m / z 224.1 (M+H).

[0795] Synthesis 103 4-(3-fluorophenyl)pyrimidine-5-carboxylic acid

[0796] [ka] MS (ES-) m / z 217.0 (M-H).

[0797] Synthesis 104 3-(3-fluorophenyl)-5-methyl-isoxazole-4-carboxylic acid

[0798] [ka] Prepared as described in Method H from ethyl 3-(3-fluorophenyl)-5-methyl-isoxazole-4-carboxylate (30 mg, 0.12 mmol, 1.00 equiv.) and sodium hydroxide (4.9 mg, 0.12 mmol, 1.00 equiv.) in water (1.5 mL) and THF (3.7 mL) to afford the title compound 3-(3-fluorophenyl)-5-methyl-isoxazole-4-carboxylic acid (22 mg, 0.099 mmol, 83%) as a colorless oil. MS (ES+) m / z 222.0 (M+H). 1 H NMR (300 MHz, CDCl3) δ 7.57 - 7.35 (m, 3H), 7.27 - 7.10 (m, 1H), 2.77 (s, 3H) ppm. 19 F {1H} NMR (282 MHz, CDCl3) δ -113.07 ppm.

[0799] The following intermediate compounds were similarly prepared using Method H using the appropriate ester.

[0800] Synthesis 105 4-(2-chlorophenyl)thiazole-5-carboxylic acid

[0801] [ka] MS (ES+) m / z 240.1 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 7.58 - 7.51 (m, 1H), 7.50 - 7.37 (m, 3H) ppm.

[0802] Synthesis 106 4-(m-Tolyl)thiazole-5-carboxylic acid

[0803] [ka] MS (ES+) m / z 220.0 (M+H); used in next step without further purification.

[0804] Synthesis 107 4-(3-fluorophenyl)oxazole-5-carboxylic acid

[0805] [ka] MS (ES-) m / z 206.0 (M-H). 1 H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 7.98-7.90 (m, 2H), 7.54 (td, J= 8.2, 6.2 Hz, 1H), 7.31 (tdd, J= 8.5, 2.6, 1.1 Hz, 1H) ppm. 19F {1H} NMR (282 MHz, DMSO-d6) δ -113.24 ppm.

[0806] Synthesis 108 3-(3-fluorophenyl)pyridine-2-carboxylic acid

[0807] [ka] MS (ES+) m / z 218.2 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 13.39 (s, 1H), 8.64 (dd, J= 4.7, 1.6 Hz, 1H), 7.95 (dd, J= 7.9, 1.6 Hz, 1H), 7.62 (dd, J= 7.9, 4.7 Hz, 1H), 7.57-7.47 (m, 1H), 7.32-7.23 (m, 3H) ppm. 19 F {1H} NMR (282 MHz, DMSO-d6) δ -113.11 ppm.

[0808] Synthesis 109 4-(2-fluorophenyl)thiazole-5-carboxylic acid

[0809] [ka] MS (ES+) m / z 224.1 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 13.43 (s, 1H), 9.34 (s, 1H), 7.60-7.46 (m, 2H), 7.34-7.24 (m, 2H) ppm. 19 F {1H} NMR (282 MHz, DMSO-d6) δ -114.21 ppm.

[0810] Synthesis 110 3-(3-fluorophenyl)thiophene-2-carboxylic acid

[0811] [ka] MS (ES-) m / z 220.9 (MH). 1 H NMR (300 MHz, DMSO-d6) δ 12.98 (s, 1H), 7.89 (d, J= 5.1 Hz, 1H), 7.49-7.39 (m, 1H), 7.35-7.27 (m, 2H), 7.25-7.16 (m, 2H) ppm. 19 F {1H} NMR (282 MHz, DMSO-d6) δ -114.22 ppm.

[0812] Synthesis 111 4-(2-thienyl)thiazole-5-carboxylic acid

[0813] [ka] MS (ES+) m / z 212.1 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 13.63 (s, 1H), 9.23 (s, 1H), 8.34 (dd, J= 3.8, 1.2 Hz, 1H), 7.72 (dd, J= 5.1, 1.2 Hz, 1H), 7.18 (dd, J= 5.1, 3.8 Hz, 1H) ppm.

[0814] Synthesis 112 4-(3,5-difluorophenyl)thiazole-5-carboxylic acid

[0815] [ka] MS (ES-) m / z 239.9 (M−H). 1H NMR (300 MHz, DMSO-d6) δ 13.67 (s, 1H), 9.32 (s, 1H), 7.58-7.46 (m, 2H), 7.36 (tt, J= 9.4, 2.4 Hz, 1H) ppm. 19 F {1H} NMR (282 MHz, DMSO-d6) δ -110.58 ppm.

[0816] Synthesis 113 4-(3-fluorophenyl)-2-methyl-thiazole-5-carboxylic acid

[0817] [ka] MS (ES+) m / z 238.9 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 13.39 (s, 1H), 7.61-7.52 (m, 2H), 7.46 (td, J= 8.0, 6.0 Hz, 1H), 7.32-7.21 (m, 1H), 2.70 (s, 3H) ppm. 19 F {1H} NMR (282 MHz, DMSO-d6) δ -114.06 ppm.

[0818] Synthesis 114 2-(3-methyl-1,2,4-oxadiazol-5-yl)-N-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzamide (ALDHI-1008)

[0819] [ka] 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (50 mg, 0.245 mmol, 1.00 equiv; commercially available intermediate), 6-amino-3,4-dihydroquinolin-2(1H)-one (40 mg, 0.245 mmol, 1.00 equiv), N,N-diisopropylethylamine (0.085 mL, 0.490 mmol, 2.00 equiv) and 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3, Prepared from 3-tetramethyluronium hexafluorophosphate (HATU) (102 mg, 0.269 mmol, 1.10 equiv.) as described in Method I to give the title compound 2-(3-methyl-1,2,4-oxadiazol-5-yl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)benzamide (29 mg, 0.0821 mmol, 34%) as a yellow powder after purification by preparative HPLC-MS (high pH). MS (ES+) m / z 349.1 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 10.05 (s, 1H), 8.07-7.99 (m, 1H), 7.83-7.67 (m, 3H), 7.51 (d, J= 2.3 Hz, 1H), 7.35 (dd, J= 8.5, 2.3 Hz, 1H), 6.82 (d, J= 8.5 Hz, 1H), 2.87 (t, J= 7.5 Hz, 2H), 2.49-2.41 (m, 2H), 2.38 (s, 3H) ppm.

[0820] The following examples were similarly prepared using Method I with the appropriate carboxylic acid.

[0821] Synthesis 115 3-(3-Fluorophenyl)-5-methyl-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)isoxazole-4-carboxamide (ALDHI-1009)

[0822] [ka] MS (ES+) m / z 366.3 (M+H). 1 H NMR (300 MHz, CDCl3) δ 7.64 - 7.51 (m, 1H), 7.51 - 7.39 (m, 3H), 7.34 (d, J = 6.0 Hz, 2H), 6.94 (d, J = 26.9 Hz, 2H), 6.65 (d, J = 8.4 Hz, 1H), 2.96 (t, J = 7.5 Hz, 2H), 2.81 (s, 3H), 2.63 (dd, J = 8.6, 6.5 Hz, 2H) ppm. 19 F {1H} NMR (282 MHz, CDCl3) δ -110.09 ppm.

[0823] Synthesis 116 N-(2-オキソ-3,4-ジヒドロ-1H-キノリン-6-イル)-5-(3-ピリジル)チアゾール-4-カルボキサミド (ALDHI-1010)

[0824]

change

[0825] Synthesis 117 N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-5-(3-thienyl)thiazole-4-carboxamide (ALDHI-1011)

[0826] [ka] MS (ES+) m / z 356.0 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 10.24 (s, 1H), 10.04 (s, 1H), 9.14 (s, 1H), 8.04 (dd, J = 3.0, 1.3 Hz, 1H), 7.68 - 7.62 (m, 2H), 7.49 (dd, J = 8.5, 2.4 Hz, 1H), 7.44 (dd, J = 5.0, 1.4 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 2.86 (t, J = 7.5 Hz, 2H), 2.44 (dd, J = 8.5, 6.5 Hz, 2H) ppm.

[0827] Synthesis 118 4-(2-chlorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)thiazole-5-carboxamide (ALDHI-1012)

[0828] [ka] MS (ES+) m / z 384.0 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 10.04 (d, J = 4.3 Hz, 2H), 9.29 (s, 1H), 7.59 - 7.49 (m, 2H), 7.47 - 7.42 (m, 2H), 7.38 (s, 1H), 7.23 (d, J = 8.9 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 2.82 (t, J = 7.5 Hz, 2H), 2.45 - 2.38 (m, 2H) ppm.

[0829] Synthesis 119 4-(m-Tolyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)thiazole-5-carboxamide (ALDHI-1013)

[0830] [ka] MS (ES+) m / z 364.3 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 10.06 (s, 1H), 9.25 (s, 1H), 7.66 - 7.19 (m, 6H), 6.81 (d, J = 8.5 Hz, 1H), 2.85 (t, J = 7.5 Hz, 2H), 2.44 (dd, J = 8.5, 6.5 Hz, 2H), 2.32 (s, 3H) ppm.

[0831] Synthesis 120 5-(3-Fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)thiazole-4-carboxamide (ALDHI-1014)

[0832] [ka] MS (ES+) m / z 368.2 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 10.03 (s, 1H), 9.25 (s, 1H), 7.67 - 7.52 (m, 2H), 7.52 - 7.39 (m, 4H), 7.29 (dddd, J = 9.1, 7.8, 2.8, 1.2 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 2.85 (t, J = 7.5 Hz, 2H), 2.47 - 2.38 (m, 2H) ppm. 19 F {1H} NMR (282 MHz, DMSO-d6) δ -113.34 ppm.

[0833] Synthesis 121 N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-4-[3-(trifluoromethyl)phenyl]thiazole-5-carboxamide (ALDHI-1015)

[0834] [ka] MS (ES+) m / z 417.9 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 10.53 (s, 1H), 10.07 (s, 1H), 9.32 (s, 1H), 8.09 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.41 (s, 1H), 7.29 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 2.85 (t, J = 7.5 Hz, 2H), 2.46 - 2.41 (m, 2H) ppm. 19 F {1H} NMR (282 MHz, DMSO-d6) δ -61.32 ppm.

[0835] Synthesis 122 4-(3-Fluorophenyl)-N-(3-oxo-4H-1,4-benzoxazin-7-yl)thiazole-5-carboxamide (ALDHI-1016)

[0836] [ka] MS (ES+) m / z 370.2 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 10.69 (s, 1H), 10.59 (s, 1H), 9.29 (s, 1H), 7.60 - 7.45 (m, 3H), 7.28 (d, J = 1.5 Hz, 1H), 7.26 - 7.23 (m, 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 4.57 (s, 2H) ppm. 19 F {1H} NMR (282 MHz, DMSO-d6) δ -112.95 ppm.

[0837] Synthesis 123 4-(4-Fluorophenyl)-N-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)thiazole-5-carboxamide (ALDHI-1017)

[0838] [ka] MS (ES+) m / z 367.9 (M+H). 1H NMR (300 MHz, CD3OD) δ 9.14 (s, 1H), 7.81 (dd, J = 8.7, 5.5 Hz, 2H), 7.40 (s, 1H), 7.31 (dd, J = 8.5, 2.4 Hz, 1H), 7.25 - 7.14 (m, 2H), 6.85 (d, J = 8.5 Hz, 1H), 2.95 (t, J = 7.6 Hz, 2H), 2.58 (dd, J = 8.5, 6.7 Hz, 2H) ppm. 19 F {1H} NMR (282 MHz, CD3OD) δ -114.36 (s) ppm.

[0839] Synthesis 124 4-(3-フルオロフェニル)-N-(2-オキソ-3,4-ジヒドロ-1H-キノリン-6-イル)ピリミジン-5-カルボキサミド (ALDHI-1018)

[0840]

change

[0841] Synthetic 125 4-(3-Fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)oxazole-5-carboxamide (ALDHI-1019)

[0842] [ka] MS (ES+) m / z 352.3 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 10.44 (s, 1H), 10.09 (s, 1H), 8.76 (s, 1H), 8.09 (dt, J= 11.0, 2.1 Hz, 1H), 8.03 (dt, J= 7.9, 1.1 Hz, 1H), 7.65-7.60 (m, 1H), 7.58-7.45 (m, 2H), 7.29 (tdd, J= 8.4, 2.7, 1.0 Hz, 1H), 6.84 (d, J= 8.5 Hz, 1H), 2.89 (t, J= 7.5 Hz, 2H), 2.48-2.42 (m, 2H) ppm. 19 F {1H} NMR (282 MHz, DMSO-d6) δ -113.16 ppm.

[0843] Synthesis 126 3-(3-Fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyridine-2-carboxamide (ALDHI-1020)

[0844] [ka] MS (ES+) m / z 362.3 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 10.47 (s, 1H), 10.03 (s, 1H), 8.68 (dd, J= 4.7, 1.6 Hz, 1H), 7.95 (dd, J= 7.9, 1.6 Hz, 1H), 7.65 (dd, J=7.9, 4.8 Hz, 1H), 7.52-7.42 (m, 2H), 7.36 (dd, J= 8.5, 2.4 Hz, 1H), 7.31-7.17 (m, 3H), 6.79 (d, J= 8.5 Hz, 1H), 2.83 (t, J= 7.5 Hz, 2H), 2.47-2.37 (m, 2H) ppm. 19 F {1H} NMR (282 MHz, DMSO-d6) δ -113.43 ppm.

[0845] Synthesis 127 4-(2-フルオロフェニル)-N-(2-オキソ-3,4-ジヒドロ-1H-キノリン-6-イル)チアゾール-5-カルボキサミド (ALDHI-1021)

[0846]

change

[0847] Synthetic 128 3-(3-Fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)thiophene-2-carboxamide (ALDHI-1022)

[0848] [ka] MS (ES+) m / z 367.3 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 10.11 (s, 1H), 10.06 (s, 1H), 7.81 (d, J= 5.1 Hz, 1H), 7.49-7.13 (m, 7H), 6.77 (d, J= 8.5 Hz, 1H), 2.83 (t, J= 7.5 Hz, 2H), 2.46-2.37 (m, 2H) ppm. 19 F {1H} NMR (282 MHz, DMSO-d6) δ -113.27 ppm.

[0849] Synthesis 129 N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-4-(2-thienyl)thiazole-5-carboxamide (ALDHI-1023)

[0850] [ka] MS (ES+) m / z 356.2 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 10.67 (s, 1H), 10.11 (s, 1H), 9.21 (s, 1H), 7.63 (dd, J= 5.1, 1.1 Hz, 1H), 7.58 (dd, J= 3.7, 1.2 Hz, 1H), 7.54 (s, 1H), 7.48-7.32 (m, 1H), 7.12 (dd, J= 5.1, 3.7 Hz, 1H), 6.84 (d, J= 8.5 Hz, 1H), 2.88 (t, J= 7.5 Hz, 2H), 2.48-2.42 (m, 2H) ppm.

[0851] Synthesis 130 4-(3,5-Difluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)thiazole-5-carboxamide (ALDHI-1024)

[0852] [ka] MS (ES+) m / z 386.3 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 10.62 (s, 1H), 10.11 (s, 1H), 9.30 (s, 1H), 7.50-7.39 (m, 3H), 7.38-7.28 (m, 2H), 6.83 (d, J= 8.5 Hz, 1H), 2.86 (t, J= 7.5 Hz, 2H), 2.44 (dd, J= 8.6, 6.5 Hz, 2H) ppm. 19 F {1H} NMR (282 MHz, DMSO-d6) δ -109.39 (s) ppm.

[0853] Synthesis 131 N-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-4-(3-fluorophenyl)thiazole-5-carboxamide (ALDHI-1025)

[0854] [ka] MS (ES+) m / z 386.3 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1H), 10.20 (s, 1H), 9.29 (s, 1H), 7.70-7.45 (m, 3H), 7.36 (d, J= 8.0 Hz, 1H), 7.27 (tdd, J= 8.2, 2.7, 1.0 Hz, 1H), 6.73 (d, J= 11.3 Hz, 1H), 2.86 (t, J= 7.6 Hz, 2H), 2.53-2.42 (m, 2H) ppm. 19 F {1H} NMR (282 MHz, DMSO-d6) δ -113.16 (s), -123.59 (s) ppm.

[0855] Synthesis 132 4-(3-Fluorophenyl)-2-methyl-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)thiazole-5-carboxamide (ALDHI-1026)

[0856] [ka] MS (ES+) m / z 382.3 (M+H). 1 H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 10.09 (s, 1H), 7.60-7.40 (m, 4H), 7.34-7.18 (m, 2H), 6.80 (d, J= 8.5 Hz, 1H), 2.85 (t, J= 7.5 Hz, 2H), 2.75 (s, 3H), 2.43 (dd, J= 8.6, 6.5 Hz, 2H) ppm. 19 F {1H} NMR (282 MHz, DMSO-d6) δ -113.05 (s) ppm.

[0857] biological methods Recombinant protein production: ALDH1A3, ALDH1A1, ALDH1A2 Cloning: Open reading frames corresponding to the protein-coding sequences of full-length human ALDH1A1 (Uniprot ID P00352), ALDH1A2 (O94788), and ALDH1A3 (P47895) were polymerase chain reaction (PCR) amplified from human cDNA and inserted into the multiple cloning site of commercially available (Novagen) Escherichia coli (E. coli) expression vectors pET47b (ALDH1A1, EcoRI restriction site; ALDH1A2, BamHI and EcoRI sites) or pET28a (ALDH1A3, NdeI and BamHI sites) using standard molecular genetic techniques. Recombinant DNA products were sequence verified before use in expression studies.

[0858] Expression: The expression construct was transformed into E. coli strain Rosetta (DE3) (Merck), and individual colonies were used to inoculate 10 mL of lysogeny broth (LB) medium supplemented with 50 μg / mL kanamycin and 34 μg / mL chloramphenicol, respectively. The culture was grown to saturation overnight at 37°C and then used to subinoculate a new 1 L LB medium culture (supplemented with antibiotics as before). The 1 L culture was grown overnight at 37°C and 200 rpm until the optical density at 600 nm (OD600) reached approximately 0.8, at which point the growth temperature was reduced to 18°C ​​and 1 mM isopropyl β-d-1-thiogalactopyranoside (IPTG) was added to induce protein expression. The culture was left under these conditions overnight (at least 16 hours) and harvested the next day by centrifugation (4000 g, 10 minutes). The culture supernatant was discarded and the cell pellet was stored at −80°C until further processing.

[0859] Purification: Cell pellets were thawed on ice, resuspended in Ni affinity buffer A (20 mM HEPES pH 7.5, 300 mM NaCl, 20 mM imidazole, 1 mM tris(2-carboxyethyl)phosphine (TCEP)) containing protease inhibitors (cOmplete Ultra protease inhibitor, Roche), and lysed by sonication. The lysate was clarified by centrifugation at 18,000 xg for 40 minutes at 4°C and loaded directly onto a pre-equilibrated (in buffer A) 5 mL HisTrap Fast Flow column (GE Healthcare) via an AKTA fast protein liquid chromatography (FPLC) system. The recombinant His-tagged protein was eluted by sequentially loading the column with 6 column volumes (CV) of 100% buffer A, 8 CV of 90% buffer A:10% buffer B (20 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) pH 7.5, 300 mM NaCl, 500 mM imidazole, 1 mM TCEP), and finally with a linear gradient of 10 to 70% buffer B over 8 CV. Relevant fractions collected during elution (measured by absorbance at 280 nm) were pooled and further purified by size exclusion chromatography (Superdex200 26 / 600, GE Healthcare, running buffer 20 mM 2-(carbamoylmethylamino)ethanesulfonic acid (ACES) pH 7.5, 1 mM TCEP). Relevant fractions from this step were pooled, aliquoted and stored at -80°C until required for compound profiling assays.

[0860] Biochemical assays (primary and selectivity screening) Materials: ALDH2 was purchased from Abnova. Tris(hydroxymethyl)aminomethane (Tris) was purchased from MP Biomedicals. TCEP, ethylenediaminetetraacetic acid (EDTA), propionaldehyde, DMSO, and Tween-20 were purchased from Sigma. Nicotinamide adenine dinucleotide (NAD) was purchased from Abcam. NAD(P)H-Glo™ Detection System was purchased from Promega. White, non-binding surface 384-well plates were supplied by Corning (#3574).

[0861] Methods: Inhibition of ALDH1A3 was assessed using the NAD(P)H-Glo™ Detection System from Promega (Cat. No. G9062). This assay detects the production of NADH from NAD by ALDH1A3 via the coupled enzymatic conversion of a proluciferin reductase substrate, which generates a luminescent signal. Inhibition of ALDH1A3 with small molecule inhibitors results in a reduction or abrogation of the increase in luminescent signal above background. Inhibition of ALDH1A1, ALDH1A2, and ALDH2 (selectivity assay) was assessed using the same assay.

[0862] Compounds were dispensed into Corning 384-well assay plates using an Echo acoustic dispenser to generate 10-point curves in a 3-fold dilution series. Compounds were dispensed from 20 mM DMSO stock solutions and initially screened at a top concentration of 20 μM (ALDH1A3) or 250 μM (ALDH1A1, ALDH1A2, and ALDH2). Enzymes were added to the plates in a volume of 5 μL according to the final concentrations in Table 1 below. After preincubation with the compounds for 30 minutes at room temperature, 5 μL of substrate (propionaldehyde) and cofactor (NAD) were added to final concentrations equal to the Km values ​​shown in Table 1. The assay buffer used consisted of 40 mM Tris for 1A1 (pH 7.6), 1A2 (pH 7.6), and 1A3 (pH 9.0), and 10 mM Tris for ALDH2 (pH 8.0), supplemented with 1 mM TCEP, 0.01% Tween-20, and 0.1 mM EDTA. The reaction mix was incubated at 26°C in a shaking incubator for 30 minutes, after which 10 μL of Promega detection reagent and inhibitors for the individual isoforms were added at 100× IC. 50 After the reaction was stopped, the plate was incubated at room temperature for 60 minutes, and the luminescence signal was read using a PheraStar FS microplate reader (BMG Labtech). 50 Values ​​were calculated using Dotmatics software.

[0863] [Table 12]

[0864] The concentrations of enzyme, substrate and cofactor were chosen to ensure that the reaction was carried out under initial rate conditions.

[0865] ALDH1A3 cell assay Materials: WM266.4 cells were obtained from ATCC (WM266-4 is a metastatic human melanoma cell line). ALDEFLUOR™ Assay Kit (Cat. No. 01700) and Aldefluor Buffer (Cat. No. 01702) were obtained from StemCell Technologies. Dulbecco's Modified Eagle Medium (DMEM), FluoroBrite DMEM, Glutamax, and Hoechst 33342 were purchased from ThermoFisher. Verapamil was obtained from Fluorochem. FBS was obtained from Sigma. Echo Qualified 384-well low dead volume microplates and Echo Qualified 384-well polypropylene microplates were purchased from Labcyte, and microclear black sterile polystyrene microplates were purchased from Greiner Bio-one.

[0866] Methods: Intracellular inhibition of ALDH1A3 was assessed using the ALDEFLUOR™ Assay Kit. The activated ALDEFLUOR™ reagent, BODIPY-aminoacetaldehyde (BAAA), is a fluorescent, nontoxic substrate for the ALDH enzyme, which diffuses freely within intact and viable cells. In the presence of ALDH enzyme activity, BAAA is converted to BODIPY-aminoacetate (BAA), which is retained intracellularly. The amount of fluorescent reaction product is proportional to ALDH activity in the cells and is measured using an imaging cytometer. Active efflux of the reaction product is inhibited by an efflux inhibitor (verapamil) in the ALDEFLUOR™ Assay Buffer.

[0867] The WM266.4 melanoma cell line has been characterized and shown to predominantly express the ALDH1A3 isoform; therefore, evaluation of inhibitors in this cell line constitutes an assay for cellular ALDH1A3 activity. Frozen vials of cells were harvested into T225 flasks containing DMEM, high glucose, 10% FBS, 1% glutamax, and 1% HEPES. The next day, the medium was changed, and 72 hours after harvest, the cells were ready for assay. Cells were transferred to FluoroBrite DMEM (with 10% FBS, 1% glutamax, and 1% HEPES) and cultured at a concentration of 2.5x10 5 The cells were diluted to 7500 cells / mL. 30 μL of cells were added to each well to obtain 7500 cells / well and then incubated overnight at 37°C, 5% CO2. After overnight incubation, the medium was aspirated and replaced with 20 μL of substrate / Hoechst buffer solution. Each plate required 9 mL of solution containing 9 mL of ALDEFLUOR assay buffer, 18 μL of BAAA substrate (final concentration 500 nM), 4.5 μL of Hoechst 33342 (final concentration 5 μg / mL), and 4.5 μL of verapamil (final concentration 50 μM). Compounds were prepared for dosing using the Echo acoustic dispenser by aliquoting into the source plate and directly into the cell assay plate, resulting in a 10-point dose response per compound ranging in final concentrations from 10 μM to 0.0005 μM in 3-fold dilution steps. The plates were then incubated at 37°C and 5% CO2 for 60 minutes. The buffer was then aspirated, and the cells were washed twice with ice-cold PBS. The plates were kept on ice, and 30 μL of cold Aldefluor buffer containing 50 μM verapamil was dispensed per well. The plates were then imaged using a CellInsight fluorescence microscope. Hoechst fluorescence in the 405 nm channel indicated the intranuclear region and was used to define the intranuclear and then pericellular regions. Fluorescence in the 488 nm channel of the defined cellular region indicated ALDH1A3 activity. The percentage of cells positive for ALDH activity was plotted against compound concentration, and EC50 values ​​were generated using the curve-fitting parameters defined in Dotmatics software.

[0868] Biological data Primary biochemical assay (ALDH1A3 IC 50 ), Aldefluor cell assay (ALDH1A3 Aldefluor IC 50 ) and selectivity assay (ALDH1A1 IC 50 , ALDH1A2 IC 50 , ALDH2 IC 50 ) data are summarized in the table below.

[0869] [Table 13] TIFF0007815250000210.tif255140TIFF0007815250000211.tif142148

[0870] In vivo pharmacokinetics (PK) All procedures involving animals were performed in accordance with the UK Home Office regulations under the Animals (Scientific Procedures) Act 1986 and the guidelines set by the Institutional Animal Ethics Committee and the United Kingdom Coordinating Committee for Cancer Research's ad hoc Committee on the Welfare of Animals in Experimental Neoplasia. Six-week-old female BALB / c mice (Charles River Laboratories) were used for PK analysis. Mice were dosed orally by gavage (5 mg / kg in DMSO:water 1:19 v:v, n = 6) or intravenously in the tail vein (1 mg / kg in DMSO:Tween 20:saline 10:1:89 v:v:v, n = 6). Blood samples (approximately 20 μL) were collected from the tail vein of each group of mice (3 mice / group, in two groups) alternately at 5, 15, and 30 minutes, and 1, 2, 4, 6, and 8 hours after administration. For clarity, Group 1 was bled at 5 minutes, 30 minutes, 2 hours, and 6 hours, and Group 2 was bled at 15 minutes, 1 hour, 4 hours, and 8 hours. Plasma samples were quickly frozen in liquid nitrogen and then stored at −80°C before analysis.

[0871] Test compound solutions (1 mg / mL in DMSO) were used to generate stock solution standard curves (SCs) and quality control (QC) solutions of appropriate concentrations. Blank plasma was spiked with the stock solution to generate a nine-point standard curve ranging from 1.5 to 10,000 μg / mL. Two QC concentrations were within this range, with DMSO concentrations at 10% of the plasma volume. Plasma PK samples, standards, and QCs were added to individual Eppendorf tubes, and DMSO (10% of the plasma volume) was added to the plasma PK samples. SCs, QCs, and plasma samples were extracted with methanol (100 μL) containing the internal standard. After protein precipitation, the samples were centrifuged at 14,000 rpm for 10 minutes in a refrigerated centrifuge (4°C). The supernatant was removed to a 96-well plate and centrifuged for an additional 10 minutes at 3,700 rpm in a refrigerated centrifuge (4°C). Plasma concentrations of the sample compounds were analyzed by liquid chromatography-mass spectrometry (LC-MS / MS). Non-compartmental analysis was performed on the plasma concentration data using the Excel macro PK Solver 2.0.

[0872] The pharmacokinetic data are summarized in the table below.

[0873] [Table 14]

[0874] The foregoing has described the principles, preferred embodiments, and modes of operation of the present invention. However, the present invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be considered as illustrative rather than limiting. It is to be understood that modifications may be made to those embodiments by those skilled in the art without departing from the scope of the present invention. The following is one embodiment of the present invention. (1) A compound of the following formula: [ka] or a pharmaceutically acceptable salt or solvate thereof: [Wherein -J is [ka] and During the ceremony, Ring A is an aromatic monocyclic ring having 5 or 6 ring atoms, one or more substituents -R A and optionally substituted by -R A are each independently -R AA 、-R AAX , -OH, -OR AA , -OR AAX , -F, -Cl, -Br, -I, -NH 2 , -NHR AA , -NR AA 2 、-R AAN , -C(=O)R AA , -C(=O)OH, -C(=O)OR AA , -OC(=O)R AA , -NHC(=O)R AA , -C(=O)NH 2 , -C(=O)NHR AA , -C(=O)NR AA 2 , -C(=O)R AAN , -S(=O) 2 R AA , -S(=O) 2 NH 2 , -S(=O) 2 NHR AA , -S(=O) 2 NR AA 2 , -S(=O) 2 R AAN , -CN or -NO 2 and -R AA are each independently a linear or branched saturated C 1~4 Alkyl or saturated C 3~6 is cycloalkyl, -R AAX are each independently a linear or branched saturated C 1~4 is haloalkyl, -R AAN are each independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or 1,1-dioxo-thiomorpholino; -R AA , -OH and -OR AA and optionally substituted with one or more substituents selected from -M 1 teeth,

change

change

change

change

change

change

change

change

change

[0875] References Publications are cited herein in order to more fully describe the state of the art to which this invention pertains. Full citations for these references are provided below.

[0876] Each of these publications is herein incorporated by reference in its entirety into the present disclosure to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference. Aissa et al., 2021, “Single-cell transcriptional changes associated with drug tolerance and response to combination therapies in cancer”, Nature Communications, Vol. 12, Article 1628. Bazewicz et al., 2019, “Aldehyde dehydrogenase in regulatory T-cell development, immunity and cancer”, Immunology, Vol. 156, No. 1, pp. 47-55. Burke et al., 2017, “db / db Mice exhibit features of human type 2 diabetes that are not present in weight-matched C57BL / 6J mice fed a Western diet", Journal of Diabetes Research, Article ID 8503754. Burke et al., 2018, “Pancreatic deletion of the interleukin-1 receptor disrupts whole body glucose homeostasis and promotes islet β-cell de-differentiation", Molecular Metabolism, Vol. 14, pp. 95-107. Cai et al., 2021, “TNRC6C Functions as a Tumor Suppressor and Is Frequently Downregulated in Papillary Thyroid Cancer", International Journal of Endocrinology, Article ID 6686998. Casanova-Salas et al., 2015, “MiR-187 targets the androgen-regulated gene ALDH1A3 in prostate cancer", PLOS One, Vol. 10, No. 5, e0125576. Chefetz et al., 2019, “A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells", Cell Rep., Vol. 26, No. 11, pp. 3061-3075.e6. Chen et al., 2016, “ALDH1A3, the Major Aldehyde Dehydrogenase Isoform in Human Cholangiocarcinoma Cells, Affects Prognosis and Gemcitabine Resistance in Cholangiocarcinoma Patients", Clin Cancer Res, Vol. 22, No. 16. pp. 4225-4235. Cheng et al., 2016, “FOXD1-ALDH1A3 Signaling Is a Determinant for the Self-Renewal and Tumorigenicity of Mesenchymal Glioma Stem Cells", Cancer Res., Vol. 76, No. 24, pp. 7219-7230. Cinti et al., 2016, “Evidence of β-cell dedifferentiation in human type 2 diabetes", Journal of Clinical Endocrinology and Metabolism, Vol. 101, No. 3, pp. 1044-54. Cioce et al., 2021, “Insights into Intra-Tumoral Heterogeneity: Transcriptional Profiling of Chemoresistant MPM Cell Subpopulations Reveals Involvement of NFkB and DNA Repair Pathways and Contributes a Prognostic Signature", Int. J. Mol. Sci., Vol. 22, No. 21, 12071. Croker et al., 2017, “Differential Functional Roles of ALDH1A1 and ALDH1A3 in Mediating Metastatic Behavior and Therapy Resistance of Human Breast Cancer Cells", Int. J. Mol. Sci., Vol. 18, No. 10, 2039. Dinavahi et al., 2019, “Aldehyde Dehydrogenase Inhibitors for Cancer Therapeutics", Trends Pharmacol. Sci., Vol. 40, No. 10, pp. 774-789. Duan et al., 2016, “ALDH1A3, a metabolic target for cancer diagnosis and therapy", Int. J. Cancer, Vol. 139, No. 5, pp. 965-975. Durinikova et al., 2018, “ALDH1A3 upregulation and spontaneous metastasis formation is associated with acquired chemoresistance in colorectal cancer cells", BMC Cancer, Vol. 18, No. 1, 848. Esposito et al., “Heterocyclic Compounds and Uses Thereof", international (PCT) patent publication number WO 2021 / 151062 A1 published 29 July 2021. Esposito et al., “Tetrahydroquinolino derivatives for the treatment of metastatic and chemoresistant cancers", international (PCT) patent publication number WO 2020 / 028461 A1 published 06 February 2020. Flahaut et al., 2016, “Aldehyde dehydrogenase activity plays a key role in the aggressive phenotype of neuroblastoma", BMC Cancer, Vol. 16, No. 1, 781. Gelardi et al., 2021, “A Selective Competitive Inhibitor of Aldehyde Dehydrogenase 1A3 Hinders Cancer Cell Growth, Invasiveness and Stemness In Vitro", Cancers (Basel), Vol. 13, No. 2, 356. Gerner Seitzberg et al., 2016, “Compounds active towards bromodomains", international (PCT) patent publication number WO 2016 / 016316 A1 published 04 February 2016. Ginestier et al., 2007, “ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome", Cell Stem Cell, Vol. 1, No. 5, pp. 555-567. Grimley et al., 2021, “Aldehyde dehydrogenase inhibitors promote DNA damage in ovarian cancer and synergize with ATM / ATR inhibitors", Theranostics, Vol. 11, No. 8, pp. 3540-3551. Haldar et al., “Methods And Compositions For Targeting Retinoic Acid For Solid Tumor Immunotherapy", US patent publication number US 2020 / 0352958 A1 published 12 November 2020. Huang et al., 2021, “Diethyldithiocarbamate-copper complex (CuET) inhibits colorectal cancer progression via miR-16-5p and 15b-5p / ALDH1A3 / PKM2 axis-mediated aerobic glycolysis pathway", Oncogenesis, Vol. 10, Article No. 4. Huddle et al., 2018, “Structure-Based Optimization of a Novel Class of Aldehyde Dehydrogenase 1A (ALDH1A) Subfamily-Selective Inhibitors as Potential Adjuncts to Ovarian Cancer Chemotherapy", J. Med. Chem., Vol. 61, No. 19, pp. 8754-8773. Huddle et al., 2021, “Development of 2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of aldehyde dehydrogenase 1A (ALDH1A) as potential adjuncts to ovarian cancer chemotherapy", Eur. J. Med. Chem., Vol. 211, 113060. Ibrahim et al., 2021, “Design, Synthesis, Biological Evaluation and In Silico Study of Benzyloxybenzaldehyde Derivatives as Selective ALDH1A3 Inhibitors", Molecules, Vol. 26, No. 19, 5770. Kamada et al., 2021, “Functional inhibition of cancer stemness-related protein DPP4 rescues tyrosine kinase inhibitor resistance in renal cell carcinoma", Oncogene, Vol. 40, No. 22, pp. 3899-3913. Kawakami et al., 2020, “ALDH1A3-mTOR axis as a therapeutic target for anticancer drug-tolerant persister cells in gastric cancer", Cancer Science, Vol. 111, No. 3, pp. 962-973. Kim-Muller et al., 2016, “Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic β cells in diabetic mice", Nat. Commun., Vol. 7, 12631. Koga et al., 1997, “Carbostyril derivatives as antithrombic agents", international (PCT) patent publication number WO 97 / 12869 A1 published 10 April 1997. Kong et al., 2016, “A subset of metastatic pancreatic ductal adenocarcinomas depends quantitatively on oncogenic Kras / Mek / Erk-induced hyperactive mTOR signalling", Gut, Vol. 65, No. 4, pp. 647-657. Koppaka et al., 2012, “Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application", Pharmacol. Rev., Vol. 64, No. 3, pp. 520-539. Kozovska et al., 2016, “Malignant melanoma: diagnosis, treatment and cancer stem cells", Neoplasma, Vol. 63, No. 4, pp. 510-517. Larsen et al., “Small molecule inhibitors of ALDH and uses thereof", international (PCT) patent publication number WO 2017 / 223086 A1 published 28 December 2017. Laskar and Younus, 2019, “Aldehyde toxicity and metabolism: the role of aldehyde dehydrogenases in detoxification, drug resistance and carcinogenesis", Drug Metab. Rev., Vol. 51, No. 1, pp. 42-64. Li et al., 2018, “ALDH1A3 induces mesenchymal differentiation and serves as a predictor for survival in glioblastoma", Cell Death Dis., Vol. 9, No. 12, 1190. Li et al., 2021, “ALDH1A3 coordinates metabolism with gene regulation in pulmonary arterial hypertension", Circulation, Vol. 143, pp. 2074-2090. Luo et al., 2012, “ALDH1A isozymes are markers of human melanoma stem cells and potential therapeutic targets", Stem Cells, Vol. 30, No. 10, pp. 2100-2013. Mao et al., 2013, “Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3", Proc. Natl. Acad. Sci. U S A, Vol. 110, No. 21, pp. 8644-8649. Marayati et al., 2021, “PIM kinases mediate resistance to cisplatin chemotherapy in hepatoblastoma", Scientific Reports, Vol. 11, No. 1, 5984. Marcato et al., 2011a, “Aldehyde dehydrogenase: its role as a cancer stem cell marker comes down to the specific isoform", Cell Cycle, Vol. 10, No. 9, pp. 1378-1384. Marcato et al., 2011b, “Aldehyde dehydrogenase activity of breast cancer stem cells is primarily due to isoform ALDH1A3 and its expression is predictive of metastasis", Stem Cells, Vol. 29, No. 1, pp. 32-45. Marcato et al., 2015, “Aldehyde dehydrogenase 1A3 influences breast cancer progression via differential retinoic acid signaling", Mol. Oncol., Vol. 9, No. 1, pp. 17-31. Masui et al., 2008, “Nirogenous heterocyclic derivatives substituted with cyclic groups", European patent publication number EP 1988077 A1 published 05 November 2008. Matsunaga et al., 2018, “Optimized Dosing Schedule Based on Circadian Dynamics of Mouse Breast Cancer Stem Cells Improves the Antitumor Effects of Aldehyde Dehydrogenase Inhibitor", Cancer Res., Vol. 78, No. 13, pp. 3698-3708. Morgan et al., 2015, “N,N-diethylaminobenzaldehyde (DEAB) as a substrate and mechanism-based inhibitor for human ALDH isoenzymes", Chem. Biol. Interact., Vol. 234, pp. 18-28. Ni et al., 2020, “High expression of ALDH1A3 might independently influence poor progression-free and overall survival in patients with glioma via maintaining glucose uptake and lactate production", Cell Biol. Int., Vol. 44, No. 2, pp. 569-582. Nie et al., 2020, “ALDH1A3 accelerates pancreatic cancer metastasis by promoting glucose metabolism", Front. Oncol., Vol. 10, 915. Nishi et al., 1987, “Carbostyryl derivatives, process for preparing them, pharmaceutical compositions, and use", European patent publication number EP 0240015 A2 published 07 October 1987. Opdenaker et al., 2014, “Immunohistochemical analysis of aldehyde dehydrogenase isoforms and their association with estrogen-receptor status and disease progression in breast cancer", Breast Cancer (Dove Med Press), Vol. 6, pp. 205-209. Pattabiraman et al., 2014, “Tackling the cancer stem cells - what challenges do they pose?", Nat. Rev. Drug Discov., Vol. 13, No. 7, pp. 497-512. Perez-Alea et al., 2017, “ALDH1A3 is epigenetically regulated during melanocyte transformation and is a target for melanoma treatment", Oncogene, Vol. 36, No. 41, pp. 5695-5708. Pors et al., 2014, “Aldehyde dehydrogenases in cancer: an opportunity for biomarker and drug development?", Drug Discov. Today, Vol. 19, No. 12, pp. 1953-1963. Rodriguez-Torres and Allan, 2016, “Aldehyde dehydrogenase as a marker and functional mediator of metastasis in solid tumors", Clin. Exp. Metastasis, Vol. 33, No. 1, pp. 97-113. Rodriguez-Zavala et al., 2019, “Role of Aldehyde Dehydrogenases in Physiopathological Processes", Chem. Res. Toxicol., Vol. 32, No. 3, pp. 405-420. Schmidtova et al., 2019, “Disulfiram Overcomes Cisplatin Resistance in Human Embryonal Carcinoma Cells", Cancers, Vol. 11, No. 9, 1224. Shao et al., 2014, “Essential role of aldehyde dehydrogenase 1A3 for the maintenance of non-small cell lung cancer stem cells is associated with the STAT3 pathway", Clin. Cancer Res., Vol. 20, No. 15, pp. 4154-4166. Simoes et al., 2015, “Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity", Cell Rep., Vol. 12, No. 12, pp. 1968-1977. Takasugi et al., 2002, “Amide Compounds", international (PCT) patent publication number WO 02 / 090347 A1 published 14 November 2002. Thomas et al., 2016, “Citral reduces breast tumor growth by inhibiting the cancer stem cell marker ALDH1A3", Mol. Oncol., Vol. 10, No. 9, pp. 1485-1496. Tominaga et al., 1982, “Cardiotonic agent", Japanese patent publication number JP S5780322 A published 19 May 1982. Vasilogiannakopoulou et al., 2018, “Impact of Aldehyde Dehydrogenase Activity on Gliomas", Trends Pharmacol. Sci., Vol. 39, No. 7, pp. 605-609. Xie et al., 2019, “ALDH1A3 Regulations of Matricellular Proteins Promote Vascular Smooth Muscle Cell Proliferation", iScience, Vol. 27, pp. 872-882. Yang et al., 2013, “Positive ALDH1A3 and negative GPX3 expressions are biomarkers for poor prognosis of gallbladder cancer", Dis. Markers, Vol. 35, No. 3, pp. 163-172. Yasgar et al., 2017, “A High-Content Assay Enables the Automated Screening and Identification of Small Molecules with Specific ALDH1A1-Inhibitory Activity", PLOS One, Vol. 12, No. 1, e0170937. Zhang et al., 2013, “Genome-wide DNA methylation profiling identifies ALDH1A3 promoter methylation as a prognostic predictor in G-CIMP- primary glioblastoma", Cancer Lett., Vol. 328, No. 1, pp. 120-125.

Claims

1. A compound of the formula: 【Chemistry 1】 or a pharmaceutically acceptable salt or solvate thereof: [Wherein -J is 【Chemistry 2】 and During the ceremony, Ring A is an aromatic monocyclic ring having 5 or 6 ring atoms, one or more substituents -R A and optionally substituted by -R A are each independently -R AA , -R AAX , -OH, -OR AA , -OR AAX , -F, -Cl, -Br, -I, -NH 2 , -NHR AA , -NR AA 2 , -R AAN , -C(=O)R AA , -C(=O)OH, -C(=O)OR AA , -OC(=O)R AA , -NHC(=O)R AA , -C(=O)NH 2 , -C(=O)NHR AA , -C(=O)NR AA 2 , -C(=O)R AAN , -S(=O) 2 R AA , -S(=O) 2 NH 2 , -S(=O) 2 NHR AA , -S(=O) 2 NR AA 2 , -S(=O) 2 R AAN , -CN or -NO 2 and -R AA are each independently a linear or branched saturated C 1～4 Alkyl or saturated C 3～6 is cycloalkyl, -R AAX are each independently a linear or branched saturated C 1～4 is haloalkyl, -R AAN are each independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or 1,1-dioxo-thiomorpholino; -R AA , -OH and -OR AA and optionally substituted with one or more substituents selected from -M 1 teeth, 【Transformation 3】 (In the formula, -R M1a and -R M1e are each independently -H or -R M1-オルト and -R M1b and -R M1d are each independently -H or -R M1-メタ and -R M1c are independently -H or -R M1-パラ and However, -R M1a , -R M1b , -R M1c , -R M1d and -R M1e is provided that they are not all -H, Each-R M1-オルト , each -R M1-メタ , -R M1-パラ are independent, -R M11 , -R M11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br, -I, -NH 2 , -NHR M11 , -NR M11 2 , -R M11N , -C(=O)R M11 , -C(=O)OH, -C(=O)OR M11 , -OC(=O)R M11 , -NHC(=O)R M11 , -C(=O)NH 2 , -C(=O)NHR M11 , -C(=O)NR M11 2 , -C(=O)R M11N , -S(=O) 2 R M11 , -S(=O) 2 NH 2 , -S(=O) 2 NHR M11 , -S(=O) 2 NR M11 2 , -S(=O) 2 R M11N , -CN or -NO 2 and -M 1 -M 1 and a ring carbon atom of ring A. Or or -M 1 is an aromatic monocyclic heterocycle having 5 or 6 ring atoms, one or more substituents -R M1 and optionally substituted by -R M1 are each independently -R M11 , -R M11X , -OH, -OR M11 , -OR M11X , -F, -Cl, -Br, -I, -NH 2 , -NHR M11 , -NR M11 2 , -R M11N , -C(=O)R M11 , -C(=O)OH, -C(=O)OR M11 , -OC(=O)R M11 , -NHC(=O)R M11 , -C(=O)NH 2 , -C(=O)NHR M11 , -C(=O)NR M11 2 , -C(=O)R M11N , -S(=O) 2 R M11 , -S(=O) 2 NH 2 , -S(=O) 2 NHR M11 , -S(=O) 2 NR M11 2 , -S(=O) 2 R M11N , -CN or -NO 2 and -R M11 are each independently a linear or branched saturated C 1～4 is alkyl, -R M11X are each independently a linear or branched saturated C 1～4 is haloalkyl, -R M11N are each independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or 1,1-dioxo-thiomorpholino; -R M11 , -OH and -OR M11 and optionally substituted with one or more substituents selected from -M 1 -M 1 is connected to ring A by a bond between a ring carbon atom of Either one of the following: -Q- is independent, -CH 2 -CR Q1 R Q2 - -O-CR Q1 R Q2 - -S-CR Q1 R Q2 -or -CH 2 -CH 2 -CR Q1 R Q2 - and -R Q1 are each independently -H or -R QQ and -R Q2 are each independently -H or -R QQ and -R QQ are each independently a linear or branched saturated C 1～4 is alkyl, -R 1 are independently -H or -R 11 and -R 3 are independently -H or -R 33 and -R 4 are independently -H or -R 44 and R 11 are independently -R, -R X , -OH, -OR, -OR X , -F, -Cl, -Br, -I, -NH 2 , -NHR, -NR 2 , -R N , -CN or -NO 2 and R 33 are independently -R, -R X , -OH, -OR, -OR X , -F, -Cl, -Br, -I, -NH 2 , -NHR, -NR 2 , -R N , -CN or -NO 2 and R 44 are independently -R, -R X , -OH, -OR, -OR X , -F, -Cl, -Br, -I, -NH 2 , -NHR, -NR 2 , -R N , -CN or -NO 2 and - R is independently a linear or branched saturated C 1～4 is alkyl, -R X are each independently a linear or branched saturated C 1～4 is haloalkyl, -R N are each independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or 1,1-dioxo-thiomorpholino, and are optionally substituted with one or more substituents selected from -R, -OH, and -OR. And, provided that the compound is not a compound of one of the following formulas, or a pharmaceutically acceptable salt or solvate thereof: Table 1 provided that the compound is not a compound of one of the following formulas, or a pharmaceutically acceptable salt or solvate thereof: Table 2 provided that the compound is not a compound of one of the following formulas, or a pharmaceutically acceptable salt or solvate thereof: Table 3 【change】 provided that the compound is not a compound of one of the following formulas, or a pharmaceutically acceptable salt or solvate thereof: Table 4 The compound described above, or a pharmaceutically acceptable salt or solvate thereof.

2. -Q- is -CH 2 -CR Q1 R Q2 - and -R Q1 is -H, and -R Q2 is -H, 2. The compound of claim 1.

3. -R 1 is -H, -R 3 is -H or -R 3 Ga-R 33 and -R 33 is independently —R, —F, or —Cl; and -R 4 is -H, 3. The compound of claim 1 or 2.

4. Ring A is an aromatic monocyclic ring having 5 ring atoms and is A 4. The compound of claim 1, optionally substituted by:

5. Ring A is thiazolyl and the substituent -R A and optionally substituted by Optionally, the thiazolyl is a thiazolyl of the formula: 1 represents the point of attachment to -C(=O)-, and (#) represents the point of attachment of the group -J to -C(=O)-; 【Chemistry 4】 5. A compound according to any one of claims 1 to 4.

6. -R A are each independently, -R AA , -NR AA 2 or -R AAN and -R AA are each independently -Me or -Et, and -R AAN are each independently azetidino, pyrrolidino, piperidino, piperazino, or morpholino, and -R AA , -OH and -OR AA optionally substituted with one or more substituents selected from 6. A compound according to any one of claims 1 to 5.

7. -M 1 but, 【Transformation 5】 7. The compound of any one of claims 1 to 6, wherein

8. -R M1-オルト are -F, respectively, -R M1-メタ are -F, and -R M1-パラ are -F respectively 8. A compound according to any one of claims 1 to 7.

9. -M 1 but, 【Transformation 6】 7. The compound of any one of claims 1 to 6, wherein

10. -M 1 is an aromatic monocyclic heterocycle having 5 ring atoms and is substituted with one or more substituents -R M1 or -M 1 is thienyl and one or more substituents -R M1 and optionally substituted by -R M1 But independently -R M11 , -F, -Cl, -Br or -I, and -R M11 are independently -Me or -Et; 7. A compound according to any one of claims 1 to 6.

11. A compound of one of the following formulas, or a pharmaceutically acceptable salt or solvate thereof: 【Transformation 7】 【change】 【change】 【change】 2. The compound of claim 1, wherein:

12. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier or diluent.

13. A method for inhibiting the aldehyde dehydrogenase enzyme ALDH1A3 in vitro, comprising contacting the enzyme with an effective amount of a compound described in any one of claims 1 to 11.

14. 12. A composition comprising a compound according to any one of claims 1 to 11 for use in a method of treatment of the human or animal body by therapy.

15. (1) methods of treating proliferative disorders; (2) Methods for treating obesity or complications of obesity, including type II diabetes; (3) a method for treating diabetes, including type II diabetes; or (4) Methods for treating cardiovascular disorders, including restenosis, intimal hyperplasia, intimal hyperplasia after vascular reconstruction, intimal hyperplasia after coronary angioplasty / stenting, intimal hyperplasia after bypass vein grafting, intimal hyperplasia after arteriovenous fistula, intimal hyperplasia after allografting, and pulmonary arterial hypertension.

12. A composition comprising a compound according to any one of claims 1 to 11 for use in

16. The proliferative disorder is (a) cancer, or (b) melanoma, fibrosarcoma, breast cancer, glioma, glioblastoma, lung cancer, mesothelioma, thyroid cancer, renal cell carcinoma, pancreatic cancer, gastric cancer, colorectal cancer, gallbladder cancer, cholangiocarcinoma, neuroblastoma, testicular germ cell cancer, ovarian cancer, or prostate cancer 16. The composition of claim 15, wherein

17. Cancer (a) or (b) is (i) Characterized by abnormal expression of ALDH1A3, (ii) characterized by overexpression of ALDH1A3; (iii) characterized as chemotherapy-resistant and / or radiotherapy-resistant cancer; (iv) characterized as an immunotherapy-resistant cancer; or (v) characterized as an immunotherapy-resistant cancer characterized by the presence or elevated abundance of regulatory T cells; 17. The composition of claim 16.

Images