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 relates to United Kingdom (GB) Patent Application No. 2019475.9, filed December 10, 2020, the entire contents of which are incorporated herein by reference.

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

[0003] Publications are cited herein 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 this disclosure to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference. It is.

[0004] Throughout this specification, including the claims that follow, unless the context requires otherwise, the word "comprise" and its variations, such as "comprises" and "Comprising" means including the specified integer or step, or group of integers or steps, but excluding any other integer or step, or group of integers or steps. It will be understood that this is not the case.

[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. Must be. 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 expressing such a range, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when a value is expressed as an approximation by use of the prefix "about," it will be understood that the specific value constitutes another embodiment.

[0007] This disclosure includes information that may be useful in understanding the present invention. It is not assumed that any information presented herein is prior art or relates to the invention claimed herein or is specifically or implicitly referred to. There is no admission that any publication is prior art.

[0008] aldehyde dehydrogenase enzyme Aldehyde dehydrogenase enzyme (ALDH) (EC1.2.1.3) is an evolutionarily conserved NAD(P)-dependent oxidase that catalyzes the oxidation of various exogenous and endogenous aldehydes to their corresponding carboxylic acids. -A class of reductases (19 human isoforms).

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

[0010] ALDH1A3 overexpression 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 decreased insulin production by pancreatic islet cells. ALDH1A3 is a marker of dedifferentiated pancreatic β-cells with impaired insulin secretion and mitochondrial function (see, eg, Kim-Muller, 2016; Cinti et al., 2016; Burke et al., 2018). Treatment of mice with pharmacological ALDH1A3 inhibitors restores insulin secretion and improves blood glucose control (see, eg, 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 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 associated with a subpopulation 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 a heterogeneous tumor defined by their ability to self-renew and produce differentiated daughter cells during asymmetric division. They are characterized by an increased likelihood of tumor dissemination, are involved in tumor progression, metastasis, and are associated with chemoresistance and radioresistance. Although current treatments target bulk tumor cells, CSCs escape, resulting in tumor recurrence and treatment failure (see, eg, Pattabiraman, 2014). As a result, tumors may initially appear to be eradicated, but later recur as a small subpopulation of CSCs survive. This concept is clinically important as it highlights the critical need to target CSCs to achieve sustained responses. Therefore, therapeutic targeting of the survival mechanisms used by CSCs will 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, eg, Ginestier, 2007). In numerous tumor types, ALDH1A3 has been reported as the major isoform and is responsible for Aldefluor activity. ALDH1A3 is an important functional driver of CSC survival, growth, metastasis and resistance, and is associated with poor prognosis and overall disease in patients suffering from numerous tumor types, such as melanoma, breast and glioblastoma. It is also associated with poor survival (see, e.g., Duan, 2016; Rodriguez-Torres, 2016).

[0015] In particular, the underlying mechanism by which ALDH1A3 contributes to the survival and progression of cancer cells and CSCs remains unclear. It has been suggested that ALDH1A3 has two main functions: detoxification of cytotoxic aldehydes and biosynthesis of retinoic acid (RA) (see, eg, Duan, 2016).

[0016] Oxidative stress as a result of chemotherapy or other factors is a recurrent feature in cancer cells and CSCs, resulting in increased intracellular reactive oxygen species (ROS). A consequence of this increase in ROS is the peroxidation of phospholipids and the production of reactive aldehydes such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). Abnormal accumulation of aldehydes can lead to oxidative damage to cells and apoptosis. These apoptotic aldehydes need to be metabolized to less toxic carboxylic acids by overexpression of ALDH1A3 to preserve homeostasis of cancer cells and CSCs (see, eg, Laskar, 2019).

[0017] ALDH1A3, along with other members of the ALDH1A subfamily, is involved in the biosynthesis of RA from the retina, as well as in stemness and proliferation through the interaction of RA with the nuclear RA receptors RAR and RXR. It also plays an important role in the expression of sex genes (see, eg, Duan, 2016).

[0018] In ovarian cancer, not only ALDH1A3 but also ALDH1A1 is overexpressed in a number of cell lines according to the Cancer Cell Line Encyclopedia (CCLE), and ALDH1A3 is particularly found in ovarian cancer derived from several serous adenocarcinomas. It is the predominant isoform in cancer cell lines (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 in resistant cell lines and tumor spheroids derived from patients with high-grade serous ovarian cancer, chemotherapy (e.g., Taxol) (see, e.g., Huddle et al., 2021) , and synergize with DNA damage checkpoint inhibitors (ATMi / ATRi) in vitro and in vivo (see, eg, Grimley et al., 2021).

[0019] In melanoma, ALDH1A3 is the most expressed isoform in various cell lines, including patient-derived cells (CCLE), whereas its expression is lower in non-malignant human epidermal melanocytes and is regulated by epigenetic mechanisms. (see, e.g., Perez-Alea, 2017). ALDH1A3 is associated with CSCs (see, eg, Luo, 2012; Kozovska, 2016) and plays an important role in melanoma formation, progression and metastasis. It has been suggested that a role in eliminating cytotoxic 4-HNE and MDA explains the effects 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, eg, Luo, 2012). Its inhibition by genetic knockdown (ALDH1A3 shRNA) results in reduced numbers of colonies and spheres formed in vitro and reduced tumor growth in vivo (e.g., Perez-Alea, 2017) when using various cell lines. ), as well as sensitization of paclitaxel-resistant ALDH+1205Lu and A375 cells to drug-induced cell death (see, eg, Luo, 2012). Of note, genetic knockdown of both ALDH1A1 and ALDH1A3 by shRNA or their inhibition by the pan-ALDH1A inhibitor DIMATE led to excellent effects both in vitro and in vivo (e.g. (see Perez-Alea, 2017).

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

[0021] In glioma patients, abnormal expression of ALDH1A3 is associated with most advanced high-grade glioblastomas and is a marker of poor prognosis and poor overall survival (e.g., Mao, 2013; (See Zhang, 2013; Li, 2018; Ni, 2020). At the cellular level, ALDH1A3 is overexpressed in the more advanced radiotherapy-resistant mesenchymal subtype of glioma stem cells (Mes-GSCs) (see, e.g., Ni, 2020) and in proneural (Pn-GSC) to mesenchymal subtype (see e.g. Li, 2018) and processes such as cell proliferation, ECM organization, cell adhesion and ECM related to receptor interactions (see, e.g., Vasilogiannakopoulou, 2018). Mes- It has been suggested that ALDH1A3 is involved in GSC maintenance and tumorigenesis.

[0022] ALDH1A3 is also associated with pancreatic cancer (see, e.g., Kong, 2016; Nie, 2020), gallbladder cancer (see, e.g., Yang, 2013), and prostate cancer (e.g., elevated levels of miR-187). (see, e.g., Casanova-Salas, 2015), papillary thyroid cancer (see, e.g., Cai et al., 2021), malignant phenotype in neuroblastoma (e.g., Flahaut, 2016), as well as poor prognosis and metastasis in patients with chemoresistance and metastasis in colorectal cancer models (see, eg, Durinikova, 2018). ALDH1A3 has been linked to testicular germ cell tumors (see, e.g., Schmidtova et al., 2019), gastric cancer (see, e.g., Kawakami et al., 2020) and cholangiocellular carcinoma (see, e.g., Chen et al., 2016). It is also related to ALDH1A3 has an essential role in maintaining CSC populations 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, eg, Malayati et al., 2021) and sunitinib-resistant renal cell carcinoma (see, eg, Kamada et al., 2021). ALDH1A3 expression is responsible for the survival and activity of malignant pleural mesothelioma (MPM) chemoresistant cell subpopulations (see, eg, 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 the driver of increased glycolysis in CRC tumors (see, eg, 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 within tumor tissue, leading to increased tumor immunity and tumor rejection (see, eg, Bazewicz et al., 2019). Genetic knockout of ALDH1A3 (RALDH3) in a fibrosarcoma tumor model results in robust T cell infiltration and impaired tumor growth in immunocompetent mice, and interactions with immune checkpoint inhibitors, e.g. anti-PD1 antibodies brought about. Therefore, ALDH1A3 inhibitors can increase anti-tumor responses to immunotherapy, such as anti-PD1, anti-PDL1, anti-CTLA4, anti-IL3 antibodies (see, eg, Haldar et al., 2020).

[0024] ALDH1A3 exhibits all the attributes of a promising therapeutic target in cancer. Moreover, the targeted toxicity of potential ALDH1A3 inhibitors is limited due to their low expression level and small physiological role in non-malignant cells.

[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 Neointimal formation has been reported. This reduction in lumen space leads to pathologies such as neointimal hyperplasia (NIH), a major cause of restenosis and pulmonary arterial hypertension (PAH). Genetic inhibition of ALDH1A3 in vitro blocks vascular and pulmonary artery SMC proliferation. In vivo, perivascular administration of disulfiram reduces NIH in a rat angioplasty model, whereas ALDH1A3 gene knockout mice do not develop hypoxia-induced PAH.

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

[0027] There are currently no ALDH1A3 selective inhibitors approved or in clinical development. Several non-selective broad spectrum inhibitors of ALDH1A1, ALDH2 and / or ALDH3A1, ALDH inhibitors, have been reported in the literature to also inhibit ALDH1A3. These inhibitors exhibit off-target toxicity, poor pharmacokinetic (PK) properties including short half-life and lack of oral bioavailability, and / or lack of in vivo efficacy. Early 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 show in vivo reductions in tumor growth and / or metastasis in various models, particularly breast and melanoma (see, e.g., Thomas, 2016; Perez-Alea, 2017; Matsunaga, 2018). I want to be). 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, e.g. DSF, currently in clinical development for patients with advanced lung cancer, but may be produced in vivo. It is unclear which of a given metabolite and what pharmacological activity is responsible for 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), all three ALDH1A isoforms. shows inhibition of 673A showed in vivo reductions in tumor growth in combination with cisplatin in several models of ovarian cancer (see, eg, Chefetz, 2019). These compounds lack oral bioavailability. Recently reported non-selective pan-ALDH1A family pyrazolopyrimidinone inhibitors were shown to have efficacy in ovarian cancer cell models (see, e.g., Huddle et al., 2021). ).

[0029] A series of tetrahydroquinoline derivatives that selectively inhibit ALDH1A3 were recently reported (see, eg, Esposito, 2020). Compound MBE-1.5 showed in vivo reductions in tumor growth and metastasis in mice when combined with paclitaxel in a paclitaxel-resistant model of breast cancer. Like other reported compounds, these analogs are not administered by the oral route.

[0030] Additional heterocyclic inhibitors of ALDH1A3 have been described that show anti-metastatic efficacy and restore insulin secretion when combined with paclitaxel in diabetic mouse models (see, eg, Esposito et al., 2021). NR6, an imidazopyridine ALDH1A3 inhibitor (see e.g. Gelardi et al., 2021), exhibits anti-metastatic activity in wound healing and in invasion assays in glioblastoma and colorectal cancer cells; No chemical efficacy (IC50 approximately 5 μM). Benzyloxybenzaldehyde ALDH1A3 inhibitors have been reported, but pharmacokinetic data are lacking (see, eg, Ibrahim et al., 2021). [Summary of the invention] [Problem to be solved by the invention]

[0031] There is a clear need for potent selective ALDH1A3 inhibitors with good pharmacokinetic properties and suitable for oral administration with minimal or no toxicity. [Means to solve the problem]

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

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

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

[0035] Another aspect of the invention relates to a method of 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 invention is a method of inhibiting an ALDH1A3 enzyme (e.g., inhibiting or reducing or blocking the activity or function of an ALDH1A3 enzyme) in vitro or in vivo, the method comprising: A method comprising contacting an ALDHI compound described herein.

[0037] Another aspect of the invention is a method of inhibiting the ALDH1A3 enzyme (e.g., inhibiting or reducing or blocking the activity or function of the ALDH1A3 enzyme) in vitro or in vivo in a cell, the method comprising: contacting an ALDHI compound as described herein.

[0038] Another aspect of the invention is for use in a method of treatment of the human or animal body by therapy, e.g. , relating to the ALDHI compounds described herein.

[0039] Another aspect of the invention provides the methods 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. Regarding the use of ALDHI compounds.

[0040] Another aspect of the invention is the method described herein, e.g. in the manufacture of a medicament for use in a method of treatment of a disorder (e.g. disease) described herein. Regarding the use of ALDHI compounds.

[0041] Another aspect of the invention is a method of treatment, e.g., a method of treatment of a disorder (e.g., disease) described herein, wherein the method of treating a subject in need of treatment, preferably in the form of a pharmaceutical composition. of a therapeutically effective amount of an ALDHI compound described herein.

[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 invention provides that (a) the ALDHI compounds described herein are preferably provided as a composition (e.g., a pharmaceutical composition) in a suitable container and / or in suitable packaging; and (b) a kit containing instructions for use, e.g., written instructions on how to administer the compound, e.g., in a method of treating a disorder (e.g., disease) described herein.

[0045] Another aspect of the invention relates to ALDHI compounds obtainable by the synthetic methods described herein or by methods comprising the synthetic methods described herein.

[0046] Another aspect of the invention relates to ALDHI compounds obtainable by the synthetic methods described herein or by methods comprising the synthetic methods described herein.

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

[0048] Another aspect of the invention relates to the use of such novel intermediates described herein in the synthetic methods described herein.

[0049] As will be recognized by those skilled in the art, the features and preferred embodiments of one aspect of the invention also relate to other aspects of the invention. [Details for carrying out the invention]

[0050] Compound One embodiment of the present invention provides compounds of the following general formula (wherein -Q-, -J, R 1 ,R 3 and R 4are 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 present compounds include: (1) Compounds of the following formula:

[0053] [ka] or a pharmaceutically acceptable salt or solvate thereof: [In the formula, -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 has been optionally replaced 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 N.H. 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 linear or branched saturated C 1~4 Alkyl or saturated C 3~6 cycloalkyl, -R AAX are each independently 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, and -R AA , -OH and -OR AA 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 is independently -H or -R M1-パラ and However, -R M1a ,-R M1b ,-R M1c ,-R M1d and -R M1e provided that all are not -H, Each-R M1-オルト , each -R M1-メタ ,-R M1-パラ is 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 N.H. 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 is attached to ring A by a bond between the ring carbon atom of and the ring carbon atom of ring A) Is it? or -M 1 is an aromatic monocyclic heterocycle having 5 or 6 ring atoms, one or more substituents -R M1 has been optionally replaced 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 N.H. 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 linear or branched saturated C 1~4 is alkyl, -R M11X are each independently 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, and -R M11 , -OH and -OR M11 optionally substituted with one or more substituents selected from -M 1 -M 1 Is it attached to ring A by a bond between the ring carbon atom of and the ring carbon atom of ring A? Either one of the Or in the formula, -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 is independently -R JJ ,-L JJ -OH, -L JJ -NH 2 ,-L JJ -NHR JJ or -L JJ -NR JJ 2 and -R J4 are independently -H, -R JJ ,-L JJ -OH, -L JJ -NH 2 ,-L JJ -NHR JJ or -L JJ -NRJJ 2 and -R J5 are independently -H, -R JJ ,-L JJ -OH, -L JJ -NH 2 ,-L JJ -NHR JJ or -L JJ -NR JJ 2 is, Or -R J4 and -R J5 together form =O, -R JJ are each independently linear or branched saturated C 1~4 is alkyl, -L JJ - are each independently 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 has been optionally replaced by optionally replaced by and / or =O, -R B1 are each independently -R BB ,-R BBX , -OH, -OR BB ,-OR BBX , -F, -Cl, -Br, -I, -NH 2 ,-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)NH 2 , -C(=O)NHR BB , -C(=O)NR BB 2 , -C(=O)R BBN , -S(=O) 2 R BB , -S(=O) 2 N.H. 2 , -S(=O) 2 NHR BB , -S(=O) 2 NR BB 2 , -S(=O) 2 R BBN , -CN or -NO 2 and Ring B2 is a heteroaromatic monocyclic ring having 5 or 6 ring atoms, one or more substituents -R B2 has been optionally replaced by -R B2 are each independently -R BB ,-R BBX , -OH, -OR BB ,-OR BBX , -F, -Cl, -Br, -I, -NH 2 ,-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)NH 2 , -C(=O)NHR BB , -C(=O)NR BB 2 , -C(=O)R BBN , -S(=O) 2 R BB , -S(=O) 2 N.H. 2 , -S(=O) 2 NHR BB , -S(=O) 2 NR BB 2 , -S(=O) 2 R BBN , -CN or -NO 2 and -R BB are each independently linear or branched saturated C 1~4 Alkyl or saturated C 3~6 cycloalkyl, -R BBX are each independently 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, and -R BB , -OH and -OR BB optionally substituted with one or more substituents selected from -M 2 is independently, phenyl and one or more substituents -R M2 optionally replaced by or an aromatic monocyclic heterocycle having 5 or 6 ring atoms, one or more substituents -R M2 has been optionally replaced by -R M2 are each independently -R M22 ,-R M22X , -OH, -OR M22 ,-OR M22X , -F, -Cl, -Br, -I, -NH 2 ,-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)NH 2 , -C(=O)NHR M22 , -C(=O)NR M22 2 , -C(=O)R M22N , -S(=O) 2 R M22 , -S(=O) 2 N.H. 2 , -S(=O) 2 NHR M22 , -S(=O) 2 NR M22 2 , -S(=O) 2 R M22N , -CN or -NO 2 and -R M22 are each independently linear or branched saturated C 1~4 is alkyl, -R M22X are each independently 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, and -R M22 , -OH and -OR M22 optionally substituted with one or more substituents selected from) and -Q- is independently: -CH 2 -CR Q1 R Q2 -, -O-CR Q1 R Q2 -, -S-CR Q1 R Q2 -, -CH 2 -CH 2 -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 is independently -H or -R QQ and -R Q4 is independently -H or -R QQ and -R QQ are each independently linear or branched saturated C 1~4 is alkyl, -R 1 is independently -H or -R 11 and -R 3 is independently -H or -R 33 and -R 4 is 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 ,-RN , -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 each independently a linear or branched saturated C 1~4 is alkyl, -R X are each independently 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, with one or more substituents selected from -R, -OH and -OR ] And, provided, however, that said compound is not a compound of one of the following formulas, or a pharmaceutically acceptable salt or solvate thereof:

[0057]

table 1

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

[0059] [Table 3] TIFF2023552469000009.tif130142 provided that the above compound is not a compound of one of the following formulas, or a pharmaceutically acceptable salt or solvate thereof:

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

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

[0062] For the avoidance of doubt, the group -Q-, described 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 -, then 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 the ring atom N in a ring containing -Q- is substituted; instead, the ring atom N in a ring containing -Q- is unsubstituted. is intended.

[0065] For the avoidance of doubt, the groups -Q-, -J, -R 1 ,-R 3 and -R 4 are not intended to be linked other than through the ring atoms to which they are attached. For example, -Q- and -R 1 are not intended to be taken together to form a fused ring structure; -R 1 and -J are not intended to be taken together to form a fused ring system; -J and -R 3 are not intended to be taken together to form a fused ring structure; -R 3 and -R 4 are not intended to be taken together to form a fused ring system; -Q- and -J are not intended to be taken together to form a fused ring system; -R 1 and -R 3 are not intended to be taken together to form a fused ring structure; and so on.

[0066] Unless otherwise indicated, when a compound is shown or described that has one or more chiral centers and more than one stereoisomer is possible, all such stereoisomers are considered to be either are also disclosed and included individually (e.g., as isolated from other stereoisomers) and in mixtures (e.g., as 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 are both individually (e.g., isolated from the other enantiomer) (as), and as a mixture (eg, as an equimolar or non-equimolar mixture of two enantiomers).

[0067] For example, -Q- is -O-CR Q1 R Q2 - and -R Q1 and -R Q2 -R if different 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 (S) configuration.

[0068] [ka]

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

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

[0071] The term “linear or branched saturated C 1~4 "Haloalkyl" means a linear or branched saturated carbon substituted with one or more halo groups (e.g. -F, -Cl, -Br, -I) 1~4 means an alkyl group, for example, "linear or branched saturated C 1~4 "Fluoroalkyl", e.g. -CF 3 ,-CHF 2 ,-CH 2 C.F. 3 ,-CH 2 CH 2 F, -CH 2 CHF 2 , -CH(CH 3 )CF 3 ,-CH 2 C(CH 3 ) 2 F, -CH 2 C.F. 2 CH 3 ,-CH 2 CH 2 C.F. 2 CH 3 ,-CH 2 CH 2 CHF 2 and-CH 2 CH 2 C.F. 3 including.

[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" is a divalent linear or branched saturated C 1~4 means an alkyl group, for example -CH 2 -,-CH 2 CH2 -,-CH 2 CH 2 CH 2 -,-CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )-and-CH 2 CH(CH 3 )-including.

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

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

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

[0077] (3) -Q- is -CH 2 -CR Q1 R Q2 -,for example:

[0078] [ka] A compound according to (1), which is

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

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

[0081] [ka] A compound according to (1), which is

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

[0083] [ka] A compound according to (1), which is

[0084] (7) -Q- is -CH 2 -CH 2 -CR Q1 R Q2 -,for example:

[0085] [ka] A compound according to (1), which is

[0086] (8)-Q-but-CR Q3 =CR Q4 -,for example:

[0087] [ka] A compound according to (1), which is

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

[0089] (10)-R Q1 -R if present, respectively QQ A compound according to any one of (1) to (8), which is

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

[0091] (12)-R Q2 -R if present, respectively QQ A compound according to any one of (1) to (10), which is

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

[0093] (14)-R Q3 -R if present, respectively QQ A compound according to any one of (1) to (12), which is

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

[0095] (16)-R Q4 -R if present, respectively QQ A compound according to any one of (1) to (14), which is

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

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

[0098] (19)-R QQ A compound according to any one of (1) to (16), where, 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), which is

[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), which is

[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), which is

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

[0106] (27)-R 11 is present, independently -R, -R X , -F or -Cl, according to any one of (1) to (25).

[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), where, if present, is -F.

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

[0110] (31)-R 33 is present, independently -R, -R X , -F or -Cl, according to any one of (1) to (29).

[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 is present, independently -R, -R X , -OH, -OR, -OR X , -F, -Cl, -Br or -I.

[0114] (35)-R 44 is present, independently -R, -R X , -F or -Cl, according to any one of (1) to (33).

[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), where, if present, is -F.

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

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

[0119] (40) A compound according to any one of (1) to (37), wherein each -R, when present, is -Me.

[0120] Group-R X (41)-R X are independently linear or branched saturated C 1~3 A compound according to any one of (1) to (40) that is haloalkyl.

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

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

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

[0124] Group-J (Part 1) (45)-J is

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

[0126] Ring A (heteroaryl) (46) If ring A exists, C 5~6 a heteroaryl group with one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by.

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

[0128] (48) If ring A exists, C 5 a heteroaryl group with one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by.

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

[0130] (50) Ring A, when present, is independently thienyl, oxazolyl, isoxazolyl, thiazolyl, and pyrazolyl, and 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 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 the substituent -R A A compound according to any one of (1) to (45), optionally substituted by.

[0133] (53) When ring A is present, thiazolyl of the following formula (wherein (*) is -M 1 (#) represents the bonding point 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] It is.

[0136] (54) When ring A is present, thiazolyl of the following formula (wherein (*) is -M 1 (#) represents the bonding point 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, unsubstituted thiazolyl of the following formula (wherein (*) is -M 1 Compounds according to any one of (1) to (45), where (#) represents the point of attachment of the group -J to -C(=O)-):

[0140] [ka]

[0141] (57) When ring A is present, unsubstituted thiazolyl of the following formula (wherein (*) is -M 1 Compounds according to any one of (1) to (45), where (#) represents the point of attachment of the group -J to -C(=O)-):

[0142] [ka]

[0143] (58) Ring A, if present, is pyrazolyl and 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, has one of the following formulas: pyrazolyl, where (*) is -M 1 (#) 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 one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by.

[0148] (62) When ring A is present, thienyl of the following formula (wherein (*) is -M 1 (#) 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) When ring A is present, oxazolyl of the following formula (wherein (*) is -M 1 (#) represents the bonding point 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) When ring A is present, isoxazolyl of the following formula (wherein (*) is -M 1 (#) represents the bonding point 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) If ring A exists, C 6 a heteroaryl group 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 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 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 one or more substituents -R A A compound according to any one of (1) to (45), optionally substituted by.

[0163] (74) When ring A is present, pyridyl of the following formula (wherein (*) is -M 1 (#) 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 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, pyrimidinyl of the following formula (wherein (*) is -M 1 (#) 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 is unsubstituted.

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

[0171] Group-R A (80)-R A -R, respectively, if present, independently 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)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 , -CN or -NO 2 A compound according to any one of (1) to (79), which is

[0172] (81)-R A -R, respectively, if present, independently AA ,-R AAX , -OH, -OR AA ,-OR AAX , -F, -Cl, -Br, -I, -NH 2 ,-NHR AA ,-NR AA 2 ,-R AAN , -CN or -NO 2 A compound according to any one of (1) to (79), which is

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

[0174] (83)-R A -R if present, respectively AA A compound according to any one of (1) to (79), which is

[0175] (84)-R A -R if present, respectively AAN A compound according to any one of (1) to (79), which is

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

[0177] Group-R AA (86)-R AA are independently linear or branched saturated C 1~4 A compound according to any one of (1) to (85), which is alkyl.

[0178] (87)-R AA are independently linear or branched saturated C 1~3 A compound according to any one of (1) to (85), which is alkyl.

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

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

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

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

[0183] Group-R AAN (92)-R AAN each, if present, is independently azetidino, pyrrolidino, piperidino, piperazino or morpholino, and -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, when present, is independently azetidino, pyrrolidino, piperidino, piperazino or morpholino.

[0185] Group-M 1 (Carboaryle) As expected, -M 1 -M 1 Note that it is attached to ring A by a bond between the ring carbon atom of and the ring carbon atom of ring A.

[0186] (94)-M 1 If exists,

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

[0188] (95)-M 1 If exists,

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

[0190] (96)-M 1 If exists,

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

[0192] (97)-M 1 If exists,

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

[0194] (98)-M 1 If exists,

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

[0196] (99)-M 1 If exists,

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

[0198] (100)-M 1 If exists,

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

[0200] (101)-M 1 If exists,

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

[0202] (102)-M 1 If exists,

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

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

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

[0206] Group-R M1b (105)-R M1bA compound according to any one of (1) to (104), where, if present, is -H.

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

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

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

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

[0211] (110)-R M1d is 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), where, if present, is -H.

[0213] (112)-R M1e is 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 -R, respectively, if present, independently 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)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 , -CN or -NO 2 A compound according to any one of (1) to (112), wherein

[0215] (114)-R M1-オルト -R, respectively, if present, independently M11 ,-R M11X , -OH, -OR M11 ,-OR M11X , -F, -Cl, -Br, -I, -NH 2 ,-NHR M11 ,-NR M11 2 ,-R M11N , -S(=O) 2 R M11 , -CN or -NO 2 A compound according to any one of (1) to (112), wherein

[0216] (115)-R M1-オルト -R, respectively, if present, independently M11 ,-R M11X , -OH, -OR M11 ,-OR M11X , -F, -Cl, -Br, -I, -NH 2 ,-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 -R, respectively, if present, independently M11 ,-R M11X , -OH, -OR M11 ,-OR M11X , -F, -Cl, -Br or -I.

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

[0219] (118)-R M1-オルト -R, respectively, if present, independently M11 , -OH, -OR M11 or -F, the compound according to any one of (1) to (112).

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

[0221] (120)-R M1-オルト -R, respectively, if present, independently M11 or -F, the compound according to any one of (1) to (112).

[0222] (121)-R M1-オルト A compound according to any one of (1) to (112), wherein each, when 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), where each is -F when present.

[0224] Group-R M1-メタ (123)-R M1-メタ -R, respectively, if present, independently 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)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 , -CN or -NO 2 A compound according to any one of (1) to (122), wherein

[0225] (124)-R M1-メタ -R, respectively, if present, independently M11 ,-R M11X , -OH, -OR M11 ,-OR M11X , -F, -Cl, -Br, -I, -NH 2 ,-NHR M11 ,-NR M11 2 ,-R M11N , -S(=O) 2 R M11 , -CN or -NO 2 A compound according to any one of (1) to (122), wherein

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

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

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

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

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

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

[0233] Group-R M1-パラ (132)-R M1-パラ -R, respectively, if present, independently 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)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 , -CN or -NO 2 A compound according to any one of (1) to (131), wherein

[0234] (133)-R M1-パラ -R, respectively, if present, independently M11 ,-R M11X , -OH, -OR M11 ,-OR M11X , -F, -Cl, -Br, -I, -NH 2 ,-NHR M11 ,-NR M11 2 ,-R M11N , -S(=O) 2 R M11 , -CN or -NO 2 A compound according to any one of (1) to (131), wherein

[0235] (134)-R M1-パラ -R, respectively, if present, independently M11 , -OH, -OR M11 , -F, -Cl, -Br, -I, -NH 2 ,-NHR M11 ,-NR M11 2 ,-R M11N , -S(=O) 2 R M11 , -CN or -NO 2 A compound according to any one of (1) to (131), wherein

[0236] (135)-R M1-パラ -R, respectively, if present, independently M11 ,-R M11X , -OH, -OR M11 ,-OR M11X , -F, -Cl, -Br, -I, -NH 2 ,-NHR M11 ,-NR M11 2 ,-R M11N or -CN, the compound according to any one of (1) to (131).

[0237] (136)-R M1-パラ -R, respectively, if present, independently M11 , -OH, -F, -Cl, -Br, -I, -NH 2 ,-NHR M11 ,-NR M11 2 ,-R M11N or -CN, the compound according to any one of (1) to (131).

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

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

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

[0241] (140)-R M1-パラ A compound according to any one of (1) to (131), wherein each, when 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), in which, if each is present, -F.

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

[0245] specific group-M 1 (144)-M 1 If exists,

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

[0247] (145)-M 1 If exists,

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

[0249] (146)-M 1 If exists,

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

[0251] Group-M 1 (heteroaryl) As expected, -M 1 -M 1 Note that it is attached to ring A by a bond between the ring carbon atom of and the ring carbon atom of ring A.

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

[0253] (148)-M 1 exists, then C 5~6 a heteroaryl group with 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 exists, then C 5 a heteroaryl group with 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 M1 A compound according to any one of (1) to (93), optionally substituted by.

[0260] (155)-M 1 is thien-2-yl, if present, 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 oxadiazolyl, if present, 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 1,2,4-oxadiazol-5-yl, if present, and one or more substituents -R M1 A compound according to any one of (1) to (93), optionally substituted by.

[0263] (158)-M 1 exists, then C 6 a heteroaryl group with 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 -R, respectively, if present, independently 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)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 , -CN or -NO 2 A compound according to any one of (1) to (159), which is

[0266] (161)-R M1 -R, respectively, if present, independently M11 ,-R M11X , -OH, -OR M11 ,-OR M11X , -F, -Cl, -Br, -I, -NH 2 ,-NHR M11 ,-NR M11 2 ,-R M11N , -S(=O) 2 R M11 , -CN or -NO 2 A compound according to any one of (1) to (159), which is

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

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

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

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

[0271] (166)-R M1 -R if present, respectively M11 A compound according to any one of (1) to (159), which is

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

[0273] Group-R M11 (168)-R M11 are independently linear or branched saturated C 1~3 A compound according to any one of (1) to (167), which is alkyl.

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

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

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

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

[0278] Group-R M11N (173)-R M11N each, if present, is independently azetidino, pyrrolidino, piperidino, piperazino or morpholino, and -R M11 , -OH and -ORM11 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, when present, is independently azetidino, pyrrolidino, piperidino, piperazino or morpholino.

[0280] Group-J (Part 2) (175)-J independently,

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

[0282] (176)-J is

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

[0284] (177)-J is

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

[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 with one or more substituents -R B1 A compound according to any one of (1) to (44), (175), (176) and (178), optionally substituted by and / or optionally substituted by =O.

[0289] (181) Ring B1, if present, is independently azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, and one or more substituents -R B1 A compound according to any one of (1) to (44), (175), (176) and (178), optionally substituted by and / or optionally substituted by =O.

[0290] (182) Ring B1, if present, is pyrrolidinyl and one or more substituents -R B1 A compound according to any one of (1) to (44), (175), (176) and (178), optionally substituted by and / or optionally substituted by =O.

[0291] Ring B2 (183) If ring B2 exists, C 5~6 a heteroaryl group with 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 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) If ring B2 exists, C 5 a heteroaryl group 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 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 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 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 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 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 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 -R, respectively, if present, independently BB ,-R BBX , -OH, -OR BB ,-OR BBX , -F, -Cl, -Br, -I, -NH 2 ,-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)NH 2 , -C(=O)NHR BB , -C(=O)NR BB 2 , -C(=O)R BBN , -S(=O) 2 R BB , -CN or -NO 2 A compound according to any one of (1) to (44), (175), (176), (178) and (180) to (182), wherein

[0301] (193)-R B1 -R, respectively, if present, independently BB ,-R BBX , -OH, -OR BB ,-OR BBX , -F, -NH 2 ,-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)NH 2 , -C(=O)NHR BB , -C(=O)NR BB 2 , -C(=O)R BBN , -S(=O) 2 R BB or -CN, the compound according to any one of (1) to (44), (175), (176), (178) and (180) to (182).

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

[0303] (195)-R B1 -R, respectively, if present, independently BB ,-R BBX , -OH, -OR BB ,-OR BBX , -F, -Cl, -Br, -I or -S(=O) 2 R BB A compound according to any one of (1) to (44), (175), (176), (178) and (180) to (182), wherein

[0304] (196)-R B1 -R, respectively, if present, independently BB ,-R BBX , -OH, -OR BB ,-OR BBX , -S(=O) 2 R BB or -F, the compound according to any one of (1) to (44), (175), (176), (178) and (180) to (182).

[0305] (197)-R B1 -R, respectively, if present, independently BB , -OH, -OR BB , -S(=O) 2 R BB or -F, the compound according to any one of (1) to (44), (175), (176), (178) and (180) to (182).

[0306] (198)-R B1 -R, respectively, if present, independently BB , -OH, -S(=O) 2 R BB or -F, the compound according to any one of (1) to (44), (175), (176), (178) and (180) to (182).

[0307] Group-R B2 (199)-R B2 -R, respectively, if present, independently BB ,-R BBX , -OH, -OR BB ,-OR BBX , -F, -Cl, -Br, -I, -NH 2 ,-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)NH 2 , -C(=O)NHR BB , -C(=O)NR BB 2 , -C(=O)R BBN , -S(=O) 2 R BB , -CN or -NO 2 A compound according to any one of (1) to (44), (175), (176), (179) and (183) to (191), wherein

[0308] (200)-R B2 -R, respectively, if present, independently BB ,-R BBX , -OH, -OR BB ,-OR BBX , -F, -Cl, -Br, -I, -NH 2 ,-NHR BB ,-NR BB 2 ,-R BBN , -S(=O) 2 R BB , -CN or -NO 2 A compound according to any one of (1) to (44), (175), (176), (179) and (183) to (191), wherein

[0309] (201)-R B2 -R, respectively, if present, independently BB ,-R BBX , -OH, -OR BB ,-OR BBX , -F, -Cl, -Br, -I, -NH 2 ,-NHR BB ,-NR BB 2 ,-R BBN or -CN, the compound according to any one of (1) to (44), (175), (176), (179) and (183) to (191).

[0310] (202)-R B2 -R, respectively, if present, independently 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) Compound.

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

[0312] Group-R BB (204)-R BB are independently linear or branched saturated C 1~4 A compound according to any one of (1) to (44) and (175) to (203), which is alkyl.

[0313] (205)-R BB are independently linear or branched saturated C 1~3 A compound according to any one of (1) to (44) and (175) to (203), which is alkyl.

[0314] (206)-R BB A compound according to any one of (1) to (44) and (175) to (203), each of which, 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 is -Me when present.

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

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

[0318] Group-R BBN (210)-R BBN each, if present, is independently azetidino, pyrrolidino, piperidino, piperazino or morpholino, and -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), each of which, when present, is independently azetidino, pyrrolidino, piperidino, piperazino or morpholino.

[0320] Group-M 2 (Carboaryle) (212)-M 2 is phenyl, if present, 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 exists, then C 5~6 a heteroaryl group with 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 2exists, then C 5 a heteroaryl group with 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 2 exists, then C 6 a heteroaryl group with 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 pyridyl, if present, 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 -R, respectively, if present, independently M22 ,-R M22X , -OH, -OR M22 ,-OR M22X , -F, -Cl, -Br, -I, -NH 2 ,-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)NH 2 , -C(=O)NHR M22 , -C(=O)NR M22 2 , -C(=O)R M22N , -S(=O) 2 R M22 , -CN or -NO 2 A compound according to any one of (1) to (44) and (175) to (222), wherein

[0332] (224)-R M2 -R, respectively, if present, independently M22 ,-R M22X , -OH, -OR M22 ,-OR M22X , -F, -Cl, -Br, -I, -NH 2 ,-NHR M22 ,-NR M22 2 ,-R M22N , -S(=O) 2 R M22 , -CN or -NO 2 A compound according to any one of (1) to (44) and (175) to (222), wherein

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

[0334] (226)-R M2 -R, respectively, if present, independently M22 ,-R M22X , -OH, -OR M22 ,-OR M22X , -F, -Cl, -Br or -I, according to any one of (1) to (44) and (175) to (222).

[0335] (227)-R M2 -R, respectively, if present, independently M22 , -OH, -OR M22 , -F, -Cl, -Br or -I, according to any one of (1) to (44) and (175) to (222).

[0336] (228)-R M2 -R, respectively, if present, independently M22 , -F, -Cl, -Br or -I, according to any one of (1) to (44) and (175) to (222).

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

[0338] Group-R M22 (230)-R M22 are independently linear or branched saturated C 1~3 A compound according to any one of (1) to (44) and (175) to (229), which is alkyl.

[0339] (231)-R M22 A compound according to any one of (1) to (44) and (175) to (229), each of which, 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 is -Me when present.

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

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

[0343] Group-R M22N (235)-R M22N each, if present, is independently azetidino, pyrrolidino, piperidino, piperazino or morpholino, and -R M22 , -OH and -OR M22 A 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), each of which, when 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 is -H when present.

[0346] (238)-R J1 -R if present, respectively JJ A compound according to any one of (1) to (44) and (175) to (236), wherein

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

[0348] (240)-R J2 -R if present, respectively JJ A compound according to any one of (1) to (44) and (175) to (238), wherein

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

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

[0353] (245)-R J4 is present, then -H and -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 are independently linear or branched saturated C 1~3 A compound according to any one of (1) to (44) and (175) to (245), which is alkyl.

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

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

[0358] (250)-L JJ -, if present, independently -CH 2 -,-CH 2 CH 2 -or-CH 2 CH 2 CH 2 - A compound according to any one of (1) to (44) and (175) to (248).

[0359] (251)-L JJ -, if present, independently -CH 2 -or-CH 2 CH 2 - A compound according to any one of (1) to (44) and (175) to (248).

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

[0361] [Table 6] TIFF2023552469000047.tif255139TIFF2023552469000048.tif250137TIFF2023552469000049.tif77139

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

[0363] [Table 7] TIFF2023552469000051.tif251152TIFF2023552469000052.tif250152TIFF2023552469000053.tif245153TIFF2023552469000054.tif95154

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

[0365] [Table 8] TIFF2023552469000056.tif27155

[0366] combination It will be 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, various features of the compounds that are, for brevity, 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 4 All combinations of embodiments with respect to chemical groups represented by Each and every combination is disclosed herein to the extent that it encompasses compounds that are (compounds that can be used and whose biological activity can be tested) just as if individually and expressly disclosed. Furthermore, all subcombinations of chemical groups listed in the embodiments describing such variables are also specifically encompassed by this disclosure, and each and every such subcombination of chemical groups is individually and expressly encompassed by this disclosure. herein as if specifically disclosed herein.

[0367] Substantially purified form One aspect of the present invention relates to ALDHI compounds described herein in substantially purified 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%, such as at least 70%, such as at least 80%, such as at least 90%, such as at least 95%, such as At least 97% by weight, such as at least 98% by weight, such as at least 99% by weight.

[0369] Unless otherwise specified, 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, ie, one that is purified with respect to other compounds. In one embodiment, a substantially purified form refers to one stereoisomer, eg, 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 (ie, a racemic mixture, racemate). In one embodiment, a substantially purified form refers to one enantiomer, eg, an optically pure enantiomer.

[0370] In one embodiment, the impurity is less than or equal to 50% by weight, such as less than or equal to 40%, such as less than or equal to 30%, such as less than or equal to 20%, such as less than or equal to 10%, such as less than or equal to 5%, e.g. It represents 3% by weight or less, for example 2% by weight or less, for example 1% by weight or less.

[0371] Unless specified, impurities refer to other compounds, ie, 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 desired stereoisomer or enantiomer). (not stereoisomers or enantiomers), such as at least 70% optically pure, such as at least 80% optically pure, such as at least 90% optically pure, such as at least 95% optically pure, e.g. At least 97% optically pure, such as at least 98% optically pure, such as at least 99% optically pure.

[0373] isomer Certain compounds include, but are 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; body; (+) and (-) body; keto body, enol body and enolate body; syn body and anti body; synclinal body and anticlinal body; α body and β body; axial body and equatorial body; boat body, chair body, one or more specific geometrical, optical, enantiomer, diastereomeric, epimeric, atropic, stereoisomeric, tautomer, and They can exist in mutant, steric or anomeric forms, hereinafter collectively referred to as "isomers" (or "isomeric forms").

[0374] When referring to a class of structures, structural isomeric forms that fall within that class may of course be included (e.g., C 1~7 Alkyl includes n-propyl and iso-propyl; 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 bonding between atoms rather than by position in space. For example, when referring to a methoxy group, -OCH 3 is its structural isomer hydroxymethyl group, i.e. -CH 2 It should not be construed as stating OH. Similarly, references to ortho-chlorophenyl should not be construed as references to its structural isomer meta-chlorophenyl.

[0375] The above exclusions include, for example, the following tautomeric pairs: keto / enol (exemplified below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, N-nitroso / hydroxyazo and nitro / aci-nitro, and does not relate to tautomers, such as keto, enol and enolate forms. In this specification, when one tautomer is mentioned, it is intended to include 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. In this specification, when one is mentioned, it is intended to include both.

[0378] [ka]

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

[0380] Unless otherwise specified, references to a particular compound include all such isomers, including mixtures thereof (eg, racemic mixtures). Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallization and chromatographic means) of such isomers are known in the art or as taught herein; Alternatively, it can be easily obtained in a known manner by adapting a known method.

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

[0382] For example, if the compound is anionic, or a functional group that can be anionic (e.g. -COOH is replaced by -COO - ), the salt can be formed using a suitable cation. 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+ , as well as ammonium ions (i.e., NH 4 + ) is included. Examples of suitable organic cations include, but are not limited to, substituted ammonium ions (e.g., NH 3 R + , N.H. 2 R 2 + , N.H.R. 3 + ,NR 4 + ), for example, here 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 Alkyl, and the phenyl group is optionally substituted. Examples of some suitable substituted ammonium ions are ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine and tromethamine, and amino acids such as lysine. and those derived from arginine. An example of a common quaternary ammonium ion is N(CH 3 ) 4 + It is.

[0383] If the compound is cationic, or if it is protonated, it can become cationic (e.g. -NH 2 is -NH 3 + salts may be formed with suitable anions.

[0384] For example, if the parent structure is a cationic group (e.g. -NMe) 2 + ) or when protonated, it can become cationic (e.g. -NH 2 is -NH 3 + salts may be formed with suitable anions. In the case of quaternary ammonium compounds, a counteranion is generally always present to counteract the positive charges. If the compound contains a cationic group (e.g. -NMe 2 + ,-NH 3 + ), an inner salt (also called a zwitterion) may be formed if it also contains a group capable of forming an anion (eg -COOH).

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

[0386] Examples of suitable organic anions include, but are not limited to, 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, lactobic acid, lauric acid Acid, maleic acid, malic acid, methanesulfonic acid, mucilage 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, carboxymethylcellulose.

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

[0388] Solvates and hydrates It may be convenient or desirable to prepare, purify and / or handle corresponding solvates of compounds. The term "solvate" is used herein in its conventional sense and refers to a complex of a solute (eg, a compound, a salt of a compound) and a solvent. When the solvent is water, the solvate may conveniently be referred to as a hydrate, such as a monohydrate, dihydrate, 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 chemically protected forms of a compound. The term "chemically protected form" is used herein in a conventional chemical sense, in which one or more reactive functional groups are protected under certain conditions (e.g., pH, temperature, radiation, solvent, Relating to compounds that are protected from undesired chemical reactions (such as reactive chemical reagents). In practice, well-known chemical methods are used to reversibly yield unreactive functional groups that would otherwise be reactive under certain conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (alternatively as a masked or masking group or a blocked or blocking group). It is in. By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be carried out without affecting the protected group. Usually, in subsequent steps, protecting groups can be removed, or masking groups can be transformed, without substantially affecting the rest of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th edition; 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 with two non-equivalent reactive functional groups (both of which are reactive under certain conditions) can be derivatized to convert one of the functional groups into a "protected" state, ie, unreactive under certain conditions, and so protected, the compound can be used as a reactant having effectively only one reactive functional group. After the desired reaction (including other functional groups) is complete, the protected group can be "deprotected" to return the protected group to its original functional group.

[0392] For example, hydroxy groups can be used as ethers (-OR) or esters (-OC(=O)R), such as t-butyl ether; benzyl, benzhydryl (diphenylmethyl) or trityl (triphenylmethyl) ether; trimethylsilyl or t-butyl Dimethylsilyl ether; or acetyl ester (-OC(=O)CH 3 , -OAc).

[0393] For example, an amine group can be used as, for example, amide (-NRCO-R), such as: acetamide (-NHCO-CH 3 ); or as carbamate (-NRCO-OR), for example: benzyloxycarbamate (-NHCO-OCH 2 C 6 H 5 , -NH-Cbz), t-butoxycarbamate (-NHCO-OC(CH 3 ) 3 , -NH-Boc);2-biphenyl-2-propoxycarbamate (-NHCO-OC(CH 3 ) 2 C 6 H 4 C 6 H 5 , -NH-Bpoc), 9-fluorenylmethoxycarbamate (-NH-Fmoc), 6-nitroberatryloxycarbamate (-NH-Nvoc), 2-trimethylsilylethyloxycarbamate (-NH-Teoc) as 2,2,2-trichloroethyloxycarbamate (-NH-Troc), as allyloxyamide (-NH-Alloc) or as 2(-phenylsulfonyl)ethyloxycarbamate (-NH-Psec); or as suitable (eg, cyclic amines), as a nitroxide radical (>N-O●); or, where appropriate (eg, heterocyclic nitrogens), as 2-trimethylsilylethoxymethyl (N-SEM).

[0394] prodrug It may be convenient or desirable to prepare, purify, and / or handle compounds in prodrug form. The term "prodrug" as used herein relates 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 provide advantageous handling, administration, or metabolic properties.

[0395] For example, some prodrugs are esters (eg, physiologically acceptable, metabolically labile esters) of the active compound. During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters may optionally be used to esterify, for example, any carboxylic acid group (-C(=O)OH) in the parent compound before protecting any other reactive groups present in the parent compound. and then deprotected if necessary.

[0396] Composition Similarly, compositions (eg, pharmaceutical compositions) comprising an ALDHI compound described herein and a pharmaceutically acceptable carrier, diluent or excipient are described herein.

[0397] Similarly, a method of preparing a composition (e.g., a pharmaceutical composition) comprising mixing an ALDHI compound described herein and a pharmaceutically acceptable carrier, diluent or excipient includes As described herein.

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

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

[0400] Use in methods of inhibiting the ALDH1A3 enzyme Similarly, a method of inhibiting an ALDH1A3 enzyme (e.g., inhibiting or reducing or blocking the activity or function of an ALDH1A3 enzyme) in vitro or in vivo, comprising: A method is described herein that includes contacting an ALDHI compound that has been treated with an ALDHI compound.

[0401] Similarly, a method of inhibiting an ALDH1A3 enzyme (e.g., inhibiting or reducing or blocking the activity or function of an ALDH1A3 enzyme) in a cell in vitro or in vivo, comprising: administering an effective amount of the present invention to a cell; Methods are described herein that include contacting a described ALDHI compound.

[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] Those skilled in the art can readily determine whether a candidate compound inhibits the ALDH1A3 enzyme (eg, 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 readily determine whether a candidate compound inhibits the ALDH1A3 enzyme (eg, inhibits, reduces, or blocks the activity or function of the ALDH1A3 enzyme) in a cell. 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 those cells can be observed. As an example of an "effect", the morphological state of a cell (eg, alive or dead) can be determined. If the compound is found to have an effect on a cell, this is a prognostic or diagnostic marker of the compound's effectiveness in a method of treating a subject (e.g., a patient) having cells of the same cell type. can be used as As another example of "effect," direct interaction of the compound with a target in a cell can be measured using, for example, colorimetric, fluorescent, or luminescent readings (e.g., "target engagement assay”).

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

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

[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, blood (including e.g. neutrophils, eosinophils, basophils, lymphocytes, monocytes, red blood cells, platelets), lungs, gastrointestinal tract (e.g. including intestines, colon), chest (breasts), Any type of cell can be treated or targeted, including ovarian, prostate, liver, kidney, bladder, pancreatic, brain and skin cells.

[0413] Those skilled in the art can readily determine whether a candidate compound modulates (eg, inhibits) cell proliferation or the like. For example, assays that can be conveniently used to assess the activity produced by a particular compound are described herein and / or known in the art.

[0414] ALDHI compounds described herein can inhibit cell migration and invasion, eg, 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 development of resistance to another drug in a cell population.

[0417] Use in methods of treatment Similarly, 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. Described ALDHI compounds are described herein.

[0418] Similarly, the use of an ALDHI compound as described herein in a method of treatment of the human or animal body by therapy, e.g., in a method of treatment of a disorder (e.g., disease) described herein. are described herein.

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

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

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

[0422] Disorders Treated - Disorders ameliorated by inhibition of the ALDH1A3 enzyme In one embodiment (e.g., a compound for use in a method of treatment, use in a method of treatment, use in the manufacture of a medicament, method of treatment), treating comprises inhibiting the ALDH1A3 enzyme (e.g., the activity of the ALDH1A3 enzyme). treatment of a disorder (eg, disease) that is ameliorated (by inhibition or reduction or blockade of function).

[0423] The disorder being treated In one embodiment (e.g., a compound for use in a method of treatment, use in a method of treatment, use in the manufacture of a medicament, method of treatment), treatment refers to a compound described herein (e.g., disease), such as proliferative disorders, cancer, diabetes, cardiovascular disorders, etc.

[0424] proliferative disorder 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, such as neoplasia or hypertrophic growth.

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

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

[0428] In one embodiment, the cancer is: Sarcomas of bone or muscle, such as: bone cancer; osteosarcoma; chondrosarcoma; Ewing's sarcoma; heart cancer; leiomyosarcoma; malignant fibrous histiocytoma of bone; osteosarcoma; or rhabdomyosarcoma; Brain and nervous system cancers, such as: Astrocytoma; brain cancer; brainstem glioma; cerebellar astrocytoma; cerebral astrocytoma; ependymoma; glioblastoma; glioma; medulloblastoma; neuroblastoma; oligodendroglial 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; or tubular carcinoma; Cancers of the endocrine system, such as: adrenal cancer; adrenocortical cancer; papillary thyroid cancer; follicular thyroid cancer; pancreatic islet cell carcinoma; multiple endocrine tumor syndrome; parathyroid cancer; pheochromocytoma; thyroid cancer; cancer; Eye cancers, such as: retinoblastoma; or uveal melanoma; Gastrointestinal cancer, for example: Anal cancer; appendiceal cancer; bile duct cancer; intestinal cancer; cholangiocellular carcinoma; colon adenocarcinoma; colon adenoma; colon cancer; exocrine pancreatic cancer; extrahepatic bile duct cancer; gallbladder cancer; gastric ( gastric (stomach) cancer; gastrointestinal cancer; gastrointestinal carcinoid tumor; gastrointestinal stromal tumor (GIST); hepatocellular carcinoma; hepatoblastoma; kidney cancer; colorectal 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 tumors; genitourinary cancer; gestational trophoblastic tumor; gynecological 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; urethral cancer; uterine sarcoma; vaginal cancer; vulvar cancer; or Wilms tumor; Cancers of the head and neck, such as: esophageal cancer; head and neck cancer; head and neck squamous cell carcinoma; hypopharyngeal cancer; nasopharyngeal cancer; nasopharyngeal cancer; oral cancer; oropharyngeal cancer; and nasal cavity cancer; pharyngeal cancer; or salivary gland cancer; Hematopoietic tissue cancers, for example: plasma cell tumors, such as plasmacytoma or multiple myeloma; Leukemias, such as: 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; undifferentiated 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 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 lymphoma Histological 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; exudative lymphoma; Sézary syndrome; or splenic marginal zone lymphoma; or myelodysplastic syndrome; Skin cancers, such as: basal cell carcinoma; dermatofibrosarcoma protuberans; fibrosarcoma; keratoacanthocytoma; malignant melanoma; melanoma; Merkel cell carcinoma; sebaceous 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; cellular lung cancer; thymic carcinoma; or thymoma carcinoma; HIV / AIDS-related cancers, such as 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, described above) is characterized by abnormal expression of ALDH1A3.

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

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

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

[0434] In one embodiment, the cancer (eg, described above) is characterized or further characterized as an immunotherapy-resistant cancer characterized by the presence or increased 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 complications 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 following revascularization.

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

[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., disease), refers to achieving some desired therapeutic effect, such as inhibiting the progression of the disorder (e.g., slowing the rate of progression, The present invention relates to treatment of humans or animals (eg, in veterinary applications) in which a reduction in the symptoms of a disorder, an amelioration of the disorder, and a cure of the disorder (including halting the rate of progression), amelioration of the disorder, and cure of the disorder are achieved. Also included is treatment as a prophylactic measure (ie, prophylaxis). For example, use is encompassed by the term "treatment" in the case of subjects (eg, patients) who have not yet developed the disorder, but who are at risk of developing the disorder.

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

[0449] The term "therapeutically effective amount," as used herein, is that amount of a compound or substance, composition containing the compound, or dosage form that, when administered in accordance with a desired treatment regimen, produces a certain desired result. relating to an amount effective to produce a therapeutic effect and commensurate with a reasonable benefit / risk ratio.

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

[0451] Accordingly, the ALDHI compounds described herein in combination with one or more (e.g., one, two, three, four, etc.) additional therapeutic agents also include the compounds described herein. There is.

[0452] The particular combination is at the discretion of the physician who selects the dosage 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, on different individual dosage schedules, and by different routes. Good too. For example, if the drugs are administered sequentially, they may be administered at close intervals (e.g., over a period of 5 to 10 minutes) or at longer intervals (e.g., 1 hour, 2 hours, 3 hours, 4 hours or more). The exact dosage regimen will be consistent with the properties of the therapeutic agent.

[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, each agent may be individually administered. They may be formulated and provided together in the form of a kit, optionally with instructions for their use.

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

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

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

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

[0459] kit Similarly, (a) an ALDHI compound as described herein, preferably supplied as a composition (e.g., a pharmaceutical composition) in a suitable container and / or in suitable packaging; and (b) For example, kits are described herein that include instructions for use, e.g., written instructions on how to administer the compounds, in methods of treatment of the disorders (e.g., diseases) described herein. .

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

[0461] Route of administration An ALDHI compound, or a pharmaceutical composition comprising an ALDHI compound, may be administered to a subject by any convenient route of administration, whether systemically / peripherally or locally (i.e., at the desired site of action).

[0462] Administration routes include, for example, oral (e.g., by taking); buccal; sublingual; transdermal (including, for example, through patches, plasters, etc.); transmucosal (e.g., through patches, plasters, etc.). intranasal (e.g. by intranasal spray); ocular (e.g. by eye drops); pulmonary (e.g. by mouth or nose, e.g. by aerosol, e.g. by inhalation or inhalation therapy) ;rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intrathecal, intracapsular, subcapsular. parenterally, by injection, including intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, intrathecal, and intrasternal; for example, by subcutaneous or intramuscular implantation of a depot or reservoir.

[0463] subject The subject (e.g., patient) can be an invertebrate, vertebrate, mammal, placental mammal, marsupial (e.g., kangaroo, wombat), rodent (e.g., guinea pig, hamster, rat, mouse). , Muridae (e.g., mice), Lagomorpha (e.g., rabbits), Aves (e.g., birds), Canidae (e.g., dogs), Felidae (e.g., cats), Equidae (e.g., horses), Pigidae (e.g., pigs), ovine (e.g., sheep), bovid (e.g., cow), primate, ape (e.g., monkey or ape), ape (e.g., marmoset, baboon), ape (e.g., gorilla, It can be a chimpanzee, orangutan, gibbon) or a human.

[0464] Additionally, the subject (eg, patient) may be in any form of development, eg, a fetus.

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

[0466] formulation Although an ALDHI compound can be administered alone, at least one ALDHI compound described herein may be combined with one or more other pharmaceutically acceptable ingredients (e.g., pharmaceutical physically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g. wetting agents), It is preferred to present the compound as a pharmaceutical formulation (eg, a composition, preparation, medicament), including masking agents, colorants, flavoring agents, and sweetening agents). The formulation may further include other active agents, such as other therapeutic or prophylactic agents.

[0467] Thus, a pharmaceutical composition as defined above and at least one ALDHI compound as described herein may be combined with one or more other pharmaceutically acceptable ingredients, such as carriers, diluents, etc., well known to those skilled in the art. Also described herein are methods of making pharmaceutical compositions that include mixing together excipients, excipients, and the like. When formulated as discrete units (eg, tablets, etc.), each unit contains a predetermined amount (dose) of the compound.

[0468] The term "pharmaceutically acceptable," as used herein, refers to the ability to contact tissue of the subject (e.g., human) in question without undue toxicity, irritation, allergic reactions, or other problems or complications. The invention relates to compounds, ingredients, substances, compositions, dosage forms, etc., which are suitable for use as a drug and which, within the scope of sound medical judgment, are commensurate with a reasonable benefit / risk ratio. 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, e.g., Remington: The Science and Practice of Pharmacy, 21st Edition, Lippinott Williams and Wilkins, 2005; Remington: The Science and Practice of Pharmacy, Vol. 22nd Edition, Pharmaceutical Press, 2012; and Handbook of Pharmaceutical Excipients, 7th Edition, 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 bringing into association the compound with the carrier which constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing the compound into association with a carrier (eg, a liquid carrier, finely divided solid carrier, etc.) and, if necessary, shaping the product.

[0471] The formulations may be prepared to provide rapid or slow release; immediate, delayed, timed or sustained release, or combinations thereof.

[0472] Formulations may be liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries. agents, mouthwashes, drops, tablets (including, for example, coated tablets), granules, powders, lozenges, pastels, capsules (including, for example, hard and soft gelatin capsules), cachets, pills, In the form of ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists or aerosols. may be suitable.

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

[0474] The compounds may be dissolved, suspended, or mixed with one or more other pharmaceutically acceptable ingredients. The compounds may be delivered in liposomes or other microparticles in which the compounds are designed to target, for example, 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 buccal administration include mouthwashes, lozenges, pastels, as well as patches, adhesive plasters, depots and reservoirs. Lozenges usually contain the compound in a flavored base, usually sucrose and acacia or tragacanth. Pastels usually contain the compounds in an inert matrix, such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically include the compound in a suitable liquid carrier.

[0477] Formulations suitable for sublingual administration include tablets, lozenges, pastels, 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). molds), mouthwashes, lozenges, pastels, 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, 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] A tablet may be made by conventional means, eg compression or molding, optionally with one or more accessory ingredients. Compressed tablets may contain binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropyl methylcellulose); fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. 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. The present compounds in free-flowing form, e.g. powders or granules, optionally mixed with one or more of the following: methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavors, flavor enhancers and sweeteners can be prepared by compressing in suitable equipment. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or stamped and may be formulated using, for example, hydroxypropyl methylcellulose in varying proportions to achieve slow or controlled release of the compound in the tablet. can be modified to achieve the desired release profile. The tablets may optionally be provided with a release coating, eg an enteric coating, to achieve release in parts of the gastrointestinal tract other than the stomach.

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

[0483] Creams are usually prepared from the compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base can contain polyhydric alcohols, i.e. alcohols with two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycols, as well as mixtures thereof, for example at least about 30% w / w. Topical formulations may desirably include compounds that enhance absorption or penetration of the compound from the skin or other affected area. 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, optionally containing an emulsifier (otherwise known as an emulsifier), or emulsions are prepared from at least one emulsifier. It may also include mixtures with fats or oils or with both fats and oils. Preferably, a hydrophilic emulsifier is included along with a lipophilic emulsifier which acts as a stabilizer. It is also preferred that the hydrophilic emulsifier contains both oil and fat. At the same time, emulsifiers with or without stabilizers constitute so-called emulsifying waxes, as well as waxes together with oils and / or fats, so-called emulsifying ointment bases, which form the oily dispersed phase of cream formulations. Configure.

[0485] Suitable emulsion and emulsion stabilizers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. Since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low, the selection of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. . Therefore, creams should preferably be non-greasy, non-staining and washable products with suitable consistency to avoid leakage from tubes or other containers. Straight-chain or branched monobasic or dibasic alkyl esters, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, palmitic acid 2-Ethylhexyl or a blend of branched chain esters (known as Crodamol CAP) may be used, with the last three being the 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] When the carrier is a liquid, formulations suitable for intranasal administration include, for example, by nasal spray, nasal drops, or aerosol administration via a nebulizer, including aqueous or oily solutions of the compound.

[0487] When the carrier is a solid, formulations suitable for intranasal administration are administered in the manner in which snuffs are ingested, i.e., by rapid inhalation through the nasal passages from a container of powder held close to the nose. , for example, those supplied as coarse powders having particle sizes ranging from about 20 to about 500 microns.

[0488] Formulations suitable for pulmonary administration (e.g., by inhalation or inhalation therapy) can be prepared by adding a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Including those delivered as an aerosol spray from a pressure pack.

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

[0490] Formulations suitable for rectal administration are, for example, as suppositories containing a suitable base comprising natural or hydrogenated oils, waxes, fats, semi-liquid or liquid polyols, such as cocoa butter or salicylates; or for treatment by enema. It may be supplied as a solution or suspension.

[0491] Formulations suitable for vaginal administration include pessaries, tampons, creams, gels, pastes, foams containing, in addition to the compound, such carriers as are known in the art to be suitable. It may also be supplied as a formulation or a spray formulation.

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

[0493] Dose It will be appreciated by those skilled in the art that appropriate dosages of ALDHI compounds, and compositions comprising ALDHI compounds, may vary from subject to subject (eg, patient to patient). Determining optimal dosage generally involves balancing the level of therapeutic benefit with any risks or adverse side effects. The selected dosage level will depend on the particular ALDHI compound, the route of administration, the time of administration, the rate of elimination of the ALDHI compound, the duration of treatment, other drugs, concomitant compounds and / or substances, the severity of the disorder, and the subject (e.g. , the patient)'s species, sex, age, weight, condition, general health, and medical history. The amount and route of administration of the ALDHI compound is ultimately at the discretion of the physician, veterinarian, or clinician, but in general, the amount administered is such that it will be sufficient to achieve the desired effect at the site of action without causing significant harm or harmful side effects. One will choose to achieve a local concentration that achieves the desired effect.

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

[0495] Generally, suitable doses of ALDHI compounds range from 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] If the compound is a salt, solvate, ester, amide, prodrug, etc., the amount administered will be calculated based on the parent compound and the actual weight used will therefore be 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]undecar-7-ene. DCM: dichloromethane (methylene chloride). DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. DIAD: Diisopropylazodicarboxylate. DIPEA: N,N-diisopropylethylamine. DME: 1,2-dimethoxyethane. DMP: Des-Martin periodinane. DMAP: 4-(dimethylamino)pyridine. DMSO: dimethyl sulfoxide. ES: Electrospray ionization. Et 2 O: 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). NaBH 4 :Sodium borohydride. NaOtBu: Sodium tert-butoxide. NBS: N-bromosuccinimide. NaHCO 3 :sodium hydrogen carbonate. N.H. 4 Cl: Ammonium chloride. Pd / C: Palladium on carbon. pTSA: p-toluenesulfonic acid monohydrate. RT: Room temperature. Na 2 S 2 O 3 :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-high performance liquid chromatography.

[0498] General experiment Flash chromatography was performed using prefilled 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 were used without further drying. HPLC grade solvents were obtained from Fisher Chemicals Ltd.

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

[0500] proton( 1 H) and carbon ( 13 C) NMR spectra were recorded on a 300MHz Bruker spectrometer. Solutions were chemically shifted relative to tetramethylsilane (TMS) or deuterated solvents as internal standards, and deuterated chloroform (CDCl). 3 ), usually prepared in either deuterated methanol (methanol-d4) or deuterated dimethyl sulfoxide (DMSO-d6). 1 H NMR data includes chemical shifts (δ), integral values ​​(e.g. 1 H), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; dd, doublet of doublet) and coupling constant (J) (in Hz). and report. Deuterated solvents were purchased from Sigma-Aldrich Chemical Company, Goss or Fluorochem.

[0501] AnalyticalLC-MS LCMS analysis was performed using a BEH C with a diode array detector connected to an SQD mass spectrometer. 18 Waters Acquity UPLC using a 1.7μM column (2.1x50mm) or BEH C with a diode array detector connected to a QDa mass spectrometer 18 Performed on an Acquity I-Class UPLC using a 1.7μM column (2.1x50mm). Analyzes were performed in either buffered acidic or buffered basic solvents using gradients as described below. Low pH: Solvent A - water + 10mM ammonium bicarbonate + 0.1% formic acid. Solvent B - MeCN+5% water+0.1% formic acid.

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

[0503] [Table 9]

[0504] Preparative HPLC-MS Some compounds are Phenomonex Gemini NX 5μm C 18 , a Waters FractionLynx MS automated purification system with a 100 mm x 21.2 mm i.d. column (for low pH runs), or UV diode array detection (210-400 nm) and mass-directed collection (positive mass ions and Waters XBridge 5μm C with negative mass ion detection) 18 , purified by preparative HPLC on a 100 mm x 19 mm i.d. column (for high pH runs).

[0505] Purification was performed using buffered acidic or basic solvent systems, as appropriate. Retention times of compounds in the system were routinely evaluated using 30-50 μL test injections and standard gradients, and then, based on the observed retention times, appropriately selected as described below. Purification was performed using a street-specific gradient.

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

[0507] High pH: Solvent A - water + 10mM 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 chemical synthesis of compounds of the invention are described herein. These and / or other well known methods may be modified and / or adapted in known manner 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] 6-hydroxy-3,4-dihydro-2(1H)-quinolinone (1.0 g, 6.13 mmol, 1 eq.) and K in MeCN (30 mL) under nitrogen 2 C.O. 3 To a mixture of (1.69 g, 12.3 mmol, 2 eq.) was added 1-bromo-2-chloroethane (2.6 mL, 30.6 mmol, 5 eq.). This mixture was refluxed for 3 days. The mixture was cooled, filtered, washed with MeCN (3 x 10 mL) and concentrated in vacuo. The resulting solid was stirred in DCM (25 mL) for 0.5 h, filtered and washed with DCM (3 x 25 mL) and concentrated in vacuo. The solid was purified using 5-95% MeCN:H as eluent. 2 Chromatography using O (C 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, CDCl 3 ) 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-aryl cyclic amines with 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (1 eq.), 2-substituted cyclic amine (1.2-2.4 eq.) in MeCN (0.02M-0.11M), K 2 C.O. 3 (2 to 3 equivalents) and KI (0.2 to 1 equivalent) was heated to reflux under nitrogen for 3 to 6 days. If necessary, additional 2-aryl cyclic amine and KI were added to complete the reaction. The mixture was cooled, water was added then 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 with MeOH:DCM (optionally 1% aqueous NH 3 normal phase chromatography using a gradient of SiO 2 ), MeCN:H 2 Reversed phase chromatography using a gradient of O (C 18 ) and / or by preparative HPLC-MS using a gradient of high pH or low pH aqueous MeCN. If necessary, Et. 2 Further purification by trituration with O or petroleum ether.

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

[0517] [ka] 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (30 mg, 0.133 mmol, 1 eq), 2-(3-methoxy-phenyl)-pyrrolidine in MeCN (2.5 mL) Hydrochloride (43mg, 0.199mmol, 1.5eq), K 2 C.O. 3 (55 mg, 0.399 mmol, 3 eq.), KI (22 mg, 0.133 mmol, 1 eq.) as described in Method A and after preparative HPLC-MS (high pH) the title compound (27 mg, 0.0723 mmol, 54%) was obtained as a white powder. MS (ES+) m / z 367.3 (M+H). 1 H NMR (300 MHz, methanol-d 4 ) 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 example compounds were similarly prepared using Method A using the appropriate 2-substituted cyclic amines.

[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-d 6 ) 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, CDCl 3 ) 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). 1 H NMR (300 MHz, CDCl 3 ) 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] Synthesis 6 6-[2-[2-(o-tolyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2012)

[0526] [ka] MS (ES+) m / z 351.3 (M+H). 1 H NMR (300 MHz, CDCl 3) δ 7.62 - 7.55 (m, 1H), 7.36 (s, 1H), 7.22 - 7.14 (m, 1H), 7.13 - 7.08 (m, 2H), 6.69 - 6.56 (m, 3H), 3.98 (t, J = 6.2 Hz, 2H), 3.60 (t, J = 8.2 Hz, 1H), 3.50 - 3.41 (m, 1H), 3.01 - 2.86 (m, 3H), 2.63 - 2.55 (m, 2H), 2.55 - 2.44 ( m, 1H), 2.44 - 2.34 (m, 1H), 2.33 (s, 3H), 2.29 - 2.15 (m, 1H), 2.02 - 1.75 (m, 2H), 1.66 - 1.45 (m, 1H).

[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, CDCl 3 ) 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). 1 H NMR (300 MHz, CDCl 3 ) 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-pyridyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2006)

[0532] [ka] MS (ES+) m / z 338.3 (M+H). 1 H NMR (300 MHz, CDCl 3 ) δ 8.53 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 8.00 (s, 1H), 7.63 (td, J = 7.6, 1.8 Hz, 1H), 7.50 (dt, J = 7.9, 1.1 Hz, 1H), 7.13 (ddd, J = 7.4, 4.9, 1.3 Hz, 1H), 6.80 - 6.56 (m, 3H), 3.95 (t, J = 6.1 Hz, 2H), 3.63 (t, J = 8.0 Hz, 1H) ), 3.51 - 3.38 (m, 1H), 3.03 - 2.84 (m, 3H), 2.75 - 2.64 (m, 1H), 2.62 - 2.55 (m, 2H), 2.55 - 2.43 (m, 1H), 2.37 - 2.19 (m, 1H), 2.08 - 1.70 (m, 4H).

[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-d 4 ) 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). 1 H NMR (300 MHz, CDCl 3 ) 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, CDCl 3 ) δ -113.48.

[0537] Synthesis 12 6-[2-[(2S)-2-(3-fluorophenyl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2018)

[0538] [ka] MS (ES+) m / z 355.3. 1 H NMR (300 MHz, CDCl 3 ) δ 7.35 (s, 1H), 7.29 - 7.19 (m, 1H), 7.18 - 7.08 (m, 2H), 6.95 - 6.86 (m, 1H), 6.68 - 6.56 (m, 3H), 3.95 (t, J = 6.1 Hz, 2H), 3.47 - 3.34 (m, 2H), 2.98 - 2.85 (m, 3H), 2.64 - 2.48 (m, 3H), 2.41 (q, J = 8.8 Hz, 1H), 2.24 - 2.10 ( m, 1H), 2.01 - 1.60 (m, 3H). 19 F { 1 H} NMR (282 MHz, CDCl 3 ) δ -113.49.

[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, CDCl 3) 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, CDCl 3 ) 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, CDCl 3 ) 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 = 8.8 Hz, 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, CDCl 3 ) 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). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) 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, CDCl 3 ) 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). 1 H NMR (300 MHz, CDCl 3 ) 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-methylthiazol-4-yl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2033)

[0552] [ka] MS (ES+) m / z 358.3 (M+H). 1 H NMR (300 MHz, methanol-d 4 ) δ 7.24 (d, J = 0.6 Hz, 1H), 6.83 - 6.64 (m, 3H), 4.01 (t, J = 5.7 Hz, 2H), 3.70 (t, J = 7.7 Hz, 1H), 3.46 - 3.36 (m, 1H), 3.04 (dt, J = 13.1, 5.8 Hz, 1H), 2.97 - 2.86 (m, 2H), 2.77 - 2.62 (m, 4H), 2.60 - 2.43 (m, 3H), 2.32 - 2.15 (m, 1H), 2.06 - 1.79 (m, 3H).

[0553] Synthesis 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, CDCl 3 ) 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). 1 H NMR (300 MHz, CDCl 3 ) 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-methylpyrrol-2-yl)pyrrolidin-1-yl]ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2017)

[0558] [ka] MS (ES+) m / z 340.3 (M+H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.40 (s, 1H), 6.68 - 6.56 (m, 3H), 6.54 (t, J = 2.3 Hz, 1H), 6.05 (d, J = 2.3 Hz, 2H), 3.91 (t, J = 6.1 Hz , 2H), 3.68 (s, 3H), 3.47 (t, J = 8.0 Hz, 1H), 3.41 - 3.31 (m, 1H), 3.01 (dt, J = 12.4, 6.1 Hz, 1H), 2.94 - 2.86 ( m, 2H), 2.63 - 2.46 (m, 3H), 2.39 - 2.24 (m, 1H), 2.17 - 2.01 (m, 1H), 2.00 - 1.75 (m, 3H).

[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-d 6 ) 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-d 6 ) 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, CDCl 3 ) 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, CDCl 3 ) 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). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) δ -113.35.

[0565] Synthesis 26 6-[2-(4-methylsulfonyl-2-phenyl-piperazin-1-yl)ethoxy]-3,4-dihydro-1H-quinolin-2-one (ALDHI-2046)

[0566] [ka] MS (ES+) m / z 430.3 (M+H). 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 7.48 - 7.28 (m, 5H), 6.86 - 6.55 (m, 3H), 3.93 (t, J = 6.0 Hz, 2H), 3.61 - 3.40 (m, 2H), 3.39 - 3.25 (m, 2H), 3.02 - 2.85 (m, 4H), 2.85 - 2.66 (m, 4H), 2.56 - 2.50 (m, 1H), 2.44 - 2.30 (m, 3H).

[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-d 4 ) 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, 5.1Hz, 1H). 19 F {1H} NMR (282 MHz, methanol-d 4 ) 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). 1 H 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-d 6 ) 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] 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (60 mg, 0.266 mmol, 1 eq), tert-butyl 3-phenylpiperazine-1-carboxylate in MeCN (5 mL) (105mg, 0.399mmol, 1.5eq), K 2 C.O. 3 A mixture of KI (75 mg, 0.532 mmol, 2 eq.) and KI (44 mg, 0.266 mmol, 1 eq.) 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 organic extracts were combined, filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was chromatographed (SiO 2 ). The residue was dissolved in DCM (5 mL) and trifluoroacetic acid (2.0 mL, 26.0 mmol, 97.6 eq.) was added. The mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with DCM (20 mL) and saturated aqueous NaHCO 3 (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 Et 2 Trituration with O and drying in vacuo at 50° C. gave the title compound (15 mg, 0.0435 mmol, 16%) as a white powder. MS (ES+) m / z 352.3 (M+H). 1 H NMR (300 MHz, DMSO-d 6 ) 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] 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (30 mg, 0.133 mmol, 1 eq), 2-phenyl-1H-imidazole (29 mg, 0.199 in MeCN (2.5 mL)) mmol, 1.5 eq), K 2 C.O. 3 (37 mg, 0.266 mmol, 2 eq.) and KI (22 mg, 0.133 mmol, 1.0 eq.) as described in Method A and after purification by preparative HPLC-MS (high pH), the title compound ( 16.2 mg, 0.0486 mmol, 37%) was obtained as a white powder. MS (ES+) m / z 334.3 (M+H). 1 H NMR (300 MHz, DMSO-d 6 ) 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] 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (100 mg, 0.400 mmol, 1 eq), 3-(3-fluorophenyl)-1H-pyrazole in MeCN (8 mL) Hydrochloride (118.8mg, 0.600mmol, 1.5eq), K 2 C.O. 3 (165.4 mg, 1.2 mmol, 3 eq.) and KI (66.2 mg, 0.400 mmol, 1 eq.) as described in Method A and after purification by preparative HPLC-MS (high pH), the title The compound (10 mg, 0.0296 mmol, 7%) was obtained as a white powder. 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, CDCl 3 ) 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 A mixture of tert-butyl 2-oxopyrrolidine-1-carboxylate (1.8 mL, 10.8 mmol, 1 eq) in THF (40 mL) was added to 3-fluorophenylmagnesium bromide (3-fluorophenylmagnesium bromide in THF) at -78 °C under nitrogen. 1M, 16mL, 16.2mmol, 1.5eq) was added dropwise. The mixture was stirred for 18 hours while 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, filtered and the phases were separated. Brine the organic phase (3 x 100 mL), saturated aqueous NaHCO 3 (3 x 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 eq.) was added. This mixture was stirred at 90°C for 2 hours. Cool this mixture and add saturated aqueous NaHCO 3 The combined extracts were filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was chromatographed (SiO 2 ) 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, CDCl 3 ) 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, CDCl 3 ) δ -113.03.

[0581] Step 2: 2-(3-fluorophenyl)-2-methyl-pyrrolidine Diethyl boron trifluoride was added to a solution of 5-(3-fluorophenyl)-3,4-dihydro-2H-pyrrole (775 mg, 4.27 mmol, 1 eq.) in THF (45 mL) at -78°C for about 5 minutes. Ethelate (1.1 mL, 8.55 mmol, 2 eq.) was added. The mixture was stirred for 40 minutes, then methyllithium (6.7 mL, 10.7 mmol, 2.5 eq.) was added dropwise over 10 minutes. The mixture was stirred for 16 hours and slowly warmed to room temperature. Water (40 mL) was added, followed by aqueous HCl (2M, 10 mL), then EtOAc (50 mL) and the phases were separated. The organic phase was washed with aqueous HCl (1M, 25 mL) and the aqueous phases were combined. The aqueous phase was basified to pH 12 with aqueous NaOH (2M), extracted with EtOAc (2 x 50mL), the extract was washed with brine (100mL), filtered through a hydrophobic frit and concentrated in vacuo. , 2-(3-fluorophenyl)-2-methyl-pyrrolidine (669 mg, 0.448 mmol, 10%, ~12% purity by LCMS) was obtained as an orange oil and used in the next step without further purification. did. 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 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (30 mg, 0.133 mmol, 1 eq), 2-(3-fluorophenyl)-2-methyl in MeCN (5 mL) -pyrrolidine (300mg, 0.201mmol, 1.5eq, ~12% purity by LCMS), K 2 C.O. 3 (37 mg, 0.266 mmol, 2 eq.) and KI (22 mg, 0.133 mmol, 1 eq.) as described in Method A, with 5-95% MeCN:H as eluent. 2 Reversed phase chromatography using O (C 18 ) and subsequent purification by preparative HPLC-MS (high pH), the title compound (10.1 mg, 0.0274 mmol, 21%) was obtained as a light beige powder. MS (ES+) m / z 369.3 (M+H). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) 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 Triethylamine (0.48 mL, 3.45 mmol, 3 eq.), DMAP (7 mg, 0.0574 mmol, 0.05 eq.) and di-tert-butyl dicarbonate (276 mg, 1.26 mmol, 1.1 eq.). The reaction mixture was stirred at room temperature for 16 hours, then quenched with water (20 mL) and extracted with DCM (2 x 25 mL). The extract was washed with brine (50 mL), filtered through a hydrophobic frit, and concentrated in vacuo. The obtained residue was eluted with 5~95% MeCN:H. 2 Chromatography using O (C 18 ) to give tert-butyl 2-(3-fluorophenyl)-4-hydroxy-pyrrolidine-1-carboxylate (238 mg, 0.846 mmol, 74%) as an off-white powder, which was followed without further purification. It was used in the process. MS (ES+) m / z 262.12 m / z (M+H-tBu).

[0586] Step 2: tert-butyl 4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate A solution of tert-butyl 2-(3-fluorophenyl)-4-hydroxy-pyrrolidine-1-carboxylate (100 mg, 0.355 mmol, 1 eq.) in DCM (10 mL) was added with BAST (50% %, 0.27mL, 0.533mmol, 1.5eq) was added. The mixture was stirred at room temperature for 16 h, then aqueous NaOH (1M, 5 mL) was added and stirred for 0.5 h. The phases were separated and the organic layer was washed with brine (3 x 10 mL) and dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was chromatographed (SiO 2 ) to give tert-butyl 4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate (40 mg, 0.141 mmol, 40%) as a colorless oil that solidified on standing. MS (ES+) m / z 228.1 (M+H). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) δ -114.08, -170.17.

[0587] Step 3: 4-fluoro-2-(3-fluorophenyl)pyrrolidine hydrochloride A solution of tert-butyl 4-fluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate (33 mg, 0.116 mmol, 1 eq.) in 1,4-dioxane (2 mL) was added with HCl (in 1,4-dioxane). (4M, 2.0 mL, 8.00 mmol, 69 eq.) was added and the mixture was heated to 60° C. for 1 h. This mixture is then cooled and concentrated in vacuo, and the resulting solid is purified with Et 2 Trituration with O and drying in vacuo at 50° C. gave 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-d 6 ) 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-d 6 ) 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 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (22 mg, 0.0956 mmol, 0.9 eq), 4-fluoro-2-(3-fluorophenyl) in MeCN (2.5 mL) ) Pyrrolidine hydrochloride (23 mg, 0.105 mmol, 1 eq.), K 2 C.O. 3 (44 mg, 0.315 mmol, 3 eq.) and KI (17 mg, 0.105 mmol, 1 eq.) as described in Method A and after purification by preparative HPLC-MS (low pH), the title compound ( 10 mg, 0.0256 mmol, 23%) was obtained as a white powder. MS (ES+) m / z 373.3 (M+H). 1 H NMR (300 MHz, methanol-d 4 ) 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-d 4 ) 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 eq.) in DCM (5 mL) was added DMP (289 mg, 0.682 mmol, 1.2 eq.). added. The reaction mixture was stirred at room temperature for 40 hours, then aqueous NaOH (1M, 5 mL) was added and the mixture was stirred for 1 hour. 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 (SiO 2 ) to give 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 (M-H-tBu). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) δ -111.94 - -113.63 (m).

[0592] Step 2: tert-butyl 4,4-difluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate A solution of tert-butyl 2-(3-fluorophenyl)-4-oxo-pyrrolidine-1-carboxylate (133 mg, 0.476 mmol, 1 eq.) in DCM (10 mL) was added with BAST (50% in toluene, 0.36 mL, 0.714 mmol, 1.5 eq) was added via syringe. This mixture was stirred at room temperature for 18 hours. 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 (SiO 2 ) to give tert-butyl 4,4-difluoro-2-(3-fluorophenyl)pyrrolidine-1-carboxylate (113 mg, 0.375 mmol, 79%) as a colorless oil, which was carried directly into the next step. used. MS (ES+) m / z 246.1 (M+H-tBu). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) 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 HCl (1,4- 4M in dioxane, 2.0 mL, 8.00 mmol, 22 eq.) was added. The mixture was heated to 60° C. for 1 hour, then cooled to room temperature and concentrated in vacuo. Et the obtained solid 2 Triturated with O 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-d 6) 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-d 6 ) 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 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (25 mg, 0.111 mmol, 1 eq.), 4,4-difluoro-2-(3- fluorophenyl)pyrrolidine hydrochloride (29mg, 0.122mmol, 1.1eq), K 2 C.O. 3 (47 mg, 0.332 mmol, 3 eq.) and KI (18 mg, 0.111 mmol, 1 eq.) as described in Method A and after purification by preparative HPLC-MS (low pH) as a white powder. The title compound (10 mg, 0.0256 mmol, 23%) was obtained. MS (ES+) m / z 391.3 (M+H). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) 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] 7-hydroxy-4H-1,4-benzoxazin-3-one (100 mg, 0.606 mmol, 1 eq.) in MeCN (5 mL) under nitrogen (La et al., Journal of Medicinal Chemistry, 2008, 51, 1695 ~Prepared as reported on page 1705) and K 2 C.O. 3 To a mixture consisting of (167 mg, 1.21 mmol, 2 eq.) was added 1-bromo-2-chloroethane (0.25 mL, 3.03 mmol, 5 eq.). The mixture was heated to reflux for 3 days, then cooled to room temperature and water (10 mL) was added followed by DCM (10 mL). 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 solid was chromatographed (SiO 2 ) to give the title compound (41 mg, 0.180 mmol, 30%) as an orange powder. MS (ES-) m / z 226.1 / 228.1 (M-H), Cl isotope pattern. 1 H NMR (300 MHz, CDCl 3 ) 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 = 5.8 Hz, 2H).

[0599] General method B: Alkylation of 2-substituted cyclic amines with 7-(2-chloroethoxy)-4H-1,4-benzoxazin-3-one 7-(2-chloroethoxy)-4H-1,4-benzoxazin-3-one (1 eq.), 2-substituted cyclic amine (1.5 eq.) in MeCN (0.04M~0.05M), K 2 C.O. 3 (2 eq.) and KI (1 eq.) was heated to reflux under nitrogen for 3 days, then cooled to room temperature. Water was added followed by DCM 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] 7-(2-chloroethoxy)-4H-1,4-benzoxazin-3-one (20 mg, 0.0879 mmol, 1 eq), 1-methyl-4-(pyrrolidin-2-yl) in MeCN (2.5 mL) )-1H-pyrazole (20mg, 0.132mmol, 1.5eq), K 2 C.O. 3 (24 mg, 0.176 mmol, 2 eq.) and KI (15 mg, 0.0879 mmol, 1 eq.) as described in Method B to give the title compound (17 mg, 0.0497 mmol, 57%) by preparative HPLC- Obtained as a colorless gum after purification by MS (high pH). MS (ES+) m / z 343.3 (M+H). 1 H NMR (300 MHz, methanol-d 4 ) 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 example compounds were similarly prepared using Method B using the appropriate 2-substituted cyclic amines.

[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). 1 H NMR (300 MHz, methanol-d 4 ) 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] 7-Hydroxy-4H-1,4-benzothiazin-3-one (89 mg, 0.491 mmol, 1 eq.) in MeCN (5 mL) under nitrogen (Zhang et al., Chemical and Pharmaceutical Bulletin, 2010, 58, 326~ prepared as reported on page 331) and K 2 C.O. 3 (136 mg, 0.982 mmol, 2 eq.) was added 1-bromo-2-chloroethane (0.20 mL, 2.46 mmol, 5 eq.). The mixture was heated to reflux for 3 days, then cooled to room temperature and water (10 mL) was added followed by DCM (10 mL). 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 solid was eluted with 0~5% MeOH:DCM (+1% aqueous NH 3 ) using chromatography (SiO 2 ) to give 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, CDCl 3 ) 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 7-(2-chloroethoxy)-4H-1,4-benzothiazin-3-one (1 eq), 2-substituted cyclic amine (1.5 eq), K in MeCN (0.03~0.05M) 2 C.O. 3 A mixture consisting of (2 eq.) and KI (1 eq.) was heated to reflux for 3 days, then cooled to room temperature. Water was added followed by DCM 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] 7-(2-chloroethoxy)-4H-1,4-benzothiazin-3-one (20 mg, 0.0821 mmol, 1 eq), 1-methyl-4-(pyrrolidin-2-yl) in MeCN (1.5 mL) -1H-pyrazole (19mg, 0.123mmol, 1.5eq), K 2 C.O. 3 (23 mg, 0.164 mmol, 2 eq.), KI (14 mg, 0.0821 mmol, 1 eq.) as described in Method C and after preparative HPLC-MS (high pH) the title compound (19 mg, 0.053 mmol, 65%) was obtained as the formate salt as a colorless gum. MS (ES+) m / z 359.3 (M+H). 1 H NMR (300 MHz, CDCl 3 ) 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 example compounds were similarly prepared using Method C using the appropriate 2-substituted cyclic amines.

[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). 1 H NMR (300 MHz, CDCl 3 ) 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-pyridyl)pyrrolidin-1-yl]ethoxy]-4H-1,4-benzothiazin-3-one (ALDHI-2028)

[0616] [ka] MS (ES+) m / z 356.2 (M+H). 1 H NMR (300 MHz, methanol-d 4 ) δ 8.58 - 8.52 (m, 1H), 8.44 - 8.36 (m, 1H), 7.89 (dt, J = 7.9, 2.0 Hz, 1H), 7.38 (dd, J = 7.9, 4.9 Hz, 1H), 6.89 - 6.76 (m, 2H), 6.69 (dd, J = 8.8, 2.7 Hz, 1H), 4.06 - 3.88 (m, 2H), 3.57 (t, J = 8.2 Hz, 1H), 3.48 (ddd, J = 10.1, 7.6, 3.1 Hz, 1H), 3.38 (s, 2H), 2.98 - 2.84 (m, 1H), 2.72 - 2.59 (m, 1H), 2.53 (q, J = 8.9 Hz, 1H), 2.37 - 2.19 (m , 1H), 2.07 - 1.83 (m, 2H), 1.81 - 1.62 (m, 1H).

[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). 1 H NMR (300 MHz, methanol-d 4 ) 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, 4.7 Hz, 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 DDQ (226 mg, 0.997 mmol, 1.5 eq) was added and the reaction mixture was heated to reflux for 16 h, then cooled to room temperature, diluted with water (25 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with brine (50 mL) and dried (MgSO 4 ), filtered and the solvent removed in vacuo. The residue was chromatographed (SiO 2 ) 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-d 6 ) 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 6-(2-chloroethoxy)-1H-quinolin-2-one (54 mg, 0.241 mmol, 1 eq), 2-(3-fluorophenyl)pyrrolidine (60 mg, 0.362 mmol, 1.5 eq) in MeCN (5 mL) ni, K 2 C.O. 3 (67 mg, 0.483 mmol, 2 eq.) and KI (4 mg, 0.0241 mmol, 0.1 eq.) were added 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 and 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 obtained residue was purified with 5-95% MeCN:H as eluent. 2 Chromatography using O (C 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-d 6 ) 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 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (1 eq), 2-substituted alkylamine (1.5 eq), K in MeCN (0.04M~0.05M) 2 C.O. 3 (2 to 3 equivalents) and KI (1 equivalent) was heated to reflux under nitrogen for 3 to 7 days. If necessary, additional 2-arylamine was added to complete the reaction. The mixture was cooled to room temperature, water was added then 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 with MeOH:DCM (optionally 1% aqueous NH 3 normal phase chromatography using a gradient of SiO 2 ) or by preparative HPLC-MS using a gradient of high pH or low pH aqueous MeCN. If the resulting solid was isolated as a salt, the solid was dissolved in saturated aqueous NaHCO 3 The free base was extracted with DCM and concentrated in vacuo to give the free base. If necessary, Et. 2 Further purification was performed by trituration with O.

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

[0627] [ka] 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (30 mg, 0.133 mmol, 1 eq) in MeCN (2.5 mL), N-methyl-N-(3-pyridylmethyl ) Amine (24mg, 0.199mmol, 1.5eq), K 2 C.O. 3 (37 mg, 0.266 mmol, 2 eq.) and KI (22 mg, 0.133 mmol, 1 eq.) as described in Method D and after purification by preparative HPLC-MS (high pH), the title compound ( 18 mg, 0.0562 mmol, 42%) was obtained as an orange gum. MS (ES+) m / z 312.2 (M+H). 1 H NMR (300 MHz, CDCl 3 ) 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 example compounds were similarly prepared using Method D using 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). 1 H NMR (300 MHz, CDCl 3 ) 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). 1H NMR (300 MHz, DMSO-d 6 ) 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 (MH). 1 H NMR (300 MHz, CDCl 3 ) 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, CDCl 3 ) 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-d 6 ) 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-d 4 ) 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-d 4 ) -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). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) 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-d 6 ) 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-d 4 ) 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-d 6 ) 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-d 6 ) 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 A solution of 2-(tert-butyldimethylsilyloxy)ethanamine (0.20 mL, 1.14 mmol, 1.25 eq) was added. The mixture was stirred at room temperature for 16 h, then NaBH 4 (34 mg, 0.908 mmol, 1 eq.) was added and stirring continued for 3 hours. Additional NaBH 4 (34 mg, 0.908 mmol, 1 eq.) was added and the mixture was stirred for a further 18 h, then aqueous saturated NH 4 Quenched with Cl (5 mL) and extracted with EtOAc (2 x 10 mL). The combined extracts were washed with brine (10 mL), filtered through a hydrophobic frit, and concentrated in vacuo. The resulting residue was eluted with 0~5% MeOH:DCM (+1% aqueous NH 3 ) using chromatography (SiO 2 ), 2-[tert-butyl(dimethyl)silyl]oxy-N-[(1-methylpyrazol-4-yl)methyl]ethanamine (192 mg, 0.713 mmol, 78%) was dissolved as a colorless oil (approximately 10% w / w of 2-(tert-butyldimethylsilyloxy)ethanamine). 1 H NMR (300 MHz, methanol-d 4 ) 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-quinoline- 2-on 6-(2-chloroethoxy)-3,4-dihydro-1H-quinolin-2-one (50 mg, 0.222 mmol, 1 eq.), 2-[tert-butyl(dimethyl)silyl] in MeCN (2.5 mL) Oxy-N-[(1-methylpyrazol-4-yl)methyl]ethanamine (90mg, 0.332mmol, 1.5eq), K 2 C.O. 3 (62 mg, 0.443 mmol, 2 eq.) and KI (37 mg, 0.222 mmol, 1 eq.) as described in Method D, 0-5% MeOH:DCM (+1% aqueous NH 3 ) using normal phase chromatography (SiO 2 ), followed by 6-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl-[(1-methylpyrazol-4-yl)methyl]amino]ethoxy]-3,4-dihydro-1H-quinoline- 2-one (66 mg, 0.144 mmol, 65%) was obtained as a colorless residue. Used directly in 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 6-[2-[2-[tert-butyl(dimethyl)silyl]oxyethyl-[(1-methylpyrazol-4-yl)methyl]amino]ethoxy]-3,4-dihydro-1H-quinolin-2-one To a solution of (65 mg, 0.142 mmol, 1 eq.) in THF (5 mL) was added TBAF (1M in THF, 0.15 mL, 0.149 mmol, 1.05 eq.). The mixture was stirred at room temperature for 1 h, then saturated aqueous NaHCO 3 (10 mL) and extracted with DCM (2 x 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 (SiO 2 ) and then purified by preparative HPLC (high pH) to give 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-d 6 ) 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] 2-(3-fluorophenyl)pyrrolidine (2.4 mL, 15.7 mmol, 1 eq.), 2-bromoethanol (2.2 mL, 31.4 mmol, 2 eq.) and K in MeCN (20 mL). 2 C.O. 3 (4.34 g, 31.5 mmol, 2 eq.) was refluxed for 18 hours. 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 eluted with 0~5% MeOH:DCM (+1% aqueous NH 3 ) using chromatography (SiO 2 ) 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-d 6 ) 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 DIAD (1.5 equivalents), then the appropriately substituted phenol (1-1.1 equivalents) was added. The mixture was stirred at room temperature under nitrogen for 18 hours. 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 first dissolved in MeOH:DCM (optionally 1% aqueous NH 3 normal phase chromatography using a gradient of SiO 2 ), then MeCN:H 2 Reversed phase chromatography using a gradient of O (C 18 ), or purified by preparative HPLC-MS using a gradient of high pH 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) was prepared as described in Method E with 0-70% EtOAc:Petroleum as eluent. Normal phase chromatography using ether (SiO 2 ), and then 5-95% MeCN:H as eluent. 2 Reversed phase chromatography using O (C 18 ), the title compound (16 mg, 0.0434 mmol, 9%) was obtained as a white solid powder. MS (ES+) m / z 369.3 (M+H). 1 H NMR (300 MHz, DMSO-d 6 ) 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 example compounds were similarly prepared using Method E using 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). 1 H NMR (300 MHz, CDCl 3 ) 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, CDCl 3 ) 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). 1 H NMR (300 MHz, DMSO-d 6 ) 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). 1 H NMR (300 MHz, DMSO-d 6 ) 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 bromide

[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 eq.) in THF (10 mL) at 0 °C was added sodium hydride (60% in mineral oil, 79 mg, 1.99 mmol, 1.2 eq.) . The mixture was stirred for 0.5 h, then a solution of 2-nitrobenzaldehyde (250 mg, 1.65 mmol, 1 eq) in THF (10 mL) was added and stirring was continued at room temperature overnight. water (5 mL) then saturated aqueous NaHCO 3 (10 mL) was added dropwise. This mixture was extracted with EtOAc (3 x 25 mL). The organic phase was separated, washed with brine (50 mL) and dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was chromatographed using 0-20% EtOAc:petroleum ether (SiO 2) to give a yellow oil. This oil was dissolved in EtOH (26 mL) and passed through 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. An off-white powder was obtained. 1 Contains about 10% unreduced product according to H NMR. Used directly in next step. MS (ES+) m / z 162.0 (M+H). 1 H NMR (DMSO-d 6 ) 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 NBS (214 mg, 1.20 mmol, 1 eq.) was added to a solution of 3-methyl-3,4-dihydro-1H-quinolin-2-one (194 mg, 1.20 mmol, 1 eq.) in DMF (5 mL) cooled to 0 °C. Added little by little. The mixture was warmed to room temperature and stirred for 2 hours, then poured into water and extracted with EtOAc (2 x 25 mL). Organic phase is aqueous Na 2 S 2 O 3 (25 mL), washed with brine (25 mL) and dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was chromatographed using 0-50% EtOAc:petroleum ether (SiO 2 ) 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-d 6 ) 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-bromoacetate

[0676] [ka] A mixture consisting of 2-amino-5-bromophenol (1.1~1.2 equivalents), DBU (1.1~1.2 equivalents), substituted methyl 2-bromoacetate (1 equivalent), and NMP (0.22~0.51 M) was subjected to a microwave reaction. It was heated in a container at 180°C for 3 minutes. The reaction was partitioned between EtOAc (25 mL) and water (25 mL). The organic phase was separated, washed with water (25 mL), brine (3 x 25 mL) and dried (MgSO 4 ), filtered and concentrated in vacuo. The crude material was purified by normal phase chromatography using an EtOAc:petroleum ether gradient (SiO 2 ). If necessary, this material was triturated with water for further purification.

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

[0678] [ka] 2-Amino-5-bromophenol (249 mg, 1.33 mmol, 1.2 eq.), DBU (0.18 mL, 1.22 mmol, 1.1 eq.), methyl 2-bromobutyrate (0.13 mL, 1.10 mmol, 1 eq.) in NMP (4 mL). equivalent) from normal phase chromatography (SiO 2 ), the title compound (235 mg, 0.918 mmol, 83%) was obtained as an orange solid. MS (ES-) m / z 254.0 / 256.0 (M-H), Br isotope pattern. 1 H NMR (300 MHz, DMSO-d 6 ) 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 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-d 6 ) 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 (M-H), Br isotope pattern. 1 H NMR (DMSO-d 6 ) 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 eq) in THF (10 mL) at 0°C was added NaHCO3 (670 mg, 7.98 mmol, 3 eq) and the mixture was stirred for 10 min. A solution of 2-bromo-3-methylbutanoyl chloride (530 mg, 2.66 mmol, 1 eq.) in THF (1 mL) was added dropwise and then stirred for 6 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 20 mL). The organic extracts were washed with brine and dried (MgSO 4 ), filtered and concentrated in vacuo. The crude amide was dissolved in DMF (5 mL) and the K 2 C.O. 3 (551 mg, 3.99 mmol, 1.5 eq.) was added and stirred at room temperature for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 20 mL). The organic extracts were washed with brine (3 x 50 mL) and dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was chromatographed (SiO 2 ) to give 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-d 6 ) 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 consisting of a primary alcohol (1-2 eq.), an aryl bromide (1 eq.), tBuBrettPhos Pd G3 (0.02-0.1 eq.) and NaOtBu (1-2 eq.) in 1,4-dioxane (0.1-0.2 M). was purged with nitrogen (×3) and then heated to 80° C. for 16-36 hours. If necessary, additional tBuBrettPhos Pd G3 (0.05 eq.) was added followed by primary alcohol (0.2 eq.) to complete the reaction. The mixture was cooled and filtered through a pad of Celite, washing with EtOAc. The organic phase is washed with water, brine and filtered through a hydrophobic frit or with MgSO 4 and concentrated in vacuo. The crude material was purified by normal phase chromatography using an EtOAc:petroleum ether gradient (SiO 2 ), and / or MeCN:H 2 Reversed phase chromatography using a gradient of O (C 18 ) and / or by preparative HPLC-MS using a gradient of high pH 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] 2-[2-(3-fluorophenyl)pyrrolidin-1-yl]ethanol (0.25 g, 1.20 mmol, 2 eq.) in 1,4-dioxane (2.9 mL), 6-bromo-3-methyl-3, 4-dihydro-1H-quinolin-2-one (100 mg, 0.416 mmol, 1 eq.), tBuBrettPhos Pd G3 (36 mg, 0.0416 mmol, 0.100 eq.) and NaOtBu (48 mg, 0.500 mmol, 1.2 eq.) as described in Method G Prepared as described, with 5–95% MeCN:H as eluent. 2 Reversed phase chromatography using O (C 18 ), the title compound (8 mg, 0.0217 mmol, 5.2%) was obtained as a white powder. MS (ES+) m / z 369.2 (M+H). 1 H NMR (300 MHz, DMSO-d 6 ) 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). 1 H NMR (300 MHz, DMSO-d 6 ) 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). 1 H NMR (300 MHz, DMSO-d 6 ) 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) 1 H NMR (300 MHz, CDCl 3 ) 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). 1 H NMR (300 MHz, DMSO-d 6 ) 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). 1 H NMR (300 MHz, DMSO-d 6 ) 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) 1 H NMR (300 MHz, DMSO-d 6 ) 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 7a-phenyl-2,3,6,7-tetrahydropyrrolo[2,1-b]oxazol-5-one (758 mg, 3.73 mmol, 1 eq.) (Trapani et al., Journal of Pharmacy and Pharmacology, 1996, 48 , pp. 834-840) and triethylsilane (1.8 mL, 11.2 mmol, 3 eq.) in DCM (40 mL) under nitrogen at -78 °C. 1M in toluene, 7.5 mL, 7.46 mmol, 2 eq.) was added. The mixture was warmed to room temperature overnight, then cooled to 0°C. aqueous saturated NH 4 Cl (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 (SiO 2 ) to give 1-(2-hydroxyethyl)-5-phenyl-pyrrolidin-2-one (578 mg, 2.82 mmol, 76%) as an oil, which solidified to a white solid. MS (ES+) m / z 206.1 (M+H). 1 H NMR (300 MHz, DMSO-d 6 ) 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 1-(2-hydroxyethyl)-5-phenyl-pyrrolidin-2-one (200 mg, 0.974 mmol, 1 eq.), 6-bromo-1,2,3,4- in 1,4-dioxane (10 mL) Prepared as described in Method G from tetrahydro-2-quinolinone (220 mg, 0.974 mmol, 1 eq.), tBuBrettPhos Pd G3 (83 mg, 0.0974 mmol, 0.1 eq.) and NaOtBu (187 mg, 1.95 mmol, 2 eq.) and 5~95% MeCN:H as eluent. 2 Reversed phase chromatography using O (C 18 ), and after subsequent purification by preparative HPLC-MS (high pH), the title compound (40 mg, 0.114 mmol, 12%) was obtained as a white powder. Additional tBuBrettPhos Pd G3 (42 mg, 0.0487 mmol, 0.05 eq.) was added after 16 h, followed by 1-(2-hydroxyethyl)-5-phenyl-pyrrolidin-2-one (40 mg, 0.195 mmol, 0.2 eq.), and 80 Stirring was completed for an additional 16 hours at °C. MS (ES+) mz 351.3 (M+H). 1 H NMR (300 MHz, DMSO-d 6 ) 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 eq.) in DCM (10 mL) at 0 °C under nitrogen was added DIPEA (1.6 mL, 9.46 mmol, 1.5 eq.) followed by 2-(methylamino)ethanol ( 0.76mL, 9.46mmol, 1.5eq) was added. The mixture was stirred at room temperature for 19 hours, then quenched with water (10 mL) and the phases were separated. The organic phase was washed with aqueous HCl (1 M, 10 mL), brine (10 mL), filtered through a hydrophobic frit, concentrated in vacuo, and purified with 3-fluoro-N-(2-hydroxyethyl)-N-methyl- Benzamide (1.04g, 5.27mmol, 84%) was obtained as a colorless oil. Used directly in next step. MS (ES+) m / z 198.1 (M+H). 1 H NMR (300 MHz, CDCl 3 ) 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 3-Fluoro-N-(2-hydroxyethyl)-N-methyl-benzamide (1.01 g, 5.12 mmol, 1 eq), 6-bromo-1,2,3,4 in 1,4-dioxane (25 mL) -tetrahydro-2-quinolinone (1.16 g, 5.12 mmol, 1 eq.), NaOtBu (591 mg, 6.15 mmol, 1.2 eq.) and tBuBrettPhos Pd G3 (438 mg, 0.512 mmol, 0.1 eq.) as described in Method G. normal phase chromatography (SiO2 ), and then 5-95% MeCN:H as eluent. 2 Reversed phase chromatography using O (C 18 ), the title compound (288 mg, 0.842 mmol, 16%) was obtained as a white powder. MS (ES+) m / z 343.0 (M+H). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) 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 eq.) and HATU (1.75 g, 2.83 mmol, 1.2 eq.) in DMF (5 mL) (anhydrous) was added DIPEA (0.82 mL, 4.71 mmol, 2 eq.). . The mixture was stirred for 0.25 h, then N-[2-(tert-butyldimethylsilyloxy)ethyl]methylamine (491 mg, 2.59 mmol, 1.1 eq.) was added and stirring was continued for 24 h at room temperature. . Water (20 mL) was added and the mixture was extracted with EtOAc (2 x 10 mL). The combined extracts were washed with brine (25 mL) and dried (MgSO 4 ), filtered and concentrated in vacuo. The obtained residue was purified with 5-95% MeCN:H as eluent. 2 Chromatography using O (C 18 ) and the fractions containing the product were combined and extracted with DCM (2 x 100 mL). The organic extract was 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, CDCl 3 ) 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 N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-N-methyl-pyridine-3-carboxamide (532 mg, 1.81 mmol, 1 eq.) in THF (5 mL) was added to TBAF (in THF) under nitrogen. 1M, 1.9mL, 1.90mmol, 1.05eq) was added. The mixture was stirred at room temperature for 1 h, then saturated aqueous NaHCO 3 (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 with 5-95% MeCN:H as eluent. 2 Chromatography using O (C 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-d 6 ) 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 N-(2-hydroxyethyl)-N-methyl-pyridine-3-carboxamide (136 mg, 0.755 mmol, 1 eq.), 6-bromo-1,2,3,4- in 1,4-dioxane (5 mL). Prepared as described in Method G from tetrahydro-2-quinolinone (171 mg, 0.755 mmol, 1 eq.), tBuBrettPhos Pd G3 (64 mg, 0.0755 mmol, 0.1 eq.) and NaOtBu (87 mg, 0.906 mmol, 1.2 eq.) and 5~95% MeCN:H as eluent. 2 Reversed phase chromatography using O (C 18 ), and after subsequent purification by preparative HPLC-MS (low pH), the title compound (28 mg, 0.0861 mmol, 11%) was obtained as a yellow powder. MS (ES+) m / z 326.1 (M+H). 1 H NMR (300 MHz, DMSO-d 6 ) 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 = 7.5 Hz, 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 eq.) in DCM (60 mL) was added pTSA (291 mg, 1.53 mmol, 0.2 eq.) followed by NBS ( 1.70g, 9.57mmol, 1.25eq) was added. This mixture was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the resulting residue was dissolved in Et 2 Dissolve in O (25 mL), filter the precipitate, and 2 Washed with O (2 x 25 mL). Saturate the filtrate with aqueous NaHCO 3 (25 mL) and water (25 mL), filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was chromatographed (SiO 2 ) 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 (M-H), Br isotope pattern. 1 H NMR (300 MHz, CDCl 3 ) 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, CDCl 3) 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-oxo-propanoate (1.90 g, 6.57 mmol, 1 eq.) in EtOH (50 mL) was added thiourea (600 mg, 7.89 mmol, 1.2 eq.). . This mixture was refluxed for 2 hours. The solution was cooled and concentrated in vacuo, and the resulting residue was dissolved in DCM (20 mL) and saturated aqueous NaHCO 3 (20 mL). The aqueous layer was extracted with DCM (20 mL) and the organic extracts were combined and concentrated in vacuo. Minimum amount of solid Et 2 Stir in O, filter, and Et 2 Ethyl 2-amino-4-(3-fluorophenyl)thiazole-5-carboxylate (1.43 g, 5.37 mmol, 82%) was washed with pale yellow O (2 x 20 mL) and petroleum ether (2 x 20 mL). Obtained as a powder. MS (ES+) m / z 267.0 (M+H). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) δ -114.52.

[0721] Step 3: Ethyl 2-bromo-4-(3-fluorophenyl)thiazole-5-carboxylate Ethyl 2-amino-4-(3-fluorophenyl)thiazole-5-carboxylate (1.40 g, 5.26 mmol, 1 eq.) and copper(I) bromide (905 mg, 6.31 mmol, 1.2 eq.) in MeCN (50 mL) ) was added t-butyl nitrite (0.94 mL, 7.89 mmol, 1.5 eq.) under nitrogen. The mixture was heated to 60° C. for 1 h, then cooled and filtered through Celite, washed with MeCN (4×25 mL) and concentrated in vacuo. The residue was purified with DCM (50 mL) and saturated aqueous NaHCO. 3 (50 mL) and the phases were separated. The aqueous layer was washed with DCM (2 x 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 (SiO 2 ) to obtain 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-d 6 ) 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-d 6 ) 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 eq.) in 0.05 M EtOH (14 mL) was passed through a 10% Pd / C H cube cartridge (1 mL / min, 80℃, 40bar). The solvent was removed in vacuo and the resulting residue was chromatographed (SiO 2 ) 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-d 6 ) 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-d 6 ) δ -113.99.

[0724] General method H: Preparation of carboxylic acids

[0725] [ka] A mixture of ethyl carboxylate (1 eq.) and lithium hydroxide monohydrate (2 eq.) or sodium hydroxide (1 eq.) 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 (2M), diluted with water and the precipitate was filtered, washed with water (2 x 25 mL) and washed in vacuo for 50 min. Drying at °C yielded the desired compound.

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

[0727] [ka] Ethyl 2-bromo-4-(3-fluorophenyl)thiazole-5-carboxylate (1.18 g, 3.57 mmol, 1 eq) and lithium hydroxide monohydrate (307 mg) in water (4 mL) and THF (20 mL) , 7.15 mmol, 2 eq.) as described in Method H to give 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-d 6 ) 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-d 6 ) 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-d 6 ) 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 { 1 H} NMR (282 MHz, DMSO-d 6 ) δ -114.02.

[0731] General method I: Preparation of amides DIPEA (2 eq.) to a mixture consisting of carboxylic acid (1 eq.), 6-amino-3,4-dihydroquinolin-2(1H)-one (1 eq.) and HATU (1.1 eq.) in DMF (0.2 M) added. The mixture was stirred at room temperature for 2 hours, then quenched with brine and stirred for 0.25 hours. The resulting precipitate was filtered, washed with water and dried in vacuo at 50°C. The crude material was purified by normal phase chromatography using an EtOAc:petroleum ether gradient (SiO 2 ), or MeCN:H 2 Reversed phase chromatography using a gradient of O (C 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] 2-Bromo-4-(3-fluorophenyl)thiazole-5-carboxylic acid (1.04 g, 3.44 mmol, 1 eq) in DMF (20 mL), 6-amino-3,4-dihydroquinoline-2(1H) -one (558 mg, 3.44 mmol, 1 eq), HATU (1.44 g, 3.79 mmol, 1.1 eq) and DIPEA (1.2 mL, 6.88 mmol, 2 eq) as described in Method I and eluted. Normal phase chromatography (SiO 2 ), the title compound (730 mg, 1.64 mmol, 48%) was obtained as a pale orange powder. MS (ES+) m / z 445.8 / 447.8 (M+H), Br isotope pattern. 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) δ -112.68.

[0734] The following example compounds were similarly prepared using Method I using the appropriate carboxylic acids.

[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-d 6 ) 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-d 6 ) 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, CDCl 3 ) 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-d 6 ) 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= 7.5 Hz, 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] 2-bromo-4-(3-fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)thiazole-5-carboxamide (1) in MeCN (0.02~0.04M) equivalent), substituted amine (2 equivalent) and Cs 2 C.O. 3 (3 equivalents) or K 2 C.O. 3 (3 equivalents) was heated to reflux for 1 to 3 days. If necessary, additional substituted amine and base were added to drive the reaction to completion. The mixture was cooled and then water was added followed by DCM. At this stage, if precipitation occurred, 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 organic extracts were combined, washed with brine, filtered through a hydrophobic frit, and concentrated in vacuo. The crude material was purified with MeOH:DCM (optionally 1% aqueous NH 3 normal phase chromatography using a gradient of SiO 2 ), or preparative HPLC-MS using a gradient of high pH or low pH aqueous MeCN, or if necessary, Et 2 Purified by trituration with O or petroleum ether.

[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] 2-bromo-4-(3-fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)thiazole-5-carboxamide (40 mg, 0.0896) in MeCN (2.5 mL) mmol, 1 eq), 3-hydroxyazetidine hydrochloride (20 mg, 0.179 mmol, 2 eq) and Cs 2 C.O. 3 (88 mg, 0.269 mmol, 3 eq.) as described in Method J and after preparative HPLC-MS (high pH) gave the title compound (16 mg, 0.0358 mmol, 40%) as a pale yellow powder. Obtained. MS (ES+) m / z 439.0 (M+H). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) δ -113.61.

[0745] The following example compounds were similarly prepared using Method J using 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-d 6) 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-d 6 ) 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-d 6 ) 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-d 6 ) 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] 2-bromo-4-(3-fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)thiazole-5-carboxamide (49 mg, 0.110 in MeCN (2.5 mL)) mmol, 1 equivalent), Cs 2 C.O. 3 (108 mg, 0.329 mmol, 3 eq.) and 1-t-Boc-piperazine (41 mg, 0.220 mmol, 2 eq.) was refluxed for 5 days. The mixture was cooled and water (10 mL) was added followed by DCM (10 mL) and the resulting mixture was stirred for 0.5 h. 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 solid was eluted with 0~5% MeOH:DCM (+1% aqueous NH 3 ) using chromatography (SiO 2 ) to obtain the t-Boc protected intermediate (31 mg) as a brown powder. MS(ES+)m / z 552.3(M+H). This residue was dissolved in DCM (2 mL) and trifluoroacetic acid (0.50 mL, 6.49 mmol, 59.1 eq.) was added. The mixture was stirred for 1.5 h, concentrated in vacuo, and the resulting solid was purified with Et 2 Trituration with O and then purification by preparative HPLC-MS (low pH) gave the title compound (8 mg, 0.0177 mmol, 16%) as a yellow powder. MS (ES+) m / z 452.0 (M+H). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) δ -113.60.

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

[0753] [ka] In a solution of (1Z)-3-fluoro-N-hydroxy-benzimidoyl chloride (90 mg, 0.519 mmol, 1.00 eq.) and methyl 3-oxobutanoate (120 mg, 1.04 mmol, 2.00 eq.) in methanol (6.6724 mL), - Sodium methoxide (25% in methanol, 0.36 mL, 1.56 mmol, 3.00 eq) was added at 10°C. The reaction mixture was warmed to room temperature over 2 hours 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 using silica (SiO) using a 0-10% gradient of ethyl acetate in petroleum ether. 2 ) Purification by gel column chromatography gave 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). 1 H NMR (300, CDCl 3 ) 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 eq.) in EtOH (20 mL) was added thioacetamide (349 mg, 4.65 mmol, 1.2 eq.). Ta. The mixture was refluxed for 3 hours, then cooled and concentrated in vacuo. The resulting residue was dissolved in DCM (30 mL) and saturated aqueous NaHCO 3 (30 mL). The organic layer was filtered through a hydrophobic frit and concentrated in vacuo. The crude mixture was subjected to flash chromatography (SiO 2 ) to give a residue, which 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-ketoester To a solution of appropriately substituted phenyl 3-oxo-propionic acid ethyl ester (1 eq.) in DCM (0.13 M) was added pTSA (0.2 eq.) and NBS (1.25 eq.). The mixture was stirred at room temperature for 20 hours and then evaporated to dryness. The resulting residue was Et 2 Dissolve the precipitate in EtO and filter the precipitate. 2 Washed with O. Saturate the filtrate with aqueous NaHCO 3 and water, filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was chromatographed (SiO 2 ) to give appropriately substituted phenylethyl 2-bromo-3-oxo-propanoate.

[0759] Step 2: Formation of thiazole ring To a solution of appropriately substituted phenylethyl 2-bromo-3-oxo-propanoate (1 eq.) in EtOH (0.13 M) was added thiourea (1.2 eq.). The mixture was refluxed for 2 hours, then cooled and concentrated in vacuo. The resulting residue was dissolved in DCM and saturated aqueous NaHCO 3 Washed with The aqueous layer was extracted with DCM and the organic extracts were combined and concentrated in vacuo. The resulting solid is treated with a minimum amount of Et 2 Stir in O, filter, and Et 2 Washing with O and petroleum ether gave appropriately substituted phenylethyl 2-amino-thiazole-5-carboxylate.

[0760] Step 3: Conversion of amine to bromine substituent A mixture of appropriately substituted phenylethyl 2-amino-thiazole-5-carboxylate (1 eq.) and copper(I) bromide (1.2 eq.) in MeCN (0.1 M) was added with nitrous acid under nitrogen. t-Butyl (1.5 eq.) was added. The mixture was heated to 60° C. for 1-6 hours, then cooled and filtered through Celite, washed with MeCN and concentrated in vacuo. Saturate the residue with DCM and aqueous NaHCO 3 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 solid obtained can be used directly in the next step without further purification or chromatographed (SiO 2 ) to give appropriately substituted ethyl 2-bromo-thiazole-5-carboxylate.

[0761] Step 4: Conversion of bromine atom and hydrogen atom A solution of appropriately substituted ethyl 2-bromo-thiazole-5-carboxylate (225 mg, 1 eq.) 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 (SiO 2 ) to obtain the desired intermediate.

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

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

[0764] [ka] MS (ES+) m / z 268.1 (M+H). 1 H 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-d 6 ) 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] Pd(PPh 3 ) 4 (0.05 equivalent) and K 2 C.O. 3 (0.4M in water, 2.00 eq.) was added. The resulting mixture was degassed for 15 minutes, stirred at 85° C. for 2 hours, cooled to room temperature, then diluted with water, filtered and extracted with ethyl acetate. Combine the organic layers with anhydrous MgSO 4 , filtered and evaporated to dryness. The crude material was subjected to flash chromatography using a gradient of EtOAc in petroleum ether (SiO 2 ) to obtain the desired compound.

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

[0770] [ka] 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 (PPh) in DME (8 mL). 3 ) 4 (53 mg, 0.0455 mmol, 0.0500 equivalent) and K 2 C.O. 3 (0.4 M in water, 4.5 mL, 1.82 mmol, 2.00 eq.) as described in Method L to give the title compound, ethyl 4-(3-fluorophenyl)oxazole-5-carboxylate (48 mg, 0.196 mmol, 22%) was obtained as a yellow oil. MS (ES+) m / z 236.2 (M+H). 1 H NMR (DMSO-d 6 ) 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). 1 H NMR (DMSO-d 6 ) 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-d 6 ) 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-d 6 ) δ -114.52 ppm.

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

[0777] [ka] MS (ES+) m / z 251.2 (M+H). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) 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+NH 4 ). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) δ -110.53 ppm.

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

[0783] [ka] Pd(PPh 3 ) 4 (0.05 equivalent) and K 2 C.O. 3 (0.4M in water, 2.00 eq.) was added. The resulting mixture was degassed for 20 minutes, stirred at 110° C. for 24 hours, cooled to room temperature, then filtered through a pad of Celite and evaporated to dryness. The resulting residue was diluted with aqueous HCl 2M and extracted with diethyl ether. Combine the organic layers with anhydrous MgSO 4 , 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] 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 (PPh) in DME (9.5 mL). 3 ) 4 (61 mg, 0.05 mmol, 0.05 eq.) and potassium carbonate (0.4 M in water, 5.4 mL, 2.14 mmol, 2.00 eq.) as described in Method M to give a residue which was further purified. It was used in the next step without further treatment. 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] Ethyl 3-(3-fluorophenyl)-5-methyl-isoxazole-4-carboxylate (30 mg, 0.12 mmol, 1.00 eq) and sodium hydroxide (4.9 mg) in water (1.5 mL) and THF (3.7 mL) . %) was obtained as a colorless oil. MS (ES+) m / z 222.0 (M+H). 1 H NMR (300 MHz, CDCl 3 ) δ 7.57 - 7.35 (m, 3H), 7.27 - 7.10 (m, 1H), 2.77 (s, 3H) ppm. 19 F {1H} NMR (282 MHz, CDCl 3 ) 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-d 6 ) 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-d 6 ) 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. 19 F {1H} NMR (282 MHz, DMSO-d 6 ) 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-d 6 ) 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-d 6 ) 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-d 6 ) 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-d 6 ) δ -114.21 ppm.

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

[0811] [ka] MS (ES-) m / z 220.9 (M-H). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) 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-d 6 ) 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). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) 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-d 6 ) 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-d 6 ) 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 eq; commercially available intermediate), 6-amino-3, in DMF (1 mL), 4-dihydroquinolin-2(1H)-one (40 mg, 0.245 mmol, 1.00 eq.), N,N-diisopropylethylamine (0.085 mL, 0.490 mmol, 2.00 eq.) and 2-(7-aza-1H-benzotriazole- Prepared from preparative HPLC-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (102 mg, 0.269 mmol, 1.10 eq.) as described in Method I. After purification by MS (high pH), the title compound 2-(3-methyl-1,2,4-oxadiazol-5-yl)-N-(2-oxo-3,4-dihydro-1H-quinoline- 6-yl)benzamide (29 mg, 0.0821 mmol, 34%) was obtained as a yellow powder. MS (ES+) m / z 349.1 (M+H). 1 H NMR (300 MHz, DMSO-d 6 ) 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 example compounds were similarly prepared using Method I using the appropriate carboxylic acids.

[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, CDCl 3 ) 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, CDCl 3 ) δ -110.09 ppm.

[0823] Synthesis 116 N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-5-(3-pyridyl)thiazole-4-carboxamide (ALDHI-1010)

[0824] [ka] 1H NMR (300 MHz, DMSO-d 6 ) δ 10.29 (s, 1H), 10.03 (s, 1H), 9.30 (s, 1H), 8.76 (dd, J = 2.4, 0.9 Hz, 1H), 8.61 (dd, J = 4.8, 1.6 Hz, 1H) , 8.02 (ddd, J = 7.9, 2.4, 1.7 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.59 - 7.40 (m, 2H), 6.79 (d, J = 8.5 Hz, 1H), 2.84 (t, J = 7.6 Hz, 2H), 2.43 (dd, J = 8.5, 6.4 Hz, 2H) ppm.

[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-d 6 ) 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). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) 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). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) 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-d 6 ) 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-d 6 ) 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-d 6 ) 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-d 6 ) 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). 1 H NMR (300 MHz, CD 3 OD) 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, CD 3 OD) δ -114.36 (s) ppm.

[0839] Synthesis 124 4-(3-fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyrimidine-5-carboxamide (ALDHI-1018)

[0840] [ka] MS (ES+) m / z 363.3 (M+H). 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.59 (s, 1H), 10.07 (s, 1H), 9.38 (s, 1H), 9.04 (s, 1H), 7.64-7.51 (m, 3H), 7.45-7.33 (m, 2H), 7.30 ( dd, J= 8.5, 2.4 Hz, 1H), 6.81 (d, J= 8.5 Hz, 1H), 2.85 (dd, J= 8.6, 6.5 Hz, 2H), 2.47-2.39 (m, 2H) ppm. 19 F {1H} NMR (282 MHz, DMSO-d 6 ) δ -112.61 ppm.

[0841] Synthesis 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-d 6 ) 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-d 6 ) 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). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) δ -113.43 ppm.

[0845] Synthesis 127 4-(2-fluorophenyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)thiazole-5-carboxamide (ALDHI-1021)

[0846] [ka] MS (ES+) m / z 368.3 (M+H). 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.24 (s, 1H), 10.07 (s, 1H), 9.31 (s, 1H), 7.77-7.66 (m, 1H), 7.51-7.38 (m, 2H), 7.36-7.20 (m, 3H), 6.78 (d, J= 8.5 Hz, 1H), 2.83 (t, J= 7.5 Hz, 2H), 2.43 (dd, J= 8.6, 6.5 Hz, 2H) ppm. 19 F {1H} NMR (282 MHz, DMSO-d 6 ) δ -114.47 ppm.

[0847] Synthesis 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-d 6 ) 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-d 6 ) 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). 1 H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) 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-d 6 ) 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). 1H NMR (300 MHz, DMSO-d 6 ) 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-d 6 ) 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-d 6 ) 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-d 6 ) 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 amplified from human cDNA by polymerase chain reaction (PCR) using standard molecular genetic techniques. into the multiple cloning site of commercially available (Novagen) E. coli expression vectors pET47b (ALDH1A1, EcoRI restriction sites; ALDH1A2, BamHI and EcoRI sites) or pET28a (ALDH1A3, NdeI and BamHI sites) using the technique did. Recombinant DNA products were sequence verified before being used for expression studies.

[0858] Expression: Expression constructs were transformed into E. coli strain Rosetta (DE3) (Merck) and individual colonies were used to incubate 10 mL of lysogens supplemented with 50 μg / mL and 34 μg / mL of kanamycin and chloramphenicol, respectively. Broth (LB) medium was inoculated. Cultures were grown to saturation overnight at 37°C and then used to subinoculate new 1 L LB medium cultures (added with antibiotics as before). Grow 1L cultures at 37°C and 200rpm for 1 day until the optical density at 600nm (OD600) reaches approximately 0.8, at which point the growth temperature is reduced to 18°C ​​and 1mM isopropyl β-d-1-thiogalactopyranoside (IPTG) was added to induce protein expression. Cultures were left under these conditions overnight (at least 16 hours) and harvested the next day by centrifugation (4000G, 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 and dissolved in Ni affinity buffer A (20mM HEPES pH7.5, 300mM NaCl, 20mM imidazole, 1mM Tris(2-carboxyethyl) containing protease inhibitors (cOmplete Ultra protease inhibitor, Roche). ) Phosphine (TCEP)) and dissolved by sonication. The lysate was clarified by centrifugation at 18,000 G for 40 min at 4°C and loaded onto a pre-equilibrated (buffer A) 5 mL HisTrap Fast Flow column (GE Healthcare) using AKTA fast protein liquid chromatography (FPLC). Loaded directly via the system. 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 , 300mM NaCl, 500mM imidazole, 1mM TCEP), and finally 8CV with a linear gradient of buffer B from 10 to 70% to elute the recombinant His-tagged protein. Relevant fractions collected during elution (measured by absorbance at 280 nm) were pooled and subjected to size exclusion chromatography (Superdex200 26 / 600, GE Healthcare, running buffer 20 mM 2-(carbamoylmethylamino)ethanesulfonic acid (ACES)). Further purification was performed by pH 7.5, 1mM TCEP). Relevant fractions from this step were pooled, aliquoted, and stored at -80°C until needed 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 through coupled enzymatic conversion of a proluciferin reductase substrate that generates a luminescent signal. Inhibition of ALDH1A3 by small molecule inhibitors results in a reduction or abolition 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, and a 10-point curve was obtained in a 3-fold dilution series. Compounds were aliquoted from a 20 mM DMSO stock solution and initially screened at a maximum concentration of 20 μM (ALDH1A3) or 250 μM (ALDH1A1, ALDH1A2 and ALDH2). To this plate, enzyme was added in a volume of 5 μL according to the final concentration in Table 1 below, and after pre-incubation with the compound for 30 minutes at room temperature, 5 μL of substrate (propionaldehyde) and cofactor (NAD) were added; The final concentration was made equal to the Km shown in Table 1. The assay buffer used was 40mM Tris for 1A1 (pH 7.6), 1A2 (pH 7.6) and 1A3 (pH 9.0), and 10mM Tris for ALDH2 (pH 8.0). was supplemented with 1mM TCEP, 0.01% Tween-20, 0.1mM EDTA. After incubating the reaction mix for 30 min at 26 °C in a shaking incubator, add 10 µL of Promega detection reagent and individual isoform inhibitors to 100x IC. 50 It was stopped by adding After stopping the reaction, the plate was incubated at room temperature for 60 minutes, and the luminescent signal was read on a PheraStar FS microplate reader (BMG Labtech), and the obtained IC 50 Values ​​were calculated using Dotmatics software.

[0863] [Table 12]

[0864] Enzyme, substrate and cofactor concentrations 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 Hoechst33342 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, non-toxic substrate for the ALDH enzyme, which diffuses freely into intact and viable cells. In the presence of ALDH enzyme activity, BAAA is converted to BODIPY-aminoacetate (BAA), which is retained within the cell. The amount of fluorescent reaction product is proportional to ALDH activity in the cells and is measured using an imaging cytometer. Active efflux of reaction products 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, and therefore evaluation of inhibitors in this cell line is important for cellular ALDH1A3 activity. Configure the assay. Cryovials of cells were collected into T225 flasks containing DMEM, high glucose, 10% FBS, 1% glutamax, 1% HEPES. The next day, the medium was changed and cells were ready for assay after 72 hours of harvest. Transfer cells to FluoroBrite DMEM (and 10% FBS, 1% glutamax and 1% HEPES) and add 2.5x10 5 Diluted to cells / mL. Add 30 μL of cells to each well to obtain 7500 cells / well, then incubate at 37 °C, 5% CO 2 and incubated overnight. After overnight incubation, the medium was aspirated and replaced by 20 μL substrate / Hoechst buffer solution. Each plate requires 9 mL of solution containing 9 mL of ALDEFLUOR assay buffer, 18 μL of BAAA substrate (final concentration of 500 nM), 4.5 μL of Hoechst 33342 (final concentration of 5 μg / mL) and 4.5 μL of verapamil (final concentration of 50 μM). shall be. Compounds are prepared for administration using an Echo acoustic dispenser by aliquoting into the source plate and directly into the cell assay plate, with a final dilution from 10 μM to 0.0005 μM in 3-fold dilution steps. A 10-point dose response per compound was obtained for a range of concentrations. Next, store the plate at 37°C, 5% CO 2 and incubated for 60 minutes. The buffer was then aspirated and cells were washed twice in ice-cold PBS. 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, which was used to demarcate the intranuclear and then surrounding cellular regions. Fluorescence in the 488 nm channel of defined cell areas indicates ALDH1A3 activity. The percentage of cells positive for ALDH activity was plotted against compound concentration and EC50 values ​​were generated using defined curve fitting parameters 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 ) are summarized in the table below.

[0869] [Table 13] TIFF2023552469000210.tif255140TIFF2023552469000211.tif142148

[0870] In vivo pharmacokinetics (PK) All procedures involving animals are subject to the UK Home Office Regulations under the Animals (Scientific Procedures) Act 1986 and the Institutional Animal Ethics Committee and the UK Cancer Research Coordination for the Welfare of Animals in Oncology Experiments. The study was carried out in compliance with the guidelines set by 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 treated either orally by gavage (5 mg / kg in DMSO:water 1:19v:v, n=6) or intravenously in the tail vein (DMSO:Tween20:saline 10:1:89v:v:v). medium, 1 mg / kg, n=6). Blood samples (approx. 20 μL) was collected. For clarity, group 1 had blood drawn at 5 minutes, 30 minutes, 2 hours and 6 hours, and group 2 had blood drawn at 15 minutes, 1 hour, 4 hours and 8 hours. Plasma samples were quickly frozen in liquid nitrogen and then stored at -80°C prior to analysis.

[0871] Test compound solutions (1 mg / mL in DMSO) were used to generate stock solution standard curve (SC) and quality control (QC) solutions at appropriate concentrations. Blank plasma was spiked with stock solution to generate a 9-point standard curve ranging from 1.5 to 10,000ug / mL. The 2QC concentration was within this range and the DMSO concentration was 10% of plasma volume. Plasma PK samples, standards and QC were added to individual Eppendorf tubes, and DMSO (10% of plasma volume) was added to the plasma PK samples. SC, QC and plasma samples were extracted with methanol (100 μL) containing internal standards. After protein precipitation, the samples were centrifuged for 10 minutes at 14000 rpm in a refrigerated centrifuge (4°C). The supernatant was removed to a 96-well plate and centrifuged for an additional 10 minutes at 3700 rpm in a refrigerated centrifuge (4°C). The plasma concentration of the sample compound was analyzed by liquid chromatography mass spectrometry (LC-MS / MS). Non-compartmental analysis was performed on plasma concentration data using Excel macro PK Solver 2.0.

[0872] Pharmacokinetic data are summarized in the table below.

[0873] [Table 14]

[0874] The foregoing describes the principles, preferred embodiments, and modes of operation of the invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the embodiments described above should be viewed as illustrative rather than limiting. It should be understood that modifications may be made to these embodiments by those skilled in the art without departing from the scope of the invention.

[0875] References Publications are cited herein 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 this disclosure to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference. It is. 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. 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Claims

1. A compound of the formula: 【Chemistry 1】 or a pharma- ceutically acceptable salt or solvate thereof: [In the formula, -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; AA , -OH and -OR AA and optionally substituted with one or more substituents selected from -M 1 teeth, 【Chemistry 3】 (In the formula, -R M1a and -R M1e each independently represents -H or -R M1-オルト and -R M1b and -R M1d each independently represents -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 to ring A by a bond between a ring carbon atom of 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; 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 -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 each independently represents -H or -R QQ and -R Q2 each independently represents -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 each 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 each 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 each 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, With the proviso that the compound is not one of the following formulas or a pharma- ceutically acceptable salt or solvate thereof: 【Table 1】 With the proviso that the compound is not one of the following formulas or a pharma- ceutically acceptable salt or solvate thereof: 【Table 2】 With the proviso that the compound is not one of the following formulas or a pharma- ceutically acceptable salt or solvate thereof: 【Table 3】 【change】 With the proviso that the compound is not one of the following formulas or a pharma- ceutically acceptable salt or solvate thereof: 【Table 4】 The compound described above, or a pharma- ceutically 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 is -R 33 , which is independently -R, -F or -Cl; and -R4 is -H; 3. A compound according to claim 1 or 2.

4. Ring A is C 5 Heteroaryl groups, each of which may be one or more substituents -R A 4. The compound according to claim 1, optionally substituted by:

5. Ring A is thiazolyl and the substituent -R A and optionally substituted by Optionally, the thiazolyl is of the formula: where (*) represents the point of attachment to -M 1 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 -RAAN, -R AA is, independently, -Me or -Et; and each -RAAN is independently azetidino, pyrrolidino, piperidino, piperazino, or morpholino, optionally substituted with one or more substituents selected from -RAA, -OH, and -ORAA; 6. A compound according to any one of claims 1 to 5.

7. -M 1 but, 【Chemistry 5】 7. The compound according to 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, 【Chemistry 6】 7. The compound according to any one of claims 1 to 6, wherein

10. -M 1 But, C 5 Heteroaryl groups, each of which may be one or more substituents -R M1 or -M 1 is thienyl, optionally substituted by one or more substituents -R M1 ; -R M1 is independently -R M11 , -F, -Cl, -Br or -I; and -R M11 is 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 pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 7】 【change】 【change】 【change】 2. The compound of claim 1,

12. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and a pharma- ceutically 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. A method for treating a proliferative disorder comprising: Preferably, 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; and Optionally, the 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) is characterized as an immunotherapy-resistant cancer; or (v) is characterized as an immunotherapy-resistant cancer characterized by the presence or increased abundance of regulatory T cells; method; (2) Methods for treating obesity or complications of obesity, including type II diabetes; (3) a method for the treatment of 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

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