Heterocyclic compounds and uses thereof

Abstract

Heterocyclic compounds and uses thereof are provided. Provided herein are novel heterocyclic compounds, e.g., compounds having Formula I, IP, II, II-P, or III. Also provided herein are pharmaceutical compositions containing the compounds and methods of using the same, e.g., in inhibiting aldehyde dehydrogenase and / or for treating various cancers, cancer metastasis, type 2 diabetes, pulmonary arterial hypertension (PAH), or neointimal hyperplasia (NIH). JPEG2026042873000228.jpg5685

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 965,371, filed January 24, 2020, and U.S. Provisional Patent Application No. 63 / 094,741, filed October 21, 2020, the contents of each of which are incorporated herein by reference in their entirety.

[0002] In various embodiments, the present disclosure relates generally to novel heterocyclic compounds, pharmaceutical compositions, and methods of using them, such as for the inhibition of aldehyde dehydrogenase, the treatment of various cancers, cancer metastasis, metabolic diseases such as type 2 diabetes, pulmonary arterial hypertension (PAH), or neointimal hyperplasia (NIH). [Background technology]

[0003] Aldehyde dehydrogenases (ALDHs) belong to a superfamily of NAD(P+)-dependent enzymes that play a role in aldehyde metabolism by irreversibly catalyzing the oxidation of both endogenously and exogenously produced aldehydes to their respective carboxylic acids. ALDHs have a wide range of biological activities, including retinoic acid (RA) biosynthesis, lipid peroxide oxidation, and alcohol metabolism.

[0004] The ALDH enzyme family contains 19 members with diverse functions. Enzymes within this family irreversibly catalyze the oxidation of aldehydes to the corresponding carboxylic acids, reducing NAD+ / NADP+ to NADH / NADPH. These enzymes are found in several cellular compartments, but most are localized in the cytoplasm or mitochondria. Summary of the Invention [Means for solving the problem]

[0005] Several ALDH enzymes participate in global metabolism through expression in the liver, where they function to detoxify acetylaldehyde formed from alcohol dehydrogenase, biosynthesize vitamin A from retinal stereoisomers, or detoxify other reactive aldehydes. In contrast, most ALDH enzymes are expressed in a cell- or disease-specific manner and are regulated by cellular biochemistry, often with unknown mechanisms of action.

[0006] The present disclosure is based, in part, on the discovery that aldehyde dehydrogenase (Aldh, ALDH), particularly ALDH isoform 1a3 (ALDH1a3), is involved in various diseases or disorders, such as proliferative diseases or disorders, metabolic diseases or disorders, endothelial cell or smooth muscle cell diseases or disorders, cancer and metastasis. The present disclosure further demonstrates that inhibition of ALDH enzymes, such as ALDH1a3, may be useful for treating or preventing various cancers, cancer metastasis, and other ALDH1a3-mediated diseases and disorders, such as metabolic diseases, such as type 2 diabetes, pulmonary arterial hypertension (PAH), and neointimal hyperplasia (NIH). See also PCT / US2019 / 044278, filed July 31, 2019, the contents of which are incorporated by reference in their entirety.

[0007] Thus, in various embodiments, the present disclosure provides novel compounds and pharmaceutical compositions useful for inhibiting aldehyde dehydrogenase (Aldh, ALDH), particularly ALDH isoform 1a3 (ALDH1a3). In some embodiments, the present disclosure also provides novel compounds and pharmaceutical compositions useful for treating various diseases or disorders, such as various cancers, cancer metastasis, metabolic diseases, such as type 2 diabetes, pulmonary arterial hypertension (PAH), and neointimal hyperplasia (NIH). Also provided herein are methods of using the novel compounds and pharmaceutical compositions.

[0008] Some embodiments of the disclosure provide a compound of formula I, IP, II, II-P, or III, or a pharmaceutically acceptable salt thereof: [ka] wherein the variables are defined herein. In some embodiments, a compound of Formula I may be characterized by having a subformula of Formula I defined herein, such as Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C. In some embodiments, a compound of Formula II may be characterized by having a subformula of Formula II defined herein, such as Formula II-1, II-2, II-3, or II-4. In some embodiments, a compound of Formula III may be characterized by having a subformula of Formula III defined herein, such as Formula III-1, III-2, or III-3. In some embodiments, the present disclosure also provides specific compounds, Compound Nos. 1-138, or pharmaceutically acceptable salts thereof.

[0009] Certain embodiments of the present disclosure are directed to pharmaceutical compositions comprising a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formulas IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), Formula IP, Formula II (e.g., Formula II-1, II-2, II-3, or II-4), Formula II-P, Formula III (e.g., Formula III-1 or III-2), or Compound Nos. 1-138, or a pharmaceutically acceptable salt thereof), and optionally a pharmaceutically acceptable excipient. The pharmaceutical compositions described herein can be formulated for different routes of administration, such as oral administration, parenteral administration, or inhalation. It can be formulated into a pharmaceutical preparation.

[0010] Some embodiments of the present disclosure are directed to methods of inhibiting aldehyde dehydrogenase, particularly ALDH1a3, in a subject in need thereof.

[0011] In some embodiments, the present disclosure provides a method for treating or preventing an aldehyde dehydrogenase-associated disease or disorder, preferably an aldehyde dehydrogenase isoform 1a3 (ALDH1a3)-associated disease or disorder, in a subject in need thereof. In some embodiments, the disease or disorder is a proliferative disease (e.g., as described herein), such as cancer, associated with aldehyde dehydrogenase isoform 1a3 (ALDH1a3). In some embodiments, the disease or disorder is a metabolic disease, such as type 2 diabetes, associated with aldehyde dehydrogenase isoform 1a3 (ALDH1a3). In some embodiments, the disease or disorder is an endothelial cell or smooth muscle cell disease or disorder, such as pulmonary arterial hypertension or neointimal hyperplasia, associated with aldehyde dehydrogenase isoform 1a3 (ALDH1a3).

[0012] In some embodiments, the present disclosure provides a method for treating cancer in a subject in need of cancer treatment. In some embodiments, the cancer is associated with ALDH1a3 activity, e.g., having cancer cells with a high expression level compared to a control, and / or having cancer cells with ALDH1a3 activity, e.g., positive in an Aldefluor™ assay, which can be reduced with an ALDH1a3 inhibitor or gene knockout or knockdown. In some embodiments, the cancer is a solid cancer. In some embodiments, the cancer is a metastatic cancer or chemotherapy-resistant cancer. In some embodiments, the cancer may be breast cancer, colorectal cancer, kidney cancer, ovarian cancer, gastric cancer, thyroid cancer, testicular cancer, cervical cancer, nasopharyngeal cancer, esophageal cancer, bile duct cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, blood cancer, brain cancer, liver cancer, mesothelioma, melanoma, and / or sarcoma.

[0013] In some embodiments, the present disclosure provides a method for treating or preventing cancer metastasis in a subject in need thereof. In some embodiments, the cancer has already metastasized. In some embodiments, the cancer has not metastasized before treatment with the methods herein, and the methods delay or prevent cancer metastasis. In some embodiments, the cancer is associated with ALDH1a3 activity.

[0014] In some embodiments, the present disclosure provides methods of treating a metabolic disease, such as type 2 diabetes, in a subject in need thereof. In some embodiments, the present disclosure further provides methods of treating an endothelial cell or smooth muscle cell disease or disorder, such as pulmonary arterial hypertension or neointimal hyperplasia, in a subject in need thereof.

[0015] The methods described herein typically involve administering to a subject an effective amount of a compound of the disclosure (e.g., a compound of Formula I (e.g., Formulas IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), Formula IP, Formula II (e.g., Formula II-1, II-2, II-3, or II-4), Formula II-P, Formula III (e.g., Formula III-1 or III-2), or Compound Nos. 1-138, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition described herein. Administration is not limited to any particular route of administration. For example, in some embodiments, administration may be oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral. In some embodiments, the compounds of the present disclosure may be administered as the sole active ingredient(s). In some embodiments, the compounds of the present disclosure can be used in combination with additional therapies such as conventional surgery or radiation therapy, immunotherapy, cell therapy, therapeutic antibodies, or chemotherapy.

[0016] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention herein. [Brief explanation of the drawings]

[0017] [Figure 1A] Flow cytometry spectra showing that gene knockout of ALDH1a3 in MDA-MB-468 breast cancer cells (middle and rightmost spectra, two different ALDH1a3-targeting CRISPR gRNAs) substantially reduces ALDEFLUOR™ activity compared to control MDA-MB-468 cells (leftmost spectrum). [Figure 1B] FIG. 1 is a line graph of tumor volume (mm3) versus time (days) showing that gene knockout of ALDH1a3 (KO#1 and KO#2) in MDA-MB-468 breast cancer cells delays primary tumor growth and sensitizes tumors to paclitaxel (ptx) compared to control cells (Vec). [Figure 1C] Bar graph of tumor burden (g) versus ALDH1a3 gene knockout (KO#1 and KO#2) showing that gene knockout of ALDH1a3 in MDA-MB-468 breast cancer cells delays primary tumor growth compared to control (Vec) and sensitizes tumors to paclitaxel (ptx). [Figure 2A] Flow cytometry spectra showing that genetic knockout of ALDH1a3 in Sum159-M1a breast cancer cells nearly abolishes ALDEFLUOR™ activity in the cells, and ALDEFLUOR™ activity can be rescued by transducing the cells with a rescue vector encoding ALDH1a3 compared to an empty vector. [Figure 2B] FIG. 10 is a line graph of bone metastases measured by bioluminescence (ph / s) versus time (days), showing that knockout of ALDH1a3 in Sum159-M1a breast cancer cells slows the growth of bone metastases. [Figure 2C]Kaplan-Meier plot of bone metastasis-free survival over time, showing that knockout of ALDH1a3 in Sum159-M1a breast cancer cells significantly extends survival. Statistics from the Cox proportional hazards model. [Figure 3A] Line graph of bioluminescence (ph / s) versus time (days) showing the development of lung metastases in mice injected with SUM159-M1b cells transduced with vectors encoding three ALDH enzymes, ALDH1a1, ALDH1a3, and ALDH3a1, compared with the empty vector (Vector). [Figure 3B] Figure 3B is a plot of lung nodules counted ex vivo at the endpoint of the experiment described in Figure 3A. Two-tailed Student's t-test assuming unequal variances. [Figure 3C] Sample images of bioluminescence at day 1 (left) and endpoint (right) from the experiment described in Figures 3A and 3B are shown. [Figure 4A] Survival curves for patients stratified by high (red) and low (black) Aldh1a3 expression based on the data analysis tool hosted at kmplot.com, showing distant metastasis-free survival of breast cancer patients as a function of ALDH1a3 expression level. [Figure 4B] Patient survival curves stratified by high (red) and low (black) Aldh1a3 expression based on the data analysis tool hosted at kmplot.com, showing overall survival of patients with renal clear cell carcinoma as a function of ALDH1a3 expression level. [Figure 4C] Patient survival curves stratified by high (red) and low (black) Aldh1a3 expression based on the data analysis tool hosted at kmplot.com, showing overall survival of gastric cancer patients as a function of ALDH1a3 expression level. [Figure 4D] Patient survival curves stratified by high (red) and low (black) Aldh1a3 expression based on the data analysis tool hosted at kmplot.com, showing overall survival of bladder cancer patients as a function of ALDH1a3 expression level. [Figure 4E]Patient survival curves stratified by high (red) and low (black) Aldh1a3 expression based on the data analysis tool hosted at kmplot.com, showing overall survival of ovarian cancer patients as a function of ALDH1a3 expression level. [Figure 4F] Patient survival curves stratified by high (red) and low (black) Aldh1a3 expression based on the data analysis tool hosted at kmplot.com, showing overall survival of patients with lung squamous cell carcinoma as a function of ALDH1a3 expression level. [Figure 4G] Patient survival curves stratified by high (red) and low (blue) Aldh1a3 expression based on survival time series data and patient-level RNA expression data from The Cancer Genome Atlas, showing overall survival of colorectal cancer patients as a function of ALDH1a3 expression level. [Figure 4H] Patient survival curves stratified by high (red) and low (blue) Aldh1a3 expression based on survival time series data and patient-level RNA expression data from The Cancer Genome Atlas, showing overall survival of patients with low-grade glioma as a function of ALDH1a3 expression level. [Figure 5A] Graph of Aldh1a3 mRNA expression from the METABRIC clinical breast cancer dataset, showing Aldh1a3 expression by breast cancer subtype and chemotherapy history. Statistics by two-tailed Student's t-test. [Figure 5B] A set of survival curves based on the Erasmus Medical Center-Memorial Sloan-Kettering (EMC-MSK) dataset showing survival of breast cancer patients by subtype and stratification by median ALDH1a3 expression level. Statistics based on the Cox proportional hazards model. [Figure 6A]1 is a bar graph of the percentage of ALDEFLUOR™-positive cells in the presence of various compounds described herein, showing the percentage of SUM159-M1a-Aldh1a3 cells above background fluorescence levels as detected by flow cytometry after incubation using the standard ALDEFLUOR™ protocol described herein with a 100 nanomolar concentration of compound. Gating for background fluorescence was performed using 1 millimolar N,N-diethylaminobenzaldehyde (DEAB) as a negative control. [Figure 6B] 1 is a line graph of the percentage of ALDEFLUOR™-positive cells in the presence of various concentrations of MBE1 or MBE1.5, showing the percentage of SUM159-M1a-Aldh1a3 cells above background fluorescence levels as detected by flow cytometry after incubation according to the standard ALDEFLUOR™ protocol described herein in combination with increasing doses of MBE1 or MBE1-5. The [inh-min] threshold was set at the lower limit of two standard deviations of the control samples, while the IC50 threshold was set at 50% of the mean of the control samples. [Figure 6C] 1 is a graph of ALDEFLUOR™ activity in SUM159-M1a-Aldh1a3 cells versus the concentration of various inhibitors described herein, showing the ALDEFLUOR™ inhibitory activity of several compounds described herein at concentrations of 10 nM and 100 nM. [Figure 7A] 1 is a Western blot showing the expression of various ALDH isoforms, including 1a1, 1a2, 1a3, and 3a1, in MCF7 and SUM 159 cells. [Figure 7B] 1 is a line graph of the percentage of ALDEFLUOR™-positive MCF7 cells expressing the indicated ALDH isoforms versus the logarithm of MBE1.5 concentration, showing that MBE1.5 specifically inhibits ALDH1a3 at concentrations below 10 μM. [Figure 7C]1 is a line graph of the percentage of ALDEHLUOR™-positive SUM159 cells expressing the indicated ALDH isoforms versus the logarithm of MBE1.5 concentration, showing that MBE1.5 specifically inhibits ALDH1a3 at concentrations below 10 μM. [Figure 8] 1 is a bar graph of ALDEFLUOR™ activity in various cancer types in the presence of 1 mM DEAB (a pan-ALDH inhibitor) or 100 nM MBE1.5 (a specific ALDH1a3 inhibitor described herein), showing that the majority of human cancer cell lines exhibit Aldh1a3 activity. [Figure 9A] Diagram of the dosing strategy used to administer MBE1 and paclitaxel to mice injected with M1a-Aldh1a3 cells via tail vein i.v. Figure 1 shows the design of an in vivo experiment designed to test the efficacy of MBE1 in treating metastatic cancer. [Figure 9B] Line graph of lung metastases measured using bioluminescence imaging (BLI) versus time (days) comparing lung metastases in the presence and absence of MBE1 in mice from the experiment outlined in Figure 9A. Two-tailed Student's t-test assuming unequal variances. [Figure 10A] Diagram of the dosing strategy used to administer MBE1 and paclitaxel to mice injected with M1a-Aldh1a3 cells via intracardiac injection. Figure 1 shows the design of an in vivo experiment designed to test the efficacy of MBE1 in treating metastatic cancer. [Figure 10B] 10A is a line graph of bone metastasis measured using BLI versus time (days) comparing bone metastasis in the presence and absence of MBE1 in mice from the experiment outlined in FIG. 10A. One-tailed Student's t-test assuming unequal variances. [Figure 11A]Line graph of lung metastases measured by bioluminescence imaging (BLI) versus time (days) showing that three doses of 50 mg / kg MBE1.5 in combination with 25 mg / kg paclitaxel administered on days 17, 19, and 21 caused regression of established metastatic disease in a mouse xenograft model. Two-tailed Student's t-test assuming unequal variances. [Figure 11B] Images of all mice shown with equal exposure settings from the experiment described in Figure 11A are shown. [Figure 12A] 1 is a line graph of body weight (g) versus time (days) showing that there was no significant toxicity associated with MBE1.5 treatment in this study. [Figure 12B] Line graph of tumor volume (mm) versus time (days) showing that 12 days of treatment with MBE1.5, in combination with 4 doses of paclitaxel administered to both groups, caused regression of MDA-MB-468 primary breast tumors compared to vehicle. Statistics by Student's t-test. [Figure 12C] Images of primary tumors at the endpoint of the experiment described in Figure 12B are shown, with images missing for two tumors in the MBE1.5 group due to complete exclusion. [Figure 13A] Line graph of lung metastasis bioluminescence versus time (days) showing progression of lung metastases before and after treatment with MBE1.5 or vehicle. Statistics by Student's t-test. [Figure 13B] Kaplan-Meier plot of mouse survival over time as a function of treatment group, showing that 12 days of treatment with MBE1.5 extended survival in mice with late-stage, established breast cancer lung metastases. Statistics from a Cox proportional hazards model. [Figure 13C] Bioluminescence images of samples from each treatment group before and after treatment are shown. [Figure 14]14 is a line graph of colorectal metastasis bioluminescence versus time (days), showing the progression of colorectal metastasis after treatment with MBE1.5 or vehicle. Figure 14 shows that combination therapy with MBE1.5 and paclitaxel delays colorectal cancer metastasis. Statistics by Student's t-test. *p<0.05. [Figure 15] (FIG. 15A) Line graph of the pharmacokinetics of compound MBE1, showing that oral gavage (PO) and intravenous (IV) administration of compound MBE1 results in plasma concentrations greater than 5-fold the IC50 for >10 hours. Data points are the average of biological replicates, n=3 mice per group. (FIG. 15B) Line graph of the pharmacokinetics of compound MBE1.5, showing that oral gavage (PO) and intravenous (IV) administration of compound MBE1.5 results in plasma concentrations greater than 5-fold the IC50 for >10 hours. Data points are the average of biological replicates, n=3 mice per group. [Figure 16A] Bar graph showing LC-MS quantification of the medium-chain fatty acid aldehyde adipic acid semialdehyde in HEK293T cells treated with vehicle control or compound MBE1.5 (10 μM) for 1 hour, demonstrating that inhibition of Aldh1a3 leads to the accumulation of medium-chain fatty acid aldehydes, which are involved in the pathogenesis of type II diabetes associated with PAH and endothelial proliferation. n=3 cells per group. [Figure 16B] 1 is a bar graph showing LC-MS quantification of reduced NADH in HEK293T cells treated with vehicle control or compound MBE1.5 (10 μM) for 1 hour, demonstrating that inhibition of Aldh1a3 leads to a decrease in NADH in cells. n=3 cells per group. [Figure 17] 1 is a line graph of ELISA quantification of plasma insulin levels in mice administered MBE1 once daily for 14 days and challenged with a standard fasting and refeeding assay to measure insulin secretion. n=10 mice per group. [Figure 18]Bar graph of pancreatic islet cells extracted from diet-induced diabetic or healthy C57 / BL6 mice isolated into single cell suspensions, assessed via the ALDEFLUOR™ assay in the presence of DMSO (vehicle), 1 mM DEAB, 10 μM MBE1.5 (n=2 biological replicates per group), showing that only diabetic mouse islet cells express Aldh1a3, which is inhibited by the compound MBE1.5. DETAILED DESCRIPTION OF THE INVENTION

[0018] As described in more detail in the Examples section, Aldh1a3 was found to be an essential driver of tumor metastasis and chemotherapy resistance. The data herein demonstrate that genetic ablation of Aldh1a3 in triple-negative breast cancer models Sum159-M1a and MDA-MB-468 sensitizes orthotopic tumors to paclitaxel treatment. Aldh1a3 was found to be a critical determinant of metastasis initiation and growth, both as a single genetic element and in combination with chemotherapy. Genetic experiments demonstrate that Aldh1a3 is required for lung and bone metastasis in triple-negative breast cancer metastasis. Furthermore, clinical analyses of multiple cancer types support Aldh1a3 as a differentiated Aldh isoform that predicts poorer outcomes across multiple solid tumor indications. For example, high Aldh1a3 expression predicts worse overall survival in patients with more metastatic and aggressive estrogen receptor-negative (ER-) breast cancer, and this prognosis is even worse if these patients receive neoadjuvant chemotherapy (Table 1).

[0019] As shown herein, genetic knockout of ALDH1a3 or inhibition of ALDH1a3 using a representative ALDH1a3 inhibitor can slow primary tumor growth, sensitize tumors to chemotherapy, delay metastasis, and prolong survival. As detailed in Biological Example 6, in a mouse xenograph model, ALDH1a3 inhibitors (MBE1 or MBE1.5) in combination with a chemotherapeutic agent (paclitaxel) are effective in treating established metastatic disease, causing primary tumor regression, delaying various metastases, and prolonging survival. Research has also shown that diseases such as type 2 diabetes, pulmonary arterial hypertension (PAH), or neointimal hyperplasia (NIH) are also caused by ALDH1a3 expression and / or activity.

[0020] As also detailed herein, the compounds described herein are orally available and exhibit sufficient pharmacokinetic exposure to effectively inhibit Aldh1a3 in mouse models.

[0021] Furthermore, Aldh1a3 was found to be a key driver of the progression of type 2 diabetes. The data herein demonstrate that ALDH1a3 is involved in the metabolism of medium-chain fatty acids, which are known to cause the pathogenesis of type 2 diabetes and various endothelial disorders such as PAH and NIH. The data herein also demonstrate that pharmacological inhibition of Aldh1a3 in the leptin-deficient db / db mouse strain effectively treats type 2 diabetes by restoring insulin secretion and subsequent glycemic control.

[0022] As also shown herein, pancreatic islet cells isolated from obese diabetic C57 / BL6 wild-type mice express active Aldh1a3, which is inhibited by the compound MBE1.5, whereas pancreatic islet cells from non-obese, non-diabetic C57 / BL6 mice do not express Aldh1a3.

[0023] Thus, in various embodiments, the present disclosure provides novel compounds and compositions useful for inhibiting ALDH, such as ALDH1a3, and methods of using them, for example, to treat metabolic diseases such as various cancers, cancer metastasis, type 2 diabetes, pulmonary arterial hypertension (PAH), or neointimal hyperplasia (NIH).

[0024] compound Provided herein is a range of compounds useful for inhibiting ALDH1a3. In PCT / US2019 / 044278, filed July 31, 2019, certain tetrahydroquinolinone compounds, such as Compounds Nos. 1-17, were shown to be capable of inhibiting ALDH1a3, for example, in the ALDEFLUOR™ assay. Furthermore, Compound MBE1 (Compound No. 1) was shown to shrink metastatic lesions in mice without toxicity. The present disclosure describes additional compounds as ALDH inhibitors, particularly ALDH1a3 inhibitors.

[0025] Formula I In some embodiments, the disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X at each occurrence is independently O, NR 10 , and C.R. 20 R 21 wherein at most one X is selected from O and NR 10 is selected from n is 1, 2, 3, or 4; J 1 , J 2 , and J. 3 are each independently, CR 22 or N, preferably J 1 , J 2 , and J. 3 At least one of is not N, R 1 and R 2are each independently hydrogen, optionally substituted alkyl (e.g., optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), or a nitrogen protecting group; R 3 and R 4 are linked to an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted carbocycle (e.g., C 3~8 carbocyclic ring), or an optionally substituted heterocyclic ring (e.g., a 3- to 8-membered heterocyclic ring), Z is O and R 5 is hydrogen, -NR 11 R 12 , -CR 23 R 24 R 25 , or -OR 30 Or Or Z is O and R 3 , R 4 and R 5 are linked to form an optionally substituted bicyclic or polycyclic ring system, wherein the ring system is aryl, heteroaryl, carbocyclic, or heterocyclic; or or R 5 and Z are linked to optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocycle (e.g., C 3~8 carbocyclic ring) or an optionally substituted heterocyclic ring (e.g., a 3- to 8-membered heterocyclic ring), In Formula I [ka] indicates that the bond is, if the balance permits, an aromatic bond, a double bond, or a single bond, and in the case of a single bond, the two carbons forming the bond can optionally be further substituted if the balance permits; During the ceremony, R at each occurrence 10 are independently hydrogen, a nitrogen protecting group, an optionally substituted alkyl (e.g., an optionally substituted C 1~6alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), optionally substituted C 3~8 a carbocyclic ring or an optionally substituted 3- to 8-membered heterocyclic ring; R at each occurrence 20 and R 21 are each independently hydrogen, halogen, -OR 31 , -NR 13 R 14 , optionally substituted alkyl (e.g., optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), optionally substituted C 3~8 or an optionally substituted 5- to 10-membered carbocycle, an optionally substituted 3- to 8-membered heterocycle, an optionally substituted phenyl, or an optionally substituted 5- to 10-membered heteroaryl; R 10 and R 20 and R 21 are linked to form a bond, an optionally substituted 4- to 8-membered heterocycle, or an optionally substituted 5- or 6-membered heteroaryl ring, and R 20 and R 21 another of which is as defined above or R 20 and R 21 together with the carbon to which they are both attached, -C(O)-, optionally substituted C 3~8 forming a carbocyclic or optionally substituted 3- to 8-membered heterocyclic ring, or 1 CR 20 R 21 R in 20 and R 21 One of them is a different CR 20 R 21 R in 20 and R 21 a bond, optionally substituted C 3~8forming a carbocyclic or optionally substituted 3- to 8-membered heterocyclic ring, R 20 and R 21 another of which is defined above, R at each occurrence 22 are independently hydrogen, halogen, optionally substituted alkyl (e.g., optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), -CN, -S(O)-alkyl (e.g., -S(O)-C 1~6 alkyl), -S(O)2-alkyl (e.g., -S(O)2-C 1~6 alkyl), or -OR 31 and R 11 and R 12 is a hydrogen or nitrogen protecting group, and R 11 and R 12 The other of these may be hydrogen, a nitrogen protecting group, an optionally substituted alkyl (e.g., an optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C ~6 alkynyl), optionally substituted C 3~8 carbocycle, an optionally substituted 3- to 8-membered heterocycle, an optionally substituted phenyl, or an optionally substituted 5- to 10-membered heteroaryl; R 23 , R 24 , and R 25 One of the groups may be hydrogen, halogen, optionally substituted alkyl (e.g., optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), optionally substituted C 3~8carbocycle, optionally substituted 3- to 8-membered heterocycle, optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, -OR 31 , or -NR 13 R 14 and R 23 , R 24 , and R 25 are independently selected from hydrogen, fluorine, or methyl, and preferably -CR 23 R 24 R 25 is not -CH3, R 30 is hydrogen, an oxygen protecting group, an optionally substituted alkyl (e.g., an optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), optionally substituted C 3~8 a carbocyclic ring or an optionally substituted 3- to 8-membered heterocyclic ring; During the ceremony, R at each occurrence 13 and R 14 each independently being hydrogen, a nitrogen protecting group, an optionally substituted alkyl (e.g., an optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), optionally substituted C 3~8 carbocycle, an optionally substituted 3- to 8-membered heterocycle, an optionally substituted phenyl, or an optionally substituted 5- to 10-membered heteroaryl, or R 13 and R 14 are linked to form an optionally substituted 3- to 8-membered heterocycle or an optionally substituted 5- to 10-membered heteroaryl; R at each occurrence 31 is hydrogen, an oxygen protecting group, an optionally substituted alkyl (e.g., an optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), optionally substituted C 3~8 It is a carbocycle, an optionally substituted 3- to 8-membered heterocycle, an optionally substituted phenyl, or an optionally substituted 5- to 10-membered heteroaryl.

[0026] Typically, Z in formula I is O and the compound can be characterized as having the formula IO, [ka] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , J 1 , J 2 , J 3 , X and n are defined herein.

[0027] Typically, in Formula I (e.g., Formula IO), R 3 and R 4 are connected and can be arbitrarily placed substituted phenyl, for example, optionally substituted 5- or 6-membered heteroaryl having 1 or 2 ring nitrogen atoms, optionally substituted C 4~7 Specifically, in Formula I, R 3 and R 4 are said to be linked to form a ring system as described herein, R 3 and R 4 It should be understood that the is joined together with the two intervening carbon atoms to form a ring system.

[0028] In some embodiments, in Formula I (e.g., Formula IO), R 3 and R 4 may be linked to form an optionally substituted phenyl ring, i.e., [ka] Part [ka] where R 5 is defined herein, and the phenyl may be, for example, F; Cl; hydroxyl; C optionally substituted with 1 to 3 fluorines; 1~4 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, or —CF3; C optionally substituted with 1 to 3 fluorines 1~4 Alkoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, or -OCF; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 It may be further optionally substituted at any available position with one or two substituents independently selected from cycloalkyl, preferably cyclopropyl or cyclobutyl; and -CN. In some embodiments, preferred are R 5 But, -OR 30 or -CR 23 R 24 R 25 For example, in some embodiments, R 5 is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, -CH-CHF, -CH-CF, -CF, -CH-cyclopropyl, -CH-cyclobutyl, -CH-O-CH, -CH-O-C2H, -CH-On-propyl, -CH-O-isopropyl, -C2H-cyclopropyl, -C2H-cyclobutyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, -O-CH-CF, -O-CF, -O-CH-cyclopropyl, -O-CH-cyclobutyl, -O-C2H-cyclopropyl, or -O-C2H-cyclobutyl. 5 is hydrogen.

[0029] In some embodiments, in Formula I (e.g., Formula IO), R 3 and R 4 can be linked to form an optionally substituted 5- or 6-membered heteroaryl, such as those described herein. For example, in some embodiments, in Formula I (e.g., Formula IO), R 3 and R 4 optionally substituted pyrazole, imidazole, oxazole, thiazole, isoxazole, isothiazole, pyridyl, pyrimidinyl, pyridazinyl, For example, in some embodiments, the compound of Formula I (e.g., Formula 10) can form a pyrazinyl group. [ka] The part can be selected from: [ka] In the formula, R 5 is defined herein, and pyridyl or pyridone may be, for example, a C substituted with, for example, F; Cl; OH; C optionally substituted with 1 to 3 fluorines at any available position, including in the case of pyridone, the ring nitrogen. 1~4 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, or —CF3; C optionally substituted with 1 to 3 fluorines 1~4 Alkoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, or -OCF; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 In some embodiments, the aryl group in Formula I may be optionally further substituted with one or two (preferably one) substituents independently selected from cycloalkyl, preferably cyclopropyl or cyclobutyl; and -CN. [ka] The part is [ka] wherein R 5 is defined herein, and pyridyl may be, for example, F; Cl; C optionally substituted with 1 to 3 fluorines; 1~4 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, or —CF3; C optionally substituted with 1 to 3 fluorines 1~4 Alkoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, or -OCF; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 It may be further optionally substituted at any available position with one or two substituents (preferably one) independently selected from cycloalkyl, preferably cyclopropyl or cyclobutyl; and -CN. In some embodiments, preferred are R 5 But, -OR 30 or -CR 23 R 24 R 25 For example, in some embodiments, R 5 is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, -CH-CHF, -CH-CF, -CF, -CH-cyclopropyl, -CH-cyclobutyl, -CH-O-CH, -CH-O-C2H, -CH-On-propyl, -CH-O-isopropyl, -C2H-cyclopropyl, -C2H-cyclobutyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, -O-CH-CF, -O-CF, -O-CH-cyclopropyl, -O-CH-cyclobutyl, -O-C2H-cyclopropyl, or -O-C2H-cyclobutyl. 5 may also be hydrogen.

[0030] In some embodiments, in Formula I (e.g., Formula IO), R 3 and R 4may be linked to form an optionally substituted 5- or 6-membered saturated ring system optionally containing 1 or 2 (preferably 1) ring heteroatoms selected from O or N, such as cyclopentyl, cyclohexyl, tetrahydropyranyl, piperidinyl, etc. Typically, when substituted, the 5- or 6-membered saturated ring system is selected from C substituted with F and optionally 1 to 3 fluorines. 1~4 In some embodiments, the aryl group of Formula I is optionally further substituted with one or two substituents independently selected from alkyl. [ka] Part [ka] wherein R 5 is defined herein, and tetrahydropyranyl may be C substituted at any available position, for example, with F and optionally 1 to 3 fluorines. 1~4 In some embodiments, R is an alkyl group, as defined herein, and is preferably R 5 But, -OR 30 or -CR 23 R 24 R 25 For example, in some embodiments, R 5 is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, -CH2-CHF2, -CH2-CF3, -CF3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-O-CH3, -CH2-O-C2H5, -CH2-On-propyl, -CH2-O-isopropyl, -C2H4-cyclopropyl, -C2H4-cyclobutyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, -O-CH2-CF3, -O-CF3, -O-CH2-cyclopropyl -cyclobutyl, -O-CH2-cyclobutyl, -O-C2H4-cyclopropyl, or -O-C2H4-cyclobutyl.

[0031] In some embodiments, R in Formula I (e.g., Formula IO) 5 However, typically, R in Formula I (e.g., Formula IO) 5 is -NR 11 R 12 , -CR 23 R 24 R 25 , or -OR 30 , more typically, -CR 23 R 24 R 25 -OR 30 where R 11 , R 12 , R 23 , R 24 , R 25 , and R 30 is defined herein. For example, in any of the embodiments described herein, unless otherwise specified or clearly contradicted by context, R in Formula I (e.g., Formula IO) 5 But, -CR 23 R 24 R 25 wherein R 23 is hydrogen or fluorine, R 24 is hydrogen or fluorine, R 25 is hydrogen, halogen, optionally substituted C 1~4 Alkyl, optionally substituted C 3~6 It is a carbocycle, an optionally substituted 3- to 6-membered heterocycle, an optionally substituted phenyl, or an optionally substituted 5- or 6-membered heteroaryl.

[0032] In some embodiments, R 25 may be fluorine. In some embodiments, R 25 Fluorine, hydroxyl, fluoro-substituted C 1~4 Alkyl (e.g., CF3), C 1~4 Alkoxy, Fluoro-substituted C 1~4 Alkoxy (e.g., -OCF3), NH2, -NH(C 1~4alkyl), -N(C 1~4 Alkyl)(C 1~4 alkyl), C 3~6 C optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from cycloalkyl, and 3- to 6-membered heterocycle 1~4 As used herein, —N(C 1~4 Alkyl)(C 1~4 Two "C" in alkyl 1~4 The "alkyl" groups may be the same or different. In some embodiments, R 25 However, fluorine, C 1~4 Alkyl, Fluoro-substituted C 1~4 Alkyl (e.g., CF3), C 1~4 Alkoxy, Fluoro-substituted C 1~4 Alkoxy (e.g., -OCF3), NH2, -NH(C 1~4 alkyl), and -N(C 1~4 Alkyl)(C 1~4 C optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from 3~6 It may also be cycloalkyl, such as cyclopropyl or cyclobutyl. In some embodiments, R 25 R may also be an optionally substituted 3- to 6-membered heterocyclic ring, such as an oxetanyl ring. 25 may be optionally substituted phenyl. In some embodiments, R 25 may be an optionally substituted 5- or 6-membered heteroaryl, such as a heteroaryl described herein.

[0033] In some embodiments, R in Formula I (e.g., Formula IO) 5 But, -CR 23 R 24 R 25 wherein R 23 is hydrogen or fluorine, R 24 is hydrogen or fluorine, R 25is hydrogen; fluorine; 1 to 3 fluorines and / or C 3~6 C optionally substituted with cycloalkyl 1~4 Alkyl; 1 to 3 fluorines and / or C 3~6 C optionally substituted with cycloalkyl 1~4 Alkoxy; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 Cycloalkoxy; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 cycloalkyl; or a 3- to 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl; Preferably, R 23 , R 24 , and R 25 At least one of R is not hydrogen. 25 fluorine; 1 to 3 fluorines and / or C 3~6 C optionally substituted with cycloalkyl 1~4 alkyl; or C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 Cycloalkyl (e.g., cycloalkyl) For clarity, C 1~4 The alkyl group may contain 1 to 3 fluorine atoms and / or C 3~6 When referred to as optionally substituted cycloalkyl, unsubstituted C 1~4 Alkyl, C substituted with 1 to 3 fluorines 1~4 Alkyl (e.g., CF3), C 3~6 Cycloalkyl-substituted C 1~4 Alkyl (e.g., -CH2-cyclopropyl), and 1 to 3 fluorines and C 3~6 Cycloalkyl-substituted C 1~4 It should be understood to include alkyl (e.g., -CF2-CH2-cyclopropyl). Other similar expressions should be construed similarly.

[0034] In some embodiments, R in Formula I (e.g., Formula IO)5 is -CH2R 25 wherein R 25 is defined herein, for example, R 25 is hydrogen; fluorine; 1 to 3 fluorines and / or C 3~6 C optionally substituted with cycloalkyl 1~4 Alkyl; 1 to 3 fluorines and / or C 3~6 C optionally substituted with cycloalkyl 1~4 Alkoxy; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 Cycloalkoxy; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 cycloalkyl; or a 3- to 6-membered heterocycle optionally substituted with 1 to 3 substituents selected from fluorine and methyl, preferably R 25 In any of the embodiments described herein, unless otherwise specified or clearly contradicted by context, R in Formula I (e.g., Formula IO) 5 But -CH2R 25 wherein R 25 but 1 to 3 fluorine and / or C 3~6 C optionally substituted with cycloalkyl 1~4 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, or —CF; or C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl; 3~6 In any of the embodiments described herein, unless otherwise specified or clearly contradicted by context, R in Formula I (e.g., Formula IO) is 5 But -CH2R 25 wherein R 25 may be methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, —CH2—CF3, —CH2-cyclopropyl, cyclopropyl, or cyclobutyl.

[0035] In any of the embodiments described herein, unless otherwise specified or clearly contradicted by context, R in Formula I (e.g., Formula IO) 5 is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, -CH2-CHF2, -CH2-CF3, -CF3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-O-CH3, -CH2-O-C2H5, -CH2-On-propyl, -CH2-O-isopropyl, -C2H4-cyclopropyl, -C2H4-cyclobutyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, -O-CH2-CF3, -O-CF3, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -O-C2H4-cyclopropyl or -O-C2H4-cyclobutyl.

[0036] In some embodiments, the compound of formula IO is R 3 , R 4 , and R 5 may be characterized in that: [ka] is optionally substituted, [ka] It may be.

[0037] In some embodiments, Z in formula I is R 5 and optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocycle (e.g., C 3~8 For example, in some embodiments, Z in Formula I is R 5and linked to form an optionally substituted heteroaryl. In some embodiments, the compound of formula I may have the formula of formula IF: [ka] where R at each occurrence 101 are independently selected from halogen, optionally substituted alkyl (e.g., optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), -CN, or -OR 31 is selected from m is 0, 1, 2, or 3, preferably m is 0 or 1; In the formula, R 1 , R 2 , R 3 , R 4 , R 31 , J 1 , J 2 , J 3 , X, and n are defined herein. In some embodiments, in formula IF, R 3 and R 4 are linked to an optionally substituted phenyl, for example an optionally substituted 5- or 6-membered heteroaryl having 1 or 2 ring nitrogen atoms, an optionally substituted C 4~7 cycloalkyl groups (e.g., cyclopentyl or cyclohexyl), or optionally substituted 4- to 7-membered (e.g., 6-membered) heterocycles having 1 or 2 ring heteroatoms, and in some embodiments, R 3 and R 4 are linked to an optionally substituted phenyl, for example, unsubstituted phenyl, or a C1 optionally substituted with F; Cl; ~4 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, or —CF3; C optionally substituted with 1 to 3 fluorines 1~4Alkoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, or -OCF; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 In some embodiments, in formula IF, R may be substituted with one or two substituents selected from cycloalkyl, preferably cyclopropyl or cyclobutyl; and -CN. 3 and R 4 can be linked to form an optionally substituted 5- or 6-membered heteroaryl.

[0038] In certain embodiments, compounds of formula I can be characterized as having formula I-1 or I-2: [ka] During the ceremony, R at each occurrence 100 are independently selected from halogen, optionally substituted alkyl (e.g., optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), -CN, or -OR 31 is selected from p is 0, 1, 2, or 3, preferably p is 0 or 1; R 1 , R 2 , R 5 , R 31 , J 1 , J 2 , J 3 , X, and n are defined herein. In some embodiments, in formula I-1 or I-2, R at each occurrence 100 are independently selected from the group consisting of F, Cl, and C optionally substituted with 1 to 3 fluorines. 1~4 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, or —CF3; C optionally substituted with 1 to 3 fluorines 1~4Alkoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, or -OCF; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 In some embodiments, in Formula I-1 or I-2, p is 0. In some embodiments, in Formula I-1 or I-2, p is 1. In some embodiments, in Formula I-1 or I-2, p is 1 and R 100 is F, Cl, methyl, ethyl, n-propyl, isopropyl, -CF, methoxy, ethoxy, n-propoxy, isopropoxy, -OCF, cyclopropyl, or -CN. In some embodiments, in Formula I-1 or I-2, p is 1 and R 100 In some embodiments, in formula I-1 or I-2, p is 1 and R 100 is F, Cl, OH, methyl, or ethyl.

[0039] In some particular embodiments, the compound of Formula I can be characterized as having Formula I-1-A or Formula I-2-A, [ka] In the formula, R 1 , R 2 , R 23 , R 24 , R 25 , R 100 , J 1 , J 2 , J 3 , X, p, and n are defined herein. In some embodiments, in formula I-1-A or I-2-A, R 23 is hydrogen or fluorine, R 24 is hydrogen or fluorine, R 25 is hydrogen; fluorine; 1 to 3 fluorines and / or C 3~6 C optionally substituted with cycloalkyl1~4 Alkyl; 1 to 3 fluorines and / or C 3~6 C optionally substituted with cycloalkyl 1~4 Alkoxy; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 Cycloalkoxy; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 cycloalkyl; or a 3- to 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl; Preferably, R 23 , R 24 , and R 25 At least one of the is not hydrogen.

[0040] In some embodiments, in formula I-1-A or I-2-A, R 23 is hydrogen. In some embodiments, in formula I-1-A or I-2-A, R 23 and R 24 and are both hydrogen. In some embodiments, in formula I-1-A or I-2-A, R 25 But 1 to 3 fluorine and / or C 3-6 C optionally substituted with cycloalkyl 1~4 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, or -CF3, or optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl; 3~6 For example, in some embodiments, in Formula I-1-A or I-2-A, R 25 is methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, —CH2—CF3, —CH2-cyclopropyl, cyclopropyl, or cyclobutyl.

[0041] In some embodiments, the compound of formula I-1-A or I-2-A can be characterized as having formula I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, or I-2-A3, [ka] In the formula, R 1 , R 25 , R 100 , J 1 , J 2 , J 3 , X, p, and n are defined herein. In some embodiments, in Formula I-1-A1, Formula I-1-A2, Formula I-1-A3, Formula I-2-A1, Formula I-2-A2, or Formula I-2-A3, R 25 but 1 to 3 fluorine and / or C 3~6 C optionally substituted with cycloalkyl 1~4 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, or -CF3, or C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl; 3~6 In some particular embodiments, in Formula I-1-A1, Formula I-1-A2, Formula I-1-A3, Formula I-2-A1, Formula I-2-A2, or Formula I-2-A3, R 25 may be methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, —CH 2 —CF 3 , —CH 2 -cyclopropyl, cyclopropyl, or cyclobutyl.

[0042] In some embodiments, in Formula I-1-A1, Formula I-1-A2, Formula I-2-A1, or Formula I-2-A2, R at each occurrence 100 are independently selected from the group consisting of F, Cl, and C optionally substituted with 1 to 3 fluorines. 1~4 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, or —CF3; C optionally substituted with 1 to 3 fluorines 1~4 Al oxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, or -OCF; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 In some embodiments, in Formula I-1-A1, Formula I-1-A2, Formula I-2-A1, or Formula I-2-A2, R is selected from cycloalkyl, preferably cyclopropyl or cyclobutyl; and —CN. 100 An example of may be hydroxyl. In some embodiments, in Formula I-1-A1 or I-2-A1, p is 1. In some embodiments, in Formula I-1-A1 or I-2-A1, p is 2. In some embodiments, in Formula I-1-A1 or I-2-A1, p is 1 and R 100 is F, Cl, methyl, ethyl, n-propyl, isopropyl, -CF, methoxy, ethoxy, n-propoxy, isopropoxy, -OCF, cyclopropyl, or -CN. In some embodiments, in Formula I-1-A1 or I-2-A1, p is 1 and R 100 is F, Cl, or methyl. In some embodiments, in Formula I-1-A2 or Formula I-2-A2, R 100 is F, Cl, methyl, ethyl, n-propyl, isopropyl, -CF3, methoxy, ethoxy, n-propoxy, isopropoxy, -OCF3, cyclopropyl, or -CN. In some embodiments, in Formula I-1-A2 or Formula I-2-A2, R 100 is F, Cl, or methyl.

[0043] In some embodiments, the compound of Formula I-1 or I-2 can be characterized as having formula I-1-B, I-1-C, I-2-B, or I-2-C, [ka] In the formula, R 1 , R 2 , R 30 , R 11 , R 12 , R 100 , J 1, J 2 , J 3 , X, p, and n are defined herein. In some embodiments, in formula I-1-B or I-2-B, R 30 is hydrogen; 1 to 3 fluorine and / or C 3~6 C optionally substituted with cycloalkyl 1~4 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, -CH2-CF3, or - CH2-cyclopropyl; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 cycloalkyl, preferably cyclopropyl or cyclobutyl; or a 3- to 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl, preferably [ka] In some embodiments, R 30 may be methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, —CH—CF, or —CH-cyclopropyl. 30 is cyclopropyl, cyclobutyl, or [ka] In some embodiments, in formula I-1-C or I-2-C, R 11 and R 12 is a hydrogen or nitrogen protecting group, and R 11 and R 12 The other of these is hydrogen, a nitrogen protecting group, 1-3 fluorines or C 3~6 C optionally substituted with cycloalkyl 1~4 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, -CH2-CF3, or -CH2-cyclopropyl; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl;3~6 cycloalkyl, preferably cyclopropyl or cyclobutyl; or a 3- to 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl, preferably [ka] is.

[0044] In some embodiments, in formula I-1-B, I-1-C, I-2-B, or I-2-C, R at each occurrence 100 are independently selected from the group consisting of F, Cl, and C optionally substituted with 1 to 3 fluorines. 1~4 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, or —CF3; C optionally substituted with 1 to 3 fluorines 1~4 Alkoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, or -OCF; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 In some embodiments, the cycloalkyl group is selected from cycloalkyl, preferably cyclopropyl or cyclobutyl; and —CN. ... In some embodiments, in formula I-1-B, I-1-C, I-2-B, or I-2-C, p is 1. In some embodiments, in formula I-1-B, I-1-C, I-2-B, or I-2-C, p is 1 and R 100 is F, Cl, methyl, ethyl, n-propyl, isopropyl, -CF3, methoxy, ethoxy, n-propoxy, isopropoxy, -OCF3, cyclopropyl, or -CN.

[0045] In some embodiments, the compound of Formula I-1 or I-2 can be characterized as having formula I-1-B1, I-1-B2, I-2-B1, I-2-B2, [ka] In the formula, R 1, R 30 , R 100 , J 1 , J 2 , J 3 , X, p, and n are defined herein. In some embodiments, R 30 is hydrogen; 1 to 3 fluorine and / or C 3~6 C optionally substituted with cycloalkyl 1~4 alkyl, preferably methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, -CH2-CF3, or -CH2-cyclopropyl; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl; 3~6 cycloalkyl, preferably cyclopropyl or cyclobutyl; or a 3- to 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl, preferably [ka] In some embodiments, R 30 can be hydrogen, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, —CH—CF, —CH-cyclopropyl, cyclopropyl, or cyclobutyl. In some embodiments, in Formula I-1-B1 or I-2-B1, R 100 However, F, Cl, methyl , ethyl, n-propyl, isopropyl, -CF3, methoxy, ethoxy, n-propoxy, isopropoxy, -OCF3, cyclopropyl, or -CN.

[0046] In some particular embodiments, in Formula I (e.g., any of the applicable subformulas), [ka] The moiety may have a structure according to one of the following: [ka]

[0047] In some particular embodiments, in Formula I (e.g., any of the applicable subformulas), [ka] The moiety may have a structure according to one of the following: [ka]

[0048] In some embodiments, in Formula I (e.g., any of the applicable subformulas), [ka] may have the structure of any of the corresponding moieties of Compound Nos. 1-138 disclosed herein, where applicable. In some embodiments, in Formula I (e.g., any of the applicable subformulas), [ka] may have any of the structures of the corresponding moieties in specific compounds disclosed herein that have activity levels of A or B shown in Table 3 of the present disclosure in inhibiting hALDH1a3, as applicable.

[0049] Typically, in Formula I, R 1 and R 2 are both hydrogen. For example, in some embodiments, the formulas IO, IF, I-1, I-2, I-1-A, I-2-A, I-1- In any of the subformulas of formula I, such as A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C, R 1 and R 2 However, both may be hydrogen.

[0050] Typically, J in Formula I (e.g., Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C) 1 In some embodiments, J in Formula I (including any subformula of Formula I) is CH. 1 may also be N.

[0051] Typically, J in Formula I (e.g., Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C) 2 But, CR 22 and R 22 is defined herein. In some embodiments, R 22 is hydrogen, F, Cl, CN, or methyl. In some embodiments, J in Formula I (including any subformula of Formula I) 2 may also be N.

[0052] Typically, J in Formula I (e.g., Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C) 3 In some embodiments, J in Formula I (including any subformula of Formula I) is CH. 3 may also be N.

[0053] Typically, in Formula I (e.g., Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), J 1 , J 2 , and J. 3 At least one of J is not N. 1, J 2 , and J. 3 None of the above is N, for example, J 1 may be CH, and J 2 But, CR 22 J 3 may be CH, and R 22 is hydrogen, F, Cl, CN, or methyl.

[0054] Typically, in formula I, n is 1, 2, or 3. Preferably, n is 2.

[0055] In Formula I, each instance of X is O, NR 10 , or CR 20 R 21 wherein at most one X is selected from O and NR 10 In some embodiments, at least one instance of X is selected from CR 20 R 21 and R 20 and R 21 is defined herein.

[0056] In some embodiments, n is 1 and X is O. In some embodiments, n is 1 and X is NR 10 and R 10 is defined herein and is, for example, hydrogen or C 1~4 In some embodiments, n is 1 and X is CR 20 R 21 and R 20 and R 21 is defined herein. In some embodiments, CR 20 R 21 In units, R 20 and R 21 are both methyl, R 20 and R 21 One of the groups is methyl, and R 20 and R 21 the other of which is ethyl or methoxy, or R 20 and R 21 But together with the carbon to which they are both attached, C 3~6 In some embodiments, CR 2 forms a cycloalkyl (preferably cyclopropyl, cyclobutyl, or cyclopentyl) or oxetanyl ring. 20 R 21 In units, R 20 and R 21 One of the groups is methyl, and R 20 and R 21 and the other of CR is hydrogen. 20 R 21 In units, R 20 and R 21 are both hydrogen. In some embodiments, CR 20 R 21 In units, R 20 and R 21 are both fluorine.

[0057] In some embodiments, n is 2, one example of X is O, and one example of X is CR 20 R 21 and R 20 and R 21 is defined herein. In some embodiments, n is 2 and one example of X is NR 10 and an example of X is CR 20 R 21 and R 10 , R 20 and R 21 is as defined herein. In some embodiments, n is 2 and both instances of X are CR as defined herein. 20 R 21 In some embodiments, R 20 and R 21 are independently hydrogen or C 1~4 alkyl or R 20 and R 21 But together with the carbon to which they are both attached, C 3~6In some embodiments, R 10 is hydrogen or C 1~4 In some embodiments, the compound has at least one CR alkyl. 20 R 21 Includes units, R 20 and R 21 are both methyl, R 20 and R 21 One of the groups is methyl, and R 20 and R 21 the other of which is ethyl or methoxy, or R 20 and R 21 together with the carbon to which they are both attached form a cyclopropyl, cyclobutyl, or oxetanyl ring. In some embodiments, at least one CR 20 R 21 In units, R 20 and R 21 One of the groups is methyl, and R 20 and R 21 The others are hydrogen. In some embodiments, CR 20 R 21 In units, R 20 and R 21 are both hydrogen.

[0058] In some embodiments, n is 3, one instance of X is O, and two instances of X are independently selected CR 20 R 21 and R 20 and R 21 is defined herein. In some embodiments, n is 3 and one instance of X is NR 10 and two instances of X are chosen independently. 20 R 21 and R 10 , R 20 and R 21is as defined herein. In some embodiments, n is 3 and all instances of X are CR as defined herein. 20 R 21 In some embodiments, R 20 and R 21 are independently hydrogen or C 1~4 alkyl or R 20 and R 21 But together with the carbon to which they are both attached, C 3~6 In some embodiments, R 10 is hydrogen or C 1~4 In some embodiments, the compound has at least one CR alkyl. 20 R 21 Includes units, R 20 and R 21 are both methyl, R 20 and R 21 One of the groups is methyl, and R 20 and R 21 the other of which is ethyl or methoxy, or R 20 and R 21 together with the carbon to which they are both attached form a cyclopropyl, cyclobutyl, or oxetanyl ring. In some embodiments, at least one CR 20 R 21 In units, R 20 and R 21 One of the groups is methyl, and R 20 and R 21 and another of the CR is hydrogen. 20 R 21 In units, R 20 and R 21 are both hydrogen.

[0059] In some embodiments, in Formula I (e.g., Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), [ka] You can choose from the following: [ka] During the ceremony, J. 1 , J 2 , J 3 , R 20 and R 21 is defined herein. In some embodiments, J 1 is CH. In some embodiments, J 2 But N or CR 22 where R 22 is defined herein, e.g., hydrogen, F, Cl, CN, or methyl. In some embodiments, J 3 is CH. In some embodiments, R 20 and R 21 are independently hydrogen or C 1~4 alkyl (e.g., methyl, ethyl, etc.) or R 20 and R 21 together with the carbon to which they are both attached form a cyclopropyl, cyclobutyl, cyclopentyl, or oxetanyl ring. In some embodiments, CR 20 R 21 In units: R 20 and R 21 are both methyl or R 20 and R 21 One of the groups is methyl, and R 20 and R 21 the other of which is ethyl or methoxy, or R 20 and R 21together with the carbon to which they are both attached form a cyclopropyl, cyclobutyl, or oxetanyl ring. In some embodiments, CR 20 R 21 In units, R 20 and R 21 One of the groups is methyl, and R 20 and R 21 In some embodiments, the other of CR 20 R 21 In units, R 20 and R 21 are both hydrogen.

[0060] In some embodiments, in Formula I (e.g., Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), [ka] You can choose from the following: [ka] During the ceremony, R 10 are independently hydrogen or C 1~4 alkyl (e.g., methyl, ethyl, etc.) , R 20 and R 21 are independently hydrogen or C 1~4 alkyl (e.g., methyl, ethyl, etc.) or R 20 and R 21 together with the carbon to which they are both attached form a cyclopropyl, cyclobutyl, cyclopentyl, or oxetanyl ring. In some embodiments, R 20 and R 21 One of the groups is methyl, and R 20 and R 21 The other of R is hydrogen.20 and R 21 are both hydrogen.

[0061] In some embodiments, in Formula I (e.g., Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), [ka] You can choose from the following: [ka] In the formula, R 10 , R 20 , and R 21 is defined herein. In some embodiments, R 10 are independently hydrogen or C 1~4 alkyl (e.g., methyl, ethyl, etc.). In some embodiments, R 20 and R 21 are independently hydrogen or C 1~4 alkyl (e.g., methyl, ethyl, etc.) or R 20 and R 21 together with the carbon to which they are both attached form a cyclopropyl, cyclobutyl, cyclopentyl, or oxetanyl ring. In some embodiments, CR 20 R 21 In units: R 20 and R 21 are both methyl, R 20 and R 21 One of the groups is methyl, and R 20 and R 21 the other of which is ethyl or methoxy, or R 20 and R 21together with the carbon to which they are both attached form a cyclopropyl, cyclobutyl, or oxetanyl ring. In some embodiments, R 20 and R 21 One of the groups is methyl, and R 20 and R 21 and the other of R is hydrogen. 20 and R 21 are both hydrogen.

[0062] In some embodiments, in Formula I (e.g., Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), [ka] You can choose from the following: [ka] In the formula, R 10 , R 20 , and R 21 is defined herein. In some embodiments, R 10 are independently hydrogen or C 1~4 alkyl (e.g., methyl, ethyl, etc.). In some embodiments, R 20 and R 21 are independently hydrogen or C 1~4 alkyl (e.g., methyl, ethyl, etc.) or R 20 and R 21 together with the carbon to which they are both attached form a cyclopropyl, cyclobutyl, cyclopentyl, or oxetanyl ring. In some embodiments, CR 20 R 21 In units: R 20 and R 21 are both methyl, R 20 and R21 One of the groups is methyl, and R 20 and R 21 the other of which is ethyl or methoxy, or R 20 and R 21 together with the carbon to which they are both attached form a cyclopropyl, cyclobutyl, or oxetanyl ring. In some embodiments, R 20 and R 21 One of the groups is methyl, and R 20 and R 21 and the other of R is hydrogen. 20 and R 21 are both hydrogen.

[0063] In some embodiments, in Formula I (e.g., Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), [ka] You can choose from the following: [ka] In the formula, X 1 and X 2 independently, O, NR 10 , or CH2, where X 1 and X 2 At least one of R is CH2; 10 , R 20 , and R 21 is defined herein. In some embodiments, X 1 and X 2 and X are CH. In some embodiments, X 1 and X 2 One of them is NR 10 In some embodiments, R 10 are independently hydrogen or C1~4 alkyl (e.g., methyl, ethyl, etc.). In some embodiments, R 20 and R 21 are independently hydrogen or C 1~4 alkyl (e.g., methyl, ethyl, etc.) or R 20 and R 21 together with the carbon to which they are both attached form a cyclopropyl, cyclobutyl, cyclopentyl, or oxetanyl ring. In some embodiments, CR 20 R 21 In units, R 20 and R 21 are both methyl, R 20 and R 21 One of the groups is methyl, and R 20 and R 21 the other of which is ethyl or methoxy, or R 20 and R 21 together with the carbon to which they are both attached form a cyclopropyl, cyclobutyl, or oxetanyl ring. In some embodiments, CR 20 R 21 In units, R 20 and R 21 One of the groups is methyl, and R 20 and R 21 and the other of CR is hydrogen. 20 R 21 In units, R 20 and R 21 are both hydrogen.

[0064] In some embodiments, in Formula I (e.g., Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), [ka] can be selected from the following: [ka]

[0065] In some embodiments, in Formula I (e.g., Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), [ka] can be selected from the following: [ka]

[0066] In some embodiments, in Formula I (e.g., Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), [ka] can be selected from the following: [ka]

[0067] In some embodiments, in Formula I (e.g., Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), [ka] can be selected from the following: [ka]

[0068] In some embodiments, in Formula I (e.g., Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), [ka] can be selected from the following: [ka]

[0069] In some embodiments, in Formula I (e.g., Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), [ka] can be selected from the following: [ka]

[0070] In some embodiments, in Formula I (e.g., Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), [ka] can be any of the corresponding moieties shown in compounds 1-138 disclosed herein, as appropriate.

[0071] In some embodiments, the present disclosure also provides compounds of the general formula IP, or a pharmaceutically acceptable salt thereof: [ka] wherein Het represents an optionally substituted heterocyclic or heteroaryl ring system, preferably a 5- or 6-membered heterocyclic or 5- or 6-membered heteroaryl ring; 1 , R 2 , R 5 , J 1 , J 2 , J 3 , X and n can be any of those defined herein for formula I (including subformulas thereof). Preferably, when Z is O, Het is a 5- or 6-membered heteroaryl, and in formula IP, R 5 is at the ortho position of -C(=Z)- In addition, in the formula IP, R is bonded to Het as long as balance allows. 5 It will also be understood that may be attached to a ring nitrogen.

[0072] In some embodiments, in formula IP, Z is O and R 2 is hydrogen or methyl, [ka] and R 5 may be any of those described for Formula I (including subformulas thereof), and Het is an optionally substituted 5- or 6-membered heteroaryl as described herein, for example, Het is a 5- or 6-membered heteroaryl, preferably pyrazole, imidazole, oxazole, thiazole, isoxazole, isothiazole, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, which are optionally, independently, selected from the group consisting of F; Cl; C optionally substituted with 1 to 3 fluorines; 1~4 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, or —CF3; C optionally substituted with 1 to 3 fluorines 1~4Alkoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, or -OCF; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 Cycloalkoy; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 In some embodiments, in formula IP, the compound is substituted with one or two (preferably one) substituents selected from cycloalkyl, preferably cyclopropyl or cyclobutyl; and —CN. [ka] can be selected from the following: [ka]

[0073] In some embodiments, preferred are R in formula IP as defined herein. 5 But, -OR 30 or -CR 23 R 24 R 25 In some embodiments, R in formula IP is 5 is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, -CH2-CHF2, -CH2-CF3, -CF3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-O-CH3, -CH2-O-C2H5, -CH2-On-propyl, -CH2-O-isopropyl, -C2H4-cyclopropyl propyl, -C2H4-cyclobutyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, -O-CH2-CF3, -O-CF3, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -O-C2H4-cyclopropyl, or -O-C2H4-cyclobutyl.

[0074] Formula II Some embodiments of the present disclosure are directed to compounds of formula II, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, W is -N(R 1 )-C(O)-, -N(R 1 )-S(O)-, or -N(R 1 )-S(O)2-, L is -(CR A1 R B1 ) t1 -Q 1 -Q 2 -Q 3 -(CR A2 R B2 ) t2 - and Q 1 and Q 3 but independently none, O or NR 2 and Q 2 is absent, -C(O)-, -C(=Z)-, -S(O)-, or -S(O)2-; t1 is 0, 1, 2, or 3; t2 is 0, 1, 2, or 3; R at each occurrence A1 , R B1 , R A2 , and R B2 are independently hydrogen, C 1~4 alkyl (e.g., methyl), or fluorine, or Two adjacent CRs A1 R B1 Or two adjacent CRs A2 R B2 but, -C(R A1 )=C(R B1 )-, -C(R A2 )=C(R B2 )-,or [ka] can be formed, and R A1 , R B1, R A2 and R B2 are independently hydrogen, C 1~4 alkyl (e.g., methyl), or fluorine; X at each occurrence is independently O, NR 10 , and C.R. 20 R 21 wherein at most one X is selected from O and NR 10 is selected from n is 1, 2, 3, or 4; J 1 , J 2 , and J. 3 are each independently, CR 22 or N, preferably J 1 , J 2 , and J. 3 At least one of is not N, R at each occurrence 1 and R 2 are each independently hydrogen, optionally substituted alkyl (e.g., optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), or a nitrogen protecting group; R 3 and R 4 are linked to an optionally substituted aryl, an optionally substituted heteroaryl, optionally substituted carbocyclic rings (e.g., C 3~8 carbocyclic ring), or an optionally substituted heterocyclic ring (e.g., a 3- to 8-membered heterocyclic ring), R 5 is hydrogen, -NR 11 R 12 , -CR 23 R 24 R 25 , or -OR 30 Or R 3 , R 4 and R 5are linked to form an optionally substituted bicyclic or polycyclic ring system, wherein the ring system is aryl, heteroaryl, carbocyclic, or heterocyclic; or or Q 2 If -C(=Z)-, R 5 and Z are linked to optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocycle (e.g., C 3~8 carbocyclic ring) or an optionally substituted heterocyclic ring (e.g., a 3- to 8-membered heterocyclic ring), In Formula II [ka] indicates that the bond is, if the balance permits, an aromatic bond, a double bond, or a single bond, and in the case of a single bond, the two carbons forming the bond can optionally be further substituted if the balance permits; During the ceremony, R at each occurrence 10 are independently hydrogen, a nitrogen protecting group, an optionally substituted alkyl (e.g., an optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), optionally substituted C 3~8 a carbocyclic ring or an optionally substituted 3- to 8-membered heterocyclic ring; R at each occurrence 20 and R 21 are each independently hydrogen, halogen, -OR 31 , -NR 13 R 14 , optionally substituted alkyl (e.g., optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), optionally substituted C 3~8 or an optionally substituted 5- to 10-membered carbocycle, an optionally substituted 3- to 8-membered heterocycle, an optionally substituted phenyl, or an optionally substituted 5- to 10-membered heteroaryl; R 10 and R 20 and R 21 are linked to form a bond, an optionally substituted 4- to 8-membered heterocycle, or an optionally substituted 5- or 6-membered heteroaryl ring, and R 20 and R 21 another of which is as defined above or R 20 and R 21 together with the carbon to which they are both attached, -C(O)-, optionally substituted C 3~8 forming a carbocyclic or optionally substituted 3- to 8-membered heterocyclic ring, or 1 CR 20 R 21 R in 20 and R 21 One of them is a different CR 20 R 21 R in 20 and R 21 a bond, optionally substituted C 3~8 forming a carbocyclic or optionally substituted 3- to 8-membered heterocyclic ring, R 20 and R 21 another of which is defined above, R at each occurrence 22 are independently hydrogen, halogen, optionally substituted alkyl (e.g., optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), -CN, -S(O)-alkyl, -S(O)2-alkyl, or -OR 31 and R 11 and R 12 is a hydrogen or nitrogen protecting group, and R 11 and R 12 The other of these may be hydrogen, a nitrogen protecting group, an optionally substituted alkyl (e.g., an optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), optionally substituted C 3~8 Carbocyclic, optionally substituted 3- to 8-membered heterocyclic rings , optionally substituted phenyl, or optionally substituted 5-10 membered heteroaryl; R 23 , R 24 , and R 25 One of the groups may be hydrogen, halogen, optionally substituted alkyl (e.g., optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), optionally substituted C 3~8 carbocycle, optionally substituted 3- to 8-membered heterocycle, optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, -OR 31 , or -NR 13 R 14 and R 23 , R 24 , and R 25 are independently selected from hydrogen, fluorine, or methyl, and preferably -CR 23 R 24 R 25 is not -CH3, R 30 is hydrogen, an oxygen protecting group, an optionally substituted alkyl (e.g., an optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), optionally substituted C 3~8 a carbocyclic ring or an optionally substituted 3- to 8-membered heterocyclic ring; During the ceremony, R at each occurrence 13 and R 14 each independently being hydrogen, a nitrogen protecting group, an optionally substituted alkyl (e.g., an optionally substituted C 1~6alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), optionally substituted C 3~8 carbocycle, an optionally substituted 3- to 8-membered heterocycle, an optionally substituted phenyl, or an optionally substituted 5- to 10-membered heteroaryl, or R 13 and R 14 are linked to form an optionally substituted 3- to 8-membered heterocycle or an optionally substituted 5- to 10-membered heteroaryl; R at each occurrence 31 is hydrogen, an oxygen protecting group, an optionally substituted alkyl (e.g., an optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), optionally substituted C 3~8 It is a carbocycle, an optionally substituted 3- to 8-membered heterocycle, an optionally substituted phenyl, or an optionally substituted 5- to 10-membered heteroaryl.

[0075] Typically, in Formula II, the variable R 3 , R 4 , R 5 , J 1 , J 2 , J 3 , X, and n can be any of those described above in connection with Formula I and its subformulas. For example, in some embodiments, in Formula II, R 3 and R 4 are linked to an optionally substituted phenyl, for example an optionally substituted 5- or 6-membered heteroaryl having 1 or 2 ring nitrogen atoms, an optionally substituted C 4~7 In some embodiments, the cycloalkyl group of Formula II is a cycloalkyl group (preferably cyclopentyl or cyclohexyl), or an optionally substituted 4- to 7-membered (preferably 6-membered) heterocycle having one or two ring heteroatoms. [ka] Part [ka] where R 5 is defined herein, and phenyl or pyridyl may be, for example, F; Cl; C optionally substituted with 1 to 3 fluorines; 1~4 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, or —CF3; C optionally substituted with 1 to 3 fluorines 1~4 Alkoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, or -OCF; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 It may be further optionally substituted at any available position with one or two substituents independently selected from cycloalkyl, preferably cyclopropyl or cyclobutyl; and -CN. In some embodiments, preferred are R 5 But, -OR 30 or -CR 23 R 24 R 25 In some embodiments, R 5 is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, -CH-CHF, -CH-CF, -CF, -CH-cyclopropyl, -CH-cyclobutyl, -CH-O-CH, -CH-O-C2H, -CH-On-propyl, -CH-O-isopropyl, -C2H-cyclopropyl, -C2H-cyclobutyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, -O-CH-CF, -O-CF, -O-CH-cyclopropyl, -O-CH-cyclobutyl, -O-C2H-cyclopropyl, or -O-C2H-cyclobutyl. In some embodiments, n is 2. In some embodiments, J 1 is CH. In some embodiments, J 2 But N or CR 22 and R22 is defined herein. In some embodiments, R 22 is hydrogen, F, Cl, CN, or methyl. In some embodiments, J 3 In some embodiments, each instance of X in formula II is independently selected from the group consisting of: 20 R 21 and R 20 and R 21 are independently hydrogen or C 1~4 alkyl (e.g., methyl, ethyl, etc.) or R 20 and R 21 together with the carbon to which they are both attached form a cyclopropyl, cyclobutyl, cyclopentyl, or oxetanyl ring. In some embodiments, CR 20 R 21 In units, R 20 and R 21 are both methyl, R 20 and R 21 One of the groups is methyl, and R 20 and R 21 the other of which is ethyl or methoxy, or R 20 and R 21 together with the carbon to which they are both attached form a cyclopropyl, cyclobutyl, or oxetanyl ring. In some embodiments, CR 20 R 21 In units, R 20 and R 21 One of the groups is methyl, and R 20 and R 21 and the other of CR is hydrogen. 20 R 21 In units, R 20 and R 21 are both hydrogen.

[0076] W in formula II is typically —N(R 1 )-C(O)- or -N(R 1)—S(O)—, where either the nitrogen atom, or C(O)— or S(O)— can be directly attached to X; in other words, the formula is bidirectional. Typically, R 1 is hydrogen or C 1~4 For example, in some embodiments, the compound of Formula II can have the formula II-1, II-2, II-3, or II-4: [ka] In the formula, R 3 , R 4 , R 5 , L., J. 1 , J 2 , J 3 , X, and n are defined herein.

[0077] L in Formula II (e.g., Formula II-1, II-2, II-3, or II-4) is typically -(CR A1 R B1 ) t1 -Q 1 -Q 2 -Q 3 -(CR A2 R B2 ) t2 - in which (1)Q 2 is -C(O)- and Q 1 and Q 3 One of the is None, and Q 1 and Q 3 and the other of the two is NR as defined herein. 2 wherein t1 is 0 or 1, t2 is 0 or 1, and preferably both t1 and t2 are 0; and R 2 is hydrogen or methyl, (2)Q 1 , Q 2 , and Q 3 is zero, t1 is 0, t2 is 2, and two adjacent CRs, as defined herein, A2 R B2 but, -C(R A2 )=C(RB2 )-, preferably R A2 and R B2 are both hydrogen, or (3)Q 2 is nothing, and Q 1 and Q 3 One of the is None, and Q 1 and Q 3 and the other of which is NR as defined herein. 2 wherein t1 is 0 or 1, t2 is 0 or 1, and preferably R 2 is hydrogen or methyl, and t1 and t2 are not both 0.

[0078] Also, in formula II, the bivalent linker L, -(CR A1 R B1 ) t1 -Q 1 -Q 2 -Q 3 -(CR A2 R B2 ) t2 - allows the rest of the structure to be chained in either direction. For example, [ka] The unit is the linker -(CR A1 R B1 ) t1 Terminal or linker (CR A2 R B2 ) t2 In some preferred embodiments, NR 2 teeth [ka] It is directly connected to the unit.

[0079] In some embodiments, in Formula II (e.g., Formula II-1, II-2, II-3, or II-4), [ka] The units may be, for example, those suitable in relation to formula I herein below: [ka] may be selected from any of those described as [ka]

[0080] In some embodiments, the present disclosure also provides a compound of formula II-P, or a pharmaceutically acceptable salt thereof: [ka] wherein Het represents an optionally substituted heterocyclic or heteroaryl ring system, preferably a 5- or 6-membered heterocyclic or 5- or 6-membered heteroaryl ring; 5 , J 1 , J 2 , J 3 , L, W, X, and n can be any of those defined herein for Formula II (including subformulas thereof). Preferably, Het is a 5- or 6-membered heteroaryl, and in Formula II-P, R 5 is attached to Het at the ortho position of the linker L. In Formula II-P, R 5 However, it will also be understood that they may be attached to the ring nitrogen as long as balance permits.

[0081] In some embodiments, in Formula II-P, Het is an optionally substituted 5- or 6-membered heteroaryl as described herein, e.g., Het is a 5- or 6-membered heteroaryl, preferably pyrazole, imidazole, oxazole, thiazole, isoxazole, isothiazole, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, which are independently selected from the group consisting of F; Cl; C optionally substituted with 1 to 3 fluorines. 1~4 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, or —CF3; C optionally substituted with 1 to 3 fluorines 1~4Alkoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, or -OCF; C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 C optionally substituted with 1 to 3 substituents independently selected from cycloalkoxy, fluorine, and methyl 3~6 Optionally substituted with one or two (preferably one) substituents selected from cycloalkyl, preferably cyclopropyl or cyclobutyl; and -CN. In some embodiments, preferred are R 5 But, -OR 30 or -CR 23 R 24 R 25 In some embodiments, R 5 is ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, -CH2-CHF2, -CH2-CF3, -CF3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-O-CH3, -CH2-O-C2H5, -CH2-On-propyl, -CH2-O-isopropyl, -C2H4-cyclopropyl, -C2H4-cyclobutyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, -O-CH2-CF3, -O-CF3, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -O-C2H4-cyclopropyl or -O-C2H4-cyclobutyl.

[0082] Formula III In some embodiments, the present disclosure provides a compound of formula III, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X at each occurrence is independently O, NR 10 , and C.R. 20 R 21 Selected from At most one X is O and NR 10 is selected from n is 1, 2, 3, or 4; J 1 , J 2 , and J. 3 are each independently, CR 22 or N, preferably J 1 , J 2 , and J. 3 At least one of them is not N. R 1 is hydrogen, optionally substituted alkyl (e.g., optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), or a nitrogen protecting group; L is selected from NH, O, or [ka] G 1 is optionally substituted phenyl, optionally substituted heteroaryl (e.g., 5- or 6-membered heteroaryl, or 8- to 10-membered bicyclic heteroaryl), or optionally substituted heterocyclyl; During the ceremony, R at each occurrence 10 are independently hydrogen, a nitrogen protecting group, an optionally substituted alkyl (e.g., an optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), optionally substituted C 3~8 a carbocyclic ring or an optionally substituted 3- to 8-membered heterocyclic ring; R at each occurrence 20 and R 21 are each independently hydrogen, halogen, -OR 31 , -NR 13 R 14 , optionally substituted alkyl (e.g., optionally substituted C 1~6alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), optionally substituted C 3~8 or an optionally substituted 5- to 10-membered carbocycle, an optionally substituted 3- to 8-membered heterocycle, an optionally substituted phenyl, or an optionally substituted 5- to 10-membered heteroaryl; R 10 and R 20 and R 21 are linked to form a bond, an optionally substituted 4- to 8-membered heterocycle, or an optionally substituted 5- or 6-membered heteroaryl ring, and R 20 and R 21 another of which is as defined above or R 20 and R 21 together with the carbon to which they are both attached, -C(O)-, optionally substituted C 3~8 forming a carbocyclic or optionally substituted 3- to 8-membered heterocyclic ring, or 1 CR 20 R 21 R in 20 and R 21 One of them is a different CR 20 R 21 R in 20 and R 21 a bond, optionally substituted C 3~8 forming a carbocyclic or optionally substituted 3- to 8-membered heterocyclic ring, R 20 and R 21 another of which is defined above, R at each occurrence 22 are independently hydrogen, halogen, optionally substituted alkyl (e.g., optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), -CN, -S(O)-alkyl (e.g., -S(O)-C 1~6alkyl), -S(O)2-alkyl (e.g., -S(O)2-C 1~6 alkyl), or -OR 31 and During the ceremony, R at each occurrence 13 and R 14 each independently being hydrogen, a nitrogen protecting group, an optionally substituted alkyl (e.g., an optionally substituted C 1~6 alkyl), optionally substituted Alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), optionally substituted C 3~8 carbocycle, an optionally substituted 3- to 8-membered heterocycle, an optionally substituted phenyl, or an optionally substituted 5- to 10-membered heteroaryl, or R 13 and R 14 are linked to form an optionally substituted 3- to 8-membered heterocycle or an optionally substituted 5- to 10-membered heteroaryl; R at each occurrence 31 is hydrogen, an oxygen protecting group, an optionally substituted alkyl (e.g., an optionally substituted C 1~6 alkyl), optionally substituted alkenyl (e.g., optionally substituted C 2~6 alkenyl), optionally substituted alkynyl (e.g., optionally substituted C 2~6 alkynyl), optionally substituted C 3~8 It is a carbocycle, an optionally substituted 3- to 8-membered heterocycle, an optionally substituted phenyl, or an optionally substituted 5- to 10-membered heteroaryl.

[0083] In some embodiments, the compound of formula III can have formula III-1 or III-2: [ka] In the formula, R 1 , G 1 , J 1 , J 2 , J 3 , X and n are defined herein.

[0084] In some embodiments, in formula III (e.g., III-1 or III-2), [ka] may be any of those described for Formula I (including subformulas thereof). For example, in some embodiments, in Formula III (e.g., III-1 or III-2), [ka] can be selected from the following: [ka]

[0085] In some embodiments, in Formula III (e.g., III-1 or III-2), [ka] can be selected from the following: [ka]

[0086] In some embodiments, in Formula III (e.g., III-1 or III-2), [ka] can be selected from the following: [ka]

[0087] In some embodiments, in Formula III (e.g., Formula III-1 or III-2), [ka] may be any of the corresponding moieties shown in Compound Nos. 1-138 disclosed herein, as appropriate.

[0088] G in Formula III 1 is typically an optionally substituted phenyl or an optionally substituted heteroaryl, including any of those described herein.

[0089] In some embodiments, the compound of formula III is characterized by having the formula III-1, wherein G 1 is an optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 8- to 10-membered bicyclic heteroaryl. In some embodiments, the compound of formula III is characterized by having the formula III-1, wherein G 1 is selected from the following: [ka] wherein each of the groups is optionally selected from, for example, each independently, halogen (e.g., Cl), C 1~4 Alkyl, CN, hydroxyl, COOH, C(O)-O-(C 1~4 In some embodiments, the compound of formula III is characterized by having the formula III-1, wherein G is further substituted with one or two substituents such as alkyl. 1 but: [ka] The bicyclic heteroaryl is unsubstituted or further substituted with one or two (preferably one) substituents. When substituted, the substituents can be independently selected from Cl, methyl, and hydroxyl. G in Formula III-1 1 Representative heteroaryls suitable as are shown in the compounds exemplified herein.

[0090] In some embodiments, the compound of formula III is characterized by having the formula III-2, wherein G 1 is in formula I [ka] can be any of those described herein suitable as a moiety (e.g., any applicable subformula). For example, in some embodiments, the compound of formula III is characterized by having the formula III-2, wherein G 1 can be selected from any of the following: [ka]

[0091] In some embodiments, the present disclosure also provides a compound selected from Compound Nos. 1-138, or a pharmaceutically acceptable salt thereof: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8]

[0092] In some embodiments, to the extent applicable, the genera of compounds described herein also exclude any specifically known single compound(s) prior to the present disclosure. In some embodiments, to the extent applicable, any sub-genus of compounds prior to the present disclosure that is entirely within the genus of compounds described herein may also be excluded from such genus herein.

[0093] Synthesis method The compounds of the present disclosure may be readily synthesized by one of ordinary skill in the art in light of the present disclosure, and exemplary syntheses are also provided in the Examples section.

[0094] The synthesis of compounds of formula I-1 shown in Scheme 1 is representative of methods for preparing compounds herein. [ka]

[0095] As shown in Scheme 1, compounds of formula I-1 can typically be prepared by an amide coupling reaction between suitable coupling partners S-1 and S-2. Amide coupling reaction conditions are generally known to those skilled in the art and are also exemplified in the Examples section of this specification. Typically, acid S-1 can be converted to an activated form, such as an acyl chloride, anhydride, or activated ester, and then reacted with amine S-2 to form compounds of formula I-1. For example, the Examples section describes a representative EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide)-mediated amide coupling reaction. Acid S-1 and amine S-2 are readily available or can be prepared by those skilled in the art in light of the present disclosure. R 1 , R 2 , R 5 , R 100 , J 1, J 2 , J 3 The variables X, p, and n are defined herein in relation to formula I-1. Typically, R in S-2 2 is hydrogen. Other compounds of formula I, IP, II, or II-P having an amide bond can be prepared similarly.

[0096] Compounds of Formula I, IP, II, II-P, or III that are not connected by an amide bond can typically be prepared by other cross-coupling reactions known to those skilled in the art, such as various palladium-catalyzed cross-coupling reactions, such as the Hartwig-Buchwald amination, the Heck reaction, the Suzuki reaction, etc. Exemplary procedures are described in the Examples section herein.

[0097] As will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting particular functional groups, are well known in the art. For example, numerous protecting groups are described in "Protective Groups in Organic Synthesis," 4 th ed. P.G.M.Wuts; T.W.Greene, John Wiley, 2007, and the references cited therein. The reagents for the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) and Sigma (St. Louis, Missouri, USA). Others are described, for example, in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (Wiley, 7 th These compounds can be prepared by the procedures described in any of the standard reference texts, such as "The Organic Synthesis of Plants," ...

[0098] Pharmaceutical Composition Certain embodiments are directed to pharmaceutical compositions comprising one or more compounds of the present disclosure.

[0099] The pharmaceutical composition may optionally contain a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), Formula IP, Formula II (e.g., Formula II-1, II-2, II-3, or II-4), Formula II-P, Formula III (e.g., Formula III-1 or III-2), or any of Compound Nos. 1-138, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are known in the art. Non-limiting examples of suitable excipients include encapsulating materials or additives such as absorbance enhancers, antioxidants, binders, buffers, carriers, coating agents, colorants, diluents, disintegrants, emulsifiers, bulking agents, fillers, flavoring agents, humectants, lubricants, flavoring agents, preservatives, propellants, release agents, sterilizing agents, sweeteners, solubilizers, wetting agents, and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 21st Edition, A.R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005, incorporated herein by reference), which discloses various excipients used in formulating pharmaceutical compositions and known techniques for their preparation.

[0100] The pharmaceutical composition may comprise any one or more of the compounds of the present disclosure. For example, in some embodiments, the pharmaceutical composition comprises a compound of Formula I (e.g., Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), Formula IP, Formula II (e.g., Formula II-1, II-2, II-3, or II-4), Formula II-P, Formula III (e.g., Formula III-1 or III-2), or any of Compound Nos. 1 to 138, or a pharmaceutically acceptable salt thereof, for example, in a therapeutically effective amount. In any of the embodiments described herein, a pharmaceutical composition may include a therapeutically effective amount of a compound selected from Compound Nos. 1-138 (e.g., any of the compounds having an activity level of A or B shown in Table 3 of the present disclosure), or a pharmaceutically acceptable salt thereof. In some preferred embodiments, a pharmaceutical composition may include a therapeutically effective amount of any compound of the present disclosure having an efficacy in inhibiting ALDH1a3 comparable to that of Compound 1 or more, e.g., as measured by any of the methods described herein. In some preferred embodiments, a pharmaceutical composition may include a therapeutically effective amount of any compound of the present disclosure having an IC50 value of less than 250 nM (preferably less than 100 nM, e.g., about 1-100 nM, about 10-100 nM, about 10-50 nM, about 20-100 nM, about 20-50 nM, etc.) in inhibiting hALDH1a3, as measured by the methods described herein according to Biological Example 5B.

[0101] Pharmaceutical compositions may also be formulated for delivery via any of the known delivery routes, including, but not limited to, oral, parenteral, inhalation, etc. For example, in some embodiments, a pharmaceutical composition is administered to a subject orally, nasally, transdermally, pulmonary, inhalation, buccal, sublingually, intraperitoneally, or intradermally. It may be formulated for administration intravenously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally or parenterally.

[0102] In some embodiments, pharmaceutical compositions can be formulated for oral administration.Oral preparations can be presented in individual units such as capsules, pills, cachets, lozenges or tablets, each containing a predetermined amount of active compound as powder or granules, as a solution or suspension in aqueous or non-aqueous liquid, or as oil-in-water or water-in-oil emulsion.The excipients used to prepare compositions for oral administration are known in the art. Non-limiting examples of suitable excipients include agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, peanut oil, hydroxypropyl methylcellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol sorbitol), soybean oil, stearic acid, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

[0103] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (intravenous injection or infusion, subcutaneous or intramuscular injection, etc.). Parenteral formulations may be, for example, aqueous solutions, suspensions, or emulsions. Excipients for the preparation of parenteral formulations are known in the art. Non-limiting examples of suitable excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, peanut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, USP or saline solution, water, and mixtures thereof.

[0104] In some embodiments, pharmaceutical compositions are formulated for inhalation.Inhalable formulations can be formulated as aerosols that can be administered through nasal sprays, dry powders, or metered dose inhalers.The excipients used to prepare inhalation formulations are known in the art.Non-limiting suitable excipients include, for example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, and mixtures of these substances.Sprays can also contain propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0105] The compounds of the present disclosure can be used alone, in combination with each other, or in combination with one or more additional therapeutic agents, such as metformin, recombinant insulin, liraglutide, semaglutide, empagliflozin, paclitaxel, doxorubicin, 5-fluorouracil, tamoxifen, octreotide, etc. When used in combination with one or more additional therapeutic agents, the compounds of the present disclosure or the pharmaceutical compositions herein can be administered to a subject in any order, either simultaneously or sequentially, with such additional therapeutic agents. In some embodiments, the pharmaceutical composition can contain one or more compounds of the present disclosure and one or more additional therapeutic agents in a single composition. In some embodiments, the pharmaceutical composition containing one or more compounds of the present disclosure can be included in a kit that also contains a separate pharmaceutical composition containing one or more additional therapeutic agents.

[0106] As discussed herein, the compounds of the present disclosure can sensitize cancer to chemotherapy treatment.In some embodiments, the compounds of the present disclosure can be used in combination with chemotherapeutic agents, for example, to treat cancer.Any known chemotherapeutic agent can be used in combination with one or more compounds of the present disclosure. Non-limiting useful examples of chemotherapeutic agents include antineoplastic agents and combinations thereof, for example, DNA alkylating agents (e.g., nitrogen mustards such as cisplatin, oxaliplatin, carboplatin, cyclophosphamide, ifosfamide, etc., nitrosoureas such as bendamustine, melphalan, chlorambucil, busulfan, temozolamide, and carmustine), antimetabolites (e.g., antifolates such as gemcitabine and fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea), antitumor antibiotics (e.g., adriamycin, bleomycin, doxorubicin, liposomal doxorubicin, pirarubicin, daunomycin, valrubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin, amuromycin, rifametidine ... anthracyclines such as vicine, and mithramycin), mitotic inhibitors (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids such as taxol, taxotere, and polokinase inhibitors), and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, irinotecan, topotecan, and camptothecin), inhibitors of DNA repair mechanisms such as CHK kinase, DNA-dependent protein kinase inhibitors, inhibitors of poly(ADP-ribose) polymerase (PARP inhibitors including olaparib), and Hsp90 inhibitors such as tanespimycin and retaspimycin, inhibitors of ATR kinase (e.g., AZD6738), and inhibitors of WEE1 kinase (e.g., AZD1775 / MK-1775).

[0107] In some embodiments, compounds of the present disclosure may also be used to treat type 2 diabetes in combination with one or more additional therapeutic agents useful in the treatment of type 2 diabetes, such as metformin, recombinant insulin, liraglutide, semaglutide, empagliflozin, etc.

[0108] A pharmaceutical composition may contain various amounts of the compound of the present disclosure, depending on various factors such as the intended use and efficacy and selectivity of the compound. In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of the compound of the present disclosure. In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of the compound of the present disclosure and a pharmaceutically acceptable excipient. As used herein, the therapeutically effective amount of the compound of the present disclosure is an amount effective to treat the disease or disorder described herein, and may depend on the recipient to be treated, the disease or disorder to be treated and its severity, the composition containing the compound, the timing of administration, the route of administration, the duration of treatment, the efficacy of the compound, its clearance rate, and whether another drug is administered in combination.

[0109] Treatment method The compounds of the present disclosure have various uses.For example, the compounds of the present disclosure can be used as therapeutic active substances for the treatment and / or prevention of aldehyde dehydrogenase-related diseases or disorders, preferably aldehyde dehydrogenase isoform 1a3 (ALDH1a3)-related diseases or disorders, such as proliferative diseases or disorders, metabolic diseases or disorders, endothelial cell or smooth muscle cell diseases or disorders, metastasis, etc.Therefore, some embodiments of the present disclosure also relate to the method of using one or more compounds of the present disclosure to inhibit ALDH enzymes, such as ALDH1a3, and to treat or prevent various cancers, cancer metastasis, and / or other ALDH1a3-mediated diseases and disorders, such as type 2 diabetes, pulmonary arterial hypertension (PAH) and neointimal hyperplasia (NIH).

[0110] Aldehyde dehydrogenase isoform 1a3 (ALDH1a3) is a cell- and disease-specific isoform / isoenzyme of the ALDH1a subfamily that is crucial for RA biosynthesis and RA signaling regulation. ALDH1a3 was known as ALDH6 before 2000, but has been known as Raldh3 in developmental studies since 2000–2007. Under normal conditions, ALDH1a3 is required only during embryonic development and is dispensable in healthy adult mice. In adult physiology, humans with homozygous inactivating mutations in Aldh1a3 have been described as having incompletely penetrant anophthalmia and no other documented pathology. In contrast to its minor role in normal physiology, ALDH1a3 has recently been shown to be a major determinant of ALDEFLUOR™ responsiveness in most cancer types and dedifferentiated pancreatic islet cells. ALDEFLUOR activity has long been used as a marker to distinguish aggressive cancer cells from the majority of tumors, despite significant ignorance regarding whether ALDEFLUOR activity influences tumor progression.

[0111] ALDEFLUOR™ activity driven by ALDH1a3 has been found to be a functional driver of cancer aggressiveness and important for tumor progression, metastasis, and resistance to chemotherapy. Thus, human ALDH1a3 (UniProtKB Accession Number: P47895) is a functional driver of chemotherapy resistance and metastatic phenotypes in cancers, including breast cancer. Therefore, ALDH1a3 represents a potential therapeutic target in multiple pathologies, and targeting ALDH1a3 may overcome current barriers in the treatment of stage 3 / 4 patients whose tumors are resistant to conventional forms of therapy.

[0112] ALDH1a3 in developmental and adult physiology, mechanism of action While certain enzymes within the ALDH family have well-characterized substrate preferences, regulation, and functions, most members of this family are poorly studied or their primary mechanisms of action are not understood. For example, it has been shown how ALDH1L1 and ALDH1L2 function in folate metabolism by oxidizing 10-formyl-THF. Another important example of a well-characterized ALDH enzyme is ALDH3a1, which constitutes 50% of soluble corneal protein and functions to protect the retina and cornea from UV-induced oxidative damage by oxidizing 4-hydroxynonenal. Perhaps the most studied ALDH enzyme is ALDH2, which is a key catalyst for the oxidation of acetylaldehyde to acetate in liver mitochondria. ALDH2 is inhibited by ANTABUSE® (disulfiram), a therapy given to alcoholics to prevent substance abuse. On the other hand, the ALDH1a subfamily has shown widespread importance in developmental biology and various pathologies, but its mechanism of action and tumor-related regulatory factors remain unclear.

[0113] The ALDH1a subfamily is the most disease-associated group of the ALDH family and has recently been the focus of considerable research, given its importance to developmental biology and the remarkable ability of the ALDEFLUOR™ assay (Stem Cell Technology) to identify stem-like cells, particularly in cancer. As described herein, the ALDEFLUOR™ assay primarily measures activity from ALDH1a3, such as pancreatic cells from diabetic mice.

[0114] Complete knockout of ALDH1a3 results in postnatal death in mice due to a nasal closure defect. Importantly, this phenotype can be rescued by supplementation with all-trans retinoic acid during a short period of gestation, allowing normal adulthood. In humans, homozygous mutations in ALDH1a3 are associated with small-eye disease, although this phenotype is not fully penetrant and no additional pathology is evident. No mention has been made of this. Further supporting the idea that ALDH1a3 is developmentally restricted, recent studies have shown that ALDH1a3 is specifically suppressed in certain developmental tissues, preventing vitamin A signaling. Additional analysis has shown that ALDH1a3 is not required for the developing ovary, but is expressed only in the adult prostate and salivary gland. Among the colon, liver, lung, bladder, prostate, and ovary, only the ovary has a significant ALDEFLUOR™-positive population, and this small population is only partially inhibited by ALDH1a3 inhibitors.

[0115] In metabolic diseases, ALDH1a3 is a marker of pancreatic islet cell dysfunction. Evidence indicates that pancreatic beta cells do not die during the progression of type 2 diabetes, but rather dedifferentiate into non-exocrine cells that are no longer capable of regulating blood glucose through insulin secretion. The FOXO1 transcription factor represses Aldh1a3 in normal pancreatic cells, but this repression is lost during progression to type 2 diabetes. Studies on pancreatic islets extracted from clinical patients with type 2 diabetes have observed dedifferentiation and verified that these cells are marked with Aldh1a3. Interventions to reduce the progression of type 2 diabetes, such as pair-feeding, similarly reduce Aldh1a3 expression. Additional studies have shown that ALDH1a3 expression directly reduces insulin secretion by islet cell clones while increasing glucagon secretion. Treatment of diabetic Otsuka Long-Evans Tokushima Fatty rats with disulfiram, a broad-specificity inhibitor of the Aldh1a enzyme, increases insulin secretion while lowering plasma glucose and triglyceride levels. This suggests that ALDH1a3 may also contribute to the pathology of metabolic diseases such as type 2 diabetes.

[0116] ALDH1a3 is also involved in diseases or disorders of endothelial cells or smooth muscle cells, such as pulmonary arterial hypertension (PAH) and neointimal hyperplasia (NIH), see, for example, Rabinovitch, M. et al. NIH Project No. 2R01HL074186-14, Li, D. et al. Circulation 138(Supp.1):abstract 17192(2018), and Xie, X. et al. iScience 19:872-882(2019).

[0117] Taken together, these results suggest that targeted inhibition of ALDH1a3 may be effective in treating various diseases described herein, including various cancers, metastases, and metabolic syndromes such as type 2 diabetes. These studies also suggest that ALDH1a3 may be ablated without significant target toxicity. The data indicate that ALDH1a3 is dispensable in adult mammals. Inhibition of ALDH1a3 during pregnancy is likely contraindicated due to loss of retinoic acid signaling.

[0118] Published studies primarily support two mechanisms for the cancer-promoting effects of ALDH1a3. These can be divided into detoxification of reactive oxygen species or oxidation of retinal to bioactive retinoic acid. There are multiple reasons why the number of papers detailing the functional consequences of ALDH1a3 expression is inconsistent compared to those addressing its mechanism of action. Primarily, reactive oxygen species are transient and difficult to detect. Current methods use fluorescent reporters such as DCFDA and DHE, both of which are insensitive. Furthermore, oxidative stress in vitro does not reflect in vivo conditions. While attempts have been made to induce oxidative stress in vitro using paclitaxel and detect it via DCFDA, the detection range of this assay is smaller than the inherent deviations in the data. However, additional literature evidence supports an ROS-related mechanism: ALDH1a3 has been found to detoxify 4-HNE in stallion sperm samples, which leads to improved motility. In type 2 diabetes, disease progression occurs in some instances as a result of lipotoxicity caused by a high-fat diet. Considering the pathological mechanisms of Aldh1a3 in type 2 diabetes, Aldh1a3 may be an important mediator of pancreatic beta cell dedifferentiation. ALDH1a3 also plays a key role in the radioactivity of head and neck squamous cell carcinoma (SCC). It is also induced by radiotherapy, indicating that it may respond to cell damage.

[0119] Interestingly, a high-profile study in melanoma has shown that oxidative stress is a major determinant of metastatic dissemination. In this study, while oxidative stress is absent in primary tumors, it is dramatically induced, affecting the fitness of metastatic cells. Systemic antioxidant delivery can then promote lung metastasis in normally nonmetastatic cells. Manipulation of ALDH1a3 expression does not strongly affect primary tumor growth until challenged with oxidative stressors such as chemotherapy. Meanwhile, the greatest effect of ALDH1a3 inhibition has been observed in lung or bone metastases, sites of high levels of oxidative stress (Figures 9A-10B).

[0120] Studying ALDH1a3-dependent retinoic acid (RA) signaling is similarly challenging because it requires exogenous supplementation of retinal in tissue culture conditions, far removed from the tumor microenvironment. Data have been developed demonstrating genetic correlations between each of the ALDH1a enzymes and components of the RA signaling pathway in tumors from breast cancer patients, and among ALDH1a1, ALDH1a2, and ALDH1a3, ALDH1a3 is least correlated with components of the RA signaling pathway in breast tumors.

[0121] The functional importance of ALDH1a3 for treatment resistance, tumor progression, and metastasis across most solid tumor types makes it an attractive target for drug discovery. Combined with its low potential for target toxicity, systemic pharmacological inhibition of ALDH1a3 alone or in combination with other therapeutic agents (e.g., approved therapeutics) is expected to be useful in treating primary cancers, as well as late-onset and overt metastatic disease.

[0122] In some embodiments, the present disclosure provides a method of inhibiting aldehyde dehydrogenase, particularly ALDH1a3, in a subject in need thereof. In some embodiments, the method comprises administering an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formulas 10-13), 11-14, 11-15, 11-16, 11-17, 11-18, 11-19, 11-20, 11-21, 11-22, 11-23, 11-24, 11-25, 11-26, 11-27, 11-28, 11-29, 11-30, 11-31, 11-32, 11-33, 11-34, 11-35, 11-36, 11-37, 11-38, 11-40, 11-41, 11-42, 11-43, 11-44, 11-45, 11-46, 11-47, 11-48, 11-49, 11-50, 11-51, 11-52, 11-53, 11-54, 11-55, 11-56, 11-57, 11-58, 11-59, 11-60, 11-61, 11-62, 11-63, 11-64, 11-65, 11-66, 11-67, 11-68, 11-69, 11-70, 11-71, 11-72, 11-73, 11-74, 11-75, 11- In some embodiments, the subject suffers from a disease or disorder associated with aldehyde dehydrogenase, preferably a disease or disorder associated with aldehyde dehydrogenase isoform 1a3 (ALDH1a3) in a subject in need thereof. For example, in some embodiments, the subject suffers from a proliferative disease (e.g., as described herein) such as cancer. In some embodiments, the subject suffers from a metabolic disease such as type 2 diabetes. In some embodiments, the subject suffers from an endothelial cell or smooth muscle cell disease or disorder such as pulmonary arterial hypertension or neointimal hyperplasia.

[0123] In some embodiments, the present disclosure also provides a method of treating a disease or disorder associated with aldehyde dehydrogenase, preferably a disease or disorder associated with aldehyde dehydrogenase isoform 1a3 (ALDH1a3), in a subject in need thereof. In some embodiments, the method includes administering an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formulas I-O, I-F, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), Formula IP, Formula II (e.g., Formula II-1, II-2, II-3, or II-4), Formula II-P, Formula III (e.g., Formula III-1 or III-2), or any of Compound Nos. 1-138). The method comprises administering a compound or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition described herein. In some embodiments, the disease or disorder is associated with aldehyde dehydrogenase isoform 1a3 (ALDH1a3) in the subject. For example, in some embodiments, the disease or disorder is a proliferative disease (e.g., as described herein), such as cancer, associated with aldehyde dehydrogenase isoform 1a3 (ALDH1a3). In some embodiments, the disease or disorder is a metabolic disease, such as type 2 diabetes, associated with aldehyde dehydrogenase isoform 1a3 (ALDH1a3). In some embodiments, the disease or disorder is an endothelial cell or smooth muscle cell disease or disorder, such as pulmonary arterial hypertension or neointimal hyperplasia, associated with aldehyde dehydrogenase isoform 1a3 (ALDH1a3).

[0124] In some embodiments, the present disclosure provides a method of treating cancer in a subject in need thereof. In some embodiments, the method includes administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formulas I-O, I-F, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), Formula IP, Formula II (e.g., Formula II-1, II-2, II-3, or II-4), Formula II-P, Formula III (e.g., Formula III-1 or III-2), or any of Compound Nos. 1-138, or a pharmaceutically acceptable salt thereof), or a therapeutically effective amount of a pharmaceutical composition described herein.

[0125] The methods herein are not particularly limited to any particular cancer type. As shown in the Examples section, many cancer types have been shown to have ALDH1a3 activity that can be inhibited by representative compounds of the present disclosure. In some embodiments, the cancer is a solid cancer. In some embodiments, the cancer is a metastatic cancer or chemotherapy-resistant cancer. In some embodiments, the cancer may be breast cancer, colorectal cancer, kidney cancer, ovarian cancer, gastric cancer, thyroid cancer, testicular cancer, cervical cancer, nasopharyngeal cancer, esophageal cancer, bile duct cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, blood cancer, brain cancer, liver cancer, mesothelioma, melanoma, and / or sarcoma. In some embodiments, the cancer is breast cancer (e.g., (e.g., ER-negative breast cancer, triple-negative breast cancer, basal-like breast cancer, or HER2-positive breast cancer), clear cell renal cell carcinoma, gastric cancer, bladder cancer, ovarian cancer, squamous cell lung cancer, colorectal cancer, or glioma (e.g., low-grade glioma). In some embodiments, the cancer may also be any of those described as treatable with ALDH1a3 inhibitors in PCT / US2019 / 044278, international filing date July 31, 2019, the contents of which are incorporated by reference in their entirety.

[0126] In some embodiments, the cancer has already metastasized. In some embodiments, the cancer has not metastasized before treatment using the methods herein, and the method comprises administering an effective amount of one or more compounds of the present disclosure to delay or prevent metastasis of the cancer. In any of the embodiments described herein, the cancer is associated with ALDH1a3 activity, e.g., has a high expression level compared to a control, and / or has cancer cells with ALDH1a3 activity, e.g., positive in an Aldefluor™ assay, which can be reduced with an ALDH1a3 inhibitor or gene knockout or knockdown. In some embodiments, the method further comprises administering to the subject an effective amount of a second anti-cancer therapy, e.g., a chemotherapeutic agent (e.g., paclitaxel, as described herein) or a therapeutic antibody.

[0127] In some embodiments, the present disclosure provides a method of treating metastatic cancer in a subject in need thereof, the method comprising administering to a subject a therapeutically effective amount of a compound of the present disclosure (e.g., of Formula I (e.g., Formulas I-O, I-F, I-1, I-2, I-1-A, I-2-A, I-1-A) The present invention relates to a method for treating metastatic cancer, the method comprising administering to a subject a compound of Formula I-1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), Formula IP, Formula II (e.g., Formula II-1, II-2, II-3, or II-4), Formula II-P, Formula III (e.g., Formula III-1 or III-2), or any of Compound Nos. 1-138, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments, the metastatic cancer is a solid cancer. In some embodiments, the metastatic cancer may be metastatic breast cancer, metastatic colorectal cancer, metastatic kidney cancer, metastatic ovarian cancer, metastatic gastric cancer, metastatic thyroid cancer, metastatic testicular cancer, metastatic cervical cancer, metastatic nasopharyngeal cancer, metastatic esophageal cancer, metastatic bile duct cancer, metastatic lung cancer, metastatic pancreatic cancer, metastatic prostate cancer, metastatic bone cancer, metastatic blood cancer, metastatic brain cancer, metastatic liver cancer, metastatic mesothelioma, metastatic melanoma, and / or metastatic sarcoma. In some embodiments, the cancer is metastatic breast cancer (e.g., ER-negative breast cancer, triple-negative breast cancer, basal-like breast cancer, or HER2-positive breast cancer), metastatic clear cell renal cell carcinoma, metastatic gastric cancer, metastatic bladder cancer, metastatic ovarian cancer, metastatic squamous cell lung cancer, metastatic colorectal cancer, or metastatic glioma (e.g., low-grade glioma). In some embodiments, the metastatic cancer is associated with ALDH1a3 activity. In some embodiments, the metastatic cancer may be breast cancer with established lung, colorectal, and / or bone metastases. In some embodiments, the method further includes administering to the subject an effective amount of a second anti-cancer therapy, e.g., a chemotherapeutic agent (e.g., as described herein, such as paclitaxel) or a therapeutic antibody.

[0128] In some embodiments, the present disclosure provides a method of treating chemotherapy-resistant cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula 10, 1F, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), Formula IP, Formula II (e.g., Formula II-1, II-2, II-3, or II-4), Formula II-P, Formula III (e.g., Formula III-1 or III-2), or any of Compound Nos. 1-138, or a pharmaceutically acceptable salt thereof), or a therapeutically effective amount of a pharmaceutical composition described herein to the subject. As used herein, "chemoresistant cancer" refers to a cancer that does not respond to treatment with one or more chemotherapeutic agents. "Chemoresistant cancer" includes cancers that do not respond to treatment with one or more therapeutic agents at the start of treatment, and cancers that do not respond to treatment with one or more therapeutic agents during treatment. Chemoresistant cancers particularly suitable for treatment using the methods described herein include, but are not limited to, cancers that are resistant to treatment with paclitaxel and / or doxorubicin. In some embodiments, the chemotherapy resistant cancer is a solid cancer. In some embodiments, the chemotherapy resistant cancer may be breast cancer, colorectal cancer, kidney cancer, ovarian cancer, gastric cancer, thyroid cancer, testicular cancer, cervical cancer, nasopharyngeal cancer, esophageal cancer, bile duct cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, blood cancer, brain cancer, liver cancer, mesothelioma, melanoma, and / or sarcoma. In some embodiments, the cancer may be breast cancer (e.g., triple-negative breast cancer), clear cell renal cell carcinoma, gastric cancer, bladder cancer, ovarian cancer, squamous cell lung cancer, colorectal cancer, or glioma (e.g., low-grade glioma). In some embodiments, the chemotherapy-resistant cancer is associated with ALDH1a3 activity. In some embodiments, the method further comprises administering to the subject an effective amount of a second anti-cancer therapy, for example, a chemotherapeutic agent (e.g., paclitaxel, etc., as described herein) or a therapeutic antibody.

[0129] In some embodiments, the present disclosure provides a method of sensitizing cancer to chemotherapy in a subject in need thereof, the method comprising administering to a subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formulas IO, IF, I-1, I-2, I-1-A, I-2-B, I-2-C, I-2-D, I-2-E, I-2-F, I-2-G, I-2-H, I-2-I ... The method includes administering to a subject a compound of Formula I-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), Formula IP, Formula II (e.g., Formula II-1, II-2, II-3, or II-4), Formula II-P, Formula III (e.g., Formula III-1 or III-2), or any of Compound Nos. 1-138, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition described herein. Typically, this method can cause the cancer to be more responsive to treatment with a chemotherapeutic agent. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer may be breast cancer, colorectal cancer, kidney cancer, ovarian cancer, gastric cancer, thyroid cancer, testicular cancer, cervical cancer, nasopharyngeal cancer, esophageal cancer, bile duct cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, blood cancer, brain cancer, liver cancer, mesothelioma, melanoma, and / or sarcoma. In some embodiments, the cancer is associated with ALDH1a3 activity. In some embodiments, the method further comprises administering to the subject an effective amount of a second anti-cancer therapy, for example, a chemotherapeutic agent (e.g., paclitaxel, etc., as described herein) or a therapeutic antibody.

[0130] In some embodiments, the present disclosure provides a method of treating or preventing cancer metastasis in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula 10, 1F, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), Formula IP, Formula II (e.g., Formula II-1, II-2, II-3, or II-4), Formula II-P, Formula III (e.g., Formula III-1 or III-2), or any of Compound Nos. 1-138, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition described herein. In some embodiments, the cancer is a solid cancer. In some embodiments, the cancer may be breast cancer, colorectal cancer, kidney cancer, ovarian cancer, gastric cancer, thyroid cancer, testicular cancer, cervical cancer, nasopharyngeal cancer, esophageal cancer, bile duct cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, blood cancer, brain cancer, liver cancer, mesothelioma, melanoma, and / or sarcoma. In some embodiments, the cancer is associated with ALDH1a3 activity. In some embodiments, the cancer has already metastasized. In some embodiments, the cancer has not metastasized before treatment with the methods herein, and the methods delay or prevent metastasis of the cancer. In some embodiments, the methods further include administering to the subject an effective amount of a second anti-cancer therapy, such as a chemotherapeutic agent (e.g., paclitaxel, etc.) or a therapeutic antibody.

[0131] In some embodiments, the present disclosure provides a method of treating or preventing a metabolic disease, such as type 2 diabetes, in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formulas 10-18, 11-19, 12-20, 13-21, 13-22, 13-23, 13-24, 13-25, 13-26, 13-27, 13-28, 13-29, 13-30, 13-31, 13-32, 13-33, 13-34, 13-35, 13-36, 13-37, 13-38, 13-39, 13-40, 13-41, 13-42, 13-43, 13-44, 13-45, 13-46, 13-47, 13-48, 13-49, 13-50, 13-51, 13-52, 13-53, 13-54, 13-55, 13-56, 13-57, 13-58, 13-59, 13-60, 13-61, 13-62, 13-63, 13-64, 13-65, 13-66, 13-67, 13-68, 13-69, 13-70, 13-71, 13-72, 13-73, 13-74, 13-75, 13-76, 13-77, 13-78, 13-79, 13-80, 1 As discussed herein, metabolic diseases such as type 2 diabetes are associated with pathology caused by ALDH1a3 activity. In some embodiments, the method further comprises administering to the subject an effective amount of an additional anti-metabolic disease agent, such as an anti-2 diabetes agent. Suitable additional anti-metabolic disease agents include, but are not limited to, incretin mimetics, recombinant insulin, biguanides, SGLT2 inhibitors, therapeutic antibodies, and the like. For example, any known type 2 diabetes treatment can be used in combination with the compounds of the present disclosure to treat type 2 diabetes (e.g., as described herein) or to treat or prevent other metabolic syndromes.

[0132] In some embodiments, the present disclosure provides a method of treating an endothelial cell or smooth muscle cell disease or disorder, such as pulmonary arterial hypertension or neointimal hyperplasia, in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formulas I-O, I-F, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), Formula IP, Formula II (e.g., Formula II-1, II-2, II-3, or II-4), Formula II-P, Formula III (e.g., Formula III-1 or III-2), or any of Compound Nos. 1-138, or a pharmaceutically acceptable salt thereof), or a therapeutically effective amount of a pharmaceutical composition described herein to the subject. In some embodiments, the endothelial cell or smooth muscle cell disease or disorder is associated with a pathology caused by ALDH1a3 activity. In some embodiments, the endothelial cell or smooth muscle cell disease or disorder is pulmonary arterial hypertension. In some embodiments, the endothelial cell or smooth muscle cell disease or disorder is neointimal hyperplasia.

[0133] Also provided herein are methods for inhibiting the proliferation of cancer cells (e.g., metastatic cancer cells, chemotherapy-resistant cancer cells). The methods include administering (e.g., an effective amount of) one or more compounds of the present disclosure to the cells. In certain embodiments, the cancer cells are breast cancer cells (e.g., basal-like breast cancer cells or HER-2-positive breast cancer cells). The cells may be cultured cells (e.g., cell lines) or cells of a subject. In certain embodiments, the cells are present in a human subject (e.g., a human subject with cancer).

[0134] In any of the embodiments described herein, the compounds of the present disclosure listed in the methods herein can be any of the compounds having an activity level of A or B shown in Table 3 of the present disclosure. In some embodiments, the compounds of the present disclosure listed in the methods herein can also be any compound of the present disclosure having an efficacy in inhibiting ALDH1a3 comparable to that of Compound 1 or more, as measured, for example, by any of the methods described herein. In some preferred embodiments, the compounds of the present disclosure listed in the methods herein can be any compound of the present disclosure having an IC50 value of less than 250 nM (preferably less than 100 nM, e.g., about 1-100 nM, about 10-100 nM, about 10-50 nM, about 20-100 nM, about 20-50 nM, etc.) in inhibiting hALDH1a3, as measured by the methods described herein according to Biological Example 5B.

[0135] The administration in the method herein is not limited to any particular administration route.For example, in some embodiments, administration can be oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal and parenteral.In some embodiments, administration is oral.

[0136] As discussed herein, the compounds of the present disclosure can be used as monotherapy or combination therapy. In some embodiments according to the methods described herein, the compounds of the present disclosure can be administered as the sole active ingredient(s). In some embodiments according to the methods described herein, the compounds of the present disclosure can be used in combination with conventional surgery or radiation therapy, immunotherapy, cell therapy, therapeutic antibodies, or chemotherapy. In some embodiments, the compounds of the present disclosure can be used in combination with chemotherapy (e.g., paclitaxel, doxorubicin, tamoxifen, cisplatin, mitomycin, 5-fluorouracil, sorafenib, octreotide, dacarbazine (DTIC), cis-platinum, cimetidine, cyclophosphamide), radiation therapy (e.g., proton beam therapy), hormone therapy (e.g., anti-estrogen therapy, androgen deprivation therapy (ADT), luteinizing hormone-releasing hormone (LH-RH) agonists, aromatase inhibitors), or other anti-inflammatory drugs (e.g., anti-inflammatory drugs ... In some embodiments, the compounds of the present disclosure can be used in combination with conventional therapy, SGLT inhibitors, cell therapy, therapeutic antibodies, or incretin analogs.

[0137] In some embodiments according to the methods described herein, the compounds of the present disclosure may also be co-administered to a subject in need thereof with additional pharmaceutically active compounds, either simultaneously or sequentially, in any order. In some embodiments, the additional pharmaceutically active compound may be a chemotherapeutic agent, a therapeutic antibody, or the like. Any of the known chemotherapies, immunotherapies, cell therapies, or therapeutic antibodies may be used in combination with the compounds of the present disclosure, for example, to treat cancer (e.g., as described herein) or to treat or prevent metastasis.Some examples of such additional pharmaceutically active compounds, such as chemotherapeutic agents, are illustrated herein, including, for example, DNA alkylating agents (e.g., nitrogen mustards such as cisplatin, oxaliplatin, carboplatin, cyclophosphamide, ifosfamide, etc.; nitrosoureas such as bendamustine, melphalan, chlorambucil, busulfan, temozolamide, and carmustine); antimetabolites (e.g., antifolates such as gemcitabine and fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexate, methotrexate, cytosine arabinoside, and hydroxyurea); antitumor antibiotics (e.g., adriamycin, bleomycin, doxorubicin, liposomal doxorubicin, pirarubicin, daunomycin, valrubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin, etc.); antimitotics (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids such as taxol and polo kinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, irinotecan, topotecan, and camptothecin); inhibitors of DNA repair mechanisms such as CHK kinase, DNA-dependent protein kinase inhibitors, inhibitors of poly(ADP-ribose) polymerase (PARP inhibitors including olaparib), and Hsp90 inhibitors such as tanespimycin and retaspimycin, inhibitors of ATR kinase (e.g., AZD6738), and inhibitors of WEE1 kinase (e.g., AZD1775 / MK-1775). In some embodiments, the additional pharmaceutically active compound may be an incretin mimetic, recombinant insulin, biguanide, therapeutic antibody, etc. For example, any of the known type 2 diabetes treatments can be used in combination with the compounds of the present disclosure to treat type 2 diabetes (e.g., as described herein) or to treat or prevent other metabolic syndromes.

[0138] Dosage regimens, including dosages, for the methods described herein can be varied and adjusted, and may depend on the recipient of treatment, the disease or disorder being treated and its severity, the composition containing the compound, the timing of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether another agent is administered concomitantly.

[0139] definition It is to be understood that appropriate atomic valences are maintained for all moieties and combinations thereof.

[0140] It should also be understood that a particular embodiment of a variable moiety herein may be the same as or different from another particular embodiment having the same identifier.

[0141] Suitable groups in the compounds of Formula I, II, IP, II-P, III, or subformulas thereof, where applicable, are independently selected. The described embodiments of the present disclosure can be combined. Such combinations are contemplated and within the scope of the present disclosure. For example, R of Formula I 1 , R 2 , R 3 , R 4 , R 5 , J 1 , J 2 , J 3 , Z, X, and any one or more definitions of n may be optionally added to R of Formula I. 1 , R 2 , R 3 , R 4 , R 5 , J 1 , J 2 , J 3 It is contemplated that the above formulas may be combined with any one or more of the other definitions of Z, X, and n, and the compounds resulting from the combinations are within the scope of this disclosure. Other combinations of variables for other formulas should be understood similarly.

[0142] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside cover, and specific functional groups are generally defined as described therein. Further, general principles of organic chemistry, as well as specific functional groups and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999, and Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley&Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, and Carruthers, Some Modern Methods of Organic Synthesis, 3. rd Edition, Cambridge University Press, Cambridge, 1987. The present disclosure is not intended to be limited in any way by the exemplary list of substituents set forth herein.

[0143] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving See Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers, including racemic mixtures.

[0144] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, C 1~6 are C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C3~4 , C 4~6 , C 4~5 , and C 5~6 is intended to encompass.

[0145] As used herein, the term "compound(s) of the disclosure" refers to a compound or compounds described herein according to Formula I (e.g., Formula IO, IF, I-1, I-2, I-1-A, I-2-A, I-1-A1, I-1-A2, I-1-A3, I-2-A1, I-2-A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), Formula IP, Formula II (e.g., Formula II-1, II-2, II-3, or II-4), Formula II-P, Formula III (e.g., Formula III-1 or III-2). The term "compound" refers to any of the compounds of the present disclosure, or Compound Nos. 1-138, its isotopically labeled compound(s) (such as deuterated analogs in which one or more of the hydrogen atoms are replaced with deuterium atoms having an abundance greater than its natural abundance), its possible stereoisomers (including diastereoisomers, enantiomers, racemic mixtures), its tautomers, its conformational isomers, and / or its pharmaceutically acceptable salts (e.g., acid addition salts such as HCl salts, or base addition salts such as Na salts). Hydrates and solvates of the compounds of the present disclosure are considered compositions of the present disclosure, in which the compound(s) are associated with water or a solvent, respectively.

[0146] The compounds of the present disclosure can be present in isotopically labeled or enriched form, containing one or more atoms with atomic masses or mass numbers different from the atomic masses or mass numbers of the most abundant atoms in nature.Isotopes can be radioactive or non-radioactive isotopes.Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 32 P, 35 S, 18 F, 36 Cl, and 125Compounds containing other isotopes of these and / or other atoms are within the scope of this invention, including, but not limited to, I.

[0147] As used herein, the phrase "administration" of a compound, "administering" a compound, or other variations thereof means providing a compound or a prodrug of a compound to an individual in need of treatment.

[0148] As used herein, the term "alkyl" by itself or as part of another group refers to a straight or branched chain aliphatic saturated hydrocarbon. In some embodiments, alkyl groups have 1 to 12 carbon atoms (i.e., C 1~12 alkyl) or alkyl, which may contain the specified number of carbon atoms. In one embodiment, the alkyl group is a straight-chain C 1~10 In another embodiment, the alkyl group is a branched C 3~10 In another embodiment, the alkyl group is a straight-chain C 1~6 In another embodiment, the alkyl group is a branched C 3~6 In another embodiment, the alkyl group is a straight-chain C 1~4 As used herein, for example, C 1~4 An alkyl group refers to a group selected from methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and iso-butyl. 1~4 Alkyl groups are defined as C, optionally substituted with one or more permissible substituents as described herein. 1~4 Refers to an alkyl group.

[0149] As used herein, the term "alkenyl" by itself or as part of another group refers to a straight or branched chain aliphatic hydrocarbon containing one or more, e.g., one, two, or three, carbon-carbon double bonds. In one embodiment, an alkenyl group is a C 2~6 In another embodiment, the alkenyl group is C 2~4Alkenyl groups. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0150] As used herein, by itself or as part of another group, the term "alkynyl" refers to a straight or branched chain aliphatic hydrocarbon containing one or more, e.g., 1 to 3, carbon-carbon triple bonds. In one embodiment, an alkynyl is an alkyl group containing one or more carbon-carbon triple bonds. In one embodiment, the alkynyl group has the formula: 2~6 In another embodiment, the alkynyl group is C 2~4 Alkynyl groups. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0151] As used herein, the term "alkoxy" by itself or as part of another group refers to a group of the formula OR a1 where R a1 is alkyl.

[0152] As used herein, the term "cycloalkoxy" by itself or as part of another group refers to a group of the formula OR a1 where R a1 is cycloalkyl.

[0153] As used herein, the term "haloalkyl" by itself or as part of another group refers to an alkyl substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In preferred embodiments, a haloalkyl is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, a haloalkyl group is C 1~10 In one embodiment, the haloalkyl group is C 1~6 In one embodiment, the haloalkyl group is a C 1~4 It is a haloalkyl group.

[0154] Used by itself or as part of another group, "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 10 ring carbon atoms ("C 3~10 "Carbocyclyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having zero heteroatoms ("monocyclic carbocyclyl") and zero heteroatoms. A carbocyclyl group may be monocyclic ("monocyclic carbocyclyl") or contain fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic carbocyclyl"), and may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocycle, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the carbocycle; in such cases, the number of carbons continues to indicate the number of carbons in the carbocyclic ring system. Non-limiting exemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl.

[0155] In some embodiments, "carbocyclyl" refers to a monocyclic, saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group is a group having 3 to 8 ring carbon atoms (C 3~8 In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms (C 3~6 In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms (C 5~6 In some embodiments, the cycloalkyl group has 5 to 10 ring carbon atoms (C 5~10 cycloalkyl).

[0156] Used by itself or as part of another group, "heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be carbon or nitrogen atom, as valence permits. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl") or may contain fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also refers to a heterocycle, as defined above, fused to one or more carbocyclyl groups and bonded to one or more carbocyclyl groups. Also included are ring systems in which the point of attachment is on the heterocyclic ring, or in which a heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups and the point of attachment is on the heterocyclic ring, in which case the number of ring members continues to indicate the number of ring members of the heterocyclic ring system.

[0157] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6 bicyclic heterocycles) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6 bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0158] "Aryl," when used by itself or as part of another group, refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in the cyclic array) radical having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl. In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl" or "aryl ring" as defined above also includes ring systems in which an aryl ring is fused to one or more carbocyclyl or heterocyclyl groups, and the radical or point of attachment is on the aryl ring; in such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system.

[0159] "Aralkyl," by itself or as part of another group, refers to an alkyl substituted with one or more aryl groups, preferably one aryl group. Examples of aralkyls include benzyl, phenethyl, and the like. When an aralkyl is said to be optionally substituted, either the alkyl or the aryl portion of the aralkyl may be optionally substituted. Either one can be optionally substituted.

[0160] Used by itself or as part of another group, "heteroaryl" refers to the radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared by the cyclic array) having ring carbon atoms and 1 to 4 ring heteroatoms provided to the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring; in such cases, the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring; in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, etc.) can have the point of attachment on either ring, i.e., the ring bearing a heteroatom (e.g., 2-indolyl) or the ring not bearing a heteroatom (e.g., 5-indolyl).

[0161] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Examples of 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0162] "Heteroaralkyl," used alone or as part of another group, refers to an alkyl substituted with one or more heteroaryl groups, preferably one heteroaryl group. When a heteroaralkyl is said to be optionally substituted, either the alkyl or the heteroaryl portion of the heteroaralkyl can be optionally substituted.

[0163] Optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl "Optionally substituted" groups, such as optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl groups, refer to the respective groups, whether unsubstituted or substituted. Generally, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen atom present on the group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent whose substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a substituent may be present at one or more substitutable positions of the group, and when multiple positions in any given structure are substituted, the substituent may be the same or different at each position. Typically, when substituted, the optionally substituted groups herein may be substituted with 1 to 5 substituents. The substituent may be a carbon atom substituent, a nitrogen atom substituent, an oxygen atom substituent, or a sulfur atom substituent, as applicable. Any two of the substituents may be bonded to form an optionally substituted cycloalkyl, heterosilyl, aryl, or heteroaryl ring. Substitutions may occur on any available carbon, oxygen, or nitrogen atom, forming a spirocyclic ring. Typically, substitutions herein do not result in OO, ON, SS, SN (excluding SO2-N bonds), heteroatom halogen, or -C(O)-S bonds or three or more consecutive heteroatoms, excluding O-SO2-O, O-SO2-N, and N-SO2-N, although some such bonds or connections may be tolerated in the case of a stable aromatic system.

[0164] In a broad aspect, the permissible substituents herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more of the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. The substituting agent can include any of the substituents described herein, e.g., halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, cycloalkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aryl, or heteroaryl, each of which can be optionally substituted.

[0165] Exemplary substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -aryl-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, acyl, -C(O)-aryl, halo, -NO, -CN, -SF, -C(O)OH, -C(O)O-alkyl, -C(O)O-aryl, -C(O)O-alkylene-aryl, -S(O)-alkyl, -S(O)-alkyl, -S(O)-aryl, -S and -O)-aryl, -S(O)-heteroaryl, -S(O)-heteroaryl, -S-alkyl, -S-aryl, -S-heteroaryl, -S-alkylene-aryl, -S-alkylene-heteroaryl, -S(O)-alkylene-aryl, -S(O)-alkylene-heteroaryl, cycloalkyl, heterocycloalkyl, -OC(O)-alkyl, -OC(O)-aryl, -OC(O)-cycloalkyl, -C(=N-CN)-NH, -C(=NH)-NH, -C(=NH)-NH(alkyl), -N(Y)(Y), -alkylene-N(Y)(Y), -C(O)N(Y)(Y) and -S(O)N(Y)(Y), wherein Y and Y are the same. may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and -alkylene-aryl.

[0166] Some examples of suitable substituents include, but are not limited to, (C1-C8) alkyl groups, (C2-C8) alkenyl groups, (C2-C8) alkynyl groups, (C3-C 10) cycloalkyl groups, halogen (F, Cl, Br or I), halogenated (C1-C8) alkyl groups (such as, but not limited to, -CF3), -O-(C1-C8) alkyl groups, -OH, -S-(C1-C8) alkyl groups, -SH, -NH(C1-C8) alkyl groups, -N((C1-C8) alkyl) groups, -NH2, -C(O)NH2, -C(O)NH(C1-C8) alkyl groups, -C(O)N((C1-C8) alkyl)2, -NHC(O)H, -NHC(O)(C1-C8) alkyl groups, -NHC(O)(C3-C8) cycloalkyl groups, -N((C1-C8) alkyl)C(O)H, -N((C1-C8) alkyl)C(O)(C1-C8) alkyl groups, -NHC(O)NH2, -NHC(O)NH(C1-C 8)アルキル基、-N((C1~C8) alkyl)C(O)NH2 group, -NHC(O)N((C1~C8) alkyl)2 group, -N((C1~C8) alkyl)C(O)N((C1~C8) alkyl)2 group, -N((C1~C8) alkyl)C(O)NH((C1~C8) alkyl), -C(O)H, -C(O)(C1~C8) alkyl group, -CN, -NO2, -S(O)(C1~C8) alkyl group, -S(O)2(C1~C8) alkyl group, -S(O)2N((C1~C8) alkyl)2 group, - S(O)2NH(C1-C8) alkyl group, -S(O)2NH(C3-C8) cycloalkyl group, -S(O)2NH2 group, -NHS(O)2(C1-C8) alkyl group, -N((C1-C8) alkyl)S(O)2(C1-C8) alkyl group, -(C1-C8) alkyl-O-(C1-C8) alkyl group, -O-(C1-C8) alkyl-O-(C1-C8) alkyl group, -C(O)OH, -C(O)O(C1-C8) alkyl group, NHOH, NHO(C1-C8) Alkyl groups, -O-halogenated (C1-C8) alkyl groups (such as, but not limited to, -OCF3), -S(O)2-halogenated (C1-C8) alkyl groups (such as, but not limited to, -S(O)2CF3), -S-halogenated (C1-C8) alkyl groups (such as, but not limited to, -SCF3), -(C1-C6)heterocyclyl (such as, but not limited to, pyrrolidine, tetrahydrofuran, pyran, or morpholine), -( and -C1-C6)heteroaryl (such as, but not limited to, tetrazole, imidazole, furan, pyrazine, or pyrazole), -phenyl, -NHC(O)O-(C1-C6)alkyl group, -N((C1-C6)alkyl)C(O)O-(C1-C6)alkyl group, -C(=NH)-(C1-C6)alkyl group, -C(=NOH)-(C1-C6)alkyl group, or -C(=NO-(C1-C6)alkyl)-(C1-C6)alkyl group.

[0167] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkylamino, dialkylamino, amido, sulfonamido, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, etc. For example, exemplary carbon atom substituents include F, Cl, —CN, —SO 2 , H, —SO 3 H, —OH, —OC 1~6 Alkyl, -NH2, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), -SH, -SC 1~6 Alkyl, -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6 alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(= O)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 It may include aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal substituents may be linked to form =0.

[0168] Nitrogen atoms can be substituted or unsubstituted, where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, acyl groups, esters, sulfones, sulfoxides, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 The nitrogen atom may be substituted with an alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl ring, and may be further substituted as defined herein. In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also called an amino protecting group). Nitrogen protecting groups are well known in the art and are described in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 399-402, incorporated herein by reference. rdedition, John Wiley & Sons, 1999. Exemplary nitrogen protecting groups include, but are not limited to, those that form carbamates, such as carbobenzyloxy (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC), Troc, 9-fluorenylmethyloxycarbonyl (Fmoc) groups; those that form amides, such as acetyl, benzoyl; those that form benzylamines, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl; those that form sulfonamides, such as tosyl, nosyl, and others, such as p-methoxyphenyl.

[0169] Exemplary oxygen atom substituents include, but are not limited to, acyl groups, esters, sulfonates, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, each of which may be further substituted as defined herein. In certain embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also called a hydroxyl protecting group). Oxygen protecting groups are well known in the art and are described in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3001, pp. 111-114, which is incorporated herein by reference. rdedition, John Wiley & Sons, 1999. Exemplary oxygen protecting groups include, but are not limited to, those which form alkyl ethers or substituted alkyl ethers such as methyl, allyl, benzyl, substituted benzyl such as 4-methoxybenzyl, methoxylmethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), those which form silyl ethers such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), those which form acetals or ketals such as tetrahydropyranyl (THP), those which form esters such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, methanesulfonate (mesylate), benzylsulfonate, tosylate, and the like. and those which form carbonates or sulfonates such as carboxylate (Ts).

[0170] Unless expressly stated to the contrary, combinations of substituents and / or variables are permissible only if such combinations are chemically permissible and result in stable compounds. A "stable" compound is one that can be prepared and isolated and whose structure and properties remain essentially unchanged, or can be made to remain unchanged, for a period of time sufficient to permit use of the compound for the purposes described herein (e.g., therapeutic administration to a subject).

[0171] In some embodiments, the "optionally substituted" alkyl, alkenyl, alkynyl, carbocyclic, cycloalkyl, alkoxy, cycloalkoxy, heterocyclic groups herein are unsubstituted or are substituted with F, Cl, -OH, protected hydroxyl, oxo (where applicable), NH, protected amino, NH(C 1~4 alkyl) or its protected derivatives, N(C 1~4 Alkyl ((C 1~4 alkyl), C 1~4 Alkyl, C 2~4Alkenyl, C 2~4 Alkynyl, C 1~4 Alkoxy, C 3~6 Cycloalkyl, C 3~6 and 3- to 7-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the aforementioned alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy phenyl, heteroaryl, and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from F, —OH, oxo (if applicable), C 1~4 Alkyl, Fluoro-substituted C 1~4 Alkyl (e.g., CF3), C 1~4 Alkoxy and Fluoro Substituted C 1~4 In some embodiments, an "optionally substituted" aryl or heteroaryl group herein is unsubstituted or is substituted with one, two, or three substituents independently selected from F, Cl, -OH, -CN, NH, protected amino, NH(C 1~4 alkyl) or its protected derivatives, N(C 1~4 Alkyl ((C 1~4 alkyl), -S(=O)(C 1~4 alkyl), -SO2(C 1~4 alkyl), C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~4 Alkoxy, C 3~6 Cycloalkyl, C 3~6and 3- to 7-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of the aforementioned alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from F, —OH, oxo (if applicable), C 1~4 Alkyl, Fluoro-substituted C 1~4 Alkyl, C 1~4 Alkoxy and Fluoro Substituted C 1~4 Optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy.

[0172] "Halo" or "halogen" means fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0173] The term "pharmaceutically acceptable salt" refers to salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0174] The term "tautomer" or "tautomerism" refers to two or more interconvertible compounds resulting from the formal migration of at least one hydrogen atom and at least one change in valency (e.g., from a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of isomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction that produces a tautomeric pair) may be catalyzed by acid or base. Exemplary tautomerizations include keto and enol, amide and imide, lactam and lactim, enamine and imine, and enamine-to-enamine (different enamine) tautomerizations.

[0175] The term "subject" (alternatively referred to herein as "patient"), as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0176] As used herein, the terms "treat," "treating," "treatment," and the like refer to eliminating, reducing, or ameliorating a disease or condition and / or its associated symptoms. Although not excluded, treating a disease or condition does not require the complete elimination of the disease, condition, or symptoms associated therewith. As used herein, the terms "treat," "treating," "treatment," and the like can include "prophylactic treatment," which refers to reducing the likelihood of a disease or condition recurring or the recurrence of a previously controlled disease or condition in a subject who has not recurred or has a disease or condition recurrence, but is at risk or susceptible to the disease or condition. The term "treat" and cognate terms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment. [Example]

[0177] The various starting materials, intermediates, and compounds of the preferred embodiments can be isolated and purified, if necessary, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds can be carried out using conventional methods such as melting point, mass spectrometry, nuclear magnetic resonance, and various other spectroscopic analyses. Exemplary embodiments of steps for carrying out the synthesis of the products described herein are described in more detail below.

[0178] Abbreviations used in the Examples section should be understood to have their ordinary meaning in the art unless specifically indicated otherwise or clearly contradicted by context. Below is a list of some of the abbreviations used in the Examples section: [Table 3] [ka]

[0179] Step 1: To a stirred solution of NaNO (7.41 g, 107.47 mmol, 2 equiv.) in water HO (80 mL) was added Amberlyst A26-OH (28 g). The resulting mixture was stirred at 25 °C for 0.5 h, and then the polymer-supported resin was filtered and washed with water until the pH of the filtrate was neutral. Polymer-supported nitrite was obtained. Step 2: To a solution of 4-fluoro-1,2-dinitro-benzene (10 g, 53.74 mmol, 1 equiv.) and methyl prop-2-enoate (4.63 g, 53.74 mmol, 4.84 mL, 1 equiv.) in MeOH (100 mL), p-toluenesulfonic acid monohydrate (10.22 g, 53.74 mmol, 1 equiv.), Pd(OAc) (193.02 mg, 859.77 μmol, 0.016 equiv.) were added, followed by slow addition of polymer-supported nitrite. The mixture was stirred at 60 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product, methyl (E)-3-(4-fluoro-2-nitro-phenyl)prop-2-enoate (6 g, crude), was obtained as a yellow solid.

[0180] Step 2: To a solution of methyl (E)-3-(4-fluoro-2-nitro-phenyl)prop-2-enoate (6 g, 26.65 mmol, 1 equiv.) in MeOH (50 mL) was added 10% Pd / C (800 mg, 26.65 mmol, 1.00 equiv.) under H2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred at 40 °C under H2 (15 Psi) for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether / ethyl acetate = 50:1 (6 mL) at 25 °C for 10 min. Compound 7-fluoro-3,4-dihydro-1H-quinolin-2-one (3 g, 18.16 mmol, 68.17% yield) was obtained as a white solid.

[0181] Step 3: To a solution of 7-fluoro-3,4-dihydro-1H-quinolin-2-one (3 g, 18.16 mmol, 1 equiv.) in HSO (20 mL) was added KNO (1.84 g, 18.16 mmol, 1 equiv.) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was cooled at 0 °C, and the resulting solution was stirred at 0 °C for 15 min. The reaction was quenched by adding 100 mL of H0 / ice. The mixture was filtered, and the filter cake was concentrated under reduced pressure to give a residue. The crude product, 7-fluoro-6-nitro-3,4-dihydro-1H-quinolin-2-one (2.5 g, 11.90 mmol, 65.49% yield), was obtained as a white solid.

[0182] Step 4: To a solution of 7-fluoro-6-nitro-3,4-dihydro-1H-quinolin-2-one (1.5 g, 7.14 mmol, 1 equiv.) in MeOH (10 mL) was added 10% Pd / C (200 mg, 7.14 mmol) under an H atmosphere. The suspension was degassed. , and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 25°C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether / ethyl acetate = 10:1 (11 mL) at 25°C for 10 minutes. The compound 6-amino-7-fluoro-3,4-dihydro-1H-quinolin-2-one (0.8 g, 4.44 mmol, 62.21% yield) was obtained as a white solid. LCMS: (M+H) + :181.4.

[0183] Step 5: To a solution of 6-amino-7-fluoro-3,4-dihydro-1H-quinolin-2-one (100 mg, 555.00 umol, 1 equiv.) and 3-ethylpyridine-4-carboxylic acid (83.90 mg, 555.00 umol, 1 equiv.) in N,N-dimethylformamide ("DMF") (5 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ("EDCI") (127.67 mg, 666.01 umol, 1.2 equiv.) and pyridine ("Py.") (65.85 mg, 832.51 umol, 67.20 uL, 1.5 equiv.) were added. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with HO (10 mL) and extracted with 15 mL of EtOAc (5 mL * 3). The combined organic layers were washed with 10 mL of brine, dried over [NaSO], filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate = 0:1). Compound No. 1, 3-ethyl-N-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyridine-4-carboxamide (65 mg, 203.72 μmol, 36.71% yield, 98.2% purity), was obtained as a white solid. The reported purity refers to the area % observed in LCMS analysis. Unless otherwise specified or contrary to the context, other purities reported herein should be understood as well. LCMS: (M+H) + :314.1. 1 HNMR(400MHz,MeOD,ppm):δ8.55(s,1H),8.50(d,J=5.2Hz,1H),7.60(d,J=8Hz,1H),7.48(d,J=4.8Hz,1H),6.7 5(d,J=11.2Hz,1H),2.98(t,J=7.2Hz,2H),2.88(q,J=7.6Hz,2H),2.60(t,J=7.2Hz,2H),1.29(t,J=7.6Hz,3H). [ka]

[0184] Step 1: To a mixture of 3,4-dihydro-1H-quinolin-2-one (5 g, 33.97 mmol, 1 equiv.) and 1-(chloromethyl)-4-methoxy-benzene (6.92 g, 44.17 mmol, 6.01 mL, 1.3 equiv.) in DMF (50 mL), K2CO3 (7.04 g, 50.96 mmol, 1.5 equiv.) was added under N2. The mixture was stirred at 60 °C for 10 h. The reaction mixture was diluted with 50 mL of HO, and the mixture was cooled to 15 °C. The suspension was filtered, and the filtrate cake was concentrated under reduced pressure to give a residue. The compound 1-[(4-methoxyphenyl)methyl]-3,4-dihydroquinolin-2-one (6.2 g, 23.19 mmol, 68.27% yield) was obtained as a white solid. LCMS: (M+H) + :268.3.

[0185] Step 2: To a mixture of 1-[(4-methoxyphenyl)methyl]-3,4-dihydroquinolin-2-one (2 g, 7.48 mmol, 1 equiv) in THF (20 mL) was added LiHMDS (1 M, 8.23 ​​mL, 1.1 equiv) in one portion at -70 °C under N. The mixture was stirred at -70 °C for 30 min. Then MeI (1.17 g, 8.23 ​​mmol, 512.33 uL, 1.1 equiv) was added. The mixture was heated to 15 °C and stirred for 5.5 h. The reaction mixture was quenched by the addition of 30 mL of HO and extracted with 60 mL of EtOAc (20 mL*3). The combined organic layers were washed with NaSO. 4で乾燥させ , filtered and concentrated under reduced pressure to give a residue. The crude product was used directly in the next step. The crude product 1-[(4-methoxyphenyl)methyl]-3-methyl-3,4-dihydroquinolin-2-one (2.1 g, crude) was obtained as a yellow oil. LCMS: (M+H) + :282.4.

[0186] Step 3: To a mixture of 1-[(4-methoxyphenyl)methyl]-3-methyl-3,4-dihydroquinolin-2-one (2.1 g, 7.46 mmol, 1 equiv) in THF (20 mL) was added LiHMDS (1 M, 8.21 mL, 1.1 equiv) in one portion at −70° C. under N. The mixture was stirred at −70° C. for 30 minutes. Then, MeI (1.27 g, 8.96 mmol, 557.60 uL, 1.2 equiv) was added. The mixture was heated to 15° C. and stirred for 11.5 hours. The reaction mixture was quenched by the addition of 30 mL of HO and extracted with 60 mL of EtOAc (20 mL*3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to obtain the compound 1-[(4-methoxyphenyl)methyl]-3,3-dimethyl-4H-quinolin-2-one (750 mg, 2.54 mmol, yield 34.02%) as a yellow oil.

[0187] Step 4: To a mixture of 1-[(4-methoxyphenyl)methyl]-3,3-dimethyl-4H-quinolin-2-one (750 mg, 2.54 mmol, 1 equiv.) in dichloromethane (“DCM”) (6 mL), trifluoroacetic acid (TFA) (2 mL) was added in one portion at 15° C. under N. The mixture was stirred at 50° C. for 12 hours. The reaction mixture was diluted with 15 mL of saturated aqueous NaHCO and extracted with 30 mL of EtOAc (10 mL*3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). Compound 3,3-dimethyl-1,4-dihydroquinolin-2-one (300 mg, 1.71 mmol, 67.43% yield) was obtained as a white solid. LCMS: (M+H) + :176.5.

[0188] Step 5: To a solution of 3,3-dimethyl-1,4-dihydroquinolin-2-one (250 mg, 1.43 mmol, 1 equiv) in concentrated HSO (6.6 mL) and HO (2.2 mL) was added slowly at -10 °C. The mixture was stirred for 30 minutes. HNO (179.80 mg, 2.85 mmol, 128.43 uL, 2 equiv) was then added, and the reaction was stirred at -10 °C for 4.5 hours. The reaction mixture was cooled at 0 °C, and the resulting solution was stirred at 0 °C for 15 minutes. The reaction was then quenched by adding 100 mL of HO / ice. The mixture was then filtered, and the filter cake was concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether / ethyl acetate = 10:1 (11 mL). The suspension was filtered, and the filter cake was concentrated under reduced pressure to give a residue. The compound 3,3-dimethyl-6-nitro-1,4-dihydroquinolin-2-one (260 mg, 1.18 mmol, yield 82.75%) was obtained as a white solid.

[0189] Step 6: 3,3-dimethyl-6-nitro-1,4-dihydrazine in MeOH (5 mL) To a solution of 1,4-dihydroquinolin-2-one (260 mg, 1.18 mmol, 1 equiv.) was added 10% Pd / C (100 mg). The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 25 °C for 5 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether / ethyl acetate = 10:1 (11 mL). The suspension was filtered, and the filter cake was concentrated under reduced pressure to give a residue. The compound 6-amino-3,3-dimethyl-1,4-dihydroquinolin-2-one (200 mg, 1.05 mmol, yield 89.05%) was obtained as a white solid.

[0190] Step 7: To a solution of 6-amino-3,3-dimethyl-1,4-dihydroquinolin-2-one (83.06 mg, 436.62 umol, 1.2 equiv.) in pyridine (2 mL), EDCI (83.70 mg, 436.62 umol, 1.2 equiv.) and 3-ethylpyridine-4-carboxylic acid (55 mg, 363.85 umol, 1 equiv.) were added. The mixture was stirred at 45° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove pyridine. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate=0:1). Compound No. 18, N-(3,3-dimethyl-2-oxo-1,4-dihydroquinolin-6-yl)-3-ethyl-pyridine-4-carboxamide (106 mg, 319.59 μmol, 87.83% yield, 97.5% purity) was obtained as a white solid. LCMS (ES, m / z): [M+H] + =324.2, 1 HNMR(400MHz,MeOD,ppm):δ8.55(s,1H),8.50(d,J=4.8Hz,1H),7.54(s,1H),7.46(m ,2H),6.87(d,J=8.4Hz,1H),2.83-2.89(m,4H),1.28(t,J=7.6Hz,3H),1.17(s,6H). [ka]

[0191] Step 1: To a solution of 3-methylbut-2-enoyl chloride (1.27 g, 10.74 mmol, 1.19 mL, 1 equiv) in DCM (200 mL) was added diisopropylethylamine (2.63 g, 20.32 mmol, 3.54 mL, 1.89 equiv) and aniline (1 g, 10.74 mmol, 980.39 uL, 1 equiv). The mixture was stirred at 20 °C for 2 h. The reaction was quenched by the addition of saturated sodium bicarbonate. The organic layer was separated and washed with saturated NaHCO (50 mL) and 100 mL of water (50 mL × 2). The resulting solution was dried over NaSO, and the filtrate was evaporated. The crude product was triturated with petroleum ether / ethyl acetate = 20:1 (21 mL) at 20 °C for 20 min. The mixture was filtered to give the compound 3-methyl-N-phenyl-but-2-enamide (1.4 g, 7.99 mmol, 74.40% yield) as a brown solid. LCMS: (M+H) + :176.5.

[0192] Step 2: To a solution of 3-methyl-N-phenyl-but-2-enamide (1.4 g, 7.99 mmol, 1 equiv.) in DCM (100 mL) was added AlCl (1.60 g, 12.02 mmol, 656.82 μL, 1.50 equiv.). The mixture was stirred at 50 °C for 5 h. The mixture was treated with 1 N HCl (20 mL) and extracted with 60 mL of DCM (30 mL × 2). The solution was then washed with 100 mL of brine (50 mL × 2) and dried over Na SO . The filtrate was evaporated. The crude product was triturated with petroleum ether / ethyl acetate = 20:1 (21 mL) at 25 °C for 20 min. The mixture was filtered to give compound 4,4-dimethyl-1,3-dihydroquinolin-2-one (1.2 g, 6.85 mmol, 85.71% yield) as a brown solid.

[0193] Step 3: 4,4-Dimethyl-1,3-dihydroquinolin-2-one (1.2 g, 6.85 mmol, 1 equiv) was dissolved in concentrated HSO (25 mL) and HO (7.5 mL) at 0 °C. The mixture was stirred for 10 minutes. HNO (863.06 mg, 13.70 mmol, 616.47 uL, 2 equiv) was then added, and the reaction was stirred at 0 °C for 1 hour. The reaction mixture was cooled at 0 °C, and the resulting solution was stirred at 0 °C for 15 minutes. The reaction was quenched by adding 100 mL of HO / ice. The mixture was filtered, and the filter cake was concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether / ethyl acetate = 20:1 (21 mL) at 25 °C for 20 minutes. The mixture was filtered to obtain the compound 4,4-dimethyl-6-nitro-1,3-dihydroquinolin-2-one (1 g, 4.54 mmol, yield 66.31%) as a brown solid. LCMS: (M+H) + :221.4.

[0194] Step 4: To a solution of 4,4-dimethyl-6-nitro-1,3-dihydroquinolin-2-one (1 g, 4.54 mmol, 1 equiv.) in MeOH (10 mL) was added 10% Pd / C (200 mg) under H atmosphere. The suspension was degassed and purged with H three times. The mixture was stirred under H (15 Psi) at 25 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether / ethyl acetate = 20:1 (42 mL) at 25 °C for 20 min. The mixture was filtered to give the compound 6-amino-4,4-dimethyl-1,3-dihydroquinolin-2-one (0.8 g, 4.21 mmol, 92.61% yield) as a white solid.

[0195] Step 5: To a solution of 6-amino-4,4-dimethyl-1,3-dihydroquinolin-2-one (200 mg, 1.05 mmol, 1 equiv.) and 3-ethylpyridine-4-carboxylic acid (158.92 mg, 1.05 mmol, 1 equiv.) in pyridine (2 mL), EDCI (241.84 mg, 1.26 mmol, 1.2 equiv.) was added. The mixture was stirred at 45 °C for 2 h. The reaction mixture was diluted with HO (10 mL) and extracted with 15 mL of EtOAc (5 mL * 3). The combined organic layers were washed with 10 mL of brine, dried over [NaSO], filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate = 0:1). Compound No. 19, N-(4,4-dimethyl-2-oxo-1,3-dihydroquinolin-6-yl)-3-ethyl-pyridine-4-carboxamide (217 mg, 664.98 μmol, 63.25% yield, 99.1% purity) was obtained as a white solid. LCMS (ES, m / z): [M+H] + =324.1, 1 HNMR(400MHz,MeOD,ppm):δ8.55(s,1H),8.50(d,J=5.2Hz,1H),7.68(d,J=2Hz,1H),7.51(dd,J=8.8 and 2Hz,1H),7 .46(d,J=4.8Hz,1H),6.90(d,J=8.8Hz,1H),2.86(q,J=8Hz,2H),2.46(s,2H),1.32(s,6H),1.28(t,J=7.6Hz,3H). [ka]

[0196] Step 1: To a solution of N-methyl-1-(2-nitrophenyl)methanamine (500 mg, 3.01 mmol, 1 equiv.) in MeOH (20 mL) was added 10% Pd / C (200 mg) under an H atmosphere. The suspension was degassed and purged with H three times. The mixture was stirred at 25 °C under H (15 Psi) for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether / ethyl acetate = 10:1 (11 mL) at 25 °C for 10 min. The mixture was filtered to give compound 2-(methylaminomethyl)aniline (260 mg, 1.91 mmol, 63.45% yield) as a white solid.

[0197] Step 2: To a solution of 2-(methylaminomethyl)aniline (260 mg, 1.91 mmol, 1 equiv.) in THF (10 mL) was added CDI (174.37 mg, 1.08 mmol, 5.63 e-1 equiv.). The mixture was stirred at 60 °C for 2 h. The reaction mixture was diluted with HO (5 mL) and extracted with 6 mL of EtOAc (2 mL * 3). The combined organic layers were washed with 10 mL of brine, dried over [NaSO], filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO, dichloromethane:methanol = 5 / 1). Compound 3-methyl-1,4-dihydroquinazolin-2-one (200 mg, 1.23 mmol, 64.59% yield) was obtained as a white solid.

[0198] Step 3: To a solution of 3-methyl-1,4-dihydroquinazolin-2-one (200 mg, 1.23 mmol, 1 equiv.) in concentrated HSO (8 mL) was added KNO (99.74 mg, 986.51 umol, 0.8 equiv.) at 0° C. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was cooled at 0° C. and quenched by adding 10 mL of H2O / ice. The mixture was filtered, and the filter cake was concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether / ethyl acetate = 10:1 (5 mL) at 25° C. for 10 minutes. The mixture was filtered to give compound 3-methyl-6-nitro-1,4-dihydroquinazolin-2-one (195 mg, 941.18 umol, 76.32% yield) as a white solid. LCMS: (M+H)+ :208.4.

[0199] Step 4: To a solution of 3-methyl-6-nitro-1,4-dihydroquinazolin-2-one (195 mg, 941.18 umol, 1 equiv.) in MeOH (10 mL) was added 10% Pd / C (50 mg, 941.18 umol, 1 equiv.) under H2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 25 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether / ethyl acetate = 10:1 (11 mL) at 25 °C for 10 min. The mixture was filtered to give compound 6-amino-3-methyl-1,4-dihydroquinazolin-2-one (150 mg, 846.49 umol, 89.94% yield) was obtained as a white solid.

[0200] Step 5: To a solution of 6-amino-3-methyl-1,4-dihydroquinazolin-2-one (50 mg, 282.16 μmol, 1.07 equiv) in pyridine (2 mL) was added EDCI (55.80 mg, 291.08 μmol, 1.1 equiv) and 3-ethylpyridine-4-carboxylic acid (40 mg, 264.62 μmol, 1 equiv). The mixture was stirred at 45° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove pyridine. The residue was purified by preparative TLC (SiO, DCM:MeOH=5:1). The product was then triturated with petroleum ether / ethyl acetate=5:1 (12 mL) at 25° C. for 10 minutes. The mixture was filtered to give compound number 20, 3-ethyl-N-(3-methyl-2-oxo-1,4-dihydroquinazolin-6-yl)pyridine-4-carboxamide (43 mg, 0.14 mmol, 49% yield, 98.6% purity) as a white solid. LCMS (ES, m / z): [M+H] + =311.1. [ka]

[0201] Step 1: To a solution of 6-nitro-3,4-dihydro-1H-quinolin-2-one (1 g, 5.20 mmol, 1 equiv.) in DMF (8 mL) was added MeI (2.95 g, 20.81 mmol, 1.30 mL, 4 equiv.) and K2CO3 (863.02 mg, 6.24 mmol, 1.2 equiv.). The mixture was stirred at 20 °C for 10 h. Water (20 mL) was added, and the reaction mixture was extracted with 40 mL of EtOAc (20 mL*2), washed with brine (20 mL), dried over [Na2SO4], filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1). The compound 1-methyl-6-nitro-3,4-dihydroquinolin-2-one (620 mg, 3.01 mmol, yield 57.78%) was obtained as a white solid. LCMS: (M+H) + :207.4.

[0202] Step 2: To a solution of 1-methyl-6-nitro-3,4-dihydroquinolin-2-one (620 mg, 3.01 mmol, 1 equiv.) in MeOH (10 mL) was added 10% Pd / C (100 mg, 9.70 mmol) under H atmosphere. The suspension was degassed and purged with H three times. The mixture was stirred under H (15 Psi) at 25 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether / ethyl acetate = 10:1 (11 mL) at 25 °C for 10 min. The mixture was filtered to give compound 6-amino-1-methyl-3,4-dihydroquinolin-2-one (450 mg, 2.55 mmol, 84.93% yield) as a white solid. LCMS: (M+H) + :177.5.

[0203] To a solution of 6-amino-1-methyl-3,4-dihydroquinolin-2-one (150 mg, 851.23 umol, 1.12 equiv.) in pyridine (4 mL) was added EDCI (175.01 mg, 912.93 umol, 1.2 equiv.) and 3-ethylpyridine-4-carboxylic acid (115 mg, 760.77 umol, 1 equiv.). The mixture was stirred at 45° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove pyridine. The residue was purified by preparative TLC (SiO, DCM:MeOH=10:1). The product was then further triturated with petroleum ether / ethyl acetate=10:1 (11 mL) at 25° C. for 10 minutes. The mixture The residue was filtered to give compound number 23, 3-ethyl-N-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)pyridine-4-carboxamide (purity 98.4%) (235 mg) as a white solid. LCMS: (M+H) + :310.1. 1 HNMR(400MHz,MeOD,ppm):δ8.55(s,1H),8.50(d,J=4.8Hz,1H),7.57-7.59(m,2H),7.46(d,J=5.2Hz,1H),7.14(d,J= 9.2Hz,1H),3.31(s,3H),2.94(t,J=7.2Hz,2H),2.86(q,J=7.6Hz,2H),2.64(t,J=7.2Hz,2H),1.28(t,J=7.6Hz,3H). [ka]

[0204] To a solution of 6-amino-3,4-dihydro-2H-isoquinolin-1-one (100 mg, 616.57 μmol, 1.17 equiv.) in pyridine (3 mL) was added EDCI (121.75 mg, 635.08 μmol, 1.2 equiv.) and 3-ethylpyridine-4-carboxylic acid (80 mg, 529.23 μmol, 1 equiv.). The mixture was stirred at 45° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove pyridine. The residue was purified by preparative TLC (SiO, DCM:MeOH=10:1). The product was then triturated with petroleum ether / ethyl acetate=10:1 (11 mL) at 25° C. for 10 minutes. The mixture was filtered to give compound number 25, 3-ethyl-N-(1-oxo-3,4-dihydro-2H-isoquinolin-6-yl)pyridine-4-carboxamide (155 mg, 0.79 mmol, 85% yield, 99% purity) as a white solid. LCMS: (M+H) + :296.1. 1 HNMR(400MHz,MeOD,ppm):δ8.56(s,1H),8.52(d,J=4.8Hz,1H),7.93(d,J=7.6Hz,1H),7.92(s,1H),7.59(d,J=6.8Hz,1 H),7.48(d,J=5.2Hz,1H),3.52(t,J=6.8Hz,2H),3.00(t,J=6.4HzHz,2H),2.85(q,J=7.2Hz,2H),1.28(t,J=7.6Hz,3H). [ka]

[0205] Step 1: To a solution of 3-ethylpyridine-4-carboxylic acid (100 mg, 661.54 umol, 1 equiv.) in toluene ("Tol.") (5 mL), diphenylphosphoryl azide ("DPPA") (218.47 mg, 793.85 umol, 172.02 uL, 1.2 equiv.) and triethylamine ("TEA") (100.41 mg, 992.31 umol, 138.12 uL, 1.5 equiv.) were added at 25° C. After the addition, the mixture was stirred at this temperature for 1 hour, and then t-BuOH (980.69 mg, 13.23 mmol, 1.27 mL, 20 equiv.) was added dropwise. The resulting mixture was stirred at 110° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the toluene. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate=0:1). Compound tert-butyl N-(3-ethyl-4-pyridyl)carbamate (140 mg, 629.83 umol, yield 95.21%) was obtained as a white solid. LCMS: (M+H) + :223.5.

[0206] Step 2: To a solution of tert-butyl N-(3-ethyl-4-pyridyl)carbamate (140 mg, 629.83 umol, 1 eq.) in HCl / dioxane (4 M, 5 mL, 31.75 eq.). The mixture was stirred at 25° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to remove HCl / dioxane (5 mL). The crude product 3-ethylpyridin-4-amine (70 mg, crude) was obtained as a white solid. LCMS: (M+H) + :123.1.

[0207] Step 3: To a solution of 3-ethylpyridin-4-amine (50 mg, 409.27 umol, 1 equiv.) in pyridine (2 mL), EDCI (94.15 mg, 491.13 umol, 1.2 equiv.) and 2-oxo-3,4-dihydro-1H-quinoline-6-carboxylic acid (93.90 mg, 491.13 umol, 1.2 equiv.) were added. The mixture was stirred at 45° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove pyridine (2 mL). The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate=0:1). The product was then triturated with petroleum ether / ethyl acetate=10:1 (12 mL). The mixture was filtered, and the filter cake was concentrated under reduced pressure to give a residue. Compound No. 26, N-(3-ethyl-4-pyridyl)-2-oxo-3,4-dihydro-1H-quinoline-6-carboxamide (purity 98.3%) (120 mg) was obtained as a white solid. LCMS: (M+H) + :296.1. 1 HNMR(400MHz,MeOD,ppm):δ8.43(s,1H),8.36(d,J=5.6Hz,1H),7.80-7.84(m,2H),7.73(d,J=5.2Hz,1H),6 .99(d,J=8.4Hz,1H),3.05(t,J=8Hz,2H),2.80(q,J=7.6Hz,2H),2.64(t,J=8Hz,2H),1.24(t,J=7.6Hz,3H). [ka]

[0208] To a mixture of 6-amino-3,4-dihydro-1H-quinolin-2-one (100 mg, 616.57 μmol, 1 equiv) and 1-bromoisoquinoline (153.94 mg, 739.88 μmol, 1.2 equiv) in 1,4-dioxane (5 mL), Pd(OAc) (34.61 mg, 154.14 μmol, 0.25 equiv), Xantphos (57.08 mg, 98.65 μmol, 0.16 equiv), and CsCO (401.78 mg, 1.23 mmol, 2 equiv) were added in one portion under N at 15 °C. The mixture was stirred at 110 °C for 10 h. The reaction mixture was filtered, and the filtrate was diluted with 6 mL of HO and extracted with 15 mL of EtOAc (5 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate=2:1). The crude product was then triturated with EtOAc at 15°C for 2 hours. The mixture was filtered to give compound No. 22, 6-(1-isoquinolylamino)-3,4-dihydro-1H-quinolin-2-one (32 mg, 108.83 umol, 17.65% yield, 98.4% purity) as a yellow solid. LCMS: (M+H) + :290.1. 1 HNMR(400MHz,DMSO-d6,ppm):δ9.99(s,1H),9.02(s,1H),8.49(d,J=4.4Hz,1H),7.93(d,J=5.6Hz,1H),7.78-7.80(m,2H) ,7.67-7.69(m,1H),7.57-7.61(m,2H),7.10(d,J=6Hz,1H),6.81(d,J=8.4Hz,1H),2.86-2.90(m,2H),2.43-2.47(m,2H). [ka]

[0209] Step 1: To a mixture of 6-amino-3,4-dihydro-1H-quinolin-2-one (500 mg, 3.08 mmol, 1 equiv.) in THF (10 mL), paraformaldehyde (194.39 mg, 2.16 mmol, 0.7 equiv.) was added in one portion at 20° C. under N. The mixture was stirred at 20° C. for 3 h. NaBHCN (135.61 mg, 2.16 mmol, 0.7 equiv.) was then added, and the mixture was stirred for an additional 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by preparative HPLC [water (10 mM NHHCO)-acetonitrile ("ACN")]. Compound 6-(methyl (amino)-3,4-dihydro-1H-quinolin-2-one (140 mg, 794.49 umol, 25.77% yield) was obtained as a yellow solid. LCMS: (M+H) + :177.1.

[0210] Step 2: To a mixture of 6-(methylamino)-3,4-dihydro-1H-quinolin-2-one (50 mg, 283.74 umol, 1 equiv.) and 3-ethylpyridine-4-carboxylic acid (42.89 mg, 283.74 umol, 1 equiv.) in pyridine (3 mL) was added EDCI (54.39 mg, 283.74 umol, 1 equiv.) in one portion at 25° C. The mixture was stirred at 25° C. for 10 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:methanol=4:1). The crude product was then triturated with petroleum ether:ethyl acetate=8 mL:1 mL at 20° C. for 1 hour. Compound number 27, 3-ethyl-N-methyl-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyridine-4-carboxamide (17 mg, 100% purity, 19.4% yield) was obtained as a white solid. LCMS: (M+H) + :310.1. 1HNMR(400MHz,MeOD,ppm):δ8.34(s,1H),8.20(d,J=5.2Hz,1H),7.16(d,J=5.2Hz,1H),7.08(s,1H),6.96(dd,J=8.4 and 2Hz,1H) ,6.68(d,J=8.4Hz,1H),3.45(s,3H),2.84(t,J=7.6Hz,2H),2.68(q,J=7.2Hz,2H),2.48(t,J=7.6Hz,2H),1.26(t,J=7.6Hz,3H). [ka]

[0211] Step 1: To a mixture of 4-amino-3-iodo-benzonitrile (4 g, 16.39 mmol, 1 equiv.) and methyl prop-2-enoate (5.64 g, 65.57 mmol, 5.90 mL, 4 equiv.) in DMSO (80 mL), AIBN (10.77 g, 65.57 mmol, 4 equiv.) and Bu3SnH (7.16 g, 24.59 mmol, 6.51 mL, 1.5 equiv.) were added dropwise under N2. The mixture was stirred at 120 °C for 10 h. The mixture was cooled to 20 °C, poured into ice-water (w / w=1 / 1) (80 mL), and stirred for 15 min. The aqueous phase was extracted with ethyl acetate (80 mL*3). The combined organic layers were washed with brine (80 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated with petroleum ether: EtOAc = 1:1 (30 mL) at 20 °C for 60 min to obtain the compound 2-oxo-3,4-dihydro-1H-quinoline-6-carbonitrile (0.42 g, 1.94 mmol, 11.82% yield, 79.4% purity) as a yellow solid. Obtained. LCMS: (M+H) + :173.4.

[0212] Step 2: To a mixture of 2-oxo-3,4-dihydro-1H-quinoline-6-carbonitrile (220 mg, 1.28 mmol, 1 equiv.) in EtOH (25 mL) and NH3.HO (2 mL), Ni (7.50 mg, 127.77 μmol) was added under Ar2. The mixture was stirred at 50 °C under 50 Psi for 3 h. The mixture was cooled to 20 °C, filtered, and concentrated in vacuo to give the crude product. The residue was purified by preparative TLC (ethyl acetate:MeOH = 0:1). Compound 6-(aminomethyl)-3,4-dihydro-1H-quinolin-2-one (160 mg, 907.98 μmol, 71.06% yield) was obtained as a white solid.

[0213] Step 3: To a mixture of 6-(aminomethyl)-3,4-dihydro-1H-quinolin-2-one (60 mg, 340.49 umol, 1 equiv.) and 3-ethylpyridine-4-carboxylic acid (51.47 mg, 340.49 umol, 1 equiv.) in pyridine (5 mL), EDCI (65.27 mg, 340.49 umol, 1 equiv.) was added in N 2 The mixture was added in one portion at 40° C. under reduced pressure. The mixture was stirred at 40° C. for 10 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:methanol=3:1). Compound No. 28, 3-ethyl-N-[(2-oxo-3,4-dihydro-1H-quinolin-6-yl)methyl]pyridine-4-carboxamide (20 mg, purity 99.7%) was obtained as a white solid. LCMS: (M+H) + :310.1. 1 HNMR(400MHz,MeOD,ppm):δ8.49(s,1H),8.43(d,J=5.2Hz,1H),7.3(d,J=5.2Hz,1H),7.17-7.21(m,2H),6.86(d,J= 7.6Hz,1H),4.48(s,2H),2.96(t,J=7.6Hz,2H),2.77(q,J=7.2Hz,2H),2.57(t,J=7.2Hz,2H),1.19(t,J=7.2Hz,3H). [ka]

[0214] Step 1: To a mixture of 6-bromo-3,4-dihydro-1H-quinolin-2-one (2 g, 8.85 mmol, 1 equiv.) and pyridine; 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane (2.55 g, 10.62 mmol, 1.2 equiv.) in toluene (40 mL), EtOH (8 mL), and HO (2 mL), Pd(PPh3)4 (1.02 g, 884.68 mmol, 0.1 equiv.) and Na2CO3 (2.81 g, 26.54 mmol, 3 equiv.) were added under N2. The mixture was heated to 90 °C and stirred for 16 h. The mixture was cooled to 20 °C, poured into ice water (60 mL), and stirred for 15 min. The aqueous phase was extracted with ethyl acetate (80 mL*3). The combined organic layer was washed with brine (50 mL) and anhydrous NaSO 4で乾燥させて、濾過し The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=50:1 to 0:1). The compound 6-vinyl-3,4-dihydro-1H-quinolin-2-one (1.05 g, 6.06 mmol, yield 68.52%) was obtained as a yellow solid. LCMS: (M+H) + :173.4.

[0215] Step 2: 6-Vinyl-3,4-dihydro-1H-quinolin-2-one (50 mg, 288.67 μmol, 1 equiv.), 4-bromo-3-methyl-pyridine (30.09 mg, 144.33 μmol, 0.5 equiv., HCl), Pd(OAc) (5.18 mg, 23.09 μmol, 0.08 equiv.), tris-o-tolylphosphane (17.57 mg, 57.73 μmol, 0.2 equiv.), and TEA (87.63 mg, 866.00 μmol, 120.54 μL, 3 equiv.) were placed in a microwave tube containing DMF (3 mL). The sealed tube was heated at 130 °C for 3 h in a microwave oven. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN] to obtain compound number 30, 6-[(E)-2-(3-methyl-4-pyridyl)vinyl]-3,4-dihydro-1H-quinolin-2-one (17.6 mg, 100% purity) as a white solid. LCMS: (M+H) + :265.1. 1 HNMR(400MHz,MeOD,ppm):δ8.30-8.32(m,2H),7.63(d,J=5.2Hz,1H),7.51(s,1H),7.46(dd,J=8.0 and 1.6Hz,1H),7.25-7.34(2H),6.90(d,J=8Hz,1H),3.01(t,J=8Hz,2H),2.60(t,J=8Hz,2H),2.44(s,3H). [ka]

[0216] Step 1: A solution of 3-ethylpyridine-4-carboxylic acid (500 mg, 3.31 mmol, 1 equiv.) in THF (20 mL) was added to a mixture of LAH (125.54 mg, 3.31 mmol, 1 equiv.) in THF (40 mL) at 0 °C. The mixture was then stirred at 15 °C for 1 h. The reaction mixture was quenched at 0 °C by the addition of saturated Na2CO3 (15 mL), then diluted with HO (15 mL), and extracted with EtOAc (10 mL * 5). The combined organic layers were washed with brine (25 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 2 / 1 to 0 / 1). The compound (3-ethyl-4-pyridyl)methanol (150 mg, 1.09 mmol, 33.06% yield) was obtained as a white solid. LCMS: (M+H) + :138.1.

[0217] Step 2: A solution of (3-ethyl-4-pyridyl)methanol (150 mg, 1.09 mmol, 1 equiv.) in SOCl (4.92 g, 41.35 mmol, 3 mL, 37.82 equiv.) was stirred at 60 °C for 10 h. The reaction mixture was concentrated under reduced pressure to remove SOCl. The residue was purified by preparative TLC (SiO, DCM:MeOH = 10:1). Compound 4-(chloromethyl)-3-ethyl-pyridine (140 mg, 899.60 umol, 82.27% yield) was obtained as a white solid. LCMS: (M+H) + :156.1.

[0218] Step 3: 4-(chloromethyl)-3-ethyl-pyridine (1 mL) in DMF (2 mL) To a solution of 2-(3-ethyl-4-pyridyl)acetonitrile (80 mg, 547.24 umol, 85.16% yield) was added NaCN (47.24 mg, 963.86 umol, 1.5 eq). The mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (15 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product 2-(3-ethyl-4-pyridyl)acetonitrile (80 mg, 547.24 umol, 85.16% yield) was obtained as a white solid. LCMS: (M+H) + :147.1.

[0219] Step 4: To a solution of 2-(3-ethyl-4-pyridyl)acetonitrile (80 mg, 547.24 umol, 1 eq.) in EtOH (2 mL) and HO (2 mL), NaOH (43.78 mg, 1.09 mmol, 2 eq.) was added. The mixture was stirred at 100 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove EtOH and HO. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobile phase: [water (0.04% HCl)-ACN]; B%: 1%~10%, 8 min). Compound 2-(3-ethyl-4-pyridyl)acetic acid (40 mg, 242.15 umol, 44.25% yield) was obtained as a white solid. LCMS: (M+H) + :166.0.

[0220] Step 5: To a mixture of 2-(3-ethyl-4-pyridyl)acetic acid (35 mg, 211.88 umol, 1 eq.) and 6-amino-3,4-dihydro-1H-quinolin-2-one (34.36 mg, 211.88 umol, 1 eq.) in pyridine (1 mL), EDCI (40.62 mg, 211.88 umol, 1 eq.) was added in one portion at 40° C. The mixture was stirred at 40° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:methanol=4:1). Compound 2-(3-ethyl-4-pyridyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)acetamide (14.3 mg, 100% pure) was obtained. LCMS: (M+H)+ :310.1. [ka]

[0221] To a solution of 6-amino-7-fluoro-3,3-dimethyl-1,4-dihydroquinolin-2-one (20 mg, 96.05 umol, 1 eq., see Example 21 for the synthesis of this compound) in pyridine (1 mL) was added EDCI (22.09 mg, 115.26 umol, 1.2 eq.) and 3-ethylpyridine-4-carboxylic acid (14.52 mg, 96.05 umol, 1 eq.). The mixture was stirred at 40° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove pyridine. The residue was purified by preparative TLC (SiO, petroleum ether: EtOAc = 0:1). Compound 2-ethyl-N-(7-fluoro-3,3-dimethyl-2-oxo-1,4-dihydroquinolin-6-yl)pyridine-4-carboxylic acid was obtained. Ruboxamide (27 mg, 100% pure) was obtained. LCMS: (M+H) + :342.1. [ka]

[0222] To a mixture of 6-amino-7-fluoro-3,3-dimethyl-1,4-dihydroquinolin-2-one (20 mg, 96.05 umol, 1 eq.) and 3-methoxypyridine-4-carboxylic acid (17.65 mg, 115.26 umol, 1.2 eq.) in pyridine (2 mL), EDCI (22.09 mg, 115.26 umol, 1.2 eq.) was added in one portion at 40° C. The mixture was stirred at 40° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:methanol=4:1). Compound N-(7-fluoro-3,3-dimethyl-2-oxo-1,4-dihydroquinolin-6-yl)-3-methoxy-pyridine-4-carboxamide (20 mg, 100% pure) was obtained. LCMS: (M+H) + :344.1. [ka]

[0223] Step 1: To a mixture of 2-bromo-4-cyano-benzoic acid (600 mg, 2.65 mmol, 1 equiv.), K2CO3 (403.56 mg, 2.92 mmol, 1.1 equiv.) in DMF (10 mL), MeI (414.46 mg, 2.92 mmol, 181.78 uL, 1.1 equiv.) was added under N2. The mixture was stirred at 40 °C for 2 h. The reaction mixture was quenched by the addition of HO (10 mL) and then extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (15 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). Compound methyl 2-bromo-4-cyano-benzoate (450 mg, crude) was obtained as a white solid.

[0224] Step 2: Methyl 2-bromo-4-cyanobenzoate (100 mg, 416.57 μmol, 1 equiv.), ethylboronic acid (61.56 mg, 833.15 μmol, 2 equiv.), Pd(PPh3)4 (48.14 mg, 41.66 μmol, 0.1 equiv.), and K3PO4 (176.85 mg, 833.15 μmol, 2 equiv.) were placed in a microwave tube with DME (3 mL). The sealed tube was heated in a microwave oven at 150 °C for 15 min. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 15 / 1 to 5 / 1). The compound methyl 4-cyano-2-ethylbenzoate (53 mg, 280.11 μmol, 22.41% yield) was obtained as a white solid.

[0225] Step 3: To a mixture of methyl 4-cyano-2-ethyl-benzoate (53 mg, 280.11 umol, 1 equiv.) in MeOH (2 mL), LiOH.HO (17.63 mg, 420.17 umol, 1.5 equiv.) and HO (1 mL) were added. The mixture was stirred at 20 °C for 5 h. The reaction mixture was filtered and concentrated under reduced pressure to remove MeOH. HCl (1 N) was added to the solution until no more solids precipitated. The mixture was filtered to give the title compound, 4-cyano-2-ethyl-benzoic acid (20 mg, 114.17 umol, 40.76% yield) as a white solid.

[0226] Step 4: To a solution of 6-amino-7-fluoro-3,3-dimethyl-1,4-dihydroquinolin-2-one (15 mg, 72.04 umol, 1 eq.) in pyridine (2 mL), EDCI (16.57 mg, 86.44 umol, 1.2 eq.) and 4-cyano-2-ethyl-benzoic acid (15.00 mg, 85.62 umol, 1.19 eq.) were added. The mixture was stirred at 45° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove pyridine. The residue was purified by preparative TLC (SiO, petroleum ether: EtOAc = 1:1). The compound 4-cyano-2-ethyl-N-(7-fluoro-3,3-dimethyl-2-oxo-1,4-dihydroquinolin-6-yl)benzamide (21 mg, 100% pure) was obtained. LCMS: (M+H) + :366.1. [ka]

[0227] 6-Amino-3,4-dihydro-1H-quinolin-2-one ( To a mixture of 3-ethylimidazole-4-carboxylic acid (43.20 mg, 308.28 umol, 1 eq.) and 3-ethylimidazole-4-carboxylic acid (43.20 mg, 308.28 umol, 1 eq.), EDCI (70.92 mg, 369.94 umol, 1.2 eq.) was added in one portion. The mixture was stirred at 40° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:methanol=10:1). The compound 3-ethyl-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)imidazole-4-carboxamide (75 mg, 100% pure) was obtained as a white solid. LCMS: (M+H) + :285.1. [ka]

[0228] Step 1: To a solution of 2-fluoro-3-iodo-pyridine (4 g, 17.94 mmol, 1 equiv) in THF (20 mL) was added dropwise a solution of LDA (2 M, 8.98 mL, 1 equiv) in THF (40 mL) at −78 °C under N. The mixture was stirred at the same temperature for 1 h. To the reaction mixture was added dropwise a solution of CHCHI (2.80 g, 17.94 mmol, 1.43 mL, 1 equiv) in THF (20 mL), and the mixture was stirred at −78 °C for 4 h. After the addition of water (5 ml), the reaction mixture was warmed to room temperature and diluted with brine (10 mL*2). The mixture was extracted with EtOAc (20 mL*3). The organic layer was dried over NaSO, filtered, and then evaporated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 20 / 1). The compound 3-ethyl-2-fluoro-4-iodo-pyridine (3.6 g, 14.34 mmol, yield 79.94%) was obtained as a colorless oil. LCMS: (M+H) + :252.0.

[0229] Step 2: To a solution of 3-ethyl-2-fluoro-4-iodo-pyridine (600 mg, 2.39 mmol, 1 equiv.) in HO (2 mL) and dioxane (2 mL), concentrated HCl (12 M, 4 mL, 20.08 equiv.) was added. The mixture was stirred at 100° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The crude product was triturated with a mixture of petroleum ether and EtOAc (10:1, 11 mL) at 25° C. for 10 minutes. The mixture was filtered, and the filter cake was concentrated under reduced pressure to give a residue. Compound 3-ethyl-4-iodo-1H-pyridin-2-one (570 mg, 2.29 mmol, 95.76% yield) was obtained as a white solid. LCMS: (M+H) + :250.0.

[0230] Step 3: A suspension of 3-ethyl-4-iodo-1H-pyridin-2-one (570 mg, 2.29 mmol, 1 equiv.), DPPP (471.98 mg, 1.14 mmol, 0.5 equiv.), and Pd(OAc) (256.92 mg, 1.14 mmol, 0.5 equiv.) in EtOH (15 mL) was degassed and purged with CO three times. The mixture was stirred at 80 °C under CO (50 Psi) for 72 h. The reaction mixture was diluted with brine (10 mL*2) and then extracted with EtOAc (20 mL*3). The organic layer was dried over NaSO, filtered, and then evaporated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1). Compound ethyl 3-ethyl-2-oxo-1H-pyridine-4-carboxylate (60 mg, 307.35 umol, yield 13.43%) was obtained as a white solid.

[0231] Step 4: To a mixture of ethyl 3-ethyl-2-oxo-1H-pyridine-4-carboxylate (60 mg, 307.35 umol, 1 equiv.) in THF (5 mL) and HO (5 mL) was added LiOH.HO (25.80 mg, 614.71 umol, 2 equiv.) in one portion at 25° C. The mixture was stirred at 25° C. for 5 hours. The reaction mixture was concentrated under reduced pressure to remove THF. The aqueous solution was then adjusted to pH=3 with 3 M aqueous HCl. The suspension was filtered, and the filter cake was concentrated under reduced pressure to give a residue. The crude product was triturated with a mixture of petroleum ether and ethyl acetate (5:1, 6 mL). The suspension was filtered, and the filter cake was concentrated under reduced pressure to give a residue. The product, 3-ethyl-2-oxo-1H-pyridine-4-carboxylic acid (50 mg, 299.11 umol, 97.32% yield), was obtained as a white solid.

[0232] Step 5: To a mixture of 3-ethyl-2-oxo-1H-pyridine-4-carboxylic acid (50 mg, 299.11 μmol, 1 equiv.) and 6-amino-3,4-dihydro-1H-quinolin-2-one (53.36 mg, 329.02 μmol, 1.1 equiv.) in pyridine (3 mL), EDCI (68.81 mg, 358.93 μmol, 1.2 equiv.) was added in one portion at 40° C. The mixture was stirred at 40° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:methanol=5:1). Compound 3-ethyl-2-oxo-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-1H-pyridine-4-carboxamide (80 mg, purity 96.7%) was obtained. LCMS: (M+H) + :312.0. [ka]

[0233] To a mixture of quinoline-4-carboxylic acid (50 mg, 288.74 μmol, 1 equiv.) and 6-amino-3,4-dihydro-1H-quinolin-2-one (46.83 mg, 288.74 μmol, 1 equiv.) in pyridine (1 mL), EDCI (66.42 mg, 346.48 μmol, 1.2 equiv.) was added in one portion at 40°C. The mixture was stirred at 40°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 80*40 mm*3 μm, mobile phase: [water (0.04% HCl)-ACN]; B%: 20%-35%, 7 min). The compound N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)quinoline-4-carboxamide (21 mg, purity 95%) was obtained as a white solid. LCMS: (M+H) + :318.1. [ka]

[0234] To a mixture of 3-(trifluoromethyl)pyridine-4-carboxylic acid (100 mg, 523.27 μmol, 1 equiv.) and 6-amino-3,4-dihydro-1H-quinolin-2-one (84.87 mg, 523.27 μmol, 1 equiv.) in pyridine (2 mL), EDCI (120.37 mg, 627.92 μmol, 1.2 equiv.) was added in one portion at 40°C. The mixture was stirred at 40°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm, mobile phase: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN]; B%: 5% to 45%, 8 min). The compound N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-(trifluoromethyl)pyridine-4-carboxamide (103 mg, purity 95%) was obtained. [ka]

[0235] Step 1: A suspension of methyl 3-allylpyridine-4-carboxylate (50 mg, 282.17 umol, 1 equiv) and 10% Pd / C (20 mg) in THF (5 mL) was degassed and purged with H three times. The mixture was heated under H (15 Psi) at 25 °C for 5 h. The mixture was stirred for 10 minutes. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with a mixture of petroleum ether and EtOAc (10:1, 11 mL) at 25° C. for 10 minutes. The suspension was filtered, and the filter cake was concentrated under reduced pressure to give a residue. Compound methyl 3-propylpyridine-4-carboxylate (45 mg, 251.09 umol, yield 88.99%) was obtained as a white solid. LCMS: (M+H) + :180.1.

[0236] Step 2: To a mixture of methyl 3-propylpyridine-4-carboxylate (45 mg, 251.09 umol, 1 equiv.) in THF (1 mL) and HO (1 mL), LiOH.HO (21.07 mg, 502.19 umol, 2 equiv.) was added in one portion at 20 °C under N. The mixture was stirred at 20 °C for 5 h. The reaction mixture was concentrated under reduced pressure to remove THF. The mixture was adjusted to pH = 3 with 3 M (HCl). The suspension was filtered. The crude product was triturated with petroleum ether: EtOAc (5:1, 6 mL). The suspension was filtered, and the filter cake was concentrated under reduced pressure to give a residue. The product, 3-propylpyridine-4-carboxylic acid (40 mg, 242.15 umol, 96.44% yield), was obtained as a white solid.

[0237] Step 3: To a mixture of 3-propylpyridine-4-carboxylic acid (40 mg, 242.15 μmol, 1 equiv.) and 6-amino-3,4-dihydro-1H-quinolin-2-one (43.20 mg, 266.36 μmol, 1.1 equiv.) in pyridine (1 mL), EDCI (55.70 mg, 290.58 μmol, 1.2 equiv.) was added in one portion at 40° C. The mixture was stirred at 40° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, DCM:MeOH=10:1). Compound N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-propyl-pyridine-4-carboxamide (26.8 mg, 100% pure) was obtained. LCMS: (M+H) + :310.1. [ka]

[0238] Step 1: To a mixture of NaNO (152 g, 2.20 mol, 8.72 equiv.) and Amberlyst A26 (286 g) in HO (3000 mL) was added in one portion under N at 20° C. The mixture was stirred for 30 minutes at 20° C. The reaction was filtered and the pH was adjusted to 7. Step 2: A solution of 4-fluoro-1,2-dinitro-benzene (47 g, 252.56 mmol, 1 equiv.), 4-methylbenzenesulfonic acid (143.52 g, 833.44 mmol, 3.3 equiv.), and palladium acetate (5.67 g, 25.26 mmol, 0.1 equiv.) in MeOH (500 mL) was added to the product from Step 1, followed by methyl prop-2-enonate (108.71 g, 1.26 mol, 113.72 mL, 5 equiv.) in one portion at 60 °C under N. The mixture was stirred at 60 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 15 / 1 to 2 / 1). The compound methyl (E)-3-(4-fluoro-2-nitro-phenyl)prop-2-enoate (9 g, 39.97 mmol, 15.83% yield) was obtained as a white solid.

[0239] Step 2: To a mixture of methyl (E)-3-(4-fluoro-2-nitro-phenyl)prop-2-enoate (9 g, 39.97 mmol, 1 equiv.) in MeOH (100 mL) and THF (20 mL), 10% Pd / C (3 g) was added in one portion at 20° C. under N2. The mixture was stirred at 20° C. for 10 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound methyl 3-(2-amino-4-fluoro-phenyl)propanoate (9 g, crude) was obtained as a white solid.

[0240] Step 3: To a mixture of methyl 3-(2-amino-4-fluoro-phenyl)propanoate (5.3 g, 26.88 mmol, 1 equiv.) was added MeOH (50 mL) at 60 °C under N2. The mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove MeOH (50 mL). The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1). Compound 7-fluoro-3,4-dihydro-1H-quinolin-2-one (3.4 g, 20.59 mmol, 76.60% yield) was obtained as a white solid.

[0241] Step 4: To a solution of 7-fluoro-3,4-dihydro-1H-quinolin-2-one (1 g, 6.05 mmol, 1 equiv.) in DMF (20 mL) was added PMB-Cl (1.33 g, 8.48 mmol, 1.15 mL, 1.4 equiv.) and K2CO3 (1.67 g, 12.11 mmol, 2 equiv.). The mixture was stirred at 60 °C for 12 h. The reaction mixture was cooled to room temperature and extracted with 30 mL (15 mL*2) of EtOAc. The combined organic layers were washed with 30 mL (15 mL*2) of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1). The compound 7-fluoro-1-[(4-methoxyphenyl)methyl]-3,4-dihydroquinolin-2-one (1 g, 3.50 mmol, 57.89% yield) was obtained as a yellow oil. LCMS: (M+H) + :286.1.

[0242] Step 5: To a mixture of 7-fluoro-1-[(4-methoxyphenyl)methyl]-3,4-dihydroquinolin-2-one (1 g, 3.50 mmol, 1 equiv) in THF (5 mL) was added LiHMDS (1 M, 7.71 mL, 2.2 equiv) under N at −70° C. The mixture was stirred at −70° C. for 30 minutes, and then MeI (2.98 g, 21.03 mmol, 1.31 mL, 6 equiv) was added. The mixture was heated to 15° C. and stirred for 5.5 hours. The reaction mixture was quenched by the addition of 10 mL of HO, then diluted with 10 mL of HO and extracted with 30 mL of EtOAc (10 mL*3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The crude product 7-fluoro-1-[(4-methoxyphenyl)methyl]-3-methyl-3,4-dihydroquinolin-2-one (750 mg, 2.51 mmol, 71.49% yield) was obtained as a yellow oil. LCMS: (M+H) + :300.2.

[0243] Step 6: To a solution of 7-fluoro-1-[(4-methoxyphenyl)methyl]-3-methyl-3,4-dihydroquinolin-2-one (600 mg, 2.00 mmol, 1 equiv) in THF (5 mL) was added LiHMDS (1 M, 4.41 mL, 2.2 equiv) at -70 °C. The mixture was stirred at -70 °C for 30 minutes. Then, MeI (1.71 g, 12.03 mmol, 748.70 uL, 6 equiv) was added. The mixture was heated to 15 °C and stirred for 5.5 hours. The reaction mixture was quenched by the addition of 5 mL of HO, then diluted with 5 mL of HO and extracted with 9 mL of EtOAc (3 mL * 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, PE:EA = 3:1). The compound 7-fluoro-1-[(4-methoxyphenyl)methyl]-3,3-dimethyl-4H-quinolin-2-one (550 mg, 1.76 mmol, 87.56% yield) was obtained as a yellow oil.

[0244] Step 7: To a mixture of 7-fluoro-1-[(4-methoxyphenyl)methyl]-3,3-dimethyl-4H-quinolin-2-one (550 mg, 1.76 mmol, 1 equiv.) in DCM (2 mL) was added TFA (6.16 g, 54.02 mmol, 4 mL, 30.78 equiv.). The mixture was stirred at 65° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was analyzed by preparative TLC (SiO, petroleum ether / ethyl acetate=2:1). The compound 7-fluoro-3,3-dimethyl-1,4-dihydroquinolin-2-one (310 mg, 1.60 mmol, 91.41% yield) was obtained as a white solid. LCMS: (M+H) + :194.1.

[0245] Step 8: To a solution of 7-fluoro-3,3-dimethyl-1,4-dihydroquinolin-2-one (200 mg, 1.04 mmol, 1 equiv) in concentrated HSO (5 mL) was added KNO (104.65 mg, 1.04 mmol, 1 equiv) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was cooled at 0 °C, and the resulting solution was stirred at 0 °C for 15 min. The reaction was quenched by adding 100 mL of H0 / ice, filtered, and the filter cake was concentrated under reduced pressure to give a residue. The crude product was triturated with PE:EA = 10:1 (11 mL) at 25 °C for 20 min. The mixture was filtered, and the filter cake was concentrated under reduced pressure to give a residue. The compound 7-fluoro-3,3-dimethyl-6-nitro-1,4-dihydroquinolin-2-one (180 mg, 755.62 umol, yield 73.00%) was obtained as a white solid. LCMS: (M+H) + :239.1.

[0246] Step 9: To a solution of 7-fluoro-3,3-dimethyl-6-nitro-1,4-dihydroquinolin-2-one (180 mg, 755.62 umol, 1 equiv.) in MeOH (10 mL) was added 10% Pd / C (50 mg) under an H atmosphere. The suspension was degassed and purged with H three times. The mixture was stirred under H (45 Psi) at 25 °C for 1 h. TLC showed the reaction was clean. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with PE:EA = 10:1 (11 mL) at 25 °C for 10 min. The mixture was filtered, and the filter cake was concentrated under reduced pressure to give a residue. Compound 6-amino-7-fluoro-3,3-dimethyl-1,4-dihydroquinolin-2-one (130 mg, 624.30 umol, 82.62% yield) was obtained as a white solid.

[0247] Step 10: To a mixture of methyl 2,5-dichloropyridine-4-carboxylate (2 g, 9.71 mmol, 1 equiv.), Fe(acac) (171.42 mg, 485.38 umol, 0.05 equiv.), and NMP (4 mL) in THF (40 mL) was added MeMgBr (3 M, 3.88 mL, 1.2 equiv.) in one portion at 0 °C under N. The mixture was stirred at 20 °C for 10 h. The reaction mixture was quenched by the addition of 50 mL of aqueous NaCl, then diluted with 30 mL of aqueous NaCl, and extracted with 300 mL of EtOAc (100 mL * 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound methyl 5-chloro-2-methyl-pyridine-4-carboxylate (230 mg, 1.24 mmol, 12.77% yield) was a white solid.

[0248] Step 11: To a mixture of methyl 5-chloro-2-methyl-pyridine-4-carboxylate (200 mg, 1.08 mmol, 1 equiv.) in MeOH (2.5 mL) and HO (2.5 mL), LiOH.HO (90.43 mg, 2.16 mmol, 2 equiv.) was added with N 2下, was added in one portion at 20°C. The mixture was stirred at 20°C for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. 3M (HCl) was added to adjust the pH to 3. The crude product, 5-chloro-2-methyl-pyridine-4-carboxylic acid (160 mg, 932.51 umol, 86.54% yield), was obtained as a white solid.

[0249] Step 12: To a solution of 5-chloro-2-methyl-pyridine-4-carboxylic acid (128.54 mg, 749.17 umol, 1.2 equiv.) in pyridine (3 mL), EDCI (143.62 mg, 749.17 umol, 1.2 equiv.) and 6-amino-7-fluoro-3,3-dimethyl-1,4-dihydroquinolin-2-one (130 mg, 624.30 umol, 1 equiv.) were added. The mixture was stirred at 45 °C for 2 hours. The reaction mixture was reduced to 100 mL. The mixture was concentrated under reduced pressure to remove pyridine (3 mL). The residue was purified by preparative TLC (SiO, PE:EA=0:1). Compound 5-chloro-N-(7-fluoro-3,3-dimethyl-2-oxo-1,4-dihydroquinolin-6-yl)-2-methyl-pyridine-4-carboxamide (120 mg, 330.28 μmol, yield 52.90%, purity 99.58%) was obtained.

[0250] Step 13: 5-Chloro-N-(7-fluoro-3,3-dimethyl-2-oxo-1,4-dihydroquinolin-6-yl)-2-methyl-pyridine-4-carboxamide (100 mg, 276.40 μmol, 1 equiv.), 4,4,5,5-tetramethyl-2-(2-methylprop-1-enyl)-1,3,2-dioxaborolane (60.39 mg, 331.68 μmol, 1.2 equiv.), KCO (76.40 mg, 552.80 μmol, 2 equiv.), and Pd(PPh) (15.97 mg, 13.82 μmol, 0.05 equiv.) were placed in a microwave tube containing dioxolane (2 mL) and HO (0.4 mL). The sealed tube was heated at 120 °C for 3 h in a microwave oven. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 5:1). Compound N-(7-fluoro-3,3-dimethyl-2-oxo-1,4-dihydroquinolin-6-yl)-2-methyl-5-(2-methylprop-1-enyl)pyridine-4-carboxamide (65 mg, 165.50 umol, yield 59.88%, purity 97.12%) was obtained. LCMS: (M+H) + :382.1.

[0251] Step 14: To a solution of N-(7-fluoro-3,3-dimethyl-2-oxo-1,4-dihydroquinolin-6-yl)-2-methyl-5-(2-methylprop-1-enyl)pyridine-4-carboxamide (25 mg, 65.54 umol, 1 equiv) in MeOH (2 mL) was added 10% Pd / C (10 mg, 65.54 umol) under an H atmosphere. The suspension was degassed and purged with H three times. The mixture was stirred under H (15 Psi) at 25 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, PE:EA = 0:1). It was then triturated with PE:EA = 10:1 (11 mL) at 25 °C for 10 min. It was then filtered, and the filter cake was concentrated under reduced pressure to give a residue. The compound N-(7-fluoro-3,3-dimethyl-2-oxo-1,4-dihydroquinolin-6-yl)-5-isobutyl-2-methyl-pyridine-4-carboxamide (purity 97.2%) (31 mg) was obtained. LCMS: (M+H) + :384.1. [ka]

[0252] Step 1: To a solution of 3-fluoroaniline (1 g, 9.00 mmol, 862.07 uL, 1 equiv.) in DCM (10 mL) was added DIPEA (2.33 g, 18.00 mmol, 3.14 mL, 2 equiv.) and 3-methylbut-2-enoyl chloride (1.07 g, 9.00 mmol, 997.19 uL, 1 equiv.) at 0 °C. The resulting mixture was warmed to 15 °C and stirred at 15 °C for 2 h. Saturated NaHCO (20 mL) was then added slowly to quench the reaction. The organic layer was separated and washed with saturated NaHCO (50 mL) and water (50 mL * 2). The resulting solution was dried over NaSO, and the filtrate was evaporated. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1). The compound 3-methyl-N-phenyl-but-2-enamide N-(3-fluorophenyl)-3-methyl-but-2-enamide (800 mg, 4.14 mmol, 46.01% yield) was obtained as a colorless oil.

[0253] Step 2: To a solution of N-(3-fluorophenyl)-3-methyl-but-2-enamide (120 mg, 621.06 umol, 1 eq) in DCM (10 mL) was added AlCl (165.63 mg, 1.24 mmol, 67.88 uL, 2 eq). The mixture was stirred at 50 °C for 2 h. Saturated sodium bicarbonate (50 mL) was added to quench the reaction. The organic layer was separated and washed with saturated NaHCO (100 mL) and water (50 mL * 3). The resulting solution was dried over NaSO, and the filtrate was evaporated. The residue was purified by preparative TLC (SiO, petroleum ether: EtOAc = 0:1). Compound 7-fluoro-4,4-dimethyl-1,3-dihydroquinolin-2-one (50 mg, 258.78 umol, 41.67% yield) was obtained as a white solid.

[0254] Step 3: To a solution of 7-fluoro-4,4-dimethyl-1,3-dihydroquinolin-2-one (50 mg, 258.78 umol, 1 equiv.) in concentrated H2SO4 (2 mL) was added KNO3 (26.16 mg, 258.78 umol, 1 equiv.) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The reaction mixture was cooled at 0 °C, and the resulting solution was quenched by adding 10 mL of ice / H2O. The suspension was filtered, and the filter cake was concentrated under reduced pressure to give a residue. The crude product was triturated with a mixture of petroleum ether and EtOAc (10:1, 5.5 mL) at 25 °C for 20 minutes. The suspension was filtered, and the filter cake was concentrated under reduced pressure to give a residue. The compound 7-fluoro-4,4-dimethyl-6-nitro-1,3-dihydroquinolin-2-one (44 mg, 184.71 umol, yield 71.38%) was obtained as a white solid.

[0255] Step 4: To a solution of 7-fluoro-4,4-dimethyl-6-nitro-1,3-dihydroquinolin-2-one (44 mg, 184.71 umol, 1 eq.) in HO (1 mL) and EtOH (1 mL), NH4Cl (49.40 mg, 923.54 umol, 5 eq.) and Fe (51.57 mg, 923.54 umol, 5 eq.) were added. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 5:1). Compound 6-amino-7-fluoro-4,4-dimethyl-1,3-dihydroquinolin-2-one (30 mg, 144.07 umol, 78.00% yield) was obtained as a white solid. LCMS: (M+H) + :209.1

[0256] Step 5: To a solution of 6-amino-7-fluoro-4,4-dimethyl-1,3-dihydroquinolin-2-one (30 mg, 144.07 umol, 1 equiv.) in pyridine (2 mL), EDCI (33.14 mg, 172.88 umol, 1.2 equiv.) and 3-ethylpyridine-4-carboxylic acid (21.78 mg, 144.07 umol, 1 equiv.) were added. The mixture was stirred at 40° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove pyridine. The residue was purified by preparative TLC (SiO, petroleum ether: EtOAc = 0:1). Compound 3-ethyl-N-(7-fluoro-4-methyl-2-oxo-3,4- Dihydro-1H-quinolin-6-yl)pyridine-4-carboxamide (23.5 mg, 100% pure) was obtained. LCMS: (M+H) + :342.1. [ka]

[0257] Step 1: To a solution of 1-[(4-methoxyphenyl)methyl]-3-methyl-3,4-dihydroquinolin-2-one (400 mg, 1.42 mmol, 1 equiv) in THF (2 mL) was added LiHMDS (2 M, 1.56 mL, 2.2 equiv) at −70° C. The mixture was stirred at −70° C. for 30 minutes. Then, EtI (1.33 g, 8.53 mmol, 682.28 uL, 6 equiv) was added at −70° C. The mixture was allowed to warm to 15° C. and stirred for 5.5 hours. The reaction mixture was quenched by the addition of HO (15 mL), then diluted with HO (15 mL) and extracted with EtOAc (5 mL*3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to obtain the compound 3-ethyl-1-[(4-methoxyphenyl)methyl]-3-methyl-4H-quinolin-2-one (300 mg, 969.61 umol, yield 68.20%) as a yellow oil.

[0258] Step 2: A mixture of 3-ethyl-1-[(4-methoxyphenyl)methyl]-3-methyl-4H-quinolin-2-one (300 mg, 969.61 umol, 1 eq.) in DCM (1 mL) and TFA (15.40 g, 135.06 mmol, 10.00 mL, 139.29 eq.) was stirred at 65 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate = 2:1). The compound 3-ethyl-3-methyl-1,4-dihydroquinolin-2-one (152 mg, 803.16 umol, 82.83% yield) was obtained as a white solid.

[0259] Step 3: To a solution of 3-ethyl-3-methyl-1,4-dihydroquinolin-2-one (152 mg, 803.16 umol, 1 equiv) in concentrated H2SO4 (2 mL) was added KNO3 (81.20 mg, 803.16 umol, 1 equiv) at 0 °C. The mixture was stirred at 25 °C for 30 minutes. The reaction mixture was cooled at 0 °C, and the resulting solution was stirred at 0 °C for 15 minutes. The mixture was then quenched by adding 50 mL of H2O / ice. The suspension was filtered, and the filter cake was concentrated under reduced pressure to give a residue. The crude product was triturated with a mixture of petroleum ether and EtOAc (10:1, 11 mL) at 25 °C for 20 minutes. The suspension was filtered, and the filter cake was concentrated under reduced pressure to give a residue. The compound 3-ethyl-3-methyl-6-nitro-1,4-dihydroquinolin-2-one (156 mg, 665.95 u mol, yield 82.92%) as a white solid. LCMS: (M+H) + :235.1.

[0260] Step 4: A suspension of 3-ethyl-3-methyl-6-nitro-1,4-dihydroquinolin-2-one (156 mg, 665.95 umol, 1 equiv.) and 10% Pd / C (50 mg) in THF (2 mL) was degassed and purged with H2 three times. The mixture was stirred under H2 (45 Psi) at 25 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with a mixture of petroleum ether and EtOAc (10:1, 11 mL) at 25 °C for 10 min. The suspension was filtered, and the filter cake was concentrated under reduced pressure to give a residue. Compound 6-amino-3-ethyl-3-methyl-1,4-dihydroquinolin-2-one (100 mg, 489.55 umol, 73.51% yield) was obtained as a white solid.

[0261] Step 5: To a mixture of 6-amino-3-ethyl-3-methyl-1,4-dihydroquinolin-2-one (100 mg, 489.55 umol, 1 eq.) and 3-ethylpyridine-4-carboxylic acid (81.40 mg, 538.51 umol, 1.1 eq.) in pyridine (3 mL), EDCI (112.62 mg, 587.46 umol, 1.2 eq.) was added in one portion at 40° C. The mixture was stirred at 40° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, DCM:MeOH=10:1). Compound 3-ethyl-N-(3-ethyl-3-methyl-2-oxo-1,4-dihydroquinolin-6-yl)pyridine-4-carboxamide (7 mg, purity 95.4%) was obtained. LCMS: (M+H) + :338.1 [ka]

[0262] Step 1: To a mixture of 1-[(4-methoxyphenyl)methyl]-3-methyl-3,4-dihydroquinolin-2-one (500 mg, 1.78 mmol, 1 equiv.) in DCM (5 mL) and TFA (7.70 g, 67.53 mmol, 5 mL, 38.00 equiv.), the mixture was stirred at 65 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1). Compound 3-methyl-3,4-dihydro-1H-quinoline-2-one was obtained. The ion (250 mg, 1.55 mmol, 87.27% yield) was obtained as a white solid.

[0263] Step 2: To a solution of 3-methyl-3,4-dihydro-1H-quinolin-2-one (250 mg, 1.55 mmol, 1 equiv) in concentrated HSO (2 mL) was added KNO (156.80 mg, 1.55 mmol, 1 equiv) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was cooled at 0 °C, and the resulting solution was stirred at 0 °C for 15 min. The mixture was then quenched by adding 50 mL of H0 / ice. The suspension was filtered, and the filter cake was concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether: EtOAc (10:1, 11 mL) at 25 °C for 20 min. The suspension was filtered, and the filter cake was concentrated under reduced pressure to give a residue. The compound 3-methyl-6-nitro-3,4-dihydro-1H-quinolin-2-one (260 mg, 1.26 mmol, yield 81.30%) was obtained as a white solid. LCMS: (M+H) + :207.1.

[0264] Step 3: A suspension of 3-methyl-6-nitro-3,4-dihydro-1H-quinolin-2-one (260 mg, 1.26 mmol, 1 equiv.) and 10% Pd / C (100 mg) in THF (5 mL) was degassed and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 25 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with petroleum ether: EtOAc (10:1, 11 mL) at 25 °C for 10 min. The suspension was filtered, and the filter cake was concentrated under reduced pressure to give a residue. Compound 6-amino-3-methyl-3,4-dihydro-1H-quinolin-2-one (150 mg, 851.23 umol, 67.51% yield) was obtained as a white solid.

[0265] Step 4: To a mixture of 6-amino-3-methyl-3,4-dihydro-1H-quinolin-2-one (150 mg, 851.23 umol, 1 eq.) and 3-ethylpyridine-4-carboxylic acid (141.54 mg, 936.36 umol, 1.1 eq.) in pyridine (2 mL), EDCI (195.82 mg, 1.02 mmol, 1.2 eq.) was added in one portion at 40° C. The mixture was stirred at 40° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, DCM:MeOH=10:1). Compound 3-ethyl-N-(3-methyl-2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyridine-4-carboxamide (35.8 mg, purity 96.7%) was obtained. LCMS: (M+H) + :310.1. [ka]

[0266] Step 1: To a solution of 7-fluoro-3,4-dihydro-1H-quinolin-2-one (150 mg, 908.19 umol, 1 equiv) in DMF (5 mL) was added NBS (177.81 mg, 999.01 umol, 1.1 equiv) portionwise at 0 °C. The mixture was stirred at 20 °C for 5 hours. The reaction mixture was poured into water (15 mL) to give a suspension. The white solid was filtered and washed with H O (5 mL). The filter cake was diluted with EtOAc (10 mL) and extracted with EtOAc (5 mL * 2). The combined organic layer was washed with brine (5 mL * 2), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether: EtOAc = 2:1). The compound 6-bromo-7-fluoro-3,4-dihydro-1H-quinolin-2-one (120 mg, 491.68 umol, 54.14% yield) was obtained as a white solid. LCMS: (M+H) + :244.0.

[0267] Step 2: To a mixture of 6-bromo-7-fluoro-3,4-dihydro-1H-quinolin-2-one (120 mg, 491.68 μmol, 1 equiv.), 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane (95.33 mg, 590.02 μmol, 1.2 equiv.), and NaCO (156.34 mg, 1.48 mmol, 3 equiv.) in toluene (20 mL), EtOH (4 mL), and HO (1 mL), Pd(PPh) (56.82 mg, 49.17 μmol, 0.1 equiv.) was added in one portion under N. The mixture was heated to 90 °C and stirred for 12 h. The mixture was cooled to 20 °C and poured into ice water (15 mL). The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic layer was washed with brine (30 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: EtOAc = 0:1). 7-Fluoro-6-vinyl-3,4-dihydro-1H-quinolin-2-one (81 mg, 423.64 umol, 86.16% yield) was obtained as a yellow solid. LCMS: (M+H) + :192.1.

[0268] Step 3: 4-Bromo-3-ethyl-pyridine (78.82 mg, 423.64 μmol, 1 equiv.), 7-fluoro-6-vinyl-3,4-dihydro-1H-quinolin-2-one (81 mg, 423.64 μmol, 1 equiv.), tris-o-tolylphosphane (64.47 mg, 211.82 μmol, 0.5 equiv.), TEA (128.60 mg, 1.27 mmol, 176.89 μL, 3 equiv.), and Pd(OAc) (7.61 mg, 33.89 μmol, 0.08 equiv.) were placed in a microwave tube containing DMF (5 mL). The sealed tube was heated at 130 °C for 3 h in a microwave oven. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether: EtOAc = 1:1) to give compound 45, 6-[(E)-2-(3-ethyl-4-pyridyl) vinyl]-7-fluoro-3,4-dihydro-1H-quinolin-2-one (36 mg, purity 97.5%). LCMS: (M+H) + :297.1. 1HNMR(400MHz,MeOD,ppm):δ8.32-8.34(m,2H),7.58-7.64(m,2H),7.39(s,2H),6.68(d,J=12.0H z,1H),3.0(t,J=7.2Hz,2H),2.85(q,J=7.6Hz,2H),2.61(t,J=7.2Hz,2H),1.26(t,J=7.6Hz,3H). [ka]

[0269] Step 1: To a mixture of 3-ethylpyridine (2 g, 18.66 mmol, 2.10 mL, 1 equiv.) in DCM (40 mL) was added m-CPBA (3.79 g, 18.66 mmol, 85% purity, 1 equiv.) portionwise at 0 °C. The mixture was then stirred at 25 °C for 16 h. To the mixture was added saturated NaSO (50 mL). The mixture was then stirred at 25 °C for 1 h. The mixture was extracted with DCM (25 mL * 3). The combined organic layer was washed with brine (30 mL * 2), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo to give compound 3-ethyl-1-oxide-pyridin-1-ium (1.2 g, crude) as a white solid.

[0270] Step 2: A mixture of 3-ethyl-1-oxide-pyridin-1-ium (1.2 g, 9.74 mmol, 1 equiv) and CHCl (4.56 g, 29.23 mmol, 2.34 mL, 3 equiv) was stirred at 50° C. for 1 hour. The mixture was then cooled to 15° C. Petroleum ether (50 mL) was added to the mixture and filtered. The filter cake was added to HO (30 mL). NaCN (955.06 mg, 19.49 mmol, 2 equiv) in HO (10 mL) was then added dropwise to the mixture at 15° C. The mixture was stirred at 50° C. for 1 hour. The mixture was adjusted to pH=12 with 1 M NaOH. The aqueous phase was extracted with ethyl acetate (15 mL*3). The combined organic layers were washed with brine (10 mL*2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (SiO 2 , petroleum ether:ethyl acetate=0:1) to obtain compound 3-ethylpyridine-4-carbonitrile (0.6 g, 4.54 mmol, yield 46.59%) as a white solid.

[0271] Step 3: To a mixture of 3-ethylpyridine-4-carbonitrile (0.6 g, 4.54 mmol, 1 equiv.) in EtOH (6 mL) and HO (3 mL), NaOH (363.16 mg, 9.08 mmol, 2 equiv.) was added. The mixture was stirred at 95 °C for 5 h. The mixture was adjusted to pH = 5-6 with 1 N HCl and then concentrated in vacuo. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 0:1) to give 3-ethylpyridine-4-carboxylic acid (0.45 g, 2.98 mmol, 65.57% yield). Obtained as a white solid.

[0272] Step 4: Section A: Amberyst A-26(OH) (60 g) and NaNO (35 g, 507.28 mmol, 7.72 equiv.) in HO (1300 mL) were stirred at 25 °C for 0.5 h. The mixture was filtered, and the filter cake was washed with HO (500 mL). Section B: To a mixture of 4-methyl-2-nitro-aniline (10 g, 65.72 mmol, 1 equiv.) and TsOH.HO (37.51 g, 197.17 mmol, 3 equiv.), Pd(OAc) (1.48 g, 6.57 mmol, 0.1 equiv.) in MeOH (150 mL) was added the product from Section A. To the mixture was then added methyl prop-2-enoate (28.29 g, 328.62 mmol, 29.59 mL, 5 equiv) dropwise at 0° C., after which the mixture was warmed to 60° C. and stirred at 60° C. for 1 h. The mixture was filtered. The filter cake was washed with EtOAc (100 mL). The combined organic phase was concentrated in vacuo. The residue was diluted with H2O (200 mL). The aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to obtain the compound methyl (E)-3-(4-methyl-2-nitro-phenyl)prop-2-enoate (11 g, 49.03 mmol, yield 74.60%, purity 98.6%) as a pale yellow solid.

[0273] Step 5: To a solution of methyl (E)-3-(4-methyl-2-nitro-phenyl)prop-2-enoate (11 g, 49.73 mmol, 1 equiv.) in MeOH (110 mL) was added 10% Pd / C (1 g) under N. The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (15 Psi) at 25 °C for 5 h. The reaction mixture was filtered, and the filtrate was concentrated to give the compound methyl 3-(2-amino-4-methyl-phenyl)propanoate (7.5 g, 38.81 mmol, 78.05% yield) as an off-white solid without further purification. LCMS: (M+H) + :194.1, 0.270 minutes

[0274] Step 6: A mixture of methyl 3-(2-amino-4-methyl-phenyl)propanoate (7.5 g, 38.81 mmol, 1 equiv.) in MeOH (200 mL) was stirred at 60° C. for 12 hours. The mixture was concentrated under reduced pressure. The crude product was triturated with a solution (petroleum ether:ethyl acetate=10:1, 50 mL) at 25° C. for 30 minutes. The mixture was filtered. The filter cake was concentrated under reduced pressure. 7-Methyl-3,4-dihydro-1H-quinolin-2-one (4.8 g, 29.78 mmol, 76.72% yield) was obtained as an off-white solid.

[0275] Step 7: To a mixture of 7-methyl-3,4-dihydro-1H-quinolin-2-one (2 g, 12.41 mmol, 1 eq.) in HSO (20 mL) was added KNO (1.51 g, 14.89 mmol, 1.2 eq.) dropwise at 0 °C. The mixture was then stirred at 0 °C for 1 hour. The mixture was poured into ice water (100 mL). The mixture was then filtered. The filter cake was triturated with a solution (30 mL, petroleum ether:ethyl acetate = 2:1) at 25 °C for 30 minutes, then filtered, and the filtrate was concentrated under reduced pressure to obtain compound 7-methyl-6-nitro-3,4-dihydro-1H-quinolin-2-one (1.1 g, 5.33 mmol, 43.00% yield) as an off-white solid. LCMS: (M+H) + :207.1.

[0276] Step 8: To a solution of 7-methyl-6-nitro-3,4-dihydro-1H-quinolin-2-one (1.1 g, 5.33 mmol, 1 equiv.) in MeOH (15 mL) was added 10% Pd / C (0.1 g) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 10 h. The mixture was filtered and concentrated in vacuo. 6-amino-7-methyl-3,4-dihydro-1H-quinolin-2-one (1.1 g, 5.33 mmol, 1 equiv.) in MeOH (15 mL) was added 10% Pd / C (0.1 g) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 10 h. The mixture was filtered and concentrated in vacuo. The one (800 mg, 4.54 mmol, 85.10% yield) was obtained as a purple solid without further purification. LCMS: (M+H) + :177.1.

[0277] Step 9: A mixture of 6-amino-7-methyl-3,4-dihydro-1H-quinolin-2-one (60 mg, 340.49 umol, 1 eq.) and 3-ethylpyridine-4-carboxylic acid (51.47 mg, 340.49 umol, 1.0 eq.), EDCI (84.86 mg, 442.64 umol, 1.3 eq.) in pyridine (2 mL) was stirred at 50 °C for 1 hour. The mixture was concentrated in vacuo. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 0:1). 3-Ethyl-N-(7-methyl-2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyridine-4-carboxamide (36 mg, 100% pure) was obtained. LCMS: (M+H) + :310.1. [ka]

[0278] Step 1: To a mixture of 7-bromo-3,4-dihydro-1H-quinolin-2-one (1 g, 4.42 mmol, 1 equiv.) in HSO (10 mL) was added KNO (536.65 mg, 5.31 mmol, 1.2 equiv.) portionwise at 0 °C. The mixture was then stirred at 0 °C for 1 h. The reaction mixture was poured onto ice (100 mL). The mixture was filtered, and the filter cake was washed with ice water (20 mL). The filter cake was concentrated in vacuo to give 7-bromo-6-nitro-3,4-dihydro-1H-quinolin-2-one (1 g, 3.69 mmol, 83.40% yield) as an off-white solid. LCMS: (M+H) + :272.9.

[0279] Step 2: A mixture of 7-bromo-6-nitro-3,4-dihydro-1H-quinolin-2-one (1 g, 3.69 mmol, 1 equiv.) and CuCN (660.82 mg, 7.38 mmol, 1.61 mL, 2 equiv.) in DMF (10 mL) was stirred at 120 °C for 6 h. The mixture was cooled to 25 °C. HO (50 mL) was added to the mixture and filtered. The filter cake was washed with HO (10 mL * 2). The filter cake was added to a solution (100 mL, THF:DCM = 3:1). The mixture was stirred at 25 °C for 1 h and filtered. The filtrate was concentrated in vacuo. 6-nitro-2-oxo-3,4-dihydro-1H-quinoline-7-carbonitrile (550 mg, 2.53 mmol, 68.65% yield) was obtained as a yellow solid. LCMS: (M+H) + :218.0.

[0280] Step 3: To a mixture of 6-nitro-2-oxo-3,4-dihydro-1H-quinoline-7-carbonitrile (50 mg, 230.22 μmol, 1 equiv.) in HOAc (2 mL), Zn (75.27 mg, 1.15 mmol, 5 equiv.) was added at 0° C. The mixture was stirred at 0° C. for 5 h. The reaction mixture was adjusted to pH=7-8 with saturated aqueous NaHCO3, then extracted with 30 mL of EtOAc (10 mL*3). The combined organic layer was washed with 1 mL of brine. 0 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 6-amino-2-oxo-3,4-dihydro-1H-quinoline-7-carbonitrile (40 mg, crude) as a yellow solid. LCMS: (M+H) + :188.0.

[0281] Step 4: To a solution of 6-amino-2-oxo-3,4-dihydro-1H-quinoline-7-carbonitrile (40 mg, 213.68 umol, 1 eq.) and 3-ethylpyridine-4-carboxylic acid (32.30 mg, 213.68 umol, 1 eq.) in pyridine (5 mL), EDCI (45.06 mg, 235.05 umol, 1.1 eq.) was added. The mixture was stirred at 60° C. for 2 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, DCM:MeOH=10:1) to give compound N-(7-cyano-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-ethyl-pyridine-4-carboxamide (23 mg, purity 98%). LCMS: (M+H) + :321.3. [ka]

[0282] To a solution of 6-amino-4,4-dimethyl-1,3-dihydroquinolin-2-one (100 mg, 525.65 μmol, 1 equiv.) and 1-bromoisoquinoline (131.24 mg, 630.78 μmol, 1.2 equiv.) in toluene (3 mL) was added Pd(OAc) (29.50 mg, 131.41 μmol, 0.25 equiv.), CsCO (342.53 mg, 1.05 mmol, 2 equiv.), and Xantphos (48.66 mg, 84.10 μmol, 0.16 equiv.). The mixture was stirred at 110 °C for 6 h. The reaction mixture was filtered, and the filtrate was diluted with 6 mL of HO and extracted with 15 mL of EtOAc (5 mL * 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um, mobile phase: [water (0.05% NH3H2O ​​+ 10mM NH4HCO3)-ACN]; B%: 30%-60%, 8 min). Compound 6-(1-isoquinolylamino)-4,4-dimethyl-1,3-dihydroquinolin-2-one (41.3 mg, purity 100%) was obtained. LCMS: (M+H) + :318.1. [ka]

[0283] To a solution of 6-amino-3,4-dihydro-1H-quinolin-2-one (100 mg, 616.57 μmol, 1 equiv.) and 2-bromoquinoline (153.94 mg, 739.88 μmol, 1.2 equiv.) in toluene (5 mL) was added Pd(OAc) (34.61 mg, 154.14 μmol, 0.25 equiv.), Xantphos (57.08 mg, 98.65 μmol, 0.16 equiv.), and CsCO (401.78 mg, 1.23 mmol, 2 equiv.). The mixture was stirred at 110 °C for 6 h. The reaction mixture was filtered, and the filtrate was diluted with 6 mL of HO and extracted with 15 mL of EtOAc (5 mL * 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um, mobile phase: [water (0.05% NH3H2O ​​+ 10mM NH4HCO3)-ACN]; B%: 25%-55%, 8 min). Compound 6-(2-quinolylamino)-3,4-dihydro-1H-quinolin-2-one (38.6 mg, purity 100%) was obtained. LCMS: (M+H) + :290.1 [ka]

[0284] To a solution of 6-amino-3,4-dihydro-1H-quinolin-2-one (100 mg, 616.57 μmol, 1 equiv.) and 2-bromopyridine (116.90 mg, 739.88 μmol, 70.42 μL, 1.2 equiv.) in toluene (5 mL), Pd(OAc) (34.61 mg, 154.14 μmol, 0.25 equiv.), Xantphos (57.08 mg, 98.65 μmol, 0.16 equiv.), and CsCO (401.78 mg, 1.23 mmol, 2 equiv.) were added. The mixture was stirred at 110° C. for 6 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, PE:EA=1:1). The compound 6-(2-pyridylamino)-3,4-dihydro-1H-quinolin-2-one (97.5 mg, purity 100%) was obtained. LCMS: (M+H) + :240.1. [ka]

[0285] To a solution of 6-amino-3,3-dimethyl-1,4-dihydroquinolin-2-one (50 mg, 262.82 μmol, 1 equiv.) and 2-bromoquinoline (65.62 mg, 315.39 μmol, 1.2 equiv.), CsCO (171.27 mg, 525.65 μmol, 2 equiv.), and Xantphos (24.33 mg, 42.05 μmol, 0.16 equiv.) in dioxane (5 mL), Pd(OAc) (14.75 mg, 65.71 μmol, 0.25 equiv.) was added under a N atmosphere. The mixture was stirred at 110° C. under N for 6 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether: EtOAc = 0:1). The product was then triturated with a mixture of petroleum ether and EtOAc (10:1, 11 mL). The suspension was filtered, and the filter cake was concentrated under reduced pressure to obtain a residue. Compound 3,3-dimethyl-6-(2-quinolylamino)-1,4-dihydroquinolin-2-one (25 mg, purity 100%) was obtained. LCMS: (M+H) + :318.1. [ka]

[0286] To a solution of 6-amino-7-fluoro-3,4-dihydro-1H-quinolin-2-one (100 mg, 555.00 μmol, 1 equiv.) and 2-bromoquinoline (138.57 mg, 666.01 μmol, 1.2 equiv.), CsCO (361.66 mg, 1.11 mmol, 2 equiv.), and Xantphos (51.38 mg, 88.80 μmol, 0.16 equiv.) in dioxane (5 mL), Pd(OAc) (31.15 mg, 138.75 μmol, 0.25 equiv.) was added under a N atmosphere. The mixture was stirred at 110 °C for 6 h. The reaction mixture was filtered, and the filtrate was diluted with HO (6 mL) and EtOAc (5 mL). The resulting mixture was extracted with HCl (HCl, ... + :308.1. [ka]

[0287] To a solution of 6-amino-7-fluoro-3,3-dimethyl-1,4-dihydroquinolin-2-one (40 mg, 192.09 μmol, 1 equiv.) and 2-bromoquinoline (47.96 mg, 230.51 μmol, 1.2 equiv.), CsCO (125.18 mg, 384.19 μmol, 2 equiv.), and Xantphos (17.78 mg, 30.74 μmol, 0.16 equiv.) in dioxane (5 mL), Pd(OAc) (10.78 mg, 48.02 μmol, 0.25 equiv.) was added under a N atmosphere. The mixture was stirred at 110 °C for 6 h. The reaction mixture was filtered, and the filtrate was diluted with HO (6 mL) and extracted with EtOAc (5 mL*3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, DCM:MeOH=10:1). The compound 7-fluoro-3,3-dimethyl-6-(2-quinolylamino)-1,4-dihydroquinolin-2-one (25 mg, purity 95.9%) was obtained. LCMS: (M+H) + :336.1. [ka]

[0288] Step 1: 5-Bromoquinoline (1 g, 4.81 mmol, 1 equiv.), Pd(PPh3)4 (1.11 g, 961.29 umol, 0.2 equiv.), and Zn(CN)2 (846.59 mg, 7.21 mmol, 457.62 uL, 1.5 equiv.) were taken in a microwave tube with DMF (10 mL). The sealed tube was heated in a microwave at 150 °C for 60 min. To the mixture, HO (250 mL) was added. The mixture was adjusted to pH = 12 with 1N aqueous NaOH solution. The aqueous phase was extracted with ethyl acetate (100 mL * 3). The combined organic layers were washed with brine (100 mL * 4), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 25 / 1 to 3 / 1). Quinoline-5-carbonitrile (2 g, 12.97 mmol, 53.98%) was obtained as a yellow solid.

[0289] Step 2: To a mixture of quinoline-5-carbonitrile (2 g, 12.97 mmol, 1 equiv.) in DCM (60 mL) was added m-CPBA (3.08 g, 14.27 mmol, 80% purity, 1.1 equiv.) portionwise at 0 °C. The mixture was then stirred at 25 °C for 16 h. To this mixture was added saturated Na2SO3 (100 mL). The mixture was stirred at 25 °C for 1 h. The mixture was then extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated with a solution (30 mL, petroleum ether:ethyl acetate = 3:1) at 25 °C for 30 min. 1-Oxidoquinolin-1-ium-5-carbonitrile (0.7 g, 4.11 mmol, 31.71% yield) was obtained as a white solid. LCMS: (M+H) + :171.0.

[0290] Step 3: To a solution of POBr3 (3.03 g, 10.58 mmol, 1.08 mL, 3 equiv.) was added 1-oxidoquinolin-1-ium-5-carbonitrile (0.6 g, 3.53 mmol, 1 equiv.) at 25 °C. The mixture was then stirred at 55 °C for 1 h. The mixture was cooled to 25 °C and poured into ice water (100 mL). The mixture was stirred at 25 °C for 1 h. The mixture was extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with brine (30 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1). A mixture of 3-bromoquinoline-5-carbonitrile and 2-bromoquinoline-5-carbonitrile (0.2 g, crude) was obtained as a yellow solid. LCMS: (M+H) + :234.2

[0291] Step 4: To a mixture of 3-bromoquinoline-5-carbonitrile (643.60 μmol, 1 equiv.) and 2-bromoquinoline-5-carbonitrile (150 mg, 643.60 μmol, 1 equiv.), 6-amino-3,4-dihydro-1H-quinolin-2-one (93.95 mg, 579.24 μmol, 0.9 equiv.) in 1,4-dioxane (10 mL), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenylphosphane (74.48 mg, 128.72 μmol, 0.2 equiv.), CsCO (419.39 mg, 1.29 mmol, 2 equiv.), and Pd(OAc) (28.90 mg, 128.72 μmol, 0.2 equiv.) were added. The mixture was then stirred at 110° C. for 12 hours. The mixture was filtered. The filter cake was washed with EtOAc (20 mL). The combined organic phases were concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C 18 Purification was performed using a 150x40mmx10um column (mobile phase: water (0.05% NH3H2O ​​+ 10mM NH4HCO3)-ACN); B%: 20%-50%, 8 min. 2-[(2-oxo-3,4-dihydro-1H-quinolin-6-yl)amino]quinoline-5-carbonitrile (86, 12 mg, purity 98%) and 3-[(2-oxo-3,4-dihydro-1H-quinolin-6-yl)amino]quinoline-5-carbonitrile (100, 13 mg, purity 94%) were obtained. [ka]

[0292] Step 1: To a solution of 5-methylquinoline (1 g, 6.98 mmol, 1 eq) in DCM (20 mL) was added m-CPBA (1.66 g, 7.68 mmol, 80% purity, 1.1 eq) portionwise at 0 °C. The mixture was stirred at 25 °C for 10 h. To this mixture was added saturated NaSO (50 mL). Then the mixture was stirred at 25 °C for 1 h. The mixture was extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. Compound 5-methyl-1-oxide-quinolin-1-ium (1.1 g, crude) was obtained as a white solid. LCMS: (M+H) + :160.1.

[0293] Step 2: To a mixture of 5-methyl-1-oxide-quinolin-1-ium (0.9 g, 5.65 mmol, 1 equiv.) in CHCl3 (15 mL) was added POBr3 (2.43 g, 8.48 mmol, 862.16 uL, 1.5 equiv.) at 0 °C. The mixture was then stirred at 0 °C for 1 hour. The reaction mixture was slowly poured into saturated Na2CO3 (50 mL). The mixture was then extracted with 60 mL (20 mL * 3) of CHCl2. The combined organic layers were washed with 40 mL (20 mL * 2) of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO2, PE:EA = 10:1). Compounds 2-bromo-5-methyl-quinoline (A: 170 mg) and 3-bromo-5-methyl-quinoline (B: 190 mg) were obtained.

[0294] Step 3: To a solution of 2-bromo-5-methyl-quinoline (200 mg, 900.57 umol, 1 equiv.), 6-amino-3,4-dihydro-1H-quinolin-2-one (146.06 mg, 900.57 umol, 1 equiv.), and Cs2CO3 (586.85 mg, 1.80 mmol, 2 equiv.) in 1,4-dioxane (20 mL), Pd(OAc)2 (40.44 mg, 180.11 umol, 0.2 equiv.) and (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenylphosphane (104.22 mg, 180.11 umol, 0.2 equiv.) were added. The mixture was stirred at 110 °C for 12 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, PE:EA=0:1). The compound 6-[(5-methyl-2-quinolyl)amino]-3,4-dihydro-1H-quinolin-2-one (87:60 mg, purity 95%) was obtained. LCMS: (M+H) + :304.1.

[0295] Step 4: 3-Bromo-5-methyl-quinoline (210 mg, 945.60 umol, 1 equiv.), 6-amino-3,4-dihydro-1H- in 1,4-dioxane (5 mL) To a solution of quinolin-2-one (153.37 mg, 945.60 umol, 1 eq.) and Cs2CO3 (616.19 mg, 1.89 mmol, 2 eq.) was added Pd(OAc)2 (42.46 mg, 189.12 umol, 0.2 eq.) and (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenylphosphane (109.43 mg, 189.12 umol, 0.2 eq.). The mixture was stirred at 110 °C for 12 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, PE:EA = 0:1). The compound 6-[(5-methyl-3-quinolyl)amino]-3,4-dihydro-1H-quinolin-2-one (101, 70 mg, crude) was obtained. LCMS: (M+H) + :304.1. [ka]

[0296] Step 1: To a solution of 6-bromoquinolin-2-ol (2 g, 8.93 mmol, 1 eq.) in NMP (30 mL) was added CuCN (1.60 g, 17.85 mmol, 3.90 mL, 2 eq.). The mixture was stirred at 180° C. for 5 hours. The reaction mixture was cooled to 25° C. Then, 100 mL of HO was added to the mixture. The mixture was filtered, and the filter cake was washed with HO to obtain a residue. Compound 2-hydroxyquinoline-6-carbonitrile (2.5 g, crude) was obtained as a black solid.

[0297] Step 2: 2-Hydroxyquinoline-6-carbonitrile (1.3 g, 7.64 mmol, 1 equiv.) in POCl3 (13.20 g, 86.09 mmol, 8 mL, 11.27 equiv.) was stirred at 110 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was slowly added to 100 mL of H2O at 25 °C. The mixture was extracted with 150 mL of EtOAc (50 mL*3). The combined organic layers were washed with 30 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Compound 2-chloroquinoline-6-carbonitrile (400 mg, crude) was obtained as a black solid without further purification. LCMS: (M+H) + :189.0.

[0298] Step 3: To a solution of 2-chloroquinoline-6-carbonitrile (200 mg, 1.06 mmol, 1 equiv.) and 6-amino-3,4-dihydro-1H-quinolin-2-one (171.98 mg, 1.06 mmol, 1 equiv.) in dioxane (5 mL), Pd(OAc) (47.61 mg, 212.07 µmol, 0.2 equiv.), CsCO (690.98 mg, 2.12 mmol, 2 equiv.), and Xantphos (122.71 mg, 212.07 µmol, 0.2 equiv.) were added. The mixture was stirred at 80 °C under N for 10 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um, mobile phase: [water (0.05% NH3H2O ​​+ 10mM NH4HCO3)-ACN]; B%: 35%~65%, 8 min) to give 2-[(2-oxo-3,4-dihydro-1H-quinolin-6-yl)amino]quinoline-6-carbonitrile (88.19mg, purity 99%). LCMS: (M+H) + :315.1, and 2-[[1-(6-cyano-2-quinolyl)-2-oxo-3,4-dihydroquinolin-6-yl ]amino]quinoline-6-carbonitrile (20 mg, 98% purity), LCMS: (M+H) + :467.2 was obtained. [ka]

[0299] A mixture of 2-bromo-6-methyl-quinoline (100 mg, 450.29 μmol, 1 equiv.), CsCO (293.42 mg, 900.57 μmol, 2 equiv.), 6-amino-3,4-dihydro-1H-quinolin-2-one (73.03 mg, 450.29 μmol, 1 equiv.), Pd(OAc) (20.22 mg, 90.06 μmol, 0.2 equiv.), and (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (52.11 mg, 90.06 μmol, 0.2 equiv.) in 1,4-dioxane (5 mL) was stirred at 110° C. for 16 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, PE:EA=0:1). The compound 6-[(6-methyl-2-quinolyl)amino]-3,4-dihydro-1H-quinolin-2-one (30 mg, purity 100%) was obtained. LCMS: (M+H) + :304.1. [ka]

[0300] Step 1: 7-Bromoquinoline (1 g, 4.81 mmol, 1 equiv.), Pd(PPh3)4 (555.41 mg, 480.64 umol, 0.1 equiv.), and Zn(CN)2 (846.59 mg, 7.21 mmol, 457.62 uL, 1.5 equiv.) were taken in a microwave tube with DMF (10 mL). The sealed tube was heated in a microwave at 150 °C for 60 minutes. The mixture was filtered. The filter cake was washed with EtOAc (50 mL). To the filtrate, HO (100 mL) was added. The mixture was then extracted with ethyl acetate (50 mL * 2). The combined organic layers were washed with brine (30 mL * 4), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). Quinoline-7-carbonitrile (1.35 g) was obtained as an off-white solid. LCMS: (M+H) + :155.0.

[0301] Step 2: To a solution of quinoline-7-carbonitrile (1.35 g, 8.76 mmol, 1 equiv.) in DCM (20 mL) was added m-CPBA (2.08 g, 9.63 mmol, 80% purity, 1.1 equiv.) in one portion at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was added to saturated NaSO (50 mL). The mixture was stirred for 30 min. The residue was extracted with 50 mL (25 mL*2) of CHCl. ​​The combined organic layers were washed with 15 mL of brine, dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. Compound 1-oxidoquinolin-1-ium-7-carbonitrile (1.3 g, crude) was obtained as a yellow solid. LCMS: (M+H) + :171.0.

[0302] Step 3: To a solution of 1-oxidoquinolin-1-ium-7-carbonitrile (0.7 g, 4.11 mmol, 1 equiv.) in CHCl3 (8 mL) was added POBr3 (1.77 g, 6.17 mmol, 627.29 μL, 1.5 equiv.) at 0 °C. The mixture was stirred at 60 °C for 1 h. Saturated Na2CO3 (30 mL) was slowly added to the reaction mixture. The mixture was extracted with 20 mL (10 mL * 2) of EtOAc. The combined organic layers were washed with 20 mL (10 mL * 2) of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 30 / 1) to give 2-bromoquinoline-7-carbonitrile (200 mg) as a white solid.

[0303] Step 4: To a solution of 2-bromoquinoline-7-carbonitrile (100 mg, 429.07 μmol, 1 equiv.) and 6-amino-3,4-dihydro-1H-quinolin-2-one (69.59 mg, 429.07 μmol, 1 equiv.) in dioxane (5 mL), Pd(OAc) (19.27 mg, 85.81 μmol, 0.2 equiv.), Xantphos (49.65 mg, 85.81 μmol, 0.2 equiv.), and CsCO (279.60 mg, 858.13 μmol, 2 equiv.) were added. The mixture was stirred at 80° C. for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um, mobile phase: [water (0.05% NH3H2O ​​+ 10mM NH4HCO3)-ACN]; B%: 30%-60%, 8 min) to give 2-[(2-oxo-3,4-dihydro-1H-quinolin-6-yl)amino]quinoline-7-carbonitrile (35 mg, purity 100%). LCMS: (M+H) + :315.1. [ka]

[0304] To a mixture of 2-chloro-7-methyl-quinoline (90 mg, 506.67 μmol, 1 equiv.) and 6-amino-3,4-dihydro-1H-quinolin-2-one (82.18 mg, 506.67 μmol, 1 equiv.) in 1,4-dioxane (10 mL), Pd(OAc) (22.75 mg, 101.33 μmol, 0.2 equiv.), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenylphosphane (58.63 mg, 101.33 μmol, 0.2 equiv.), and CsCO (330.17 mg, 1.01 mmol, 2 equiv.) were added. The mixture was stirred at 110° C. for 12 hours. The mixture was cooled to 25° C. The mixture was filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate=0:1) to give 6-[(7-methyl-2-quinolyl)amino]-3,4-dihydro-1H-quinolin-2-one (33 mg, 98% purity). LCMS: (M+H) + :304.1. [ka]

[0305] To a solution of 2-bromoquinoxaline (54.94 mg, 262.82 umol, 1 equiv.) and 6-amino-3,3-dimethyl-1,4-dihydroquinolin-2-one (100 mg, 525.65 umol, 2 equiv.) in dioxane (2 mL), Pd(OAc) (11.80 mg, 52.56 umol, 0.2 equiv.), CsCO (256.90 mg, 788.47 umol, 3 equiv.), and Xantphos (30.41 mg, 52.56 umol, 0.2 equiv.) were added. The mixture was stirred at 80 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Purification using Xbridge Prep OBD C18 150*40mm*10um, mobile phase: [water (0.05% NH3H2O ​​+ 10mM NH4HCO3)-ACN]; B%: 25%-55%, 8 min) gave 3,3-dimethyl-6-(quinoxalin-2-ylamino)-1,4-dihydroquinolin-2-one (46 mg, 100% purity). LCMS: (M+H) + :319.2 [ka]

[0306] To a solution of 2-bromoquinazoline (54.94 mg, 262.83 umol, 1 equiv.) and 6-amino-3,3-dimethyl-1,4-dihydroquinolin-2-one (100 mg, 525.65 umol, 2 equiv.) in dioxane (2 mL), Pd(OAc) (11.80 mg, 52.57 umol, 0.2 equiv.), CsCO (256.90 mg, 788.48 umol, 3 equiv.), and Xantphos (30.41 mg, 52.57 umol, 0.2 equiv.) were added. The mixture was stirred at 80°C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Purification using Xbridge Prep OBD C18 150*40mm*10um, mobile phase: [water (0.05% NH3H2O ​​+ 10mM NH4HCO3)-ACN]; B%: 25%-55%, 8 min) gave 3,3-dimethyl-6-(quinazolin-2-ylamino)-1,4-dihydroquinolin-2-one (49 mg, 100% purity). LCMS: (M+H) + :319.1 [ka]

[0307] To a solution of 2-bromo-1,7-naphthyridine (54.94 mg, 262.82 μmol, 1 equiv.) and 6-amino-3,3-dimethyl-1,4-dihydroquinolin-2-one (100 mg, 525.65 μmol, 2 equiv.) in dioxane (2 mL) was added Pd(OAc) (11.80 mg, 52.56 μmol, 0.2 equiv.), CsCO (256.90 mg, 788.47 μmol, 3 equiv.), and Xantphos (30.42 mg, 52.56 μmol, 0.2 equiv.). The mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um, mobile phase: [water (0.05% NH3H2O ​​+ 10mM NH4HCO3)-ACN]; B%: 25%-55%, 8 min) to give 3,3-dimethyl-6-(1,7-naphthyridin-2-ylamino)-1,4-dihydroquinolin-2-one (29 mg, purity 100%). LCMS: (M+H) + :319.2 [ka]

[0308] To a solution of 2-chloro-1,6-naphthyridine (43.26 mg, 262.82 μmol, 1 equiv.) and 6-amino-3,3-dimethyl-1,4-dihydroquinolin-2-one (100 mg, 525.65 μmol, 2 equiv.) in dioxane (2 mL) was added Pd(OAc) (11.80 mg, 52.56 μmol, 0.2 equiv.), CsCO (256.90 mg, 788.47 μmol, 3 equiv.), and Xantphos (30.42 mg, 52.56 μmol, 0.2 equiv.). The mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um, mobile phase: [water (0.04% HCl)-ACN]; B%: 5% to 15%, 8 min) to give 3,3-dimethyl-6-(1,6-naphthyridin-2-ylamino)-1,4-dihydroquinolin-2-one (9 mg, 100% purity, HCl). LCMS: (M+H) + :319.1. [ka]

[0309] To a solution of 6-chloro-2,3-dimethyl-pyridine (74.43 mg, 525.65 μmol, 1 equiv.) and 6-amino-3,3-dimethyl-1,4-dihydroquinolin-2-one (100 mg, 525.65 μmol, 1 equiv.) in dioxane (2 mL) was added Pd(OAc) (23.60 mg, 105.13 μmol, 0.2 equiv.), CsCO (513.80 mg, 1.58 mmol, 3 equiv.), and Xantphos (60.83 mg, 105.13 μmol, 0.2 equiv.). The mixture was stirred at 100° C. for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um, mobile phase: [water (0.05% NH3H2O ​​+ 10mM NH4HCO3)-ACN]; B%: 25%-55%, 8 min) to give 6-[(5,6-dimethyl-2-pyridyl)amino]-3,3-dimethyl-1,4-dihydroquinolin-2-one (59 mg, purity 99%). LCMS: (M+H) + :296.1. [ka]

[0310] To a solution of 6-bromo-2,3-dichloro-pyridine (59.63 mg, 262.82 μmol, 1 equiv.) and 6-amino-3,3-dimethyl-1,4-dihydroquinolin-2-one (50 mg, 262.82 μmol, 1 equiv.) in dioxane (2 mL), Pd(OAc) (11.80 mg, 52.56 μmol, 0.2 equiv.), CsCO (256.90 mg, 788.47 μmol, 3 equiv.), and Xantphos (30.42 mg, 52.56 μmol, 0.2 equiv.) were added. The mixture was stirred at 100° C. for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um, mobile phase: [water (0.05% NH3H2O ​​+ 10mM NH4HCO3)-ACN]; B%: 30%-60%, 8 min) to give 6-[(5,6-dichloro-2-pyridyl)amino]-3,3-dimethyl-1,4-dihydroquinolin-2-one (31 mg, purity 97%). LCMS: (M+H) + :336.1. [ka]

[0311] To a solution of 2-bromo-1H-benzimidazole (103.57 mg, 525.65 umol, 1 equiv) and 6-amino-3,3-dimethyl-1,4-dihydroquinolin-2-one (100 mg, 525.65 umol, 1 equiv) in HO (0.4 mL) and EtOH (2 mL) was added concentrated HCl (0.1 mL). The mixture was placed in a microwave tube. The sealed tube was heated at 120 °C in a microwave for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um, mobile phase: [water (0.04% NH3H2O ​​+ 10mM NH4HCO3)-ACN]; B%: 20%-50%, 8 min) to give 6-(1H-benzimidazol-2-ylamino)-3,3-dimethyl-1,4-dihydroquinolin-2-one (56 mg, purity 93%). LCMS: (M+H) +:307.1. [ka]

[0312] To a solution of 2-chloro-1,3-benzoxazole (40.36 mg, 262.82 umol, 29.90 uL, 1 equiv) and 6-amino-3,3-dimethyl-1,4-dihydroquinolin-2-one (50 mg, 262.82 umol, 1 equiv) in DMF (2 mL) was added DIPEA (67.94 mg, 525.65 umol, 91.56 uL, 2 equiv). The mixture was stirred at 130 °C for 1 h. The reaction mixture was quenched at 20 °C by the addition of HO mL, then extracted with 15 mL (5 mL * 3) of EtOAc. The combined organic layers were washed with 10 mL (5 mL * 2) of brine, dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, PE:EA=1:1) to give 6-(1,3-benzoxazol-2-ylamino)-3,3-dimethyl-1,4-dihydroquinolin-2-one (19 mg, 97% purity). LCMS: (M+H) + :308.1. [ka]

[0313] To a solution of 6-bromoisoquinoline (54.68 mg, 262.82 μmol, 1 equiv.) and 6-amino-3,3-dimethyl-1,4-dihydroquinolin-2-one (100 mg, 525.65 μmol, 2 equiv.) in dioxane (3 mL), Pd(OAc) (11.80 mg, 52.56 μmol, 0.2 equiv.), Xantphos (30.41 mg, 52.56 μmol, 0.2 equiv.), and CsCO (256.90 mg, 788.47 μmol, 3 equiv.) were added. The mixture was stirred at 80° C. for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um, mobile phase: [water (0.04% NH3H2O ​​+ 10mM NH4HCO3)-ACN]; B%: 25%-55%, 8 min) to give 6-(6-isoquinolylamino)-3,3-dimethyl-1,4-dihydroquinolin-2-one (29 mg, purity 93%). LCMS: (M+H) + :318.2. [ka]

[0314] To a solution of 7-bromoisoquinoline (54.68 mg, 262.83 μmol, 1 equiv.) and 6-amino-3,3-dimethyl-1,4-dihydroquinolin-2-one (100 mg, 525.65 μmol, 2 equiv.) in dioxane (3 mL), Pd(OAc) (11.80 mg, 52.57 μmol, 0.2 equiv.), Xantphos (30.42 mg, 52.57 μmol, 0.2 equiv.), and CsCO (256.90 mg, 788.48 μmol, 3 equiv.) were added. The mixture was stirred at 80° C. for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, PE:EA=0:1) to give 6-(7-isoquinolylamino)-3,3-dimethyl-1,4-dihydroquinolin-2-one (13 mg, 98% purity). LCMS: (M+H) + :318.1. [ka]

[0315] Step 1: To a solution of pyridine-3-carbaldehyde (20 g, 186.72 mmol, 17.54 mL, 1 equiv.) in THF (200 mL) was added trimethyl(trifluoromethyl) To the mixture was added tetrabutylammonium fluoride trihydrate (1M, 18.67 mL, 0.1 equiv.) in THF (50 mL) at 0° C. The mixture was stirred at 25° C. for 2 hours. The reaction was slowly quenched with 1N HCl (10 mL), and then the mixture was neutralized with sodium bicarbonate (50 mL). The mixture was extracted with ethyl acetate (150 mL*3). The combined organic layers were washed with brine (50 mL*3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Compound 2,2,2-trifluoro-1-(3-pyridyl)ethanol (35 g, crude) was obtained as a brown oil.

[0316] Step 2: To a solution of 2,2,2-trifluoro-1-(3-pyridyl)ethanol (25 g, 141.14 mmol, 1 equiv.) and TEA (21.42 g, 211.72 mmol, 29.47 mL, 1.5 equiv.) in DCM (250 mL), TsCl (40.36 g, 211.72 mmol, 1.5 equiv.) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into ice-water (150 mL). The aqueous phase was extracted with DCM (100 mL*3). The combined organic layers were washed with brine (30 mL*3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 15 / 1 to 0 / 1). The compound [2,2,2-trifluoro-1-(3-pyridyl)ethyl] 4-methylbenzenesulfonate (26 g, 78.48 mmol, 55.60% yield) was obtained as a yellow solid.

[0317] Step 3: To a solution of [2,2,2-trifluoro-1-(3-pyridyl)ethyl] 4-methylbenzenesulfonate (26 g, 78.48 mmol, 1 equiv) in MeOH (300 mL) was added 10% Pd / C (0.2 g) under N. The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (50 Psi) at 50 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in H0 (80 mL) and adjusted to pH = 8 with NaOH, then the mixture was extracted with 150 mL DCM (50 mL * 3). The combined organic layers were washed with 60 mL brine (20 mL * 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The compound 3-(2,2,2-trifluoroethyl)pyridine (7.5 g, crude) was obtained as a brown oil.

[0318] Step 4: To a solution of 3-(2,2,2-trifluoroethyl)pyridine (8 g, 49.65 mmol, 1 eq.) in DCM (150 mL) was added m-CPBA (9.07 g, 44.69 mmol, 85% purity, 0.9 eq.). The mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched by the addition of 150 mL of saturated Na2SO3 at 20 °C and stirred at 20 °C for 0.5 h. The mixture was then extracted with DCM (100 mL * 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Compound 1-oxido-3-(2,2,2-trifluoroethyl)pyridin-1-ium (9 g, crude) was obtained as a yellow solid.

[0319] Step 5: A mixture of 1-oxido-3-(2,2,2-trifluoroethyl)pyridin-1-ium (7 g, 39.52 mmol, 1 eq.) and EtI (18.49 g, 118.56 mmol, 9.48 mL, 3 eq.) was degassed and purged with N2 three times, and then the mixture was stirred at 60 °C under a N2 atmosphere for 36 h. The reaction mixture was washed with petroleum ether (150 ml), and then the mixture was concentrated under reduced pressure. The compound 1-ethoxy-3-(2,2,2-trifluoroethyl)pyridin-1-ium iodide (10 g, crude) was obtained as a brown oil.

[0320] Step 6: To a solution of 1-ethoxy-3-(2,2,2-trifluoroethyl)pyridin-1-ium iodide (6 g, 29.10 mmol, 1 equiv.) in HO (60 mL), add NaCN (2.41 g, 49.17 mmol, 1.69 equiv.) in HO (20 mL). was added dropwise at 50°C. The mixture was stirred at 50°C for 1 hour. The mixture was cooled to 25°C. The mixture was extracted with ethyl acetate (60 mL*3). The combined organic layers were washed with brine (40 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluent of 0-9% ethyl acetate / petroleum ether gradient, 40 mL / min). Compound 3-(2,2,2-trifluoroethyl)pyridine-4-carbonitrile (0.35 g, 1.88 mmol, yield 6.46%) was obtained as a yellow oil.

[0321] Step 7: A mixture of 3-(2,2,2-trifluoroethyl)pyridine-4-carbonitrile (50 mg, 268.62 umol, 1 equiv) in HBr (3 mL) was degassed and purged with N 2 three times, then the mixture was purged with N 2 2 The mixture was stirred under atmosphere at 130° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The compound 3-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid (0.1 g, crude, HBr) was obtained as a brown solid.

[0322] Step 8: To a mixture of 3-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid (80 mg, 389.99 μmol, 2.00 equiv.) and 6-amino-3,4-dihydro-1H-quinolin-2-one (31.63 mg, 194.99 μmol, 1 equiv.) in pyridine (1 mL), EDCI (44.86 mg, 233.99 μmol, 1.2 equiv.) was added. The mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=0:1). Compound N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (0.04 g, purity 96.6%) was obtained. LCMS: (M+H)+: 350.0. [ka]

[0323] To a mixture of 3-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid (50 mg, 243.74 umol, 1.00 equivalents) and 6-amino-7-fluoro-3,4-dihydro-1H-quinolin-2-one (43.92 mg, 243.74 umol, 1 equivalent) in pyridine (1 mL) was added EDCI (56.07 mg, 292.49 umol, 1.2 equivalents). The mixture was stirred at 60 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:MeOH = 10:1). Compound N-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (25 mg, 100% pure) was obtained. LCMS: (M+H) + :318.1. [ka]

[0324] Step 1: To a solution of methyl 3-bromopyridine-4-carboxylate (2 g, 9.26 mmol, 1 equiv.) in dioxane (35 mL), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.11 g, 18.52 mmol, 2 equiv.), CsCO (6.03 g, 18.52 mmol, 2 equiv.), and Pd(PPh) (1.07 g, 925.79 mmol, 0.1 equiv.) were added. The mixture was stirred at 100 °C under N for 10 h. The reaction mixture was filtered and evaporated under reduced pressure to give a residue. The crude product, methyl 3-allylpyridine-4-carboxylate (2 g, crude), was obtained as a yellow oil.

[0325] Step 2: To a mixture of methyl 3-allylpyridine-4-carboxylate (0.2 g, 1.13 mmol, 1 equiv) in DCM (10 mL) was added ZnEt (1 M, 11.29 mL, 10 equiv) dropwise and stirred at −10° C. Then, to the mixture was added chloro(iodo)methane (4.18 g, 23.70 mmol, 1.72 mL, 21 equiv) in DCM (10 mL) at −10° C. and then stirred at −10° C. for 0.5 h. The mixture was then stirred at 25° C. for 11.5 h. The reaction mixture was quenched with saturated NH4Cl (5 mL) at 0° C. The mixture was extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with 2N NaOH (20 mL), brine (5 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate=3:1). Compounds methyl 3-allylpyridine-4-carboxylate and methyl 3-(cyclopropylmethyl)pyridine-4-carboxylate (45 mg) were obtained as white solids. LCMS (M+H + ):346.1, 2.212 minutes

[0326] Step 3: To a solution of methyl 3-allylpyridine-4-carboxylate and methyl 3-(cyclopropylmethyl)pyridine-4-carboxylate (45 mg, 1 equiv.) in THF (2 mL) and HO (2 mL) was added LiOH.HO (19.75 mg, 470.64 umol, 2 equiv.). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was adjusted to pH=4 with 2N HCl, and then the mixture was concentrated under reduced pressure to give a residue. The crude products, 3-allylpyridine-4-carboxylic acid and 3-(cyclopropylmethyl)pyridine-4-carboxylic acid (40 mg, 225.73 umol, 95.92% yield), were used in the next step without further purification. LCMS (M+H) + ):178.1

[0327] Step 4: To a mixture of 40 mg of 3-(cyclopropylmethyl)pyridine-4-carboxylic acid and 3-allylpyridine-4-carboxylic acid and 6-amino-3,4-dihydro-1H-quinolin-2-one (36.61 mg, 225.73 umol, 1 equiv.) in pyridine (1 mL), EDCI (51.93 mg, 270.88 umol, 1.2 equiv.) was added. The mixture was stirred at 45 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 80*40mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 14% to 25%, 5.5 min). Compound 59, 3-(cyclopropylmethyl)-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyridine-4-carboxamide (3.9 mg, HCl), was obtained by LCMS (M+H). + Compound 71, 3-allyl-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyridine-4-carboxamide (3.3 mg, HCl) was obtained, and LCMS (M+H) + ):308.1. [ka]

[0328] To a solution of 6-amino-7-fluoro-3,4-dihydro-1H-quinolin-2-one (100 mg, 555.00 umol, 1 eq.) and 3-(cyclopropylmethyl)pyridine-4-carboxylic acid (177.87 mg, 832.51 umol, 1.5 eq., HCl) in pyridine (1 mL), EDCI (127.67 mg, 666.01 umol, 1.2 eq.) was added. The mixture was stirred at 45 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:MeOH = 10:1). The compound 3-(cyclopropylmethyl)-N-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyridine-4-carboxamide (0.065 g, purity 98%) was obtained. LCMS: (M+H) + :340.2. [ka]

[0329] Step 1: To a mixture of 2,3-dichloropyridine-4-carboxylic acid (5 g, 26.04 mmol, 1 eq.) in EtOH (50 mL), SOCl (6.20 g, 52.08 mmol, 3.78 mL, 2 eq.) was added dropwise at 0 °C. The mixture was stirred at 60 °C for 5 h. The mixture was poured into saturated NaHCO (150 mL). The aqueous phase was extracted with ethyl acetate (30 mL * 3). The combined organic layers were washed with brine (20 mL * 4), dried over anhydrous NaSO, filtered, and concentrated in vacuo. Compound ethyl 2,3-dichloropyridine-4-carboxylate (4.6 g, 20.90 mmol, 80.27% yield) was obtained as a yellow liquid. LCMS: (M+H) + :219.9

[0330] Step 2: To a mixture of ethyl 2,3-dichloropyridine-4-carboxylate (2 g, 9.09 mmol, 1 equiv.), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (2.74 g, 10.91 mmol, 3.05 mL, 50% purity, 1.2 equiv.), and K2CO3 (1.88 g, 13.63 mmol, 1.5 equiv.) in dioxane (40 mL), Pd(PPh3)4 (1.05 g, 908.87 μmol, 0.1 equiv.) was added in one portion under N2 at 25 °C. The mixture was stirred at 110 °C for 12 h. The mixture was then filtered. The filter cake was washed with EtOAc (50 mL). The combined organic phase was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 15 / 1). Ethyl 3-chloro-2-methyl-pyridine-4-carboxylate (360 mg, crude) was obtained as a colorless oil. LCMS: (M+H) + :200.1.

[0331] Step 3: To a mixture of ethyl 3-chloro-2-methyl-pyridine-4-carboxylate (0.36 g, 1.80 mmol, 1 equiv.) in HO (1 mL) and dioxane (10 mL), KCO (747.68 mg, 5.41 mmol, 3 equiv.) and pyridine; 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane (2.17 g, 9.02 mmol, 5 equiv.) were added in one portion at 25 °C under N. Then, Pd(PPh) (208.38 mg, 180.33 µmol, 0.1 equiv.) was added, and the mixture was stirred at 110 °C for 16 h. The reaction mixture was poured into brine (30 mL). The aqueous phase was extracted with 150 mL of EtOAc (50 mL*3), and the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) and preparative TLC ( Purified by SiO2, petroleum ether / ethyl acetate=3:1) Ethyl 2-methyl-3-vinyl-pyridine-4-carboxylate (20 mg, 104.59 umol, 5.80% yield).

[0332] Step 4: To a mixture of ethyl 2-methyl-3-vinyl-pyridine-4-carboxylate (20 mg, 104.59 umol, 1 eq.) in HO (2 mL) and EtOH (4 mL) was added LiOH.HO (8.78 mg, 209.18 umol, 2 eq.) at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product 2-methyl-3-vinyl-pyridine-4-carboxylic acid (46 mg, crude) was obtained as a white solid and used in the next step without further purification. LCMS: (M+H) + :164.1.

[0333] Step 5: To a mixture of 2-methyl-3-vinyl-pyridine-4-carboxylic acid (20 mg, 122.57 umol, 1 eq.) and 6-amino-3,4-dihydro-1H-quinolin-2-one (19.88 mg, 122.57 umol, 1 eq.) in pyridine (1 mL), EDCI (28.20 mg, 147.08 umol, 1.2 eq.) was added in one portion at 25° C. The mixture was stirred at 45° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product, 2-methyl-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-vinyl-pyridine-4-carboxamide (70 mg, crude) was obtained as a yellow solid. LCMS: (M+H) + :308.2

[0334] Step 6: To a solution of 2-methyl-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-vinyl-pyridine-4-carboxamide (69.55 mg, 226.30 umol, 1 equiv) in MeOH (3 mL) was added 10% Pd / C (10 mg) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 Psi) at 25 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (column: Welch Xtimate C18 100*25 mm*3 um, mobile phase: [water (0.05% HCl)-ACN]; B%: 15%-35%, 8 min). The compound 3-ethyl-2-methyl-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyridine-4-carboxamide (11 mg, HCl) was obtained. LCMS (M+H + ):310.1. [ka]

[0335] Step 1: To a mixture of 3-methylpyridine-4-carbonitrile (2 g, 16.93 mmol, 1 equiv.) and NBS (3.01 g, 16.93 mmol, 1 equiv.), AIBN (347.50 mg, 2.12 mmol, 0.125 equiv.) was added in 1,2-dichloroethane (10 mL). The mixture was then stirred at 80 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product, 3-(bromomethyl)pyridine-4-carbonitrile (2 g, crude), as a yellow oil was used in the next step without further purification. LCMS: (M+H) + :197.0, 199.0.

[0336] Step 2: 3-(Bromomethyl)pyridine-4-carbonitrile (2 g, 10.15 mmol, 1 equiv.) in MeNH (2 M in THF, 25.38 mL, 5 equiv.) was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 30 / 1). The desired 3-[(dimethylamino)methyl]pyridine-4-carbonitrile (0.98 g, 6.08 mmol, 59.89% yield) was obtained as a yellow oil.

[0337] Step 3: To a mixture of 3-[(dimethylamino)methyl]pyridine-4-carbonitrile (920 mg, 5.71 mmol, 1 equiv.) in EtOH (10 mL) and HO (1 mL) was added KOH (3.20 g, 57.07 mmol, 10 equiv.) in one portion at 25 °C under N. The mixture was stirred at 85 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. 3-[(dimethylamino)methyl]pyridine-4-carboxylic acid (4 g, crude) was obtained as a yellow solid. LCMS: (M+H) + :181.0.

[0338] Step 4: To a mixture of 6-amino-3,4-dihydro-1H-quinolin-2-one (163.64 mg, 1.01 mmol, 1 equiv.) and 3-[(dimethylamino)methyl]pyridine-4-carboxylic acid (200 mg, 1.11 mmol, 1.1 equiv.) in pyridine (3 mL), EDCI (232.10 mg, 1.21 mmol, 1.2 equiv.) was added in one portion at 25° C. under N2. The mixture was stirred at 45° C. for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, DCM:MeOH=10:1). Compound 3-[(dimethylamino)methyl]-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyridine-4-carboxamide (37 mg, 93% purity) was obtained. LCMS (M+H) + ):325.1. [ka]

[0339] Step 1: To a solution of nitridoxanium tetrafluoroborate (3.25 g, 27.82 mmol, 1.29 equiv.) in DCM (50 mL) was added methyl 2-amino-5-bromo-pyridine-4-carboxylate (5 g, 21.64 mmol, 1 equiv.) in DCM (15 mL) dropwise at 0° C. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was then quenched by slowly adding water (60 mL) at 0° C. The reaction mixture was extracted with 100 mL of DCM (50 mL*2). The combined organic layers were washed with 30 mL of brine (10 mL*3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, eluent of 0-10% ethyl acetate / petroleum ether gradient, 40 mL / min). The compound methyl 5-bromo-2-fluoro-pyridine-4-carboxylate (3.6 g, 15.38 mmol, 71.08% yield) was obtained as a colorless oil. LCMS: (M+H) + :235.9.

[0340] Step 2: To a solution of methyl 5-bromo-2-fluoro-pyridine-4-carboxylate (0.5 g, 2.14 mmol, 1 equiv.) in THF (5 mL) was added pyridine; 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane (1.29 g, 5.34 mmol, 2.5 equiv.) and CsF (973.64 mg, 6.41 mmol, 236.32 uL, 3 equiv.). To the mixture was then added Pd(dppf)Cl (156.33 mg, 213.65 umol, 0.1 equiv.). The mixture was stirred at 70 °C under N for 2 hours. The reaction mixture was filtered. The filter cake was washed with EtOAc (15 mL). The combined organic layers were washed with 10 mL of brine, dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, elution with a gradient of 0-10% ethyl acetate / petroleum ether, 40 mL / min). The compound methyl 2-fluoro-5-vinyl-pyridine-4-carboxylate (0.24 g, 1.32 mmol, 62.01% yield) was obtained as a white solid. LCMS: (M+H) + :182.1.

[0341] Step 3: To a solution of methyl 2-fluoro-5-vinyl-pyridine-4-carboxylate (150 mg, 827.98 umol, 1 eq) in MeOH (10 mL) was added 10% Pd / C (0.02 g). The mixture was stirred under H2 (15 Psi) at 25 °C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound methyl 5-ethyl-2-fluoro-pyridine-4-carboxylate (100 mg, crude) was obtained as a white solid. LCMS: (M+H) + :184.0.

[0342] Step 4: To a solution of methyl 5-ethyl-2-fluoro-pyridine-4-carboxylate (100 mg, 545.91 umol, 1 eq.) in HO (1 mL) and THF (1 mL), LiOH.HO (34.36 mg, 818.87 umol, 1.5 eq.) was added. The mixture was stirred at 25 °C for 2 hours. The mixture was adjusted to pH = 3 with HCl (1 N). The mixture was then concentrated under reduced pressure to obtain a residue. Compound 5-ethyl-2-fluoro-pyridine-4-carboxylic acid (50 mg, crude) was obtained as a white solid.

[0343] Step 5: To a solution of 5-ethyl-2-fluoro-pyridine-4-carboxylic acid (40 mg, 194.54 umol, 1 eq.) in pyridine (1 mL), EDCI (44.75 mg, 233.45 umol, 1.2 eq.) was added. The mixture was stirred at 45° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:MeOH=10:1). The compound 5-ethyl-2-fluoro-N-(2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyridine-4-carboxamide (18 mg, purity 97.4%) was obtained. LCMS: (M+H) + :314.1. [ka]

[0344] To a solution of 5-ethyl-2-methyl-pyridine-4-carboxylic acid (0.035 g, 173.57 umol, 1 eq., HCl) and 6-amino-7-fluoro-3,4-dihydro-1H-quinolin-2-one (31.27 mg, 173.57 umol, 1 eq.) in pyridine (1 mL), EDCI (39.93 mg, 208.28 umol, 1.2 eq.) was added. The mixture was stirred at 60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=1:0). The compound 5-ethyl-N-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-2-methyl-pyridine-4-carboxamide (3 mg, purity 98.7%) was obtained. LCMS: (M+H) + :328.2. [ka]

[0345] To a solution of 6-amino-7-fluoro-3,4-dihydro-1H-quinolin-2-one (100 mg, 555.00 umol, 1 eq.) and 2-chloro-5-ethyl-pyridine-4-carboxylic acid (147.90 mg, 666.01 umol, 1.2 eq., HCl) in pyridine (1 mL), EDCI (127.67 mg, 666.01 umol, 1.2 eq.) was added. The mixture was stirred at 45 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:MeOH = 10:1). The compound 2-chloro-5-ethyl-N-(7-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyridine-4-carboxamide (22 mg, 100% pure) was obtained. LCMS: (M+H) + :348.1. [ka]

[0346] Step 1: To a mixture of tert-butyl N-(6-chloro-4-iodo-3-pyridyl)carbamate (0.5 g, 1.41 mmol, 1 equiv.), ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (478.21 mg, 2.12 mmol, 1.5 equiv.), and NaCO (298.92 mg, 2.82 mmol, 2 equiv.) in dioxane (5 mL) and HO (1 mL), Pd(dppf)Cl (103.18 mg, 141.02 mmol, 0.1 equiv.) was added. The mixture was stirred at 100 °C under N for 12 h. The mixture was filtered. The filter cake was washed with EtOAc (50 mL). The combined organic layers were washed with brine (10 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, elution with a 0-12% ethyl acetate / petroleum ether gradient at 40 mL / min). Ethyl (E)-3-[5-(tert-butoxycarbonylamino)-2-chloro-4-pyridyl]prop-2-enoate (0.35 g, 1.07 mmol, 75.95% yield) was obtained as a yellow solid.

[0347] Step 2: To a solution of ethyl (E)-3-[5-(tert-butoxycarbonylamino)-2-chloro-4-pyridyl]prop-2-enoate (0.2 g, 612.04 μmol, 1 equiv) and CoCl2.6H2O (14.56 mg, 61.20 μmol, 0.1 equiv) in MeOH (10 mL) and THF (5 mL), NaBH4 (140 mg, 3.70 mmol, 6.05 equiv) was added in one portion at 0 °C under N2. The mixture was stirred at 25 °C for 2 h. Water (10 ml) was added dropwise to the mixture at 0 °C. The mixture was stirred at 25 °C for 0.5 h and concentrated in vacuo to remove THF and MeOH. The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (5 mL), dried over anhydrous NaSO, filtered and concentrated in vacuo to give ethyl 3-[5-(tert-butoxycarbonylamino)-2-chloro-4-pyridyl]propanoate (100 mg, crude) as a yellow solid. LCMS: (M+H) + :329.2.

[0348] Step 3: Ethyl 3-[5-(tert-butoxycarbonylamino)-2-chloro-4-pyridyl]propanoate (100 mg) in HCl / EtOAc (4 M, 2 mL) A mixture of 6-chloro-3,4-dihydro-1H-1,7-naphthyridin-2-one (35 mg, 191.67 umol, 63.02% yield) was stirred at 25° C. for 12 hours. The mixture was filtered. The filter cake was concentrated in vacuo. 6-chloro-3,4-dihydro-1H-1,7-naphthyridin-2-one (35 mg, 191.67 umol, 63.02% yield) was obtained as a white solid. LCMS: (M+H) + :183.1.

[0349] Step 4: To a mixture of quinoxalin-2-amine (27.82 mg, 191.67 umol, 1 equiv.) and 6-chloro-3,4-dihydro-1H-1,7-naphthyridin-2-one (35 mg, 191.67 umol, 1 equiv.) in dioxane (5 mL), Pd(dba) (17.55 mg, 19.17 umol, 0.1 equiv.), CsCO (187.35 mg, 575.01 umol, 3 equiv.), and Xantphos (11.09 mg, 19.17 umol, 0.1 equiv.) were added. The mixture was stirred at 120 °C for 12 h. The mixture was filtered. The filter cake was washed with EtOAc (50 mL). The filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100*30mm*5um, mobile phase: [water (0.04% HCl)-ACN]; B%: 10% to 40%, 10 min). 6-(quinoxalin-2-ylamino)-3,4-dihydro-1H-1,7-naphthyridin-2-one (5 mg, HCl salt, 100% purity) was obtained. LCMS: (M+H) + :292.1. [ka]

[0350] Step 1: To a mixture of methyl 5-bromo-2-oxo-1H-pyridine-4-carboxylate (1 g, 4.31 mmol, 1 equiv.) and pyridine; 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane (2.07 g, 8.62 mmol, 2 equiv.) in a solution of DMF (10 mL) and HO (0.5 mL), Pd(PPh3)4 (498.02 mg, 430.98 µmol, 0.1 equiv.) and Na2CO3 (1.37 g, 12.93 mmol, 3 equiv.) were added. The mixture was stirred at 90 °C for 5 h. The mixture was filtered. The filter cake was washed with EtOAc (20 mL). Water (40 mL) was added to the solution. The aqueous phase was extracted with ethyl acetate (20 mL * 3). The combined organic layers were washed with brine (10 mL*3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 25 / 1 to 10 / 1) to give methyl 2-oxo-5-vinyl-1H-pyridine-4-carboxylate (150 mg) as a yellow oil.

[0351] Step 2: To a solution of methyl 2-oxo-5-vinyl-1H-pyridine-4-carboxylate (110 mg, 613.93 umol, 1 equiv) in MeOH (10 mL) was added 10% Pd / C (0.05 g) under N. The suspension was degassed under vacuum and purged with H several times....

Claims

[Claim 1] The invention described in the specification.

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