Heterocyclic compounds and uses thereof

Abstract

To provide a heterocyclic compound and its use.SOLUTION: Provided herein are novel heterocyclic compounds, e.g., compounds having Formula I, I-P, II, II-P, III, or IV. Also provided herein are pharmaceutical compositions comprising the compounds and methods of using the same, for example, in the inhibition of aldehyde dehydrogenase, retinoid pathway activation, and / or to treat various cancers, cancer metastasis, type 2 diabetes, pulmonary arterial hypertension (PAH), or neointimal hyperplasia (NIH), or as a male contraceptive.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 178,309, filed April 22, 2021, the contents of which are incorporated herein by reference in their entirety for all purposes. [Background technology]

[0002] Aldehyde dehydrogenase (ALDH) belongs to a superfamily of NAD(P+)-dependent enzymes, which play a role in aldehyde metabolism by irreversibly catalyzing the oxidation of both endogenously and exogenously produced aldehydes to their respective carboxylic acids. ALDH has a wide range of biological activities, including retinoic acid (RA) biosynthesis, lipid peroxide oxidation, and alcohol metabolism.

[0003] 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.

[0004] ALDH enzymes can be divided into three major groups: 1) the broad-specificity ALDH1 family, containing ALDH1a1, 1a2, 1a3, 1b1, and ALDH2, which are known to oxidize retinal, acetaldehyde, GABA, medium-chain lipid aldehydes, cyclophosphamide metabolites, and potentially other aldehyde species; 2) the long-chain fatty acid aldehyde-specific ALDH3A1-3B2; and 3) the structurally diverse enzymes ALDH4A1, 5A1, 6A1, 7A1, 8A1, 9A1, 18A1, 1L1, and 1L2, which catalyze the oxidation of individual metabolites or semialdehydes (e.g., glutamate, succinate, methylmalonate, 10-formyl-THF). Summary of the Invention

[0005] Some 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] Of particular interest to human health and disease is the ALDH1a subfamily, with ALDH1a3 being significantly upregulated in endothelial disease, across solid tumor subpopulations, pancreatic beta cell dysfunction, and proliferating smooth muscle cells. ALDH1a3 has also been used to distinguish tumorigenic and chemotherapy-resistant cancer cells. Despite >100 publications investigating ALDH1a3 in cancer, a cohesive understanding of its function remains lacking. Our findings resolve this paradox by showing that tumor-expressed ALDH1a3 modulates the tumor microenvironment through the production of paracrine retinoic acid, which suppresses antitumor immunity.

[0007] A less studied but equally important ALDH1a enzyme is ALDH1a2, which has been implicated as the major myeloid-expressed ALDH1a isoform. Like ALDH1a3, ALDH1a2 catalyzes retinaldehyde oxidation, and this activity is regulated by ALDH1a2 regulates normal immune tolerance through the induction of nodal T cells and M2 macrophages. However, little research has been conducted on the role of ALDH1a2 in regulating immune tolerance in cancer or other pathologies.

[0008] Although insights into the complementary roles of ALDH1a2 and ALDH1a3 in regulating the immunosuppressive niche are novel, retinoid signaling via the RAR nuclear receptor is arguably the most studied trophic pathway in inflammatory diseases and cancer. Initial studies established retinoic acid as a highly effective intervention in acute promyelocytic leukemia (APL) through targeting a fusion oncogene unique to APL. However, numerous subsequent clinical trials testing retinoid agonism in solid tumors unexpectedly revealed a pro-tumorigenic role for retinoid signaling across solid tumor types, resulting in numerous premature terminations due to excess mortality and increased cancer incidence. Therapeutic retinoid agonism has also been associated with hyperlipidemia, osteoarthritis, and various other pathologies caused by immunosuppression.

[0009] Despite these unexpected clinical findings that retinoid activation drives the progression of solid tumors and is associated with other pathologies, no retinoid pathway antagonists have progressed into clinical trials.

[0010] The present disclosure is based, in part, on the discovery that aldehyde dehydrogenases (Aldhs, ALDHs), particularly ALDH isoform 1a3 (ALDH1a3) and / or ALDH isoform 1a2 (ALDH1a2), are involved in a variety of diseases or disorders, including proliferative diseases or disorders, immunosuppression, diseases or disorders associated with retinoid pathway activation, metabolic diseases or disorders, endothelial cell or smooth muscle cell diseases or disorders, and cancer and metastasis. The present disclosure further demonstrates that inhibition of ALDH enzymes, such as ALDH1a3 and / or ALDH1a2, may be useful for treating or preventing a variety of cancers, cancer metastasis, and other ALDH1a2- and / or 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. The present disclosure is further based, in part, on the discovery that various compounds described herein can potently and / or selectively inhibit one or more ALDH enzymes, such as ALDH1a3 and / or ALDH1a2, inhibit retinoid pathway activation, and treat various diseases, such as cancer and type 2 diabetes.

[0011] 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) and / or ALDH isoform 1a2 (ALDH1a2), or inhibiting the retinoid pathway. In some embodiments, the present disclosure also provides methods of using the novel compounds and pharmaceutical compositions herein 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), or in male contraception.

[0012] Some embodiments of the present disclosure are directed to a compound of formula I, IP, II, II-P, or III, or a pharmaceutically acceptable salt thereof: [ka] [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. In some embodiments, the present disclosure also provides specific compounds, Compound Nos. 139-202 or 139-165, or pharmaceutically acceptable salts thereof.

[0013] In embodiments, the present disclosure provides a compound of formula (IV) [ka] or a pharmaceutically acceptable salt thereof, In the formula, rings A, L, R 22 , R 22’ , R 32 , R 33 , p, and R 100 is defined herein.

[0014] In embodiments, the present disclosure provides a compound of formula (IV-A): [ka] In the formula, ring A, L1, R 22 , R 22’ , R 32 , R 33 , p, and R 100 is defined herein.

[0015] In embodiments, the present disclosure provides a compound of formula (IV-B): [ka] In the formula, Z 1 , Z 2 , Z 3 , Z 4 , R 22 , R 22’ , R 32 , R 33 , p, and R 100 is defined herein.

[0016] In embodiments, the present disclosure provides a compound of formula (IV-C): [ka] In the formula, R 20 , R 21 , R 20’ , R 21’ , R 22 , R 22’ , p, and R 100 is defined herein.

[0017] In embodiments, the present disclosure provides a compound of formula (IV-D): [ka] In the formula, R 22 , R 22’ , p, and R 100 is defined herein.

[0018] Certain embodiments of the present disclosure are directed to pharmaceutical compositions comprising one or more compounds 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), Formula IV (e.g., IV-A, IV-B, IV-C, or IV-D), or any of Compound Nos. 139-202 or 139-165, or a pharmaceutically acceptable salt thereof), and optionally a pharmaceutically acceptable excipient. The pharmaceutical compositions described herein may be formulated for different routes of administration, such as oral administration, parenteral administration, or inhalation.

[0019] Some embodiments of the present disclosure are directed to methods of inhibiting aldehyde dehydrogenase, particularly ALDH1a3 and / or ALDH1a2, in a subject in need thereof.

[0020] Some embodiments of the present disclosure are directed to methods of inhibiting the retinoid pathway in a subject in need thereof. reg In some embodiments, the present disclosure provides methods for inhibiting M2 macrophage formation in a subject in need thereof. In some embodiments, the present disclosure provides methods for treating a disease or disorder associated with retinoid pathway activation, e.g., as described herein.

[0021] In some embodiments, the present disclosure also provides methods of treating or preventing a disease or disorder associated with aldehyde dehydrogenase, preferably a disease or disorder associated with aldehyde dehydrogenase isoform 1a3 (ALDH1a3) and / or ALDH1a2, 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) and / or ALDH1a2. In some embodiments, the disease or disorder is a metabolic disease, such as type 2 diabetes or hyperlipidemia, associated with aldehyde dehydrogenase isoform 1a3 (ALDH1a3) and / or ALDH1a2. In some embodiments, the disease or disorder is an endothelial or smooth muscle cell disease or disorder, such as pulmonary arterial hypertension or neointimal hyperplasia, associated with aldehyde dehydrogenase isoform 1a3 (ALDH1a3) and / or ALDH1a2. In some embodiments, the disease or disorder is an immunologically driven disease or disorder associated with aldehyde dehydrogenase isoform 1a3 (ALDH1a3) and / or ALDH1a2, such as acute graft-versus-host disease or osteoarthritis pain.

[0022] In some embodiments, the present disclosure provides methods of treating cancer in a subject in need thereof. In some embodiments, the cancer is associated with ALDH1a3 and / or ALDH1a2 activity, e.g., has cancer cells with elevated expression levels compared to a control, and / or has cancer cells with ALDH1a3 and / or ALDH1a2 activity, e.g., positive in an Aldefluor™ assay, which can be reduced with an ALDH1a3 and / or ALDH1a2 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 a chemotherapy-resistant cancer. In some embodiments, the cancer may be breast cancer, colorectal cancer, kidney cancer, ovarian cancer, gastric cancer, thyroid cancer, urothelial 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, hematologic cancer, leukemia, lymphoma, and / or sarcoma. In some embodiments, the cancer may also be gastrointestinal stromal tumor, peripheral nerve sheath tumor, The cancer may be a tumor, myeloma, and / or endometrial cancer. In some embodiments, the cancer is refractory to one or more immunotherapies, e.g., anti-PD-1, anti-CTLA4, anti-LAG-3, anti-TIGIT, or anti-PD-L1 antibodies. In some embodiments, the subject has developed resistance to one or more immunotherapies, e.g., anti-PD-1 antibodies or anti-PD-L1 antibodies. In some embodiments, the method further comprises administering to the subject one or more immunotherapies (e.g., as described herein).

[0023] In some embodiments, the disclosure provides methods of treating or preventing metastasis of cancer in a subject in need thereof. In some embodiments, the cancer has already metastasized. In some embodiments, the cancer has not metastasized prior to treatment with the methods herein, and the methods delay or prevent metastasis of the cancer. In some embodiments, the cancer is associated with ALDH1a3 and / or ALDH1a2 activity.

[0024] 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 provides methods of treating or hyperlipidemia 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. In some embodiments, the present disclosure provides methods of inducing male contraception in a subject in need thereof.

[0025] The methods described herein typically include administering to a subject an effective amount of a compound of the present disclosure (e.g., any of the compounds of Formula I (e.g., Formula 10-18, 11-19, 12-20, 13-21, 14-22, 14-23, 14-24, 14-25, 14-26, 14-27, 14-28, 14-29, 15-30, 15-31, 15-32, 15-33, 15-34, 15-35, 15-36, 15-37, 15-40, 15-41, 15-42, 15-43, 15-44, 15-45, 15-46, 15-47, 15-48, 15-50, 15-51, 15-52, 15-53, 15-54, 15-55, 15-56, 15-57, 15-58, 15-59, 15-60, 15-61, 15-62, 15-63, 15-64, 15-65, 15-70, 15-71, 15-72, 15-73, 15-74, 15-75, 15-80, 15-81, 15-82, 15-83, 15-84, 15-85, 15-86, 15-87, 15-88, 15-89, 15-90, 15-91, 15-92, 15-93, 15-94, 15-95, 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. In some embodiments, the compounds of the present disclosure may be used in combination with conventional surgery or additional therapies such as radiation therapy, immunotherapy, cell therapy, therapeutic antibodies, or chemotherapy.

[0026] 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. In certain embodiments, for example, the following are provided: (Item 1) Compound of formula (IV) [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ring A is a heterocycle or heteroaryl; L is -NH-, -C(O)-NH-, -S(O)NH-, -S(O)NH-, -S(O)-, or -S(O)-; R 22 But halo, -CN, -C 1~6 Alkyl, -C 1~6 Alkyl-CN, -C 1~6 haloalkyl or carbocyclyl; R 22’ But, H, halo, -C 1~6 Alkyl or -C 1~6 haloalkyl, or R 22 and R 22’ are linked to form a heteroaryl, carbocyclyl, or heterocyclyl, each of which is optionally substituted with one or more halo; R 32 and R 33 are linked to form a heterocyclyl, substituted with oxo, and said heterocycle is substituted with one or more R 101 and optionally further substituted with p is 0, 1, or 2; Each R 100 independently, halo, -C 1~6 Alkyl, -C 1~6 Alkylene-carbocyclyl, -C 1~6 alkylene-heterocyclyl, or -C 1~6 is haloalkyl, Each R 101 are independently hydrogen, halo, or -C 1~6 alkyl, or a pharmaceutically acceptable salt thereof. (Item 2) The compound is a compound of formula (IV-A) [ka] or a pharmaceutically acceptable salt thereof, wherein: The compound according to item 1, wherein L1 is absent, -C(O)-, -S(O)-, or -S(O)2-. (Item 3) The compound according to item 1 or 2, wherein ring A is a 5- or 6-membered heteroaryl, a 5,6-bicyclic heteroaryl, a 5,6-bicyclic heterocyclyl, a 6,6-bicyclic heterocyclyl, a 6,6-bicyclic heteroaryl, or a 3- to 8-membered heterocyclyl. (Item 4) The compound according to item 3, wherein ring A is pyridyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, or morpholinyl. (Item 5) A-(R 100 ) p but, [ka] Item 1. The compound according to item 1, (Item 6) Ring A-(R 100 ) p but, [ka] Item 6. The compound according to item 5, wherein (Item 7) Ring A-(R 100 ) p but, [ka] Item 7. The compound according to item 6, wherein (Item 8) 8. The compound according to any one of items 2 to 7, wherein L1 is —C(O)—. (Item 9) The compound is a compound of formula (IV-B) [ka] or a pharmaceutically acceptable salt thereof; During the ceremony, Z 1 , Z 2 , Z 3 , and Z 4 each independently is CH or N; Z 1 , Z 2 , Z 3 , and Z 4 The compound according to any one of items 1 to 3, wherein at least one of (Item 10) Z 1 , Z 2 , Z 3 , and Z 4 The compound according to item 9, wherein one or two of are —N and the rest are —CH. (Item 11) Z 2 is N and Z 1 , Z 3 , and Z 4 is CH or Z 1 and Z 2 is N and Z 3 and Z 4 is CH or Z 2 and Z 4 is N and Z 1 and Z 3 is CH or Z 1 and Z 3 is N and Z 2 and Z 4 is CH, or Z 2 and Z 3 is N and Z 1 and Z 4 is CH. (Item 12) Z 2 is N and Z 1 , Z 3 , and Z 4 is CH, or Z 1 and Z 2 is N and Z3 and Z 4 Item 12. The compound according to item 11, wherein is CH. (Item 13) R 32 and R 33 are linked to form a heterocycle containing at least one N atom in the ring and substituted with oxo. (Item 14) Compound of formula (IV-C) [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 20 , R 21 , R 20’ , R 21’ are each independently hydrogen, halo, or -C 1~4 alkyl, or R 20 and R 21 One of them is R 20’ and R 21’ optionally substituted C in conjunction with one of 3~8 forming a carbocyclic ring or an optionally substituted 3- to 8-membered heterocyclic ring, R 22 But halo, -CN, -C 1~6 Alkyl, -C 1~6 Alkyl-CN, -C 1~6 haloalkyl or carbocyclyl; R 22’ But, H, halo, -C 1~6 Alkyl or -C 1~6 haloalkyl or R 22 and R 22’ taken together form a heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo; p is 0, 1, or 2; Each R 100 independently, halo, -C 1~6 Alkyl, -C 1~6 Alkylene-carbocyclyl, -C 1~6Alkylene-heterocyclyl, or -C 1~6 haloalkyl, or When p is 2, two adjacent R 100 may link to form a carbocyclyl or heterocyclyl, each of which may be substituted with one or more halo, or a pharmaceutically acceptable salt thereof. (Item 15) R 20 and R 21 are independently -H, C 1~4 alkyl or halo, R 20’ and R 21’ is hydrogen, or R 20 But R 20’ and R form a cyclopropyl ring or a 5- to 6-membered heterocycle. 21 and R 21’ Item 15. The compound according to item 14, wherein is —H. (Item 16) R 20 and R 21 are independently —H, methyl, or fluoro; R 20’ and R 21’ Item 15. The compound according to item 14, wherein is hydrogen. (Item 17) R 20 But R 20’ and R form a 5-6 membered heterocyclyl containing one or two heteroatoms independently selected from a cyclopropyl ring, N, and O; 21 and R 21’ Item 15. The compound according to item 14, wherein is —H. (Item 18) The compound is a compound of formula (IV-D) [ka] 18. The compound according to any one of items 14 to 17, which is: (Item 19) R 22 But halo, -CN, -C 1~6 Alkyl, or C 1~619. The compound according to any one of items 1 to 18, which is haloalkyl. (Item 20) R 22 But halo or -C 1~4 Item 19. The compound according to item 19, wherein the alkyl is alkyl. (Item 21) R 22 19. The compound according to any one of items 1 to 18, wherein the aryl is -Cl, -F, -CN, -CH3, -CH2CH3, -CH2CN, -CF3, -CH2CF3, or cyclopropyl. (Item 22) R 22 22. The compound according to item 21, wherein is -Cl, -F, -CN, -CH3, or -CH2CH3. (Item 23) R 22 22. The compound according to item 21, wherein is -Cl, -F, -CH3, or -CH2CH3. (Item 24) R 22 22. The compound according to item 21, wherein is -Cl, -F, or -CH3. (Item 25) R 22 25. The compound according to item 24, wherein is -Cl. (Item 26) R 22 25. The compound according to item 24, wherein is -F. (Item 27) R 22 25. The compound according to item 24, wherein is —CH3. (Item 28) R 22 and R 22’ Together, (i) a 5- to 6-membered heteroaryl containing one or two heteroatoms independently selected from N, O, and S; (ii) a 5-membered carbocyclyl optionally substituted with one or more fluoro; or (iii) A compound according to any one of items 1 to 18, which forms a 6-membered heterocyclyl containing one or two heteroatoms independently selected from N and O, optionally substituted with one or more fluoro. (Item 29) R 22 and R 22’ taken together form a 6-membered heteroaryl containing one nitrogen atom. (Item 30) R 22’ 28. The compound according to any one of items 1 to 27, wherein is -H, -F, -CH3, or -CF3. (Item 31) R 22’ is -H or halo, or -C 1~6 28. The compound according to any one of items 1 to 27, wherein the aryl group is alkyl. (Item 32) R 22’ 32. The compound according to item 31, wherein is -H, -F, or -CH3. (Item 33) R 22’ 28. The compound according to any one of items 1 to 27, wherein is —H or halo. (Item 34) R 22’ 34. The compound according to item 33, wherein is -H or -F. (Item 35) R 22’ 35. The compound according to item 34, wherein is —H. (Item 36) Each R 100 independently, halo, -C 1~6 Alkyl, -C 1~6 Alkylene Carboxylate Krill, or -C 1~6 36. The compound according to any one of items 1 to 35, which is haloalkyl. (Item 37) Each R 100 are independently -CH2CH3, -CH3, -CH2-cyclopropyl, -Cl, -CH2-CF3, -CH2-cyclobutyl, -CH2-oxetanyl, -CF2CH3, or two adjacent R 100 may link to form a C5-6 carbocyclyl or a 5-membered heterocyclyl containing an N or O heteroatom, said carbocyclyl being optionally substituted with one or more fluoro. (Item 38) Each R 100 is independently -CH2CH3, -CH3, -CH2-cyclopropyl, -Cl, -CH2-CF3, -CH2-cyclobutyl, or -CH2-oxetanyl. (Item 39) Each R 100 is independently -CH2CH3, -CH3, -CH2-cyclopropyl, -Cl, or -CH2-CF3. (Item 40) 40. The compound according to any one of items 1 to 39, wherein p is 1 or 2. (Item 41) p is 1 and R 100 But -C 2~6 Alkyl, -C 1~6 Alkylene-carbocyclyl, or -C 1~6 40. The compound according to any one of items 1 to 39, which is haloalkyl. (Item 42) R 100 42. The compound according to item 41, wherein is -CH2CH3, -CH2-cyclopropyl, or -CH2-CF3. (Item 43) p is 1 and R 100 is substituted at the meta position of the pyridine. (Item 44) p is 2 and R 100 independently, halo and -C 2~6 41. The compound according to any one of items 1 to 40, wherein the aryl group is alkyl. (Item 45) p is 2 and R 100 45. The compound according to item 44, wherein is -CH2CH3 and -Cl. (Item 46) p is 2 and two R 100can link to form a C5-6 carbocyclyl or a 5-membered heterocyclyl containing an N or O heteroatom, said carbocyclyl being optionally substituted with one or more fluoro. (Item 47) p is 2 and R 100 is substituted at the meta and ortho positions of the pyridine. (Item 48) Compound of formula (V) [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Z 1 and Z 2 are independently -CH- or -N-; R 22 But -H or -C 1~6 is alkyl, R 32 and R 33 are linked to form a heterocycle containing at least one N atom in the ring and substituted with oxo, said heterocycle containing one or more R 101 and optionally further substituted with R 101 are independently hydrogen, halo, or C 1~6 alkyl, or a pharmaceutically acceptable salt thereof. (Item 49) The compound is a compound of formula (VA) [ka] or a pharmaceutically acceptable salt thereof; During the ceremony, R 20’ But halo or -C 1~6 is alkyl, R 21’ But halo or -C 1~6 49. The compound according to item 48, wherein the alkyl is alkyl. (Item 50) Compound of formula (VB) [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Z 1 and Z 2 are independently -CH- or -N-; R 22 But H or -C 1~6 is alkyl, R 20 But halo or -C 1~6 is alkyl, R 21 But halo or -C 1~6 alkyl, or a pharmaceutically acceptable salt thereof. (Item 51) [ka] [ka] [ka] [ka] [ka] A compound selected from: (Item 52) [ka] [ka] [ka] [ka] 52. The compound according to item 51, selected from: (Item 53) 53. A pharmaceutical composition comprising the compound according to any one of items 1 to 52 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. (Item 54) 52. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of items 1 to 52 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 53. (Item 55) 52. A method for treating metastatic cancer or chemotherapy-resistant cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of items 1 to 52 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 53. (Item 56) 52. A method for treating or preventing cancer metastasis in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound according to any one of items 1 to 52 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 53. (Item 57) Item 58. A method for sensitizing cancer to chemotherapy in a subject in need thereof, comprising administering to the subject an effective amount of the compound according to any one of items 1 to 52 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 53. 58. The method of any one of items 54 to 57, further comprising administering to the subject an effective amount of a second anti-cancer therapy, such as a chemotherapeutic agent, a receptor tyrosine kinase inhibitor, or a therapeutic antibody. (Item 59) The cancer is breast cancer, colorectal cancer, kidney cancer, ovarian cancer, stomach cancer, thyroid cancer, or testicular cancer. 59. The method according to any one of items 54 to 58, wherein the cancer is selected from the group consisting of 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, sarcoma, gastrointestinal stromal tumor, peripheral nerve sheath tumor, myeloma, and / or endometrial cancer. (Item 60) 52. A method for treating or preventing type 2 diabetes in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound according to any one of items 1 to 52 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 53. (Item 61) 52. A method for treating or preventing a metabolic disease in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound according to any one of items 1 to 52 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 53. (Item 62) A method for inhibiting aldehyde dehydrogenase in a subject in need thereof, comprising administering to the subject an effective amount of the compound according to any one of items 1 to 52 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 53. (Item 63) A method for treating a disease or disorder associated with aldehyde dehydrogenase, preferably a disease or disorder associated with aldehyde dehydrogenase isoform 1a3 (ALDH1a3) and / or (ALDH1a2), in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of items 1 to 52 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item 53. (Item 64) 64. The method of item 63, wherein the disease or disorder is a proliferative disease or disorder or a metabolic disease or disorder. (Item 65) 52. A method for 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 to the subject an effective amount of a compound according to any one of items 1 to 52 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item 53. (Item 66) A method for antagonizing the retinoid pathway in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound according to any one of items 1 to 52 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 53. (Item 67) 52. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of items 1 to 52 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 53, in combination with immunotherapy. (Item 68) 68. The method of item 67, wherein the immunotherapy comprises administering to the subject an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA4 antibody, IL-2, autologous T cell therapy, bispecific antibody therapy, an anti-TGFβ antibody, a JAK / STAT inhibitor, or any combination thereof. (Item 69) 69. The method of item 67 or 68, wherein the cancer is 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, sarcoma, gastrointestinal stromal tumor, peripheral nerve sheath tumor, myeloma, and / or endometrial cancer. (Item 70) 52. A method of treating cancer in a subject in need thereof, wherein the cancer is unresponsive to one or more immunotherapies or the subject has developed resistance to one or more immunotherapies, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of items 1 to 52 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 53, and optionally administering an immunotherapy to the subject. (Item 71) 71. The method of claim 70, wherein the cancer is unresponsive to treatment with an anti-PD-1 or anti-PD-L1 antibody. (Item 72) 71. The method of claim 70, wherein the subject has developed resistance to anti-PD-1 or anti-PD-L1 antibody-based therapy. (Item 73) 73. The method of any one of items 70 to 72, comprising administering to the subject an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA4 antibody, IL-2, autologous T-cell therapy, bispecific antibody therapy, an anti-TGFβ antibody, a JAK / STAT inhibitor, or any combination thereof. (Item 74) 74. The method according to any one of items 70 to 73, wherein the cancer is 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, sarcoma, gastrointestinal stromal tumor, peripheral nerve sheath tumor, myeloma, and / or endometrial cancer. (Item 75) A method of treating a disease or disorder associated with retinoid pathway activation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of items 1 to 52 or a pharmaceutical salt thereof, or the pharmaceutical composition according to item 53. (Item 76) The disease or disorder is characterized by immune tolerance, T reg 76. The method of claim 75, wherein the method is associated with induction of M1 and / or M2 macrophages and / or suppression of effector T cells. (Item 77) 77. The method of item 75 or 76, wherein the disease or disorder is cancer. (Item 78) 78. The method of item 77, wherein the cancer is breast cancer, colorectal cancer, kidney cancer, ovarian cancer, gastric cancer, thyroid cancer, urothelial 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, blood cancer, sarcoma, gastrointestinal stromal tumor, peripheral nerve sheath tumor, myeloma, and / or endometrial cancer. (Item 79) 79. The method of any one of items 75 to 78, further comprising administering to the subject an immunotherapy (e.g., an immune checkpoint inhibitor). (Item 80) 80. The method of item 79, wherein administering the immunotherapy comprises administering to the subject an anti-PD-1 antibody, anti-PD-L1 antibody, anti-CTLA4 antibody, anti-LAG-3, anti-TIGIT, IL-2, autologous T cell therapy, bispecific antibody therapy, anti-TGFβ antibody, a JAK / STAT inhibitor, or any combination thereof. (Item 81) 52. A method for providing male contraception in a subject in need thereof, said method comprising administering an effective amount of a compound according to any one of items 1 to 52 or a pharmaceutically acceptable salt thereof, or 54. A method comprising administering to the subject the pharmaceutical composition of item 53. (Item 82) T reg 52. A method for inhibiting cell and / or M2 macrophage formation in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound according to any one of items 1 to 52 or a pharmaceutical salt thereof, or the pharmaceutical composition according to item 53. (Item 83) 83. The method of claim 82, wherein the subject is characterized by having a cancer that is refractory to one or more immunotherapies or the subject has developed resistance to one or more immunotherapies. [Brief explanation of the drawings]

[0027] [Figure 1A] Flow cytometry spectra showing that gene knockout of ALDH1a3 (middle and rightmost spectra, two different ALDH1a3-targeting CRISPR gRNAs) in MDA-MB-468 breast cancer cells 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] 1 is a 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 delays 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 empty vector (Vector). [Figure 3B] Plot of lung nodules counted ex vivo at the endpoint of the experiment described in Figure 3 A. 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] Patient survival curves 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 squamous cell lung cancer 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 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. [Figure 6B] 1 is a 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 7] Expression of ALDH1a2 and ALDH1a3 mRNA in patient-derived xenograft models from multiple human cancers demonstrates expression of the ALDH1a2 and ALDH1a3 enzymes across multiple tumor types. [Figure 8]q-rtPCR of STRA6 mRNA to measure retinoid pathway activity in MCF7 cells expressing each ALDH isoform of interest, demonstrating that only ALDH1a2 and ALDH1a3 induce retinoid pathway activation. Results were tested in both regular DMEM + FBS and DMEM + charcoal-stripped FBS. [Figure 9] In vivo imaging of SCP28 cells containing a retinoid response element-driven firefly luciferase reporter was performed. These cells were stably transduced with ALDH1a1, 1a2, 1a3, or a vector control and then injected into the mammary glands of Nu / Nu female mice. In vivo imaging demonstrates that ALDH1a2 and ALDH1a3 drive retinoid pathway activation in solid tumors in vivo. From top to bottom, the plots are Aldh1a3, Aldh1a2, Aldh1a1, and the vector control, based on the last data point. [Figure 10A] Figures 10A to 10C. STRA6 levels by q-rtPCR in MCF7 cells stably expressing DMSO or vector control treated with various doses of MBE1 (Figure 10A), compound 140 (Figure 10B), or compound 151 (Figure 10C) demonstrate that compounds 140 and 151 effectively inhibit both ALDH1a2 and ALDH1a3 in cell-based assays at therapeutically advantageous levels (<50 nM) with IC50 values ​​for MBE1 of 1666 nM (ALDH1a2) and 3.67 nM (ALDH1a3), for 140 of 27.6 nM (ALDH1a2) and 6.97 nM (ALDH1a3), and for 151 of 55.3 nM (ALDH1a2) and 1.25 nM (ALDH1a3). [Figure 10B]Figures 10A to 10C. STRA6 levels by q-rtPCR in MCF7 cells stably expressing DMSO or vector control treated with various doses of MBE1 (Figure 10A), compound 140 (Figure 10B), or compound 151 (Figure 10C) demonstrate that compounds 140 and 151 effectively inhibit both ALDH1a2 and ALDH1a3 in cell-based assays at therapeutically advantageous levels (<50 nM) with IC50 values ​​for MBE1 of 1666 nM (ALDH1a2) and 3.67 nM (ALDH1a3), for 140 of 27.6 nM (ALDH1a2) and 6.97 nM (ALDH1a3), and for 151 of 55.3 nM (ALDH1a2) and 1.25 nM (ALDH1a3). [Figure 10C] Figures 10A to 10C. STRA6 levels by q-rtPCR in MCF7 cells stably expressing DMSO or vector control treated with various doses of MBE1 (Figure 10A), compound 140 (Figure 10B), or compound 151 (Figure 10C) demonstrate that compounds 140 and 151 effectively inhibit both ALDH1a2 and ALDH1a3 in cell-based assays at therapeutically advantageous levels (<50 nM) with IC50 values ​​for MBE1 of 1666 nM (ALDH1a2) and 3.67 nM (ALDH1a3), for 140 of 27.6 nM (ALDH1a2) and 6.97 nM (ALDH1a3), and for 151 of 55.3 nM (ALDH1a2) and 1.25 nM (ALDH1a3). [Figure 11A] Figures 11A and 11B. Daily treatment of T3-MCA fibrosarcoma cell line allografts implanted subcutaneously in C57BL6 syngeneic mice with compound 140 or MBE1.5 for the indicated treatment periods demonstrates successful inhibition of tumor growth as a single agent, as shown by caliper measurements (Figure 11A) and tumor burden at endpoint (Figure 11B). [Figure 11B]Figures 11A and 11B. Daily treatment of T3-MCA fibrosarcoma cell line allografts implanted subcutaneously in C57BL6 syngeneic mice with compound 140 or MBE1.5 for the indicated treatment periods demonstrates successful inhibition of tumor growth as a single agent, as shown by caliper measurements (Figure 11A) and tumor burden at endpoint (Figure 11B). [Figure 12A] Figures 12A and 12B. Daily treatment of K-Ras, p53- / - undifferentiated pleomorphic sarcoma cell line allografts implanted subcutaneously in C57BL6 syngeneic mice with compound 140 or MBE1.5 for the indicated treatment periods demonstrates successful inhibition of tumor growth as a single agent for compound 140, but not MBE1.5, as shown by caliper measurements (Figure 12A) and tumor burden at endpoint (Figure 12B). [Figure 12B] Figures 12A and 12B. Daily treatment of K-Ras, p53- / - undifferentiated pleomorphic sarcoma cell line allografts implanted subcutaneously in C57BL6 syngeneic mice with compound 140 or MBE1.5 for the indicated treatment periods demonstrates successful inhibition of tumor growth as a single agent for compound 140, but not MBE1.5, as shown by caliper measurements (Figure 12A) and tumor burden at endpoint (Figure 12B). [Figure 13A] Figures 13A-13D. Pharmacokinetic analysis of plasma half-life in CD-1 mice after a single oral dose of 10 mg / kg of compounds MBE1 (Figure 13A), MBE1.5 (Figure 13B), compound 140 (Figure 13C), and compound 151 (Figure 13D) demonstrates superior pharmacokinetic dosing of compounds with 8'-methyl substitution. [Figure 13B] Figures 13A-13D. Pharmacokinetic analysis of plasma half-life in CD-1 mice after a single oral dose of 10 mg / kg of compounds MBE1 (Figure 13A), MBE1.5 (Figure 13B), compound 140 (Figure 13C), and compound 151 (Figure 13D) demonstrates superior pharmacokinetic dosing of compounds with 8'-methyl substitution. [Figure 13C]Figures 13A-13D. Pharmacokinetic analysis of plasma half-life in CD-1 mice after a single oral dose of 10 mg / kg of compounds MBE1 (Figure 13A), MBE1.5 (Figure 13B), compound 140 (Figure 13C), and compound 151 (Figure 13D) demonstrates superior pharmacokinetic dosing of compounds with 8'-methyl substitution. [Figure 13D] Figures 13A-13D. Pharmacokinetic analysis of plasma half-life in CD-1 mice after a single oral dose of 10 mg / kg of compounds MBE1 (Figure 13A), MBE1.5 (Figure 13B), compound 140 (Figure 13C), and compound 151 (Figure 13D) demonstrates superior pharmacokinetic dosing of compounds with 8'-methyl substitution. [Figure 14] Treatment of T3-MCA fibrosarcoma cell line allografts implanted subcutaneously in C57BL6 syngeneic mice with oral Compound 140 and / or anti-PD-1 antibody at the indicated doses for the indicated treatment periods demonstrates successful inhibition of tumor growth as single agents and synergistic effects with anti-PD-1 antibody in causing tumor regression. From top to bottom: control chow, anti-PD-1, Compound 140, and Compound 140 + anti-PD-1. [Figure 15A] Figures 15A and 15B. Treatment of T3-MCA fibrosarcoma cell line allografts implanted subcutaneously in C57BL6 syngeneic mice with 40 mg / kg oral Compound 140 or Compound 151 once daily for 12 days demonstrates successful inhibition of tumor growth (Figure 15A), while being well tolerated (Figure 15B). [Figure 15B] Figures 15A and 15B. Treatment of T3-MCA fibrosarcoma cell line allografts implanted subcutaneously in C57BL6 syngeneic mice with 40 mg / kg oral Compound 140 or Compound 151 once daily for 12 days demonstrates successful inhibition of tumor growth (Figure 15A), while being well tolerated (Figure 15B). [Figure 16] Figure 1 shows the CYP inhibitory properties of compounds MBE1, 140, 151 tested at 10 uM using human CYP enzymes and standard operating protocols. DETAILED DESCRIPTION OF THE INVENTION

[0028] As described in more detail in the Examples section, Aldh1a3 has been 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 has been 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).

[0029] 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. Studies have shown that in mouse xenograph models, ALDH1a3 inhibitors (MBE1 or MBE1.5, shown below and disclosed in PCT / US2021 / 014883) in combination with a chemotherapy 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. [ka]

[0030] As also detailed in the Examples section herein, the present disclosure demonstrates that, of the isoforms tested, only ALDH1a2 and ALDH1a3 induce retinoid pathway activation, and that ALDH1a2 and ALDH1a3 drive retinoid pathway activation in solid tumors in vivo. Furthermore, as shown in Figure 7, expression of ALDH1a2 and ALDH1a3 mRNA in patient-derived xenograft models from multiple human cancers demonstrates expression of the ALDH1a2 and ALDH1a3 enzymes across multiple tumor types. Exemplary ALDH1a2 and / or ALDH1a3 inhibitors are also shown herein to be effective in inhibiting tumor growth in vivo, either as single agents or in synergistic combination treatment with immune checkpoint inhibitors (anti-PD-1 antibodies).

[0031] As also detailed herein, the compounds described herein are orally available and exhibit sufficient pharmacokinetic exposure to effectively inhibit Aldh1a3 and / or Aldh1a2 in mouse models.

[0032] Furthermore, Aldh1a3 was found to be a key driver of the progression of type 2 diabetes. The data herein indicate 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.

[0033] 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 cells from non-obese, non-diabetic C57 / BL6 mice do not express Aldh1a3. Accordingly, in various embodiments, the present disclosure provides novel compounds and compositions useful for inhibiting ALDHs, such as ALDH1a3 and / or Aldh1a2, and methods of using the same, e.g., to inhibit retinoid pathway activation, to treat various diseases or disorders associated with ALDH1a3 and / or Aldh1a2, to treat various diseases or disorders associated with retinoid pathway activation, to treat various cancers, cancer metastasis, metabolic diseases such as type 2 diabetes, pulmonary arterial hypertension (PAH) or neointimal hyperplasia (NIH), or as a male contraceptive.

[0034] compound Provided herein is a range of compounds that may be useful in inhibiting ALDH, particularly ALDH1a3 and / or Aldh1a2.

[0035] Formula I In some embodiments, the present 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 CR 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, R1 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, an optionally substituted carbocycle (e.g., C 3~8 carbocyclic), or optionally substituted heterocyclic forming a 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 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), In Formula I, " [ka] " indicates that the bond is, as 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 as the balance permits; During the ceremony, R at each occurrence 10are 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 carbocycle, an optionally substituted 3- to 8-membered heterocycle, an optionally substituted phenyl, or an optionally substituted 5- to 10-membered heteroaryl; or R 10 and R 20 and R 21 are linked to one another to form a bond, an optionally substituted 4- to 8-membered heterocycle, or an optionally substituted 5- or 6-membered heteroaryl ring; 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 21a 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 1~6 alkyl), -S(O)2-alkyl (e.g., -S(O)2-C 1~6 alkyl), or -OR 31 or two adjacent R 22 are linked together to form an arbitrarily substituted C 3~8 forming an optionally substituted ring structure such as a carbocycle, an optionally substituted 4- to 8-membered heterocycle, an optionally substituted phenyl, or an optionally substituted 5- or 6-membered heteroaryl ring; 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 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; R 23 , R 24 , and R 25 One of the groups may be hydrogen, halogen, 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 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 1~6 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 a 3- to 8-membered optionally substituted heterocyclic or a 5- to 10-membered optionally substituted 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.

[0036] 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.

[0037] Typically, in Formula I (e.g., Formula IO), 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 Specifically, in Formula I, the aryl group forms 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. IteR 3 and R 4 are said to be linked to form a ring system 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.

[0038] In some embodiments, in Formula I (e.g., Formula IO), R 3 and R 4 are linked to form an optionally substituted phenyl ring, i.e., in formula I [ka] part is, [ka] where R 5 is defined herein, and phenyl is optionally substituted at any available position with, for example, F, Cl, hydroxyl, 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 -OCF3, optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl. 3~6 It may be further optionally substituted with one or two substituents independently selected from cycloalkyl, preferably cyclopropyl or cyclobutyl, and —CN. In some embodiments, R 5 But, -OR 30 or -CR 23 R 24 R 25 For example, in some embodiments, R 5is 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.

[0039] In some embodiments, in Formula I (e.g., Formula IO), R 3 and R 4 can link 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 can link to form an optionally substituted pyrazole, imidazole, oxazole, thiazole, isoxazole, isothiazole, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl. For example, in some embodiments, [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 optionally substituted with, for example, F, Cl, OH, 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 1~4Alkoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, or -OCF3, optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl. 3~6 It may be further optionally substituted with one or two (preferably one) substituents independently selected from cycloalkyl, preferably cyclopropyl or cyclobutyl, and —CN. In some embodiments, in Formula I, [ka] The part is [ka] wherein R 5 is defined herein, and pyridyl is C optionally substituted at any available position with, for example, F, Cl, 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 -OCF3, optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl. 3~6 It may be further optionally substituted with one or two (preferably one) substituents independently selected from cycloalkyl, preferably cyclopropyl or cyclobutyl, and —CN. In some embodiments, R 5 But, -OR 30 or -CR 23 R 24 R 25 For example, in some embodiments, R 5is 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.

[0040] In some embodiments, in Formula I (e.g., Formula IO), R 3 and R 4 may 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 in Formula I may be further optionally substituted with one or two substituents independently selected from alkyl. [ka] part is, [ka] wherein R 5 is defined herein, and tetrahydropyranyl or morpholinyl may be substituted at any available position with, for example, F and optionally 1 to 3 fluorines, such as C 1~4 In some embodiments, R is an alkyl group, as defined herein. 5But, -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, -O-CH2-cyclobutyl, -O-C2H4-cyclopropyl or -O-C2H4-cyclobutyl.

[0041] 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, R24 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.

[0042] 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), NH 2. -NH(C 1~4 alkyl), -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 The two "C" 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 25R 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.

[0043] 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 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 C optionally substituted with 1 to 3 substituents independently selected from alkoxy, fluorine and methyl 3~6 C optionally substituted with 1 to 3 substituents independently selected from cycloalkoxy, fluorine and methyl 3~6 a 3- to 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, fluorine, and methyl; Preferably, R 23 , R 24 , and R 25 At least one of R is not hydrogen. 25 is fluorine, 1 to 3 fluorines and / or C 3~6 C optionally substituted with cycloalkyl 1~4 C optionally substituted with 1 to 3 substituents independently selected from alkyl, fluorine, and methyl 3~6 cycloalkyl (e.g., cyclopropyl or cyclobutyl). 1~4The 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.

[0044] 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 C optionally substituted with 1 to 3 substituents independently selected from alkoxy, fluorine and methyl 3~6 C optionally substituted with 1 to 3 substituents independently selected from cycloalkoxy, 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 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 1 to 3 fluorine and / or C 3~6 C optionally substituted with cycloalkyl 1~4alkyl, 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 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, —CH 2 —CF 3 , —CH 2 -cyclopropyl, cyclopropyl, or cyclobutyl.

[0045] 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.

[0046] 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.

[0047] 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 5 and 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 4~7In some embodiments, R in formula IF forms a cycloalkyl group (e.g., cyclopentyl or cyclohexyl) or an optionally substituted 4- to 7-membered (e.g., 6-membered) heterocycle having 1 or 2 ring heteroatoms. 3 and R 4 are linked to an optionally substituted phenyl, for example, unsubstituted phenyl, or C optionally substituted with F, Cl, 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 3、 C optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl 3~6 In some embodiments, in formula IF, R 3 and R 4 may be linked to form an optionally substituted 5- or 6-membered heteroaryl.

[0048] In some particular 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 , R2 , 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 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 -OCF3, optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl. 3~6 Cycloalkyl is preferably selected from cyclopropyl or cyclobutyl, and -CN.

[0049] 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, -CF3, methoxy, ethoxy, n-propoxy, isopropoxy, -OCF3, 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.

[0050] 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 , R25 , 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 cycloalkyl 1~4 Alkyl, 1 to 3 fluorines and / or C 3~6 C optionally substituted with cycloalkyl 1~4 C optionally substituted with 1 to 3 substituents independently selected from alkoxy, fluorine and methyl 3~6 C optionally substituted with 1 to 3 substituents independently selected from cycloalkoxy, fluorine and methyl 3~6 a 3- to 6-membered heterocycle optionally substituted with 1 to 3 substituents independently selected from cycloalkyl, fluorine, and methyl; Preferably, R 23 , R 24 , and R 25 At least one of the is not hydrogen. In some embodiments, in formula I-1-A or I-2-A, R 23 is hydrogen.

[0051] In some embodiments, in formula I-1-A or I-2-A, R 23 and R 24 and R are both hydrogen. 25 But 1 to 3 fluorine and / or C 3~6 optionally substituted with cycloalkyl C 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.

[0052] 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 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.

[0053] 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 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 -OCF3, 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 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, -CF3, methoxy, ethoxy, n-propoxy, isopropoxy, -OCF3, 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, -CF, methoxy, ethoxy, n-propoxy, isopropoxy, -OCF, cyclopropyl, or -CN. In some embodiments, in Formula I-1-A2 or Formula I-2-A2, R 100 is F, Cl, or methyl.

[0054] 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, 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 heterocyclic ring 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] It may be.

[0055] In some embodiments, in formula I-1-C or I-2-C, R11 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 to 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, 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.

[0056] 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 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 -OCF3, optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl. 3~6 In some embodiments, in Formula I-1-B, I-1-C, I-2-B, or I-2-C, p is 0. 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 100is F, Cl, methyl, ethyl, n-propyl, isopropyl, -CF3, methoxy, ethoxy, n-propoxy, isopropoxy, -OCF3, cyclopropyl, or -CN.

[0057] In some embodiments, the compound of formula I-1 or I-2 is of formula I-1-B1, I-1 -B2, formula I-2-B1, formula 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, 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] It may be.

[0058] In some embodiments, R 30 may 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 100may be F, Cl, methyl, ethyl, n-propyl, isopropyl, -CF3, methoxy, ethoxy, n-propoxy, isopropoxy, -OCF3, cyclopropyl, or -CN.

[0059] 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]

[0060] 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]

[0061] 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]

[0062] 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. 139-202 or 139-165 disclosed herein, as applicable. In some embodiments, in Formula I (e.g., any of the applicable subformulas), [ka] portion has an activity level of A or B shown in Table 3A of the present disclosure in inhibiting hALDH1a3, and / or an IC shown in Table 3B of less than 250 nM in inhibiting hALDA1a2, as applicable. 50 and may have any of the structures of the corresponding moieties in the specific compounds disclosed herein.

[0063] Typically, in Formula I, R 1 and R 2 For example, in some embodiments, in any of the subformulas of formula I, 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, R 1 and R 2 However, both may be hydrogen.

[0064] 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.

[0065] In some embodiments, 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 But, CR22 In some embodiments, J of formula I is 1 is CR 22 and R 22 is hydrogen, F, Cl, CN, or C 1~4 It is alkyl (preferably methyl). As shown in the examples herein, it has been unexpectedly found that the substituent at this position can affect the selectivity of the compound for different ALDH isoforms. For example, the data herein show that J 1 is CR 22 and R 22 is substituted, e.g., methyl, and representative compounds are 1 has significantly enhanced activity in inhibiting hALDH1a2 compared to other identical compounds, except that CH is CH.

[0066] 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.

[0067] 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.

[0068] 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. In some embodiments, J 1 , J 2 , and J 3 None of the above is N, for example, J 1 is CR 22 J 2 may be CH, and J 3 may be CH, and R 22 is hydrogen, F, Cl, CN, or C 1~4 In some embodiments, J is alkyl (preferably methyl). 1 , J 2 , and J 3 None of the above is N, for example, J 1 is CR 22 J 2 is CR 22 J 3 may be CH, and at each occurrence R 22 are independently hydrogen, F, Cl, CN, or C 1~4 It is alkyl (preferably methyl).

[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), J 1 and J 2 Both are CR 22 and J 3 is CR 22 or N, and two adjacent R 22 (i.e., J 1 and J 2 (from) are linked together to form an optionally substituted C 3~8 It forms an optionally substituted ring structure such as a carbocyclic ring, an optionally substituted 4- to 8-membered heterocyclic ring, an optionally substituted phenyl, or an optionally substituted 5- or 6-membered heteroaryl ring, e.g., a pyridine ring.

[0070] Typically, in formula I, n is 1, 2, or 3. Preferably, n is 2.

[0071] In Formula I, each instance of X is O, NR 10 , or CR 20 R 21 wherein at most one X is 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.

[0072] 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 may be, 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, CR20 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.

[0073] In some embodiments, n is 2, one instance of X is O, and one instance of X is CR 20 R 21 and R 20 and R 21 is defined herein. In some embodiments, n is 2 and one instance of X is NR 10 and one instance 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 3~6 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. 1 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.

[0074] 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 R21 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 21 is 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.

[0075] 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 terms of form, J 1 is CH. In some embodiments, J 2 But N or CR 22 where R 22 is defined herein and is, for example, hydrogen, F, Cl, CN, or methyl. In some embodiments, J 3 is CH. In some embodiments, J 1 is CR 22 J 2 may be CH, and J 3 may be CH, and R 22 is hydrogen, F, Cl, CN, or C 1~4 In some embodiments, J is alkyl (preferably methyl). 1 is CR 22 J 2 is CR 22 J 3 may be CH, and R at each occurrence 22 are independently hydrogen, F, Cl, CN, or C 1~4In 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 In some embodiments, the other of CR 20 R 21 In units, R 20 and R 21 are both hydrogen.

[0076] 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.), 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, 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.

[0077] 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 1~4alkyl (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, 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.

[0078] 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 20 and R 21 is defined herein. In some embodiments, R 20 and R 21 are independently hydrogen or C 1~4alkyl (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, 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.

[0079] 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 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, 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.

[0080] 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, R20 and R 21 is defined herein. 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, 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.

[0081] 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 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 21 together with the carbon to which they are both attached, form cyclopropyl, cyclopropyl, In some embodiments, CR 20 R 21 In units, R 20 and R 21 One of the groups is methyl, and R 20 and R21 In some embodiments, the other of CR 20 R 21 In units, R 20 and R 21 are both hydrogen.

[0082] 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] may be selected from the following: [ka]

[0083] 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] may be selected from the following: [ka]

[0084] 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] may be selected from the following: [ka]

[0085] In some embodiments, 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) is selected from the group consisting of: -A2, I-2-A3, I-1-B, I-2-B, I-1-C, or I-2-C), [ka] teeth, [ka] is.

[0086] 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] may be selected from the following: [ka]

[0087] 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] may be selected from the following: [ka]

[0088] 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] may be selected from the following: [ka]

[0089] 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] may be selected from the following: [ka]

[0090] 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), hand, [ka] can be any of compounds 139-202 disclosed herein, or the corresponding moieties shown in 139-165, where applicable.

[0091] In some embodiments, the present disclosure also provides a compound 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 bonded to Het at the ortho position of -C(=Z)-. Also, in formula IP, R 5 It will also be understood that may be attached to a ring nitrogen.

[0092] 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, substituted with F, Cl, 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 -OCF3, optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl. 3~6C optionally substituted with 1 to 3 substituents independently selected from cycloalkoxy, fluorine, and methyl 3~6 Cycloalkyl, preferably cyclopropyl or or cyclobutyl, and -CN. In some embodiments, the compound of formula IP is substituted with one or two (preferably one) substituents selected from -CN. [ka] may be selected from the following: [ka] [ka] In some embodiments, R in formula IP, as defined herein, 5 -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, -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.

[0093] Formula II Some embodiments of the present disclosure are directed to a compound 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 are 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 Archi aryl (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] and R at each occurrence 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 CR 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, 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), R 5 is hydrogen, -NR 11 R 12 , -CR 23 R 24 R 25 , or -OR 30 Or 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 Q 2 If -C(=Z)-, R 5 and Z are linked to an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted carbocycle (e.g., C 3~8carbocyclic 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, as 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 as 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 carbocycle, an optionally substituted 3- to 8-membered heterocycle, an optionally substituted phenyl, or an optionally substituted 5- to 10-membered heteroaryl; or R 10 and R 20 and R 21 are linked to one another to form a bond, an optionally substituted 4- to 8-membered heterocycle, or an optionally substituted 5- or 6-membered heteroaryl ring; R 20 and R 21 another of which is defined above, R20 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 or two adjacent R 22 are linked together to form an arbitrarily substituted C 3~8 forming an optionally substituted ring structure such as a carbocycle, an optionally substituted 4- to 8-membered heterocycle, an optionally substituted phenyl, or an optionally substituted 5- or 6-membered heteroaryl ring; 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 2~6alkynyl), 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 3~8 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, wherein 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 2~6alkynyl), 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 a 3- to 8-membered optionally substituted heterocyclic or a 5- to 10-membered optionally substituted 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.

[0094] Typically, in Formula II, the variable R 3 , R 4 , R 5 , J 1 , J 2 , J 3 , X, and n may be any of those described above in relation to 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 forms 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] The part is [ka] where R 5 is defined herein, and phenyl or pyridyl is optionally substituted at any available position with, for example, F, Cl, 1-3 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 -OCF3, optionally substituted with 1 to 3 substituents independently selected from fluorine and methyl. 3~6 It may be further optionally substituted with one or two substituents independently selected from cycloalkyl, preferably cyclopropyl or cyclobutyl, and —CN. In some embodiments, 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 R 22 is defined herein. In some embodiments, R 22 is hydrogen, F, Cl, CN, or methyl. In some embodiments, J 3is CH. In some embodiments, J 1 is CR 22 J 2 may be CH, and J 3 may be CH, and R 22 is hydrogen, F, Cl, CN, or C 1~4 In some embodiments, J is alkyl (preferably methyl). 1 is CR 22 J 2 is CR 22 J 3 may be CH, and R at each occurrence 22 are independently hydrogen, F, Cl, CN, or C 1~4 In some embodiments, each instance of X in formula II is independently selected from the group consisting of alkyl, methyl ... 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 21One 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.

[0095] 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.

[0096] 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 them is None, and Q 1 and Q 3 and one of the two is NR as defined herein. 2wherein t1 is 0 or 1, t2 is 0 or 1, and preferably both t1 and t2 are 0; R 2 is hydrogen or methyl, (2)Q 1 , Q 2 , and Q 3 is absent, t1 is 0, t2 is 2, and two adjacent CR A2 R B2 is —C(R A2 )=C(R B2 )-, preferably R A2 and R B2 are both hydrogen, or (3)Q 2 But there is no Q 1 and Q 3 One of them is None, and Q 1 and Q 3 and one of the two 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. Also, in formula II, the bivalent linker L, -(CR A1 R B1 ) t1 -Q 1 -Q 2 -Q 3 -(CR A2 R B2 ) t2 - can connect the rest of the structure 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 embodiments, NR 2 teeth, [ka] It is directly connected to the unit.

[0097] 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] or selected from any of those described as [ka] Or it may be selected from the following: [ka]

[0098] 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. 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.

[0099] 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, each of which is independently selected from the group consisting of F, Cl, C optionally substituted with 1 to 3 fluorines, C 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 -OCF3, 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, 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. [ka] The units may be selected from the following: [ka] [ka]

[0100] 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 CR 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 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 1is 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 1~6 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 10 and R 20 and R 21 are linked to one another to form a bond, an optionally substituted 4- to 8-membered heterocycle, or an optionally substituted 5- or 6-membered heteroaryl ring; R 20 and R 21 another of which is defined above, 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 CR20 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 1~6 alkyl), -S(O)2-alkyl (e.g., -S(O)2-C 1~6 alkyl), or -OR 31 or two adjacent R 22 are linked together to form an arbitrarily substituted C 3~8 forming an optionally substituted ring structure such as a carbocycle, an optionally substituted 4- to 8-membered heterocycle, an optionally substituted phenyl, or an optionally substituted 5- or 6-membered heteroaryl 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 R14 are linked to form a 3- to 8-membered optionally substituted heterocyclic or a 5- to 10-membered optionally substituted 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.

[0101] 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.

[0102] 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] may be selected from the following: [ka] [ka]

[0103] In some embodiments, in Formula III (e.g., III-1 or III-2), [ka] may be selected from the following: [ka]

[0104] In some embodiments, in Formula III (e.g., III-1 or III-2), [ka] may be selected from the following: [ka]

[0105] In some embodiments, in Formula III (e.g., III-1 or III-2), [ka] teeth, [ka] It could be.

[0106] 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. 139-202, or 139-165, disclosed herein, where applicable.

[0107] G in Formula III 1is typically an optionally substituted phenyl or an optionally substituted heteroaryl, including any of those described herein.

[0108] 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 may 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.

[0109] In some embodiments, the compound of formula III is characterized by having the formula III-2, wherein G 1 is in formula I [ka] The moiety (e.g., any applicable subformula) of formula III may be any of those described herein suitable. For example, in some embodiments, the compound of formula III is characterized by having formula III-2, wherein G 1 may be selected from any of the following: [ka] In some embodiments, the compound of formula III is characterized by having the formula III-2, 1 may be selected from any of the following: [ka]

[0110] Formula (IV) In embodiments, the present disclosure provides a compound of formula (IV) [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Ring A is a heterocycle or heteroaryl; L is -NH-, -C(O)-NH-, -S(O)NH-, -S(O)NH-, -S(O)-, or -S(O)-; R 22 But halo, -CN, -C 1~6 Alkyl, -C 1~6 Alkyl-CN, -C 1~6 haloalkyl, or carbocyclyl; R 22’ But, H, halo, -C 1~6 Alkyl or -C 1~6 haloalkyl, or R 22 and R 22’ are linked to form a heteroaryl, carbocyclyl, or heterocyclyl, each of which is optionally substituted with one or more halo; R 32 and R 33are linked to form a heterocyclyl, substituted with oxo, and the heterocycle is joined to one or more R 101 and optionally further substituted with p is 0, 1, or 2; Each R 100 independently, halo, -C 1~6 Alkyl, -C 1~6 Alkylene-carbocyclyl, -C 1~6 alkylene-heterocyclyl, or -C 1~6 is haloalkyl, Each R 101 are independently hydrogen, halo, or -C 1~6 It is alkyl.

[0111] In embodiments of a compound of formula (IV), L is -NH-, -C(O)-NH-, -S(O)NH-, -S(O)NH-, -S(O)-, or -S(O)-. In embodiments, L is -NH-. In embodiments, L is -C(O)-NH-. In embodiments, L is -S(O)NH-. In embodiments, L is -S(O)NH-. In embodiments, L is -S(O)NH-. In embodiments, L is -S(O)-. In embodiments, L is -S(O)-.

[0112] In an embodiment, the compound of formula (IV) is a compound of formula (IV-A) [ka] or a pharmaceutically acceptable salt thereof, wherein: L1 is absent, -C(O)-, -S(O)-, or -S(O)2-; Ring A is a heterocycle or heteroaryl; R 22 But halo, -CN, -C 1~6 Alkyl, -C 1~6 Alkyl-CN, -C 1~6 haloalkyl or carbocyclyl; R 22’ But, H, halo, -C 1~6 Alkyl or -C 1~6 haloalkyl, or R22 and R 22’ are linked to form a heteroaryl, carbocyclyl, or heterocyclyl, each of which is optionally substituted with one or more halo; R 32 and R 33 are linked to form an oxo-substituted heterocyclyl, wherein the heterocyclyl is selected from the group consisting of one or more R 101 and optionally further substituted with p is 0, 1, or 2; Each R 100 independently, halo, -C 1~6 Alkyl, -C 1~6 Alkylene-carbocyclyl, -C 1~6 alkylene-heterocyclyl, or -C 1~6 is haloalkyl, Each R 101 are independently hydrogen, halo, or -C 1~6 It is alkyl.

[0113] In an embodiment of the compound of Formula (IV-A), L 1 is absent, —C(O)—, —S(O)—, or —S(O) 2 —.

[0114] In an embodiment of the compound of Formula (IV-A), L1 is -C(O)-, -S(O)-, or -S(O)2-.

[0115] In an embodiment of the compound of formula (IV-A), L 1 is absent.

[0116] In an embodiment of the compound of Formula (IV-A), L1 is -C(O)-.

[0117] In an embodiment of the compound of Formula (IV-A), L1 is -S(O)-.

[0118] In an embodiment of the compound of Formula (IV-A), L1 is -S(O)2-.

[0119] In an embodiment of the compound of Formula (IV) or Formula (IV-A), ring A is heteroaryl.

[0120] In an embodiment of the compound of Formula (IV) or Formula (IV-A), ring A is a heterocycle.

[0121] In an embodiment of the compound of Formula (IV) or Formula (IV-A), ring A is a 5- or 6-membered heteroaryl, a 5,6-bicyclic heteroaryl, a 5,6-bicyclic heterocyclyl, a 6,6-bicyclic heterocyclyl, a 6,6-bicyclic heteroaryl, or a 3- to 8-membered heterocyclyl.

[0122] In an embodiment of the compound of Formula (IV) or Formula (IV-A), Ring A is a 5- or 6-membered heteroaryl, a 5,6-bicyclic heteroaryl, a 6,6-bicyclic heteroaryl, or a 3- to 8-membered heterocyclyl.

[0123] In an embodiment of a compound of Formula (IV) or Formula (IV-A), Ring A is a 5- or 6-membered heteroaryl. In an embodiment, Ring A is a 5-membered heteroaryl. In an embodiment, Ring A is a 6-membered heteroaryl.

[0124] In an embodiment of the compound of Formula (IV) or Formula (IV-A), Ring A is a 5,6-bicyclic heteroaryl.

[0125] In an embodiment of the compound of Formula (IV) or Formula (IV-A), Ring A is a 6,6-bicyclic heteroaryl or a 3-8 membered heterocyclyl.

[0126] In an embodiment of the compound of Formula (IV) or Formula (IV-A), Ring A is selected from the group consisting of pyridyl, pyrimidinyl, and the like. nyl, pyridazinyl, quinazolinyl, quinoxalinyl, or morpholinyl.

[0127] In an embodiment of a compound of Formula (IV) or Formula (IV-A), Ring A is pyridyl. In an embodiment, Ring A is pyrimidinyl. In an embodiment, Ring A is pyridazinyl. In an embodiment, Ring A is quinazolinyl. In an embodiment, Ring A is quinoxalinyl. In an embodiment, Ring A is morpholinyl.

[0128] In an embodiment of the compound of Formula (IV) or Formula (IV-A), Ring A-(R 100 ) p teeth, [ka] is.

[0129] In an embodiment of the compound of Formula (IV) or Formula (IV-A), Ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] is.

[0130] In an embodiment of the compound of Formula (IV) or Formula (IV-A), Ring A-(R 100 ) p teeth, [ka] is.

[0131] In an embodiment of the compound of Formula (IV) or Formula (IV-A), Ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] In embodiments, ring A-(R 100 ) p teeth, [ka] is.

[0132] In an embodiment, the ring A-(R 100 ) p teeth, [ka] is.

[0133] In an embodiment, the compound of formula (IV) is a compound of formula (IV-B) [ka] or a pharmaceutically acceptable salt thereof; During the ceremony, Z 1 , Z 2 , Z 3 , and Z 4 each independently is CH or N; Z 1 , Z 2 , Z 3 , and Z 4 at least one of is N, R 22 But halo, -CN, -C 1~6 Alkyl, -C 1~6 Alkyl-CN, -C 1~6 haloalkyl or carbocyclyl; R 22’ But, H, halo, -C 1~6 Alkyl or -C 1~6 haloalkyl, or R 22 and R 22’ are linked to form a heteroaryl, carbocyclyl, or heterocyclyl, each of which is optionally substituted with one or more halo; R 32 and R 33 are linked to form an oxo-substituted heterocyclyl, wherein the heterocyclyl is selected from the group consisting of one or more R 101 and optionally further substituted with p is 0, 1, or 2; Each R 100 independently, halo, -C 1~6 Alkyl, -C 1~6Alkylene-carbocyclyl, -C 1~6 alkylene-heterocyclyl, or -C 1~6 is haloalkyl, Each R 101 are independently hydrogen, halo, or -C 1~6 It is alkyl.

[0134] In an embodiment of the compound of formula (IV-B), Z 1 , Z 2 , Z 3 , and Z 4 One or two of the groups are —N, and the rest are —CH.

[0135] In an embodiment of the compound of formula (IV-B), Z 2 is N and Z 1 , Z 3 , and Z 4 is CH or Z 1 and Z 2 But N and Z 3 and Z 4 is CH or Z 2 and Z 4 is N and Z 1 and Z 3 is CH or Z 1 and Z 3 But N and Z 2 and Z 4 is CH, or Z 2 and Z 3 But N and Z 1 and Z 4 But it is CH.

[0136] In an embodiment of the compound of formula (IV-B), Z 2 is N and Z 1 , Z 3 , and Z 4 is CH, or Z 1 and Z 2 But N and Z 3and Z 4 But it is CH.

[0137] In an embodiment of the compound of formula (IV-B), Z 2 is N and Z 1 , Z 3 , and Z 4 But it is CH.

[0138] In an embodiment of the compound of formula (IV-B), Z 1 and Z 2 But N and Z 3 and Z 4 But it is CH.

[0139] In an embodiment of the compound of formula (IV-B), Z 2 and Z 4 is N and Z 1 and Z 3 But it is CH.

[0140] In an embodiment of the compound of formula (IV-B), Z 1 and Z 3 But N and Z 2 and Z 4 But it is CH.

[0141] In an embodiment of the compound of formula (IV-B), Z 2 and Z 3 But N and Z 1 and Z 4 But it is CH.

[0142] In embodiments of the compounds of Formula (IV), Formula (IV-A), or Formula (IV-B), R 32 and R 33 are linked to form a heterocycle containing at least one N atom in the ring and substituted with oxo.

[0143] In embodiments of the compounds of Formula (IV), Formula (IV-A), or Formula (IV-B), R 32 and R 33 are linked to form a 6- to 7-membered heterocycle containing at least one N atom in the ring and substituted with oxo.

[0144] In embodiments of the compounds of Formula (IV), Formula (IV-A), or Formula (IV-B), R 32 and R 33 are linked to form a 6-membered heterocycle containing one N atom in the ring and substituted with oxo.

[0145] In embodiments, the present disclosure provides a compound of formula (IV-C) [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 20 , R 21 , R 20’ , R 21’ are each independently hydrogen, halo, or -C 1~4 alkyl, or R 20 and R 21 One of them is R 20’ and R 21’ C 3~8 forming a carbocyclic ring or a 3- to 8-membered heterocyclic ring, R 22 But halo, -CN, -C 1~6 Alkyl, -C 1~6 Alkyl-CN, -C 1~6 haloalkyl or carbocyclyl; R 22’ But, H, halo, -C 1~6 Alkyl or -C 1~6 Is it a haloalkyl? or R 22 and R 22’ taken together form a heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo; p is 0, 1, or 2; Each R 100 independently, halo, -C 1~6 Alkyl, -C 1~6 Alkylene-carbocyclyl, -C 1~6Alkylene-heterocyclyl, or -C 1~6 haloalkyl, or When p is 2, two adjacent R 100 may link to form a carbocyclyl or heterocyclyl, each of which may be substituted with one or more halo.

[0146] In an embodiment of the compound of formula (IV-C), R 20 and R 21 are independently -H, C 1~4 alkyl or halo, and R 20’ and R 21’ is hydrogen, or R 20 But R 20’ and R form a cyclopropyl ring or a 5- to 6-membered heterocycle. 21 and R 21’ But it is -H.

[0147] In an embodiment of the compound of formula (IV-C), R 20 and R 21 are independently —H, methyl, or fluoro; R 20’ and R 21’ is hydrogen.

[0148] In an embodiment of the compound of formula (IV-C), R 20 and R 21 is hydrogen.

[0149] In an embodiment of the compound of formula (IV-C), R 20 and R 21 is methyl.

[0150] In an embodiment of the compound of formula (IV-C), R 20 and R 21 But it's fluoro.

[0151] In an embodiment of the compound of formula (IV-C), R 20’ and R 21’ is hydrogen.

[0152] In an embodiment of the compound of formula (IV-C), R 20 But R 20’ and R form a cyclopropyl ring or a 5- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N and O; 21 and R 21’ But it is -H.

[0153] In an embodiment of the compound of formula (IV-C), R 20 But R 20’ and R form a cyclopropyl ring. 21 and R 21’ But it is -H.

[0154] In an embodiment of the compound of formula (IV-C), R 20 But R 20’ and R form a 5- to 6-membered heterocyclyl containing one or two heteroatoms independently selected from N and O; 21 and R 21’ But it is -H.

[0155] In embodiments, R 20 is R 20’ and R form a pyrrolidinyl ring. 21 and R 21’ is -H.

[0156] In embodiments, R 20 is R 20’ and R form a morpholinyl ring. 21 and R 21’ is -H.

[0157] In embodiments, the present disclosure provides a compound of formula (IV-D): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 22 But halo, -CN, -C 1~6 Alkyl, -C 1~6 Alkyl-CN, -C1~6 haloalkyl or carbocyclyl; R 22’ But, -H, halo, -C 1~6 Alkyl, -C 1~6 Is it a haloalkyl? or R 22 and R 22’ taken together form a heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo; p is 0, 1, or 2; Each R 100 independently, halo, -C 1~6 Alkyl, -C 1~6 Alkylene-carbocyclyl, -C 1~6 Alkylene-heterocyclyl, or -C 1~6 Is it a haloalkyl? Or, when p is 2, two R 100 may link to form a carbocyclyl or heterocyclyl, each of which may be substituted with one or more halo.

[0158] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 Halo, -CN, -C 1~6 Alkyl, -C 1~6 Alkyl-CN, -C 1~6 It is haloalkyl, or carbocyclyl.

[0159] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 Halo, -CN, -C 1~6 Alkyl, or C 1~6 It is haloalkyl.

[0160] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 is halo, -CN, or -C 1~6 It is alkyl.

[0161] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 Halo, -C 1~6 Alkyl or -C 1~6 It is haloalkyl.

[0162] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 Halo, -C 1~4 Alkyl or -C 1~4 It is haloalkyl.

[0163] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 is halo or -C 1~4 It is alkyl.

[0164] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 is a halo.

[0165] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 -Cl, or -F. In embodiments, R 22 In an embodiment, , R 22 -F,

[0166] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 is -CN.

[0167] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 -C 1~6 In embodiments, R 22 -C 1~4 It is alkyl.

[0168] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 is —CH or —CHCH. In embodiments, R 22 is —CH3. In an embodiment, R 22 is -CH2CH3.

[0169] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 -C 1~6 It is alkyl-CN.

[0170] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 is -CHCN.

[0171] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 -C 1~6 In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 -C 1~4 It is haloalkyl.

[0172] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 is —CF. In embodiments, R 22 is -CH2CF3.

[0173] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 is a carbocyclyl.

[0174] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 is cyclopropyl.

[0175] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 -Cl, -F, -CN, -CH3, -CH2CH3, -CH2CN, -CF3, -CH2CF3, or cyclopropyl.

[0176] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 is -Cl, -F, -CN, -CH3, or -CH2CH3.

[0177] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 is -Cl, -F, -CH3, or -CH2CH3.

[0178] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 is -Cl, -F, or -CH3.

[0179] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 and R 22’ Together, (i) a 5- to 6-membered heteroaryl containing one or two heteroatoms independently selected from N, O, and S; (ii) a 5-membered carbocyclyl optionally substituted with one or more fluoro; or (iii) forming a 6-membered heterocyclyl containing one or two heteroatoms independently selected from N and O;

[0180] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 and R 22’ together form a 5-6 membered heteroaryl containing 1 or 2 heteroatoms independently selected from N, O, and S.

[0181] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 and R 22’ together form a 5-membered carbocyclyl optionally substituted with one or more fluoro.

[0182] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 and R 22’ together form a 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N and O.

[0183] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 and R 22’ together form a 6-membered heteroaryl containing one nitrogen atom.

[0184] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22’ -H, halo, -C 1~6 Alkyl or -C 1~6 It is haloalkyl.

[0185] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22’ is -H or halo, or -C 1~6 It is alkyl.

[0186] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22’ is —H or halo.

[0187] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22’ is -H.

[0188] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22’ is halo. In embodiments, R 22 is -F.

[0189] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22’ -C 1~6 In embodiments, R 22’ is -CH3.

[0190] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22’ -C 1~6 In embodiments, R 22’ is -CF3.

[0191] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22 is -H, -F, -CH3, or -CF3.

[0192] Compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D) In an embodiment of the present invention, R 22’ is -H, -F, or -CH3.

[0193] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 22’ is -H or -F.

[0194] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 100 independently, halo, -C 1~6 Alkyl, -C 1~6 Alkylene-carbocyclyl, -C 1~6 alkylene-heterocyclyl, or -C 1~6It is haloalkyl.

[0195] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), each R 100 independently, halo, -C 1~6 Alkyl, -C 1~6 Alkylene-carbocyclyl, -C 1~6 alkylene-heterocyclyl, or -C 1~6 haloalkyl, or when p is 2, two adjacent R 100 may link to form a carbocyclyl or heterocyclyl, each of which may be substituted with one or more halo.

[0196] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 100 independently, halo, -C 1~6 Alkyl, -C 1~6 Alkylene-carbocyclyl, or -C 1~6 It is haloalkyl.

[0197] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 100 are independently -CH2CH3, -CH3, -CH2-cyclopropyl, -Cl, -CH2-CF3, -CH2-cyclobutyl, -CH2-oxetanyl, -CF2CH3, or two adjacent R 100 can link to form a C5-6 carbocyclyl or a 5-membered heterocyclyl containing an N or O heteroatom, wherein the carbocyclyl is optionally substituted with one or more fluoro.

[0198] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 100 -C 1~6 In embodiments, R 100 -C 1~4 In embodiments, R 100 -C 1~3In embodiments, R 100 is —CH3. In an embodiment, R 100 is -CH2CH3.

[0199] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 100 is halo. In embodiments, R 100 is -Cl.

[0200] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 100 -C 1~6 In embodiments, R 100 -C 1~4 In embodiments, R 100 is —CH—CF. In embodiments, R 100 is -CF2CH3.

[0201] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 100 -C 1~6 In an embodiment, R is an alkylene-carbocyclyl. 100 is -CH-cyclopropyl. In embodiments, R 100 is -CH2-cyclobutyl.

[0202] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 100 -C 1~6 In an embodiment, R is an alkylene-heterocyclyl. 100 is -CH2-oxetanyl.

[0203] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 100is independently for each occurrence -CH2CH3, -CH3, -CH2-cyclopropyl, -Cl, -CH2-CF3, -CH2-cyclobutyl, or -CH2-oxetanyl.

[0204] In embodiments of compounds of formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), R 100 is independently for each occurrence -CH2CH3, -CH3, -CH2-cyclopropyl, -Cl, or -CH2-CF3.

[0205] In embodiments of the compounds of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 0, 1, or 2.

[0206] In embodiments of the compounds of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 1 or 2.

[0207] In an embodiment of the compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 0.

[0208] In an embodiment of the compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 1.

[0209] In an embodiment of the compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 2.

[0210] In an embodiment of a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 1 and R 100 independently, halo, -C 1~6 Alkyl, -C 1~6 Alkylene-carbocyclyl, -C 1~6 alkylene-heterocyclyl, or -C 1~6 It is haloalkyl.

[0211] In an embodiment of a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 1 and R 100 independently, halo, -C 2~6 Alkyl, -C 1~6 Alkylene-carbocyclyl, -C 1~6 alkylene-heterocyclyl, or -C 1~6 It is haloalkyl.

[0212] In an embodiment of a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 1 and R 100 independently, halo, -C 2~6 Alkyl, -C 1~6 Alkylene-carbocyclyl, -C 1~6 alkylene-heterocyclyl, or -C 2~6 It is haloalkyl.

[0213] In an embodiment of a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 1 and R 100 -C 1~6 Alkyl, -C 1~6 Alkylene-carbocyclyl, or -C 1~6 It is haloalkyl.

[0214] In an embodiment of a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 1 and R 100 -C 2~6 Alkyl, -C 1~6 Alkylene-carbocyclyl, or -C 1~6 It is haloalkyl.

[0215] In an embodiment of a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 1 and R 100 -C 2~6 Alkyl, -C 1~6 Archi -carbocyclyl, or -C 2~6 It is haloalkyl.

[0216] In an embodiment of a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 1 and R 100 is -CH2CH3, -CH2-cyclopropyl, or -CH2-CF3.

[0217] In an embodiment of the compound of Formula (IV-C) or (IV-D), p is 1 and R 100 is substituted at the meta position of the pyridine.

[0218] In an embodiment of the compound of Formula (IV-C) or (IV-D), p is 1 and R 100 is substituted at the ortho position of the pyridine.

[0219] In an embodiment of a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 2 and R 100 independently, halo, -C 1~6 Alkyl, -C 1~6 Alkylene-carbocyclyl, -C 1~6 alkylene-heterocyclyl, or -C 1~6 It is haloalkyl.

[0220] In an embodiment of a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 2 and R 100 independently, halo, -C 2~6 Alkyl, -C 1~6 Alkylene-carbocyclyl, -C 1~6 alkylene-heterocyclyl, or -C 1~6 It is haloalkyl.

[0221] In an embodiment of a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 2 and R 100 independently, halo, -C 2~6 Alkyl, -C 1~6 Alkylene-carbocyclyl, -C 1~6 alkylene-heterocyclyl, or -C 2~6 It is haloalkyl.

[0222] In an embodiment of a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 2 and R 100 independently, halo and -C 1~6 It is alkyl.

[0223] In an embodiment of a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 2 and R 100 independently, halo and -C 2~6 It is alkyl.

[0224] In an embodiment of a compound of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 2 and R 100 are -CH2CH3 and -Cl.

[0225] In embodiments of compounds of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 2 and two R 100 can link to form a C5-6 carbocyclyl or a 5-membered heterocyclyl containing an N or O heteroatom, wherein the carbocyclyl is optionally substituted with one or more fluoro.

[0226] In embodiments of compounds of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 2 and two R 100 are linked to form a C5_6 carbocyclyl, which carbocyclyl is optionally substituted with one or more fluoro. In embodiments, the C5_6 carbocyclyl is substituted with two fluoro.

[0227] In embodiments of compounds of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 2 and two R 100 are linked to form a five-membered ring containing an N atom. Forming a telocyclyl.

[0228] In embodiments of compounds of Formula (IV), (IV-A), (IV-B), (IV-C), or (IV-D), p is 2 and two R 100 are linked to form a 5-membered heterocyclyl containing an O atom.

[0229] In an embodiment of the compound of Formula (IV-C) or (IV-D), p is 2 and R 100 is substituted at the meta and ortho positions of the pyridine.

[0230] Formula V In embodiments, provided herein are compounds of formula (V) [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Z 1 and Z 2 are independently CH or N; R 22 But -H or -C 1~6 is alkyl, R 32 and R 33 are linked to form a heterocycle containing at least one N atom in the ring and substituted with oxo, and the heterocycle is 101 and optionally further substituted with R 101 are independently hydrogen, halo, or C 1~6 It is alkyl.

[0231] In an embodiment, the compound of formula (V) is a compound of formula (VA) [ka] or a pharmaceutically acceptable salt thereof; During the ceremony, R 20’ But halo or C 1~6 is alkyl, R 21’ But halo or C 1~6 It is alkyl.

[0232] In an embodiment of the compound of formula (V) or (VA), Z 1 is -CH- and Z 2 is -N-.

[0233] In an embodiment of the compound of formula (V) or (VA), Z 1 is -N- and Z 2 is -CH-.

[0234] In an embodiment of the compound of formula (V), R 32 and R 33 are linked to form a heterocycle with one N atom in the ring, substituted with oxo.

[0235] In an embodiment of the compound of formula (V), R 22 is -H or -C 1~6 In embodiments, R 22 is H or -CH3.

[0236] In an embodiment of the compound of formula (VA), R 20’ is halo. In an embodiment of the compound of formula (VA), R 20’ is -F.

[0237] In an embodiment of the compound of formula (VA), R 21’ -C 1~6 In embodiments, R 21’ is -CH3.

[0238] In embodiments, the present disclosure provides a compound of formula (VB) [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Z 1 and Z 2 are independently -CH- or -N-; R 22 But H or -C 1~6 is alkyl, R 20But halo or -C 1~6 is alkyl, R 21 But halo or -C 1~6 It is alkyl.

[0239] In an embodiment of the compound of formula (VB), Z 1 is -CH- and Z 2 is -N-.

[0240] In an embodiment of the compound of formula (VB), Z 1 is -N- and Z 2 is -CH-.

[0241] In an embodiment of the compound of formula (VB), R 22 is -CH3.

[0242] In an embodiment of the compound of formula (VB), R 20 is halo. In embodiments, R 20 is -F.

[0243] In an embodiment of the compound of formula (VB), R 21 is halo. In embodiments, R 21 is -F.

[0244] In an embodiment of the compound of formula (VB), R 20 -C 1~6 In embodiments, R 20 is -CH3.

[0245] In an embodiment of the compound of formula (VB), R 21 -C 1~6 In embodiments, R 21 is -CH3.

[0246] In some embodiments, the present disclosure also provides a compound selected from Compound Nos. 139-202, or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, the present disclosure also provides a compound selected from Compound Nos. 139-165, or a pharmaceutically acceptable salt thereof. [Table 1-A-1] [Table 1-A-2] [Table 1-A-3] [Table 1-A-4] [Table 1-A-5] [Table 1-A-6]

[0248] In some embodiments, to the extent applicable, the genera of compounds described herein also exclude any specifically known single compounds 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 genera of compounds described herein may also be excluded from such genera herein.

[0249] 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.

[0250] The synthesis of compounds of formula I-1 shown in Scheme 1 is representative of methods for preparing compounds herein. [ka] 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 herein. 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.

[0251] 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.

[0252] As will be apparent to one 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 thed. PGM Wuts; T.W. Greene, John Wiley, 2007, and 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), Sigma (St. Louis, Missouri, USA), etc. 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 Standard reference texts such as "The Organic Transformations of Organic Compounds" (Wiley-VCH, 1999), and "The Organic Transformations of Organic Compounds" (Wiley-VCH, 1999), and other references available at the time of this filing. This can be prepared by the procedures described in any of the available updates, or obvious modifications thereof.

[0253] Pharmaceutical Composition Certain embodiments are directed to pharmaceutical compositions comprising one or more compounds of the present disclosure.

[0254] 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 10, 11, 12, 11-A, 11-A, 11-A, 11-A, 11-A, 11-A, 11-B, 11-B, 11-C, or 11-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), Formula IV (e.g., IV-A, IV-B, IV-C, or IV-D), or any of Compounds Nos. 139-202, 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, coloring agents, 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 the formulation of pharmaceutical compositions and known techniques for their preparation.

[0255] Pharmaceutical compositions can include any one or more of the compounds of the present disclosure. For example, in some embodiments, the pharmaceutical composition includes 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), Formula IV (e.g., IV-A, IV-B, IV-C, or IV-D), or Compound Nos. 139-202 or 139-165, or a pharmaceutically acceptable salt thereof, e.g., in a therapeutically effective amount. In any of the embodiments described herein, the pharmaceutical composition comprises a therapeutically effective amount of a compound selected from Compound Nos. 139-202 or 139-165 (e.g., a compound having an activity level of A or B against hALDH1a3 as shown in Table 3A of the present disclosure, or an IC50 of less than 250 nM against hALDH1a2 as shown in Table 3B of the present disclosure). 50or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition may include a therapeutically effective amount of any compound of the present disclosure having an efficacy in inhibiting ALDH1a3 comparable to compound 1 or more, e.g., as measured by any of the methods described herein. In some embodiments, the 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. In some embodiments, the pharmaceutical composition comprises a therapeutic agent containing 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 hALDH1a2, as measured by the methods described herein according to Biological Example 5C. In some embodiments, the pharmaceutical composition may comprise 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 both hALDH1a3 and hALDH1a2, as measured by the methods described herein according to Biological Examples 5B and 5C.

[0256] 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, pharmaceutical compositions may be formulated for oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, or parenteral administration to a subject.

[0257] In some embodiments, the pharmaceutical composition may be formulated for oral administration. Oral formulations may be presented as discrete units such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound as a powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion.

[0258] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (such as intravenous injection or infusion, subcutaneous or intramuscular injection). The parenteral formulation may be, for example, an aqueous solution, suspension, or emulsion.

[0259] In some embodiments, the pharmaceutical composition is formulated for inhalation. The inhalable formulation can be formulated, for example, as a nasal spray, dry powder, or aerosol that can be administered via a metered dose inhaler.

[0260] 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, a 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, a 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.

[0261] 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, such as 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, anthracyclines such as pirarubicin, daunomycin, valrubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin, amrubicin, and mithramycin), antimitotics (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids such as taxol and taxotere and polo kinase inhibitors), and topoisomerase inhibitors (e.g., epiposide, e.g., etoposide, teniposide, and These include 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 (such as AZD6738), and inhibitors of WEE1 kinase (such as AZD1775 / MK-1775).

[0262] 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.

[0263] A pharmaceutical composition may contain various amounts of a compound of the present disclosure, depending on various factors, such as the intended use and the efficacy and selectivity of the compound. In some embodiments, a pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure. In some embodiments, a pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of a compound of the present disclosure is an amount effective to treat a disease or disorder described herein, and may depend on the recipient receiving 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 drug is administered concomitantly.

[0264] Treatment method The compounds of the present disclosure have a variety of utilities. 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 diseases or disorders associated with aldehyde dehydrogenase isoforms 1a3 (ALDH1a3) and / or 1a2 (ALDH1a2), such as proliferative diseases or disorders, metabolic diseases or disorders, endothelial cell or smooth muscle cell diseases or disorders, and metastasis. Accordingly, some embodiments of the present disclosure are also directed to methods of using one or more compounds of the present disclosure to inhibit ALDH enzymes, such as ALDH1a3 and / or ALDH1a2, and to treat or prevent various cancers, cancer metastasis, and / or other ALDH1a2- and / or ALDH1a3-mediated diseases and disorders, such as type 2 diabetes, pulmonary arterial hypertension (PAH), and neointimal hyperplasia (NIH), or as male contraceptives. In some embodiments, the present disclosure also provides methods of using one or more compounds of the present disclosure to antagonize the retinoid pathway. Without wishing to be bound by theory, retinoid pathway activation is thought to contribute to immune tolerance, T reg It is believed that this may result in the induction of M2 macrophages and / or M3 macrophages, and / or the suppression of effector T cells. Inhibition of ALDH1a2 and / or ALDH1a3 by one or more compounds of the present disclosure may inhibit such retinoid signaling, which may be used to treat diseases or disorders associated with undesired retinoid pathway activation, for example, to restore or activate a subject's immune response to cancer cells. For example, in some embodiments, compounds of the present disclosure may be used in combination with immunotherapy (e.g., immune checkpoint inhibitors) to treat diseases or disorders that are unresponsive to immunotherapy or to treat subjects who have developed resistance to immunotherapy.

[0265] Aldehyde dehydrogenase isoform 1a3 (ALDH1a3) is involved in the biosynthesis of RA. ALDH1a3 is an isoform / isoenzyme of the ALDH1a subfamily that is crucial for regulating RA signaling and is cell- and disease-specific. ALDH1a3 was known as ALDH6 before 2000, but has been known as Raldh3 since 2000–2007 in developmental studies. 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 with no other pathology explained. 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.

[0266] 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.

[0267] As detailed in the Examples section herein, the present disclosure demonstrates that, of the ALDH isoforms tested, only ALDH1a2 and ALDH1a3 induce retinoid pathway activation, and that ALDH1a2 and ALDH1a3 drive retinoid pathway activation in solid tumors in vivo. Furthermore, as shown in Figure 7, expression of ALDH1a2 and ALDH1a3 mRNA in patient-derived xenograft models from multiple human cancers demonstrates expression of the ALDH1a2 and ALDH1a3 enzymes across multiple tumor types.

[0268] The compounds of the present disclosure can inhibit ALDH1a2 and / or ALDH1a3, inhibit retinoid signaling, and can be used to treat various diseases or disorders associated with ALDH1a2 and / or ALDH1a3, as well as diseases or disorders associated with retinoid pathway activation.

[0269] In some embodiments, the present disclosure provides methods of inhibiting aldehyde dehydrogenase, particularly ALDH1a3, ALDH1a2, or a combination of ALDH1a3 and ALDH1a2, in a subject in need thereof. In some embodiments, the method is for inhibiting ALDH1a3. In some embodiments, the method is for inhibiting ALDH1a2. In some embodiments, the method is for inhibiting both ALDH1a3 and ALDH1a2. In some embodiments, the method includes administering an effective amount of a compound of the present disclosure (e.g., any of the compounds of Formula I (e.g., Formula 10-18, 11-19, 12-20, 12-21, 12-22, 12-23, 12-24, 12-25, 12-26, 12-27, 12-28, 12-29, 12-30, 12-31, 12-32, 12-33, 12-34, 12-35, 12-36, 12-37, 12-38, 12-39, 12-40, 12-41, 12-42, 12-43, 12-44, 12-45, 12-46, 12-47, 12-48, 12-49, 12-50, 12-51, 12-52, 12-53, 12-54, 12-55, 12-56, 12-57, 12-58, 12-59, 12-60, 12-61, 12-62, 12-63, 12-64, 12-65, 12-66, 12-67, 12-68, 12-69, 12-70, 12-71, 12-72, 12-73, 12-74, 12-75, 12-76, 12-77, 12-78, 12-79, 12-80, 12-81, 12-82, 12-83, 12-84, 12 In some embodiments, the subject is suffering from a disease or disorder associated with aldehyde dehydrogenase, preferably a disease or disorder associated with aldehyde dehydrogenase isoform 1a3 (ALDH1a3) and / or 1a2 (ALDH1a2), in a subject in need thereof. For example, in some embodiments, the subject is suffering from a proliferative disease (e.g., as described herein) such as cancer. In some embodiments, the subject is suffering from a metabolic disease such as type 2 diabetes. In some embodiments, the subject is suffering from an endothelial cell or smooth muscle cell disease or disorder such as pulmonary arterial hypertension or neointimal hyperplasia.

[0270] In some embodiments, the present disclosure also provides methods of treating a disease or disorder associated with aldehyde dehydrogenase, preferably a disease or disorder associated with aldehyde dehydrogenase isoform 1a3 (ALDH1a3) and / or 1a2 (ALDH1a2), 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., any of the compounds of Formula I (e.g., Formula 10-18, 11-19, 12-20, 13-21, 14-22, 14-23, 15-24, 16-25, 17-26, 18-27, 19-30, 20-31, 21-32, 22-33, 23-34, 24-35, 25-26, 26-36, 27-37, 28-38, 29-40, 30-31, 31-32, 32-33, 33-34, 34-35, 35-36, 37-38, 38-41, 39-42, 40-43, 41-44, 42-45, 43-46, 44-47, 44-48, 45-49, 46-47, 48-49, 49-50, 51-52, 53-54, 55-56, 57-58, 58-59, 59-60, 60-61, 61-62, 62-63, 63-64, 64-65, 65-66, 66-67, 67-68, 68-70, 69-71, 72-72, 73-74, 74-75, 75-76, 76-77, 77-78, 78-79, 79-80, 80-81, 82-83, 83-84, 84 In some embodiments, the disease or disorder is associated with aldehyde dehydrogenase isoform 1a2 (ALDH1a2) in the subject. In some embodiments, the disease or disorder is associated with aldehyde dehydrogenase isoforms 1a3 (ALDH1a3) and 1a2 (ALDH1a2) in the subject. For example, in some embodiments, the disease or disorder is a proliferative disease (e.g., as described herein) associated with aldehyde dehydrogenase isoforms 1a3 (ALDH1a3) and / or 1a2 (ALDH1a2). In some embodiments, the disease or disorder is a metabolic disease, such as type 2 diabetes, associated with aldehyde dehydrogenase isoforms 1a3 (ALDH1a3) and / or 1a2 (ALDH1a2). In some embodiments, the disease or disorder is an endothelial or smooth muscle cell disease or disorder associated with aldehyde dehydrogenase isoforms 1a3 (ALDH1a3) and / or 1a2 (ALDH1a2), such as pulmonary arterial hypertension or neointimal hyperplasia.In embodiments, the disease or disorder is an immunologically driven disease or disorder associated with aldehyde dehydrogenase isoform 1a3 (ALDH1a3) and / or ALDH1a2, such as acute graft-versus-host disease or osteoarthritis pain.

[0271] In some embodiments, the present disclosure provides methods 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., Formula 10-18, 11-19, 12-20, 13-21, 14-22, 14-23, 14-24, 14-25, 14-26, 14-27, 14-28, 14-29, 15-30, 15-31, 15-32, 15-33, 15-34, 15-35, 15-36, 15-37, 15-40, 15-41, 15-42, 15-43, 15-44, 15-45, 15-46, 15-47, 15-48, 15-50, 15-51, 15-52, 15-53, 15-54, 15-55, 15-55, 15-56, 15-57, 15-58, 15-59, 15-60, 15-61, 15-62, 15-63, 15-64, 15-65, 15-70, 15-71, 15-72, 15-73, 15-74, 15-75, 15-76, 15-77, 15-78, 15-79, 15-80, 15-81, 15-82, 15-83, 15-84, 15-85, 15-86, 15-87, 15-88, 15-89, 15-90,

[0272] 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. Also, as shown in Figure 7, many cancer types have been shown to express ALDH1a2 and ALDH1a3 enzymes, the activity of which 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 metastatic or chemotherapy-resistant cancer. In some embodiments, the cancer is resistant to one or more immunotherapies, such as immune checkpoint inhibitors, such as anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA4 antibodies, IL-2, autologous T-cell therapy, bispecific antibody therapy, anti-TGFβ antibodies, JAK / STAT inhibitors, or any combination thereof.

[0273] In some embodiments, the cancer is breast cancer, colorectal cancer, kidney cancer, ovarian cancer, gastric cancer, thyroid cancer, urothelial 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, blood cancer, sarcoma, gastrointestinal stromal tumor, peripheral nerve sheath tumor, myeloma, and / or endometrial cancer.

[0274] In some embodiments, the cancer is 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 gastrointestinal stromal tumor, peripheral nerve sheath tumor, myeloma, leukemia, lymphoma, and / or endometrial cancer. In some embodiments, The cancer may also be any of the cancers shown in Figure 7 herein, such as bladder, brain, breast, cervix, bile duct, esophagus, gallbladder, stomach, head and neck, liver, lung, melanoma, ovarian, pancreatic, prostate, kidney, sarcoma, sarcoma-GIST, and / or uterine cancer. In some embodiments, the cancer may also be any described as treatable with an ALDH1a3 inhibitor in PCT / US2019 / 044278, international filing date July 31, 2019, the contents of which are incorporated by reference in its entirety.

[0275] 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 include 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 has cancer cells with ALDH1a3 and / or ALDH1a2 activity associated with ALDH1a3 and / or ALDH1a2 activity, e.g., having elevated expression levels compared to a control, and / or positive ALDH1a3 and / or ALDH1a2 activity, e.g., in an Aldefluor™ assay, which can be reduced with an ALDH1a3 and / or ALDH1a2 inhibitor or gene knockout or knockdown, if applicable. In some embodiments, the methods further include 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), a receptor tyrosine kinase inhibitor, or a therapeutic antibody. In some embodiments, the methods further include administering to the subject an effective amount of an immunotherapy, such as an immune checkpoint inhibitor. Suitable immunotherapies for the methods described herein may include, but are not limited to, any of those known in the art, such as an anti-PD-1 antibody (e.g., nivolumab, pembrolizumab, lambrolizumab, pidilizumab, BMS-936559, or AMP-224), an anti-PD-L1 antibody (e.g., atezolizumab, durvalumab, avelumab, YW243.55.S70, MEDI-4736, MSB-0010718C, LY3300054, BMS-936559, MPDL3280A, or MDX-1105), IL-2, autologous T-cell therapy, bispecific antibody therapy, an anti-TGFβ antibody, a JAK / STAT inhibitor, or any combination thereof.

[0276] In some embodiments, the present disclosure provides a method for treating metastatic cancer in a subject in need thereof. the method comprises administering to a subject a therapeutically effective amount of a compound of the present disclosure (e.g., any of the compounds of Formula I (e.g., Formula 10-18, 11-19, 12-20, 12-21, 12-22, 12-23, 12-24, 12-25, 12-26, 12-27, 12-28, 12-29, 12-30, 12-31, 12-32, 12-33, 12-34, 12-35, 12-36, 12-37, 12-38, 12-39, 12-40, 12-41, 12-42, 12-43, 12-44, 12-45, 12-46, 12-47, 12-48, 12-49, 12-50, 12-51, 12-52, 12-53, 12-54, 12-55, 12-56, 12-57, 12-58, 12-59, 12-60, 12-61, 12-62, 12-63, 12-64, 12-65, 12-66, 12-67, 12-68, 12-69, 12-70, 12-71, 12-72, 12-73, 12-74, 12-75, 12-75, 12-76, 12-77, 12-78, 12-79, 12-80, 12-81, 12-82, 12-83, 1 In some embodiments, the metastatic cancer can 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 may be selected from gastrointestinal stromal tumor, peripheral nerve sheath tumor, myeloma, and / or endometrial cancer. In some embodiments, the metastatic cancer may be selected from bladder, brain, breast, cervix, bile duct, esophagus, gallbladder, stomach, head and neck, liver, lung, melanoma, ovarian, pancreas, prostate, kidney, sarcoma, sarcoma-GIST, and / or uterine cancer. In some embodiments, the metastatic cancer is associated with ALDH1a3 and / or ALDH1a2 activity. In some embodiments, the metastatic cancer may be breast cancer with established lung metastases, colorectal metastases, and / or bone metastases.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., as described herein, such as paclitaxel), a receptor tyrosine kinase inhibitor, or a therapeutic antibody.

[0277] In some embodiments, the 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 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), a compound of Formula IP, The present invention relates to a method for treating cancers, the method comprising administering to a subject a compound of 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), Formula IV (e.g., IV-A, IV-B, IV-C, or IV-D), or Compound Nos. 139-202 or 139-165, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition described herein. 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 also be gastrointestinal stromal tumor, peripheral nerve sheath tumor, myeloma, and / or endometrial cancer. In some embodiments, the cancer may also be bladder, brain, breast, The cancer may be cervical, bile duct, esophageal, gallbladder, stomach, head and neck, liver, lung, melanoma, ovarian, pancreatic, prostate, kidney, sarcoma, sarcoma-GIST, and / or uterine cancer. 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 and / or ALDH1a2 activity. In some embodiments, the method further includes administering to the subject an effective amount of a second anti-cancer therapy, such as a chemotherapeutic agent (e.g., as described herein, such as paclitaxel), a receptor tyrosine kinase inhibitor, or a therapeutic antibody.

[0278] In some embodiments, the disclosure provides a method of sensitizing cancer to chemotherapy in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the disclosure (e.g., a compound of Formula I (e.g., Formula 10, 11, 12, 11-A, 11-A, 11-A, 11-A, 11-A, 11-A, 11-B, 11-B, 11-C, or 11-C), Formula I-P, 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), Formula IV (e.g., IV-A, IV-B, IV-C, or IV-D), or Compound Nos. 139-202 or 139-165, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition described herein. Typically, this method may make the cancer more responsive to treatment with a chemotherapeutic agent. 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 may also be gastrointestinal stromal tumor, peripheral nerve sheath tumor, myeloma, and / or endometrial cancer. In some embodiments, the cancer may also be bladder, brain, breast, cervix, bile duct, esophagus, gallbladder, stomach, head and neck, liver, lung, melanoma, ovary, pancreas, prostate, kidney, sarcoma, sarcoma-GIST, and / or uterine cancer. In some embodiments, the cancer is associated with ALDH1a3 and / or ALDH1a2 activity. 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., as described herein, such as paclitaxel), a receptor tyrosine kinase inhibitor, or a therapeutic antibody.

[0279] In some embodiments, the present disclosure provides methods of treating and preventing cancer metastasis in a subject in need thereof, the methods 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 10-18, 11-19, 12-20, 13-21, 14-22, 14-23, 14-24, 14-25, 14-26, 14-27, 14-28, 14-29, 15-30, 15-31, 15-32, 15-33, 15-34, 15-35, 15-36, 15-37, 15-38, 15-40, 15-41, 15-42, 15-43, 15-44, 15-45, 15-46, 15-47, 15-48, 15-50, 15-51, 15-52, 15-53, 15-54, 15-55, 15-55, 15-56, 15-57, 15-58, 15-59, 15-60, 15-61, 15-62, 15-63, 15-64, 15-65, 15-70, 15-71, 15-72, 15-73, 15-74, 15-75, 15-75, 15-76, 15-77, 15-78, 15-79, 15-80, 15-81, 15-82, 15-83, 15-84, 15-85, 15 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 may also be gastrointestinal stromal tumor, peripheral nerve sheath tumor, myeloma, and / or endometrial cancer. In some embodiments, the cancer may also be bladder, brain, breast, cervix, bile duct, esophagus, gallbladder, stomach, head and neck, liver, lung, melanoma, ovarian, pancreatic, prostate, kidney, sarcoma, sarcoma-GIST, and / or uterine ... In some embodiments, the cancer is associated with ALDH1a3 and / or ALDH1a2 activity. In some embodiments, the cancer has already metastasized. In some embodiments, the cancer has not metastasized prior to 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, e.g., a chemotherapeutic agent (e.g., as described herein, such as paclitaxel), a receptor tyrosine kinase inhibitor, or a therapeutic antibody.

[0280] In some embodiments, the cancer is refractory to one or more immunotherapies, e.g., anti-PD-1, anti-CTLA4, anti-LAG-3, anti-TIGIT, or anti-PD-L1 antibodies. In some embodiments, the subject has developed resistance to one or more immunotherapies, e.g., anti-PD-1 antibodies or anti-PD-L1 antibodies. In some embodiments, the method further comprises administering to the subject one or more immunotherapies (e.g., as described herein).

[0281] In some embodiments, the present disclosure provides methods of antagonizing the retinoid pathway in a subject in need thereof. In some embodiments, the methods include administering to the subject an effective amount of an ALDH1a2 inhibitor. In some embodiments, the methods include administering to the subject an effective amount of an ALDH1a3 inhibitor. In embodiments, the methods of antagonizing the retinoid pathway include administering to the subject effective amounts of an ALDH1a2 inhibitor and an ALDH1a3 inhibitor, e.g., an effective amount of a dual inhibitor of ALDH1a2 and ALDH1a3, or a combination of one or more ALDH1a2 inhibitors and one or more ALDH1a3 inhibitors. In some embodiments, the method includes administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula 10-18, 11-19, 12-20, 13-21, 14-22, 14-23, 14-24, 14-25, 14-26, 14-27, 14-28, 14-29, 15-30, 15-31, 15-32, 15-33, 15-34, 15-35, 15-36, 15-37, 15-40, 15-41, 15-42, 15-43, 15-44, 15-45, 15-46, 15-47, 15-48, 15-50, 15-51, 15-52, 15-53, 15-54, 15-55, 15-55, 15-56, 15-57, 15-58, 15-59, 15-60, 15-61, 15-62, 15-63, 15-64, 15-65, 15-70, 15-71, 15-72, 15-73, 15-74, 15-75, 15-75, 15-80, 15-81, 15-82, 15-83, 15-84, 15-85, 15-86, 15-87, 15-88, 15-89, 15-90, 15-91, 15-92, 15-93, 1 In some embodiments, the subject is suffering from a disease or disorder associated with retinoid pathway activation (eg, any of those described herein).

[0282] In some embodiments, the present disclosure provides T regIn some embodiments, the method comprises administering to the subject an effective amount of an ALDH1a2 inhibitor. In some embodiments, the method comprises administering to the subject an effective amount of an ALDH1a3 inhibitor. In some embodiments, the method comprises administering to the subject an effective amount of an ALDH1a4 inhibitor. In some embodiments, the method comprises administering to the subject an effective amount of an ALDH1a5 inhibitor. reg A method for inhibiting cell and / or M2 macrophage formation includes administering to a subject an effective amount of an ALDH1a2 inhibitor and an ALDH1a3 inhibitor, for example, an effective amount of a dual inhibitor of ALDH1a2 and ALDH1a3, or a combination of one or more ALDH1a2 inhibitors and one or more ALDH1a3 inhibitors. In some embodiments, the method includes administering to the subject an effective amount of a compound of the disclosure (e.g., a compound of Formula I (e.g., Formula 10-18, 11-19, 12-20, 12-21, 12-22, 12-23, 12-24, 12-25, 12-26, 12-27, 12-28, 12-29, 12-30, 12-31, 12-32, 12-33, 12-34, 12-35, 12-36, 12-37, 12-38, 12-39, 12-40, 12-41, 12-42, 12-43, 12-44, 12-45, 12-46, 12-47, 12-48, 12-49, 12-50, 12-51, 12-52, 12-53, 12-54, 12-55, 12-56, 12-57, 12-58, 12-59, 12-60, 12-61, 12-62, 12-63, 12-64, 12-65, 12-66, 12-67, 12-68, 12-69, 12-70, 12-71, 12-72, 12-73, 12-74, 12-75, 12-75, 12-76, 12-77, 12-78, 12-79, 12-80, 12-81, 12-82, 12-83, 12 or the subject has developed resistance to one or more immunotherapies (e.g., as described herein). In some embodiments, the cancer is 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, sarcoma, gastrointestinal stromal tumor, peripheral nerve sheath tumor, myeloma, and / or endometrial cancer. In some embodiments, the cancer may also be bladder, brain, breast, cervix, bile duct, esophagus, gallbladder, stomach, head and neck, liver, lung, melanoma, ovarian, pancreatic, prostate, kidney, sarcoma, sarcoma-GIST, and / or uterine cancer. In some embodiments, the cancer is refractory to one or more immunotherapies, such as an anti-PD-1 antibody, an anti-PDL-1 antibody, an anti-CTLA4 antibody, IL-2, autologous T-cell therapy, bispecific antibody therapy, an anti-TGFβ antibody, a JAK / STAT inhibitor, or any combination thereof. In some embodiments, the subject has developed resistance to one or more immunotherapies, such as an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA4 antibody, IL-2, autologous T-cell therapy, bispecific antibody therapy, an anti-TGFβ antibody, a JAK / STAT inhibitor, or any combination thereof. In some embodiments, the method further comprises administering to the subject one or more immunotherapies, such as an immune checkpoint inhibitor. In some embodiments, the method further comprises administering to the subject an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA4 antibody, IL-2, autologous T-cell therapy, bispecific antibody therapy, an anti-TGFβ antibody, a JAK / STAT inhibitor, or any combination thereof.

[0283] In some embodiments, the present disclosure provides a method of treating a disease or disorder associated with retinoid pathway activation in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of an ALDH1a2 inhibitor. In some embodiments, the method comprises administering to the subject an effective amount of an ALDH1a3 inhibitor. In some embodiments, the method of treating a disease or disorder associated with retinoid pathway activation comprises administering to the subject effective amounts of an ALDH1a2 inhibitor and an ALDH1a3 inhibitor, for example, an effective amount of a dual inhibitor of ALDH1a2 and ALDH1a3, or a combination of one or more ALDH1a2 inhibitors and one or more ALDH1a3 inhibitors. In some embodiments, the method includes administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula 10-18, 11-19, 12-20, 13-21, 14-22, 14-23, 14-24, 14-25, 14-26, 14-27, 14-28, 14-29, 15-30, 15-31, 15-32, 15-33, 15-34, 15-35, 15-36, 15-37, 15-40, 15-41, 15-42, 15-43, 15-44, 15-45, 15-46, 15-47, 15-48, 15-50, 15-51, 15-52, 15-53, 15-54, 15-55, 15-55, 15-56, 15-57, 15-58, 15-59, 15-60, 15-61, 15-62, 15-63, 15-64, 15-65, 15-70, 15-71, 15-72, 15-73, 15-74, 15-75, 15-75, 15-80, 15-81, 15-82, 15-83, 15-84, 15-85, 15-86, 15-87, 15-88, 15-89, 15-90, 15-91, 15-92, 15-93, 1 In some embodiments, the disease or disorder is associated with immunosuppression or immune tolerance in the subject. In some embodiments, the disease or disorder is associated with T regIn some embodiments, the disease or disorder is associated with induction of M2 macrophages and / or suppression of effector T cells. In some embodiments, the disease or disorder is cancer (e.g., as described herein). In some embodiments, the cancer is 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, sarcoma, gastrointestinal stromal tumor, peripheral nerve sheath tumor, myeloma, and / or endometrial cancer. In some embodiments, the cancer may also be bladder, brain, breast, cervix, bile duct, esophagus, gallbladder, stomach, head and neck, liver, lung, melanoma, ovary, pancreas, prostate, kidney, sarcoma, sarcoma-GIST, and / or uterine cancer. In some embodiments, the cancer is refractory to one or more immunotherapies, such as anti-PD-1 antibodies, anti-PDL-1 antibodies, anti-CTLA4 antibodies, IL-2, autologous T cell therapy, bispecific antibody therapy, anti-TGFβ antibodies, JAK / STAT inhibitors, or any combination thereof. The elephant has developed resistance to one or more immunotherapies, such as an anti-PD-1 antibody, an anti-PDL-1 antibody, an anti-CTLA4 antibody, IL-2, autologous T-cell therapy, bispecific antibody therapy, an anti-TGFβ antibody, a JAK / STAT inhibitor, or any combination thereof. In some embodiments, the method further comprises administering to the subject one or more immunotherapies, such as an immune checkpoint inhibitor. In some embodiments, the method further comprises administering to the subject an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA4 antibody, IL-2, autologous T-cell therapy, bispecific antibody therapy, an anti-TGFβ antibody, a JAK / STAT inhibitor, or any combination thereof.

[0284] In some embodiments, the disclosure provides a method of treating cancer in a subject in need thereof, wherein the cancer is unresponsive to one or more immunotherapies or the subject has developed resistance to one or more immunotherapies, and the method comprises administering to a subject an effective amount of a compound of the 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), Formula IV (e.g., IV-A, IV-B, IV-C, or IV-D), or a compound of Compound Nos. 139-202 or 139-165, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition described herein. In some embodiments, the cancer is refractory to one or more immunotherapies, such as an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA4 antibody, IL-2, autologous T-cell therapy, bispecific antibody therapy, an anti-TGFβ antibody, a JAK / STAT inhibitor, or any combination thereof. In some embodiments, the cancer is refractory to treatment with an anti-PD-1 or anti-PD-L1 antibody. In some embodiments, the subject has developed resistance to one or more immunotherapies, such as an anti-PD-1 antibody, an anti-PDL-1 antibody, an anti-CTLA4 antibody, IL-2, autologous T-cell therapy, bispecific antibody therapy, an anti-TGFβ antibody, a JAK / STAT inhibitor, or any combination thereof. In some embodiments, the subject has developed resistance to an anti-PD-1 or anti-PD-L1 antibody-based therapy. In some embodiments, the method further comprises administering to the subject one or more immunotherapies, such as an immune checkpoint inhibitor. In some embodiments, the method further comprises administering to the subject an anti-PD-1 antibody, an anti-PDL-1 antibody, an anti-CTLA4 antibody, IL-2, autologous T-cell therapy, bispecific antibody therapy, an anti-TGFβ antibody, a JAK / STAT inhibitor, or any combination thereof.In some embodiments, the cancer is 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, sarcoma, gastrointestinal stromal tumor, peripheral nerve sheath tumor, myeloma, and / or endometrial cancer. In some embodiments, the cancer may also be bladder, brain, breast, cervix, bile duct, esophagus, gallbladder, stomach, head and neck, liver, lung, melanoma, ovarian, pancreatic, prostate, kidney, sarcoma, sarcoma-GIST, and / or uterine cancer.

[0285] In some embodiments, the disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering an effective amount of a compound of the 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., Formulas II-1, II-2, II-3, , or II-4), Formula II-P, Formula III (e.g., Formula III-1 or III-2), Formula IV (e.g., IV-A, IV-B, IV-C, or IV-D), or any of the compounds of Compound Nos. 139-202 or 139-165, or a pharmaceutically acceptable salt thereof), or an effective amount of a pharmaceutical composition described herein, in combination with an immunotherapy, such as an immune checkpoint inhibitor, to a subject. In some embodiments, the immunotherapy further comprises administering to the subject an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA4 antibody, IL-2, autologous T-cell therapy, bispecific antibody therapy, an anti-TGFβ antibody, a JAK / STAT inhibitor, or any combination thereof. In some embodiments, the cancer is 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, sarcoma, gastrointestinal stromal tumor, peripheral nerve sheath tumor, myeloma, and / or endometrial cancer. In some embodiments, the cancer may also be bladder, brain, breast, cervix, bile duct, esophagus, gallbladder, stomach, head and neck, liver, lung, melanoma, ovarian, pancreatic, prostate, kidney, sarcoma, sarcoma-GIST, and / or uterine cancer.

[0286] In some embodiments, the 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 to a subject a therapeutically 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), a compound of Formula IP, The method includes administering to a subject a therapeutically effective amount of a compound of 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), Formula IV (e.g., IV-A, IV-B, IV-C, or IV-D), or any of Compound Nos. 139-202 or 139-165, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. For example, in some embodiments, the method includes administering to a subject a therapeutically effective amount of a 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. As discussed herein, metabolic diseases such as type 2 diabetes are associated with pathology driven 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 a compound of the present disclosure to treat type 2 diabetes (e.g., as described herein) or to treat or prevent other metabolic syndromes.

[0287] In some embodiments, the 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 to a subject a therapeutically effective amount of a compound of the 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-D). The present invention relates to a method for treating endothelial cell disease or smooth muscle cell disease, and the method comprises administering to a subject a compound of Formula I, 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), Formula IV (e.g., IV-A, IV-B, IV-C, or IV-D), or any of the compounds of Compound Nos. 139-202 or 139-165, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments, the endothelial cell or smooth muscle cell disease or disorder is associated with a pathology driven 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.

[0288] It also inhibits the proliferation of cancer cells (e.g., metastatic cancer cells, chemotherapy-resistant cancer cells). Also provided herein are methods for treating cancer. 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).

[0289] In some embodiments, the disclosure provides a method of male contraception, the method comprising administering to a subject in need thereof an effective amount of a compound of the disclosure (e.g., a compound of Formula I (e.g., Formula 10-18, 11-19, 12-20, 13-21, 14-22, 14-23, 14-24, 14-25, 14-26, 14-27, 14-28, 14-29, 15-30, 15-31, 15-32, 15-33, 15-34, 15-35, 15-36, 15-37, 15-40, 15-41, 15-42, 15-43, 15-44, 15-45, 15-46, 15-47, 15-48, 15-50, 15-51, 15-52, 15-53, 15-54, 15-55, 15-55, 15-56, 15-57, 15-58, 15-59, 15-60, 15-61, 15-62, 15-63, 15-64, 15-65, 15-70, 15-71, 15-72, 15-73, 15-74, 15-75, 15-76, 15-77, 15-78, 15-80, 15-81, 15-82, 15-83, 15-84, 15-85, 15-86, 15-87, 15-88, 15-89, 15

[0290] In any of the embodiments described herein, unless specified or otherwise contradicted by context, the compounds of the present disclosure listed in the methods herein are compounds having an activity level of A or B as shown in Table 3A of the present disclosure against hALDH1a3, and / or an IC of less than 1 uM against hALDH1a2, as shown in Table 3B of the present disclosure. 50In some embodiments, the compounds of the present disclosure listed in the methods herein may also be any compounds of the present disclosure having an efficacy in inhibiting ALDH1a3 comparable to compound 1 or more, as measured, for example, by any of the methods described herein. In some embodiments, the compounds of the present disclosure listed in the methods herein may also be any compounds 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. In some embodiments, the compounds of the present disclosure listed in the methods herein may 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 hALDH1a2, as measured by the methods described herein according to Biological Example 5C. In some embodiments, a compound of the disclosure listed in the methods herein, e.g., for inhibiting the retinoid pathway or treating a disease or disorder associated with the retinoid pathway, such as various cancers discussed herein, for treating a disease or disorder associated with immune tolerance, or for male contraception, can be any compound of the disclosure having an IC50 value of less than 250 nM (preferably less than 100 nM, such as about 1-100 nM, about 10-100 nM, about 10-50 nM, about 20-100 nM, or about 20-50 nM) in inhibiting both hALDH1a3 and hALDH1a2, as measured by the methods described herein according to Biological Examples 5B and 5C.

[0291] The administration in the methods herein 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, administration is oral.

[0292] As discussed herein, the compounds of the present disclosure can be used as monotherapy or in combination therapy. In some embodiments according to the methods described herein, the compounds of the present disclosure can be used in combination with other compounds. The combination can be administered as the sole active ingredient. 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, 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 (AIs, e.g., anastrozole, exemestane, letrozole), estrogen receptor modulators (e.g., tamoxifen, raloxifene, toremifene), or biologic therapy, in any order, either simultaneously or sequentially. In some embodiments according to the methods described herein, compounds of the present disclosure can be used in combination with conventional therapy, SGLT inhibitors, cell therapy, therapeutic antibodies, or incretin analogs.

[0293] 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 an additional pharmaceutically active compound, 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 chemotherapy, immunotherapy, cell therapy, or therapeutic antibody can 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, dactinoside, etc.), and the like. antimitotics (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids such as taxol, taxotere, 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, a biguanide, a 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.

[0294] The administration regimens, including dosages, for the methods described herein can be varied and adjusted depending on the recipient being treated, 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 efficacy of the compound, its clearance, and other factors. The efficacy of the drug may depend on the rate of progression, the efficacy of the drug, and whether another drug is administered concomitantly.

[0295] definition It is to be understood that proper atomic valences are maintained for all moieties and combinations thereof.

[0296] 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.

[0297] 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 n in R of Formula I, where applicable. 1 , R 2 , R 3 , R 4 , R 5 , J 1 , J 2 , J 3 It is contemplated that any one or more of the other definitions of Z, X, and n may be combined, and compounds resulting from the combination are within the scope of the present disclosure. Other combinations of variables for other formulas should be understood similarly.

[0298] Definitions of specific functional groups and chemical terms are explained 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 explained 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 described herein.

[0299] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as 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. 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 Agents and Optical Resolutions. p.268(ELEliel,Ed.,Univ.of Notre Dame Press,Notre D ame, 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.

[0300] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 ” is 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.

[0301] As used herein, the term "compound of the disclosure" refers to a compound of the present disclosure 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), Formula IV (e.g., IV-A, IV-B, IV-C, or IV-D), or any of Compound Nos. 139-202 or 139-165, its isotopically labeled compounds (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, wherein the compound is associated with water or a solvent, respectively.

[0302] The compounds of the present disclosure can be present in isotopically labeled or isotopically enriched forms, 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, and125 Compounds containing other isotopes of these and / or other atoms are within the scope of this invention, including, but not limited to, I.

[0303] As used herein, the phrases "administration" of a compound, "administering" a compound, or other variations thereof, mean providing a compound or a prodrug of a compound to an individual in need of treatment.

[0304] 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 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 described herein. 1~4 Refers to an alkyl group.

[0305] "Alkylene" or "alkylene chain" refers to a fully saturated, straight-chain, or branched divalent hydrocarbon chain radical. In embodiments, alkylene has 1 to 12 carbon atoms. Non-limiting examples of C1-C12 alkylenes include methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise in the specification, an alkylene chain can be optionally substituted.

[0306] 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 2~4 Alkenyl groups. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0307] As used herein, the term "alkynyl" by itself or as part of another group 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 has one carbon-carbon triple bond. In one embodiment, an alkynyl group is C 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.

[0308] As used herein, the term "alkoxy" by itself or as part of another group refers to a group of the formula OR a1where R a1 is alkyl.

[0309] 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.

[0310] 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 embodiments, a haloalkyl is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, a haloalkyl group is a C 1~10 In one embodiment, the haloalkyl group is C 1~6 In one embodiment, the haloalkyl group is C 1~4 It is a haloalkyl group.

[0311] 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 1 or more carbon atoms ("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.

[0312] 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, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 cycloalkyl").

[0313] Used by itself or as part of another group, "heterocyclyl" or "heterocyclic" or "heterocycle" 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 (a "3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. Heterocyclyl groups may be monocyclic (a "monocyclic heterocyclyl") or may contain fused, bridged, or spiro ring systems, such as bicyclic systems (a "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 includes ring systems in which a heterocycle as defined above is fused to one or more carbocyclyl groups, and the point of attachment is on the heterocycle, or in which a heterocycle as defined above is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the heterocycle, in which case the number of ring members continues to indicate the number of ring members of the heterocycle system.

[0314] 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.

[0315] "Aryl," when used by itself or as part of another group, refers to the radical of 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) 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" includes, for example, anthracyl. "Aryl" also includes ring systems in which an aryl ring, as defined above, 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.

[0316] "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 can be optionally substituted.

[0317] 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 may be at a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may 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 refer to 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 to 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 indicates 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.) may have the point of attachment on either ring, i.e., the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0318] 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, Examples of 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, triazinyl and tetrazinyl. 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, isobenzothiophenyl, benzofuranyl, benzisofuranyl, 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.

[0319] Used by itself or as part of another group, "heteroaralkyl" 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.

[0320] "Optionally substituted" groups, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl groups, refer to the respective groups, whether unsubstituted or substituted. In general, 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, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group; when multiple positions in any given structure are substituted, the substituents 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. Substituents may be carbon atom, nitrogen atom, oxygen atom, or sulfur atom substituents, where applicable. Any two of the substituents can be linked to form an optionally substituted cycloalkyl, heterosilyl, aryl, or heteroaryl ring. Substitutions can occur on any available carbon, oxygen, or nitrogen atom to form a spirocyclic ring. Typically, substitutions herein do not result in OO, ON, SS, SN (excluding SO-N bonds), heteroatom halogens, or —C(O)—S bonds or three or more consecutive heteroatoms, excluding O—SO—O, O—SO—N, and N—SO—N, although some such bonds or connections may be tolerated in the case of stable aromatic systems.

[0321] 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 may be one or more of the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. Substituents can include any substituent described herein, e.g., halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., 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, as appropriate. can be used to replace each of them.

[0322] Exemplary substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-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, -NO2, -CN, -SF5, -C(O)OH, -C(O)O-alkyl, -C(O)O-aryl, -C(O)O-alkylene-aryl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)-aryl, -S(O)2-aryl, -S(O)-heteroaryl, -S(O)2- and -S(O)N(Y)(Y), where Y and Y may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and alkylene-aryl.

[0323] 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, halogens (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 group, -NHC(O)NH2, -NHC(O)NH(C1-C8) alkyl group, -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-C 8) 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), -(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-C, 6) An alkyl group, a -C(=NH)-(C1-C6) alkyl group, a -C(=NOH)-(C1-C6) alkyl group, or a -C(=NO-(C1-C6) alkyl)-(C1-C6) alkyl group.

[0324] 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, —SOH, —SOH, —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 1~6alkyl), -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, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 Examples include aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal substituents may be linked to form =O.

[0325] 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 Examples include aryl and 5- to 14-membered heteroaryl, or two substituents attached to the nitrogen atom join to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can 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 a carbobenzyloxy (Cbz) group, a p-methoxybenzylcarbonyl (Moz or MeOZ) group, a tert-butyloxycarbonyl (BOC) group, a Troc group, a 9-fluorenylmethyloxycarbonyl (Fmoc) group, those that form amides such as acetyl and benzoyl, those that form benzylamines such as benzyl, p-methoxybenzyl and 3,4-dimethoxybenzyl, those that form sulfonamides such as tosyl and nosyl, and others such as p-methoxyphenyl.

[0326] 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 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, and those which form carbonates or sulfonates such as methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0327] 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).

[0328] 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 2~4 Alkenyl, C 2~4Alkynyl, 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 selected from the group consisting of 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 3~6 1, 2, 3, or 4 independently selected from cycloalkoxy, phenyl, 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, and 3- to 7-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N. and substituted with substituents, wherein each of the aforementioned alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl is selected from the group consisting of F, —OH, oxo (where 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.

[0329] "Halo" or "halogen" means fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0330] 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.

[0331] 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 tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction providing a tautomeric pair) may be catalyzed by acid or base. Exemplary tautomerizations include those between keto and enol, amide and imide, lactam and lactim, enamine and imine, and enamine and (different enamine) tautomerization.

[0332] 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.

[0333] 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 had a disease or condition recurrence, but is at risk or susceptible to the disease or condition. The term "treat" and cognates contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment. [Example]

[0334] The various starting materials, intermediates, and compounds of the 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.

[0335] 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 2]

[0336] Example 1. Synthesis of Compound 142 [ka] Step 1: To a mixture of 8-chloro-3,4-dihydro-1H-quinolin-2-one (0.2 g, 1.10 mmol, 1 equiv.) in H2SO4 (2 mL) was added KNO3 (133.60 mg, 1.32 mmol, 1.2 equiv.) portionwise at 0 °C. The mixture was then stirred at 0 °C for 1 h. The mixture was slowly added to ice (20 mL). The mixture was then filtered. The filter cake was washed with water (5 mL). 8-chloro-6-nitro-3,4-dihydro-1H-quinolin-2-one (0.2 g, 882.55 umol, 80.14% yield) was obtained as a yellow solid.

[0337] Step 2: To a mixture of 8-chloro-6-nitro-3,4-dihydro-1H-quinolin-2-one (0.2 g, 882.55 μmol, 1 equiv.) in AcOH (1 mL) and EtOH (1 mL), Fe (246.43 mg, 4.41 mmol, 5 equiv.) was added. The mixture was stirred at 40° C. for 1 hour. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=1:1). Compound 6-amino-8-chloro-3,4-dihydro-1H-quinolin-2-one (55 mg, 279.71 μmol, 31.69% yield) was obtained as a white solid.

[0338] Step 3: To a mixture of 6-amino-8-chloro-3,4-dihydro-1H-quinolin-2-one (55 mg, 279.71 umol, 1 equiv.) and 3-ethylpyridine-4-carboxylic acid (50.74 mg, 335.65 umol, 1.2 equiv.) in pyridine (1 mL) was added EDCI (64.34 mg, 335.65 umol, 1.2 equiv.). The mixture was stirred at 45° C. for 2 hours. The crude product was concentrated under reduced pressure to give a residue. The residue was purified by HPLC. Purification by preparative TLC (SiO, petroleum ether:ethyl acetate 0:1) gave the compound N-(8-chloro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-ethyl-pyridine-4-carboxamide (30 mg, 90.06 μmol, yield 32.20%, purity 99%). 1H NMR(400MHz,MeOD):δ 8.56(s,1H),8.51(d,J=5.2Hz,1H),7.74(s,1H),7.45-7.47(m,2H),2.99-3 .04(m,2H),2.82(q,J=7.6Hz,2H),2.60-2.64(m,2H),1.27(t,J=7.6Hz,3H). LCMS:(M+H + )330.0.

[0339] Example 2. Synthesis of Compound 143 [ka] Step 1: To a mixture of 2,3-difluoroaniline (5 g, 38.73 mmol, 3.94 mL, 1 equiv.) and TEA (3.92 g, 38.73 mmol, 5.39 mL, 1 equiv.) in DCM (80 mL) was added 3-chloropropanoyl chloride (4.67 g, 36.79 mmol, 3.54 mL, 0.95 equiv.) dropwise at 0 °C. The mixture was then stirred at 25 °C for 1 h. To the mixture was added HO (50 mL). The mixture was then extracted with ethyl acetate (50 mL * 3). The combined organic phase was washed with brine (50 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. 3-chloro-N-(2,3-difluorophenyl)propanamide (7 g, 31.87 mmol, 82.30% yield) was obtained as a pale yellow solid.

[0340] Step 2: A mixture of 3-chloro-N-(2,3-difluorophenyl)propanamide (7 g, 31.87 mmol, 1 equiv.) in AlCl (12.75 g, 95.62 mmol, 5.23 mL, 3 equiv.) was stirred at 130 °C for 5 h. The mixture was added to ice water (100 mL). The mixture was then extracted with ethyl acetate (50 mL * 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). The crude product was then purified by preparative HPLC (column: Welch Xtimate C18 100 * 25 mm * 3 um, mobile phase: [water (0.05% HCl)-ACN]; B%: 30% to 50%, 8 min). 7,8-Difluoro-3,4-dihydro-1H-quinolin-2-one (0.22 g, 12 mmol) was obtained as a yellow solid.

[0341] Step 3: To a mixture of 7,8-difluoro-3,4-dihydro-1H-quinolin-2-one (0.22 g, 1.20 mmol, 1 equiv.) in H2SO4 (2 mL) was added KNO3 (145.73 mg, 1.44 mmol, 1.2 equiv.) portionwise at 0 °C. The mixture was then stirred at 0 °C for 1 h. The mixture was slowly poured into ice (10 mL). The mixture was then filtered. The filter cake was washed with water (10 mL). 7,8-difluoro-6-nitro-3,4-dihydro-1H-quinolin-2-one (0.28 g, crude ) was obtained as a pale yellow solid.

[0342] Step 4: To a solution of 7,8-difluoro-6-nitro-3,4-dihydro-1H-quinolin-2-one (0.28 g, 1.23 mmol, 1 equiv.) in MeOH (10 mL) was added Pd / C (0.05 g, 10%) 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 3 h. The reaction mixture was filtered, and the filtrate was concentrated. 6-amino-7,8-difluoro-3,4-dihydro-1H-quinolin-2-one (160 mg, 807.39 μmol, 65.79% yield) was obtained as a purple solid.

[0343] Step 5: A mixture of 6-amino-7,8-difluoro-3,4-dihydro-1H-quinolin-2-one (80 mg, 403.70 μmol, 1 equiv.) and 3-ethylpyridine-4-carboxylic acid (73.23 mg, 484.44 μmol, 1.2 equiv.), EDCI (92.87 mg, 484.44 μmol, 1.2 equiv.) in pyridine (1 mL) was stirred at 45° C. for 1 hour. The reaction mixture was concentrated. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=0:1). N-(7,8-difluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-ethyl-pyridine-4-carboxamide (35 mg, 105.64 μmol, 26.17% yield, 100% purity) was obtained. LCMS (M+H) + ):332.0; 1 H NMR(400MHz,MeOD):δ 8.58(s,1H),8.54(d,J=5.2Hz,1H),7.52(d,J=5.2Hz,1H),7.43(d,J=7.2Hz,1H),3 .02-3.06(m,2H),2.90(q,J=7.6Hz,2H),2.63-2.67(m,2H),1.31(t,J=7.6Hz,3H).

[0344] Example 3. Synthesis of Compound 144 [ka] Step 1: To a mixture of 8-ethyl-3,4-dihydro-1H-quinolin-2-one (0.18 g, 1.03 mmol, 1 equiv.) in H2SO4 (2 mL) was added KNO3 (124.63 mg, 1.23 mmol, 1.2 equiv.) at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was slowly poured into ice (20 mL). The mixture was filtered. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1). 8-Ethyl-6-nitro-3,4-dihydro-1H-quinolin-2-one (88 mg, crude) was obtained as a yellow solid.

[0345] Step 2: To a solution of 8-ethyl-6-nitro-3,4-dihydro-1H-quinolin-2-one (88 mg, 399.59 μmol, 1 equiv.) in THF (10 mL) was added 10% Pd / C (0.02 g) under N. The suspension was degassed under vacuum and purged several times with H. 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. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 0:1). The compound 6-amino-8-ethyl-3,4-dihydro-1H-quinolin-2-one (40 mg, 210.26 μmol, yield 52.62%) was obtained as a brown solid.

[0346] Step 3: A mixture of 6-amino-8-ethyl-3,4-dihydro-1H-quinolin-2-one (40 mg, 210.26 μmol, 1 equiv.), 3-ethylpyridine-4-carboxylic acid (38.14 mg, 252.31 μmol, 1.2 equiv.), and EDCI (48.37 mg, 252.31 μmol, 1.2 equiv.) in pyridine (1 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 45° C. for 2 hours. The reaction was concentrated in vacuo. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate=0:1). The compound 3-ethyl-N-(8-ethyl-2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyridine-4-carboxamide (15 mg, 46.38 μmol, yield 22.06%, purity 100%) was obtained. LCMS (M+H + ):324.1;1 H NMR(400MHz,MeOD):δ 8.55(s,1H),8.50(d,J=4.8Hz,1H),7.45(d,J=5.2Hz,1H),7.43(s,1H),7.37(s,1H),2.96-3.00(m,2H),2. 85(q,J=7.6Hz,2H),2.66(q,J=7.6Hz,2H),2.56-2.60(m,2H),1.27(t,J=7.6Hz,3H),1.23(t,J=7.6Hz,3H).

[0347] Example 4. Synthesis of Compound 146 [ka] Step 1: To a mixture of 3-fluoro-2-methyl-aniline (5 g, 39.95 mmol, 4.55 mL, 1 equiv.) and TEA (4.25 g, 41.95 mmol, 5.84 mL, 1.05 equiv.) in DCM (100 mL), 3-chloropropanoyl chloride (5.07 g, 39.95 mmol, 3.84 mL, 1 equiv.) was added dropwise at 0 °C under N. The mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched at 0 °C by the addition of 15 mL (5 ml * 3) of HO, and then extracted with 30 mL (10 mL * 3) of ethyl acetate. The combined organic layers were concentrated under reduced pressure to give a residue. Compound 3, chloro-N-(3-fluoro-2-methyl-phenyl)propanamide (7 g, crude) was obtained as a white solid.

[0348] Step 2: A mixture of 3-chloro-N-(3-fluoro-2-methyl-phenyl)propanamide (7 g, 32.46 mmol, 1 equiv.), AlCl (12.98 g, 97.38 mmol, 5.32 mL, 3 equiv.) was degassed and purged with N three times, then the mixture was stirred at 130 °C under N atmosphere for 5 h. The reaction mixture was added to 100 ml of ice water. The mixture was poured into 1 ml of ethyl acetate. The aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent of 0-15% ethyl acetate / petroleum ether gradient, 80 mL / min). 1.2 g of crude product was obtained. 0.48 g of crude product was purified by preparative HPLC (column: Phenomenex Gemini-NX80*40 mm*3 um, mobile phase: [water (0.04% HCl)-ACN], B%: 15%-35%, 8 min). The compound 7-fluoro-8-methyl-3,4-dihydro-1H-quinolin-2-one (110 mg, 613.87 umol, yield 1.89%) was obtained as a white solid. 7-Fluoro-8-methyl-3,4-dihydro-1H-quinolin-2-one (0.72 g, crude) was obtained as a white solid.

[0349] Step 3: To a mixture of 7-fluoro-8-methyl-3,4-dihydro-1H-quinolin-2-one (0.11 g, 613.87 umol, 1 equiv.) in H2SO4 (1 mL) was added KNO3 (68.27 mg, 675.26 umol, 1.1 equiv.) portionwise at 0 °C. The mixture was then stirred at 0 °C for 1 hour. The mixture was added to ice (10 mL). The mixture was then filtered. The filter cake was washed with water (2 mL) and concentrated in vacuo. 7-Fluoro-8-methyl-6-nitro-3,4-dihydro-1H-quinolin-2-one (98 mg, 437.13 umol, 71.21% yield) was obtained as a yellow solid.

[0350] Step 4: To a solution of 7-fluoro-8-methyl-6-nitro-3,4-dihydro-1H-quinolin-2-one (98 mg, 437.13 umol, 1 equiv.) in THF (5 mL), 10% Pd / C (0.02 g) was added 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 5 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The compound 6-amino-7-fluoro-8-methyl-3,4-dihydro-1H-quinolin-2-one (60 mg, 308.95 umol, 70.68% yield) was obtained as a white solid.

[0351] Step 5: To a solution of 6-amino-7-fluoro-8-methyl-3,4-dihydro-1H-quinolin-2-one (50 mg, 257.46 μmol, 1 equiv.) and 3-ethylpyridine-4-carboxylic acid (57.97 mg, 308.95 μmol, 1.2 equiv., HCl) in pyridine (5 mL), EDCI (59.23 mg, 308.95 μmol, 1.2 equiv.) was added. 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, petroleum ether:ethyl acetate=0:1). The compound 3-ethyl-N-(7-fluoro-8-methyl-2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyridine-4-carboxamide (20 mg, 59.81 μmol, yield 23.23%, purity 97.9%) was obtained. LCMS (M+H + ):328.1; 1 H NMR(400MHz,MeOD):δ 8.56(s,1H),8.51(d,J=5.2Hz,1H),7.48-7.50(m,2H),2.94-2.98(m,2H),2.87( q,J=7.6Hz,2H),2.57-2.61(m,2H),2.71(d,J=1.2Hz,3H),1.30(t,J=7.6Hz,3H).

[0352] Example 5. Synthesis of Compound 139 [ka] Step 1: To a mixture of 8-chloro-3,4-dihydro-1H-quinolin-2-one (0.4 g, 2.20 mmol, 1 equiv), potassium acetate (80.00 mg, 815.14 µmol, 0.37 equiv), KFe(CN)6.3HO (640.00 mg, 1.94 mmol, 533.33 µL, 8.83 e-1 equiv), tButBrettPhos (13.3 mg) in dioxane (2 mL) and HO (1.5 mL) was added tBuBrettPhos Pd G3 (188.18 mg, 220.24 µmol, 0.1 equiv) under N2. The mixture was heated at 100 °C for 4 h under N2. 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, petroleum ether: EtOAc = 1:1). The compound 2-oxo-3,4-dihydro-1H-quinoline-8-carbonitrile (240 mg, 1.39 mmol, yield 63.29%) was obtained as a white solid. LCMS: (M+H) + :173.1.

[0353] Step 2: To a solution of 2-oxo-3,4-dihydro-1H-quinoline-8-carbonitrile (240 mg, 1.39 mmol, 1 equiv) in concentrated HSO (2 mL) was added KNO (155.02 mg, 1.53 mmol, 1.1 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 a solution of petroleum ether and 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 6-nitro-2-oxo-3,4-dihydro-1H-quinoline-8-carbonitrile (220 mg, 1.01 mmol, 72.67% yield) was obtained as a white solid. LCMS: (M+H) + :218.1.

[0354] Step 3: To a solution of 6-nitro-2-oxo-3,4-dihydro-1H-quinoline-8-carbonitrile (220 mg, 1.01 mmol, 1 equiv.) in HO (3 mL) and EtOH (3 mL), Fe (282.87 mg, 5.06 mmol, 5 equiv.) and NH4Cl (270.92 mg, 5.06 mmol, 5 equiv.) were added. The mixture was stirred at 50 °C for 2 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 (SiO2, petroleum ether: EtOAc = 0:1). The crude product was 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 give a residue. The compound 6-amino-2-oxo-3,4-dihydro-1H-quinoline-8-carbonitrile (120 mg, 641.03 umol, yield 63.28%) was obtained as a white solid. LCMS: (M+H) + :188.1.

[0355] Step 4: To a mixture of 6-amino-2-oxo-3,4-dihydro-1H-quinoline-8-carbonitrile (120 mg, 641.03 μmol, 1 equiv) and 3-ethylpyridine-4-carboxylic acid (106.59 mg, 705.14 μmol, 1.1 equiv) in pyridine (2 mL) was added EDCI (122.89 mg, 641.03 μmol, 1 equiv) 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). The compound N-(8-cyano-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-ethyl-pyridine-4-carboxamide (75.6 mg, 227.74 umol, yield 35.53%, purity 96.5%) was obtained as a white solid. LCMS: (M+H) + :321.0. 1H NMR(400MHz,MeOD):δ 8.56(s,1H),8.51(d,J=4.8Hz,1H),7.92(s,1H),7.77(s,1H),7.48(d,J=5.2Hz,1H) ,3.02-3.06(m,2H),2.85(q,J=7.6Hz,2H),2.63-2.67(m,2H),1.27(t,J=7.6Hz,3H).

[0356] Example 6. Synthesis of Compound 140 [ka] Step 1: A suspension of 8-methyl-1H-quinolin-2-one (200 mg, 1.26 mmol, 1 equiv.) and 10% Pd / C (80 mg) in EtOH (10 mL) was degassed and purged with H three times. The mixture was stirred under H (15 psi) at 25 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product, 8-methyl-3,4-dihydro-1H-quinolin-2-one (180 mg, 1.12 mmol, 88.87% yield), was obtained as a white solid, which was used in the next step without further purification.

[0357] Step 2: To a solution of 8-methyl-3,4-dihydro-1H-quinolin-2-one (180 mg, 1.12 mmol, 1 equiv.) in concentrated HSO (3 mL) was added KNO (112.89 mg, 1.12 mmol, 1 equiv.) at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was cooled at 0 °C, and the resulting solution was quenched by adding 20 mL of H0 / ice. The suspension was filtered, and the filter cake was concentrated under reduced pressure to give a residue. The crude product, 8-methyl-6-nitro-3,4-dihydro-1H-quinolin-2-one (150 mg, 727.46 μmol, 65.15% yield), was obtained as a white solid.

[0358] Step 3: To a solution of 8-methyl-6-nitro-3,4-dihydro-1H-quinolin-2-one (150 mg, 727.46 μmol, 1 equiv.) in HO (3 mL) and EtOH (3 mL), Fe (203.12 mg, 3.64 mmol, 5 equiv.) and NH4Cl (194.56 mg, 3.64 mmol, 5 equiv.) were added. The mixture was heated at 50° C. for 2 h. The mixture was stirred. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO, petroleum ether: EtOAc = 0:1) to obtain a crude product. The crude product was 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. The compound 6-amino-8-methyl-3,4-dihydro-1H-quinolin-2-one (105 mg, 595.86 umol, yield 81.91%) was obtained as a white solid. LCMS: (M+H) + :177.1.

[0359] Step 4: To a mixture of 6-amino-8-methyl-3,4-dihydro-1H-quinolin-2-one (105 mg, 595.86 umol, 1 equiv.) and 3-ethylpyridine-4-carboxylic acid (90.07 mg, 480.07 umol, 8.06 e-1 equiv., HCl) in pyridine (2 mL), EDCI (137.07 mg, 715.04 umol, 1.2 equiv.) 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=5:1). The crude product was then triturated with a mixture of petroleum ether and ethyl acetate (8:1, 9 mL). The mixture was stirred at 20° C. for 1 hour. The suspension was filtered, and the filter cake was concentrated under reduced pressure to give a residue. The compound 3-ethyl-N-(8-methyl-2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyridine-4-carboxamide (71.3 mg, purity 95.7%) was obtained. LCMS: (M+H) + :310.0. 1H NMR(400MHz,MeOD):δ 8.55(s,1H),8.50(d,J=4.8Hz,1H),7.45(d,J=4.8Hz,1H),7.41(s,1H),7.34(s,1H),2.94- 2.97(m,2H),2.85(q,J=7.6Hz,2H),2.55-2.59(m,2H),2.27(s,3H),1.27(t,J=7.6Hz,3H).

[0360] Example 7. Synthesis of Compound 141 [ka] Step 1: Step A: To a mixture of NaNO (25.87 g, 374.99 mmol, 8.72 equiv) and Amberlyst A26 (38 g) in HO (520 mL) was added in one portion under N at 20° C. The mixture was stirred at 20° C. for 30 min. The suspension was filtered and the filter cake was washed with HO until the pH of the filtrate was 7. Step B: To a mixture of the product from Step A, 1-fluoro-2,3-dinitro-benzene (8 g, 42.99 mmol, 1 equiv), 4-methylbenzenesulfonic acid (24.43 g, 141.86 mmol, 3.3 equiv), and palladium diacetate (965.13 mg, 4.30 mmol, 0.1 equiv) in MeOH (80 mL) was added methyl prop-2-enoate (18.50 g, 214.94 mmol, 19.36 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 the filtrate was concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 15 / 1 to 2 / 1). Compound (E)-methyl 3-(3-fluoro-2-nitrophenyl)prop-2-enoate (5.5 g, 24.43 mmol, yield 56.82%) was obtained as a white solid. LCMS: (M+H) + :226.0.

[0361] Step 2: A suspension of (E)-methyl 3-(3-fluoro-2-nitro-phenyl)prop-2-enoate (600 mg, 2.66 mmol, 1 equiv) and 10% Pd / C (100 mg) in MeOH (10 mL) was degassed and purged with H three times. The mixture was stirred under H (15 psi) at 20° C. for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product, methyl 3-(2-amino-3-fluoro-phenyl)propanoate (400 mg), was obtained as a white solid. LCMS: (M+H) + :198.1.

[0362] Step 3: A mixture of methyl 3-(2-amino-3-fluoro-phenyl)propanoate (400 mg, 2.03 mmol, 1 equiv.) in MeOH (50 mL) was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1). Compound 8-fluoro-3,4-dihydro-1H-quinolin-2-one (190 mg, 1.15 mmol, 56.71% yield) was obtained as a white solid.

[0363] Step 4: To a solution of 8-fluoro-3,4-dihydro-1H-quinolin-2-one (1.1 g, 6.66 mmol, 1 equiv.) in concentrated HSO (5 mL) was added KNO (673.33 mg, 6.66 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 100 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 diluted with a mixture of petroleum ether and ethyl acetate (10:1, 11 mL). The mixture was stirred 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 8-fluoro-6-nitro-3,4-dihydro-1H-quinolin-2-one (800 mg, 3.81 mmol, yield 57.16%) was obtained as a white solid.

[0364] Step 5: A suspension of 8-fluoro-6-nitro-3,4-dihydro-1H-quinolin-2-one (189 mg, 899.31 umol, 1 equiv.) and 10% Pd / C (50 mg) in MeOH (10 mL) 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 obtain a residue. The crude product was triturated with a mixture of petroleum ether / ethyl acetate (10:1, 11 mL) at 25 °C for 10 minutes. The suspension was filtered, and the filter cake was concentrated under reduced pressure to obtain a residue. Compound 6-amino-8-fluoro-3,4-dihydro-1H-quinolin-2-one (150 mg, 832.51 umol, 92.57% yield) was obtained as a white solid.

[0365] Step 6: To a mixture of 6-amino-8-fluoro-3,4-dihydro-1H-quinolin-2-one (100 mg, 555.00 umol, 1 equiv.) and 3-ethylpyridine-4-carboxylic acid (100.67 mg, 666.00 umol, 1.2 equiv.) in pyridine (2 mL), EDCI (127.67 mg, 666.00 umol, 1.2 equiv.) was added in one portion. The mixture was stirred at 40° C. for 2 hours. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 um, mobile phase: water (0.05% NH3 . The compound 3-ethyl-N-(8-fluoro-2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyridine-4-carboxamide (79 mg, 252.13 μmol, yield 45.43%, purity 100%) was obtained. CMS:(M+H) + :314.1. 1H NMR(400MHz,MeOD):δ 8.55(s,1H),8.50(d,J=4.4Hz,1H),7.55(dd,J=12.4 and 2.4Hz,1H),7.45(d,J=5.2Hz,1H),7.26(d,J=1.2Hz,1H),2.99-3.03(m,2H),2.83(q,J=8.0Hz,2H),2.60-2.63(m,2H),1.27(t,J=7.6Hz,3H).

[0366] Compound 67 (14 mg) was also obtained from this Example 7.

[0367] Example 8. Synthesis of Compound 147 [ka] Step 1: To a mixture of 2,3-dimethylaniline (10 g, 82.52 mmol, 10.08 mL, 1 equiv) and TEA (9.19 g, 90.77 mmol, 12.63 mL, 1.1 equiv) in DCM (100 mL) was added 3-chloropropanoyl chloride (10.48 g, 82.52 mmol, 7.94 mL, 1 equiv) at 0 °C. The mixture was stirred at 0 °C for 1 h. To the mixture was added HO (50 mL). The aqueous phase was extracted with DCM (50 mL * 3). The combined organic phase was washed with brine (50 mL * 2), dried over NaSO, filtered, and concentrated in vacuo. 3-chloro-N-(2,3-dimethylphenyl)propanamide (15 g, crude) was obtained as an off-white solid.

[0368] Step 2: To a mixture of 3-chloro-N-(2,3-dimethylphenyl)propanamide (2 g, 9.45 mmol, 1 equiv.) in PhCl (20 mL) was added AlCl (3.78 g, 28.34 mmol, 1.55 mL, 3 equiv.) at 0 °C. The mixture was stirred at 80 °C for 12 h. The reaction mixture was added to ice (20 mL). The mixture was then extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 2 / 1). 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%: 15%-35%, 8 min) to obtain the compound 7,8-dimethyl-3,4-dihydro-1H-quinolin-2-one (115mg, 656.29umol, 23.96% yield) as a white solid.

[0369] Step 3: To a mixture of 7,8-dimethyl-3,4-dihydro-1H-quinolin-2-one (0.1 g, 570.69 umol, 1 equiv) in H2SO4 (1 mL) was added KNO3 (57.70 mg, 570.69 umol, 1.0 equiv) portionwise at 0 °C. The mixture was stirred at 0° C. for 1 hour. The mixture was slowly added to ice (20 mL). The mixture was then filtered. The filter cake was washed with water (2 mL) and concentrated in vacuo to give 7,8-dimethyl-6-nitro-3,4-dihydro-1H-quinolin-2-one (112 mg, 508.57 μmol, 89.12% yield) as a yellow solid.

[0370] Step 4: To a solution of 7,8-dimethyl-6-nitro-3,4-dihydro-1H-quinolin-2-one (101.41 mg, 460.49 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. The mixture was stirred under H (15 Psi) at 25 °C for 12 h. The mixture was filtered and concentrated in vacuo. 6-amino-7,8-dimethyl-3,4-dihydro-1H-quinolin-2-one (67 mg, 352.18 umol, 76.48% yield) was obtained as a yellow solid.

[0371] Step 5: To a mixture of 6-amino-7,8-dimethyl-3,4-dihydro-1H-quinolin-2-one (55 mg, 289.11 umol, 1 eq.) and 3-ethylpyridine-4-carboxylic acid (65.09 mg, 346.93 umol, 1.2 eq., HCl) in pyridine (1 mL), EDCI (66.51 mg, 346.93 umol, 1.2 eq.) was added. The mixture was stirred at 45 °C for 1 hour. The mixture was concentrated in vacuo. The residue was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 0:1). N-(7,8-dimethyl-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-ethyl-pyridine-4-carboxamide (16 mg, 48.49 umol, 98% purity) was obtained. LCMS: (M+H) + :324.1. 1 H NMR (400 MHz, MeOD): δ 8.56(s,1H),8.52(d,J=5.2Hz,1H),7.54(d,J=5.2Hz,1H),7.08(s,1H),2.88-2 .97(m,4H),2.55-2.59(m,2H),2.25(s,3H),2.24(s,3H),1.32(t,J=7.6Hz,3H).

[0372] Example 9. Synthesis of Compound 149 [ka] To a solution of 6-amino-8-methyl-3,4-dihydro-1H-quinolin-2-one (100 mg, 567.49 μmol, 1 equiv.) and 3-(cyclopropylmethyl)pyridine-4-carboxylic acid (218.25 mg, 1.02 mmol, 1.8 equiv., HCl) in pyridine (1 mL) was added EDCI (130.55 mg, 680.99 μmol, 1.2 equiv.). The mixture was stirred at 45° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:MeOH=10:1). The compound 3-(cyclopropylmethyl)-N-(8-methyl-2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyridine-4-carboxamide (0.065 g, 189.92 μmol, yield 63.70%, purity 98%) was obtained. LCMS: (M+H) + :336.1. 1 H NMR(400MHz,MeOD):δ 8.63(s,1H),8.52(d,J=5.2Hz,1H),7.46(d,J=5.2Hz,1H),7.41(s,1H),7.34( s,1H),2.94-2.97(m,2H),2.74(d,J=7.2Hz,2H),2.56-2.59(m,2H),2.27(s,3H) ),1.02-1.08(m,1H),0.50-0.55(m,2H),0.24-0.26(m,2H).

[0373] Example 10. Synthesis of Compound 150 [ka] Step 1: To a solution of POCl3 (10 mL) was added 3-ethyl-1-oxide-pyridin-1-ium-4-carbonitrile (1 g, 6.75 mmol, 1 equiv.). The mixture was stirred at 100 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction mixture was diluted with EtOAc (30 mL). The solution was then slowly added to water (100 mL) at 25 °C. The mixture was adjusted to pH 8 with saturated Na2CO3. The mixture was then extracted with 60 mL of ethyl acetate (20 ml*3). The combined organic phase was then 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 0-10% ethyl acetate / petroleum ether gradient at 40 mL / min). The compound 2-chloro-5-ethyl-pyridine-4-carbonitrile (0.9 g, 5.40 mmol, 80.04% yield) was obtained as a white solid. LCMS: (M+H) + :167.1.

[0374] Step 2: To a solution of 2-chloro-5-ethyl-pyridine-4-carbonitrile (0.9 g, 5.40 mmol, 1 equiv.) in EtOH (5 mL) and HO (5 mL) was added NaOH (648.18 mg, 16.21 mmol, 3 equiv.). The mixture was stirred at 90° C. for 3 hours. The crude reaction mixture was concentrated under reduced pressure to remove EtOH, and then the mixture was adjusted to pH=3 with 6N HCl (2 ml). The mixture was then filtered. The filter cake was concentrated in vacuo. Compound 2-chloro-5-ethyl-pyridine-4-carboxylic acid (485 mg, HCl, crude) was obtained as a white solid. LCMS: (M+H) + :186.1.

[0375] Step 3: To a solution of 6-amino-8-methyl-3,4-dihydro-1H-quinolin-2-one (100 mg, 567.49 μmol, 1 equiv.) and 2-chloro-5-ethyl-pyridine-4-carboxylic acid (151.23 mg, 680.99 μmol, 1.2 equiv., HCl) in pyridine (1 mL), EDCI (130.55 mg, 680.99 μmol, 1.2 equiv.) was added. The mixture was stirred at 45° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:MeOH=10:1). The compound 2-chloro-5-ethyl-N-(8-methyl-2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyridine-4-carboxamide (28 mg, 78.18 umol, yield 13.78%, purity 96%) was obtained. LCMS: (M+H) + :344.1. 1 H NMR(400MHz,MeOD):δ 8.36(s,1H),7.51(s,1H),7.40(s,1H),7.34(s,1H),2.93-2.97(m,2H),2. 81(q,J=7.6Hz,2H),2.55-2.59(m,2H),2.27(s,3H),1.25(t,J=7.6Hz,3H).

[0376] Example 11. Synthesis of Compound 151 [ka] To a mixture of 3-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid (50 mg, 243.74 μmol, 1 equiv.) and 6-amino-8-methyl-3,4-dihydro-1H-quinolin-2-one (42.95 mg, 243.74 μmol, 1 equiv.) in pyridine (1 mL) was added EDCI (56.07 mg, 292.49 μmol, 1.2 equiv.). The mixture was stirred at 45° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:MeOH=10:1). The compound N-(8-methyl-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-3-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (35 mg, 96.33 umol, yield 39.52%, purity 100%) was obtained. LCMS: (M+H) + :364.1. 1 H NMR(400MHz,MeOD):δ 8.68-8.70(m,2H),7.62(d,J=4.8Hz,1H),7.41(s,1H),7.34(s,1H),3.9 4(q,J=11.2Hz,2H),2.94-2.98(m,2H),2.56-2.60(m,2H),2.28(s,3H).

[0377] Example 12. Synthesis of Compound 145 [ka] Step 1: To a mixture of 6-bromoisoquinoline (10 g, 48.06 mmol, 1 equiv.) in H2SO4 (70 mL) was added KNO3 (6.12 g, 60.53 mmol, 1.26 equiv.) portionwise at 0 °C. The mixture was then stirred at 0 °C for 2 h. The mixture was slowly added to ice (350 mL). The solution was adjusted to pH = 8-9 with 33% aqueous NH4OH solution. The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. 6-Bromo-5-nitro-isoquinoline (10 g, 39.52 mmol, 82.22% yield) was obtained as an off-white solid. LCMS: (M+H) + :252.9,254.9.

[0378] Step 2: Ethyl prop-2-enoate (3.4 g, 33.9 mL) in DMF (40 mL) To a mixture of 6-bromo-5-nitro-isoquinoline (3 g, 11.86 mmol, 1 equiv.), Pd(OAc) (532.32 mg, 2.37 mmol, 0.2 equiv.), PPh (621.89 mg, 2.37 mmol, 0.2 equiv.), and TEA (1.80 g, 17.78 mmol, 2.48 mL, 1.5 equiv.) was added. The mixture was stirred at 110 °C for 12 hours. The mixture was cooled to 25 °C. Water (150 mL) was added to the mixture. The aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic phase was 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 3 / 1) to obtain ethyl (E)-3-(5-nitro-6-isoquinolyl)prop-2-enoate (1.1 g, 4.04 mmol, yield 34.08%) as a yellow solid.

[0379] Step 3: To a solution of (E)-ethyl 3-(5-nitro-6-isoquinolyl)prop-2-enoate (1 g, 3.67 mmol, 1 equiv.) in MeOH (20 mL) was added 10% Pd / C (0.1 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 12 h. The mixture was filtered and concentrated in vacuo. Ethyl 3-(5-amino-6-isoquinolyl)propanoate (0.72 g, 2.95 mmol, 80.24% yield) was obtained as a yellow solid. LCMS: (M+H) + :245.1.

[0380] Step 4: A mixture of ethyl 3-(5-amino-6-isoquinolyl)propanoate (0.72 g, 2.95 mmol, 1 equiv.) in toluene (5 mL) was stirred at 110 °C for 12 h. The mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, elution with a 0-50% ethyl acetate / petroleum ether gradient at 40 mL / min). 3,4-dihydro-1H-1,8-phenanthrolin-2-one (0.3 g, 1.51 mmol, 51.35% yield) was obtained as a yellow solid.

[0381] Step 5: To a mixture of 3,4-dihydro-1H-1,8-phenanthrolin-2-one (0.1 g, 504.49 umol, 1 equiv.) in H2SO4 (1 mL) was added KNO3 (56.11 mg, 554.94 umol, 1.1 equiv.) portionwise at 0 °C. The mixture was then stirred at 0 °C for 1 h. The mixture was slowly added to ice (10 mL). The mixture was filtered. The filter cake was washed with H2O (5 mL) and concentrated in vacuo. 6-nitro-3,4-dihydro-1H-1,8-phenanthrolin-2-one (45 mg, 185.02 umol, 36.67% yield) was obtained as a yellow solid. LCMS: (M+H) + :244.0.

[0382] Step 6: To a solution of 6-nitro-3,4-dihydro-1H-1,8-phenanthrolin-2-one (45 mg, 185.02 umol, 1 equiv.) in THF (30 mL) was added 10% Pd / C (0.02 g). The mixture was stirred under H2 (15 Psi) at 25 °C for 10 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The compound 6-amino-3,4-dihydro-1H-1,8-phenanthrolin-2-one (20 mg, crude) was obtained as a white solid.

[0383] Step 7: To a solution of 6-amino-3,4-dihydro-1H-1,8-phenanthrolin-2-one (15 mg, 70.34 umol, 1 eq.) and 3-ethylpyridine-4-carboxylic acid (15.84 mg, 84.41 umol, 1.2 eq., HCl) in pyridine (5 mL), EDCI (16.18 mg, 84.41 umol, 1.2 eq.) was added. The mixture was stirred at 45° 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 Gemini-NX 80*40m The compound 3-ethyl-N-(2-oxo-3,4-dihydro-1H-1,8-phenanthrolin-6-yl)pyridine-4-carboxamide (4 mg, 11.55 umol, 100% purity) was obtained. LCMS: (M+H) + :347.2. 1 H NMR(400MHz,MeOD):δ 9.37(s,1H),8.63(s,1H),8.60(d,J=4.8Hz,1H),8.53(d,J=6.4Hz,1H),8.13(d,J=6.0,1H),7.77(s,1H), 7.72(d,J=4.8Hz,1H),3.22-3.25(m,2H),2.97(q,J=7.6Hz,2H),2.74-2.77(m,2H),1.36(t,J=7.6Hz,3H).

[0384] Example 13. Synthesis of Compound 160 [ka] A solution of 6-amino-3,3,8-trimethyl-1,4-dihydroquinolin-2-one (35 mg, 171.34 μmol, 1.5 equiv) and 2-chloroquinazoline (18.80 mg, 114.23 μmol, 1 equiv) in TFA (0.01 mL) and n-BuOH (3 mL) was placed in a microwave tube. The sealed tube was heated in a microwave at 120° C. for 60 minutes. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 100*25mm*3um, mobile phase: [water (0.05% HCl)-ACN], B%: 10% to 30%, 8 min) to give 3,3,8-trimethyl-6-(quinazolin-2-ylamino)-1,4-dihydroquinolin-2-one (8 mg, 19.09 umol, yield 16.71%, purity 88%, HCl). LCMS: (M+H) + :333.1. 1 H NMR(400MHz,DMSO):δ 9.77(bs,1H),9.28(s,1H),7.90(d,J=6.8Hz,1H),7.79(m,1H),7.63-7.65 (m,2H),7.57(s,1H),7.38(m,1H),2.76(s,2H),2.24(s,3H),1.07(s,6H).

[0385] Example 14. Synthesis of Compound 161 [ka] 6-amino-3,3,8-trimethyl-1,4-dihydroquinolin-2-one (80 mg, 391.64 umol, 1.8 equiv.), 2-bromoquinoxaline (45.48 mg, 217.58 umol, 1 equiv.), [2-(2-aminophenyl)phenyl]palladium(2+)-dicyclohexyl-[2-(2 A mixture of [4,6-triisopropylphenyl]phenyl]phosphane methanesulfonate (18.42 mg, 21.76 μmol, 0.1 equiv.) and Cs2CO3 (141.78 mg, 435.16 μmol, 2 equiv.) was degassed and purged with N2 three times, and then the mixture was stirred at 80 °C under a N2 atmosphere for 3 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by reverse-phase HPLC (column: Waters Xbridge Purification using BEH C18 100*25mm*5um, mobile phase: [water (10mM NH4HCO3)-ACN], B%: 30%-55%, 10 min) gave 3,3,8-trimethyl-6-(quinoxalin-2-ylamino)-1,4-dihydroquinolin-2-one (39 mg, 111.46 umol, 51.23% yield, 95% purity). LCMS: (M+H) + :333.1. 1 H NMR(400MHz,DMSO):δ 9.77(s,1H),9.31(s,1H),8.51(s,1H),7.82(d,J=8.0Hz,1H),7.70(m,2H) ),7.60-7.62(m,2H),7.43(m,1H),2.77(s,2H),2.26(s,3H),1.07(s,6H).

[0386] Example 15. Synthesis of Compound 152 [ka] Step 1: To a mixture of 2-fluoro-3-iodo-pyridine (5 g, 22.42 mmol, 1 equiv.) in THF (60 mL) was added LDA (2 M, 13.45 mL, 1.2 equiv.) dropwise at −70° C. The mixture was then stirred at −70° C. for 1.5 hours under N2. To the mixture was added a solution of 1,3,2-dioxathiolane 2,2-dioxide (3.62 g, 29.15 mmol, 1.3 equiv.) in THF (30 mL) dropwise at −70° C. The mixture was stirred at −70° C. for 0.5 hours and at 25° C. for 2 hours. To the mixture was then added HCl (12 M, 8.41 mL, 4.5 equiv.) at 0° C. The mixture was stirred at 25° C. for 3 hours. The mixture was slowly added to saturated NaHCO3 (300 mL). The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent of 0-35% ethyl acetate / petroleum ether gradient, 40 mL / min). 2-(2-fluoro-4-iodo-3-pyridyl)ethanol (2.5 g, 9.36 mmol, 41.75% yield) was obtained as an off-white solid. LCMS: (M+H) + :268.0.

[0387] Step 2: 2-(2-fluoro-4-iodo-3-pyridyl)ethanol (1 g, 3.74 mmol, 1 equiv.) and KPO (3.9 A mixture of 4-iodo-2,3-dihydrofuro[2,3-b]pyridine (0.8 g, crude) was obtained as a yellow solid.

[0388] Step 3: To a mixture of 4-iodo-2,3-dihydrofuro[2,3-b]pyridine (0.8 g, 3.24 mmol, 1 equiv.) in EtOH (20 mL), Pd(OAc) (72.71 mg, 323.84 µmol, 0.1 equiv.), DPPP (133.57 mg, 323.84 µmol, 0.1 equiv.), and TEA (983.08 mg, 9.72 mmol, 1.35 mL, 3 equiv.) were added. The suspension was degassed under vacuum and purged with CO several times. The mixture was then stirred at 80 °C under CO (50 psi) for 16 h. The mixture was filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, elution with a 0–25% ethyl acetate / petroleum ether gradient at 40 mL / min). Ethyl 2,3-dihydrofuro[2,3-b]pyridine-4-carboxylate (0.3 g, 1.55 mmol, 47.95% yield) was obtained as a white solid. LCMS: (M+H) + :194.0.

[0389] Step 4: To a mixture of ethyl 2,3-dihydrofuro[2,3-b]pyridine-4-carboxylate (0.1 g, 517.60 umol, 1 equiv.) in THF (1 mL) and HO (1 mL) was added LiOH.HO (32.58 mg, 776.40 umol, 1.5 equiv.). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo to remove THF. The aqueous phase was adjusted to pH = 3 with 6 N HCl. The mixture was concentrated in vacuo. 2,3-Dihydrofuro[2,3-b]pyridine-4-carboxylic acid (110 mg, crude) was obtained as a white solid. LCMS: (M+H) + :166.0.

[0390] Step 5: To a mixture of 2,3-dihydrofuro[2,3-b]pyridine-4-carboxylic acid (0.09 g, 446.41 μmol, 1.2 equiv., HCl) and 6-amino-8-methyl-3,4-dihydro-1H-quinolin-2-one (65.55 mg, 372.01 μmol, 1 equiv.) in pyridine (1 mL), EDCI (85.58 mg, 446.41 μmol, 1.2 equiv.) was added. The mixture was stirred at 45° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:MeOH=10:1). The residue was then washed with a solution of petroleum ether:ethyl acetate=10:1 (3 mL). The compound N-(8-methyl-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-2,3-dihydrofuro[2,3-b]pyridine-4-carboxamide (30 mg, 88.33 umol, yield 25.2%, purity 95.2%) was obtained. LCMS: (M+H) + :324.0. 1 H NMR(400MHz,CD3OD):δ 8.02(d,J=5.6Hz,1H),7.42(s,1H),7.36(s,1H),7.18(d,J=5.6Hz,1H),4.69(t,J=8 .4Hz,2H),3.53(t,J=8.4Hz,2H),2.93-2.97(m,2H),2.55-2.59(m,2H),2.27(s,3H).

[0391] Example 16. Synthesis of Compound 153 [ka] Step 1: To a mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (5 g, 25.38 mmol, 1 equiv.) in THF (80 mL), BMS (10 M, 14.46 mL, 5.7 equiv.) was added dropwise at 25° C. The mixture was stirred at 25° C. for 1 hour. Then, the mixture was stirred at 70° C. for 16 hours. To the mixture, water (30 mL) was added dropwise at 0° C. The mixture was then stirred at 25° C. for 1 hour. The mixture was extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The compound 4-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (1.4 g, crude) was obtained as a white solid.

[0392] Step 2: To a solution of 4-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (0.5 g, 2.51 mmol, 1 equiv.) in EtOH (15 mL), Pd(OAc) (56.40 mg, 251.20 µmol, 0.1 equiv.), DPPP (103.60 mg, 251.20 µmol, 0.1 equiv.), and TEA (762.55 mg, 7.54 mmol, 1.05 mL, 3 equiv.) were added. The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred under CO (50 Psi) at 80 °C for 5 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 = 5 / 1 to 2 / 1). The compound ethyl 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (0.1 g, 447.42 μmol, yield 15.2%, purity 86%) was obtained as a white solid. LCMS: (M+H) + :193.0.

[0393] Step 3: To a mixture of ethyl 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (0.1 g, 520.25 umol, 1 eq.) in THF (1 mL), LiOH.HO (43.66 mg, 1.04 mmol, 2 eq.) in HO (1 mL) was added. The mixture was stirred at 15 °C for 1 hour. The mixture was concentrated to remove THF. The mixture was then adjusted to pH = 3 with HCl (1N) and filtered to obtain a residue. Compound 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (0.09 g, crude) was obtained as a white solid. LCMS: (M+H) + :165.1.

[0394] Step 4: To a mixture of 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (0.045 g, 274.12 μmol, 1.1 equiv) and 6-amino-8-methyl-3,4-dihydro-1H-quinolin-2-one (43.91 mg, 249.20 μmol, 1 equiv) in pyridine (1 mL) was added EDCI (57.33 mg, 299.04 μmol, 1.2 equiv). The mixture was stirred at 45° C. for 1 hour. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:MeOH=10:1). Compound N-(8-methyl-2-oxo-3,4-dihydro-1H-quinolin-6-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-4-carboxamide (25 mg, 76.31 umol, yield 31.12%, purity 98.4%) was obtained. LCMS (M+H) + :323.2. 1 H NMR(400MHz,CD3OD):δ7.76(d,J=5.6Hz,1H),7.40(s,1H),7.34(s,1H),6.73(d,J=6.0Hz,1H),3.6 4 (t, J=8.4Hz, 2H), 3.34 (overlaps with peak at 3.31, estimated 2H), 2.93-2.97 (m, 2H), 2.55-2.59 (m, 2H), 2.27 (s, 3H).

[0395] Example 17. Synthesis of Compound 155 [ka] Step 1: To methyl 3-bromopyridine-4-carboxylate (0.5 g, 2.31 mmol, 1 equiv.) and bromomethylcyclobutane (517.39 mg, 3.47 mmol, 389.01 uL, 1.5 equiv.) in DME (10 mL) was added bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine, hexafluorophosphate (25.97 mg, 23 To the reaction mixture was added 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (3.11 mg, 11.57 umol, 0.005 eq), bis(trimethylsilyl)silyl-trimethyl-silane (575.52 mg, 2.31 mmol, 714.04 uL, 1 eq), and Na2CO3 (490.62 mg, 4.63 mmol, 2 eq), dichloronickel, 1,2-dimethoxyethane (2.54 mg, 11.57 umol, 0.005 eq). The mixture was stirred at 25 °C under Ar and a blue LED for 12 h. The mixture was filtered. The filter cake was washed with EtOAc (10 mL). The filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, elution with a 0-20% ethyl acetate / petroleum ether gradient at 40 mL / min). Methyl 3-(cyclobutylmethyl)pyridine-4-carboxylate (200 mg, 974.41 μmol, 42.10% yield) was obtained as a yellow oil. LCMS: (M+H) + :206.0.

[0396] Step 2: Mixture of methyl 3-(cyclobutylmethyl)pyridine-4-carboxylate (100 mg, 487.21 umol, 1 equiv.) in THF (1 mL) and HO (1 mL). To this was added LiOH.HO (30.67 mg, 730.81 umol, 1.5 equiv). The mixture was stirred at 25° C. for 1 hour. The mixture was concentrated in vacuo to remove THF. The aqueous phase was adjusted to pH=3 with 6N HCl. The aqueous phase was concentrated in vacuo. 3-(cyclobutylmethyl)pyridine-4-carboxylic acid (120 mg, crude, HCl) was obtained as a white solid. LCMS: (M+H) + :192.2.

[0397] Step 3: To a solution of 3-(cyclobutylmethyl)pyridine-4-carboxylic acid (80 mg, 351.36 μmol, 1.55 equiv, HCl) and 6-amino-8-methyl-3,4-dihydro-1H-quinolin-2-one (0.04 g, 227.00 μmol, 1 equiv) in pyridine (1 mL) was added EDCI (52.22 mg, 272.39 μmol, 1.2 equiv). The mixture was stirred at 45° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, ethyl acetate:MeOH=10:1). The compound 3-(cyclobutylmethyl)-N-(8-methyl-2-oxo-3,4-dihydro-1H-quinolin-6-yl)pyridine-4-carboxamide (20 mg, 65.82 μmol, yield 29.00%, purity 99.2%) was obtained as a white solid. LCMS: (M+H) + :350.1. 1 H NMR(400MHz,MeOD):8.48(m,2H),7.44(d,J=5.2Hz,1H),7.41(s,1H),7.34(s,1H),2.9 1-2.97(m,4H),2.55-2.62(m,3H),2.27(s,3H),2.00-2.02(m,2H),1.74-1.84(m,4H).

[0398] Example 18. Synthesis of Compound 165 [ka] Step 1: To a mixture of CDI (92.02 mg, 567.49 μmol, 1 equiv) and DIEA (110.02 mg, 851.23 μmol, 148.27 μL, 1.5 equiv) in DCM (10 mL) was added 6-amino-8-methyl-3,4-dihydro-1H-quinolin-2-one (100 mg, 567.49 μmol, 1 equiv) in one portion at 0° C. The mixture was stirred at 20° C. for 12 hours. TLC showed the reaction was completely consumed. The mixture was concentrated in vacuo. N-(8-methyl-2-oxo-3,4-dihydro-1H-quinolin-6-yl)imidazole-1-carboxamide (250 mg, crude) was obtained as a white solid.

[0399] Step 2: To a solution of N-(8-methyl-2-oxo-3,4-dihydro-1H-quinolin-6-yl)imidazole-1-carboxamide (250 mg, 277.48 μmol, 1 equiv) and DIEA (119.41 mg, 277.48 μmol, 48.33 μL, 1 equiv) in DCM (10 mL) was added 3-ethylmorpholine (117.05 mg, 305.23 μmol, 1.1 equiv) at 0° C. The mixture was stirred at 20° C. for 8 hours. LC-MS showed the reaction was completely consumed. The mixture was concentrated in vacuo. The crude product was purified by reverse-phase HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um, mobile phase: [water (NH4HCO3)-ACN], B%: 10% to 40%, 8 min) to give 3-ethyl-N-(8-methyl-2-oxo-3,4-dihydro-1H-quinolin-6-yl)morpholine-4-carboxamide (44 mg, 138.63 umol, yield 49.96%, purity 100%) as a white solid. (M+H) + :318.1. 1 H NMR (400MHz, METHANOL-d4) δppm 7.03(d,J=11.6Hz,2H),3.90-4.10(m,3H),3.75-3.85(m,1H),3.57-3.65(m,1H),3.48-3.49(m,1H),3.2 0-3.28(m,1H),2.88-2.92(m,2H),2.51-2.55(m,2H),2.22(s,3H),1.75-1.84(m,2H),0.92-0.96(m,3H).

[0400] Example 19. Synthesis of Compound 154 [ka] Step 1: A mixture of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (1 g, 4.40 mmol, 1 equiv.), CsCO (2.87 g, 8.81 mmol, 2 equiv.), and PMB-Cl (827.68 mg, 5.29 mmol, 719.72 uL, 1.2 equiv.) in DMF (10 mL) was degassed and purged with N three times, and then the mixture was stirred at 60 °C for 2 h under a N atmosphere. Water (50 mL) was added to the mixture. The mixture was filtered and concentrated in vacuo. 6-bromo-1-[(4-methoxyphenyl)methyl]-3,4-dihydro-1,8-naphthyridin-2-one (1.3 g, 3.52 mmol, 79.83% yield, 93.9% purity) was obtained as an off-white solid.

[0401] Step 2: To 6-bromo-1-[(4-methoxyphenyl)methyl]-3,4-dihydro-1,8-naphthyridin-2-one (200 mg, 576.03 μmol, 1 equiv.), 3-ethylpyridine-4-carboxamide (95.16 mg, 633.63 μmol, 1.1 equiv.), and CsCO (375.36 mg, 1.15 mmol, 2 equiv.) in dioxane (10 mL) was added Pd(dba) (52.75 mg, 57.60 μmol, 0.1 equiv.) and Xantphos (33.33 mg, 57.60 μmol, 0.1 equiv.). The mixture was stirred at 120 °C for 2 h. The mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, elution with a 0-75% ethyl acetate / petroleum ether gradient at 40 mL / min). 3-Ethyl-N-[8-[(4-methoxyphenyl)methyl]-7-oxo-5,6-dihydro-1,8-naphthyridin-3-yl]pyridine-4-carboxamide (112 mg, 268.93 μmol, 46.69% yield) was obtained as a yellow solid. LCMS: (M+H) + :417.1.

[0402] Step 3: A mixture of 3-ethyl-N-[8-[(4-methoxyphenyl)methyl]-7-oxo-5,6-dihydro-1,8-naphthyridin-3-yl]pyridine-4-carboxamide (112 mg, 268.93 umol, 1 equiv) in DCM (2 mL) and methanesulfonic acid (0.2 mL) was stirred at 60° C. for 4 hours. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 80*40mm*3um, mobile phase: [water (0.04% HCl)-ACN], B%: 1% to 25%, 7 min). 3-Ethyl-N-(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-3-yl)pyridine-4-carboxamide (15 mg, 45.07 umol, yield 16.76%, purity 100%, HCl) was obtained. LCMS: (M+H) + :297.1. 1H NMR(400MHz,DMSO):10.91(s,1H),10.49(s,1H),8.85(s,1H),8.81(d,J=5.6Hz,1H),8.38(d,J=2.4Hz,1H),7.97(d,J=2.0 Hz,1H), 7.90(d,J=5.2Hz,1H),2.90-2.94(m,2H),2.83(q,J=7.6Hz,2H),2.52(overlaps with peak at 2.50, estimated 2H),1.22(t,J=7.6Hz,3H).

[0403] Example 20. Synthesis of Compound 159 [ka] Step 1: To a solution of 6-chloro-3,4-dihydro-1H-1,7-naphthyridin-2-one (0.14 g, 639.07 umol, 1 eq., HCl) and 1-(chloromethyl)-4-methoxy-benzene (200.17 mg, 1.28 mmol, 174.06 uL, 2 eq.) in DMF (1 mL), CsCO (624.67 mg, 1.92 mmol, 3 eq.) was added at 25 °C. The mixture was stirred at 60 °C for 2 hours. The mixture was poured into water (5 mL) and stirred for 10 minutes. The mixture was filtered to obtain a residue. The compound 6-chloro-1-[(4-methoxyphenyl)methyl]-3,4-dihydro-1,7-naphthyridin-2-one (0.144 g, crude) was obtained as a white solid. LCMS: (M+H) + :303.0.

[0404] Step 2: To a mixture of 6-chloro-1-[(4-methoxyphenyl)methyl]-3,4-dihydro-1,7-naphthyridin-2-one (220 mg, 726.66 μmol, 1 equiv.) and 3-ethylpyridine-4-carboxamide (120 mg, 799.33 μmol, 1.1 equiv.) in dioxane (1 mL), Xantphos (42.03 mg, 72.67 μmol, 0.1 equiv.), CsCO (710.04 mg, 2.18 mmol, 3 equiv.), and Pd(dba) (66.52 mg, 72.67 μmol, 0.1 equiv.) were added. The mixture was stirred at 120 °C for 3 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®, 10 g SepaFlash® silica flash column, elution with a 0-79% ethyl acetate / petroleum ether gradient at 40 mL / min). The compound 3-ethyl-N-[1-[(4-methoxyphenyl)methyl]-2-oxo-3,4-dihydro-1,7-naphthyridin-6-yl]pyridine-4-carboxamide (0.17 g, 408 ml) was obtained. 0.19 umol, 56.17% yield) was obtained as a brown solid. LCMS: (M+H) + :417.1.

[0405] Step 3: A mixture of 3-ethyl-N-[1-[(4-methoxyphenyl)methyl]-2-oxo-3,4-dihydro-1,7-naphthyridin-6-yl]pyridine-4-carboxamide (170 mg, 408.19 μmol, 1 equiv.) in DCM (2 mL) and methanesulfonic acid (0.2 mL) was stirred at 60° C. for 5 hours. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 100*25 mm*3 μm, mobile phase: [water (0.04% HCl)-ACN], B%: 1% to 25%, 8 min). 3-Ethyl-N-(2-oxo-3,4-dihydro-1H-1,7-naphthyridin-6-yl)pyridine-4-carboxamide (25 mg, 75.12 μmol, ...

Claims

Claim 1: A composition for treating type 2 diabetes in a subject in need thereof, said composition comprising a compound of formula (IV): 【Chemical 301】 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; During the ceremony, Ring A is a heterocycle or heteroaryl; L is —NH—, —C(O)—NH—, —S(O)NH—, —S(O) 2 NH—, —S(O)—, or —S(O) 2 —; R 22 is halo, —CN, —C 1-6 alkyl, —C 1-6 alkyl-CN, —C 1-6 haloalkyl, or carbocyclyl; R 22' is H, halo, -C 1-6 alkyl, or -C 1-6 haloalkyl; or R 22 and R 22′ are linked to form a heteroaryl, carbocyclyl, or heterocyclyl, each of which may be substituted with one or more halo; R 32 and R 33 are joined to form a heterocyclyl substituted with oxo, said heterocycle optionally being further substituted with one or more R 101 ; p is 0, 1, or 2; each R 100 is independently —CN, halo, —C 1-6 alkyl, —C 1-6 alkylene-carbocyclyl, —C 1-6 alkylene-heterocyclyl, or —C 1-6 haloalkyl; The composition wherein each R 101 is independently hydrogen, halo, or —C 1-6 alkyl.

2. The composition described in claim 1, wherein the composition is a pharmaceutical composition comprising an effective amount of the compound or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof and a pharmaceutically acceptable excipient.

3. The compound is a compound of formula (IV-A) 【Chemical 302】 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:

2. The composition of claim 1, wherein L 1 is absent, —C(O)—, —S(O)—, or —S(O) 2 —.

4. The composition of claim 1, wherein ring A is a 5- or 6-membered heteroaryl, a 5,6-bicyclic heteroaryl, a 5,6-bicyclic heterocyclyl, a 6,6-bicyclic heterocyclyl, a 6,6-bicyclic heteroaryl, or a 3- to 8-membered heterocyclyl.

5. The composition of claim 3, wherein ring A is pyridyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, or morpholinyl.

6. A-(R 100 ) p is 【Chemical 303】 2. The composition of claim 1, wherein:

7. Ring A-(R 100 ) p is 【Chemical 304】 The composition of claim 6, wherein

8. Ring A-(R 100 ) p is 【Chemical 305】 The composition of claim 7, wherein 9. The composition according to claim 3, wherein L 1 is —C(O)—.

10. The compound of claim 1, wherein the compound is a compound of formula (IV-B): 【Chemical 306】 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; During the ceremony, The composition of claim 1 , wherein each of Z 1 , Z 2 , Z 3 , and Z 4 is independently CH or N, and at least one of Z 1 , Z 2 , Z 3 , and Z 4 is N.

11. The composition according to claim 10, wherein one or two of Z 1 , Z 2 , Z 3 , and Z 4 are —N, and the rest are —CH.

12. Z 2 is N, and Z 1 , Z 3 and Z 4 are CH, or Z 1 and Z 2 are N and Z 3 and Z 4 are CH, or Z 2 and Z 4 are N and Z 1 and Z 3 are CH, or Z 1 and Z 3 are N and Z 2 and Z 4 are CH; or 12. The composition of claim 11, wherein Z2 and Z3 are N and Z1 and Z4 are CH.

13. Z 2 is N, and Z 1 , Z 3 and Z 4 are CH, or 13. The composition of claim 12, wherein Z1 and Z2 are N and Z3 and Z4 are CH.

14. The composition of claim 1, wherein R 32 and R 33 are linked to form a heterocycle containing at least one N atom in the ring and substituted with oxo.

15. R 22 and R 22' together represent (i) a 5- to 6-membered heteroaryl containing one or two heteroatoms independently selected from N, O, and S; (ii) a 5-membered carbocyclyl optionally substituted with one or more fluoro; or (iii) forming a 6-membered heterocyclyl containing one or two heteroatoms independently selected from N and O optionally substituted with one or more fluoro.

16. The composition of claim 15, wherein R 22 and R 22′ together form a 6-membered heteroaryl containing one nitrogen atom.

17. The composition of claim 1, wherein R 22′ is —H, —F, —CH 3 , or —CF 3 .

18. The composition of claim 1, wherein R 22′ is —H or halo, or —C 1-6 alkyl.

19. The composition of claim 18, wherein R 22′ is —H, —F, or —CH 3 .

20. The composition of claim 1, wherein R 22′ is —H or halo.

21. The composition of claim 20, wherein R 22′ is —H or —F.

22. The composition of claim 21, wherein R 22′ is —H.

23. The composition of claim 1, wherein each R 100 is independently halo, —C 1-6 alkyl, —C 1-6 alkylene-carbocyclyl, or —C 1-6 haloalkyl.

24. The composition of claim 1, wherein each R 100 is independently -CH 2 CH 3 , -CH 3 , -CH 2 -cyclopropyl, -Cl, -CH 2 -CF 3 , -CH 2 -cyclobutyl, -CH 2 -oxetanyl, -CF 2 CH 3 , or two adjacent R 100 can be linked to form a C5-6 carbocyclyl or a 5-membered heterocyclyl containing an N or O heteroatom, the carbocyclyl being optionally substituted with one or more fluoro.

25. The composition of claim 24, wherein each R 100 is independently —CH 2 CH 3 , —CH 3 , —CH 2 -cyclopropyl, —Cl, —CH 2 —CF 3 , —CH 2 -cyclobutyl, or —CH 2 -oxetanyl.

26. The composition of claim 24, wherein each R 100 is independently —CH 2 CH 3 , —CH 3 , —CH 2 -cyclopropyl, —Cl, or —CH 2 —CF 3 .

27. The compound of claim 1, 【Chemical 307】 【Chemical 308】 【Chemical 309】 【Chemical 310】 【Chemical 311】 【Chemical 312】 【Chemistry 313】 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

28. The compound of claim 1, 【Chemical 314】 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

29. The compound of claim 1, 【Chemical Industry 315】 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

30. The compound of claim 1, 【Chemical 316】 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

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