Inhibition of alphavbeta8 integrin

Abstract

The present disclosure relates to novel compounds and methods useful for inhibition of [alpha] v [beta] 8 integrin, including compounds according to Formula (I) and pharmaceutically acceptable salts thereof.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 484,782, filed February 14, 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure relates to methods that can be used to suppress α v Novel compounds and methods for β8 integrin. Background Technology

[0004] In the tumor microenvironment, α v β8 is expressed on immune cells (primarily antigen-presenting cells (APCs) and regulatory T cells (Tregs)) as well as on tumor cells and cancer-associated fibroblasts. α v The primary function of β8 is to activate growth factors TGF-β1 and β3. TGF-β is biosynthesized and stored in tissues in a latent form. The TGF-β homodimer remains latent by association with its prodimeric domain (pro-TGF-β). The prodimeric homodimer prevents TGF-β from binding to the TGF-β receptor and is known as the latency-related peptide (LAP). The latent TGF-β complex is stored in the extracellular matrix or on the cell surface for subsequent integrin-dependent activation. Integrin α v The β8 heterodimer binds to the arginine-glycine-aspartic acid motif (RGD domain) of latent TGF-β-1 and 3 to release active TGF-β cytokines from the latent complex.

[0005] TGF-β is a pleiotropic cytokine that mediates multiple biological processes, including development and homeostasis. TGF-β is a key factor in cell growth, differentiation, and apoptosis. It regulates extracellular matrix (ECM) production, thereby contributing to tissue repair processes. In the immune system, TGF-β is essential for the development of different immune cell types and for promoting immunosuppression. TGF-β's role in immune homeostasis is crucial for preventing excessive inflammatory responses and for maintaining tolerance to self-antigens to prevent autoimmunity. Due to its widespread expression, TGF-β activity requires tight regulation and can lead to disease states when exacerbated. Dysregulation of TGF-β signaling is involved in a variety of diseases, particularly cancer and fibrosis.

[0006] In cancer, the TGF-β pathway is involved in many human neoplastic diseases, including solid tumors and hematopoietic system tumors. As a potent inhibitor of cell proliferation, TGF-β acts as a tumor suppressor; however, in tumor cells, TGF-β loses its anti-proliferative response and promotes cancer progression. TGF-β-promoted tumorigenesis is primarily driven by the downregulation of anti-tumor immunity. Immunosuppressive effects lead to tumor immune tolerance. Furthermore, TGF-β promotes epithelial-to-mesenchymal transition (EMT) and angiogenesis to increase tumor invasiveness. Integrin avb8 expression in cancer is associated with TGF-β activity. It regulates the inflammatory phenotypes of APCs and Tregs, which are key cell types essential for T / NK cell-driven anti-tumor activity. v β8 integrin locally activates TGF-β to regulate crosstalk between APCs and effector cells, thereby shifting the immune response from inflammation to tolerance.

[0007] Proposed to inhibit integrin α v β8-driven TGF-β activation reverses tumor tolerance and enhances anti-tumor T / NK cell responses. Consistent with TGF-β blockade, avb8 inhibition can enhance outcomes in checkpoint inhibitor regimens or reverse checkpoint inhibitor resistance.

[0008] The widespread expression and multifunctionality of TGF-β are limited by the application of strategies that systematically block TGF-β, as those methods produce adverse side effects. This is achieved by antagonizing integrin α. v Blocking TGF-β activity with β8 improves safety and offers therapeutic advantages over overall TGF-β inhibition. It allows for tissue localization and allotype-selective TGF-β blockade within a specific immune context. Therefore, there is still a need for TGF-β inhibition... v Therapeutic compounds of β8 integrin. Summary of the Invention

[0009] This disclosure relates to methods that can be used to suppress α v Novel compounds and methods for β8 integrin.

[0010] In one aspect, the invention is characterized by a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0011]

[0012] in:

[0013] Q ring is

[0014] L is Each of them is arbitrarily assigned to 1 to 6 Rs 4 replace;

[0015] X is -CHR 1c -、-O- or -NR 2 -;

[0016] R 1a R 1b R 1c R 1d R 1e and R 1f Each independently represents H and C. 1-4 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl group, CF3, CHF2, CH2F, CN, NO2, NR a R b Or C 1-4 Alkyl-NR a R b ,

[0017] Each R 2 Independently for H and C 1-4 Alkyl or C 3-5 cycloalkyl;

[0018] R 3a It is C 1-4 Alkoxy, C 3-5 Cycloalkoxy, CF3, CHF2, CH2F, OCF3, OCHF2, or OCH2F;

[0019] R 3b It is H, halogen, CF3 or CN;

[0020] R 3c Is it H, F, CN, or C? 1-4 alkyl;

[0021] R 3d It is C 1-4 Alkyl, C 3-5 Cycloalkyl or 4-6 membered heterocycloalkyl, each optionally surrounded by 1 to 4 R... 6 replace;

[0022] R 3e It is H or F;

[0023] Each R 4 Independently for H and C 1-4 Alkyl, halogen, CF3, CHF2 or CH2F, cyclopropyl, or two geminal Rs 4 The groups together can form a spirocyclopropyl group;

[0024] Each R 6 Independently for C 1-4 Alkyl, C 1-4 alkenyl, C 3-5 cycloalkyl, C 1-4 Alkoxy, C 3-5 Cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, 5-6 heteroaryl or NR a R b ;

[0025] Each R 7 Independently for C 1-4 Alkyl or F;

[0026] R a and R b Each independently is hydrogen, C 1-4 Alkyl, C 3-5 cycloalkyl, or R a and R b Together with the nitrogen atoms to which they are attached, they form saturated or unsaturated heterocycles containing three to seven ring atoms, said rings optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally one to three selected from F, C. 1-4 The same or different groups may be substituted within the group consisting of alkyl, phenyl, and benzyl groups; and

[0027] n is 1 or 2; and

[0028] m can be 0, 1, or 2.

[0029] In one aspect, the invention is characterized by a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0030]

[0031] in:

[0032] Q ring is

[0033] L is Each of them is arbitrarily assigned to 1 to 6 Rs 4 replace;

[0034] X is -CHR 1c -、-O- or -NR 2 -;

[0035] R 1a R 1b R 1c R 1d R 1e and R 1fEach independently represents H and C. 1-4 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl group, CF3, CHF2, CH2F, CN, NO2, NR a R b Or C 1-4 Alkyl-NR a R b ,

[0036] Each R 2 Independently for H and C 1-4 Alkyl or C 3-5 cycloalkyl;

[0037] R 3a It is cyano, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-5 Cycloalkoxy, CF3, CHF2, CH2F, OCF3, OCHF2, or OCH2F;

[0038] R 3b It is H, halogen, CF3 or CN;

[0039] R 3c Is it H, F, CN, or C? 1-4 alkyl;

[0040] R 3d It is C 1-4 Alkyl, C 3-5 Cycloalkyl or 4-6 membered heterocycloalkyl, each optionally surrounded by 1 to 4 R... 6 replace;

[0041] R 3e It is H or F;

[0042] Each R 4 Independently for H and C 1-4 Alkyl, halogen, CF3, CHF2 or CH2F, cyclopropyl, or two geminal Rs 4 The groups together can form a spirocyclopropyl group;

[0043] Each R 6 Independently for C 1-4 Alkyl, C 1-4 alkenyl, C 3-5 cycloalkyl, C 1-4 Alkoxy, C 3-5Cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, 5-6 heteroaryl or NR a R b ;

[0044] Each R 7 Independently for C 1-4 Alkyl or F;

[0045] R a and R b Each independently is hydrogen, C 1-4 Alkyl, C 3-5 cycloalkyl, or R a and R b Together with the nitrogen atoms to which they are attached, they form saturated or unsaturated heterocycles containing three to seven ring atoms, said rings optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally one to three selected from F, C. 1-4 The same or different groups may be substituted within the group consisting of alkyl, phenyl, and benzyl groups; and

[0046] n is 1 or 2; and

[0047] m can be 0, 1, or 2.

[0048] In one aspect, the invention is characterized by a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0049]

[0050] in:

[0051] Q ring is

[0052] L is

[0053] R 3a It is a methoxy group;

[0054] R 3b It is H, halogen, CF3 or CN;

[0055] R 3c Is it H, F, CN, or C? 1-4 alkyl;

[0056] R 3d It is C 1-4 Alkyl, C 3-5 Cycloalkyl or 4-6 membered heterocycloalkyl, each optionally surrounded by 1 to 4 R... 6 replace;

[0057] R 3e It is H or F;

[0058] Each R 6 Independently for C 1-4 Alkyl, C 1-4 alkenyl, C 3-5 cycloalkyl, C 1-4 Alkoxy, C 3-5 Cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, 5-6 heteroaryl or NR a R b ;

[0059] Each R 7 Independently for C 1-4 Alkyl or F;

[0060] R a and R b Each independently is hydrogen, C 1-4 Alkyl, C 3-5 cycloalkyl, or R a and R b Together with the nitrogen atoms to which they are attached, they form saturated or unsaturated heterocycles containing three to seven ring atoms, said rings optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally one to three selected from F, C. 1-4 The same or different groups may be substituted within the group consisting of alkyl, phenyl, and benzyl groups; and

[0061] n is 1 or 2; and

[0062] m can be 0, 1, or 2.

[0063] In the implementation plan, the Q-ring is Where R 1c1 and R 1c2 Each independently selected from R 1c ;R 1d1 and R 1d2 Each independently selected from R 1d And R 1e1 and R 1e2 Each independently selected from R 1e .

[0064] In the implementation plan, the Q-ring is

[0065] In the implementation scheme, X is -O-.

[0066] In the implementation scheme, X is -NR 2 -

[0067] In the implementation plan, R 2 It is a methyl group.

[0068] In the implementation plan, the Q-ring is

[0069] In the implementation plan, the Q-ring is

[0070] In the implementation plan, R 1d and R 1e Each is independently represented by H.

[0071] In the implementation plan, each R 1c H stands for H independently.

[0072] In the implementation plan, each R 1a H stands for H independently.

[0073] In the implementation plan, each R 1b H stands for H independently.

[0074] In the implementation plan, each R 1b Independently OMe.

[0075] In the implementation plan, the Q-ring is Where R 1c1 and R 1c2 Each independently selected from R 1c And R 1d1 and R 1d2 Each independently selected from R 1d .

[0076] In the implementation plan, R 1c1 R 1c2 R 1d1 and R 1d2 Each of them is independently H.

[0077] In the implementation plan, the Q-ring is

[0078] In the implementation plan, the Q-ring is

[0079] In the implementation plan, the Q-ring is

[0080] In the implementation plan, R 1c and R 1d Each is independently represented by H.

[0081] In the implementation plan, R 1a R 1b and R 1f Each is independently represented by H.

[0082] In the implementation plan, L is

[0083] In the implementation plan, L is

[0084] In the implementation plan, L is And n is 1.

[0085] In the implementation plan, L is And n is 2. In the implementation scheme, R 3a It is C 1-4 Alkyl group.

[0086] In the implementation plan, R 3a It is OMe, OEt, OCF3, OCHF2, or OCH2F.

[0087] In the implementation plan, R 3a It's OMe.

[0088] In the implementation plan, R 3a Yes - CN.

[0089] In the implementation plan, R 3a It is halogen.

[0090] In the implementation plan, R 3a It is Cl.

[0091] In the implementation plan, R 3a It is C 1-4 alkyl.

[0092] In the implementation plan, R 3a It is a methyl group.

[0093] In the implementation plan, R 3a It is an ethyl group.

[0094] In the implementation plan, R 3b It is F.

[0095] In the implementation plan, R 3c It's H.

[0096] In the implementation plan, R 3d It is C 1-4 alkyl.

[0097] In the implementation plan, R 3d It is C 3-5 Cycloalkyl.

[0098] In the implementation plan, R 3d It is an oxocyclic butyl, tetrahydrofuranyl or tetrahydro-2H-pyranyl, morpholinyl or piperazine-C 1-4 alkyl.

[0099] In the implementation plan, R3d It is isopropyl.

[0100] In the implementation plan, R 3e It's H.

[0101] In the implementation plan, each R 4 It is methyl on its own.

[0102] In the implementation plan, each R 4 Independently, it is F.

[0103] In the implementation plan, each R 4 It can be CF3, CHF2 or CH2F independently.

[0104] In the implementation plan, each R 4 H stands for H independently.

[0105] In the implementation plan, each R 6 Independently for C 1-4 alkyl.

[0106] In the implementation plan, each R 6 Independently for C 1-4 Alkenyl group.

[0107] In the implementation plan, each R 6 Independently for C 3-5 Cycloalkyl.

[0108] In the implementation plan, each R 6 Independently for C 1-4 Alkyl group.

[0109] In the implementation plan, each R 6 Independently for C 3-5 Cycloalkoxy group.

[0110] In the implementation plan, each R 6 It can be F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F or OH independently.

[0111] In the implementation plan, each R 6 It is independently a 5-6 member heteroaryl group.

[0112] In the implementation plan, each R 6 H stands for H independently.

[0113] In the implementation plan, each R 7 Independently, it is F.

[0114] In the implementation plan, n is 0.

[0115] In the implementation plan, n is 1.

[0116] In the implementation plan, n is 2.

[0117] In the implementation plan, m is 0.

[0118] In the implementation plan, m is 1.

[0119] In the implementation plan, m is 2.

[0120] In the embodiments, the compound has a structure according to formula (II),

[0121]

[0122] Or its pharmaceutically acceptable salt.

[0123] In the embodiments, the compound has a structure according to formula (IIA),

[0124]

[0125] Or its pharmaceutically acceptable salt.

[0126] In the implementation scheme, the compound has a structure according to formula (III),

[0127]

[0128] Or its pharmaceutically acceptable salt.

[0129] In the embodiments, the compound has a structure according to formula (IIIA),

[0130]

[0131] Or its pharmaceutically acceptable salt.

[0132] In the implementation scheme, the compound has a structure according to formula (IV),

[0133]

[0134] Or its pharmaceutically acceptable salt.

[0135] In the embodiments, the compound has a structure according to formula (IVA),

[0136]

[0137] Or its pharmaceutically acceptable salt.

[0138] In the implementation scheme, the compound has a structure according to formula (V),

[0139]

[0140] Or its pharmaceutically acceptable salt.

[0141] In the implementation scheme, the compound has a structure according to formula (VA),

[0142]

[0143] Or its pharmaceutically acceptable salt.

[0144] In the implementation scheme, the compound has a structure according to formula (VI),

[0145]

[0146] Or its pharmaceutically acceptable salt.

[0147] In the embodiments, the compound has a structure according to formula (VIA),

[0148]

[0149] Or its pharmaceutically acceptable salt.

[0150] In one aspect, the invention is characterized by a compound of formula (VII) or a pharmaceutically acceptable salt thereof:

[0151]

[0152] Among them, L, Q, R7, R 3a R 3b R 3c R 3d R 3e Each according to any implementation described herein.

[0153] In one aspect, the invention is characterized by a compound of formula (VII) or a pharmaceutically acceptable salt thereof:

[0154]

[0155] The Q ring is

[0156] L is

[0157] n is 1 or 2;

[0158] R 3a It is a methoxy group;

[0159] R7 is either H or F;

[0160] R 3a It is a methoxy group; and

[0161] R 3b R3c R 3d R 3e As disclosed above regarding formula (I).

[0162] In the implementation plan, n is 1.

[0163] In the implementation plan, n is 2.

[0164] In the implementation plan, R 1b It is H, CH3, or OCH3.

[0165] In the implementation plan, R 3e It is H or F.

[0166] In the implementation plan, R 3d It is arbitrarily assigned to 1 R 6 Replacement C 1-4 alkyl.

[0167] In the implementation plan, R 3d yes

[0168] In the implementation plan, R 3d It is arbitrarily assigned to 1 R 6 Substituted 4-6 membered heterocyclic alkyl groups.

[0169] In the implementation plan, R 3d yes

[0170] In the implementation plan, R 3d It is arbitrarily assigned to 1 R 6 Replacement C 3-5 Cycloalkyl.

[0171] In the implementation plan, R 3d yes

[0172] In the implementation scheme, carbon marked with an asterisk (*) has an (R)- configuration.

[0173] In the implementation scheme, carbon marked with an asterisk (*) has an (S)- configuration.

[0174] In the implementation scheme, the compound is selected from any of the compounds described in Table 1 or their pharmaceutically acceptable salts.

[0175] In the implementation scheme, the compound of formula (I) is selected from the group consisting of:

[0176]

[0177]

[0178]

[0179]

[0180] Or its pharmaceutically acceptable salt.

[0181] In the implementation scheme, the compound of formula (I) is

[0182] Or a pharmaceutically acceptable salt thereof. In the embodiments, the compound is compound 1A or a pharmaceutically acceptable salt thereof. In the embodiments, the compound is compound aB or a pharmaceutically acceptable salt thereof.

[0183] In the implementation scheme, the compound of formula (I) is

[0184] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 2A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 2B or a pharmaceutically acceptable salt thereof.

[0185] In the implementation scheme, the compound of formula (I) is

[0186] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 7A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 7B or a pharmaceutically acceptable salt thereof.

[0187] In the implementation scheme, the compound of formula (I) is

[0188] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 11A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 11B or a pharmaceutically acceptable salt thereof.

[0189] In the implementation scheme, the compound of formula (I) is

[0190] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 12A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 12B or a pharmaceutically acceptable salt thereof.

[0191] In the implementation scheme, the compound of formula (I) is

[0192] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 17A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 17B or a pharmaceutically acceptable salt thereof.

[0193] In the implementation scheme, the compound of formula (I) is

[0194] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 20A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 20B or a pharmaceutically acceptable salt thereof.

[0195] In the implementation scheme, the compound of formula (I) is

[0196] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 24A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 24B or a pharmaceutically acceptable salt thereof.

[0197] In the implementation scheme, the compound of formula (I) is

[0198] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 24A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 24B or a pharmaceutically acceptable salt thereof.

[0199] In the implementation scheme, the compound of formula (I) is

[0200] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 35A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 35B or a pharmaceutically acceptable salt thereof.

[0201] In the implementation scheme, the compound of formula (I) is

[0202] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 36A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 36B or a pharmaceutically acceptable salt thereof.

[0203] In the implementation scheme, the compound of formula (I) is

[0204] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 41A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 41B or a pharmaceutically acceptable salt thereof.

[0205] In the implementation scheme, the compound of formula (I) is

[0206] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 42A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 42B or a pharmaceutically acceptable salt thereof.

[0207] In the implementation scheme, the compound of formula (I) is

[0208] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 47A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 47B or a pharmaceutically acceptable salt thereof.

[0209] In the implementation scheme, the compound of formula (I) is

[0210] Or a pharmaceutically acceptable salt thereof. In an embodiment, the compound is compound 123A or a pharmaceutically acceptable salt thereof. In an embodiment, the compound is compound 123B or a pharmaceutically acceptable salt thereof.

[0211] In the implementation scheme, the compound of formula (I) is

[0212] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 125A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 125B or a pharmaceutically acceptable salt thereof.

[0213] In the implementation scheme, the compound of formula (I) is

[0214] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 129A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 129B or a pharmaceutically acceptable salt thereof.

[0215] In the implementation scheme, the compound of formula (I) is

[0216] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 135A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 135B or a pharmaceutically acceptable salt thereof.

[0217] In the implementation scheme, the compound of formula (I) is

[0218] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 136A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 136B or a pharmaceutically acceptable salt thereof.

[0219] In the implementation scheme, the compound of formula (I) is

[0220] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 150A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 150B or a pharmaceutically acceptable salt thereof.

[0221] In the implementation scheme, the compound of formula (I) is

[0222] Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 154A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 154B or a pharmaceutically acceptable salt thereof.

[0223] In another aspect, the invention is characterized by a pharmaceutical composition comprising any compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0224] In another aspect, the invention is characterized by a method for inhibiting avb8 integrin in a patient, the method comprising administering to a patient in need a therapeutically effective amount of any of the compounds described herein or a pharmaceutically acceptable salt thereof. In an embodiment, the method is used to treat a patient with a solid tumor.

[0225] In another aspect, the invention is characterized by a method of treating a patient with a solid tumor, the method comprising administering to a patient in need (a) a therapeutically effective amount of any compound described herein or a pharmaceutically acceptable salt thereof, and (b) a therapeutically effective amount of a second active agent.

[0226] In the implementation plan, solid tumors are selected from: anal cancer, bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, fallopian tube cancer, gastric cancer, glioma, liver cancer, lung cancer, melanoma, nasopharyngeal carcinoma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, primary peritoneal cancer, prostate cancer, renal cell carcinoma, skin cancer, squamous cell carcinoma of the head and neck (SCCHN), testicular cancer, urothelial carcinoma, and uterine cancer.

[0227] In the implementation plan, solid tumors are selected from: breast cancer, squamous cell carcinoma of the head and neck (SCCHN), renal cell carcinoma, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, pancreatic cancer, bile duct cancer, endometrial cancer, melanoma, and urothelial carcinoma.

[0228] In the implementation scheme, the second active agent is an immune checkpoint inhibitor (e.g., anti-PD-1 or anti-PD-L1 therapy). In the implementation scheme, the immune checkpoint inhibitor is selected from: nivolumab, pembrolizumab, cimiprimab, dostarlimab, atezolizumab, avelumab, and durvalumab. Detailed Implementation

[0229] definition

[0230] For convenience, certain terms used in this specification, embodiments, and appended claims are collected herein before further description of the invention. These definitions should be read in light of the remainder of this disclosure and should be understood as those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0231] To facilitate understanding of the invention, certain terms and phrases are defined below and throughout the specification.

[0232] As used in this article, the article “a / an” refers to the grammatical object of one / a kind or more / a kind (i.e., at least one / a kind). For example, “a / a kind of element” refers to one / a kind of element or more / a kind of element.

[0233] As used herein in the specification and claims, the phrase “and / or” should be understood to mean “any one or both” of the elements so combined (i.e., elements that coexist in some cases and exist separately in others). Multiple elements listed with “and / or” should be understood in the same way, i.e., “one or more” of the elements so combined. In addition to the elements explicitly identified by the “and / or” clause, other elements may optionally be present, whether related to or unrelated to those explicitly identified. Thus, as a non-limiting example, when used in conjunction with open-ended language such as “comprising”, a reference to “A and / or B” may refer to only A (optionally including elements other than B) in one embodiment; only B (optionally including elements other than A) in another embodiment; both A and B (optionally including other elements) in yet another embodiment; and so on.

[0234] As used herein in the specification and claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” should be interpreted as inclusive, that is, including multiple elements or at least one element in a list of elements, but also including more than one element, as well as optional other items not listed. Only terms that clearly indicate the opposite meaning, such as “only one” or “exactly one”, or when used in the claims, “consisting of”, will refer to multiple elements or exactly one element in a list of elements. In general, the term “or” as used herein, when followed by an exclusive term (such as “any,” “one of,” “only one of,” or “exact one of”), should be interpreted only to indicate an exclusive alternative (i.e., “one or the other but not both”). “Substantially consisting of”, when used in the claims, should have the usual meaning as used in the field of patent law.

[0235] As used herein in the specification and claims, the phrase “at least one” when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of every element specifically listed in the list of elements, nor exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those expressly identified in the list of elements referred to by the phrase “at least one”, whether related to or unrelated to the expressly identified elements. Thus, as a non-limiting example, “at least one of A and B” (or equivalently, “at least one of A or B”, or equivalently, “at least one of A and / or B”) may refer to at least one A in one embodiment, optionally including more than one A, but without B (and optionally including elements other than B); in another embodiment, refer to at least one B, optionally including more than one B, but without A (and optionally including elements other than A); in yet another embodiment, refer to at least one A, optionally including more than one A, and at least one B, optionally including more than one B (and optionally including other elements); and so on.

[0236] It should also be understood that, unless the context otherwise requires, in any method claimed herein that includes more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are listed herein.

[0237] In the claims and the aforementioned description, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and “consisting of” should be understood as open-ended, meaning including but not limited to. As explained in Section 2111.03 of the U.S. Patent Examination Procedure Manual, only the transitional phrases “consisting of” and “substantially consisting of” are closed or semi-closed transitional phrases, respectively.

[0238] Certain compounds contained in the compositions of the present invention may exist in specific geometric or stereoisomeric forms. Additionally, the polymers of the present invention may also be optically active. The present invention contemplates all such compounds falling within the scope of the present invention, including cis and trans isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in substituents (such as alkyl groups). All such isomers and mixtures thereof are intended to be included in the present invention.

[0239] For example, if a specific enantiomer of the compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is isolated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, in the case where the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, and the resulting diastereomeric isomer is then resolved by fractional crystallization or chromatographic means well known in the art, and the pure enantiomer is subsequently recovered.

[0240] The structures described in this article are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, by replacing hydrogen with deuterium or tritium, or by using atoms rich in deuterium or tritium. 13 C or 14 Compounds produced by substituting carbon for carbon in C are within the scope of this invention.

[0241] The terms “αvβ8”, “avB8”, “avb8”, “α-vβ-8”, and “alphav beta 8” used in this article all refer to α. v β8.

[0242] As used herein, the phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that participates in the transport or transfer of a subject chemical from one organ or part of the body to another organ or part of the body. Each carrier must be “acceptable” in the sense that it is compatible with other components in the formulation, does not cause harm to the patient, and is substantially pyrogen-free. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) astragalus gum powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and so on. Soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic and compatible substances used in pharmaceutical preparations. In some embodiments, the pharmaceutical compositions of the present invention are pyrogen-free, i.e., they do not cause a significant increase in body temperature when administered to a patient.

[0243] The term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic acid addition salt of a compound. These salts can be prepared in situ during the final separation and purification of the compound, or by reacting the purified free base form of the compound with a suitable organic or inorganic acid and then separating the resulting salt. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, methanesulfonate, glucono-p-ethyl, lacturonate, and laurylsulfonate, etc. (See, for example, Berge et al. (1977), "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19.)

[0244] In other cases, compounds used in the methods of this invention may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic and organic base addition salt of one or more compounds. These salts can also be prepared in situ during the final separation and purification of one or more of the said compounds, or by reacting one or more purified compounds in their free acid form with a suitable base (such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation), with ammonia, or with a pharmaceutically acceptable primary, secondary, or tertiary organic amine. Representative alkali metal or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, etc. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (see, for example, Berge et al., ibid.).

[0245] The "therapeutic effective amount" (or "effective amount") of a compound used in treatment refers to the amount of a compound in a formulation which, when administered as part of a desired dosing regimen (to mammals, preferably humans), is of clinically acceptable standard or cosmetic purpose, such as to relieve symptoms, improve the condition, or slow the onset of a disease, based on a reasonable benefit / risk ratio suitable for any drug treatment.

[0246] The term "preventive or therapeutic" treatment is recognized in the art and includes the administration of one or more subject compositions to a host. Treatment is preventive (i.e., it protects the host from developing the unwanted disease) if it is administered before the clinical manifestation of an unwanted condition (e.g., a disease or other unwanted state in the host animal), and therapeutic (i.e., it is intended to alleviate, improve, or stabilize an existing unwanted condition or its side effects) if it is administered after the manifestation of the unwanted condition.

[0247] The term "patient" refers to a mammal that requires specific treatment. In some embodiments, the patient is a primate, canine, feline, or equine. In some embodiments, the patient is a human.

[0248] Whenever a term (e.g., alkyl or aryl) or any of its prefix roots (e.g., alk- or ar-) appears in the name of a substituent, the name should be interpreted to include the limitations provided herein. For example, adding the suffix "-ene" to a group indicates that the group is a divalent moiety; for instance, arylene is the divalent moiety of an aryl, heteroarylene is the divalent moiety of a heteroaryl, and heterocycloalkyl is the divalent moiety of a heterocycloalkyl. Similarly, adding the suffix "-oxy" to a group indicates that the group is attached to the parent molecule structure via an oxygen atom (-O-), such as "alkyloxy," "alkoxy," or "cycloalkoxy" as used herein.

[0249] Aliphatic chains include the alkyl, alkenyl, and alkynyl categories as defined below. Straight-chain aliphatic chains are limited to the unbranched carbon chain portion. As used herein, the term "aliphatic group" refers to a straight-chain, branched, or cyclic aliphatic hydrocarbon group and includes both saturated and unsaturated aliphatic groups such as alkyl, alkenyl, or alkynyl groups.

[0250] "Alkyl" refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having a specified number of carbon atoms, or, if not specified, 1 to 30 carbon atoms. For example, alkyl groups with 1 to 8 carbon atoms refer to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as those that are positional isomers of these moieties. Alkyl groups with 10 to 30 carbon atoms include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecanyl, octadecyl, nonadecanyl, eicosyl, dodecyl, tridecyl, and tetradecyl. In some embodiments, straight-chain or branched alkyl groups have 30 or fewer carbon atoms in their main chain (e.g., for straight-chain C1-C2). 30 For C3-C branches 30 (and more preferably 20 or fewer carbon atoms. Alkyl groups may be substituted or unsubstituted. As used herein, both "Me" and -CH3 refer to methyl groups.)

[0251] As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbon atoms, such as 2 to 12, on its longest carbon chain, having two attachment points with the remainder of the compound. Non-limiting examples of alkylenes include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, isopropylene-(CH2CH(CH3))-, etc. Alkylenes can be cyclic or acyclic, branched or unbranched carbon chain portions, and may optionally be substituted with one or more substituents.

[0252] "Cycloalkyl" refers to a monocyclic, bicyclic, bridged, spirocyclic, or polycyclic saturated carbocyclic ring, each having 3 to 12 carbon atoms. Similarly, preferred cycloalkyl groups have 3-10 carbon atoms in their ring structure, and more preferably 3-6 carbon atoms. Cycloalkyl groups can be substituted or unsubstituted. Exemplary cycloalkyl groups include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cycloheptyl (C7), and cyclooctyl (C8).

[0253] Unless otherwise specified, "lower alkyl" as used herein refers to an alkyl group as defined above, but having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, in its main chain structure, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyl groups. In some embodiments, the substituents designated as alkyl groups herein are lower alkyl groups.

[0254] As used herein, the term "aryl" includes 3 to 12-membered substituted or unsubstituted monocyclic aromatic groups, wherein each atom of the ring is a carbon (i.e., carbocyclic aryl) or one or more of the atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl comprises 5 to 12-membered rings, more preferably 6 to 10-membered rings. The term "aryl" also includes polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is aromatic, for example, other rings may be cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc. Heteroaryl groups include substituted or unsubstituted aromatic 3 to 12-membered ring structures, more preferably 5 to 12-membered rings, more preferably 5 to 10-membered rings, whose ring structure contains 1 to 4 heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryl and heteroaryl groups can be monocyclic, bicyclic, or polycyclic.

[0255] As used herein, the terms “halogen,” “halide,” or “halogen” refer to halogens and include, for example, but not limited to, fluorine, chlorine, bromine, iodine, etc., in radioactive and non-radioactive forms. In a preferred embodiment, the halogen is selected from the group consisting of fluorine, chlorine, and bromine.

[0256] The term "heterocyclic group" or "heterocyclic group" refers to a 3- to 12-membered ring structure, more preferably a 5- to 12-membered ring, and even more preferably a 5- to 10-membered ring, whose ring structure contains 1 to 4 heteroatoms. The heterocycle can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclic groups include, for example, thiophene, thiathracene, furan, pyran, isobenzofuran, chromene, oxanthracene, oxthionthanthracene, pyrrole, imidazole, pyrazole, isothiazol, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indazine, isoindole, indole, indazole, purine, quinazine, isoquinoline, quinoline, phthalazine, naphthidine, quinoxoline, quinazoline, cyclophosphine, pteridine, carbazole, caroline, phenanthridine, acridine, pyrimidine, phenanthrene-rhein, phenazine, phenpyrazine, phenothiazine, furazine, phenothiazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactone, lactam such as azacyclobutanone and pyrrolidone, sulfonamide, sulfonyl lactone, etc. The heterocycle may be substituted at one or more positions with substituents as described above, such as halogens, alkyl groups, aralkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, hydroxyl groups, amino groups, nitro groups, thioalkyl groups, imino groups, amide groups, phosphate groups, phosphonate groups, phosphonite groups, carbonyl groups, carboxyl groups, silyl groups, aminosulfonyl groups, sulfinyl groups, ethers, alkylthio groups, sulfonyl groups, ketones, aldehydes, esters, heterocyclic groups, aromatic or heteroaromatic moieties, -CF3, -CN, etc.

[0257] As used herein, the term "heterocyclic alkyl" refers to a non-aromatic heterocyclic group in which at least one atom is a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus, and the remaining atoms are carbon. Examples of heterocyclic alkyl groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropiperanyl, dihydropiperanyl, tetrahydrothiopiperanyl, piperidinyl, morpholinyl, thiomorpholinyl, oxothiohexacyclohexyl, piperazine, aziridine, oxacyclobutane, oxacyclobutane, thiohexacyclobutane, high-piperidinyl, oxacycloheptane, thiohexacycloheptane, oxacyclohexacyclothranyl, diazacyclohexa ... The heterocyclic alkyl groups include pyridyl, 2-pyrrolylyl, 3-pyrrolylyl, dihydroindolyl, 2H-piperanyl, 4H-piperanyl, dioxylyl, 1,3-dioxolanecycloyl, pyrazolinyl, dithiaylylyl, dithiopentanyl, dihydropiperanyl, dihydrothiophenyl, dihydrofuranyl, pyrazolinyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, and quinazinyl. The heterocyclic alkyl groups may be substituted or unsubstituted, for example, as described herein with respect to heterocyclic groups.

[0258] The term "carbonyl" is recognized in the art and includes a portion that can be represented by the following formula:

[0259]

[0260] Where X' is a bond or represents oxygen or sulfur, and R 15Indicates hydrogen, alkyl, alkenyl, -(CH2) m -R 10 Or a pharmaceutically acceptable salt, R 16 Indicates hydrogen, alkyl, alkenyl, or -(CH2). m -R 10 , where m and R 10 As defined above. When X' is oxygen and R 15 or R 16 When X' is not hydrogen, the formula represents "ester". When X' is oxygen, and R... 15 As defined above, this part is referred to herein as a carboxyl group, and especially when R 15 When X' is hydrogen, the formula represents "carboxylic acid". When X' is oxygen, and R... 16 When it is hydrogen, the formula represents "formate ester". On the other hand, when X' is a bond and R... 15 When it is not hydrogen, the above formula represents a "ketone" group. When X' is a bond, and R... 15 When it is hydrogen, the above formula represents an "aldehyde" group.

[0261] As used herein, the term "substituted" is intended to include all permissible substituents of an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Exemplary substituents include, for example, those described above herein, and are substituted, for example, by one or more substituents selected from alkyl, cycloalkyl, heterocyclic alkyl, halogen, OH, OMe, C(H)F2, C(F)H2, CF3, C(H)2CF3, SF5, CHFCH2amine, CH2amine, and CN. For a suitable organic compound, permissible substituents may be one or more and may be the same or different. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of an organic compound that satisfy the valence of the heteroatom as described herein. This invention is not intended to limit in any way to permissible substituents of organic compounds. It should be understood that “substitution” or “being substituted” includes the implicit condition that the substitution is consistent with the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, for example, a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, or elimination.

[0262] As used herein, the term “nitro” means -NO2; the term “halogen” means -F, -Cl, -Br or -I; the term “hydroxyl” means -OH; and the term “cyano” means -CN.

[0263] As used herein, the definition of each expression (e.g., alkyl, m, n, etc.) is intended to be independent of its definition elsewhere in the same structure when it appears more than once in any structure.

[0264] As used herein, the term "prodrug" encompasses a compound that is converted to a therapeutically active agent under physiological conditions. A common method for preparing a prodrug involves hydrolysis under physiological conditions to reveal selected portions of the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of a host animal. Thus, a prodrug includes a compound converted in vivo to produce the disclosed compound or any other pharmaceutically acceptable form of said compound. In embodiments, the prodrug may be inactive when administered to a subject, but may be converted in vivo, for example, by hydrolysis, to the active compound. See, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7–9, 21–24 (Elsevier, Amsterdam). Discussion of prodrugs is provided in Higuchi, T. et al., “Pro-drugs as Novel Delivery Systems,” ACSSymposium Series, Vol. 14, and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety. Prodrugs are typically prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff, ed., 5th ed., 1995) and Design of Prodrugs (H. Bundgaard, ed., Elselvier, New York, 1985). The term "prodrug" is also intended to include any covalently bonded carrier that, when administered to a subject, releases the active compound in vivo.

[0265] Prodrugs of the compounds described herein can be prepared by modifying functional groups present in the active compound, such that the modification is cleaved in a conventional manner or in vivo to provide the compound described herein (i.e., the parent active compound). Prodrugs include compounds in which a hydroxyl, amino, or thiol group is bonded to any group that, when administered to a subject as a prodrug of the active compound, cleaves to form a free hydroxyl, free amino, or free thiol group. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohols in the active compound, or acetamide, formamide, and benzamide derivatives of amine functional groups in the active compound. Other examples of prodrugs include compounds containing -NO, -NO2, -ONO, or -ONO2 moieties.

[0266] For the purposes of this invention, chemical elements are identified according to the periodic table, CAS edition, Handbook of Chemistry and Physics, 67th edition, 1986-87, inside cover.

[0267] Exemplary compounds of the present invention

[0268] This disclosure relates to methods that can be used to suppress α v Novel compounds and methods for β8 integrin.

[0269] Exemplary formulas and compounds are described herein. Exemplary embodiments of structural features that may be present in any of the formulas described herein are also provided. Any exemplary embodiment of a structural feature may appear in combination with any other exemplary structural feature described herein. Furthermore, unless otherwise indicated herein, any description of a formula or compound includes any pharmaceutically acceptable form of the compound, including but not limited to any pharmaceutically acceptable salts, hydrates, solvates, isomers, polymorphs, prodrugs, and isotopically labeled derivatives of the disclosed formulas and compounds.

[0270] In the implementation scheme, the compound described herein is α v Selective inhibitors of β8 integrin. In embodiments, the compounds described herein are relative to, for example, α... v β6 integrin selectively inhibits α v β8 integrin (e.g., selectivity of at least about 10×, 20×, 50×, 100×, 500× or 1000×, as measured by an assay (e.g., fluorescence polarization assay)).

[0271] This document describes certain exemplary formulas, compounds, and structural features. Any structural features and embodiments described herein may be used in any combination with any other structural features and embodiments described herein.

[0272] Formula (I)

[0273] In one aspect, the invention is characterized by a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0274]

[0275] in:

[0276] Q ring is

[0277] L is Each of them is arbitrarily assigned to 1 to 6 Rs 4 replace;

[0278] X is -CHR1c -、-O- or -NR 2 -;

[0279] R 1a R 1b R 1c R 1d R 1e and R 1f Each independently represents H and C. 1-4 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl group, CF3, CHF2, CH2F, CN, NO2, NR a R b Or C 1-4 Alkyl-NR a R b ,

[0280] Each R 2 Independently for H and C 1-4 Alkyl or C 3-5 cycloalkyl;

[0281] R 3a It is C 1-4 Alkoxy, C 3-5 Cycloalkoxy, CF3, CHF2, CH2F, OCF3, OCHF2, or OCH2F;

[0282] R 3b It is H, halogen, CF3 or CN;

[0283] R 3c Is it H, F, CN, or C? 1-4 alkyl;

[0284] R 3d It is C 1-4 Alkyl, C 3-5 Cycloalkyl or 4-6 membered heterocycloalkyl, each optionally surrounded by 1 to 4 R... 6 replace;

[0285] R 3e It is H or F;

[0286] Each R 4 Independently for H and C 1-4 Alkyl, halogen, CF3, CHF2 or CH2F, cyclopropyl, or two geminal Rs 4 The groups together can form a spirocyclopropyl group;

[0287] Each R 6 Independently for C 1-4 Alkyl, C 1-4 alkenyl, C 3-5 cycloalkyl, C 1-4 Alkoxy, C 3-5 Cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, 5-6 heteroaryl or NR a R b ;

[0288] Each R 7 Independently for C 1-4 Alkyl or F;

[0289] R a and R b Each independently is hydrogen, C 1-4 Alkyl, C 3-5 cycloalkyl, or R a and R b Together with the nitrogen atoms to which they are attached, they form saturated or unsaturated heterocycles containing three to seven ring atoms, said rings optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally one to three selected from F, C. 1-4 The same or different groups may be substituted within the group consisting of alkyl, phenyl, and benzyl groups; and

[0290] n is 1 or 2; and

[0291] m can be 0, 1, or 2.

[0292] In one aspect, the invention is characterized by a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0293]

[0294] in:

[0295] Q ring is

[0296] L is Each of them is arbitrarily assigned to 1 to 6 Rs 4 replace;

[0297] X is -CHR 1c -、-O- or -NR 2 -;

[0298] R 1a R 1b R 1c R 1d R 1e and R 1f Each independently represents H and C.1-4 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl group, CF3, CHF2, CH2F, CN, NO2, NR a R b Or C 1-4 Alkyl-NR a R b ,

[0299] Each R 2 Independently for H and C 1-4 Alkyl or C 3-5 cycloalkyl;

[0300] R 3a It is cyano, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-5 Cycloalkoxy, CF3, CHF2, CH2F, OCF3, OCHF2, or OCH2F;

[0301] R 3b It is H, halogen, CF3 or CN;

[0302] R 3c Is it H, F, CN, or C? 1-4 alkyl;

[0303] R 3d It is C 1-4 Alkyl, C 3-5 Cycloalkyl or 4-6 membered heterocycloalkyl, each optionally surrounded by 1 to 4 R... 6 replace;

[0304] R 3e It is H or F;

[0305] Each R 4 Independently for H and C 1-4 Alkyl, halogen, CF3, CHF2 or CH2F, cyclopropyl, or two geminal Rs 4 The groups together can form a spirocyclopropyl group;

[0306] Each R 6 Independently for C 1-4 Alkyl, C 1-4 alkenyl, C 3-5 cycloalkyl, C 1-4 Alkoxy, C 3-5Cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, 5-6 heteroaryl or NR a R b ;

[0307] Each R 7 Independently for C 1-4 Alkyl or F;

[0308] R a and R b Each independently is hydrogen, C 1-4 Alkyl, C 3-5 cycloalkyl, or R a and R b Together with the nitrogen atoms to which they are attached, they form saturated or unsaturated heterocycles containing three to seven ring atoms, said rings optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally one to three selected from F, C. 1-4 The same or different groups may be substituted within the group consisting of alkyl, phenyl, and benzyl groups; and

[0309] n is 1 or 2; and

[0310] m can be 0, 1, or 2.

[0311] In one aspect, the invention is characterized by a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0312]

[0313] in:

[0314] Q ring is

[0315] L is

[0316] R 3a It is a methoxy group;

[0317] R 3b It is H, halogen, CF3 or CN;

[0318] R 3c Is it H, F, CN, or C? 1-4 alkyl;

[0319] R 3d It is C 1-4 Alkyl, C 3-5 Cycloalkyl or 4-6 membered heterocycloalkyl, each optionally surrounded by 1 to 4 R... 6 replace;

[0320] R 3e It is H or F;

[0321] Each R 6 Independently for C 1-4 Alkyl, C 1-4 alkenyl, C 3-5 cycloalkyl, C 1-4 Alkoxy, C 3-5 Cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, 5-6 heteroaryl or NR a R b ;

[0322] Each R 7 Independently for C 1-4 Alkyl or F;

[0323] R a and R b Each independently is hydrogen, C 1-4 Alkyl, C 3-5 cycloalkyl, or R a and R b Together with the nitrogen atoms to which they are attached, they form saturated or unsaturated heterocycles containing three to seven ring atoms, said rings optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally one to three selected from F, C. 1-4 The same or different groups may be substituted within the group consisting of alkyl, phenyl, and benzyl groups; and

[0324] n is 1 or 2; and

[0325] m can be 0, 1, or 2.

[0326] In the implementation plan, the Q-ring is Where R 1c1 and R 1c2 Each independently selected from R 1c ;R 1d1 and R 1d2 Each independently selected from R 1d And R 1e1 and R 1e2 Each independently selected from R 1e .

[0327] In the implementation plan, the Q-ring is

[0328] In the implementation scheme, X is -O-.

[0329] In the implementation scheme, X is -NR 2 -

[0330] In the implementation plan, R 2 It is a methyl group.

[0331] In the implementation plan, the Q-ring is

[0332] In the implementation plan, the Q-ring is Where R 1c1 and R 1c2 Each independently selected from R 1c And R 1d1 and R 1d2 Each independently selected from R 1d .

[0333] In the implementation plan, R 1c1 R 1c2 R 1d1 and R 1d2 Each of them is independently H.

[0334] In the implementation plan, the Q-ring is

[0335] In the implementation plan, the Q-ring is

[0336] In the implementation plan, the Q-ring is

[0337] In the implementation plan, R 1d and R 1e Each is independently represented by H.

[0338] In the implementation plan, each R 1c H stands for H independently.

[0339] In the implementation plan, each R 1a H stands for H independently.

[0340] In the implementation plan, each R 1b H stands for H independently.

[0341] In the implementation plan, each R 1b Independently OMe.

[0342] In the implementation plan, the Q-ring is

[0343] In the implementation plan, R 1c and R 1d Each is independently represented by H.

[0344] In the implementation plan, R 1a R 1b and R 1f Each is independently represented by H.

[0345] In the implementation plan, L is And n is 1.

[0346] In the implementation plan, L is And n is 2.

[0347] In the implementation plan, L is

[0348] In the implementation plan, L is

[0349] In the implementation plan, R 3a It is C 1-4 Alkyl group.

[0350] In the implementation plan, R 3a It is OMe, OEt, OCF3, OCHF2, or OCH2F.

[0351] In the implementation plan, R 3a It's OMe.

[0352] In the implementation plan, R 3a Yes - CN.

[0353] In the implementation plan, R 3a It is halogen.

[0354] In the implementation plan, R 3a It is Cl.

[0355] In the implementation plan, R 3a It is C 1-4 alkyl.

[0356] In the implementation plan, R 3a It is a methyl group.

[0357] In the implementation plan, R 3a It is an ethyl group.

[0358] In the implementation plan, R 3b It is F.

[0359] In the implementation plan, R 3c It's H.

[0360] In the implementation plan, R 3d It is C 1-4 alkyl.

[0361] In the implementation plan, R 3d It is C 3-5 Cycloalkyl.

[0362] In the implementation plan, R 3d It is an oxocyclic butyl, tetrahydrofuranyl or tetrahydro-2H-pyranyl, morpholinyl or piperazine-C 1-4 alkyl.

[0363] In the implementation plan, R 3d It is isopropyl.

[0364] In the implementation plan, R 3e It's H.

[0365] In the implementation plan, each R 4 It is methyl on its own.

[0366] In the implementation plan, each R 4 Independently, it is F.

[0367] In the implementation plan, each R 4 It can be CF3, CHF2 or CH2F independently.

[0368] In the implementation plan, each R 4 H stands for H independently.

[0369] In the implementation plan, each R 6 Independently for C 1-4 alkyl.

[0370] In the implementation plan, each R 6 Independently for C 1-4 Alkenyl group.

[0371] In the implementation plan, each R 6 Independently for C 3-5 Cycloalkyl.

[0372] In the implementation plan, each R 6 Independently for C 1-4 Alkyl group.

[0373] In the implementation plan, each R 6 Independently for C 3-5 Cycloalkoxy group.

[0374] In the implementation plan, each R 6 It can be F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F or OH independently.

[0375] In the implementation plan, each R 6 It is independently a 5-6 member heteroaryl group.

[0376] In the implementation plan, each R 6 H stands for H independently.

[0377] In the implementation plan, each R 7 Independently, it is F.

[0378] In the implementation plan, each R 7F is independent and m is 0 or 1.

[0379] In the implementation plan, each R 7 It is methyl on its own.

[0380] In the implementation plan, each R 7 It is independently methyl and m is 0 or 1.

[0381] In the implementation plan, n is 0.

[0382] In the implementation plan, n is 1.

[0383] In the implementation plan, n is 2.

[0384] In the implementation plan, m is 0.

[0385] Equations (II)-(VII)

[0386] In the embodiments, the compound has a structure according to formula (II),

[0387]

[0388] Or a pharmaceutically acceptable salt thereof, wherein R 1b R 3a R 3b R 3c R 3d R 3e Each according to any implementation described herein.

[0389] In the embodiments, the compound has a structure according to formula (IIA),

[0390]

[0391] Or a pharmaceutically acceptable salt thereof, wherein R 1b R 3d and R 3e Each according to any implementation described herein.

[0392] In the implementation scheme, the compound has a structure according to formula (III),

[0393]

[0394] Or a pharmaceutically acceptable salt thereof, wherein R 1b R 3a R 3b R 3c R 3d R 3e Each according to any implementation described herein.

[0395] In the embodiments, the compound has a structure according to formula (IIIA),

[0396]

[0397] Or a pharmaceutically acceptable salt thereof, wherein R 1b R 3d and R 3e Each according to any implementation described herein.

[0398] In the implementation scheme, the compound has a structure according to formula (IV),

[0399]

[0400] Or a pharmaceutically acceptable salt thereof, wherein R 1b R 3a R 3b R 3c R 3d R 3e Each according to any implementation described herein.

[0401] In the embodiments, the compound has a structure according to formula (IVA),

[0402]

[0403] Or a pharmaceutically acceptable salt thereof, wherein R 1b R 3d and R 3e Each according to any implementation described herein.

[0404] In the implementation scheme, the compound has a structure according to formula (V),

[0405]

[0406] Or a pharmaceutically acceptable salt thereof, wherein n, R 1b R 3a R 3b R 3c R 3d R 3e Each according to any implementation described herein.

[0407] In the implementation scheme, the compound has a structure according to formula (VA),

[0408]

[0409] Or a pharmaceutically acceptable salt thereof, wherein n, R 1b R 3d and R3e Each according to any implementation described herein.

[0410] In the implementation scheme, the compound has a structure according to formula (VI),

[0411]

[0412] Or a pharmaceutically acceptable salt thereof, wherein n, R 1b R 3a R 3b R 3c R 3d R 3e Each according to any implementation described herein.

[0413] In the embodiments, the compound has a structure according to formula (VIA),

[0414]

[0415] Or a pharmaceutically acceptable salt thereof, wherein n, R 1b R 3d and R 3e Each according to any implementation described herein.

[0416] In one aspect, the invention is characterized by a compound of formula (VII) or a pharmaceutically acceptable salt thereof:

[0417]

[0418] Among them, L, Q, R7, R 3a R 3b R 3c R 3d R 3e Each according to any implementation described herein.

[0419] In one aspect, the invention is characterized by a compound of formula (VII) or a pharmaceutically acceptable salt thereof:

[0420]

[0421] The Q ring is

[0422] L is

[0423] n is 1 or 2;

[0424] R 3a It is a methoxy group;

[0425] R7 is either H or F;

[0426] R 3a It is a methoxy group; and

[0427] R 3b R 3c R 3d R 3e As disclosed above regarding formula (I).

[0428] In the implementation plan, n is 1.

[0429] In the implementation plan, n is 2.

[0430] In the implementation plan, R 1b It is H, CH3, or OCH3.

[0431] In the implementation plan, R 3e It is H or F.

[0432] In the implementation plan, R 3d It is arbitrarily assigned to 1 R 6 Replacement C 1-4 alkyl.

[0433] In the implementation plan, R 3d yes

[0434] In the implementation plan, R 3d It is arbitrarily assigned to 1 R 6 Substituted 4-6 membered heterocyclic alkyl groups.

[0435] In the implementation plan, R 3d yes

[0436] In the implementation plan, R 3d It is arbitrarily assigned to 1 R 6 Replacement C 3-5 Cycloalkyl.

[0437] In the implementation plan, R 3d yes

[0438] In the implementation scheme, carbon marked with an asterisk (*) has an (R)- configuration.

[0439] In the implementation scheme, carbon marked with an asterisk (*) has an (S)- configuration.

[0440] In the implementation scheme, the compound is selected from any of the compounds described in Table 1 or their pharmaceutically acceptable salts.

[0441] Other exemplary implementations

[0442] This document describes further exemplary implementations of the variables in exemplary formulas (I)-(VII), which may exist in any combination of valences allowed.

[0443] In the implementation plan, the Q-ring is In the implementation plan, X is -CHR 1c - In the implementation, X is -O-. In the implementation, X is -NR. 2 -

[0444] In the implementation plan, the Q-ring is In the implementation plan, the Q-ring is In the implementation plan, the Q-ring is In the implementation plan, the Q-ring is In the implementation plan, the Q-ring is In the implementation plan, the Q-ring is In the implementation plan, the Q-ring is In the implementation plan, the Q-ring is In the implementation plan, the Q-ring is In the implementation plan, the Q-ring is In the implementation plan, the Q-ring is In the implementation plan, the Q-ring is In the implementation plan, the Q-ring is

[0445] In the implementation plan, the Q-ring is In the implementation plan, X is -CHR 1c - In the implementation, X is -O-. In the implementation, X is -NR. 2 -

[0446] In the implementation plan, the Q-ring is In the implementation plan, the Q-ring is In the implementation plan, the Q-ring is

[0447] In the implementation scheme, L is optionally divided by 1 to 6 R. 4 Replacement In the implementation scheme, L is not replaced. In the implementation scheme, L is represented by 1 to 6 R. 4 Replaced. In the implementation scheme, L is replaced by 1, 2, or 3 Rs. 4 Replaced. In the implementation scheme, L is replaced by 1 R. 4 Replaced. In the implementation scheme, L is replaced by 2 R. 4 Replaced. In the implementation scheme, L is replaced by 3 Rs. 4 Replaced. In the implementation scheme, L is replaced by 4 R. 4 Replaced. In the implementation scheme, L is replaced by 5 R. 4Replaced. In the implementation scheme, L is replaced by 6 R. 4 replace.

[0448] In the implementation scheme, L is optionally divided by 1 to 6 R. 4 Replacement In the implementation scheme, L is not replaced. In the implementation scheme, L is represented by 1 to 6 R. 4 Replaced. In the implementation scheme, L is replaced by 1, 2, or 3 Rs. 4 Replaced. In the implementation scheme, L is replaced by 1 R. 4 Replaced. In the implementation scheme, L is replaced by 2 R. 4 Replaced. In the implementation scheme, L is replaced by 3 Rs. 4 Replaced. In the implementation scheme, L is replaced by 4 R. 4 Replaced. In the implementation scheme, L is replaced by 5 R. 4 Replaced. In the implementation scheme, L is replaced by 6 R. 4 replace.

[0449] In the implementation plan, R 1a It is H. In the implementation plan, R 1a It is C 1-4 Alkyl group. In the implementation scheme, R 1a It is a halogen (e.g., F). In the implementation, R 1a It is C 1-4 Alkyl group. In the implementation scheme, R 1a It is OH. In the implementation scheme, R 1a It is C 1-4 Alkyl-OH. In the embodiments, R 1a It is C 1-4 Alkyl-C 1-4 Alkyl group. In the implementation scheme, R 1a It is C 1-4 Alkoxy-C 1-4 Alkyl group. In the implementation scheme, R 1a It is CF3. In the implementation plan, R 1a It is CHF2. In the implementation plan, R 1a It is CH2F. In the implementation plan, R 1a It is CN. In the implementation plan, R 1a It is NO2. In the implementation plan, R 1a It is NR a R b In the implementation plan, R 1a It is C 1-4 Alkyl-NR a R b .

[0450] In the implementation plan, R 1b It is H. In the implementation plan, R1b It is C 1-4 Alkyl group. In the implementation scheme, R 1b It is a halogen (e.g., F). In the implementation, R 1b It is C 1-4 Alkyl group. In the implementation scheme, R 1b It is OH. In the implementation scheme, R 1b It is C 1-4 Alkyl-OH. In the embodiments, R 1b It is C 1-4 Alkyl-C 1-4 Alkyl group. In the implementation scheme, R 1b It is C 1-4 Alkoxy-C 1-4 Alkyl group. In the implementation scheme, R 1b It is CF3. In the implementation plan, R 1b It is CHF2. In the implementation plan, R 1b It is CH2F. In the implementation plan, R 1b It is CN. In the implementation plan, R 1b It is NO2. In the implementation plan, R 1b It is NR a R b In the implementation plan, R 1b It is C 1-4 Alkyl-NR a R b .

[0451] In the implementation plan, R 1c It is H. In the implementation plan, R 1c It is C 1-4 Alkyl group. In the implementation scheme, R 1c It is a halogen (e.g., F). In the implementation, R 1c It is C 1-4 Alkyl group. In the implementation scheme, R 1c It is OH. In the implementation scheme, R 1c It is C 1-4 Alkyl-OH. In the embodiments, R 1c It is C 1-4 Alkyl-C 1-4 Alkyl group. In the implementation scheme, R 1c It is C 1-4 Alkoxy-C 1-4 Alkyl group. In the implementation scheme, R 1c It is CF3. In the implementation plan, R 1c It is CHF2. In the implementation plan, R 1c It is CH2F. In the implementation plan, R 1c It is CN. In the implementation plan, R 1bIt is NO2. In the implementation plan, R 1c It is NR a R b In the implementation plan, R 1c It is C 1-4 Alkyl-NR a R b .

[0452] In the implementation plan, R 1d It is H. In the implementation plan, R 1d It is C 1-4 Alkyl group. In the implementation scheme, R 1d It is a halogen (e.g., F). In the implementation, R 1d It is C 1-4 Alkyl group. In the implementation scheme, R 1d It is OH. In the implementation scheme, R 1d It is C 1-4 Alkyl-OH. In the embodiments, R 1d It is C 1-4 Alkyl-C 1-4 Alkyl group. In the implementation scheme, R 1d It is C 1-4 Alkoxy-C 1-4 Alkyl group. In the implementation scheme, R 1d It is CF3. In the implementation plan, R 1d It is CHF2. In the implementation plan, R 1d It is CH2F. In the implementation plan, R 1d It is CN. In the implementation plan, R 1d It is NO2. In the implementation plan, R 1d It is NR a R b In the implementation plan, R 1d It is C 1-4 Alkyl-NR a R b .

[0453] In the implementation plan, R 1e It is H. In the implementation plan, R 1e It is C 1-4 Alkyl group. In the implementation scheme, R 1e It is a halogen (e.g., F). In the implementation, R 1e It is C 1-4 Alkyl group. In the implementation scheme, R 1e It is OH. In the implementation scheme, R 1e It is C 1-4 Alkyl-OH. In the embodiments, R 1e It is C 1-4 Alkyl-C 1-4Alkyl group. In the implementation scheme, R 1e It is C 1-4 Alkoxy-C 1-4 Alkyl group. In the implementation scheme, R 1e It is CF3. In the implementation plan, R 1e It is CHF2. In the implementation plan, R 1e It is CH2F. In the implementation plan, R 1e It is CN. In the implementation plan, R 1e It is NO2. In the implementation plan, R 1e It is NR a R b In the implementation plan, R 1e It is C 1-4 Alkyl-NR a R b .

[0454] In the implementation plan, R 1f It is H. In the implementation plan, R 1f It is C 1-4 Alkyl group. In the implementation scheme, R 1f It is a halogen (e.g., F). In the implementation, R 1f It is C 1-4 Alkyl group. In the implementation scheme, R 1f It is OH. In the implementation scheme, R 1f It is C 1-4 Alkyl-OH. In the embodiments, R 1f It is C 1-4 Alkyl-C 1-4 Alkyl group. In the implementation scheme, R 1f It is C 1-4 Alkoxy-C 1-4 Alkyl group. In the implementation scheme, R 1f It is CF3. In the implementation plan, R 1f It is CHF2. In the implementation plan, R 1f It is CH2F. In the implementation plan, R 1f It is CN. In the implementation plan, R 1f It is NO2. In the implementation plan, R 1f R 1e It is NR a R b In the implementation plan, R 1f It is C 1-4 alkyl-NR a R b .

[0455] In the implementation plan, R 2 It's H.

[0456] In the implementation plan, R 2 It is C 1-4 alkyl.

[0457] In the implementation plan, R 2 It is C 3-5 Cycloalkyl.

[0458] In the implementation plan, R 3a It is C 1-4 Alkyl group.

[0459] In the implementation plan, R 3a It is C 3-5 Cycloalkoxy group.

[0460] In the implementation plan, R 3a It's CF3.

[0461] In the implementation plan, R 3a It is CHF2.

[0462] In the implementation plan, R 3a It is CH2F.

[0463] In the implementation plan, R 3a It is OCF3.

[0464] In the implementation plan, R 3a It is OCHF2.

[0465] In the implementation plan, R 3a It is OCH2F.

[0466] In the implementation plan, R 3a Yes - CN.

[0467] In the implementation plan, R 3a It is halogen.

[0468] In the implementation plan, R 3a It is Cl.

[0469] In the implementation plan, R 3a It is C 1-4 alkyl.

[0470] In the implementation plan, R 3a It is a methyl group.

[0471] In the implementation plan, R 3a It is an ethyl group.

[0472] In the implementation plan, R 3b It's H.

[0473] In the implementation plan, R 3b It is halogen.

[0474] In the implementation plan, R 3b It's CF3.

[0475] In the implementation plan, R 3b It's CN.

[0476] In the implementation plan, R 3c It's H.

[0477] In the implementation plan, R 3c It is F.

[0478] In the implementation plan, R 3c It's CN.

[0479] In the implementation plan, R 3c It is C 1-4 alkyl.

[0480] In the implementation plan, R 3d It is arbitrarily divided by 1 to 4 R 6 Replacement C 1-4 Alkyl group. In the implementation scheme, R 3d It is unreplaced C 1-4 Alkyl (e.g., methyl, ethyl, isopropyl, or tert-butyl). In the embodiments, R 3d It is by 1 R 6 Replacement C 1-4 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, or substituted with methyl, ethyl, propyl, isopropyl, oxazolyl, isoxazolyl, thiazolyl, methoxy, ethoxy, isopropoxy, dimethylamino, pyrrolyl, morpholinyl, piperidinyl, etc.; or alkyl groups substituted with NR) a R b Substituted methyl, ethyl, propyl, isopropyl, or n-butyl, wherein R a and R b Together with the nitrogen atoms to which they are attached, they form saturated or unsaturated heterocycles (e.g., azanorbornel or piperidinyl) optionally containing one or two substituents selected from methyl, fluorine, cyclopropyl, and methoxy. In embodiments, R 3d It is by 2 Rs 6 Replacement C 1-4 Alkyl group. In the implementation scheme, R 3d It is by 3 Rs 6 Replacement C 1-4 Alkyl group. In the implementation scheme, R 3d It is by 4 Rs 6 Replacement C 1-4 alkyl.

[0481] In the implementation plan, R 3d It is arbitrarily divided by 1 to 4 R 6 Replacement C3-5 Cycloalkyl. In the embodiment, R 3d It is unreplaced C 3-5 Cycloalkyl (e.g., cyclopropyl). In the embodiments, R 3d It is arbitrarily assigned to 1 R 6 Replacement C 3-5 Cycloalkyl (e.g., cyclopropyl substituted with methyl, ethyl, methoxy, or trifluoromethyl). In the embodiments, R 3d It is arbitrarily divided by 2 Rs 6 Replacement C 3-5 Cycloalkyl. In the embodiment, R 3d It is arbitrarily divided by 3 Rs 6 Replacement C 3-5 Cycloalkyl. In the embodiment, R 3d It is arbitrarily assigned to 4 Rs 6 Replacement C 3-5 Cycloalkyl.

[0482] In the implementation plan, R 3d It is arbitrarily divided by 1 to 4 R 6 Substituted 4-6 membered heterocyclic alkyl groups. In the embodiments, R 3d It is an unsubstituted 4-6 membered heterocyclic alkyl group (e.g., tetrahydrofuranyl, tetrahydropyranyl, oxetaneyl, isoxazolyl, morpholinyl, pyrrolidinyl, or piperidinyl). In the embodiments, R 3d It is by 1 R 6 Substituted 4-6-membered heterocyclic alkyl groups (e.g., tetrahydrofuranyl, tetrahydropyranyl, oxetaneyl, isoxazolyl, morpholinyl, pyrrolidinyl, or piperidinyl substituted with methyl, methoxy, or fluorine). In embodiments, R 3d It is by 2 Rs 6 Substituted 4-6-membered heterocyclic alkyl groups (e.g., tetrahydrofuranyl, tetrahydropyranyl, oxetaneyl, isoxazolyl, morpholinyl, pyrrolidinyl, piperidinyl containing two independently selected substituents chosen from methyl and fluorine). In embodiments, R 3d It is by 3 Rs 6 Substituted 4-6 membered heterocyclic alkyl groups. In the embodiments, R 3d It is by 4 Rs 6 Substituted 4-6 membered heterocyclic alkyl groups.

[0483] In the implementation plan, R 3e It's H.

[0484] In the implementation plan, R 3e It is F.

[0485] In the implementation plan, R 4 It's H.

[0486] In the implementation plan, R 4 It is C 1-4 alkyl.

[0487] In the implementation plan, R 4 It is a halogen (e.g., F).

[0488] In the implementation plan, R 4 It's CF3.

[0489] In the implementation plan, R 4 It is CHF2.

[0490] In the implementation plan, R 4 It is CH2F.

[0491] In the implementation plan, R 4 It is cyclopropyl.

[0492] In the implementation plan, two R 4 The groups together can form a spirocyclopropyl group.

[0493] In the implementation plan, R 6 It is C 1-4 alkyl.

[0494] In the implementation plan, R 6 It is C 1-4 Alkenyl group.

[0495] In the implementation plan, R 6 It is C 3-5 Cycloalkyl.

[0496] In the implementation plan, R 6 It is C 1-4 Alkyl group.

[0497] In the implementation plan, R 6 It is C 3-5 Cycloalkoxy group.

[0498] In the implementation plan, R 6 It is F.

[0499] In the implementation plan, R 6 It's CF3.

[0500] In the implementation plan, R 6 It is CHF2.

[0501] In the implementation plan, R 6 It is CH2F.

[0502] In the implementation plan, R 6 It is OCF3.

[0503] In the implementation plan, R6 It is OCHF2.

[0504] In the implementation plan, R 6 It is OCH2F.

[0505] In the implementation plan, R 6 It is OH.

[0506] In the implementation plan, R 6 It is a 5-6 nucleotide heteroaryl group.

[0507] In the implementation plan, R 6 It is NR a R b .

[0508] In the implementation plan, R 7 Independently for C 1-4 alkyl.

[0509] In the implementation plan, R 7 It is F.

[0510] In the implementation plan, R 7 It is CH3 or F.

[0511] In the implementation plan, R a It is hydrogen independently.

[0512] In the implementation plan, R a Independently for C 1-4 alkyl.

[0513] In the implementation plan, R a Independently for C 3-5 Cycloalkyl.

[0514] In the implementation plan, R b It is hydrogen independently.

[0515] In the implementation plan, R b Independently for C 1-4 alkyl.

[0516] In the implementation plan, R b Independently for C 3-5 Cycloalkyl.

[0517] In the implementation plan, R a and R b Together with the nitrogen atoms to which they are attached, they form saturated or unsaturated heterocycles containing three to seven ring atoms, wherein the rings may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and may optionally be selected from one to three heteroatoms selected from F, C. 1-4 The same or different groups can be substituted for the group consisting of alkyl, phenyl, and benzyl groups.

[0518] In the implementation plan, R a and R b Together with the nitrogen atoms they are attached to, they form saturated heterocycles. In some embodiments, the heterocycles are not substituted. In some embodiments, the heterocycles are independently selected from F, C, and N atoms, one, two, or three. 1-4 The heterocycle is substituted with groups from the group consisting of alkyl, phenyl, and benzyl. In an embodiment, the heterocycle does not contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In an embodiment, the heterocycle contains one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0519] In the implementation plan, R a and R b Together with the nitrogen atoms they are attached to, they form unsaturated heterocycles. In embodiments, the heterocycles are not substituted. In embodiments, the heterocycles are independently selected from F, C, and N atoms, one, two, or three. 1-4 The heterocycle is substituted with groups from the group consisting of alkyl, phenyl, and benzyl. In an embodiment, the heterocycle does not contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In an embodiment, the heterocycle contains one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0520] In the implementation plan, n is 0.

[0521] In the implementation plan, n is 1.

[0522] In the implementation plan, n is 2.

[0523] In the implementation plan, m is 0, 1, or 2.

[0524] In the implementation plan, R 3a It is C 1-4 Alkoxy groups (e.g., OCH3) and / or R 3b It is a halogen (e.g., F).

[0525] In the implementation plan, R 3a It is C 1-4 Alkyl groups (e.g., OCH3) and R 3b It is a halogen (e.g., F).

[0526] In the implementation plan, R 3c It is H and / or R 3e It is a halogen (e.g., F).

[0527] In the implementation plan, R 3c It is H and R 3e It is a halogen (e.g., F).

[0528] In the implementation plan, R 3c It is H and / or R 3e It's H.

[0529] In the implementation plan, R 3c It is H and R 3e It's H.

[0530] In the implementation plan, R 3b It is H and / or R 3e It's H.

[0531] In the implementation plan, R 3b It is H and R 3e It's H.

[0532] In the implementation plan, R 3a It is C 1-4 Alkyl groups (e.g., OCH3), R 3b It is a halogen (e.g., F), and / or R. 3c It's H.

[0533] In the implementation plan, R 3a It is C 1-4 Alkyl groups (e.g., OCH3), R 3b It is a halogen (e.g., F), and R 3c It's H.

[0534] In the implementation plan, R 3a It is C 1-4 Alkyl groups (e.g., OCH3), R 3b It is a halogen (e.g., F), and / or R. 3c It is F.

[0535] In the implementation plan, R 3a It is C 1-4 Alkyl groups (e.g., OCH3), R 3b It is a halogen (e.g., F), and R 3c It is F.

[0536] In the implementation plan, R 3a It is C 1-4 Alkyl groups (e.g., OCH3), R 3b It is H, and / or R 3c It's H.

[0537] In the implementation plan, R 3a It is C 1-4 Alkyl groups (e.g., OCH3), R 3b It is H, and R 3c It's H.

[0538] In the implementation plan, R 3bIt is H, R 3c It is H, and / or R 3e It's H.

[0539] In the implementation plan, R 3b It is H,R 3c It is H, and R 3e It's H.

[0540] In the implementation plan, R 3a It is C 1-4 Alkyl groups (e.g., OCH3), R 3b It is a halogen (e.g., F), R 3c It is H, R 3d It is arbitrarily divided by 1 to 4 R 6 Replacement C 1-4 Alkyl (e.g., methyl or isopropyl), and / or R 3e It's H.

[0541] In the implementation plan, R 3a It is C 1-4 Alkyl groups (e.g., OCH3), R 3b It is a halogen (e.g., F), R 3c It is H, R 3d It is arbitrarily divided by 1 to 4 R 6 Replacement C 1-4 Alkyl (e.g., methyl or isopropyl), and R 3e It's H.

[0542] In the implementation plan, R 3a It is C 1-4 Alkyl groups (e.g., OCH3), R 3b It is a halogen (e.g., F), R 3c It is F, R 3d It is arbitrarily divided by 1 to 4 R 6 Replacement C 1-4 Alkyl (e.g., methyl or isopropyl), and / or R 3e It's H.

[0543] In the implementation plan, R 3a It is C 1-4 Alkyl groups (e.g., OCH3), R 3b It is a halogen (e.g., F), R 3c It is F, R 3d It is arbitrarily divided by 1 to 4 R 6 Replacement C 1-4 Alkyl (e.g., methyl or isopropyl), and R 3e It's H.

[0544] In the implementation plan, R 3a It is C1-4 Alkyl groups (e.g., OCH3), R 3b It is a halogen (e.g., F), R 3c It is H, R 3d It is arbitrarily divided by 1 to 4 R 6 Replacement C 1-4 Alkyl (e.g., methyl or isopropyl), and / or R 3e It is F.

[0545] In the implementation plan, R 3a It is C 1-4 Alkyl groups (e.g., OCH3), R 3b It is a halogen (e.g., F), R 3c It is H, R 3d It is arbitrarily divided by 1 to 4 R 6 Replacement C 1-4 Alkyl (e.g., methyl or isopropyl), and R 3e It is F.

[0546] Exemplary compounds

[0547] Exemplary compounds include those described in Table 1 of this document and their pharmaceutically acceptable salts.

[0548] In embodiments, the compound may be used as a mixture of stereoisomers (e.g., a mixture of diastereomers or a mixture of enantiomers). In embodiments, the stereochemically enriched composition comprises the compound described herein (e.g., the composition of the compound is substantially free of any other stereoisomers of the compound).

[0549] Where the absolute stereochemistry of the stereocenter is not specified, it should be understood that embodiments of the compound encompass both (R)- and (S)- configurations in alternative embodiments. Similarly, such compounds may be used in the methods described herein as compositions comprising a mixture of stereochemicals or as stereochemically enriched compositions (e.g., compositions of compounds substantially free of any other stereoisomers of the compound).

[0550] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 1A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 1B or a pharmaceutically acceptable salt thereof.

[0551] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 2A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 2B or a pharmaceutically acceptable salt thereof.

[0552] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 3A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 3B or a pharmaceutically acceptable salt thereof.

[0553] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 4A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 4B or a pharmaceutically acceptable salt thereof.

[0554] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 5A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 5B or a pharmaceutically acceptable salt thereof.

[0555] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 6A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 6B or a pharmaceutically acceptable salt thereof.

[0556] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 7A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 7B or a pharmaceutically acceptable salt thereof.

[0557] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 8A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 8B or a pharmaceutically acceptable salt thereof.

[0558] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 9A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 9B or a pharmaceutically acceptable salt thereof.

[0559] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 10A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 10B or a pharmaceutically acceptable salt thereof.

[0560] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 11A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 11B or a pharmaceutically acceptable salt thereof.

[0561] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 12A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 12B or a pharmaceutically acceptable salt thereof.

[0562] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 13A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 13B or a pharmaceutically acceptable salt thereof.

[0563] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 14A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 14B or a pharmaceutically acceptable salt thereof.

[0564] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 15A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 15B or a pharmaceutically acceptable salt thereof.

[0565] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 16A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 16B or a pharmaceutically acceptable salt thereof.

[0566] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 17A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 17B or a pharmaceutically acceptable salt thereof.

[0567] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 18A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 18B or a pharmaceutically acceptable salt thereof.

[0568] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 19A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 19B or a pharmaceutically acceptable salt thereof.

[0569] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In an embodiment, the compound is compound 19C or a pharmaceutically acceptable salt thereof. In an embodiment, the compound is compound 19D or a pharmaceutically acceptable salt thereof.

[0570] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 20A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 20B or a pharmaceutically acceptable salt thereof.

[0571] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 21A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 21B or a pharmaceutically acceptable salt thereof.

[0572] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 22A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 22B or a pharmaceutically acceptable salt thereof.

[0573] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 23A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 23B or a pharmaceutically acceptable salt thereof.

[0574] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 24A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 24B or a pharmaceutically acceptable salt thereof.

[0575] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 25A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 25B or a pharmaceutically acceptable salt thereof.

[0576] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 26A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 26B or a pharmaceutically acceptable salt thereof.

[0577] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 27A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 27B or a pharmaceutically acceptable salt thereof.

[0578] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 28A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 28B or a pharmaceutically acceptable salt thereof.

[0579] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 29A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 29B or a pharmaceutically acceptable salt thereof.

[0580] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 30A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 30B or a pharmaceutically acceptable salt thereof.

[0581] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 31A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 31B or a pharmaceutically acceptable salt thereof.

[0582] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 32A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 32B or a pharmaceutically acceptable salt thereof.

[0583] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 33A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 33B or a pharmaceutically acceptable salt thereof.

[0584] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 34A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 34B or a pharmaceutically acceptable salt thereof.

[0585] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 35A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 35B or a pharmaceutically acceptable salt thereof.

[0586] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 36A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 36B or a pharmaceutically acceptable salt thereof.

[0587] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 37A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 37B or a pharmaceutically acceptable salt thereof.

[0588] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 38A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 38B or a pharmaceutically acceptable salt thereof.

[0589] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 39A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 39B or a pharmaceutically acceptable salt thereof.

[0590] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 40A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 40B or a pharmaceutically acceptable salt thereof.

[0591] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 41A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 41B or a pharmaceutically acceptable salt thereof.

[0592] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 42A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 42B or a pharmaceutically acceptable salt thereof.

[0593] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 43A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 43B or a pharmaceutically acceptable salt thereof.

[0594] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 44A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 44B or a pharmaceutically acceptable salt thereof.

[0595] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 45A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 45B or a pharmaceutically acceptable salt thereof.

[0596] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 46A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 46B or a pharmaceutically acceptable salt thereof.

[0597] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 47A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 47B or a pharmaceutically acceptable salt thereof.

[0598] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 48A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 48B or a pharmaceutically acceptable salt thereof.

[0599] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 49A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 49B or a pharmaceutically acceptable salt thereof.

[0600] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 50A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 50B or a pharmaceutically acceptable salt thereof.

[0601] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 51A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 51B or a pharmaceutically acceptable salt thereof.

[0602] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 52A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 52B or a pharmaceutically acceptable salt thereof.

[0603] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 53A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 53B or a pharmaceutically acceptable salt thereof.

[0604] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 54A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 54B or a pharmaceutically acceptable salt thereof.

[0605] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 100A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 100B or a pharmaceutically acceptable salt thereof.

[0606] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 101A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 101B or a pharmaceutically acceptable salt thereof.

[0607] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In an embodiment, the compound is compound 102A or a pharmaceutically acceptable salt thereof. In an embodiment, the compound is compound 102B or a pharmaceutically acceptable salt thereof.

[0608] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 103A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 103B or a pharmaceutically acceptable salt thereof.

[0609] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 104A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 104B or a pharmaceutically acceptable salt thereof.

[0610] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 105A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 105B or a pharmaceutically acceptable salt thereof.

[0611] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 106A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 106B or a pharmaceutically acceptable salt thereof.

[0612] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 107A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 107B or a pharmaceutically acceptable salt thereof.

[0613] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 108A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 108B or a pharmaceutically acceptable salt thereof.

[0614] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 109A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 109B or a pharmaceutically acceptable salt thereof.

[0615] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 110A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 110B or a pharmaceutically acceptable salt thereof.

[0616] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 111A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 111B or a pharmaceutically acceptable salt thereof.

[0617] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 112A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 112B or a pharmaceutically acceptable salt thereof.

[0618] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 113A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 113B or a pharmaceutically acceptable salt thereof.

[0619] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 114A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 114B or a pharmaceutically acceptable salt thereof.

[0620] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 115A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 115B or a pharmaceutically acceptable salt thereof.

[0621] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 116A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 116B or a pharmaceutically acceptable salt thereof.

[0622] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 117A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 117B or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 117C or a pharmaceutically acceptable salt thereof. In yet another embodiment, the compound is compound 117D or a pharmaceutically acceptable salt thereof.

[0623] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 118A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 118B or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 118C or a pharmaceutically acceptable salt thereof. In yet another embodiment, the compound is compound 118D or a pharmaceutically acceptable salt thereof.

[0624] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 119A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 119B or a pharmaceutically acceptable salt thereof.

[0625] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 120A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 120B or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 120C or a pharmaceutically acceptable salt thereof. In yet another embodiment, the compound is compound 120D or a pharmaceutically acceptable salt thereof.

[0626] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 121A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 121B or a pharmaceutically acceptable salt thereof.

[0627] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 122A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 122B or a pharmaceutically acceptable salt thereof.

[0628] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In an embodiment, the compound is compound 123A or a pharmaceutically acceptable salt thereof. In an embodiment, the compound is compound 123B or a pharmaceutically acceptable salt thereof.

[0629] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 124A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 124B or a pharmaceutically acceptable salt thereof.

[0630] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 125A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 125B or a pharmaceutically acceptable salt thereof.

[0631] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 126A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 126B or a pharmaceutically acceptable salt thereof.

[0632] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 127A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 127B or a pharmaceutically acceptable salt thereof.

[0633] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 128A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 128B or a pharmaceutically acceptable salt thereof.

[0634] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 129A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 129B or a pharmaceutically acceptable salt thereof.

[0635] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 130A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 130B or a pharmaceutically acceptable salt thereof.

[0636] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 131A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 131B or a pharmaceutically acceptable salt thereof.

[0637] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 132A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 132B or a pharmaceutically acceptable salt thereof.

[0638] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 133A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 133B or a pharmaceutically acceptable salt thereof.

[0639] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In an embodiment, the compound is compound 134A or a pharmaceutically acceptable salt thereof. In an embodiment, the compound is compound 134B or a pharmaceutically acceptable salt thereof.

[0640] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 135A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 135B or a pharmaceutically acceptable salt thereof.

[0641] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 136A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 136B or a pharmaceutically acceptable salt thereof.

[0642] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 137A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 137B or a pharmaceutically acceptable salt thereof.

[0643] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 138A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 138B or a pharmaceutically acceptable salt thereof.

[0644] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 139A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 139B or a pharmaceutically acceptable salt thereof.

[0645] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 140A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 140B or a pharmaceutically acceptable salt thereof.

[0646] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In an embodiment, the compound is compound 141A or a pharmaceutically acceptable salt thereof. In an embodiment, the compound is compound 141B or a pharmaceutically acceptable salt thereof. In an embodiment, the compound is compound 141C or a pharmaceutically acceptable salt thereof. In an embodiment, the compound is compound 141D or a pharmaceutically acceptable salt thereof.

[0647] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 142A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 142B or a pharmaceutically acceptable salt thereof.

[0648] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 143A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 143B or a pharmaceutically acceptable salt thereof.

[0649] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 144A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 144B or a pharmaceutically acceptable salt thereof.

[0650] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 145A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 145B or a pharmaceutically acceptable salt thereof.

[0651] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 146A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 146B or a pharmaceutically acceptable salt thereof.

[0652] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 147A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 147B or a pharmaceutically acceptable salt thereof.

[0653] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 148A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 148B or a pharmaceutically acceptable salt thereof.

[0654] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 149A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 149B or a pharmaceutically acceptable salt thereof.

[0655] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 150A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 150B or a pharmaceutically acceptable salt thereof.

[0656] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 151A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 151B or a pharmaceutically acceptable salt thereof.

[0657] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 152A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 152B or a pharmaceutically acceptable salt thereof.

[0658] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 153A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 153B or a pharmaceutically acceptable salt thereof.

[0659] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 154A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 154B or a pharmaceutically acceptable salt thereof.

[0660] In the implementation plan, the compound is Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is compound 155A or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is compound 155B or a pharmaceutically acceptable salt thereof.

[0661] Deuterated compounds

[0662] The compounds described herein may contain atoms exhibiting their natural isotopic abundances, or one or more of said atoms may be artificially enriched in specific isotopes having the same atomic number but different atomic mass or mass number from those found primarily in nature. The term "isotope" refers to a substance having the same chemical structure and formula as the specific compounds provided herein, except for the positions of isotopic substitution and / or the levels of isotopic enrichment at one or more positions (e.g., hydrogen versus deuterium). This invention is intended to include all suitable isotopic variants of the compounds described herein. For example, different isotopic forms of hydrogen (H) include protium (… 1 H), deuterium ( 2 H) and tritium ( 3 H), and compositions containing isotopes of any of the compounds described herein.

[0663] In the embodiments, one or more hydrogen atoms in the compounds described herein are replaced by deuterium. When a position is designated as "H" or "hydrogen," that position should be understood to mean that hydrogen is present in its natural abundance isotopic composition. When a position is designated as " 2 When "H" or "deuterium" is used, the position should be understood as having at least 3340 times the abundance of natural deuterium (i.e., the term "H"). 2 "H" or "deuterium" indicates at least 50.1% deuterium incorporation. Therefore, the invention is also characterized by compositions rich in deuterated compounds.

[0664] In the embodiments, the composition of any compound provided herein may have an isotopic enrichment factor of at least 3500 (52.5% deuterium doping), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping) for each deuterium present at a site designated as a potential deuteration site on the compound.

[0665] Exemplary pharmaceutical compositions

[0666] The compounds described herein (e.g., compounds of any one of formulas (I)-(VII)) or their pharmaceutically acceptable salts can be formulated into a variety of pharmaceutical compositions. The compounds described herein (e.g., compounds of formula (I) (including compounds of formulas (II)-(VI) and any of the compounds in Table 1 provided herein) and their pharmaceutically acceptable salts may be active pharmaceutical ingredients (APIs) in combination with one or more other ingredients to form a pharmaceutical substance (DS) pharmaceutical composition. A pharmaceutical substance (DS) pharmaceutical composition may comprise an API (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and one or more pharmaceutically acceptable carriers, diluents, and / or excipients. The carrier, diluent, or excipient may be selected to be compatible with other components of the formulation and appropriately safe and effective for the intended therapy. The desired weight concentration of the compound described herein as an active pharmaceutical ingredient (API) (e.g., a compound of formula (I)) or its pharmaceutically acceptable salt may be combined with other inactive ingredients to form a pharmaceutical substance (DS) in a batch of formulation. Pharmaceutically acceptable compositions may be formulated for administration via an appropriate route, such as oral delivery in a unit dosage form (including as capsules or tablets). Such compositions may be prepared by associating an active pharmaceutical ingredient (API) comprising a compound of formula (I) with a carrier or excipient.

[0667] In some embodiments, the present invention provides a pharmaceutical composition formulated for oral delivery of an α4β7 integrin inhibitor, the composition comprising, as an API, an α4β7 integrin inhibitor compound described herein (e.g., a compound of any one of formulas (I)-(VII), such as any compound in Table 1, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier formulated for oral therapeutic administration of the α4β7 integrin inhibitor compound.

[0668] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0669] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0670] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of formula (IIA) or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0671] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of formula (III) or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0672] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of formula (IIIA) or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0673] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of formula (IV) or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0674] In some embodiments, the present invention provides pharmaceutical compositions comprising an inclusion compound (IVA) or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0675] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of formula (V) or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0676] In some embodiments, the present invention provides pharmaceutical compositions comprising a VA compound or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0677] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of formula (VI) or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0678] In some embodiments, the present invention provides pharmaceutical compositions comprising a subdivided (VIA) compound or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0679] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of formula (VII) or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient (API).

[0680] In some embodiments, the present invention provides pharmaceutical compositions comprising the compounds of Table 1 or pharmaceutically acceptable salts thereof as active pharmaceutical ingredients (APIs).

[0681] Pharmaceutically acceptable compositions comprising the compounds described herein (e.g., compounds of formula (I)) or their pharmaceutically acceptable salts can be prepared through various procedures. For example, compounds of formula (I) can be formulated with suitable excipients, diluents, or carriers to form tablets or capsules and other suitable dosage forms.

[0682] Pharmaceutical compositions may be provided in unit dosage forms containing a predetermined amount of an API per unit dose, said API comprising the compound described herein (e.g., compound of formula (I)) or a pharmaceutically acceptable salt thereof. Such units may contain the desired amount of the compound (e.g., compound of formula (I)) or a pharmaceutically acceptable salt thereof, depending on the disease being treated, the route of administration, and the patient's age, weight, and condition. Therefore, such unit doses may be administered at the desired dosing intervals. The concentration of the active compound in the pharmaceutical composition will depend on various applicable parameters and considerations, such as the rate of absorption, inactivation, and excretion of the drug, and other factors known to those skilled in the art. It should be noted that dose values ​​will also vary depending on the severity of the disease to be alleviated. It should be further understood that for any particular subject, the specific dosing regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges set forth herein are merely exemplary and not intended to limit the scope or practice of the claimed compositions. The active ingredient may be administered once or divided into multiple smaller doses for administration at different time intervals.

[0683] In some embodiments, the active compound is administered orally. Oral compositions typically contain an inert diluent or an edible carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound may be combined with excipients and used in tablet, lozenge, or capsule form. Pharmaceutically compatible binders and / or adjuvants may be included as part of the composition. Pharmaceutical compositions formulated for oral delivery containing compounds described herein (e.g., compounds of formula (I)) or pharmaceutically acceptable salts thereof may be prepared in unit dosage forms, such as capsules at the desired dose strength (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof). For oral administration in liquid form, the oral pharmaceutical component may be combined with any orally administered, non-toxic, pharmaceutically acceptable inert carrier (such as ethanol, glycerol, water, etc.). For oral administration in tablet or capsule form, the compounds described herein (e.g., compounds of formula (I)) or pharmaceutically acceptable salts thereof may be combined with an orally administered, non-toxic, pharmaceutically acceptable inert carrier. Other examples of excipients, diluents, and carriers suitable for such formulations include: fillers and extenders such as starch and sugar; and binders such as cellulose derivatives. Furthermore, suitable binders, lubricants, disintegrants, and colorants may be incorporated into the mixture when desired or necessary. Suitable binders include starch, natural sugars, natural and synthetic gums, etc. Lubricants and / or flow aids may be used in these dosage forms.

[0684] Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds with similar properties: binders, such as microcrystalline cellulose, astragalus gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginate, sodium glycolate starch (Primogel), or corn starch; lubricants, such as magnesium stearate or sterotes; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring. When the unit dosage form is a capsule, in addition to the materials of the types mentioned above, the capsule may contain a liquid carrier such as fatty oil. Furthermore, the unit dosage form may contain a variety of other materials in physical form that modify the dosage unit, such as coatings of sugar or other enteric solvents.

[0685] The compounds can be applied as components of elixirs, suspensions, syrups, rice paper encapsulants, etc. In addition to active compounds, syrups may also contain sucrose or sweeteners as sweeteners, as well as certain preservatives, dyes and colorants, and flavorings.

[0686] Compounds may be formulated as solutions suitable for parenteral administration (e.g., via intramuscular, subcutaneous, or intravenous routes). For example, compounds described herein (e.g., compounds of formula (I)) or pharmaceutically acceptable salts thereof may be dissolved in suitable buffer solutions. Pharmaceutical compositions containing desired concentrations of compounds described herein (e.g., compounds of formula (I)) or pharmaceutically acceptable salts thereof may be formulated as injectable drug solutions (for use, for example, in preclinical animal studies).

[0687] Exemplary treatment methods

[0688] The compounds described in this article can be used to treat patients who benefit from antagonizing integrin α. v Various diseases and symptoms of β8. For example, the proposed inhibition of integrin α. v β8-driven TGFβ activation reverses tumor tolerance and enhances anti-tumor T / NK cell responses. For example, α... v β8 inhibition can enhance outcomes in checkpoint inhibitor regimens or reverse checkpoint inhibitor resistance. In embodiments, the compounds described herein can modulate antitumor immune responses (e.g., in checkpoint inhibitor-resistant tumors).

[0689] In the implementation scheme, the invention is characterized by inhibiting α in patients. v A method for β8 integrin, the method comprising administering to a patient in need a therapeutically effective amount of the compound described herein (e.g., a compound of any one of formulas (I)-(VII), such as any compound in Table 1) or a pharmaceutically acceptable salt thereof.

[0690] In an embodiment, the invention is characterized by a method of treating a patient with cancer (e.g., a solid tumor), the method comprising administering to a patient in need a therapeutically effective amount of a compound described herein (e.g., a compound of any one of formulas (I)-(VII), such as any compound in Table 1) or a pharmaceutically acceptable salt thereof. In an embodiment, the method further comprises administering a therapeutically effective amount of a second active agent.

[0691] Solid tumors

[0692] In the implementation scheme, the application of the compounds described herein (e.g., any of the compounds in formulas (I)-(VII), such as any of the compounds in Table 1) or pharmaceutically acceptable salts thereof may be used to treat solid tumors in patients in need, optionally in combination with one or more other therapies (e.g., a second active agent).

[0693] In one implementation, the solid tumor is resistant to one or more previous first-line therapies (e.g., the solid tumor is a treatment-resistant tumor). In another implementation, the solid tumor is resistant to immune checkpoint therapy.

[0694] In the implementation plan, cancer refers to solid tumors, such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovoma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, osteosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, gastric cancer, oral cancer, nasal cancer, laryngeal cancer, squamous cell carcinoma, etc. Solid tumors include: basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, non-small cell lung cancer (NSCLC), small cell lung cancer, bladder cancer, lung cancer, epithelial carcinoma, skin cancer, melanoma, neuroblastoma (NB), or retinoblastoma. In the implementation scheme, the solid tumor is an advanced solid tumor (e.g., locally advanced solid tumor). In the implementation scheme, the solid tumor is a metastatic solid tumor.

[0695] In the implementation plan, cancer (e.g., solid tumors) is anal cancer, bile duct cancer (cholangiocarcinoma), bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, fallopian tube cancer, gastric cancer, glioma, liver cancer, lung cancer, melanoma, nasopharyngeal carcinoma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, primary peritoneal cancer, prostate cancer, renal cell carcinoma, skin cancer, squamous cell carcinoma of the head and neck (SCCHN), testicular cancer, urothelial carcinoma, or uterine cancer.

[0696] In the implementation plan, the cancer (e.g., solid tumor) is breast cancer, squamous cell carcinoma of the head and neck (SCCHN), renal cell carcinoma, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, pancreatic cancer, bile duct cancer, endometrial cancer, melanoma, or urothelial carcinoma.

[0697] In the implementation scheme, the cancer (e.g., solid tumor) is advanced (e.g., locally advanced).

[0698] In the implementation plan, the cancer (e.g., a solid tumor) is metastatic.

[0699] In the implementation plan, the cancer (e.g., a solid tumor) is anal cancer.

[0700] In the implementation plan, the cancer (e.g., solid tumor) is bile duct cancer (cholangiocarcinoma).

[0701] In the implementation plan, the cancer (e.g., a solid tumor) is bladder cancer.

[0702] In the implementation plan, the cancer (e.g., a solid tumor) is breast cancer.

[0703] In the implementation plan, the cancer (e.g., a solid tumor) is cervical cancer.

[0704] In the implementation plan, the cancer (e.g., a solid tumor) is colorectal cancer.

[0705] In the implementation plan, the cancer (e.g., a solid tumor) is endometrial cancer.

[0706] In one implementation, the cancer (e.g., a solid tumor) is esophageal cancer. In another implementation, the esophageal cancer is adenocarcinoma. In yet another implementation, the esophageal cancer is squamous cell carcinoma.

[0707] In the implementation plan, the cancer (e.g., a solid tumor) is fallopian tube cancer.

[0708] In the implementation plan, the cancer (e.g., a solid tumor) is stomach cancer.

[0709] In the implementation plan, the cancer (e.g., a solid tumor) is a glioma.

[0710] In the implementation plan, the cancer (e.g., a solid tumor) is liver cancer. In the implementation plan, the liver cancer is hepatocellular carcinoma.

[0711] In the implementation plan, the cancer (e.g., a solid tumor) is lung cancer. In the implementation plan, the lung cancer is squamous cell carcinoma of the lung. In the implementation plan, the lung cancer is non-small cell lung cancer (NSCLC).

[0712] In the implementation plan, the cancer (e.g., a solid tumor) is melanoma.

[0713] In the implementation plan, the cancer (e.g., a solid tumor) is nasopharyngeal carcinoma.

[0714] In the implementation plan, the cancer (e.g., a solid tumor) is neuroblastoma.

[0715] In the implementation plan, the cancer (e.g., a solid tumor) is osteosarcoma.

[0716] In the implementation plan, the cancer (e.g., a solid tumor) is ovarian cancer.

[0717] In the implementation plan, the cancer (e.g., a solid tumor) is pancreatic cancer.

[0718] In the implementation plan, the cancer (e.g., solid tumor) is primary peritoneal cancer.

[0719] In the implementation plan, the cancer (e.g., a solid tumor) is prostate cancer.

[0720] In one implementation, the cancer (e.g., a solid tumor) is renal cell carcinoma (RCC). In another implementation, the renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). In yet another implementation, the renal cell carcinoma is papillary renal cell carcinoma (PRCC).

[0721] In the implementation, the cancer (e.g., a solid tumor) is skin cancer. In the implementation, the skin cancer is cutaneous squamous cell carcinoma (CSCC). In the implementation, esophageal cancer is basal cell carcinoma (BCC).

[0722] In the implementation plan, the cancer (e.g., a solid tumor) is head and neck squamous cell carcinoma (SCCHN).

[0723] In the implementation plan, the cancer (e.g., a solid tumor) is testicular cancer.

[0724] In the implementation plan, the cancer (e.g., a solid tumor) is urothelial carcinoma.

[0725] In the implementation plan, the cancer (e.g., a solid tumor) is uterine cancer.

[0726] In one implementation, the patient has a therapy-resistant cancer (e.g., a solid tumor, such as those described herein). In another implementation, the therapy-resistant cancer (e.g., a solid tumor) is checkpoint resistant. In yet another implementation, the therapy-resistant cancer (e.g., a solid tumor) is resistant to either anti-PD-1 or anti-PD-L1 therapy (collectively, PD-(L)1 resistant cancer).

[0727] Exemplary combination therapy and second active agent

[0728] In embodiments, the compounds described herein (e.g., any of formulas (I)-(VII), such as any compound in Table 1) or pharmaceutically acceptable salts thereof may be used in combination therapy. In embodiments, administration of the compounds described herein or pharmaceutically acceptable salts enhances the response to one or more additional therapies (e.g., a second active agent). For example, administration of the compounds described herein or pharmaceutically acceptable salts may improve the response to additional therapies (e.g., a second active agent).

[0729] For example, in the treatment of certain diseases and conditions, the compounds or pharmaceutically acceptable salts described herein may be administered in combination with one or more other therapies (e.g., a second active agent).

[0730] In embodiments, the compounds or pharmaceutically acceptable salts described herein may be administered in combination with immunotherapy. In embodiments, the immunotherapy is cancer immunotherapy. In embodiments, the cancer immunotherapy is immune checkpoint therapy (e.g., therapy including the administration of immune checkpoint inhibitors). In embodiments, the cancer immunotherapy is cellular immunotherapy, such as adoptive T-cell transfer therapy (e.g., chimeric antigen receptor (CAR) T-cell therapy, CAR natural killer (NK) cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, or endogenous T-cell (ETC) therapy). In embodiments, the cancer immunotherapy is a cancer vaccine. In embodiments, the cancer immunotherapy is a monoclonal antibody therapy (e.g., antibodies that can be used for immune checkpoint therapy, such as those described herein). In embodiments, the cancer immunotherapy is a cytokine therapy (e.g., interferon or interleukin therapy).

[0731] In the implementation scheme, the compound or pharmaceutically acceptable salt described herein is administered together with a second active agent to a patient in need to treat solid tumors (e.g., as described herein).

[0732] In the implementation scheme, the second active agent is an immune checkpoint inhibitor. In the implementation scheme, the immune checkpoint inhibitor targets PD-1 (e.g., inhibited by anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy), CTLA-4, TIM-3, TIGIT, LAG (e.g., LAG-3), CEACAM (e.g., CEACAM-1, -3, and / or -5), VISTA, BTLA, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GALS, adenosine, TGFR (e.g., TGFRβ), B7-H1, B7-H4 (VTCN1), OX-40, CD137, CD40, IDO, or CSF-1 / CSF-1R.

[0733] In some implementations, checkpoint inhibitors are small molecules, nucleic acids, peptides (e.g., antibodies), carbohydrates, lipids, metals, toxins, or conjugates. In others implementations, checkpoint inhibitors are antibodies, antibody conjugates, or antigen-binding fragments thereof.

[0734] In the implementation scheme, the immune checkpoint inhibitor is an agent that inhibits PD-1, TIM-3, CTLA-4, LAG-3, TIGIT, IDO, or CSF-1 / CSF-1R.

[0735] In the implementation plan, the immune checkpoint inhibitor is selected from: pembrolizumab. Nivolumab Cimipril Dotalimab Atezolizumab Avelumab Dvalumab Ipilimumab And rilatimab and their biosimilars.

[0736] In the implementation scheme, the second active agent is anti-PD-1 therapy or anti-PD-L1 therapy (collectively referred to as anti-PD(L)-1 therapy).

[0737] In the implementation plan, the anti-PD(L)-1 therapy is selected from the group consisting of: pembrolizumab, nivolumab, cimiprimab, dotalimab, atezolizumab, avelumab, durvalumab, PDR001, cimiprimab, BGB-A317, LY3300054, BI754091, IBI308, INCSHR-1210, JNJ-63723283, JS-001, MEDI0680 (AMP-514), MGA-012, PF-06801591, CX-072, FAZ053 and PD-L1millamolecule and their biosimilars.

[0738] In the implementation plan, the anti-PD(L)-1 therapy is selected from atezolizumab, avelumumab, BGB-A317, BI754091, CX-072, durvalumab, FAZ053, IBI308, INCSHR-1210, JNJ-63723283, JS-001, MEDI-0680, MGA-012, nivolumab, PDR001, pembrolizumab, PF-06801591, cimiprimab, dotalimab, any antibody disclosed in WO2014 / 179664, and their biosimilars. In the implementation plan, the anti-PD(L)-1 therapy is selected from the group consisting of: BGB-A317, BI754091, CX-072, FAZ053, IBI308, INCSHR-1210, JNJ-63723283, JS-001, LY3300054, MEDI-0680, MGA-012, nivolumab, PD-L1millamolecule, PDR001, pembrolizumab, PF-06801591, cimiprimab and dotalimab, and their biosimilars.

[0739] In the implementation plan, the anti-PD(L)-1 therapy is selected from pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, dotalizumab, PDR-001, tislelizumab (BGB-A317), cimiprimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI-754091, IBI-308, camrelizumab (HR- 301210), BCD-100, JS-001, CX-072, BGB-A333, AMP-514 (MEDI-0680), AGEN-2034, CS1001, Sym-021, SHR-1316, PF-06801591, LZM009, KN-035, AB122, Genomea 1 (CBT-501), FAZ-053, CK-301, AK 104, GLS-010, JTX-4014, SHR-1210, AMP-224, AUN-P12, CA-170, BMS-986189, and any PD-1 antibody disclosed in WO2014 / 179664. In the implementation scheme, the anti-PD(L)-1 therapy is selected from durvalumab, atezolizumab, avelumab, BGB-A333, SHR-1316, FAZ-053, CK-301 and PD-L1 millamolecule or derivatives thereof.

[0740] In the implementation scheme, the anti-PD(L)-1 therapy is selected from nivolumab, pembrolizumab, cimiprimab, dotalipmab, atezolizumab, avelumab, and durvalumab.

[0741] In the implementation scheme, the second active agent is an anti-CTLA-4 therapy. Specifically, the anti-CTLA-4 therapy is ipilimumab.

[0742] In the implementation scheme, the second active agent is an anti-LAG-3 therapy. In the implementation scheme, the anti-LAG-3 therapy is selected from: LAG525 (IMP701), REGN3767 (R3767), BI754,091, tebotelimab (MGD013), etimide α (IMP321), TSR-033, and FS118.

[0743] In the implementation scheme, the second active agent is an anti-TIM-3 therapy. In the implementation scheme, the anti-TIM-3 therapy is selected from MBG453, Sym023, and TSR-022.

[0744] In the implementation scheme, the second active agent is an anti-CSF-1 / R therapy. In the implementation scheme, the anti-CSF-1 / R therapy is selected from: lacnotuzumab (MCS110), LY3022855, SNDX-6352, emactuzumab (RG7155), and pexidartinib (PLX3397).

[0745] In one implementation scheme, the second active agent is an anti-TIGIT therapy. In another implementation scheme, the anti-TIGIT therapy is selected from: BMS-986207, osperlimab, tiragolumab, vibostolimab, domvanalimab, EOS448, COM902, and AAGEN307. In another implementation scheme, the second active agent is an anti-CEACAM therapy. In another implementation scheme, the anti-TIGIT therapy is selected from: CM24 and NEO-201.

[0746] In some embodiments, the compounds or uses of the present invention may be selected from one or more of the embodiments listed below.

[0747] 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0748]

[0749] in:

[0750] Q ring is

[0751] L is Each of them is arbitrarily assigned to 1 to 6 Rs 4 replace;

[0752] X is -CHR 1c -、-O- or -NR 2 -;

[0753] R 1a R 1b R 1c R 1d R 1e and R 1f Each independently represents H and C. 1-4 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C1-4 Alkyl group, CF3, CHF2, CH2F, CN, NO2, NR a R b Or C 1-4 Alkyl-NR a R b ,

[0754] Each R 2 Independently for H and C 1-4 Alkyl or C 3-5 cycloalkyl;

[0755] R 3a It is C 1-4 Alkoxy, C 3-5 Cycloalkoxy, CF3, CHF2, CH2F, OCF3, OCHF2, or OCH2F;

[0756] R 3b It is H, halogen, CF3 or CN;

[0757] R 3c Is it H, F, CN, or C? 1-4 alkyl;

[0758] R 3d It is C 1-4 Alkyl, C 3-5 Cycloalkyl or 4-6 membered heterocycloalkyl, each optionally surrounded by 1 to 4 R... 6 replace;

[0759] R 3e It is H or F;

[0760] Each R 4 Independently for H and C 1-4 Alkyl, halogen, CF3, CHF2 or CH2F, cyclopropyl, or two geminal Rs 4 The groups together can form a spirocyclopropyl group;

[0761] Each R 6 Independently for C 1-4 Alkyl, C 1-4 alkenyl, C 3-5 cycloalkyl, C 1-4 Alkoxy, C 3-5 Cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, 5-6 heteroaryl or NR a R b ;

[0762] Each R 7 Independently for C 1-4 Alkyl or F;

[0763] Ra and R b Each independently is hydrogen, C 1-4 Alkyl, C 3-5 cycloalkyl, or R a and R b Together with the nitrogen atoms to which they are attached, they form saturated or unsaturated heterocycles containing three to seven ring atoms, said rings optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally one to three selected from F, C. 1-4 The same or different groups may be substituted within the group consisting of alkyl, phenyl, and benzyl groups; and

[0764] n is 1 or 2; and

[0765] m can be 0, 1, or 2.

[0766] 2. The compound as described in embodiment 1, wherein the Q ring is

[0767] 3. The compound as described in embodiment 1 or 2, wherein X is -O-.

[0768] 4. The compound as described in embodiment 1 or 2, wherein X is -NR 2 -

[0769] 5. The compound as described in embodiment 4, wherein R 2 It is a methyl group.

[0770] 6. The compound as described in embodiment 1, wherein the Q ring is

[0771] 7. The compound as described in any one of embodiments 1-6, wherein R 1d and R 1e Each is independently represented by H.

[0772] 8. The compound as described in embodiments 6-7, wherein each R 1c H stands for H independently.

[0773] 9. The compound as described in any one of embodiments 1-8, wherein each R 1a H stands for H independently.

[0774] 10. The compound as described in any one of embodiments 1-9, wherein each R 1b H stands for H independently.

[0775] 11. The compound as described in any one of embodiments 1-9, wherein each R 1b Independently OMe.

[0776] 12. The compound as described in embodiment 1, wherein the Q ring is

[0777] 13. The compound as described in embodiment 12, wherein R 1c and R 1d H stands for H independently.

[0778] 14. The compound as described in embodiment 1 or 12-13, wherein R 1a R 1b and R 1f Each is independently represented by H.

[0779] 15. The compound as described in any one of embodiments 1-14, wherein L is

[0780] 16. The compound as described in any one of embodiments 1-14, wherein L is

[0781] 17. The compound as described in any one of embodiments 1-16, wherein R 3a It is C 1-4 Alkyl group.

[0782] 18. The compound as described in any one of embodiments 1-16, wherein R 3a It is OMe, OEt, OCF3, OCHF2, or OCH2F.

[0783] 19. The compound as described in any one of embodiments 1-16, wherein R 3a It's OMe.

[0784] 20. The compound as described in any one of embodiments 1-19, wherein R 3b It is F.

[0785] 21. The compound as described in any one of embodiments 1-20, wherein R 3c It's H.

[0786] 22. The compound as described in any one of embodiments 1-21, wherein R 3d It is C 1-4 alkyl.

[0787] 23. The compound as described in any one of embodiments 1-21, wherein R 3d It is C 3-5 Cycloalkyl.

[0788] 24. The compound as described in any one of embodiments 1-21, wherein R 3d It is an oxocyclic butyl, tetrahydrofuranyl or tetrahydro-2H-pyranyl, morpholinyl or piperazine-C1-4 alkyl.

[0789] 25. The compound as described in any one of embodiments 1-21, wherein R 3d It is isopropyl.

[0790] 26. The compound as described in any one of embodiments 1-25, wherein R 3e It's H.

[0791] 27. The compound as described in any one of embodiments 1-26, wherein each R 4 It is methyl on its own.

[0792] 28. The compound as described in any one of embodiments 1-26, wherein each R 4 Independently, it is F.

[0793] 29. The compound as described in any one of embodiments 1-26, wherein each R 4 It can be CF3, CHF2 or CH2F independently.

[0794] 30. The compound as described in any one of embodiments 1-26, wherein each R 4 H stands for H independently.

[0795] 31. The compound as described in any one of embodiments 1-30, wherein each R 6 Independently for C 1-4 alkyl.

[0796] 32. The compound as described in any one of embodiments 1-30, wherein each R 6 Independently for C 1-4 Alkenyl group.

[0797] 33. The compound as described in any one of embodiments 1-30, wherein each R 6 Independently for C 3-5 Cycloalkyl.

[0798] 34. The compound as described in any one of embodiments 1-30, wherein each R 6 Independently for C 1-4 Alkyl group.

[0799] 35. The compound as described in any one of embodiments 1-30, wherein each R 6 Independently for C 3-5 Cycloalkoxy group.

[0800] 36. The compound as described in any one of embodiments 1-30, wherein each R 6It can be F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F or OH independently.

[0801] 37. The compound as described in any one of embodiments 1-30, wherein each R 6 It is independently a 5-6 member heteroaryl group.

[0802] 38. The compound as described in any one of embodiments 1-30, wherein each R 6 H stands for H independently.

[0803] 39. The compound as described in any one of embodiments 1-38, wherein n is 0.

[0804] 40. The compound as described in any one of embodiments 1-38, wherein n is 1.

[0805] 41. The compound as described in any one of embodiments 1-38, wherein n is 2.

[0806] 42. The compound as described in any one of embodiments 1-41, wherein m is 0.

[0807] 43. The compound as described in embodiment 1, wherein the compound has a structure according to formula (II),

[0808]

[0809] Or its pharmaceutically acceptable salt.

[0810] 44. The compound as described in embodiment 43, wherein the compound has a structure according to formula (IIA),

[0811]

[0812] Or its pharmaceutically acceptable salt.

[0813] 45. The compound as described in embodiment 1, wherein the compound has a structure according to formula (III),

[0814]

[0815] Or its pharmaceutically acceptable salt.

[0816] 46. ​​The compound as described in embodiment 45, wherein the compound has a structure according to formula (IIIA),

[0817]

[0818] Or its pharmaceutically acceptable salt.

[0819] 47. The compound as described in embodiment 1, wherein the compound has a structure according to formula (IV),

[0820]

[0821] Or its pharmaceutically acceptable salt.

[0822] 48. The compound as described in embodiment 47, wherein the compound has a structure according to formula (IVA),

[0823]

[0824] Or its pharmaceutically acceptable salt.

[0825] 49. The compound as described in embodiment 1, wherein the compound has a structure according to formula (V),

[0826]

[0827] Or its pharmaceutically acceptable salt.

[0828] 50. The compound as described in embodiment 49, wherein the compound has a structure according to formula (VA),

[0829]

[0830] Or its pharmaceutically acceptable salt.

[0831] 51. The compound as described in embodiment 1, wherein the compound has a structure according to formula (VI),

[0832]

[0833] Or its pharmaceutically acceptable salt.

[0834] 52. The compound as described in embodiment 51, wherein the compound has a structure according to formula (VIA),

[0835]

[0836] Or its pharmaceutically acceptable salt.

[0837] 53. The compound as described in any one of embodiments 49-52, wherein n is 1.

[0838] 54. The compound as described in any one of embodiments 49-52, wherein n is 2.

[0839] 55. The compound as described in any one of embodiments 43-54, wherein R 1b It is H, CH3, or OCH3.

[0840] 56. The compound as described in any one of embodiments 43-55, wherein R 3e It is H or F.

[0841] 57. The compound as described in any one of embodiments 43-56, wherein R 3d It is arbitrarily assigned to 1 R 6 Replacement C 1-4 alkyl.

[0842] 58. The compound as described in embodiment 57, wherein R 3d yes

[0843] 59. The compound as described in any one of embodiments 43-56, wherein R 3d It is arbitrarily assigned to 1 R 6 Substituted 4-6 membered heterocyclic alkyl groups.

[0844] 60. The compound as described in embodiment 59, wherein R 3d yes

[0845] 61. The compound as described in any one of embodiments 43-56, wherein R 3d It is arbitrarily assigned to 1 R 6 Replacement C 3-5 Cycloalkyl.

[0846] 62. The compound as described in embodiment 61, wherein R 3d yes

[0847] 63. The compound as described in any one of embodiments 43-62, wherein the carbon marked with an asterisk (*) has an (R)-configuration.

[0848] 64. The compound of any one of embodiments 43-62, wherein the carbon marked with an asterisk (*) has an (S) configuration.

[0849] 65. The compound as described in Embodiment 1, wherein the compound is selected from any of the compounds described in Table 1 or their pharmaceutically acceptable salts.

[0850] 66. The compound as described in embodiment 1, wherein the compound is selected from:

[0851]

[0852]

[0853]

[0854]

[0855] Or its pharmaceutically acceptable salt.

[0856] 67. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0857] 68. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0858] 69. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0859] 70. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0860] 71. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0861] 72. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0862] 73. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0863] 74. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0864] 75. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0865] 76. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0866] 77. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0867] 78. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0868] 79. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0869] 80. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0870] 81. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0871] 82. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0872] 83. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0873] 84. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0874] 85. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0875] 86. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0876] 87. The compound as described in embodiment 66, wherein said compound is Or its pharmaceutically acceptable salt.

[0877] 88. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in any one of embodiments 1-87, and a pharmaceutically acceptable excipient.

[0878] 89. A method for inhibiting α in patients v A method for β8 integrin, the method comprising administering to a patient in need a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, as described in any one of embodiments 1-87.

[0879] 90. The method of embodiment 89, wherein the method is used to treat a solid tumor in a patient in need.

[0880] 91. A method of treating a patient with a solid tumor, the method comprising administering to the patient in need (a) a therapeutically effective amount of any one of embodiments 1-87 of the compound or a pharmaceutically acceptable salt thereof, and (b) a therapeutically effective amount of a second active agent.

[0881] 92. The method of embodiment 91, wherein the solid tumor is selected from: anal cancer, bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, fallopian tube cancer, gastric cancer, glioma, liver cancer, lung cancer, melanoma, nasopharyngeal carcinoma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, primary peritoneal cancer, prostate cancer, renal cell carcinoma, skin cancer, squamous cell carcinoma of the head and neck (SCCHN), testicular cancer, urothelial carcinoma, and uterine cancer.

[0882] 93. The method of embodiment 92, wherein the solid tumor is selected from: breast cancer, squamous cell carcinoma of the head and neck (SCCHN), renal cell carcinoma, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, pancreatic cancer, bile duct cancer, endometrial cancer, melanoma, and urothelial carcinoma.

[0883] 94. The method as described in any one of embodiments 91-93, wherein the second active agent is an immune checkpoint inhibitor.

[0884] 95. The method of embodiment 94, wherein the immune checkpoint inhibitor is an anti-PD-1 or anti-PD-L1 therapy.

[0885] 96. The method of embodiment 95, wherein the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, simipelimab, dotalimab, atezolizumab, avelumab, and durvalumab.

[0886] Example

[0887] General Plan

[0888] General Option 1:

[0889]

[0890] Among them, Q, L, R 7 m, R 3e R 3d R 3c R 3b R 3a As defined in formula (I), and B(OR)2 is boric acid or borate ester.

[0891] The general method for preparing compounds of formula (I) is summarized in General Scheme 1. Pyrrolidine (or pyrrolidine-HCl salt) 2-a, arylboronic acid or ester (i.e., R = H or alkyl, respectively) 2-b, oxoacetic acid, and 4A molecular sieve are treated in a solvent (i.e., DCM / hexafluoroisopropanol) at high temperature (i.e., 60 °C) to obtain diastereomers of formula (I), which can be separated by supercritical fluid chromatography (SFC) or preparative HPLC.

[0892] General Option 2:

[0893]

[0894] Among them, Q, L, R 7 m, R 3e R 3d R 3c R 3b and R 3a As defined in formula (I), and R is an alkyl group.

[0895] Alternatively, the compound of formula (I) can be prepared as outlined in general scheme 2. Treatment of 2-bromo-2-arylacetic acid ester 2-c (i.e., R = Et or t-Bu) and pyrrolidine (or pyrrolidine-HCl salt) 2-a in a solvent (i.e., acetonitrile) in the presence of a base (i.e., DIEA) at ambient temperature to a slightly elevated temperature (i.e., 25°C–50°C) yields amino ester 2-d. Hydrolysis of 2-d under alkaline conditions (i.e., for R = CH3, LiOH / MeOH) or with an acid (i.e., for R = t-Bu, formic acid or TFA) yields diastereomeric compounds of formula (I), which can be separated by supercritical fluid chromatography (SFC) or preparative HPLC.

[0896] abbreviation

[0897]

[0898]

[0899]

[0900] Analytical methods, materials and instruments

[0901] Unless otherwise specified, reagents and solvents should be used as is from the commercial supplier. Default methods, materials, and instruments are listed below.

[0902] 1 H NMR instrument information:

[0903] Proton nuclear magnetic resonance (NMR) spectra were obtained at 400 MHz on a Bruker or Varian spectrometer. Spectra are given in ppm(d) and the coupling constant J is reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard.

[0904] LCMS instrument information and analysis methods:

[0905] Mass spectra were collected using an Agilent 6120 single quadrupole mass spectrometer (ESI). Purity and low-resolution mass spectrometry data were measured using an Agilent 1260 Infinity II high-performance liquid chromatography (HPLC) system equipped with a photodiode array detector, an Agilent 1260 Infinity II evaporative light scattering detector (ELSD), and an Agilent 6120 mass spectrometer. Data were acquired using Chemstation C.01.10, and purity was characterized by UV wavelength 220 nm, ELSD, and ESI.

[0906] Method A: Column: Kinetex C182.1 x 50 mm, 5 μm; flow rate 1.0 mL / min; mobile phase A: water containing 0.04% TFA, mobile phase B: acetonitrile containing 0.02% trifluoroacetic acid; gradient: 5% B from 0 to 0.40 min, then 5% to 95% B over 2.60 min, then hold at 95% B for 1.00 min, then 95% to 5% B over 0.01 min.

[0907] Method B: Column: Xbridge C182.1 x 50 mm column (5 μm particles); flow rate: 0.8 mL / min; mobile phase A: water containing 10 mM NH4HCO3; mobile phase B: acetonitrile; gradient: from 0 to 0.40 min 5% B, then from 0.40 to 3.40 min 5% to 95% B, then hold 95% B for 0.45 min, then 95% to 5% B in 0.01 min.

[0908] SFC instrument and analytical method information:

[0909] Instrument: Waters UPCC equipped with a PDA detector

[0910] Conditions: Mobile phase A: CO2; Mobile phase B: MeOH containing 0.1% isopropylamine (or EtOH containing 0.1% isopropylamine, or isopropanol containing 0.1% isopropylamine).

[0911] Column: Daicel CHIRALPAK AD-3, 50×4.6mm ID, 3um; Daicel CHIRALCEL OD-3, 50×4.6mm ID., 3um; Daicel CHIRALCEL OJ-3, 50×4.6mm ID, 3um; Daicel CHIRALPAK IG-3, 50×4.6mm ID, 3um; Daicel CHIRALPAK AS-3, 50×4.6mmI.D., 3um; Daicel CHIRALPAKIC-3, 50×4.6mmI.D., 3um; Phenomenex Lux Cellulose-2, 50×4.6mm ID, 3um; Regis(S,S)-Whelk-O 1, 50×4.6mm ID, 3.5um

[0912] Column temperature: 35℃

[0913] Gradient: 0.0-0.2 minutes 5% B, then 0.2-1.2 minutes 5%-50% B gradient, then hold 50% B for 1.0 minute, then 2.2-2.6 minutes 50%-5% B gradient, then hold 50% B for 0.4 minutes.

[0914] Flow rate: 3.4 mL / min

[0915] Automatic back pressure regulator (ABPR): 1800 psi

[0916] Alternatively, chiral products can be analyzed by chiral SFC using an SFC-80 (Thar, Waters) instrument at a detection wavelength of 214 nm using one of the following methods:

[0917] Chiral SFCA: Column: (R,R)-Whelk-O1, 4.6*100mm, 5μm (Daicel), column temperature: 40℃, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as described in the text, flow rate: 4g / min, back pressure: 120 bar.

[0918] Chiral SFCB: Column: AD4.6*100mm, 5μm (Daicel), Column temperature: 40℃.

[0919] Mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as described in the text, flow rate: 4 g / min, back pressure: 120 bar.

[0920] Chiral SFCH: Column: (S,S)-Whelk-O1, 4.6*100mm, 5μm (Daicel), column temperature: 40℃, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as described in the text, flow rate: 4g / min, back pressure: 120 bar.

[0921] Preparative HPLC methods

[0922] Instrument: Gilson 281 semi-preparative HPLC system

[0923] Conditions: Mobile phase A: Water containing 0.2% formic acid (or water containing 0.1% TFA, or water containing 0.05% HCl, or water containing 10mM NH4HCO3, or water containing 0.04% ammonium hydroxide); Mobile phase B: Acetonitrile

[0924] Column: Phenomenex Luna C18 100x30mmx5um, Phenomenex Gemini C18 100 x 30mmx 5um; Waters Xbridge BEH C18 100 x 30mm x 10um

[0925] Column temperature: ambient temperature

[0926] LC gradient: A gradient of 5% to 50% over 10 minutes, then hold at 50% for 2 minutes; a gradient of 50% to 100% over 0.1 minutes, then hold at 100% for 2 minutes; a gradient of 100% to 5% over 0.1 minutes, then hold at 5% for 2 minutes.

[0927] LC flow rate: 25 mL / min

[0928] UV wavelengths: 220nm and 254nm

[0929] Alternatively, the crude sample can be dissolved in MeOH and purified by preparative HPLC using one of the following methods specified in the procedure on a Gilson 215 instrument at a detection wavelength of 214 nm:

[0930] Preparative HPLCA Column: XBridge C18, 21.2 x 250 mm, 10 μm; Mobile phase A: water (10 mM ammonium bicarbonate), Mobile phase B: acetonitrile; Gradient elution as described in the text; Flow rate: 20 mL / min.

[0931] "Preparative HPLC-B"Column: XBridge C18, 21.2 x 250 mm, 10 μm; Mobile phase A: water (10 mM formic acid), mobile phase B: acetonitrile; gradient elution as described in the text; flow rate: 20 mL / min.

[0932] Preparative chiral HPLC methods

[0933] Instruments: Gilson-281 semi-preparative HPLC system; UV: Gilson-156 UV

[0934] Conditions: Mobile phase A: n-heptane; Mobile phase B: Ethanol containing 0.1% ammonium hydroxide (or 2-propanol containing 0.1% ammonium hydroxide, or ethanol containing 0.1% TFA, or 2-propanol containing 0.1% TFA).

[0935] Columns: Daicel CHIRALPAK AD, 10µm, 30mm x 250mm; Daicel CHIRALPAK IH, 10µm, 30mm x 250mm; Daicel CHIRALPAK OD, 10µm, 30mm x 250mm; Daicel CHIRALPAK OJ, 10µm, 30mm x 250mm; Daicel CHIRALPAK IC, 10µm, 30mm x 250mm; Daicel CHIRALPAK IG, 10µm, 30mm x 250mm; Phenomenex Lux cellulose-2, 10µm, 30mm x 250mm; Regis(S,S)Whelk-O1, 10µm, 30mm x 250mm

[0936] Column temperature: ambient temperature

[0937] LC gradient: A:B = 80:20 or other isocratic elution modes.

[0938] LC flow rate: 25 mL / min binary pump

[0939] UV wavelengths: 220nm and 254nm

[0940] Preparative chiral SFC method

[0941] Instruments: SFC: Waters 80Q preparative SFC; UV: Waters 2489UV

[0942] Conditions: Mobile phase A: CO2; Mobile phase B: Methanol containing 0.1% ammonium hydroxide (or ethanol containing 0.1% ammonium hydroxide, or 2-propanol containing 0.1% ammonium hydroxide, or MeCN / EtOH / ammonium hydroxide 50:50:0.1)

[0943] Columns: Daicel CHIRALPAK AD, 10µm, 30mm x 250mm; Daicel CHIRALPAK IH, 10µm, 30mm x 250mm; Daicel CHIRALPAK OD, 10µm, 30mm x 250mm; Daicel CHIRALPAK OJ, 10µm, 30mm x 250mm; Daicel CHIRALPAK IC, 10µm, 30mm x 250mm; Daicel CHIRALPAK IG, 10µm, 30mm x 250mm; Phenomenex Lux cellulose-2, 10µm, 30mm x 250mm; Regis(S,S)Whelk-O1, 10µm, 30mm x 250mm

[0944] Column temperature: 40℃

[0945] LC gradient: A:B = 80:20 or other isocratic elution modes.

[0946] LC flow rate: 70g / min binary pump

[0947] UV wavelength: 220nm

[0948] System back pressure: 100 bar

[0949] Alternatively, the racemic product can be separated into individual enantiomers using a chiral preparative SFC with an SFC-80 (Thar, Waters) instrument and a detection wavelength of 214 nm, using one of the following methods.

[0950] Preparative chiral SFC A: Column: (R,R)-Whelk-O1, 20*250mm, 5μm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80g / min, back pressure: 100 bar.

[0951] Preparative chiral SFCB: Column: AD20*250mm, 10μm (Daicel), Column temperature: 35℃.

[0952] Mobile phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0953] Preparative chiral SFCH: Column: (S,S)-Whelk-O1, 20*250mm, 5μm (Daicel), column temperature: 35℃, mobile phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80g / min, back pressure: 100 bar.

[0954] Examples – Left side of exemplary compounds

[0955] Preparation of (R)-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[0956] Step 1: (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0957]

[0958] A mixture of (R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (10 g, 53.41 mmol), 5-bromopent-1-ene (23.88 g, 160.23 mmol), TBAB (1.72 g, 5.34 mmol), and NaOH (10.68 g, 267.04 mmol) in toluene (150 mL) and H₂O (150 mL) was stirred at 100 °C for 16 hours. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was subjected to rapid silica gel chromatography (…). 80g Purification was performed using a silica fast column with an eluent gradient of 0% to 100% ethyl acetate / petroleum ether at 150 mL / min. The resulting product was (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (10 g, 39.16 mmol, 76.9% yield), which appeared as a yellow oil.

[0959] Step 2: (R)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester

[0960]

[0961] 9-BBN (0.5 M in THF, 156.65 mL) was added to a solution of (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (10 g, 39.16 mmol) in 100 mL of THF at 0 °C. The mixture was stirred at 50 °C for 2 hours, and then added to a mixture of 7-chloro-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylate (10.52 g, 39.16 mmol), Cs₂CO₃ (25.52 g, 78.32 mmol), and Pd(PPh₃)₄ (2.26 g, 1.96 mmol) in 200 mL of DMF. The mixture was stirred at 100 °C under N₂ for 14 hours. The reactants were slowly quenched with ice water (500 mL), stirred at 0 °C for 30 min, and extracted with ethyl acetate (400 mL x 2). The combined organic phases were washed with brine (400 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was then subjected to rapid silica gel chromatography (…). 330g Purification was performed using a rapid silica column with an eluent gradient of 0% to 100% ethyl acetate / petroleum ether at 200 mL / min. The resulting product was (R)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester (8.75 g, 17.87 mmol, 45.63% yield), appearing as a yellow oil. 1 H NMR (400MHz, methanol-d4) δ = 7.47 (d, J = 7.7Hz, 1H), 6.96 (d, J = 7.7Hz, 1H), 4.03 (br d,J=2.8Hz,2H),3.76-3.72(m,2H),3.55(t,J=6.5Hz,1H),3.48-3.44(m,2H),2.79-2.68(m,4H),1.95-1.88(m,4H),1.76-1.67(m,3H),1.60(br d,J=7.1Hz,2H),1.51(s,9H),1.46(s,9H),1.42-1.39(m,2H). LCMS (ESI) m / z=490.3(M+1).

[0962] Step 3: (R)-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[0963]

[0964] A solution of (R)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester in HCl / MeOH (4M, 50 mL) was stirred at 50 °C for 16 hours. The mixture was then concentrated under vacuum. The racemic product was purified by preparative HPLC (column: Phenomenex luna C18 (250 x 70 mm, 15 μm); mobile phase: A water (TFA 0.1%), B MeCN 1%–30%, 20 min; flow rate (25 mL / min). A yellow oil (R)-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine (3.4 g, 11.75 mmol, 82.18% yield) was obtained. LCMS (ESI) m / z = 290.3 (M+1).

[0965] (R)-5-methoxy-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthylidine hydrochloride Preparation

[0966] Step 1: (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0967]

[0968] A solution of (R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (10 g, 53.41 mmol), 5-bromopent-1-ene (23.88 g, 160.23 mmol) in toluene (150 mL) was added to the mixture with stirring at 25 °C. The reaction mixture was then stirred at 100 °C for 16 hours. The mixture was quenched with H₂O (20 mL), extracted with EtOAc (50 mL x 3), and the organic layer was concentrated under reduced pressure to obtain the residue. The residue was subjected to rapid silica gel chromatography (…). 120g Purification was performed using a silica rapid column with an eluent gradient of 20% to 50% ethyl acetate / petroleum ether at 120 mL / min. The resulting product was (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (6.42 g, 22.88 mmol, 42.84% yield, 91% purity), which was a yellow oil. 1H NMR (400MHz, chloroform-d)δ=5.74-5.88(m,1H),4.91-5.10(m,2H),4.00(br s,1H),3.43(br s, 6H), 2.12 (q, J = 6.97Hz, 2H), 1.67 (quin, J = 6.94Hz, 2H), 1.47 (s, 9H) LCMS (ESI) m / z = 256.3 (M+1).

[0969] Step 2: (R)-3-((5-(4-methoxy-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0970]

[0971] 9-BBN (0.5M in THF, 92.32mL) was added to a solution of (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (4.42g, 17.31mmol) in THF (30mL) at 0°C. After stirring at 25°C for 2 hours, the solution was added to a suspension of 2-chloro-4-methoxy-1,8-naphthidine (2.25g, 11.56mmol), Pd(OAc)2 (259.07mg, 1.15mmol), tricyclohexylphosphine (323.60mg, 1.15mmol), and K2CO3 (3.19g, 23.08mmol) in THF (30mL) and H2O (1.3mL) at 25°C. The reaction mixture was stirred at 90°C for 16 hours. After the reaction, water (40 mL) was added, and the mixture was extracted with ethyl acetate (40 mL x 2). The organic layer was concentrated to obtain the crude product. The residue was then subjected to rapid silica gel chromatography (…). 40g Sepa Purification was performed using a rapid silica column with an eluent gradient of 0% to 33% ethyl acetate / petroleum ether at 120 mL / min. The result was a brown oily product, (R)-3-((5-(4-methoxy-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (5 g, crude). LCMS (ESI) m / z = 416.2 (M+1).

[0972] Step 3: (R)-3-((5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0973]

[0974] Pd / C (4 g, 10% purity) was added to a solution of (R)-3-((5-(4-methoxy-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (4.2 g, 10.11 mmol) in MeOH (150 mL), and the reaction mixture was stirred at 50 °C under H2 (50 psi) for 16 hours. The mixture was filtered, and the filtrate was concentrated to give the crude product. The residue was used directly in the next step without further purification. Tert-butyl (R)-3-((5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (4 g, 9.53 mmol, 94.3% yield) was obtained as a yellow oil. LCMS (ESI) m / z = 420.3 (M+1).

[0975] Step 4: (R)-5-methoxy-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine hydrochloride

[0976]

[0977] HCl / MeOH (4M, 20 mL) was added to a solution of (R)-3-((5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 4.77 mmol) in MeOH (10 mL) at 25 °C, and the reaction mixture was stirred at 50 °C for 16 hours. The solvent was distilled off under vacuum to give the crude product. (R)-5-methoxy-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidium hydrochloride (1.5 g, crude) was obtained as a red oil. 1 HNMR (400MHz, methanol-d4) δppm=6.61(s,1H)4.23-4.28(m,1H),3.99-4.04(m,3H),3.50(t,J=6.32Hz,2H),3.42(br d,J=5.75Hz,2H),3.35-3.39(m,2H),3.31(s,2H),2.71-2.76(m,2H),2.63(t,J=6.32 Hz,2H),2.15-2.23(m,2H),2.06(qd,J=9.42,5.00Hz,1H),1.88-1.91(m,2H),1.76(br d,J=7.75Hz,2H),1.63(br d,J=7.75Hz,2H),1.48(br d,J=7.13Hz,2H),1.33-1.40(m,2H). LCMS (ESI) m / z=320.2(M+1).

[0978] Preparation of (S)-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[0979] Step 1: (S)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0980]

[0981] TBAB (4.3 g, 13.36 mmol) and NaOH (26.7 g, 667.60 mmol) were added to a solution of (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (25 g, 133.52 mmol) and 5-bromopent-1-ene (49.74 g, 333.80 mmol) in toluene (375 mL) and H₂O (375 mL). The mixture was stirred at 95 °C for 16 hours. The reaction mixture was slowly quenched with ice water (1000 mL) and extracted with ethyl acetate (1000 mL x 2). The combined organic phases were washed with brine (1000 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was subjected to rapid silica gel chromatography (…). 330g Sepa Purification was performed using a silica fast column with an eluent gradient of 0% to 100% ethyl acetate / petroleum ether at 300 mL / min. The resulting product was (S)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (23 g, 90.07 mmol, 67.46% yield), a pale yellow oil. 1 ¹H NMR (400MHz, methanol-d⁴) δ=5.82(tdd,J=6.8,10.2,17.1Hz,1H), 5.06-4.92(m,2H), 4.85(s,1H), 4.06-4.01(m,1H), 3.51-3.34(m,6H), 2.12(q,J=7.1Hz,2H), 2.01-1.89(m,2H), 1.69-1.59(m,2H), 1.46(s,9H).

[0982] Step 2: (S)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester

[0983]

[0984] 9-BBN (0.5 M, 156.64 mL) was added to a solution of (S)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (10 g, 39.16 mmol) in THF (100 mL) at 0 °C. The mixture was stirred at 20 °C for 2 h, and then added to a mixture of 7-chloro-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylate (10.52 g, 39.16 mmol), Cs₂CO₃ (25.52 g, 78.32 mmol), and Pd(PPh₃)₄ (2.26 g, 1.95 mmol) in DMF (200 mL). The resulting mixture was stirred at 100 °C under N₂ for 16 h. The combined organic phases were washed with brine (500 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was subjected to rapid silica gel chromatography ( 330g Sepa Purification was performed using a rapid silica column with an eluent gradient of 0% to 100% ethyl acetate / petroleum ether at 300 mL / min. The resulting product was (S)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester (12.5 g, 25.53 mmol, 65.19% yield), appearing as a yellow oil. 1 H NMR (400MHz, methanol-d4) δ = 7.46 (d, J = 7.5Hz, 1H), 6.96 (d, J = 7.7Hz, 1H), 4.03 (br d,J=2.9Hz,1H),3.76-3.70(m,2H),3.56-3.32(m,7H),2.79-2.67(m,4H),2.00(s,2H),1. 94-1.88(m,3H),1.71(quin,J=7.7Hz,2H),1.63-1.54(m,3H),1.50(s,9H),1.45(s,11H). LCMS (ESI) m / z=490.3(M+1).

[0985] Step 3: (S)-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[0986]

[0987] A solution of (S)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester (5 g, 10.21 mmol) in HCl / MeOH (4 M, 50 mL) was stirred at 50 °C for 16 h. The mixture was concentrated under vacuum. The racemic product was purified by preparative HPLC (column: Phenomenex Luna 80 x 30 mm x 3 μm; mobile phase: A: water containing 0.1% TFA; B: MeCN 1%–30%, 20 min; flow rate: 25 mL / min). (S)-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine (2.3 g, 7.95 mmol, 77.83% yield) was obtained as a yellow oil. LCMS(ESI)m / z=290.2(M+1)

[0988] Preparation of (R)-7-(2-(2-(pyrrolidine-3-yloxy)ethoxy)ethyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[0989] Step 1: (R)-3-(2-ethoxy-2-oxoethoxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0990]

[0991] t-BuOK (8.99 g, 80.11 mmol) was added dropwise to a solution of (R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (10 g, 53.41 mmol) in THF (100 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour, and then ethyl 2-bromoacetate (13.38 g, 80.11 mmol, 8.86 mL) was added dropwise to the mixture. The resulting mixture was stirred at 20 °C for 15 hours. The reaction mixture was quenched with NH4Cl aqueous solution (150 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was subjected to rapid silica gel chromatography (…). 80g Sepa Purification was performed using a rapid silica column with an eluent gradient of 0% to 100% ethyl acetate / petroleum ether at 150 mL / min. The resulting product was (R)-3-(2-ethoxy-2-oxoethoxy)pyrrolidine-1-carboxylic acid tert-butyl ester (6 g, 21.95 mmol, 41.1% yield), which appeared as a yellow oil. 1¹H NMR (400MHz, chloroform-d) δ = 4.25–4.18 (m, 2H), 4.18–4.13 (m, 1H), 4.13–4.04 (m, 2H), 3.50–3.38 (m, 4H), 2.11–1.90 (m, 2H), 1.45 (s, 9H), 1.28 (t, J = 7.1 Hz, 3H). LCMS (ESI) m / z = 218.1 (M⁻¹⁶ + 1).

[0992] Step 2: (R)-3-(2-hydroxyethoxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0993]

[0994] DIBAL-H (1M, 3.66 mL) was added dropwise to a solution of (R)-3-(2-ethoxy-2-oxoethoxy)pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.83 mmol) in THF (10 mL) at 0 °C. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was quenched with NH4Cl aqueous solution (50 mL) at 0 °C and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was subjected to rapid silica gel chromatography (…). 20g Sepa Purification was performed using a rapid silica column with an eluent gradient of 0% to 100% ethyl acetate / petroleum ether at 120 mL / min. The resulting product was (R)-3-(2-hydroxyethoxy)pyrrolidine-1-carboxylic acid tert-butyl ester (0.2 g, 864.72 μmol, 47.3% yield), which appeared as a yellow oil. 1 ¹H NMR (400MHz, chloroform-d) δ = 4.12–4.03 (m, 1H), 3.77–3.68 (m, 2H), 3.60–3.52 (m, 2H), 3.47–3.39 (m, 4H), 2.03–1.87 (m, 3H), 1.46 (s, 12H).

[0995] Step 3: tert-butyl 7-ethynyl-3,4-dihydro-1,8-naphthidine-1(2H)-formate

[0996]

[0997] A mixture of tert-butyl 7-chloro-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylate (3 g, 11.16 mmol), K₂CO₃ (3.09 g, 22.33 mmol), Pd(CH₃CN)₂Cl₂ (289.61 mg, 1.12 mmol), and X-Phos (532.18 mg, 1.12 mmol) in CH₃CN (60 mL) was degassed and purged three times with N₂. The mixture was stirred at 20 °C for 0.5 h. Then, ethynyltrimethylsilane (4.39 g, 44.65 mmol, 6.19 mL) was injected, and the mixture was stirred at 90 °C under N₂ atmosphere for 6 h. After cooling to 20 °C, TBAF (1 M in THF, 5.58 mL) was added, and the mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to remove CH₃CN. The residue was subjected to rapid silica gel chromatography (…). 80g Sepa Purification was performed using a silica rapid column with an eluent gradient of 0% to 100% ethyl acetate / petroleum ether at 200 mL / min. The result was a brown solid, tert-butyl 7-ethynyl-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylate (2.1 g, 8.13 mmol, 72.8% yield via two steps). 1 ¹H NMR (400MHz, chloroform-d) δ = 7.34 (d, J = 7.70 Hz, 1H) 7.14 (d, J = 7.58 Hz, 1H) 3.73-3.80 (m, 2H) 3.03 (s, 1H) 2.76 (t, J = 6.54 Hz, 2H) 1.93 (quin, J = 6.33 Hz, 2H) 1.54 (s, 9H). LCMS (ESI) m / z = 331.2 (M+1).

[0998] Step 4: (R,E)-7-(2-(2-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)ethoxy)vinyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester

[0999]

[1000] KOH (81.46 mg, 1.45 mmol) was added to a solution of tert-butyl 7-ethynyl-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylate (0.375 g, 1.45 mmol) and (R)-3-(2-hydroxyethoxy)pyrrolidine-1-carboxylate (470.07 mg, 2.03 mmol) in DMSO (8 mL). The mixture was stirred in a microwave at 135 °C for 0.67 h. The reaction mixture was quenched at 0 °C by adding water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was subjected to rapid silica gel chromatography (…). 4g Sepa Purification was performed using a rapid silica column with an eluent gradient of 0% to 33% ethyl acetate / petroleum ether at 120 mL / min. The result was (R,E)-7-(2-(2-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)ethoxy)vinyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester (500 mg, 1.02 mmol, 35.2% yield) as a brown oil. LCMS (ESI) m / z = 490.2 (M+1).

[1001] Step 5: (R)-7-(2-(2-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)ethoxy)ethyl)-3,4-dihydro-1,8-naphthidine-1(2H)-formate tert-butyl ester

[1002]

[1003] Pd / C (200 mg, 10% purity) was added to a solution of (R,E)-7-(2-(2-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)ethoxy)vinyl)-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylic acid tert-butyl ester (900 mg, 1.84 mmol) in MeOH (80 mL), and the reaction mixture was stirred at 25 °C under H2 (50 psi) for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to obtain the residue. The residue was subjected to rapid silica gel chromatography (… 12g Sepa Purification was performed using a rapid silica column with an eluent gradient of 50% to 100% ethyl acetate / petroleum ether at 120 mL / min. The result was (R)-7-(2-(2-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)ethoxy)ethyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester (645 mg, 1.31 mmol, 71.4% yield) as a yellow oil. LCMS (ESI) m / z = 492.3 (M+1).

[1004] Step 6: (R)-7-(2-(2-(pyrrolidine-3-yloxy)ethoxy)ethyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1005]

[1006] A solution of (R)-7-(2-(2-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)ethoxy)ethyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester (211 mg, 429.19 μmol) in MeOH (3 mL) was added to a mixture of HCl / MeOH (4 M, 10 mL), and the reaction mixture was stirred at 30 °C for 12 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was subjected to rapid silica gel chromatography (…). 4g Sepa Purification was performed using a rapid silica column with an eluent gradient of 0% to 50% methanol / ethyl acetate at 120 mL / min. The result was (R)-7-(2-(2-(pyrrolidine-3-yloxy)ethoxy)ethyl)-1,2,3,4-tetrahydro-1,8-naphthidine (180 mg, crude), appearing as a yellow oil. LCMS (ESI) m / z = 292.2 (M+1).

[1007] (R)-5-(2-methoxyethoxy)-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8- Preparation of naphthidine

[1008] Step 1: (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1009]

[1010] A mixture of (R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (11 g, 58.75 mmol), 5-bromopent-1-ene (26.27 g, 176.25 mmol), NaOH (11.75 g, 293.75 mmol), and TBAB (1.89 g, 5.87 mmol) in toluene (150 mL) and H₂O (150 mL) was stirred at 100 °C for 16 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (350 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was subjected to rapid silica gel chromatography (…). 120g Sepa Purification was performed using a silica fast column with an eluent gradient of 0% to 50% ethyl acetate / petroleum ether at 100 mL / min to give the product (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (11.9 g, 46.60 mmol, 79.3% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ=5.69-5.86(m,1H),4.90-5.04(m,2H),3.98(br s,1H),3.32-3.42(m,2H),3.28(br dd,J=11.74,4.52Hz,2H),3.22(br d,J=11.49Hz,2H),2.00-2.08(m,2H),1.86(br d,J=3.55Hz,2H),1.52-1.60(m,2H),1.39(s,9H).

[1011] Step 2: (R)-3-((5-(4-chloro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1012]

[1013] 9-BBN (0.5 M, 73.62 mL) was added to a solution of (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (4.7 g, 18.41 mmol) in THF (70 mL) at 0 °C under N2. The mixture was stirred at 50 °C for 2 h. A mixture of 2,4-dichloro-1,8-naphthidine (5.08 g, 18.89 mmol), Cs2CO3 (13.99 g, 42.94 mmol), and Pd(dppf)Cl2.CH2Cl2 (1.40 g, 1.72 mmol) in DMF (50 mL) was added to the mixture. The mixture was stirred at 100 °C under N2 for 16 h. The reaction mixture was quenched with H2O (200 mL). The reaction mixture was filtered and the filtrate was extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (500 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was then subjected to rapid silica gel chromatography (…). 40g Purification was performed using a silica fast column with an eluent gradient of 0% to 100% ethyl acetate / petroleum ether at 80 mL / min to give the product (R)-3-((5-(4-chloro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (6.5 g, 11.68 mmol, 68.0% yield, 70% purity) as a yellow oil. 1 H NMR (400MHz, chloroform-d) δ = 9.14 (dd, J = 4.28, 1.83Hz, 1H), 8.58 (dd, J = 8.31, 1.83Hz, 1H), 7.56 (dd, J = 8.31, 4.28Hz, 1H), 7.50 (s, 1H), 3.94- 4.03(m,1H),3.34-3.47(m,6H),2.99-3.09(m,2H),1.92(dt,J=14.95,7.50Hz,4H),1.60-1.67(m,2H),1.47-1.55(m,2H),1.46(s,9H). LCMS (ESI) m / z=420.3(M+1).

[1014] Step 3: (R)-3-((5-(4-chloro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1015]

[1016] NaH (876.22 mg, 21.91 mmol, 60% purity) was added to a mixture of 2-methoxyethanol (1.67 g, 21.91 mmol) and THF (16 mL) at 0 °C. The mixture was stirred at 25 °C for 1 hour. Tert-butyl (R)-3-((5-(4-chloro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (4.6 g, 10.95 mmol) was added to the mixture at 0 °C in THF (46 mL). The mixture was stirred at 25 °C for 15 hours. The reaction mixture was quenched at 0 °C by adding H₂O (150 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (300 mL x 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The crude product was purified by reversed-phase HPLC (MeOH conditions containing 0.1% formic acid) to give (R)-3-((5-(4-(2-methoxyethoxy)-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2.4 g, 3.66 mmol, 33.3% yield), which was a yellow oil. LCMS (ESI) m / z = 460.2 (M+1).

[1017] Step 4: (R)-3-((5-(4-(2-methoxyethoxy)-5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1018]

[1019] (R)-3-((5-(4-(2-methoxyethoxy)-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2.4 g, 5.22 mmol) in MeOH (40 mL) was added to a suspension of Pd / C (1.2 g, 10% purity) in MeOH (80 mL) at 25 °C. The suspension was degassed under vacuum and purged three times with H2. The mixture was stirred at 25 °C under H2 (50 psi) for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give a residue, which yielded a yellow oily product (R)-3-((5-(4-(2-methoxyethoxy)-5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (3 g, crude). LCMS(ESI)m / z=464.4(M+1).

[1020] Step 5: (R)-5-(2-methoxyethoxy)-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1021]

[1022] To a mixture of (R)-3-((5-(4-(2-methoxyethoxy)-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (3 g, 6.47 mmol) and EtOAc (20 mL), HCl / EtOAc (4 M, 30 mL) was added. The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure to give a crude product. The crude product was dissolved in H2O (80 mL) and extracted with EtOAc (80 mL x 3). The aqueous phase was lyophilized to give the product (R)-5-(2-methoxyethoxy)-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidium (2.0 g, 5.50 mmol, 85.0% yield, 88% purity, HCl salt) as a yellow solid. 1 H NMR (400MHz, deuterium oxide) δ=6.43(br s,1H),4.29(br s,2H),3.81(br s,2H),3.18-3.58(m,12H),2.48-2.73(m,4H),2.02-2.13(m,2H),1.80(br s,2H),1.58-1.68(m,2H),1.54(br d,J=6.25Hz,2H),1.26-1.37(m,2H). LCMS (ESI) m / z=364.3(M+1).

[1023] Preparation of (R)-6-methoxy-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1024] Step 1: (R)-3-((5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1025]

[1026] Boc₂O (1.81 g, 8.28 mmol, 1.90 mL) was added to a solution of (R)-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine (2 g, 5.52 mmol, 2HCl) and NaHCO₃ (2.32 g, 27.60 mmol, 1.07 mL) in THF (20 mL) and H₂O (20 mL) at 20 °C. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was subjected to rapid silica gel chromatography (…). 10g Sepa Purification was performed using a rapid silica column with an eluent gradient of 0% to 100% ethyl acetate / petroleum ether at 50 mL / min. The resulting product was (R)-3-((5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 5.13 mmol, 93.02% yield), appearing as a yellow oil.

[1027] Step 2: (R)-3-((5-(3-bromo-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1028]

[1029] NBS (868.15 mg, 4.88 mmol) was added to a solution of (R)-3-((5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.9 g, 4.88 mmol) in CH3CN (20 mL) at 0 °C. The mixture was stirred at 0 °C for 10 minutes. The mixture was concentrated to give a crude residue. The residue was subjected to rapid silica gel chromatography (…). 20g Sepa Purification was performed using a rapid silica column with an eluent gradient of 0% to 100% THF / petroleum ether at 50 mL / min. The resulting product was (R)-3-((5-(3-bromo-5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 4.27 mmol, 87.53% yield), which appeared as a yellow oil.

[1030] Step 3: (R)-6-methoxy-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1031]

[1032] A mixture of 3-((5-(3-bromo-5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (0.3 g, 640.44 μmol), NaOMe (0.9 g, 5.00 mmol, 3 mL, 30% purity), and CuI (195.16 mg, 1.02 mmol) in DME (6 mL) was stirred at 125 °C under MW conditions (internal pressure 4 bar) for 0.5 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 x 30 mm x 5 μm; mobile phase: A - water containing 0.1% TFA; B - MeCN 5%-35%, 10 min; flow rate 25 mL / min). A yellow oil (R)-6-methoxy-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine (0.14 g, 333.69 μmol, 17.37% yield) was obtained. LCMS (ESI) m / z = 320.3 (M+1).

[1033] Preparation of (S)-2-(5-((R)-pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1034] Step 1: (R)-3-(4-bromobutoxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1035]

[1036] TBAB (2.24 g, 6.94 mmol) and NaOH (13.89 g, 347.16 mmol) were added to a solution of (3R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (13 g, 69.43 mmol) and 1,4-dibromobutane (44.97 g, 208.29 mmol, 25.12 mL) in H₂O (150 mL) and toluene (150 mL) at 25 °C. The mixture was stirred at 100 °C for 16 hours. Two parallel reactions were performed and post-processed together. The mixture was extracted with ethyl acetate (100 mL x 3), washed with brine (100 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was subjected to rapid silica gel chromatography (…). 120g Purification was performed using a rapid silica column with an eluent gradient of 0% to 20% ethyl acetate / petroleum ether at 150 mL / min. The resulting product was (3R)-3-(4-bromobutoxy)pyrrolidine-1-carboxylic acid tert-butyl ester (32.2 g, 99.93 mmol, 71.96% yield), which appeared yellow. 1 ¹H NMR (400MHz, chloroform-d) δ = 3.98 (br s, 1H), 3.49–3.28 (m, 8H), 2.00–1.84 (m, 4H), 1.76–1.63 (m, 2H), 1.45 (s, 9H).

[1037] Step 2: (R)-3-(but-3-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1038]

[1039] t-BuOK (14.02 g, 124.91 mmol) was added fractionally to a solution of (3R)-3-(4-bromobutoxy)pyrrolidine-1-carboxylic acid tert-butyl ester (16.1 g, 49.96 mmol) in THF (160 mL) at 0 °C. The mixture was stirred at 25 °C for 16 h. Two parallel reactions were performed and post-processed together. The mixture was quenched with H2O (300 mL), extracted with ethyl acetate (100 mL x 3), the combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to rapid silica gel chromatography (…). 120g Purification was performed using a rapid silica column with an eluent gradient of 0% to 20% ethyl acetate / petroleum ether at 150 mL / min. The resulting product was a yellow oil, tert-butyl (3R)-3-but-3-enoxypyrrolidine-1-carboxylate (18.6 g, 77.07 mmol, 77.13% yield). 1 ¹H NMR (400MHz, chloroform-d) δ=5.88-5.70(m,1H), 5.14-4.97(m,2H), 4.00(br s,1H), 3.53-3.25(m,6H), 2.31(q,J=6.8Hz,2H), 2.00-1.81(m,2H), 1.51-1.40(m,9H).

[1040] Step 3: 2-Allyl-1,8-Naphthidium-1(2H)-phenyl formate

[1041]

[1042] Phenyl chloroformate (18.05 g, 115.25 mmol, 14.44 mL) and AgOTf (1.97 g, 7.68 mmol) were added to a solution of 1,8-naphthidine (10 g, 76.84 mmol) in CH3CN (150 mL) at 20 °C. The mixture was stirred at 20 °C for 0.5 h. Allyltrimethylsilane (13.17 g, 115.25 mmol, 18.39 mL) was added to the mixture at 0 °C, and the mixture was stirred at 20 °C for 16 h. The mixture was diluted with MTBE (100 mL) and filtered. The filtrate was washed with an aqueous solution of NaHCO3 (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated to give the product. The residue was subjected to rapid silica gel chromatography (…). 120g Sepa Purification was performed using a silica rapid column with an eluent gradient of 0% to 100% ethyl acetate / petroleum ether at 200 mL / min. 2-Allyl-1,8-naphthyl-1(2H)-carboxylic acid phenyl ester (14 g, 47.89 mmol, 62.33% yield) was obtained as a yellow solid. 1 H NMR (400MHz, chloroform-d) δ = 8.24 (dd, J = 1.9, 4.9Hz, 1H), 7.32 (dd, J = 1.8, 7.5Hz, 1H), 7.26-7.23(m,1H),7.13-7.07(m,3H),6.96(dd,J=4.9,7.4Hz,1H),6.81-6.74( m,1H),6.73-6.68(m,1H),6.41(d,J=9.5Hz,1H),6.06(dd,J=5.8,9.5Hz,1H),5 .78-5.62(m,1H),5.11(q,J=6.8Hz,1H),5.01-4.90(m,2H),2.36-2.13(m,2H). LCMS(ESI)m / z=209.1(M+1).

[1043] Step 4: 2-((E)-5-(((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)pent-2-en-1-yl)-1,8-naphthidium-1(2H)-carboxylic acid phenyl ester

[1044]

[1045] A mixture of phenyl 2-allyl-1,8-naphthyl-1(2H)-carboxylate (5 g, 17.10 mmol), (R)-3-(but-3-en-1-yloxy)pyrrolidine-1-carboxylate tert-butyl ester (6.19 g, 25.66 mmol), and a second-generation Grubb catalyst (726.04 mg, 855.19 μmol) in DCM (60 mL) was stirred at 40 °C for 16 hours. Two parallel reactions were performed. The mixture was concentrated to give a crude residue. The residue was subjected to rapid silica gel chromatography (…). 80g Sepa Purification was performed using a rapid silica column with an eluent gradient of 0% to 100% ethyl acetate / petroleum ether at 200 mL / min. The result was phenyl 2-((E)-5-(((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)pent-2-en-1-yl)-1,8-naphthidium-1(2H)-carboxylic acid (5.05 g, 9.95 mmol, 29.08% yield), which appeared as a yellow oil.

[1046] Step 5: 2-(5-(((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid phenyl ester

[1047]

[1048] 2-((E)-5-(((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)pent-2-en-1-yl)-1,8-naphthidium-1(2H)-carboxylic acid phenyl ester (7 g, 13.84 mmol) was added to a solution of Pd / C (3 g, 10% purity) in MeOH (300 mL) under an Ar atmosphere. The suspension was degassed and purged three times with H2. The mixture was stirred at 50 °C for 16 hours under H2 (50 psi). The reaction mixture was filtered through a diatomaceous earth mat and washed with MeOH (100 mL). The filtrate was concentrated under vacuum. A mixture (6.9 g, mixture, crude) of phenyl 2-(5-((((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylate and methyl 2-(5-((((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylate was obtained as a yellow oil. LCMS(ESI) m / z = 510.3 (M+1).

[1049] Step 6: (3R)-3-((5-(1,2,3,4-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1050]

[1051] LiOH·H2O (1.70 g, 40.62 mmol) was added to a solution of phenyl 2-(5-(((R)-1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid (6.9 g, 13.54 mmol) in H2O (35 mL) and THF (70 mL), and the mixture was stirred at 80 °C for 16 hours. The reaction mixture was slowly quenched with ice water (100 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250 mm x 100 mm x 10 μm; mobile phase: A - water containing 0.1% TFA; B - MeCN 15%-45%, 20 min, flow rate 25 mL / min). A yellow oily substance, (3R)-3-((5-(1,2,3,4-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.88 g, 4.83 mmol, 35.65% yield), was obtained. LCMS (ESI) m / z = 390.3 (M+1).

[1052] Step 7: (R)-3-((5-((S)-1,2,3,4-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1053]

[1054] (3R)-3-((5-(1,2,3,4-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2.2 g, 5.65 mmol) was separated by SFC (column: REGIS(S,S)WHELK-O1 (250 mm x 25 mm, 10 μm); mobile phase: EtOH containing 0.1% ammonium hydroxide; B%: 35%-35%, 10 min).

[1055] Peak 1, arbitrarily designated as (R)-3-((5-((S)-1,2,3,4-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (420 mg, 1.08 mmol, 38.18% yield), was obtained as a white solid. 1¹H NMR (400MHz, methanol-d⁴) δ=7.69(dd,J=1.6,5.1Hz,1H),7.22(d,J=7.0Hz,1H),6.49(dd,J=5.2,7.2Hz,1H),4.07-4.03(m,1H),3.50-3.34(m,7H),2.76-2.71(m,2H),2.04-1.89(m,3H),1.63-1.43(m,18H).

[1056] Peak 2, arbitrarily designated as (R)-3-((5-((R)-1,2,3,4-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg, 1.03 mmol, 36.36% yield), was obtained as a white solid. 1 H NMR (400MHz, methanol-d4) δ = 7.69 (dd, J = 1.6, 5.1Hz, 1H), 7.22 (dd, J = 1.5, 7.1Hz, 1H), 6.49 (dd, J = 5.1, 7.1Hz, 1H), 4.04 (br d,J=3.0Hz,1H),3.53-3.36(m,7H),2.74(dd,J=5.9,7.0Hz,2H),2.02-1.91(m,3H),1.67-1.48(m,7H),1.46(s,11H).

[1057] Step 8: (S)-2-(5-((R)-pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1058]

[1059] A solution of (R)-3-((5-((S)-1,2,3,4-tetrahydro-1,8-naphthidin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (430 mg, 1.10 mmol) in HCl / MeOH (4 M, 10 mL) was stirred at 50 °C for 16 hours. The reaction mixture was concentrated under vacuum. (S)-2-(5-((R)-pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidium (450 mg, crude, 2HCl salt) was obtained as a yellow oil. 1H NMR (400MHz, methanol-d4) δ = 7.78-7.65 (m, 2H), 6.80 (t, J = 6.8Hz, 1H), 4.26 (br s,1H),3.64-3.57(m,1H),3.50(t,J=6.4Hz,2H),3.41-3.37(m,1H),3.41-3.37(m,1H),3.27(br d,J=3.9Hz,1H),2.93-2.78(m,2H),2.19(br s,1H),2.13-2.01(m,2H),1.75-1.55(m,6H),1.54-1.43(m,4H). LCMS (ESI) m / z=290.3(M+1).

[1060] Preparation of (R)-2-(5-((R)-pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1061] Step 1: (R)-2-(5-((R)-pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1062]

[1063] A solution of (R)-3-((5-((R)-1,2,3,4-tetrahydro-1,8-naphthidin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg, 1.03 mmol) in HCl / MeOH (4 M, 10 mL) was stirred at 50 °C for 16 hours. The reaction mixture was concentrated under vacuum. (R)-2-(5-((R)-pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidium (450 mg, crude, 2HCl salt) was obtained as a yellow oil. 1 H NMR (400MHz, methanol-d4) δ=7.75-7.69(m,2H),6.82(t,J=6.8Hz,1H),4.28(br s,1H),3.66-3.60(m,1H),3.52(t,J=6.4Hz,2H),3.39(br s,2H),3.30-3.25(m,1H),2.97-2.80(m,2H),2.27-2.18(m,1H),2.13-2.01(m,2H),1.75-1.60(m,6H),1.57-1.46(m,4H). LCMS (ESI) m / z=290.3(M+1).

[1064] Preparation of (R)-5-isopropoxy-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine Preparation

[1065] Step 1: (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1066]

[1067] A solution of (R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (12.5 g, 66.76 mmol) in toluene (130 mL) was added to a solution of 5-bromopent-1-ene (29.85 g, 200.28 mmol), TBAB (2.15 g, 6.68 mmol), and NaOH (13.35 g, 333.80 mmol) in H₂O (130 mL). The mixture was stirred at 100 °C for 16 hours. The reaction mixture was quenched by adding H₂O (100 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was subjected to rapid silica gel chromatography (…). 220g Sepa Purification was performed using a silica fast column with an eluent gradient of 0% to 100% ethyl acetate / petroleum ether at 100 mL / min. The resulting product was (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (23 g, 90.07 mmol, 67.46% yield), which appeared as a yellow oil. 1 H NMR (400MHz, chloroform-d) δ=5.83-5.70(m,1H),5.03-4.88(m,2H),3.96(br s,1H),3.39(br s,6H),2.08(br s,2H),1.92(br s, 2H), 1.69-1.56 (m, 2H), 1.43 (d, J = 3.4Hz, 9H).

[1068] Step 2: (R)-3-((5-(4-chloro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1069]

[1070] 9-BBN (0.5 M, 78.32 mL) was added to a solution of (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (5 g, 19.58 mmol) in THF (50 mL) at 0 °C. The mixture was stirred at 50 °C for 2 h, and then a mixture of 2,4-dichloro-1,8-naphthidine (3.90 g, 19.58 mmol), Cs₂CO₃ (12.76 g, 39.16 mmol), and Pd(PPh₃)₄ (1.13 g, 979.04 μmol) in DMF (100 mL) was added. The mixture was stirred at 100 °C under N₂ for 3 h. Both batches of reactants were post-treated together. The mixture was quenched with H₂O (500 mL), extracted with ethyl acetate (100 mL x 3), the organic layer was washed with brine (100 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by reversed-phase HPLC (water (TFA)-CH₃CN). Tert-butyl (R)-3-((5-(4-chloro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (9 g, 21.43 mmol, 36.48% yield) was obtained as a brown oil. 1 H NMR (400MHz, chloroform-d) δ = 8.87-8.93 (m, 1H), 8.34 (dd, J = 8.4, 1.6Hz, 1H), 7.32 (dd, J = 8.3, 4.3Hz, 1H), 7.04 (s, 2H), 3.76 (br s, 1H), 3.19 (br s,5H),3.03-3.17(m,2H),2.81(t,J=7.8Hz,2H),1.64-1.74(m,4H),1.40-1.46(m,2H),1.39(s,6H),1.25-1.30(m,2H),1.23(s,9H). LCMS (ESI) m / z=420.2(M+1).

[1071] Step 3: (R)-3-((5-(4-isopropoxy-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1072]

[1073] Cs₂CO₃ (6.98 g, 21.43 mmol) and i-PrOH (4.29 g, 71.44 mmol, 5.47 mL) were added to a mixture of (R)-3-((5-(4-chloro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (3 g, 7.14 mmol, 5.47 mL) in DMF (30 mL) at 25 °C. The mixture was stirred at 100 °C for 16 hours. The mixture was quenched with H₂O (50 mL), extracted with ethyl acetate (30 mL x 3), washed with brine (50 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. (R)-3-((5-(4-isopropoxy-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 4.51 mmol, 63.11% yield) was obtained as a brown oil. LCMS (ESI) m / z = 444.3 (M+1).

[1074] Step 4: (R)-3-((5-(4-isopropoxy-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1075]

[1076] A solution of (R)-3-((5-(4-isopropoxy-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.9 g, 4.28 mmol) in MeOH (60 mL) was added to a suspension of Pd / C (1.9 g, 10% purity) in MeOH (60 mL) at 25 °C under Ar conditions. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 50 °C for 16 hours under H2 (50 psi). The mixture was filtered and concentrated under vacuum to obtain a residue. The residue was used directly in the next step without further purification. (R)-3-((5-(4-isopropoxy-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester was obtained as a yellow oil (1.55 g, 3.46 mmol, 80.84% ​​yield). LCMS (ESI) m / z = 448.3 (M+1).

[1077] Step 5: (R)-3-((5-(4-isopropoxy-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1078]

[1079] HCl / MeOH (4M, 20 mL) was added to a mixture of (R)-3-((5-(4-isopropoxy-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, 3.35 mmol) in MeOH (5 mL) at 25 °C under N2. The mixture was stirred at 50 °C for 3 hours. The reaction mixture was concentrated to give a residue, which was adjusted to pH 7 to 8 with a base resin in MeOH (30 mL). The mixture was stirred at 25 °C for 0.5 hours, filtered, and concentrated under vacuum. The residue was used directly in the next step without further purification. (R)-5-isopropoxy-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidium (1.5 g, crude) was obtained as a yellow oil. LCMS(ESI)m / z=348.3(M+1).

[1080] (R)-6-(5-(pyrrolidine-3-yloxy)pentyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine preparation

[1081] Step 1: (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1082]

[1083] A solution of (R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (50 g, 267.04 mmol) in toluene (130 mL) was added to a solution of 5-bromopent-1-ene (119.39 g, 801.13 mmol), TBAB (8.61 g, 26.70 mmol), and NaOH (53.40 g, 1.34 mol) in H₂O (130 mL). The mixture was stirred at 100 °C for 16 hours. Two parallel reactions were carried out together. The reaction mixture was quenched by adding H₂O (200 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was subjected to rapid silica gel chromatography (…). 330g Sepa Purification was performed using a silica fast column with an eluent gradient of 0% to 100% ethyl acetate / petroleum ether at 80 mL / min. The resulting product was (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (76 g, 297.63 mmol, 55.73% yield), which appeared as a yellow oil. 1¹H NMR (400MHz, chloroform-d) δ=5.80(tdd,J=6.7,10.3,17.1Hz,1H),5.06-4.92(m,2H),3.99(br s,1H),3.49-3.35(m,6H),2.11(q,J=7.1Hz,2H),1.95(br d,J=3.6Hz,2H),1.69-1.61(m,2H),1.46(s,9H).

[1084] Step 2: (R)-3-((5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1085]

[1086] Add 9-BBN (0.5 M, 187.98 mL) to a solution of (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (12 g, 46.99 mmol) in THF (120 mL). Stir the mixture at 25 °C for 16 hours and use it directly in the next step. Add 6-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2 g, 9.30 mmol) to the mixture in a solution of DMF (20 mL) and H2O (1 mL) and Cs2CO3 (6.06 g, 18.60 mmol), Pd(PPh3)4 (537.35 mg, 465.01 μmol). Stir the mixture at 100 °C for 3 hours. The reaction mixture was quenched by adding H₂O (60 mL) and ethyl acetate (50 mL). The mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under vacuum to obtain a residue. The filtrate was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue. The residue was subjected to rapid silica gel chromatography (…). 40g Sepa Purification was performed using a rapid silica column with an eluent gradient of 0% to 100% ethyl acetate / petroleum ether at 80 mL / min. The resulting product was a yellow oil, (R)-3-((5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (5 g, 7.41 mmol, 79.65% yield, 58% purity). 1H NMR (400MHz, chloroform-d)δ=6.93-6.80(m,1H),6.40-6.30(m,1H),4.25-4.14(m,1H),3.97(br s,1H),3.86-3.73(m,1H),3.68-3.49(m,1H),3.46-3.24(m,6H),2.76-2.12(m,1H),1.98-1.80(m,3H),1.64-1.48(m,5H),1.44(s,9H).

[1087] Step 3: (R)-6-(5-(pyrrolidine-3-yloxy)pentyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

[1088]

[1089] A solution of (R)-3-((5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (3 g, 7.66 mmol) in HCl / MeOH (4 M, 30 mL) was stirred at 50 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the residue. The mixture was further purified by preparative HPLC (column: Phenomenex Luna 80 x 30 mm x 3 μm; mobile phase: A: water containing 0.1% TFA; B: MeCN 0%–22%, 20 min; flow rate 25 mL / min)). (R)-6-(5-(pyrrolidine-3-yloxy)pentyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (3.2 g, 10.98 mmol, 89.57% yield) was obtained as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ = 8.97 (brs, 2H), 7.37 (d, J = 8.0Hz, 1H), 6.61 (d, J = 7.9Hz, 1H), 4.22 (t, J = 4.5Hz, 2H), 4.14 (td, J = 2.1, 3.9Hz, 1H), 3.57 (br t,J=4.6Hz,2H),3.37(t,J=6.5Hz,2H),3.23-3.11(m,4H),2.63(t,J=7.6Hz,2H ),2.00-1.88(m,2H),1.63-1.56(m,2H),1.53-1.45(m,2H),1.35-1.27(m,2H). LCMS(ESI)m / z=292.2(M+1).

[1090] (R)-1-Methyl-6-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine Preparation

[1091] Step 1: Ethyl 2-((6-chloro-3-nitropyridin-2-yl)amino)acetate

[1092]

[1093] 2-Aminoethyl ethyl hydrochloride (7.59 g, 54.41 mmol) was added to a mixture of 2,6-dichloro-3-nitropyridine (10 g, 51.82 mmol) and Et3N (20.97 g, 207.27 mmol, 28.85 mL) in MTBE (100 mL) at -5 °C, and the mixture was stirred at -5 °C for 0.5 h. The mixture was then stirred at 20 °C for 12 h. H2O (100 mL) and ethyl acetate (100 mL) were added to the mixture. The layers were separated, and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was subjected to rapid silica gel chromatography (…). 220g Sepa Purification was performed using a silica fast column with an eluent gradient of 0% to 30% petroleum ether / ethyl acetate at 120 mL / min. Ethyl 2-((6-chloro-3-nitropyridin-2-yl)amino)acetate (11 g, 42.37 mmol, 81.8% yield) was obtained as a yellow oil. 1 ¹H NMR (400MHz, chloroform-d) δ = 8.63 (br s, 1H), 8.38 (d, J = 8.5Hz, 1H), 6.70 (d, J = 8.6Hz, 1H), 4.37 (d, J = 5.3Hz, 2H), 4.28 (q, J = 7.1Hz, 2H), 1.32 (t, J = 7.1Hz, 3H). LCMS (ESI) m / z = 260.0 (M+1).

[1094] Step 2: ethyl acetate 2-((tert-butoxycarbonyl)(6-chloro-3-nitropyridin-2-yl)amino)

[1095]

[1096] Boc₂O (15.72 g, 72.02 mmol, 16.55 mL) was added to a mixture of ethyl 2-((6-chloro-3-nitropyridin-2-yl)amino)acetate (11 g, 42.37 mmol), Et₃N (8.57 g, 84.73 mmol, 11.79 mL), and DMAP (517.57 mg, 4.24 mmol) in THF (120 mL) at 20 °C. The mixture was stirred at 60 °C for 12 hours. H₂O (100 mL) and ethyl acetate (100 mL) were added to the mixture. The layers were separated and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 100 / 1 to 3 / 1). Ethyl 2-((tert-butoxycarbonyl)(6-chloro-3-nitropyridin-2-yl)amino)acetate was obtained as a yellow oil (14 g, 38.91 mmol, 91.8% yield). 1 ¹H NMR (400MHz, chloroform-d) δ = 8.22 (br d, J = 8.3Hz, 1H), 7.21 (d, J = 8.4Hz, 1H), 4.64 (br s, 2H), 4.26 (q, J = 7.1Hz, 2H), 1.54–1.39 (m, 9H), 1.31 (t, J = 7.1Hz, 3H). LCMS (ESI) m / z = 360.0 (M+1).

[1097] Step 3: 2-((3-amino-6-chloropyridin-2-yl)(tert-butoxycarbonyl)amino)ethyl acetate

[1098]

[1099] Fe (10.87 g, 194.57 mmol) was added to a mixture of ethyl 2-((tert-butoxycarbonyl)(6-chloro-3-nitropyridin-2-yl)amino)acetate (14 g, 38.91 mmol) and NH4Cl (10.41 g, 194.57 mmol) in EtOH (280 mL) and H2O (90 mL) at 20 °C. The mixture was stirred at 90 °C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated. H2O (100 mL) and ethyl acetate (200 mL) were added to the mixture. The layers were separated and the aqueous phase was extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. 9 g of crude ethyl 2-((3-amino-6-chloropyridin-2-yl)(tert-butoxycarbonyl)amino)acetate was obtained as a yellow oil. LCMS(ESI)m / z=330.1(M+1).

[1100] Step 4: tert-butyl 6-chloro-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-formate

[1101]

[1102] t-BuOK (3.37 g, 30.02 mmol) was added to a mixture of ethyl 2-((3-amino-6-chloropyridin-2-yl)(tert-butoxycarbonyl)amino)acetate (9 g, 27.29 mmol) in DMF (100 mL) at 20 °C. The mixture was stirred at 20 °C for 1 hour. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with H2O (50 mL) and brine (50 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. 3.65 g (crude) of tert-butyl 6-chloro-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate was given as a yellow solid. LCMS (ESI) m / z = 284.0 (M+1).

[1103] Step 5: tert-butyl 6-chloro-1-methyl-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-formate

[1104]

[1105] NaH (566.02 mg, 14.15 mmol, 60% purity) was added to a mixture of 6-chloro-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylic acid tert-butyl ester (3.65 g, 12.87 mmol) in DMF (40 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h. MeI (1.83 g, 12.87 mmol, 800.91 μL) was added dropwise at 0 °C under N2. The mixture was then stirred at 20 °C for 12 h. The mixture was added to saturated NH4Cl (100 mL) at 0 °C. Ethyl acetate (100 mL) was added to the mixture. The layers were separated and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine (200 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). 4.2 g crude tert-butyl 6-chloro-1-methyl-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate was obtained as a yellow oil. 1H NMR (400MHz, DMSO-d6) δ = 7.66 (d, J = 8.4Hz, 1H), 7.35 (d, J = 8.5Hz, 1H), 4.37 (s, 2H), 3.32 (s, 2H), 3.28-3.19 (m, 3H), 1.46 (s, 9H). LCMS (ESI) m / z=298.0(M+1).

[1106] Step 6: (R)-6-(5-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)pentyl)-1-methyl-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-formate tert-butyl ester

[1107]

[1108] 9-BBN (0.5M, 26.87mL) was added to a solution of (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (2.06g, 8.06mmol) in THF (20mL) at 0°C. After stirring at 40°C for 3 hours, the resulting solution was added to a solution of 6-chloro-1-methyl-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate (2g, 6.72mmol), tricyclohexylphosphine (188.37mg, 671.73μmol), K2CO3 (1.86g, 13.43mmol), and Pd(dba)2 (386.25mg, 671.73μmol) in THF (12mL) and H2O (1mL). The reaction mixture was stirred at 50°C for 12 hours. Two batches were performed in parallel. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with H2O (30 mL x 2) and brine (20 mL x 2), dried over Na2SO4, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). Tert-butyl (R)-6-(5-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)pentyl)-1-methyl-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylic acid (4.2 g, 8.10 mmol, 60.3% yield) was given as a yellow oil. LCMS (ESI) m / z = 519.3 (M+1).

[1109] Step 7: (R)-3-((5-(1-methyl-1,2,3,4-tetrahydropyridino[2,3-b]pyrazin-6-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1110]

[1111] BH3 was added to a solution of (R)-6-(5-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)oxy)pentyl)-1-methyl-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylic acid tert-butyl ester (1.93 g, 3.72 mmol) in THF (20 mL) at 0 °C. . The mixture was stirred at 25°C for 2 hours using THF (1M, 37.21 mL). The reaction mixture was quenched with MeOH (10 mL) and concentrated at 0°C to give the crude product. The residue was purified by preparative HPLC (column: Waters X bridge BEHC18 250x50 mm x 10 μm; mobile phase: A: water containing 10 mmol / L NH4HCO3; B: MeCN 40%-70%, 10 min; flow rate (25 mL / min). A yellow oil (R)-3-((5-(1-methyl-1,2,3,4-tetrahydropyridino[2,3-b]pyrazin-6-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.24 mmol, 33.2% yield) was obtained. LCMS (ESI) m / z = 405.3 (M+1).

[1112] Step 8: (R)-1-methyl-6-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine

[1113]

[1114] A solution of (R)-3-((5-(1-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-6-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 741.57 μmol) in HCl / MeOH (2 mL) was stirred at 25 °C for 12 hours. The mixture was concentrated. (R)-1-methyl-6-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (300 mg, crude) was obtained as a yellow oil. LCMS (ESI) m / z = 305.2 (M+1).

[1115] (R)-N,N-Dimethyl-2-(5-(pyrrolidone-3-yloxy)pentyl)-5,6,7,8-tetrahydro-1,8-naphthyl-4-amine Preparation

[1116] Step 1: (R)-3-((5-(4-(dimethylamino)-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1117]

[1118] DIEA (4.60 g, 35.59 mmol, 6.20 mL) was added to a solution of (R)-3-((5-(4-chloro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (3.1 g, 7.38 mmol) and dimethylamine (2 M in THF, 13 mL) in NMP (30 mL), and the mixture was stirred at 100 °C for 48 hours. The reactants were concentrated under vacuum. (R)-3-((5-(4-(dimethylamino)-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (3.5 g, crude) was obtained as a yellow oil. LCMS (ESI) m / z = 429.3 (M+1).

[1119] Step 2: (R)-3-((5-(4-(dimethylamino)-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1120]

[1121] (R)-3-((5-(4-(dimethylamino)-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (3.5 g, 8.17 mmol) was added to a solution of Pd / C (2 g, 10% purity) in MeOH (60 mL) under an Ar atmosphere. The suspension was degassed and purged three times with H2. The mixture was stirred at 50 °C for 16 hours under H2 (50 psi). The reaction mixture was filtered through a diatomaceous earth mat. The filtrate was concentrated under vacuum. (R)-3-((5-(4-(dimethylamino)-5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (3.5 g, crude) was obtained as a yellow oil. LCMS (ESI) m / z = 433.3 (M+1).

[1122] Step 3: (R)-N,N-dimethyl-2-(5-(pyrrolidine-3-yloxy)pentyl)-5,6,7,8-tetrahydro-1,8-naphthidine-4-amine

[1123]

[1124] A mixture of (R)-3-((5-(4-(dimethylamino)-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (3 g, 6.93 mmol) in HCl / MeOH (4 M, 50 mL) was stirred at 50 °C for 16 h. The reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250 x 70 mm, 15 μm); mobile phase: A: water containing 0.1% TFA; B: MeCN 0%–30%, 28 min; flow rate 25 mL / min). (R)-N,N-dimethyl-2-(5-(pyrrolidine-3-yloxy)pentyl)-5,6,7,8-tetrahydro-1,8-naphthidine-4-amine (2.3 g, 5.15 mmol, 74.28% yield, TFA salt) was obtained as a yellow oil. 1 ¹H NMR (400 MHz, methanol-d⁴) δ = 6.27 (s, 1H), 4.24 (t, J = 4.4 Hz, 1H), 3.48 (t, J = 6.5 Hz, 2H), 3.42–3.35 (m, 4H), 3.34 (br) d,J=3.0Hz,1H),3.24(dd,J=4.1,12.4Hz,1H),3.05(s,6H),2.71(t,J=6.2Hz,2H),2.64-2.57(m,2H),2.19(dddd,J =1.9,3.6,6.9,12.2Hz,1H),2.09-1.98(m,1H),1.82(td,J=5.9,11.6Hz,2H),1.75-1.57(m,4H),1.51-1.38(m,2H). LCMS (ESI) m / z=333.3(M+1).

[1125] Preparation of 7-(5-((trans-4-fluoropyrrolidine-3-yl)oxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1126] Step 1: tert-butyl trans-3-fluoro-4-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate

[1127]

[1128] A solution of trans-3-fluoro-4-hydroxypyrrolidine-1-carboxylate tert-butyl ester (1.5 g, 8.01 mmol) and 5-bromopent-1-ene (3.58 g, 24.03 mmol) in n-heptane (20 mL) was added with 3 mL of 50% sodium hydroxide aqueous solution and 0.4 mmol of tetrabutylammonium bromide (105 mg). The mixture was stirred at 80 °C for 4 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL) and water (20 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (30 mL x 2). The combined organic layers were dried over Na2SO4, filtered, concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 5:1) to give the desired product, trans-3-fluoro-4-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (730 mg, 33% yield), as a pale yellow oil. ESI 274(M+H)+.

[1129] Step 2: 7-(5-((trans-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-formate tert-butyl ester

[1130]

[1131] 9-BBN (0.5 M in THF, 10.8 mL, 5.4 mmol) was added to a solution of trans-3-fluoro-4-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (730 mg, 2.67 mmol) in anhydrous THF (10 mL). The reaction mixture was stirred at 50 °C for 1.5 h, then cooled to room temperature, and 2-chloro-4-methoxy-1,8-naphthidine (718 mg, 2.67 mmol), Pd(OAc)₂ (29 mg, 0.13 mmol), PCy₃ (73 mg, 0.26 mmol), and KOH (146 mg, 2.6 mmol) were added. The reaction mixture was stirred at 80 °C for 15 h. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 2:1) to give the desired product, 7-(5-((trans-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylic acid tert-butyl ester (1.2 g, 89% yield), as a pale yellow oil. ESI 508(M+H)+.

[1132] Step 3: 7-(5-((trans-4-fluoropyrrolidine-3-yl)oxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1133]

[1134] HCl / dioxane (4M, 10 mL) was added to a solution of tert-butyl 7-(5-((trans-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthidine-1(2H)-carboxylate (1.2 g, 2.36 mmol) in dioxane (40 mL). The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed under vacuum to give the desired product 7-(5-((trans-4-fluoropyrrolidine-3-yl)oxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine (0.7 g, 96% yield) as a yellow oil. ESI 308(M+H)+.

[1135] Preparation of 7-(5-((cis-4-fluoropyrrolidine-3-yl)oxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1136] Step 1: cis-3-fluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

[1137]

[1138] DIAD (1.48 g, 7.33 mmol) was added to a solution of PPh3 (1.92 g, 7.33 mmol) in THF (20 mL) under N2 protection at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, and then tert-butyl trans-3-fluoro-4-hydroxypyrrolidine-1-carboxylate (1.00 g, 4.88 mmol) and 4-nitrobenzoic acid (815 mg, 4.88 mmol) were added to the mixture and stirred at room temperature for 6 h. The reaction mixture was quenched with H2O (20 mL) and then extracted with EtOAc (20 mL × 3). The combined organic phases were washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in a mixture of MeOH (10 mL) and 2NNaOH (5 mL) and stirred at room temperature for 3 h. The reaction mixture was extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether = 20% to 30%) to give the desired product, cis-3-fluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (350 mg), as a brown oil. Yield 35% ESI 206(M+H)+.

[1139] Step 2: tert-butyl cis-3-fluoro-4-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate

[1140]

[1141] A solution of tert-butyl cis-3-fluoro-4-hydroxypyrrolidine-1-carboxylate (350 mg, 1.71 mmol) in n-heptane (10 mL) was supplemented with 50% aqueous sodium hydroxide solution (1.64 mL, 20.52 mmol), tetrabutylammonium bromide (28 mg, 0.09 mmol), and 5-bromopent-1-ene (1.27 g, 8.55 mmol). The mixture was heated at 80 °C for 2 hours, then cooled to room temperature and diluted with EtOAc (30 mL) and water (30 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (30 mL x 2). The combined organic layers were dried over Na2SO4 and filtered. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 4:1) to give the desired product, cis-3-fluoro-4-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (360 mg), as a colorless oil. Yield 77% (ESI 274(M+H)+).

[1142] Step 3: cis-3-fluoro-4-((5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1143]

[1144] 9-BBN (0.5N in THF, 5.3 mL, 2.65 mmol) was added to a solution of cis-3-fluoro-4-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (360 mg, 1.32 mmol) under a nitrogen atmosphere. The mixture was stirred at 60 °C for 1.5 h and cooled to room temperature, and then 7-chloro-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylate tert-butyl ester (354 mg, 1.32 mmol), Pd(OAc)₂ (30 mg, 0.13 mmol), PCy₃ (73 mg, 0.26 mmol), and KOH (107 mg, 1.98 mmol) were added. The mixture was stirred at 70°C for 12 hours, concentrated, and purified by silica gel chromatography (EtOAc: petroleum ether = 0% to 70%) to give the desired product, cis-3-fluoro-4-((5-(5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (480 mg). Yield 89% (ESI 408(M+H)+).

[1145] Step 4: 7-(5-((cis-4-fluoropyrrolidine-3-yl)oxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1146]

[1147] 480 mg (1.18 mmol) of cis-3-fluoro-4-((5-(5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester was added to a solution of HCl / dioxane (5 mL, 4 N). The mixture was stirred at room temperature for 4 hours and concentrated to give the desired product 7-(5-((cis-4-fluoropyrrolidine-3-yl)oxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine (320 mg) as a white solid, which was used in the next step without further purification. Yield 88% (ESI 308(M+H)+).

[1148] Preparation of (R)-5-methyl-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1149] Step 1: (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1150]

[1151] A solution of (S)-3-hydroxypyrrolidine-1-carboxylate tert-butyl ester (10.0 g, 53.4 mmol) in n-heptane (120 mL) was added with 50% sodium hydroxide aqueous solution (11 mL, 267 mmol), tetrabutylammonium bromide (861 mg, 2.67 mmol), and 5-bromopent-1-ene (11.9 g, 80.1 mmol). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was then cooled to room temperature, and EtOAc (100 mL) and water (100 mL) were added. The organic phase was separated, and the aqueous phase was extracted with EtOAc (50 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 4:1) to give the desired product (S)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate tert-butyl ester (13 g) as a colorless oil. Yield 95% (ESI 256.2(M+H)+).

[1152] Step 2: (R)-3-((5-(4-chloro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1153]

[1154] 9-BBN (35.2 mL, 17.6 mmol, 0.5 N in THF) was added to a solution of (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (2.5 g, 9.8 mmol) in THF (5 mL) under N2 atmosphere. The mixture was stirred at 60 °C for 1.5 h and cooled to room temperature. 7-chloro-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylate tert-butyl ester (1.95 g, 9.8 mmol), Pd(OAc)2 (54 mg, 0.5 mmol), PCy3 (135 mg, 0.5 mmol), and KOH (825 mg, 14.7 mmol) were added. The mixture was stirred at 70°C for 16 hours, then concentrated and purified by silica gel chromatography (EtOAc: petroleum ether = 0% to 70%) to give the desired product (R)-3-((5-(4-chloro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (3.1 g). Yield 75% (ESI 420.2(M+H)+).

[1155] Step 3: (R)-3-((5-(4-methyl-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1156]

[1157] A mixture of (R)-3-((5-(4-chloro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (3.1 mg, 7.4 mmol), methylboronic acid (530 mg, 8.9 mmol), Pd(dppf)Cl2 (541 mg, 0.74 mmol), and K2CO3 (2.04 g, 14.8 mmol) in 30 mL of dioxane and 3 mL of H2O was stirred at 80 °C for 4 hours. The mixture was concentrated and purified by silica gel chromatography (EtOAc: petroleum ether = 0% to 70%) to give the desired product (R)-3-((5-(4-methyl-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.25 g). Yield 42% (ESI 400.2(M+H)+).

[1158] Step 4: (R)-3-((5-(4-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1159]

[1160] A mixture of (R)-3-((5-(4-methyl-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.25 g, 3.13 mmol) and Pd / C (125 mg, 10% on activated carbon) in 10 mL of MeOH was stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was filtered and the filtrate was concentrated to give the desired product (R)-3-((5-(4-methyl-5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.15 g). Yield 91% (ESI 404.3(M+H)+).

[1161] Step 5: (R)-5-methyl-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1162]

[1163] (R)-3-((5-(4-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.15 g, 2.85 mmol) was added to a solution of HCl / dioxane (10 mL, 4 N). The mixture was stirred at room temperature for 16 hours and concentrated to give the desired product (R)-5-methyl-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine (700 mg) as a white solid, which was used in the next step without further purification. Yield 100% (ESI 304.2(M+H)+).

[1164] Preparation of (R)-6-methyl-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1165] Step 1: 3-Methyl-1,8-naphthidium-2(1H)-one

[1166]

[1167] Propionyl chloride (3.39 g, 36.89 mmol) was added to a solution of 2-aminopyridinecarboxaldehyde (3.0 g, 24.59 mmol) and Et3N (4.97 g, 49.18 mmol) in dioxane (20 mL) at 0 °C. The mixture was stirred at room temperature for 2 hours, then quenched with H2O (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The obtained residue was added to a mixture of Cs2CO3 (16.13 g, 49.18 mmol) and DMF (20 mL). The reaction mixture was stirred overnight at 70 °C, then concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 1:1) to give the desired product, 3-methyl-1,8-naphthid-2(1H)-one (1.6 g), as a brown solid. Yield 41% (ESI 161[M+H]+).

[1168] Step 2: 2-Chloro-3-methyl-1,8-naphthidine

[1169]

[1170] A solution of 3-methyl-1,8-naphthidin-2(1H)-one (1.6 g, 9.94 mmol) in POCl3 (20 mL) was stirred at 110 °C for 8 hours. The reaction mixture was quenched with H2O (10 mL) and then extracted with EtOAc (30 mL × 3). The combined organic phases were washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 2:1) to give the desired product, 2-chloro-3-methyl-1,8-naphthidin (1.1 g), as a yellow solid. Yield: 62% (ESI 179 [M+H]+).

[1171] Step 3: (R)-3-((5-(3-methyl-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1172]

[1173] 9-BBN (24.6 mL, 12.3 mmol, 0.5 N in THF) was added to a solution of (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (1.57 g, 6.15 mmol) in 5 mL of THF under a nitrogen atmosphere. The mixture was stirred at 60 °C for 1.5 h and cooled to room temperature. 2-Chloro-3-methyl-1,8-naphthidine (1.1 g, 6.15 mmol), Pd(OAc)₂ (69 mg, 0.31 mmol), PCy₃ (260 mg, 0.93 mmol), and KOH (517 mg, 9.23 mmol) were then added. The mixture was stirred at 70°C for 16 hours, concentrated, and purified by silica gel chromatography (EtOAc: petroleum ether = 0% to 70%) to give the desired product (R)-3-((5-(3-methyl-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.6 g). Yield 65% (ESI 400(M+H)+).

[1174] Step 4: (R)-3-((5-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1175]

[1176] A mixture of (R)-3-((5-(3-methyl-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.6 g, 4 mmol) and Pd / C (160 mg, 20 wt%) in ethyl acetate (20 mL) was stirred at 40 °C under a H2 balloon for 16 hours. The solids were removed by filtration, the filtrate was concentrated under vacuum, and the residue was purified by silica gel column chromatography (DCM:MeOH 30:1) to give the desired product (R)-3-((5-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g) as a yellow oil. Yield 93% (ESI 404(M+H)+).

[1177] Step 5: (R)-6-methyl-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine hydrochloride

[1178]

[1179] (R)-3-((5-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, 3.72 mmol) was added to a solution of HCl / dioxane (15 mL, 4 N). The mixture was stirred at room temperature for 6 hours and concentrated to give the desired product (R)-6-methyl-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidium hydrochloride (1.1 g) as a white solid, which was used in the next step without further purification. Yield 87% (ESI 304(M+H)+).

[1180] (R)-N,N-dimethyl-2-(2-(5-(pyrrolidine-3-yloxy)pentyl)-5,6,7,8-tetrahydro-1,8-naphthidine- Preparation of 4-yl)ethyl-1-amine

[1181] Step 1: (R)-3-((5-(4-chloro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1182]

[1183] A solution of (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (5 g, 19.6 mmol) in 9-BBN (0.5 M in THF, 78.4 mL, 39.2 mmol) was stirred at 50 °C for 2 hours. After cooling to room temperature, 2,4-dichloro-1,8-naphthidine (3.9 g, 19.6 mmol), Pd(OAc)₂ (439 mg, 1.96 mmol), PCy₃ (447 mg, 1.96 mmol), and NaOH (1.18 g, 29.4 mmol) were added. The mixture was stirred at 50 °C under an argon atmosphere for 1 hour. The mixture was diluted with EtOAc and filtered. The filtrate was concentrated and purified by silica gel chromatography (EtOAc / petroleum ether = 0% to 50%) to give the desired product (R)-3-((5-(4-chloro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (3.6 g) as a colorless oil. Yield 44% (ESI 420.1(M+H)+).

[1184] Step 2: (R)-3-((5-(4-vinyl-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1185]

[1186] A mixture of (R)-3-((5-(4-chloro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (210 mg, 0.5 mmol), potassium vinyltrifluoroborate (87 mg, 0.65 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), Ru-phos (23 mg, 0.05 mmol), and Na2CO3 (160 mg, 1.5 mmol) in toluene (4 mL) and water (0.5 mL) was stirred at 100 °C under an argon atmosphere for 18 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography (EtOAc / petroleum ether = 0% to 20%) to give the desired product (R)-3-((5-(4-vinyl-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg) as a colorless oil. Yield 48% (ESI 412.1(M+H)+).

[1187] Step 3: (R)-3-((5-(4-(2-(dimethylamino)ethyl)-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1188]

[1189] A mixture of (R)-3-((5-(4-vinyl-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (740 mg, 1.8 mmol) and dimethylamine hydrochloride (438 mg, 5.4 mmol) in MeOH (10 mL) was stirred at 75 °C for 16 hours. The mixture was concentrated and the residue was purified by silica gel chromatography (EtOAc / petroleum ether = 0% to 50%) to give the desired product (R)-3-((5-(4-(2-(dimethylamino)ethyl)-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (450 mg) as a yellow solid. Yield 50% (ESI 457.1(M+H)+).

[1190] Step 4: (R)-N,N-dimethyl-2-(2-(5-(pyrrolidone-3-yloxy)pentyl)-5,6,7,8-tetrahydro-1,8-naphthidin-4-yl)ethyl-1-amine

[1191]

[1192] A mixture of (R)-3-((5-(4-(2-(dimethylamino)ethyl)-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (456 mg, 1 mmol) and Pd / C (250 mg, 10% on activated carbon) in 10 mL MeOH was stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in 10 mL DCM, and then HCl (4 N, 5 mL) in dioxane was added. The mixture was stirred at room temperature for 4 hours and concentrated under vacuum to give the desired product (R)-N,N-dimethyl-2-(2-(5-(pyrrolidine-3-yloxy)pentyl)-5,6,7,8-tetrahydro-1,8-naphthid-4-yl)ethyl-1-amine (340 mg). Yield 94% (ESI 361.2(M+H)+).

[1193] (R)-5-(2-methoxyethyl)-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthalene Preparation of pyridine

[1194] Step 1: (R)-3-((5-(4-(2-methoxyethyl)-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1195]

[1196] MeONa (162 mg, 3.0 mmol) was added to a solution of (R)-3-((5-(4-vinyl-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (411 mg, 1.0 mmol) in 10 mL of MeOH. The mixture was stirred at 60 °C for 7 h, then quenched with water (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were concentrated to give the crude product (R)-3-((5-(4-(2-methoxyethyl)-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (376 mg), which was used directly in the next step. (ESI 444.2(M+H)+).

[1197] Step 2: (R)-5-(2-methoxyethyl)-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1198]

[1199] Pd / C (10%, 76 mg) was added to a solution of (R)-3-((5-(4-(2-methoxyethyl)-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (376 mg, 0.85 mmol) in 15 mL of LEtOAc. The resulting mixture was stirred at 50 °C under a hydrogen atmosphere for 16 hours, then filtered through diatomaceous earth and concentrated under vacuum. The residue was dissolved in 5 mL of LDCM, and then HCl (4 N in 1,4-dioxane, 2 mL) was added. The mixture was stirred at room temperature for 3 hours, then concentrated under vacuum to give the desired product (R)-5-(2-methoxyethyl)-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidium (245 mg) as a pale yellow solid. ESI 348.2(M+H)+.

[1200] Preparation of (S)-2-(4-(((R)-pyrrolidine-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1201] Step 1: (R)-3-(hex-5-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1202]

[1203] A solution of (R)-3-hydroxypyrrolidine-1-carboxylate tert-butyl ester (20 g, 107 mmol) in n-heptane (250 mL) was added with 50% sodium hydroxide aqueous solution (86 mL, 1070 mmol), tetrabutylammonium bromide (3.45 g, 10.7 mmol), and 6-bromohex-1-ene (52 g, 321 mmol). The mixture was stirred at 80 °C for 2 hours, then cooled to room temperature and diluted with EtOAc (500 mL) and water (300 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (200 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 4:1) to give the desired product (R)-3-(hex-5-en-1-yloxy)pyrrolidine-1-carboxylate tert-butyl ester (26 g) as a colorless oil. Yield 90% (ESI 270(M+H)+).

[1204] Step 2: (R)-3-((5-oxopentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1205]

[1206] A mixture of (R)-3-(hex-5-en-1-yloxy)pyrrolidine-1-carboxylate tert-butyl ester (5.0 g, 18.6 mmol), potassium osmium (VI) dihydrate (343 mg, 0.93 mmol), and sodium periodate (9.95 g, 46.5 mmol) in 150 mL THF and 150 mL H₂O was stirred at room temperature for 12 hours. The mixture was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with water (200 mL), dried over Na₂SO₄, and concentrated under vacuum to give crude (R)-3-((5-oxopentyl)oxy)pyrrolidine-1-carboxylate tert-butyl ester (4.9 g) as a colorless oil. Yield 95% (ESI 272(M+H)+).

[1207] Step 3: (3R)-3-((5-hydroxyhept-6-en-1-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1208]

[1209] Vinyl magnesium bromide (1.0 M in THF, 36 mL, 36 mmol) was added dropwise to a solution of (R)-3-((5-oxopentyl)oxy)pyrrolidine-1-carboxylate tert-butyl ester (4.9 g, 18 mmol) in THF (50 mL) over 30 minutes at -10 °C. The mixture was stirred overnight at room temperature and then quenched with water (20 mL). The precipitated solid was removed by filtration and the filtrate was extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with water, dried over Na2SO4, concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 5:1) to give the desired product (3R)-3-((5-hydroxyhept-6-en-1-yl)oxy)pyrrolidine-1-carboxylate tert-butyl ester (2.01 g) as a pale yellow oil. Yield 37% (ESI 300 [M+H]+).

[1210] Step 4: (R)-3-((7-(2-chloropyridin-3-yl)-5-oxoheptyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1211]

[1212] A mixture of (3R)-3-((5-hydroxyhept-6-en-1-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2.01 g, 6.7 mmol), 2-chloro-3-iodopyridine (3.21 g, 13.4 mmol), tetrabutylammonium chloride (0.37 g, 1.34 mmol), sodium bicarbonate (2.84 g, 26.8 mmol), and Pd(OAc)₂ (0.32 g, 1.41 mmol) in DMF (50 mL) was stirred overnight at 70 °C. The mixture was cooled to room temperature, diluted with H₂O (100 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated under vacuum and the residue was purified by silica gel chromatography (EtOAc / petroleum ether = 0% to 50%) to give the desired product (R)-3-((7-(2-chloropyridin-3-yl)-5-oxoheptyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g) as a colorless oil. Yield 54% (ESI 411[M+H]+).

[1213] Step 5: (3R)-3-((5-amino-7-(2-chloropyridin-3-yl)heptyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1214]

[1215] Ammonium acetate (2.81 g, 36.5 mmol) was added to a solution of (R)-3-((7-(2-chloropyridin-3-yl)-5-oxoheptyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, 3.65 mmol) in methanol (20 mL). The mixture was stirred at room temperature for 10 min, and then sodium cyanoborohydride (692 mg, 11 mmol) was added. The mixture was stirred at room temperature for 20 h, quenched with 1 M NaOH (100 mL), and extracted with DCM (200 mL). The organic layer was concentrated under vacuum to give crude (3R)-3-((5-amino-7-(2-chloropyridin-3-yl)heptyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.4 g) as a brown oil. Yield 93% (ESI 412[M+H]+).

[1216] Step 6: (3R)-3-(4-(1,2,3,4-tetrahydro-1,8-naphthid-2-yl)butoxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1217]

[1218] Cesium carbonate (3.33 g, 10.2 mmol) was added to a solution of (3R)-3-((5-amino-7-(2-chloropyridin-3-yl)heptyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.4 g, 3.4 mmol) in DMF (20 mL). The mixture was stirred at 130 °C for 20 h. The mixture was cooled to room temperature, diluted with H2O (100 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated under vacuum, and the residue was purified by silica gel chromatography (EtOAc / petroleum ether = 0% to 50%) to give the desired product (3R)-3-(4-(1,2,3,4-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-carboxylic acid tert-butyl ester (810 mg). Yield 64% (ESI 376 [M+H]+). Racemic products were separated by preparative chiral SFC to obtain P1 (270 mg, arbitrarily designated as (R)-3-(4-((S)-1,2,3,4-tetrahydro-1,8-naphthid-2-yl)butoxy)pyrrolidine-1-carboxylic acid tert-butyl ester) and P2 (250 mg, arbitrarily designated as (R)-3-(4-((R)-1,2,3,4-tetrahydro-1,8-naphthid-2-yl)butoxy)pyrrolidine-1-carboxylic acid tert-butyl ester), which were pale yellow oils.

[1219] Step 7: (S)-2-(4-(((R)-pyrrolidine-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1220]

[1221] (R)-3-(4-((S)-1,2,3,4-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-carboxylic acid tert-butyl ester (P1, 1.1 g, 2.93 mmol) was treated with 4 M HCl / dioxane (5 mL) for 12 h at room temperature. The reaction mixture was concentrated under vacuum to give the desired product (S)-2-(4-((((R)-pyrrolidine-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthidium) (766 mg). Yield 95% (ESI 276(M+H)+).

[1222] Preparation of (R)-2-(4-(((R)-pyrrolidine-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1223]

[1224] (R)-3-(4-((R)-1,2,3,4-tetrahydro-1,8-naphthidin-2-yl)butoxy)pyrrolidine-1-carboxylic acid tert-butyl ester (P2, 1.1 g, 2.93 mmol) was treated with 4 M HCl / dioxane (5 mL) for 12 h at room temperature. The reaction mixture was concentrated under vacuum to give the desired product (R)-2-(4-(((R)-pyrrolidine-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthidium (766 mg). Yield 95% (ESI 276(M+H)+).

[1225] Preparation of (S)-2-(6-(((R)-pyrrolidine-3-yl)oxy)hexyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1226] Step 1: (R)-3-(oct-7-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1227]

[1228] A solution of (R)-3-hydroxypyrrolidine-1-carboxylate tert-butyl ester (20 g, 107 mmol) in n-heptane (250 mL) was added with 50% aqueous sodium hydroxide solution (86 mL, 1070 mmol), tetrabutylammonium bromide (3.45 g, 10.7 mmol), and 8-bromooct-1-ene (61 g, 321 mmol). The mixture was heated at 80 °C for 2 hours. The reaction mixture was cooled to room temperature and then diluted with EtOAc (500 mL) and water (300 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (200 mL x 2). The combined organic layers were dried over Na2SO4, filtered, concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 4:1) to give the desired product (R)-3-(oct-7-en-1-yloxy)pyrrolidine-1-carboxylate tert-butyl ester (32 g) as a colorless oil. Yield 99% (ESI 298(M+H)+).

[1229] Step 2: (R)-3-((7-oxohepyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1230]

[1231] A mixture of (R)-3-(oct-7-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (7.5 g, 25.2 mmol), potassium osmium (VI) dihydrate (464 mg, 1.26 mmol), and sodium periodate (16.2 g, 75.6 mmol) in 150 mL THF and 150 mL H₂O was stirred at room temperature for 12 hours. The mixture was extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with water (200 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to give crude (R)-3-((7-oxohepyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (7.5 g) as a colorless oil. Yield 99% (ESI 300(M+H)+).

[1232] Step 3: (3R)-3-((7-hydroxynon-8-en-1-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1233]

[1234] Vinyl magnesium bromide (1.0 M in THF, 50 mL, 50 mmol) was added dropwise to a solution of (R)-3-((7-oxohepyl)oxy)pyrrolidine-1-carboxylate tert-butyl ester (7.5 g, 25 mmol) in THF (50 mL) over 30 minutes at -10 °C. The mixture was stirred overnight at room temperature and then quenched with water (20 mL). The precipitated solid was removed by filtration and the filtrate was extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with water, dried over Na2SO4, concentrated under vacuum, and the residue was passed through a silica gel column (petroleum ether: EtOAc 5:1) to give the desired product (3R)-3-((7-hydroxynon-8-en-1-yl)oxy)pyrrolidine-1-carboxylate tert-butyl ester (4.3 g) as a pale yellow oil. Yield 53% (ESI 328 [M+H]+).

[1235] Step 4: (R)-3-((9-(2-chloropyridin-3-yl)-7-oxonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1236]

[1237] A mixture of (3R)-3-((7-hydroxynon-8-en-1-yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (4.3 g, 13.1 mmol), 2-chloro-3-iodopyridine (6.42 g, 26.8 mmol), tetrabutylammonium chloride (746 mg, 2.68 mmol), sodium bicarbonate (5.68 g, 53.6 mmol), and Pd(OAc)₂ (634 mg, 2.43 mmol) in DMF (100 mL) was stirred overnight at 70 °C. The mixture was cooled to room temperature, diluted with H₂O (100 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated under vacuum, and the residue was purified by silica gel chromatography (EtOAc / petroleum ether = 0% to 50%) to give the desired product (R)-3-((9-(2-chloropyridin-3-yl)-7-oxonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2.6 g) as a colorless oil. Yield 45% (ESI 438 [M+H]+).

[1238] Step 5: (3R)-3-((7-amino-9-(2-chloropyridin-3-yl)nonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1239]

[1240] Ammonium acetate (1.4 g, 18.0 mmol) was added to a solution of (R)-3-((9-(2-chloropyridin-3-yl)-7-oxonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2.6 g, 5.9 mmol) in methanol (20 mL). The mixture was stirred at room temperature for 10 min, and then sodium cyanoborohydride (692 mg, 11 mmol) was added. The mixture was stirred at room temperature for 20 h, quenched with 1 M NaOH (100 mL), and extracted with DCM (200 mL). The organic layer was concentrated under vacuum to give crude (3R)-3-((7-amino-9-(2-chloropyridin-3-yl)nonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2.5 g) as a brown oil. Yield 95% (ESI 440 [M+H]+).

[1241] Step 6: (3R)-3-((6-(1,2,3,4-tetrahydro-1,8-naphthid-2-yl)hexyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1242]

[1243] Cesium carbonate (5.0 g, 15.3 mmol) was added to a solution of (3R)-3-((7-amino-9-(2-chloropyridin-3-yl)nonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (2.5 g, 5.7 mmol) in DMF (20 mL). The mixture was stirred at 130 °C for 20 h. The mixture was cooled to room temperature, diluted with H2O (100 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated under vacuum, and the residue was purified by silica gel chromatography (EtOAc / petroleum ether = 0% to 50%) to give the desired product (3R)-3-((6-(1,2,3,4-tetrahydro-1,8-naphthidin-2-yl)hexyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.3 g). Yield 57% (ESI 403 [M+H]+). Racemic products were separated by preparative chiral SFC to obtain P1 (502 mg, arbitrarily designated as (R)-3-((6-((S)-1,2,3,4-tetrahydro-1,8-naphthid-2-yl)hexyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester) and P2 (490 mg, arbitrarily designated as (R)-3-((6-((S)-1,2,3,4-tetrahydro-1,8-naphthid-2-yl)hexyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester), which were pale yellow oils.

[1244] Step 7: (S)-2-(6-(((R)-pyrrolidine-3-yl)oxy)hexyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1245]

[1246] (R)-3-((6-((S)-1,2,3,4-tetrahydro-1,8-naphthidin-2-yl)hexyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (P1, 250 mg, 0.62 mmol) was treated with 4 M HCl / dioxane (5 mL) for 12 hours at room temperature. The reaction mixture was concentrated under vacuum to give the desired product (S)-2-(6-((((R)-pyrrolidine-3-yl)oxy)hexyl)-1,2,3,4-tetrahydro-1,8-naphthidium (185 mg). Yield 98% (ESI 304(M+H)+).

[1247] Preparation of (S)-2-(6-(((R)-pyrrolidine-3-yl)oxy)hexyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1248]

[1249] (R)-3-((6-((S)-1,2,3,4-tetrahydro-1,8-naphthidin-2-yl)hexyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (P2, 250 mg, 0.62 mmol) was treated with HCl / dioxane (4 N, 3 mL) at room temperature for 12 hours. The reaction mixture was concentrated under vacuum to give the desired product (S)-2-(6-((((R)-pyrrolidine-3-yl)oxy)hexyl)-1,2,3,4-tetrahydro-1,8-naphthidine (233 mg), which was used in the next step without further purification. Yield 100% (ESI 304.2(M+H)+).

[1250] Preparation of (R)-5-methyl-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1251] Step 1: (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1252]

[1253] A solution of (S)-3-hydroxypyrrolidine-1-carboxylate tert-butyl ester (10.0 g, 53.4 mmol) in n-heptane (120 mL) was added with 50% sodium hydroxide aqueous solution (11 mL, 267 mmol), tetrabutylammonium bromide (861 mg, 2.67 mmol), and 5-bromopent-1-ene (11.9 g, 80.1 mmol). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was then cooled to room temperature, and EtOAc (100 mL) and water (100 mL) were added. The organic phase was separated, and the aqueous phase was extracted with EtOAc (50 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 4:1) to give the desired product (S)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate tert-butyl ester (13 g) as a colorless oil. Yield 95% (ESI 256.2(M+H)+).

[1254] Step 2: (R)-3-((5-(4-chloro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1255]

[1256] 9-BBN (35.2 mL, 17.6 mmol, 0.5 N in THF) was added to a solution of (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (2.5 g, 9.8 mmol) in THF (5 mL) under N2 atmosphere. The mixture was stirred at 60 °C for 1.5 h and cooled to room temperature. 7-chloro-3,4-dihydro-1,8-naphthyl-1(2H)-carboxylate tert-butyl ester (1.95 g, 9.8 mmol), Pd(OAc)2 (54 mg, 0.5 mmol), PCy3 (135 mg, 0.5 mmol), and KOH (825 mg, 14.7 mmol) were added. The mixture was stirred at 70°C for 16 hours, then concentrated and purified by silica gel chromatography (EtOAc: petroleum ether = 0% to 70%) to give the desired product (R)-3-((5-(4-chloro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (3.1 g). Yield 75% (ESI 420.2(M+H)+).

[1257] Step 3: (R)-3-((5-(4-methyl-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1258]

[1259] A mixture of (R)-3-((5-(4-chloro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (3.1 mg, 7.4 mmol), methylboronic acid (530 mg, 8.9 mmol), Pd(dppf)Cl2 (541 mg, 0.74 mmol), and K2CO3 (2.04 g, 14.8 mmol) in 30 mL of dioxane and 3 mL of H2O was stirred at 80 °C for 4 hours. The mixture was concentrated and purified by silica gel chromatography (EtOAc: petroleum ether = 0% to 70%) to give the desired product (R)-3-((5-(4-methyl-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.25 g). Yield 42% (ESI 400.2(M+H)+).

[1260] Step 4: (R)-3-((5-(4-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1261]

[1262] A mixture of (R)-3-((5-(4-methyl-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.25 g, 3.13 mmol) and Pd / C (125 mg, 10% on activated carbon) in 10 mL of MeOH was stirred at room temperature under a hydrogen atmosphere for 16 hours. The mixture was filtered and the filtrate was concentrated to give the desired product (R)-3-((5-(4-methyl-5,6,7,8-tetrahydro-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.15 g). Yield 91% (ESI 404.3(M+H)+).

[1263] Step 5: (R)-5-methyl-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1264]

[1265] (R)-3-((5-(4-methyl-5,6,7,8-tetrahydro-1,8-naphthidin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.15 g, 2.85 mmol) was added to a solution of HCl / dioxane (10 mL, 4 N). The mixture was stirred at room temperature for 16 hours and concentrated to give the desired product (R)-5-methyl-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine (700 mg) as a white solid, which was used in the next step without further purification. Yield 100% (ESI 304.2(M+H)+).

[1266] (R)-5-methoxy-6-methyl-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine Preparation

[1267] Step 1: 3-Methyl-1,8-naphthidine-2,4-diol

[1268]

[1269] t-BuOK (9.5 g, 85 mmol) was added to a solution of methyl 2-aminonicotinic acid (5.2 g, 34 mmol) and methyl propionate (39 g, 0.44 mol) in THF (60 mL). The resulting mixture was stirred at room temperature for 0.5 h, and then heated at 100 °C for 4 h. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in H2O, and the aqueous phase was adjusted to pH 6 with 1 N HCl aqueous solution. A precipitate formed, which was filtered and dried to give the desired product, 3-methyl-1,8-naphthidine-2,4-diol (2.3 g), as a pale brown solid. Yield: 38% (ESI 177.2(M+H)+).

[1270] Step 2: 2,4-Dichloro-3-methyl-1,8-naphthidine

[1271]

[1272] A mixture of 3-methyl-1,8-naphthidine-2,4-diol (2.3 g, 13 mmol) in POCl3 (25 mL) was stirred at 120 °C for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was diluted with saturated NaHCO3 aqueous solution (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic phases were concentrated under vacuum, and the residue was purified by silica gel chromatography (EtOAc: petroleum ether = 0% to 15%) to give the desired product, 2,4-dichloro-3-methyl-1,8-naphthidine (1.12 g), as a pale brown solid. Yield 41% (ESI 213.1(M+H)+).

[1273] Step 2: (R)-3-((5-(4-chloro-3-methyl-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1274]

[1275] A solution of (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.7 g, 6.67 mmol) in 9-BBN (0.5 N in THF, 26.6 mL, 13.3 mmol) was stirred at 50 °C under an argon atmosphere for 2 hours. The resulting mixture was cooled to room temperature, and 2,4-dichloro-3-methyl-1,8-naphthidine (1.42 g, 6.67 mmol), Pd(OAc)₂ (150 mg, 0.67 mmol), PCy₃ (153 mg, 0.67 mmol), and NaOH (400 mg, 10.0 mmol) were added. The reaction mixture was stirred at 60 °C for 4 hours and then concentrated. The residue was purified by preparative HPLC-A (33%-65% MeCN) to give the desired product (R)-3-((5-(4-chloro-3-methyl-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.4 g), which was a yellow oil. Yield 50% (ESI 434.2(M+H)+).

[1276] Step 3: (R)-3-((5-(4-methoxy-3-methyl-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[1277]

[1278] A mixture of (R)-3-((5-(4-chloro-3-methyl-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.7 g, 3.9 mmol) and NaOMe (30% in MeOH, 30 mL) was stirred at 50 °C for 2 h. The resulting mixture was quenched with a saturated aqueous solution of NH4Cl (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were concentrated to give (R)-3-((5-(4-methoxy-3-methyl-1,8-naphthid-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.2 g) as a pale yellow oil. Yield 71% (ESI 430.3(M+H)+).

[1279] Step 4: (R)-5-methoxy-6-methyl-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthidine

[1280]

[1281] Pd / C (10%, 200 mg) was added to a solution of (R)-3-((5-(4-methoxy-3-methyl-1,8-naphtho-2-yl)pentyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.2 g, 2.8 mmol) in 40 mL of LEtOAc. The resulting mixture was stirred at 50 °C under a hydrogen atmosphere for 16 h, then filtered and the filtrate was concentrated under vacuum. The residue was dissolved in DCM (20 mL), and then TFA (4 mL) was added. The resulting mixture was stirred at room temperature for 16 h and concentrated to give (R)-5-methoxy-6-methyl-7-(5-(pyrrolidine-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphtho-dimidine (530 mg), which was used directly in the next step. ESI 334.2(M+H)+.

[1282] The right side of the exemplary compound

[1283] Preparation of (3-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid

[1284] Step 1: 1-(3-bromo-5-fluoro-4-hydroxyphenyl) ethyl ketone

[1285]

[1286] NBS (30 g, 168.55 mmol) was added in portions to a solution of 1-(3-fluoro-4-hydroxyphenyl)ethyl ketone (25 g, 162.19 mmol) in DMF (250 mL). The mixture was stirred at 25 °C for 16 h. Four parallel reactions were performed and post-treated together. The reaction mixture was quenched with water (1 L) and extracted with EtOAc (1 L x 3). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1-(3-bromo-5-fluoro-4-hydroxyphenyl)ethyl ketone (151.19 g, crude) as a red oil.

[1287] Step 2: 1-(3-bromo-5-fluoro-4-methoxyphenyl)ethyl ketone

[1288]

[1289] K₂CO₃ (55.60 g, 402.30 mmol) was added to a solution of 1-(3-bromo-5-fluoro-4-hydroxyphenyl)ethyl ketone (37.5 g, 160.92 mmol) in DMF (450 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Iodomethane (45.68 g, 321.84 mmol, 20.04 mL) was slowly added dropwise to the reactants from 0 °C to 5 °C. The mixture was stirred at 25 °C for 15.5 h. Four parallel reactions were performed and post-processed together. The reaction mixture was quenched with water (2 L) and extracted with EtOAc (1 L x 3). The combined organic layers were washed with brine (1 L), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give 1-(3-bromo-5-fluoro-4-methoxyphenyl) ethyl ketone (130 g, 526.19 mmol, 81.1% yield) as a yellow oil. 1 ¹H NMR (400MHz, chloroform-d) δ = 7.92 (t, J = 1.7 Hz, 1H), 7.65 (dd, J = 2.1, 11.8 Hz, 1H), 4.07 (d, J = 2.8 Hz, 3H), 2.55 (s, 3H).

[1290] Step 3: 1-Bromo-3-fluoro-2-methoxy-5-(prop-1-en-2-yl)benzene

[1291]

[1292] t-BuOK (18.85 g, 167.97 mmol) was added to a solution of methyl(triphenyl)phosphonium bromide (48.00 g, 134.38 mmol) in THF (200 mL) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Then, a solution of 1-(3-bromo-5-fluoro-4-methoxyphenyl)ethyl ketone (16.6 g, 67.19 mmol) in THF (50 mL) was added dropwise to the mixture at 0 °C, and the reaction mixture was stirred at 25 °C for 15.5 h. Water (500 mL) was added, and the mixture was extracted with ethyl acetate (300 mL x 2). The combined organic layers were washed with H2O (200 mL x 2) and brine (200 mL x 2), dried over Na2SO4, filtered, and concentrated to obtain a crude residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). 1-Bromo-3-fluoro-2-methoxy-5-(prop-1-en-2-yl)benzene (43 g, 175.45 mmol, 87.4% yield) was obtained as a yellow oil. 1 ¹H NMR (400 MHz, chloroform-d) δ = 7.42 (t, J = 1.8 Hz, 1H), 7.19–7.13 (m, 1H), 5.33 (s, 1H), 5.12 (s, 1H), 3.97 (d, J = 1.4 Hz, 3H), 2.10 (s, 3H).

[1293] Step 4: 1-Bromo-3-fluoro-5-isopropyl-2-methoxybenzene

[1294]

[1295] Pd / C (4 g, 10% purity) was added to a solution of 1-bromo-3-fluoro-2-methoxy-5-(prop-1-en-2-yl)benzene (8.1 g, 33.05 mmol) in THF (100 mL). The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 25 °C for 12 h under H2 (15 psi). The reactants (five in parallel) were filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). 1-Bromo-3-fluoro-5-isopropyl-2-methoxybenzene (34 g, 137.59 mmol, 83.27% yield) was given as a colorless oil. 1 ¹H NMR (400MHz, chloroform-d) δ=7.18(s,1H), 6.92(dd,J=1.8,12.0Hz,1H), 3.93(s,3H), 2.84(td,J=6.9,13.8Hz,1H), 1.23(s,3H), 1.21(s,3H).

[1296] Step 5: (3-Fluoro-5-isopropyl-2-methoxyphenyl)boronic acid

[1297]

[1298] n-BuLi (2.5 M, 6.07 mL) was added dropwise to a solution of 1-bromo-3-fluoro-5-isopropyl-2-methoxybenzene (2.5 g, 10.12 mmol) and triisopropyl borate (2.85 g, 15.18 mmol, 3.49 mL) in THF (50 mL) at -78 °C under N2. The resulting mixture was stirred at -78 °C for 1 hour and then at 20 °C for 1 hour. The reaction mixture was quenched with ice water (100 mL). The pH was then adjusted to 5 with aqueous HCl (1 M). The resulting mixture was extracted with ethyl acetate (100 mL x 2), the combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was subjected to rapid silica gel chromatography (…). 25g Purification was performed using a silica fast column with an eluent gradient of 0% to 50% acetone / petroleum ether at 100 mL / min. The resulting product was (1.8 g, 8.49 mmol, 83.91% yield) of (3-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid as a yellow oil. 1 ¹H NMR (400MHz, methanol-d⁴) δ = 7.00 (dd, J = 1.9, 13.4 Hz, 1H), 6.89 (s, 1H), 3.94–3.80 (m, 3H), 2.86 (td, J = 6.9, 13.8 Hz, 1H), 1.22 (d, J = 6.9 Hz, 6H). LCMS (ESI) m / z = 213.1 (M+1).

[1299] Preparation of ethyl 2-bromo-2-(4-(cyclopropylmethyl)-2-methoxyphenyl)

[1300] Step 1: 1-Bromo-4-(cyclopropylmethyl)-2-methoxybenzene

[1301]

[1302] A mixture of 4-bromo-3-methoxybenzaldehyde (1.0 g, 4.65 mmol) and 4-methylbenzenesulfonylhydrazine (1.04 g, 5.58 mmol) in MeOH (20 mL) was stirred at room temperature for 30 min. The solvent was removed under vacuum, diluted with dioxane (20 mL), and then cyclopropylboronic acid (600 mg, 7.0 mmol) and DBU (1.41 g, 9.3 mmol) were added. The mixture was stirred at 100 °C under N2 for 16 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: 100%) to give the desired product, 1-bromo-4-(cyclopropylmethyl)-2-methoxybenzene (466 mg, 1.93 mmol), as a colorless oil. Yield: 42% (ESI 241[M+H]+).

[1303] Step 2: Ethyl 2-(4-(cyclopropylmethyl)-2-methoxyphenyl)

[1304]

[1305] Zinc(II) bromide (1 M in THF, 4.8 mL) was added to a mixture of 1-bromo-4-(cyclopropylmethyl)-2-methoxybenzene (466 mg, 1.93 mmol), Q-phos (43 mg, 0.06 mmol), and Pd2(dba)3 (55 mg, 0.06 mmol) in THF (10 mL). The reaction mixture was stirred at 50 °C under N2 for 1 h. The reaction mixture was quenched with NaHCO3 (aqueous solution) and extracted with EtOAc (2 x 20 mL). The combined organic layers were concentrated under vacuum and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 15:1) to give the desired product, ethyl 2-(2-cyano-4-(cyclopropylmethyl)phenyl)acetate (440 mg, 1.77 mmol), as a red oil. Yield 92% (ESI 249 [M+H]+).

[1306] Step 3: Ethyl 2-bromo-2-(4-(cyclopropylmethyl)-2-methoxyphenyl)

[1307]

[1308] A solution of ethyl 2-(4-(cyclopropylmethyl)-2-methoxyphenyl)acetate (460 mg, 1.85 mmol) in THF (20 mL) was added dropwise to a 2.0 M solution of lithium diisopropylamino in THF / hexane (2.3 mL, 4.6 mmol). The reaction mixture was stirred at -78 °C for 30 min, then chlorotrimethylsilane (0.49 g, 4.51 mmol) was added and the mixture was stirred at -78 °C for another 30 min. Then, a solution of NBS (0.80 g, 4.51 mmol) in THF (10 mL) was added and the mixture was stirred at -78 °C for 30 min. The reaction mixture was quenched with H₂O (10 mL) and then extracted with EtOAc (20 mL × 3). The combined organic phases were washed with saturated NaHCO₃ solution and brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 0% to 10%) to give the desired product, ethyl 2-bromo-2-(4-(cyclopropylmethyl)-2-methoxyphenyl)acetate (340 mg, 56% yield), as a light brown oil, ESI 327 / 329(M+H)+.

[1309] Preparation of ethyl 2-bromo-2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)

[1310] Step 1: 3-Bromo-5-chloro-4-methoxybenzaldehyde

[1311]

[1312] MeI (2.73 g, 19.23 mmol) and K₂CO₃ (3.54 g, 25.64 mmol) were added to a solution of 3-bromo-5-chloro-4-hydroxybenzaldehyde (3.0 g, 12.82 mmol) in DMF (20 mL). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with H₂O (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated NaCl (aqueous solution), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 5:1) to give the desired product, 3-bromo-5-chloro-4-methoxybenzaldehyde (1.8 g), as a white solid. Yield 57% (ESI 249(M+H)+).

[1313] Step 2: 1-Bromo-3-chloro-5-(cyclopropylmethyl)-2-methoxybenzene

[1314]

[1315] TsNHNH2 (1.49 g, 7.986 mmol) was added to a solution of 3-bromo-5-chloro-4-methoxybenzaldehyde (1.8 g, 7.26 mmol) in MeOH (20 mL). The reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was dissolved in 1,4-dioxane (30 mL), with the addition of cyclopropylboronic acid (1.25 g, 14.52 mmol) and DBU (2.2 g, 14.52 mmol). The reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated NaCl (aqueous solution), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 10:1) to give the desired product, 1-bromo-3-chloro-5-(cyclopropylmethyl)-2-methoxybenzene (1.1 g), as a colorless oil. Yield 55% (ESI 275(M+H)+).

[1316] Step 3: Ethyl 2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)

[1317]

[1318] Zinc(II) bromide (1 M in THF, 10 mL) was added to a mixture of 1-bromo-3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl (1100 mg, 3.99 mmol), Q-phos (89 mg, 0.12 mmol), and Pd2(dba)3 (114 mg, 0.12 mmol) in THF (10 mL). The reaction mixture was stirred at 50 °C under N2 for 1 h. The reaction mixture was quenched with NaHCO3 (aqueous solution) and extracted with EtOAc (2 x 20 mL). The combined organic layers were concentrated under vacuum and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 15:1) to give the desired product, ethyl 2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)acetate (840 mg, 2.97 mmol), as a red oil. Yield 74% (ESI 283[M+H]+).

[1319] Step 4: Ethyl 2-bromo-2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)

[1320]

[1321] A solution of ethyl 2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)acetate (282 mg, 1.0 mmol) in THF (20 mL) was added dropwise to a 2.0 M solution of lithium diisopropylamino in THF / hexane (2.5 mL, 2.5 mmol). The reaction mixture was stirred at -78 °C for 30 min, followed by the addition of trichlorosilane (272 mg, 2.5 mmol), and the mixture was stirred at -78 °C for another 30 min. Then, a solution of NBS (445 mg, 2.5 mmol) in THF (5 mL) was added, and the mixture was stirred at -78 °C for 30 min. The reaction mixture was quenched with H₂O (10 mL) and then extracted with EtOAc (20 mL × 3). The combined organic phases were washed with saturated NaHCO₃ solution and brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 0% to 10%) to give the desired product, ethyl 2-bromo-2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)ethyl acetate (320 mg, 88% yield) ESI 361(M+H)+, as a pale yellow oil.

[1322] Preparation of ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-methoxyphenyl)

[1323] Step 1: 2-Bromo-4-(cyclopropylmethyl)-1-methoxybenzene

[1324]

[1325] TsNHNH2 (0.96 g, 5.12 mmol) was added to a solution of 3-bromo-4-methoxybenzaldehyde (1.0 g, 4.65 mmol) in MeOH (20 mL). The reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum, and the residue was dissolved in 1,4-dioxane (30 mL), with the addition of cyclopropylboronic acid (799 mg, 9.30 mmol) and DBU (1.42 g, 9.30 mmol). The reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated NaCl (aqueous solution), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc 10:1) to give the desired product, 2-bromo-4-(cyclopropylmethyl)-1-methoxybenzene (370 mg, 1.53 mmol), as a colorless oil. Yield 33% (ESI 241(M+H)+).

[1326] Step 2: Ethyl 2-(5-(cyclopropylmethyl)-2-methoxyphenyl)

[1327]

[1328] Zinc(II) bromide (1 M in THF, 3.8 mL) was added to a mixture of 2-bromo-4-(cyclopropylmethyl)-1-methoxyphenyl (370 mg, 1.53 mmol), Q-phos (34 mg, 0.05 mmol), and Pd2(dba)3 (44 mg, 0.05 mmol) in THF (10 mL). The reaction mixture was stirred at 50 °C under N2 for 1 h. The reaction mixture was quenched with NaHCO3 (aqueous solution) and extracted with EtOAc (2 x 20 mL). The combined organic layers were concentrated under vacuum and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 15:1) to give the desired product, ethyl 2-(5-(cyclopropylmethyl)-2-methoxyphenyl)acetate (302 mg, 1.22 mmol), as a red oil. Yield 79% (ESI 249 [M+H]+).

[1329] Step 3: Ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-methoxyphenyl)acetate

[1330]

[1331] A solution of ethyl 2-(5-(cyclopropylmethyl)-2-methoxyphenyl)acetate (248 mg, 1.0 mmol) in THF (20 mL) was added dropwise to a 2.0 M solution of lithium diisopropylamino in THF / hexane (2.5 mL, 2.5 mmol). The reaction mixture was stirred at -78 °C for 30 min, followed by the addition of trichlorosilane (272 mg, 2.5 mmol), and the mixture was stirred at -78 °C for another 30 min. Then, a solution of NBS (445 mg, 2.5 mmol) in THF (5 mL) was added, and the mixture was stirred at -78 °C for 30 min. The reaction mixture was quenched with H₂O (10 mL) and then extracted with EtOAc (20 mL × 3). The combined organic phases were washed with saturated NaHCO₃ solution and brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 0% to 10%) to give the desired product, ethyl 2-bromo-2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)ethyl acetate (287 mg, 88% yield) ESI 327(M+H)+, as a pale yellow oil.

[1332] Preparation of ethyl 2-bromo-2-(5-chloro-2-(cyclopropylmethoxy)phenyl)

[1333] Step 1: 2-Bromo-4-chloro-1-(cyclopropylmethoxy)benzene

[1334]

[1335] Add (bromomethyl)cyclopropane (976 mg, 7.28 mmol) and K₂CO₃ (1.34 g, 9.7 mmol) to a solution of 2-bromo-4-chlorophenol (1.0 g, 4.85 mmol) in DMF (10 mL). Stir the mixture at room temperature for 2 hours. Dilute the reaction mixture with H₂O (50 mL) and extract with EtOAc (3 x 50 mL). Wash the combined organic layers with saturated NaCl (aqueous solution), dry over Na₂SO₄, filter, and concentrate under vacuum. Purify the residue by silica gel column chromatography (petroleum ether: EtOAc 5:1) to the desired product 2-bromo-4-chloro-1-(cyclopropylmethoxy)benzene (940 mg) as a yellow oil. Yield 74% (ESI 261(M+H)+).

[1336] Step 2: Ethyl 2-(5-chloro-2-(cyclopropylmethoxy)phenyl)acetate

[1337]

[1338] Zinc(II) bromide (1 M in THF, 8.9 mL) was added to a mixture of 2-bromo-4-chloro-1-(cyclopropylmethoxy)benzene (940 mg, 3.59 mmol), Q-phos (80 mg, 0.12 mmol), and Pd2(dba)3 (103 mg, 0.12 mmol) in THF (10 mL). The reaction mixture was stirred at 50 °C under N2 for 1 h. The reaction mixture was quenched with NaHCO3 (aqueous solution) and extracted with EtOAc (2 x 20 mL). The combined organic layers were concentrated under vacuum and the residue was purified by silica gel column chromatography (petroleum ether: EtOAc 15:1) to give the desired product, ethyl 2-(5-chloro-2-(cyclopropylmethoxy)phenyl)acetate (780 mg, 2.90 mmol), as a red oil. Yield 81% (ESI 269 [M+H]+).

[1339] Step 3: Ethyl 2-bromo-2-(5-chloro-2-(cyclopropylmethoxy)phenyl)acetate

[1340]

[1341] A solution of ethyl 2-(5-chloro-2-(cyclopropylmethoxy)phenyl)acetate (268 mg, 1.0 mmol) in THF (20 mL) was added dropwise to a 2.0 M solution of lithium diisopropylamino in THF / hexane (2.5 mL, 2.5 mmol). The reaction mixture was stirred at -78 °C for 30 min, followed by the addition of trimethylchlorosilane (272 mg, 2.5 mmol), and the mixture was stirred at -78 °C for another 30 min. Then, a solution of NBS (445 mg, 2.5 mmol) in THF (5 mL) was added, and the mixture was stirred at -78 °C for 30 min. The reaction mixture was quenched with H₂O (10 mL) and then extracted with EtOAc (20 mL × 3). The combined organic phases were washed with saturated NaHCO₃ solution and brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 0% to 10%) to give the desired product, ethyl 2-bromo-2-(5-chloro-2-(cyclopropylmethoxy)phenyl)acetate (270 mg, 78% yield) ESI 347(M+H)+, as a pale yellow oil.

[1342] Preparation of ethyl 2-bromo-2-(2-methoxy-5-((1-methoxycyclopropyl)methyl)phenyl)ethyl acetate

[1343] Step 1: Methyl 2-(3-bromo-4-methoxyphenyl)acetate

[1344]

[1345] 1 mL of concentrated H₂SO₄ was added to a solution of 2-(3-bromo-4-methoxyphenyl)acetic acid (2 g, 8.16 mmol) in 30 mL of MeOH. The mixture was stirred at 70 °C for 16 hours. The mixture was concentrated and dissolved in 50 mL of EtOAc. The mixture was washed with water and an aqueous solution of NaHCO₃, dried over anhydrous Na₂SO₄, and concentrated to give methyl 2-(3-bromo-4-methoxyphenyl)acetate (1.92 g) as a colorless oil. Yield: 91% (ESI 259.2(M+H)+).

[1346] Step 2: 1-(3-bromo-4-methoxybenzyl)cycloprop-1-ol

[1347]

[1348] EtMgBr (6.5 mL, 13 mmol, 2 N in THF) was added to a stirred solution of methyl 2-(3-bromo-4-methoxyphenyl)acetate (1.35 g, 5.2 mmol) and Ti(i-PrO)₄ (1.57 g, 5.5 mmol) in THF (20 mL) at 0 °C. The mixture was stirred at room temperature for 12 h, quenched by addition of 1 M sulfuric acid solution, and extracted with EtOAc (20 mL x 2). The combined organic solvents were concentrated, and the residue was purified by silica gel chromatography (EtOAc: petroleum ether = 0% to 5%) to give the desired product 1-(3-bromo-4-methoxybenzyl)cycloprop-1-ol (1.2 g) as a colorless oil. Yield 90% (ESI 257.1(M+H)+).

[1349] Step 3: 2-Bromo-1-methoxy-4-((1-methoxycyclopropyl)methyl)benzene

[1350]

[1351] NaH (188 mg, 4.7 mmol, 60% in mineral oil) was added to a stirred solution of 1-(3-bromo-4-methoxybenzyl)cycloprop-1-ol (800 mg, 3.1 mmol) in 15 mL of DMF. After stirring for 30 min, MeI (666 mg, 4.7 mmol) was added. The mixture was stirred at room temperature for 8 h, quenched with water (20 mL), and extracted with EtOAc (20 mL x 2). The combined organic solvents were concentrated, and the residue was purified by silica gel chromatography (EtOAc: petroleum ether = 0% to 5%) to give the desired product, 2-bromo-1-methoxy-4-((1-methoxycyclopropyl)methyl)benzene (331 mg), as a colorless oil. Yield: 39% (ESI 271.2(M+H)+).

[1352] Step 4: Ethyl 2-(2-methoxy-5-((1-methoxycyclopropyl)methyl)phenyl)ethyl acetate

[1353]

[1354] Zinc(II) bromide (2-(tert-butoxy)-2-oxoethyl)bromide (6.5 mL, 6.5 mmol, 1 N in THF) was added to a solution of 2-bromo-1-methoxy-4-((1-methoxycyclopropyl)methyl)benzene (330 mg, 1.3 mmol), Pd2(dba)3 (65 mg, 0.067 mmol), and Q-phos (50 mg, 0.07 mmol) in 6 mL of THF under an argon atmosphere. The mixture was stirred at 60 °C for 18 hours, concentrated, and purified by silica gel column chromatography (EtOAc: petroleum ether = 0% to 10%) to give the desired product, ethyl 2-(2-methoxy-5-((1-methoxycyclopropyl)methyl)phenyl)acetate (278 mg), as an orange oil. Yield: 77% (ESI 279.1(M+H)+).

[1355] Step 5: 2-Bromo-2-(2-methoxy-5-((1-methoxycyclopropyl)methyl)phenyl)ethyl acetate

[1356]

[1357] LDA (1.25 mL, 2.5 mmol, 2N in THF) was added to a solution of ethyl 2-(2-methoxy-5-((1-methoxycyclopropyl)methyl)phenyl)acetate (278 mg, 1 mmol) in 5 mL of THF at -78 °C. After stirring for 30 min, TMSCl (270 mg, 2.5 mmol) was added at -78 °C. After stirring for another 30 min, NBS (470 mg, 2.5 mmol) was added. The mixture was stirred at -78 °C for 1 h, quenched with water (10 mL), and extracted with EtOAc (15 mL x 3). The combined organic solvents were concentrated, and the residue was purified by silica gel chromatography (EtOAc:PE = 0% to 20%) to give the desired product, ethyl 2-bromo-2-(2-methoxy-5-((1-methoxycyclopropyl)methyl)phenyl)acetate (310 mg). Yield 87% (ESI 357.0(M+H)+).

[1358] Preparation of ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-(trifluoromethoxy)phenyl)acetate

[1359] Step 1: N'-(3-bromo-4-(trifluoromethoxy)benzyl)-4-methylbenzenesulfonylhydrazine

[1360]

[1361] TsNHNH2 (1.67 g, 9 mmol) was added to a solution of 3-bromo-4-(trifluoromethoxy)benzaldehyde (2 g, 7.46 mmol) in 30 mL of MeOH. The mixture was stirred at 50 °C for 1 hour. The mixture was concentrated under vacuum, and the residue was dissolved in 20 mL of dioxane. Cyclopropylboronic acid (963 mg, 11 mmol) and DBU (2.3 g, 15 mmol) were added. The resulting mixture was stirred at 100 °C for 16 hours, concentrated, and purified by silica gel chromatography (EtOAc: petroleum ether = 0% to 20%) to give the desired product N'-(3-bromo-4-(trifluoromethoxy)benzylene)-4-methylbenzenesulfonylhydrazine (1.03 g) as a colorless oil. Yield 47% (ESI 295.1(M+H)+).

[1362] Step 2: Ethyl 2-(5-(cyclopropylmethyl)-2-(trifluoromethoxy)phenyl)acetate

[1363]

[1364] Zinc(II) bromide (2-(tert-butoxy)-2-oxoethyl)bromide (4.5 mL, 4.5 mmol, 1 N in THF) was added to a mixture of 2-bromo-4-(cyclopropylmethyl)-1-(trifluoromethoxy)benzene (441 mg, 1.5 mmol), Pd2(dba)3 (55 mg, 0.05 mmol), and Q-phos (69 mg, 0.05 mmol) in 8 mL of THF under an argon atmosphere. The mixture was stirred at 60 °C for 4 hours, concentrated, and purified by silica gel column chromatography (EtOAc: petroleum ether = 0% to 15%) to give the desired product, ethyl 2-(5-(cyclopropylmethyl)-2-(trifluoromethoxy)phenyl)acetate (342 mg), as an orange oil. Yield: 75% (ESI 303.1(M+H)+).

[1365] Step 3: Ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-(trifluoromethoxy)phenyl)acetate

[1366]

[1367] LDA (1.4 mL, 2.8 mmol, 2N in THF) was added to a solution of ethyl 2-(5-(cyclopropylmethyl)-2-(trifluoromethoxy)phenyl)acetate (342 mg, 1.1 mmol) in 8 mL of THF at -78 °C. After stirring for 30 min, TMSCl (304 mg, 2.8 mmol) was added at -78 °C. After stirring for another 30 min, NBS (501 mg, 2.8 mmol) was added. The mixture was stirred at -78 °C for 1 h, quenched with water (10 mL), and extracted with EtOAc (15 mL x 3). The combined organic solvents were concentrated to give the crude product ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-(trifluoromethoxy)phenyl)acetate (342 mg). Yield 79% (ESI 381.0(M+H)+).

[1368] Preparation of ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-(methoxymethyl)phenyl)acetate

[1369] Step 1: Methyl 3-bromo-4-(bromomethyl)benzoate

[1370]

[1371] A mixture of methyl 3-bromo-4-methylbenzoate (4.6 g, 20 mmol), N-bromosuccinimide (5.4 g, 30 mmol), and AIBN (3.6 g, 22 mmol) in CCl4 (50 mL) was heated under reflux for 4 hours. The reaction mixture was cooled to room temperature, the precipitate was filtered, and washed with CCl4. The combined filtrates were concentrated under vacuum, and the residue was purified by silica gel chromatography (5% EtOAc in hexane) to give 4.7 g of methyl 3-bromo-4-bromomethylbenzoate. Yield 76% (ESI 307.2(M+H)+).

[1372] Step 2: Methyl 3-bromo-4-(methoxymethyl)benzoate

[1373]

[1374] MeONa (2.8 g, 51 mmol) was added to a mixture of methyl 3-bromo-4-(bromomethyl)benzoate (4.5 g, 14.7 mmol) and MeOH (30 mL) at room temperature. The mixture was stirred at 50 °C for 1 hour, quenched with water (30 mL), and extracted with EtOAc (30 mL x 3). The combined organic solvents were concentrated, and the residue was purified by silica gel chromatography (EtOAc: petroleum ether = 0% to 10%) to give the desired product, methyl 3-bromo-4-(methoxymethyl)benzoate (1.9 g). Yield 50% (ESI 259.2(M+H)+).

[1375] Step 3: (3-bromo-4-(methoxymethyl)phenyl)methanol

[1376]

[1377] DIBAL-H (1 M in THF, 19 mL, 19 mmol) was added to a mixture of methyl 3-bromo-4-(methoxymethyl)benzoate (1.9 g, 7.36 mmol) in THF (20 mL) at room temperature. The mixture was stirred at 60 °C for 8 hours. The mixture was quenched with saturated NH4Cl aqueous solution and extracted with EtOAc (25 mL x 2). The combined organic solvents were concentrated, and the residue was purified by silica gel chromatography (EtOAc: petroleum ether = 0% to 25%) to give the desired product (3-bromo-4-(methoxymethyl)phenyl)methanol (1.3 g). Yield 76% (ESI 231.2(M+H)+).

[1378] Step 4: 2-Bromo-4-(bromomethyl)-1-(methoxymethyl)benzene

[1379]

[1380] NBS (1.8 g, 10.4 mmol) was added to a mixture of (3-bromo-4-(methoxymethyl)phenyl)methanol (1.6 g, 7 mmol) and PPh3 (2.7 g, 10.4 mmol) in DCM (20 mL) at 0 °C under argon atmosphere. The mixture was stirred at room temperature for 2 hours, quenched with water (25 mL), and extracted with DCM (25 mL x 2). The combined organic solvents were concentrated under vacuum, and the residue was purified by silica gel chromatography (EtOAc: petroleum ether = 0% to 15%) to give the desired product 2-bromo-4-(bromomethyl)-1-(methoxymethyl)benzene (1.9 g). Yield 93% (ESI 293.2(M+H)+).

[1381] Step 5: 2-Bromo-4-(cyclopropylmethyl)-1-(methoxymethyl)benzene

[1382]

[1383] CuI (161 mg, 0.86 mmol) was added to a stirred solution of 2-bromo-4-(bromomethyl)-1-(methoxymethyl)benzene (2.5 g, 8.5 mmol) in 25 mL of THF at 0 °C. After stirring for 30 min, cyclopropylmagnesium bromide (18 mL, 18 mmol, 1N in THF) was slowly added at 0 °C. The mixture was then stirred at room temperature for 4 h, quenched with aqueous NaHCO3 solution, and extracted with EtOAc (20 mL x 2). The combined organic solvents were concentrated, and the residue was purified by silica gel chromatography (EtOAc: petroleum ether = 0% to 15%) to give the desired product 2-bromo-4-(cyclopropylmethyl)-1-(methoxymethyl)benzene (940 mg). Yield 43% (ESI 255.1(M+H)+).

[1384] Step 6: Ethyl 2-(5-(cyclopropylmethyl)-2-(methoxymethyl)phenyl)acetate

[1385]

[1386] Zinc(II) bromide (2-ethoxy-2-oxoethyl)bromide (4.5 mL, 4.5 mmol, 1 N in THF) was added to a solution of 2-bromo-4-(cyclopropylmethyl)-1-(methoxymethyl)benzene (381 g, 1.5 mmol), Pd2(dba)3 (55 mg, 0.07 mmol), and Q-phos (69 mg, 0.07 mmol) in 8 mL of THF under an argon atmosphere. The mixture was stirred at 60 °C for 18 hours, concentrated, and purified by silica gel column chromatography (EtOAc: petroleum ether = 0% to 10%) to give the desired product, ethyl 2-(5-(cyclopropylmethyl)-2-(methoxymethyl)phenyl)acetate (304 mg), as a yellow oil. Yield: 77% (ESI 263.1(M+H)+).

[1387] Step 7: Ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-(methoxymethyl)phenyl)acetate

[1388]

[1389] LDA (1.1 mL, 2.2 mmol, 2N in THF) was added to a mixture of ethyl 2-(5-(cyclopropylmethyl)-2-(methoxymethyl)phenyl)acetate (304 mg, 1.16 mmol) in 10 mL of THF at -78 °C. After stirring for 30 min, TMSCl (241 mg, 2.2 mmol) was added at -78 °C. After stirring for another 30 min, NBS (398 mg, 2.2 mmol) was added. The mixture was stirred at -78 °C for 1 h, quenched with water, and extracted with EtOAc (15 mL x 3). The combined organic solvents were concentrated, and the residue was purified by silica gel chromatography (EtOAc:PE = 0% to 20%) to give the desired product, ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-(methoxymethyl)phenyl)acetate (280 mg). Yield 71% (ESI 341.0(M+H)+).

[1390] Preparation of (2,5-difluoro-3-isopropyl-6-methoxyphenyl)boronic acid

[1391] Step 1: 1-Bromo-2,5-difluoro-4-methoxybenzene

[1392]

[1393] A suspension of 4-bromo-2,5-difluorophenol (10 g, 47.85 mmol), K₂CO₃ (19.84 g, 143.55 mmol), and MeI (20.38 g, 143.55 mmol) in DMF (250 mL) was stirred at 60 °C for 2 hours. The mixture was cooled to 25 °C and quenched with water (600 mL). The aqueous phase was extracted with ethyl acetate (200 mL x 2). The combined organic phases were washed with brine (200 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was analyzed by MPLC (…). 80g Purification was performed using a silica rapid column with an eluent gradient of 0% to 3% ethyl acetate / petroleum ether at 150 mL / min to give 1-bromo-2,5-difluoro-4-methoxybenzene as a white solid (10.4 g, 46.63 mmol, 97.5% yield). 1 ¹H NMR (400 MHz, chloroform-d) δ = 7.27 (dd, J = 6.6, 10.1 Hz, 1H), 6.78 (dd, J = 7.4, 9.6 Hz, 1H), 3.88 (s, 3H).

[1394] Step 2: 1,4-Difluoro-2-methoxy-5-(prop-1-en-2-yl)benzene

[1395]

[1396] A solution of 1-bromo-2,5-difluoro-4-methoxybenzene (8.2 g, 36.77 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborhecyclopentane (15.45 g,...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: Q ring is L is Each of them is arbitrarily assigned to 1 to 6 Rs 4 replace; X is -CHR 1c -、-O- or -NR 2 -; R 1a R 1b R 1c R 1d R 1e and R 1f Each independently represents H and C. 1-4 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl group, CF3, CHF2, CH2F, CN, NO2, NR a R b Or C 1-4 Alkyl-NR a R b , Each R 2 Independently for H and C 1-4 Alkyl or C 3-5 cycloalkyl; R 3a It is C 1-4 Alkoxy, C 3-5 Cycloalkoxy, CF3, CHF2, CH2F, OCF3, OCHF2, or OCH2F; R 3b It is H, halogen, CF3 or CN; R 3c Is it H, F, CN, or C? 1-4 alkyl; R 3d It is C 1-4 Alkyl, C 3-5 Cycloalkyl or 4-6 membered heterocycloalkyl, each optionally surrounded by 1 to 4 R... 6 replace; R 3e It is H or F; Each R 4 Independently for H and C 1-4 Alkyl, halogen, CF3, CHF2 or CH2F, cyclopropyl, or two geminal Rs 4 The groups together can form a spirocyclopropyl group; Each R 6 Independently for C 1-4 Alkyl, C 1-4 alkenyl, C 3-5 cycloalkyl, C 1-4 Alkoxy, C 3-5 Cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, 5-6 heteroaryl or NR a R b ; Each R 7 Independently for C 1-4 Alkyl or F; R a and R b Each independently is hydrogen, C 1-4 Alkyl, C 3-5 cycloalkyl, or R a and R b Together with the nitrogen atoms to which they are attached, they form saturated or unsaturated heterocycles containing three to seven ring atoms, said rings optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally one to three selected from F, C. 1-4 The same or different groups may be substituted within the group consisting of alkyl, phenyl, and benzyl groups; and n is 1 or 2; and m can be 0, 1, or 2.

2. The compound of claim 1, wherein... aL is bX is -CHR 1c -;and c. The Q-ring is and dm is 0.

3. The compound of claim 2, wherein... aR 1a R 1c R 1d R 1e and R 1f Each is independently H; and bR 1b For H, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, NR a R b Or C 1-4 Alkyl-NR a R b .

4. The compound of claim 3, wherein the Q ring is 5. The compound according to any one of claims 1-4, wherein R 3a It is C 1-4 Alkoxy, R 3b It is halogen and R 3c It's H.

6. The compound according to any one of claims 1-5, wherein R 3a It is a methoxy group.

7. The compound according to any one of claims 1-6, wherein R 3b It is F.

8. The compound according to any one of claims 1-7, wherein R 3d It is arbitrarily assigned to 1 R 6 Replacement C 1-4 alkyl.

9. The compound according to any one of claims 1-8, wherein R 3d It is an unsubstituted isopropyl group.

10. The compound according to any one of claims 1-7, wherein R 3d It is C 3-5 Cycloalkyl or 4-6 membered heterocycloalkyl, each optionally surrounded by 1 to 4 R... 6 Replace; and R 6 C is optionally replaced by halogens 1-4 Alkyl or halogen.

11. The compound according to any one of claims 1-7, wherein R 3d yes or R 3d yes or R 3d yes or 12. The compound according to any one of claims 1-11, wherein R 6 It is C 3-5 cycloalkyl or 5-6-membered heteroaryl, wherein R 6 C optionally substituted with one or more halogens 1-4 Alkyl or halogen substitution.

13. The compound according to any one of claims 1-12, wherein R 6 It is C 3-5 Cycloalkyl or 5-6-membered heteroaryl groups.

14. The compound according to any one of claims 1-12, wherein R 6 It is methoxy, hydroxy, or NR. a R b , where R a and R b Each independently is H or C 1-4 alkyl.

15. The compound according to any one of claims 1-14, wherein n is 1.

16. The compound according to any one of claims 1-15, wherein the compound has the structure according to formula (II), or It has the structure according to formula (IIA), or It has the structure according to formula (III), Or it may have a structure according to formula (IIIA), Or it may have a structure according to formula (V), Or it may have a structure based on formula (VA), Or it may have a structure according to formula (VI), It has a structure based on formula (VIA). or It has the structure according to formula (VII), Or its pharmaceutically acceptable salt.

17. The compound of claim 16, wherein the compound has a structure according to formula (IIA), Where R 1b It's H. Or its pharmaceutically acceptable salt.

18. The compound according to any one of claims 1-17, wherein the carbon marked with an asterisk (*) has an (R)-configuration.

19. The compound according to any one of claims 1-17, wherein the carbon marked with an asterisk (*) has an (S) configuration.

20. The compound of claim 1, wherein the compound is selected from any of the compounds listed in Table 1 or their pharmaceutically acceptable salts.

21. The compound of claim 1, wherein the compound is selected from: and Or its pharmaceutically acceptable salt.

22. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

23. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

24. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

25. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

26. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

27. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

28. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

29. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

30. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

31. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

32. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

33. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

34. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

35. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

36. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

37. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

38. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

39. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

40. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

41. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

42. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

43. A pharmaceutical composition comprising the compound of any one of claims 1-42 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

44. A method for inhibiting α in patients v A method for β8 integrin, the method comprising administering to a patient in need a therapeutically effective amount of the compound of any one of claims 1-42 or a pharmaceutically acceptable salt thereof.

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