Inhibition of αvβ8 integrin

Abstract

The present disclosure provides α, including compounds according to formula (I) and pharmaceutically acceptable salts thereof: v The present invention relates to novel compounds and methods useful for inhibiting β8 integrins. [Formula 1] JPEG2026506652000857.jpg57164

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of 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.

[0002] This disclosure provides v The present invention relates to novel compounds and methods useful for inhibiting β8 integrins. [Background technology]

[0003] In the tumor microenvironment, α v β8 is expressed in immune cells, primarily antigen-presenting cells (APCs) and regulatory T cells (Tregs), as well as tumor cells and cancer-associated fibroblasts. v The main function of β8 is the activation of growth factors TGF-β1 and 3. TGF-β is biosynthesized and stored in tissues in a latent form. TGF-β homodimers are maintained latent by association with their dimeric prodomain (pro-TGF-β). The prodomain-derived homodimer prevents TGF-β from binding to the TGF-β receptor and is called latency-associated peptide (LAP). The latent TGF-β complex is stored on the extracellular matrix or 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, liberating the active TGF-β cytokines from the latent complex.

[0004] TGF-β is a pleiotropic cytokine that mediates multiple biological processes, including development and homeostasis. TGF-β plays a central role in cell proliferation, differentiation, and apoptosis. It regulates extracellular matrix (ECM) production, which contributes to tissue repair processes. In the immune system, TGF-β is required for the development of distinct immune cell types as well as promoting immunosuppression. The homeostatic role of TGF-β in immunity is essential to prevent excessive inflammatory responses and to maintain tolerance to self-antigens to prevent autoimmunity. Because TGF-β is ubiquitously expressed, its activity must be tightly regulated, and compromised regulation can lead to disease states. Dysregulation of TGF-β signaling has been implicated in multiple disorders, particularly cancer and fibrosis.

[0005] In cancer, the TGF-β pathway is involved in many human neoplastic diseases, including solid tumors and hematopoietic tumors. As a potent inhibitor of cell proliferation, TGF-β acts as a tumor suppressor; however, in tumor cells, TGF-β loses its antiproliferative response and promotes cancer progression. TGF-β-promoted tumorigenesis is primarily driven by downregulation of antitumor immunity. The immunosuppressive effect leads to tumor immune tolerance. Furthermore, TGF-β promotes epithelial-to-mesenchymal transition (EMT) and angiogenesis, enhancing tumor invasiveness. The expression of integrin avb8 in cancer correlates with the activity of TGF-β. It regulates the inflammatory phenotype of APCs and Tregs, which are the primary cell types underlying T / NK cell-driven antitumor activity. v β8 integrin locally activates TGF-β to regulate crosstalk between APCs and effector cells, biasing immunity from inflammation towards tolerance.

[0006] Integrin α v Inhibition of β8-driven TGF-β activation has been proposed to reverse tumor tolerance and enhance antitumor T / NK cell responses. Consistent with TGF-β blockade, avb8 inhibition can enhance the outcome of checkpoint inhibitor regimens or reverse checkpoint inhibitor resistance.

[0007] The ubiquitous expression and multifunctionality of TGF-β limit the application of strategies based on systemic blockade of TGF-β, as these approaches result in undesirable side effects. v Blockade of TGF-β activity by antagonizing β8 has increased safety and therapeutic advantages over general TGF-β inhibition. It allows for tissue-localized and isoform-selective TGF-β blockade in specific immunological environments. Thus, α v There remains a need for therapeutic compounds to inhibit β8 integrins. Summary of the Invention

[0008] This disclosure provides v The present invention relates to novel compounds and methods useful for inhibiting β8 integrins.

[0009] In one aspect, the invention features a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony: The Q ring is [ka] and; L is [ka] and each of these is 1 to 6 R 4 is optionally replaced by; X is -CHR 1c -, -O-, or -NR 2 - and; R 1a , R 1b , R 1c , R 1d , R 1e , and R 1f each independently represents H, C 1-4 Alkyl, halogen, C 1-4 Alkoxy, OH, C 1-4Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, CF3, CHF2, CH2F, CN, NO2, NR a R b or C 1-4 Alkyl-NR a R b and Each R 2 are independently H, C 1-4 Alkyl, or C 3-5 is cycloalkyl; R 3a is C 1-4 Alkoxy, C 3-5 cycloalkoxy, CF3, CHF2, CH2F, OCF3, OCHF2 or OCH2F; R 3b is H, halogen, CF3 or CN; R 3c is H, F, CN, or C 1-4 is alkyl; R 3d is C 1-4 Alkyl, C 3-5 cycloalkyl, or 4- to 6-membered heterocycloalkyl, each of which is selected from 1 to 4 R 6 is optionally replaced by; R 3e is H or F; Each R 4 are independently H, C 1-4 alkyl, halogen, CF3, CHF2, or CH2F, cyclopropyl, or two geminal R 4 The groups together can form a spiro-cyclopropyl; Each R 6 independently, 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 membered heteroaryl or NRa R b and; Each R 7 independently, C 1-4 is alkyl or F; R a and R b each independently represents hydrogen, C 1-4 Alkyl, C 3-5 cycloalkyl or R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and which may optionally be substituted with one to three identical or different groups selected from the group consisting of F, C1-4 alkyl, phenyl, and benzyl; n is 1 or 2; m is 0, 1, or 2.

[0010] In one aspect, the invention features a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony: The Q ring is [ka] and; L is [ka] and each of these is 1 to 6 R 4 is optionally replaced by; X is -CHR 1c -, -O-, or -NR 2 - and; R 1a , R 1b , R 1c , R 1d , R 1e , and R 1f each independently represents H, C 1-4Alkyl, 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 Alkoxy, CF3, CHF2, CH2F, CN, NO2, NR a R b or C 1-4 Alkyl-NR a R b and Each R 2 are independently H, C 1-4 Alkyl, or C 3-5 is cycloalkyl; R 3a is cyano, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-5 cycloalkoxy, CF3, CHF2, CH2F, OCF3, OCHF2 or OCH2F; R 3b is H, halogen, CF3 or CN; R 3c is H, F, CN, or C 1-4 is alkyl; R 3d is C 1-4 Alkyl, C 3-5 cycloalkyl, or 4- to 6-membered heterocycloalkyl, each of which is selected from 1 to 4 R 6 is optionally replaced by; R 3e is H or F; Each R 4 are independently H, C 1-4 alkyl, halogen, CF3, CHF2, or CH2F, cyclopropyl, or two geminal R 4 The groups together can form a spiro-cyclopropyl; Each R 6 independently, C 1-4 Alkyl, C 1-4 Alkenyl, C 3-5 Cycloalkyl, C 1-4 Alkoxy, C3-5 Cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, 5-6 membered heteroaryl or NR a R b and; Each R 7 independently, C 1-4 is alkyl or F; R a and R b each independently represents hydrogen, C 1-4 Alkyl, C 3-5 cycloalkyl or R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and which may optionally be substituted with one to three identical or different groups selected from the group consisting of F, C1-4 alkyl, phenyl, and benzyl; n is 1 or 2; m is 0, 1, or 2.

[0011] In one aspect, the invention features a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony: The Q ring is [ka] and; L is [ka] and; R 3a is methoxy; R 3b is H, halogen, CF3 or CN; R 3c is H, F, CN, or C 1-4 is alkyl; R 3d is C 1-4 Alkyl, C 3-5 cycloalkyl, or 4- to 6-membered heterocycloalkyl, each of which is selected from 1 to 4 R 6 is optionally replaced by; R 3e is H or F; Each R 6 independently, 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 membered heteroaryl or NR a R b and; Each R 7 independently, C 1-4 is alkyl or F; R a and R b each independently represents hydrogen, C 1-4 Alkyl, C 3-5 cycloalkyl or R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and which may optionally be substituted with one to three identical or different groups selected from the group consisting of F, C1-4 alkyl, phenyl, and benzyl; n is 1 or 2; m is 0, 1, or 2.

[0012] In embodiments, the Q ring is: [ka] where R 1c1 and R 1c2 are each independently R 1c Selected from;R1d1 and R 1d2 are each independently R 1d Selected from;R 1e1 and R 1e2 are each independently R 1e is selected from.

[0013] In some embodiments, the Q ring is [ka] is.

[0014] In embodiments, X is —O—.

[0015] In some embodiments, X is —NR 2 -It is.

[0016] In some embodiments, R 2 is methyl.

[0017] In some embodiments, the Q ring is [ka] is.

[0018] In some embodiments, the Q ring is [ka] is.

[0019] In some embodiments, R 1d and R 1e each independently is H.

[0020] In some embodiments, each R 1c are independently H.

[0021] In some embodiments, each R 1a are independently H.

[0022] In some embodiments, each R 1bare independently H.

[0023] In some embodiments, each R 1b is independently OMe.

[0024] In embodiments, the Q ring is: [ka] where R 1c1 and R 1c2 are each independently R 1c Selected from;R 1d1 and R 1d2 are each independently R 1d is selected from.

[0025] In some embodiments, R 1c1 , R 1c2 , R 1d1 , and R 1d2 are each independently H.

[0026] In some embodiments, the Q ring is [ka] is.

[0027] In some embodiments, the Q ring is [ka] is.

[0028] In some embodiments, the Q ring is [ka] is.

[0029] In some embodiments, R 1c and R 1d each independently is H.

[0030] In some embodiments, R 1a , R1b and R 1f each independently is H.

[0031] In some embodiments, L is [ka] is.

[0032] In some embodiments, L is [ka] is.

[0033] In some embodiments, L is [ka] and n is 1.

[0034] In some embodiments, L is [ka] and n is 2. In some embodiments, R 3a is C 1-4 It is an alkoxy.

[0035] In some embodiments, R 3a is OMe, OEt, OCF3, OCHF2, or OCH2F.

[0036] In some embodiments, R 3a is OMe.

[0037] In some embodiments, R 3a is -CN.

[0038] In some embodiments, R 3a is a halogen.

[0039] In some embodiments, R 3a is Cl.

[0040] In some embodiments, R 3a is C 1-4 It is alkyl.

[0041] In some embodiments, R 3a is methyl.

[0042] In some embodiments, R 3a is ethyl.

[0043] In some embodiments, R 3b is F.

[0044] In some embodiments, R 3c is H.

[0045] In some embodiments, R 3d is C 1-4 It is alkyl.

[0046] In some embodiments, R d3 is C 3-5 It is cycloalkyl.

[0047] In some embodiments, R 3d is oxetanyl, tetrahydrofuranyl, or tetrahydro-2H-pyranyl, morpholinyl, or piperazinyl-C 1-4 It is alkyl.

[0048] In some embodiments, R 3d is isopropyl.

[0049] In some embodiments, R 3e is H.

[0050] In some embodiments, each R 4 are independently methyl.

[0051] In some embodiments, each R 4 are independently F.

[0052] In some embodiments, each R 4 are independently CF3, CHF2, or CH2F.

[0053] In some embodiments, each R 4 are independently H.

[0054] In some embodiments, each R 6 independently, C 1-4 It is alkyl.

[0055] In some embodiments, each R 6 independently, C 1-4 It is alkenyl.

[0056] In some embodiments, each R 6 independently, C 3-5 It is cycloalkyl.

[0057] In some embodiments, each R 6 independently, C 1-4 It is an alkoxy.

[0058] In some embodiments, each R 6 independently, C 3-5 It is cycloalkoxy.

[0059] In some embodiments, each R 6 are independently F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, or OH.

[0060] In some embodiments, each R 6 is independently a 5- to 6-membered heteroaryl.

[0061] In some embodiments, each R 6 are independently H.

[0062] In some embodiments, each R 7 are independently F.

[0063] In some embodiments, n is 0.

[0064] In some embodiments, n is 1.

[0065] In some embodiments, n is 2.

[0066] In some embodiments, m is 0.

[0067] In some embodiments, m is 1.

[0068] In some embodiments, m is 2.

[0069] In embodiments, the compound has the structure according to formula (II): [ka] or a pharmaceutically acceptable salt thereof.

[0070] In embodiments, the compound has the structure according to formula (IIA): [ka] or a pharmaceutically acceptable salt thereof.

[0071] In embodiments, the compound has the structure according to formula (III): [ka] or a pharmaceutically acceptable salt thereof.

[0072] In embodiments, the compound has the structure according to formula (IIIA): [ka] or a pharmaceutically acceptable salt thereof.

[0073] In embodiments, the compound has the structure according to formula (IV): [ka] or a pharmaceutically acceptable salt thereof.

[0074] In embodiments, the compound has the structure according to formula (IVA): [ka] or a pharmaceutically acceptable salt thereof.

[0075] In embodiments, the compound has a structure according to formula (V): [ka] or a pharmaceutically acceptable salt thereof.

[0076] In embodiments, the compound has a structure according to formula (VA): [ka] or a pharmaceutically acceptable salt thereof.

[0077] In embodiments, the compound has the structure according to formula (VI): [ka] or a pharmaceutically acceptable salt thereof.

[0078] In embodiments, the compound has the structure according to formula (VIA): [ka] or a pharmaceutically acceptable salt thereof.

[0079] In one aspect, the invention features a compound of formula (VII) or a pharmaceutically acceptable salt thereof: [ka] In the formula, L, Q, R7, R 3a , R 3b , R 3c , R 3d , R 3e each independently according to any embodiment described herein.

[0080] In one aspect, the invention features a compound of formula (VII) or a pharmaceutically acceptable salt thereof: [ka] The Q ring is [ka] and; L is [ka] and; n is 1 or 2; R 3a is methoxy; R7 is H or F; R 3a is methoxy; R 3b , R 3c , R 3d , R 3e is as disclosed herein above with respect to formula (I).

[0081] In some embodiments, n is 1.

[0082] In some embodiments, n is 2.

[0083] In some embodiments, R 1b is H, CH3, or OCH3.

[0084] In some embodiments, R 3e is H or F.

[0085] In some embodiments, R 3d optionally, one R6 C replaced by 1-4 It is alkyl.

[0086] In some embodiments, R 3d teeth, [ka] is.

[0087] In some embodiments, R 3d optionally, one R 6 is a 4- to 6-membered heterocycloalkyl substituted with

[0088] In some embodiments, R 3d teeth, [ka] is.

[0089] In some embodiments, R 3d optionally, one R 6 C replaced by 3-5 It is cycloalkyl.

[0090] In some embodiments, R 3d teeth, [ka] is.

[0091] In some embodiments, the carbon marked with an asterisk (*) has the (R) configuration.

[0092] In some embodiments, the carbon marked with an asterisk (*) has the (S) configuration.

[0093] In embodiments, the compound is selected from any compound set forth in Table 1, or a pharmaceutically acceptable salt thereof.

[0094] In embodiments, the compound of formula (I) is selected from the group consisting of: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0095] In embodiments, the compound of formula (I) is [ka] (Compound 1A / 1B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 1A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound aB, or a pharmaceutically acceptable salt thereof.

[0096] In embodiments, the compound of formula (I) is [ka] (Compound 2A / 2B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 2A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 2B, or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, the compound of formula (I) [ka] (Compound 7A / 7B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 7A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 7B, or a pharmaceutically acceptable salt thereof.

[0098] In embodiments, the compound of formula (I) is [ka] (Compound 11A / 11B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 11A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 11B, or a pharmaceutically acceptable salt thereof.

[0099] In embodiments, the compound of formula (I) is [ka] (Compound 12A / 12B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 12A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 12B, or a pharmaceutically acceptable salt thereof.

[0100] In embodiments, the compound of formula (I) is [ka] (Compound 17A / 17B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 17A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 17B, or a pharmaceutically acceptable salt thereof.

[0101] In embodiments, the compound of formula (I) is [ka] (Compound 20A / 20B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 20A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 20B, or a pharmaceutically acceptable salt thereof.

[0102] In embodiments, the compound of formula (I) is [ka] (Compound 24A / B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 24A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 24B, or a pharmaceutically acceptable salt thereof.

[0103] In embodiments, the compound of formula (I) is [ka] (Compound 28A / 28B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 24A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 24B, or a pharmaceutically acceptable salt thereof.

[0104] In embodiments, the compound of formula (I) is [ka] (Compound 35A / 35B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 35A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 35B, or a pharmaceutically acceptable salt thereof.

[0105] In embodiments, the compound of formula (I) is [ka] (Compound 36A / 36B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 36A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 36B, or a pharmaceutically acceptable salt thereof.

[0106] In embodiments, the compound of formula (I) is [ka] (Compound 41A / 41B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 41A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 41B, or a pharmaceutically acceptable salt thereof.

[0107] In embodiments, the compound of formula (I) is [ka] (Compound 42A / 42B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 42A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 42B, or a pharmaceutically acceptable salt thereof.

[0108] In embodiments, the compound of formula (I) is [ka] (Compound 47A / 47B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 47A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 47B, or a pharmaceutically acceptable salt thereof.

[0109] In embodiments, the compound of formula (I) is [ka] (Compound 123A / 123B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 123A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 123B, or a pharmaceutically acceptable salt thereof.

[0110] In embodiments, the compound of formula (I) is [ka] (Compound 125A / 125B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 125A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 125B, or a pharmaceutically acceptable salt thereof.

[0111] In embodiments, the compound of formula (I) is [ka] (Compound 129A / 129B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 129A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 129B, or a pharmaceutically acceptable salt thereof.

[0112] In embodiments, the compound of formula (I) is [ka] (Compound 135A / 136B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 135A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 135B, or a pharmaceutically acceptable salt thereof.

[0113] In embodiments, the compound of formula (I) is [ka] (Compound 136A / 136B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 136A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 136B, or a pharmaceutically acceptable salt thereof.

[0114] In embodiments, the compound of formula (I) is [ka] (Compound 150A / 150B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 150A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 150B, or a pharmaceutically acceptable salt thereof.

[0115] In embodiments, the compound of formula (I) is [ka] (Compound 154A / 154B), or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 154A, or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 154B, or a pharmaceutically acceptable salt thereof.

[0116] In another aspect, the invention features a pharmaceutical composition including any compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0117] In another aspect, the invention features a method of inhibiting avb8 integrin in a patient, the method providing a method for treating, but not preventing, pain in a mammal, the method comprising administering to a patient in need thereof a therapeutically effective amount of any compound described herein, or a pharmaceutically acceptable salt thereof. In embodiments, the method is for treating a solid tumor in a patient in need thereof.

[0118] In another aspect, the invention features a method of treating a solid tumor in a patient, the method includes administering to a patient in need thereof: (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.

[0119] In some embodiments, 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.

[0120] In some embodiments, 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.

[0121] In some embodiments, the second active agent is an immune checkpoint inhibitor (e.g., an anti-PD-1 or anti-PD-L1 therapy). In some embodiments, the immune checkpoint inhibitor is selected from: nivolumab, pembrolizumab, cemiplimab, dostallimab, atezolizumab, avelumab, and durvalumab. DETAILED DESCRIPTION OF THE INVENTION

[0122] definition For convenience, before further description of the present invention, certain terms employed in the specification, examples, and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and should be understood as understood by one of ordinary skill 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.

[0123] In order to more readily understand the present invention, certain terms and phrases are defined below and throughout the specification.

[0124] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0125] The term "and / or," as used in the specification and claims, should be understood to mean "either or both" of the elements so combined, i.e., elements that may be present conjunctively or disjunctively. Multiple elements listed with "and / or" should be construed in the same manner, i.e., "one or more" elements so combined. Other elements, whether related or unrelated to the elements specifically identified by the "and / or" clause, may optionally be present other than those elements specifically identified. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," can refer in one embodiment to A only (optionally including elements other than B), in another embodiment to B only (optionally including elements other than A), in yet another embodiment to both A and B (optionally including other elements), etc.

[0126] As used in this specification and the 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" shall be construed as inclusive, i.e., the inclusion of at least one of a number or series of elements, but also two or more, optionally including additional items not listed. Only terms clearly indicated otherwise, such as "only one of" or "exactly one of," or, when used in the claims, "consisting of," shall refer to the inclusion of exactly one element of a number or series of elements. In general, as used herein, the term "or" shall only be construed as indicating exclusive alternatives (i.e., "one or the other, but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of." When used in the claims, "consisting essentially of" shall have its ordinary meaning as used in the field of patent law.

[0127] As used in this specification and claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of every element specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those elements specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to the elements specifically identified in the list of elements. Thus, as a non-limiting example, "at least one of A and B" (or, with similar implications, "at least one of A or B" or, with similar implications, "at least one of A and / or B") can refer in one embodiment to at least one A (optionally including two or more As) with no B (and optionally including elements other than B); in another embodiment to at least one B (optionally including two or more Bs) with no A (and optionally including elements other than A); in yet another embodiment to at least one A (optionally including two or more As) and at least one B (optionally including two or more Bs) (and optionally including other elements); and so forth.

[0128] It should also be understood that, unless expressly indicated otherwise, in any method claimed herein that includes more than one step or action, the order of the method steps or actions is not necessarily limited to the order in which the method steps or actions are presented.

[0129] In the claims and the above specification, all transitional phrases, such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "consisting of," etc., are to be understood to be open-ended, i.e., meaning "including, but not limited to." Only the transitional phrase "consisting of" shall be a closed transitional phrase, and only the transitional phrase "consisting essentially of" shall be a semi-closed transitional phrase, as defined in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0130] Certain compounds contained in the compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, the polymers of the present invention may also be optically active. All such compounds, including cis and trans isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, are contemplated within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents, such as alkyl groups. All such isomers, as well as mixtures, are contemplated within the scope of the present invention.

[0131] For example, if a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the formed diastereomers by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0132] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, by replacing a hydrogen with deuterium or tritium, or replacing a carbon with 13 C-enriched carbon or 14 Compounds produced by substituting C-enriched carbons are within the scope of the present invention.

[0133] As used herein, terms such as "αvβ8," "avB8," "avb8," "alpha-v beta-8," and "alpha v beta 8" all refer to α v Refers to β8.

[0134] The phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier," as used herein, means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a chemical substance from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials that can function 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 carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (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 soybean oil; (10) glycols, such as propylene glycol, (11) polyols, such as glycerin, 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) ethyl alcohol, (20) phosphate buffer, and (21) other non-toxic compatible substances used in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not cause a significant temperature increase when administered to a patient.

[0135] The term "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic and organic acid addition salts of a compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfate. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19.)

[0136] In other cases, compounds useful in the methods of the present invention may contain one or more acidic functional groups and, therefore, can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic inorganic and organic base addition salts of the compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, e.g., Berge et al., supra).

[0137] A "therapeutically effective amount" (or "effective amount") of a compound for use in therapy refers to the amount of compound in a formulation that, when administered as part of a desired dosing regimen (to a mammal, preferably a human), alleviates the symptoms, ameliorates the condition, or delays the onset of a disease state in accordance with clinically accepted criteria for the disorder or condition being treated or for cosmetic purposes, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment.

[0138] The term "prophylactic or therapeutic" treatment is art-recognized and includes administration of one or more of the compositions to a host. A treatment is prophylactic (i.e., it protects the host against the onset of the undesired condition) if it is administered prior to clinical manifestation of an undesired condition (e.g., disease or other undesired condition in a host animal), and is therapeutic (i.e., it is intended to reduce, ameliorate, or stabilize an existing undesired condition or its side effects) if it is administered after the onset of the undesired condition.

[0139] The term "patient" refers to a mammal in need of a particular treatment. In certain embodiments, the patient is a primate, dog, cat, or horse. In certain embodiments, the patient is human.

[0140] Whenever either a term (e.g., alkyl or aryl) or their prefix root (e.g., alk- or ar-) appears in a name of a substituent, the name should be interpreted as including those limitations provided herein. For example, adding the suffix "-ene" to a group indicates that the group is a divalent moiety; e.g., arylene is a divalent moiety of aryl, heteroarylene is a divalent moiety of heteroaryl, and heterocycloalkylene is a divalent moiety of heterocycloalkyl. Similarly, adding the suffix "-oxy" to a group indicates that the group is attached to the parent molecular structure through an oxygen atom (-O-), such as "alkyloxy," "alkoxy," or "cycloalkoxy" as used herein.

[0141] Aliphatic chains include alkyl, alkenyl, and alkynyl groups as defined below. Straight aliphatic chains are limited to unbranched carbon chain moieties. As used herein, the term "aliphatic group" refers to straight, branched, or cyclic aliphatic hydrocarbon groups, including saturated and unsaturated aliphatic groups, such as alkyl, alkenyl, or alkynyl groups.

[0142] "Alkyl" refers to a fully saturated, cyclic or acyclic, branched or unbranched carbon chain moiety having the specified number of carbon atoms, or, if not specified, 1 to 30 carbon atoms. For example, alkyl having 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as moieties that are positional isomers of these moieties. Alkyl having 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, and tetracosyl. In certain embodiments, a straight or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C for a straight chain). 30 , C3-C for branched chains 30 ), more preferably 20 or fewer. Alkyl groups can be substituted or unsubstituted. As used herein, "Me" and -CH3 both refer to methyl.

[0143] As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbons, e.g., 2 to 12 carbon atoms, that includes two points of attachment to the remainder of the compound on the longest carbon chain. Non-limiting examples of alkylene groups include methylene-(CH)-, ethylene-(CHCH)-, n-propylene-(CHCHCH)-, isopropylene-(CHCH(CH))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moieties, and may be optionally substituted with one or more substituents.

[0144] "Cycloalkyl" means a mono- or bicyclic, or bridged or spirocyclic, or polycyclic saturated carbocyclic ring, each having from 3 to 12 carbon atoms. Likewise, preferred cycloalkyls have from 3 to 10 carbon atoms in their ring structure, and more preferably 3 to 6 carbons in the ring structure. 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).

[0145] Unless the number of carbon atoms is otherwise specified, "lower alkyl," as used herein, refers to an alkyl group as defined above, but having 1 to 10 carbons, more preferably 1 to 6 carbon atoms, in its backbone structure, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout this application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent defined herein as alkyl is a lower alkyl.

[0146] As used herein, the term "aryl" includes 3- to 12-membered substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or one or more atoms is a heteroatom (i.e., heteroaryl). Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and at least one of the rings is aromatic; for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl groups include substituted or unsubstituted 3- to 12-membered aromatic ring structures, more preferably 5- to 12-membered rings, and even more preferably 5- to 10-membered rings, containing 1 to 4 heteroatoms in the ring structure. Examples of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Aryl and heteroaryl groups can be monocyclic, bicyclic, or polycyclic.

[0147] The terms "halo," "halide," or "halogen," as used herein, mean halogens, including, but not limited to, fluoro, chloro, bromo, iodo, and the like, in both radioactive and non-radioactive forms. In preferred embodiments, halo is selected from the group consisting of fluoro, chloro, and bromo.

[0148] The terms "heterocyclyl" or "heterocyclic group" refer to 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, and more preferably 5- to 10-membered rings, which include one to four heteroatoms in the ring structure. The heterocycle can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathine, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with substituents such as those described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, -CF, -CN, and the like.

[0149] The term "heterocycloalkyl," as used herein, refers to a non-aromatic heterocyclyl 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 heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydro Examples of heterocycloalkyl groups include pyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, and quinolidinyl. Heterocycloalkyl groups can be substituted or unsubstituted, for example, as recited for heterocyclyls described herein.

[0150] The term "carbonyl" is art-recognized and includes such moieties as may be represented by the formula: [ka]

[0151] In the formula, X' represents a bond, oxygen, or sulfur; R 15 is hydrogen, alkyl, alkenyl, -(CH2) m -R 10 or a pharmaceutically acceptable salt thereof, and R 16 is hydrogen, alkyl, alkenyl, or -(CH2) m -R 10 where m and R 10 is as defined above. X' is oxygen and R 15or R 16 is not hydrogen, the formula represents an "ester". 15 is as defined above, the moiety is referred to herein as a carboxyl group, and in particular, R 15 Where X' is an oxygen and R 16 is hydrogen, the formula represents "formic acid", while X' is a bond and R 15 Where X' is a bond and R 15 Where is hydrogen, the above formula represents an "aldehyde" group.

[0152] As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Exemplary substituents include, for example, those described herein above, e.g., substituted with one or more substituents selected from alkyl, cycloalkyl, heterocyclylalkyl, halogen, OH, OMe, C(H)F, C(F)H, CF, C(H)CF, SF, CHFCHamine, CHamine, and CN. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds. It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is subject to the allowed valence of the substituted atom and substituent, and that substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, etc.

[0153] As used herein, the term "nitro" means -NO2; the term "halogen" refers to -F, -Cl, -Br, or -I; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" means -SO2-.

[0154] As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when that expression occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0155] As used herein, the term "prodrug" encompasses compounds that are converted into therapeutically active agents under physiological conditions. A common method for making prodrugs is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, prodrugs are converted by enzymatic activity in the host animal. Thus, prodrugs include compounds that are transformed in vivo to yield the disclosed compounds or any other pharmaceutically acceptable form of the compounds. In embodiments, prodrugs may be inactive when administered to a subject, but can be converted to an active compound in vivo, for example, by hydrolysis. See, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties. Prodrugs can typically be 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 meant to include any covalently bonded carriers that release the active compound in vivo when such prodrug is administered to a subject.

[0156] Prodrugs of the compounds described herein can be prepared by modifying functional groups present in the active compounds in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to yield the compounds described herein (i.e., the parent active compounds). Prodrugs include compounds in which a hydroxy, amino, or mercapto group is bonded to any group that cleaves to form the free hydroxy, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohols, or acetamide, formamide, and benzamide derivatives of amine functional groups in the active compounds. Other examples of prodrugs include compounds containing -NO, -NO2, -ONO, or -ONO2 moieties.

[0157] For purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, inside cover of Handbook of Chemistry and Physics, 67th Ed., 1986-87.

[0158] Exemplary Compounds of the Invention This disclosure provides v The present invention relates to novel compounds and methods useful for inhibiting β8 integrins.

[0159] Exemplary formulas and compounds are described herein. Also provided herein are exemplary embodiments of structural features that may be present in any formula described herein. Any exemplary embodiment of a structural feature may be implemented in combination with any other exemplary structural feature described herein. Furthermore, unless otherwise indicated herein, any description of a formula or compound also 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.

[0160] In embodiments, the compounds described herein are v In some embodiments, the compounds described herein are selective inhibitors of, for example, α v α rather than β6 integrin v Selectively inhibits β8 integrin (eg, at least about 10×, 20×, 50×, 100×, 500×, or 1000× selectivity as measured according to an assay (eg, a fluorescence polarization assay)).

[0161] Certain exemplary formulas, compounds, and structural features are described herein. Any structural feature and embodiment described herein can be used in any combination with any other structural feature(s) and embodiment(s) described herein.

[0162] Formula (I) In one aspect, the invention features a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony: The Q ring is [ka] and; L is [ka] and each of these is 1 to 6 R 4 is optionally replaced by; X is -CHR 1c -, -O-, or -NR 2 - and; R 1a , R 1b , R 1c , R 1d , R 1e , and R 1f each independently represents H, C 1-4 Alkyl, halogen, C 1-4 Alkoxy, OH, C1-4 Alkyl-OH, C 1-4 Alkyl-C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkoxy, CF3, CHF2, CH2F, CN, NO2, NR a R b or C 1-4 Alkyl-NR a R b and Each R 2 are independently H, C 1-4 Alkyl, or C 3-5 is cycloalkyl; R 3a is C 1-4 Alkoxy, C 3-5 cycloalkoxy, CF3, CHF2, CH2F, OCF3, OCHF2 or OCH2F; R 3b is H, halogen, CF3 or CN; R 3c is H, F, CN, or C 1-4 is alkyl; R 3d is C 1-4 Alkyl, C 3-5 cycloalkyl, or 4- to 6-membered heterocycloalkyl, each of which is selected from 1 to 4 R 6 is optionally replaced by; R 3e is H or F; Each R 4 are independently H, C 1-4 alkyl, halogen, CF3, CHF2, or CH2F, cyclopropyl, or two geminal R 4 The groups together can form a spiro-cyclopropyl; Each R 6 independently, 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 membered heteroaryl or NR a R b and; Each R 7 independently, C 1-4 is alkyl or F; R a and R b each independently represents hydrogen, C 1-4 Alkyl, C 3-5 cycloalkyl or R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and which may optionally be substituted with one to three identical or different groups selected from the group consisting of F, C1-4 alkyl, phenyl, and benzyl; n is 1 or 2; m is 0, 1, or 2.

[0163] In one aspect, the invention features a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony: The Q ring is [ka] and; L is [ka] and each of these is 1 to 6 R 4 is optionally replaced by; X is -CHR 1c -, -O-, or -NR 2 - and; R 1a , R 1b , R 1c , R1d , R 1e , and R 1f each independently represents H, 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 Alkoxy, CF3, CHF2, CH2F, CN, NO2, NR a R b or C 1-4 Alkyl-NR a R b and Each R 2 are independently H, C 1-4 Alkyl, or C 3-5 is cycloalkyl; R 3a is cyano, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-5 cycloalkoxy, CF3, CHF2, CH2F, OCF3, OCHF2 or OCH2F; R 3b is H, halogen, CF3 or CN; R 3c is H, F, CN, or C 1-4 is alkyl; R 3d is C 1-4 Alkyl, C 3-5 cycloalkyl, or 4- to 6-membered heterocycloalkyl, each of which is selected from 1 to 4 R 6 is optionally replaced by; R 3e is H or F; Each R 4 are independently H, C 1-4 alkyl, halogen, CF3, CHF2, or CH2F, cyclopropyl, or two geminal R 4 The groups together can form a spiro-cyclopropyl; Each R 6 independently, C 1-4Alkyl, 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 membered heteroaryl or NR a R b and; Each R 7 independently, C 1-4 is alkyl or F; R a and R b each independently represents hydrogen, C 1-4 Alkyl, C 3-5 cycloalkyl or R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and which may optionally be substituted with one to three identical or different groups selected from the group consisting of F, C1-4 alkyl, phenyl, and benzyl; n is 1 or 2; m is 0, 1, or 2.

[0164] In one aspect, the invention features a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony: The Q ring is [ka] and; L is [ka] and; R 3a is methoxy; R 3b is H, halogen, CF3 or CN; R 3c is H, F, CN, or C 1-4 is alkyl; R 3d is C 1-4 Alkyl, C 3-5 cycloalkyl, or 4- to 6-membered heterocycloalkyl, each of which is selected from 1 to 4 R 6 is optionally replaced by; R 3e is H or F; Each R 6 independently, 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 membered heteroaryl or NR a R b and; Each R 7 independently, C 1-4 is alkyl or F; R a and R b each independently represents hydrogen, C 1-4 Alkyl, C 3-5 cycloalkyl or R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and which may optionally be substituted with one to three identical or different groups selected from the group consisting of F, C1-4 alkyl, phenyl, and benzyl; n is 1 or 2; m is 0, 1, or 2.

[0165] In embodiments, the Q ring is: [ka] where R1c1 and R 1c2 are each independently R 1c Selected from;R 1d1 and R 1d2 are each independently R 1d Selected from;R 1e1 and R 1e2 are each independently R 1e is selected from.

[0166] In some embodiments, the Q ring is [ka] is.

[0167] In embodiments, X is —O—.

[0168] In some embodiments, X is —NR 2 -It is.

[0169] In some embodiments, R 2 is methyl.

[0170] In some embodiments, the Q ring is [ka] is.

[0171] In embodiments, the Q ring is: [ka] where R 1c1 and R 1c2 are each independently R 1c Selected from;R 1d1 and R 1d2 are each independently R 1d is selected from.

[0172] In some embodiments, R 1c1 , R 1c2 , R 1d1 , and R 1d2are each independently H.

[0173] In some embodiments, the Q ring is [ka] is.

[0174] In some embodiments, the Q ring is [ka] is.

[0175] In some embodiments, the Q ring is [ka] is.

[0176] In some embodiments, R 1d and R 1e each independently is H.

[0177] In some embodiments, each R 1c are independently H.

[0178] In some embodiments, each R 1a are independently H.

[0179] In some embodiments, each R 1b are independently H.

[0180] In some embodiments, each R 1b is independently OMe.

[0181] In some embodiments, the Q ring is [ka] is.

[0182] In some embodiments, R 1c and R 1d each independently is H.

[0183] In some embodiments, R 1a , R 1b and R 1f each independently is H.

[0184] In some embodiments, L is [ka] and n is 1.

[0185] In some embodiments, L is [ka] and n is 2.

[0186] In some embodiments, L is [ka] is.

[0187] In some embodiments, L is [ka] is.

[0188] In some embodiments, R 3a is C 1-4 It is an alkoxy.

[0189] In some embodiments, R 3a is OMe, OEt, OCF3, OCHF2, or OCH2F.

[0190] In some embodiments, R 3a is OMe.

[0191] In some embodiments, R 3a is -CN.

[0192] In some embodiments, R 3ais a halogen.

[0193] In some embodiments, R 3a is Cl.

[0194] In some embodiments, R 3a is C 1-4 It is alkyl.

[0195] In some embodiments, R 3a is methyl.

[0196] In some embodiments, R 3a is ethyl.

[0197] In some embodiments, R 3b is F.

[0198] In some embodiments, R 3c is H.

[0199] In some embodiments, R 3d is C 1-4 It is alkyl.

[0200] In some embodiments, R d3 is C 3-5 It is cycloalkyl.

[0201] In some embodiments, R 3d is oxetanyl, tetrahydrofuranyl, or tetrahydro-2H-pyranyl, morpholinyl, or piperazinyl-C 1-4 It is alkyl.

[0202] In some embodiments, R 3d is isopropyl.

[0203] In some embodiments, R 3e is H.

[0204] In some embodiments, each R 4 are independently methyl.

[0205] In some embodiments, each R 4 are independently F.

[0206] In some embodiments, each R 4 are independently CF3, CHF2, or CH2F.

[0207] In some embodiments, each R 4 are independently H.

[0208] In some embodiments, each R 6 independently, C 1-4 It is alkyl.

[0209] In some embodiments, each R 6 independently, C 1-4 It is alkenyl.

[0210] In some embodiments, each R 6 independently, C 3-5 It is cycloalkyl.

[0211] In some embodiments, each R 6 independently, C 1-4 It is an alkoxy.

[0212] In some embodiments, each R 6 independently, C 3-5 It is cycloalkoxy.

[0213] In some embodiments, each R 6 are independently F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, or OH.

[0214] In some embodiments, each R 6 is independently a 5- to 9-membered heteroaryl.

[0215] In some embodiments, each R 6 are independently H.

[0216] In some embodiments, each R 7 are independently F.

[0217] In some embodiments, each R 7 is independently F, and m is 0 or 1.

[0218] In some embodiments, each R 7 are independently methyl.

[0219] In some embodiments, each R 7 is independently methyl, and m is 0 or 1.

[0220] In some embodiments, n is 0.

[0221] In some embodiments, n is 1.

[0222] In an embodiment, n is 2.

[0223] In some embodiments, m is 0.

[0224] Formulas (II)~(VII) In embodiments, the compound has the structure according to formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1b , R 3a , R 3b , R 3c , R 3d , R 3e each independently according to any embodiment described herein.

[0225] In embodiments, the compound has the structure according to formula (IIA): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1b, R 3a , and R 3e each independently according to any embodiment described herein.

[0226] In embodiments, the compound has the structure according to formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1b , R 3a , R 3b , R 3c , R 3d , R 3e each independently according to any embodiment described herein.

[0227] In embodiments, the compound has the structure according to formula (IIIA): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1b , R 3a , and R 3e each independently according to any embodiment described herein.

[0228] In embodiments, the compound has the structure according to formula (IV): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1b , R 3a , R 3b , R 3c , R 3d , R 3e each independently according to any embodiment described herein.

[0229] In embodiments, the compound has the structure according to formula (IVA): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1b , R 3d , and R 3e each independently according to any embodiment described herein.

[0230] In embodiments, the compound has a structure according to formula (V): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1b , R 3a , R 3b , R 3c , R 3d , R 3e each independently according to any embodiment described herein.

[0231] In embodiments, the compound has a structure according to formula (VA): [ka] or a pharmaceutically acceptable salt thereof, wherein n, R 1b , R 3d , and R 3e each independently according to any embodiment described herein.

[0232] In embodiments, the compound has the structure according to formula (VI): [ka] or a pharmaceutically acceptable salt thereof, wherein n, R 1b , R 3a , R 3b , R 3c , R 3d , R 3e each independently according to any embodiment described herein.

[0233] In embodiments, the compound has the structure according to formula (VIA): [ka] or a pharmaceutically acceptable salt thereof, wherein n, R 1b , R 3d , and R 3e each independently according to any embodiment described herein.

[0234] In one aspect, the invention features a compound of formula (VII) or a pharmaceutically acceptable salt thereof: [ka] In the formula, L, Q, R7, R 3a , R 3b , R 3c , R 3d , R 3e each independently according to any embodiment described herein.

[0235] In one aspect, the invention features a compound of formula (VII) or a pharmaceutically acceptable salt thereof: [ka] In the formula, the Q ring is [ka] and; L is [ka] and; n is 1 or 2; R 3a is methoxy; R7 is H or F; R 3a is methoxy; R 3b , R 3c , R 3d , R 3e is as disclosed herein above with respect to formula (I).

[0236] In some embodiments, n is 1.

[0237] In some embodiments, n is 2.

[0238] In some embodiments, R 1b is H, CH3, or OCH3.

[0239] In some embodiments, R 3e is H or F.

[0240] In some embodiments, R 3d optionally, one R 6 C replaced by 1-4 It is alkyl.

[0241] In some embodiments, R 3d teeth, [ka] is.

[0242] In some embodiments, R 3d optionally, one R 6 is a 4- to 6-membered heterocycloalkyl substituted with

[0243] In some embodiments, R 3d teeth, [ka] is.

[0244] In some embodiments, R 3d optionally, one R 6 C replaced by 3-5 It is cycloalkyl.

[0245] In some embodiments, R 3d teeth, [ka] is.

[0246] In some embodiments, the carbon marked with an asterisk (*) has the (R) configuration.

[0247] In some embodiments, the carbon marked with an asterisk (*) has the (S) configuration.

[0248] In embodiments, the compound is selected from any compound set forth in Table 1, or a pharmaceutically acceptable salt thereof.

[0249] Additional Exemplary Embodiments Further exemplary embodiments of the variables in exemplary formulas (I)-(VII), which may occur in any combination where valence allows, are described herein.

[0250] In some embodiments, the Q ring is [ka] In some embodiments, X is -CHR 1c In embodiments, X is -O-. In embodiments, X is -NR 2 -It is.

[0251] In some embodiments, the Q ring is [ka] In some embodiments, the Q ring is [ka] In some embodiments, the Q ring is [ka] In some embodiments, the Q ring is [ka] In some embodiments, the Q ring is [ka] In some embodiments, the Q ring is [ka] In some embodiments, the Q ring is [ka] In some embodiments, the Q ring is [ka] In some embodiments, the Q ring is [ka] is. In some embodiments, the Q ring is [ka] In some embodiments, the Q ring is [ka] In some embodiments, the Q ring is [ka] In some embodiments, the Q ring is [ka] is.

[0252] In some embodiments, the Q ring is [ka] In some embodiments, X is -CHR 1c In embodiments, X is -O-. In embodiments, X is -NR 2 -It is.

[0253] In some embodiments, the Q ring is [ka] In some embodiments, the Q ring is [ka] In some embodiments, the Q ring is [ka] is.

[0254] In some embodiments, L is [ka] and optionally 1 to 6 R 4 In embodiments, L is unsubstituted. In embodiments, L is substituted with 1 to 6 R 4 In some embodiments, L is substituted with 1, 2, or 3 R 4 In some embodiments, L is substituted with one R 4 In some embodiments, L is substituted with two R 4 In some embodiments, L is substituted with three R 4 In some embodiments, L is substituted with four R 4 In some embodiments, L is substituted with five R 4 In some embodiments, L is substituted with 6 R 4 is replaced by

[0255] In some embodiments, L is [ka] and optionally 1 to 6 R 4 In embodiments, L is unsubstituted. In embodiments, L is substituted with 1 to 6 R 4 In some embodiments, L is substituted with 1, 2, or 3 R 4 In some embodiments, L is substituted with one R 4In some embodiments, L is substituted with two R 4 In some embodiments, L is substituted with three R 4 In some embodiments, L is substituted with four R 4 In some embodiments, L is substituted with five R 4 In some embodiments, L is substituted with 6 R 4 is replaced by

[0256] In some embodiments, R 1a is H. In some embodiments, R 1a is C 1-4 In some embodiments, R 1a is halogen (e.g., F). In some embodiments, R 1a is C 1-4 In some embodiments, R 1a is OH. In some embodiments, R 1a is C 1-4 In some embodiments, R 1a is C 1-4 Alkyl-C 1-4 In some embodiments, R 1a is C 1-4 Alkoxy-C 1-4 In some embodiments, R 1a is CF. In some embodiments, R 1a is CHF2. In some embodiments, R 1a is CHF. In some embodiments, R 1a is CN. In some embodiments, R 1a is NO. In some embodiments, R 1a is NR a R b In some embodiments, R 1a is C 1-4 Alkyl-NR a R b is.

[0257] In some embodiments, R 1b is H. In some embodiments, R1b is C 1-4 In some embodiments, R 1b is halogen (e.g., F). In some embodiments, R 1b is C 1-4 In some embodiments, R 1b is OH. In some embodiments, R 1b is C 1-4 In some embodiments, R 1a is C 1-4 Alkyl-C 1-4 In some embodiments, R 1b is C 1-4 Alkoxy-C 1-4 In some embodiments, R 1b is CF. In some embodiments, R 1b is CHF2. In some embodiments, R 1b is CHF. In some embodiments, R 1b is CN. In some embodiments, R 1b is NO. In some embodiments, R 1b is NR a R b In some embodiments, R 1b is C 1-4 Alkyl-NR a R b is.

[0258] In some embodiments, R 1c is H. In some embodiments, R 1c is C 1-4 In some embodiments, R 1c is halogen (e.g., F). In some embodiments, R 1c is C 1-4 In some embodiments, R 1c is OH. In some embodiments, R 1c is C 1-4 In some embodiments, R 1c is C 1-4 Alkyl-C 1-4In some embodiments, R 1c is C 1-4 Alkoxy-C 1-4 In some embodiments, R 1c is CF. In some embodiments, R 1c is CHF2. In some embodiments, R 1c is CHF. In some embodiments, R 1c is CN. In some embodiments, R 1b is NO. In some embodiments, R 1c is NR a R b In some embodiments, R 1c is C 1-4 Alkyl-NR a R b is.

[0259] In some embodiments, R 1d is H. In some embodiments, R 1d is C 1-4 In some embodiments, R 1d is halogen (e.g., F). In some embodiments, R 1d is C 1-4 In some embodiments, R 1d is OH. In some embodiments, R 1d is C 1-4 In some embodiments, R 1d is C 1-4 Alkyl-C 1-4 In some embodiments, R 1d is C 1-4 Alkoxy-C 1-4 In some embodiments, R 1d is CF. In some embodiments, R 1d is CHF2. In some embodiments, R 1d is CHF. In some embodiments, R 1d is CN. In some embodiments, R 1d is NO. In some embodiments, R 1dis NR a R b In some embodiments, R 1d is C 1-4 Alkyl-NR a R b is.

[0260] In some embodiments, R 1e is H. In some embodiments, R 1e is C 1-4 In some embodiments, R 1e is halogen (e.g., F). In some embodiments, R 1e is C 1-4 In some embodiments, R 1e is OH. In some embodiments, R 1e is C 1-4 In some embodiments, R 1e is C 1-4 Alkyl-C 1-4 In some embodiments, R 1e is C 1-4 Alkoxy-C 1-4 In some embodiments, R 1e is CF. In some embodiments, R 1e is CHF2. In some embodiments, R 1e is CHF. In some embodiments, R 1e is CN. In some embodiments, R 1e is NO. In some embodiments, R 1e is NR a R b In some embodiments, R 1e is C 1-4 Alkyl-NR a R b is.

[0261] In some embodiments, R 1f is H. In some embodiments, R 1f is C 1-4 In some embodiments, R 1fis halogen (e.g., F). In some embodiments, R 1f is C 1-4 In some embodiments, R 1f is OH. In some embodiments, R 1f is C 1-4 In some embodiments, R 1f is C 1-4 Alkyl-C 1-4 In some embodiments, R 1f is C 1-4 Alkoxy-C 1-4 In some embodiments, R 1f is CF. In some embodiments, R 1f is CHF2. In some embodiments, R 1f is CHF. In some embodiments, R 1f is CN. In some embodiments, R 1f is NO. In some embodiments, R 1f R 1e is NR a R b In some embodiments, R 1f is C 1-4 Alkyl-NR a R b is.

[0262] In some embodiments, R 2 is H.

[0263] In some embodiments, R 2 is C 1-4 It is alkyl.

[0264] In some embodiments, R 2 is C 3-5 It is cycloalkyl.

[0265] In some embodiments, R 3a is C 1-4 It is an alkoxy.

[0266] In some embodiments, R 3ais C 3-5 It is cycloalkoxy.

[0267] In some embodiments, R 3a is CF3.

[0268] In some embodiments, R 3a is CHF2.

[0269] In some embodiments, R 3a is CH2F.

[0270] In some embodiments, R 3a is OCF3.

[0271] In some embodiments, R 3a is OCHF2.

[0272] In some embodiments, R 3a is OCH2F.

[0273] In some embodiments, R 3a is -CN.

[0274] In some embodiments, R 3a is a halogen.

[0275] In some embodiments, R 3a is Cl.

[0276] In some embodiments, R 3a is C 1-4 It is alkyl.

[0277] In some embodiments, R 3a is methyl.

[0278] In some embodiments, R 3a is ethyl.

[0279] In some embodiments, R 3b is H.

[0280] In some embodiments, R 3b is a halogen.

[0281] In some embodiments, R 3b is CF3.

[0282] In some embodiments, R 3b is CN.

[0283] In some embodiments, R 3c is H.

[0284] In some embodiments, R 3c is F.

[0285] In some embodiments, R 3c is CN.

[0286] In some embodiments, R 3c is C 1-4 It is alkyl.

[0287] In some embodiments, R 3d is optionally 1 to 4 R 6 C replaced by 1-4 In some embodiments, R 3d is the unsubstituted C 1-4 alkyl (e.g., methyl, ethyl, isopropyl, or tert-butyl). In some embodiments, R 3d is one R 6 (e.g., methyl, ethyl, propyl, isopropyl, or n-butyl groups substituted with methyl, ethyl, cyclopropyl, OH, oxazolyl, isoxazolyl, thiazolyl, methoxy, ethoxy, isopropyloxy, dimethylamino, pyrrolidinyl, morpholinyl, piperidinyl; or NR a R b a methyl, ethyl, propyl, isopropyl, or n-butyl group substituted by R a and R bform, together with the nitrogen atom to which they are attached, a saturated or unsaturated heterocycle (e.g., azanorbornyl or piperidinyl), optionally containing one or two substituents selected from methyl, fluoro, cyclopropyl, and methoxy) substituted with C 1-4 In some embodiments, R 3d is two R 6 C replaced by 1-4 In some embodiments, R 3d is three R 6 C replaced by 1-4 In some embodiments, R 3d is four R 6 C replaced by 1-4 It is alkyl.

[0288] In some embodiments, R 3d is optionally 1 to 4 R 6 C replaced by 3-5 In some embodiments, R 3d is the unsubstituted C 3-5 In some embodiments, R is cycloalkyl (e.g., cyclopropyl). 3d is one R 6 C optionally replaced with 3-5 cycloalkyl (e.g., cyclopropyl substituted with methyl, ethyl, methoxy, or trifluoromethyl). In embodiments, R 3d optionally, two R 6 C replaced by 3-5 In some embodiments, R 3d optionally, three R 6 C replaced by 3-5 In some embodiments, R 3d is optionally followed by four R 6 C replaced by 3-5 It is cycloalkyl.

[0289] In some embodiments, R 3d is optionally 1 to 4 R 6In some embodiments, R 3d is an unsubstituted 4-6 membered heterocycloalkyl (e.g., tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, isoxazolyl, morpholinyl, pyrrolidinyl, or piperidinyl). 3d is one R 6 (e.g., tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, isoxazolyl, morpholinyl, pyrrolidinyl, or piperidinyl substituted with methyl, methoxy, or fluoro). In some embodiments, R 3d is two R 6 (e.g., tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, isoxazolyl, morpholinyl, pyrrolidinyl, piperidinyl, each of which contains two substituents independently selected from methyl and fluoro). In some embodiments, R 3d is three R 6 In some embodiments, R 3d is four R 6 is a 4- to 6-membered heterocycloalkyl substituted with

[0290] In some embodiments, R 3e is H.

[0291] In some embodiments, R 3e is F.

[0292] In some embodiments, R 4 is H.

[0293] In some embodiments, R 4 is C 1-4 It is alkyl.

[0294] In some embodiments, R 4 is a halogen (e.g., F).

[0295] In some embodiments, R 4 is CF3.

[0296] In some embodiments, R 4 is CHF2.

[0297] In some embodiments, R 4 is CH2F.

[0298] In some embodiments, R 4 is cyclopropyl.

[0299] In some embodiments, two geminal R 4 The groups can be taken together to form a spiro-cyclopropyl.

[0300] In some embodiments, R 6 is C 1-4 It is alkyl.

[0301] In some embodiments, R 6 is C 1-4 It is alkenyl.

[0302] In some embodiments, R 6 is C 3-5 It is cycloalkyl.

[0303] In some embodiments, R 6 is C 1-4 It is an alkoxy.

[0304] In some embodiments, R 6 is C 3-5 It is cycloalkoxy.

[0305] In some embodiments, R 6 is F.

[0306] In some embodiments, R 6 is CF3.

[0307] In some embodiments, R6 is CHF2.

[0308] In some embodiments, R 6 is CH2F.

[0309] In some embodiments, R 6 is OCF3.

[0310] In some embodiments, R 6 is OCHF2.

[0311] In some embodiments, R 6 is OCH2F.

[0312] In some embodiments, R 6 is OH.

[0313] In some embodiments, R 6 is a 5- to 6-membered heteroaryl.

[0314] In some embodiments, R 6 is NR a R b is.

[0315] In some embodiments, R 7 independently, C 1-4 It is alkyl.

[0316] In some embodiments, R 7 is F.

[0317] In some embodiments, R 7 is CH3 or F.

[0318] In some embodiments, R a are independently hydrogen.

[0319] In some embodiments, R a independently, C 1-4 It is alkyl.

[0320] In some embodiments, R a independently, C 3-5 It is cycloalkyl.

[0321] In some embodiments, R b are independently hydrogen.

[0322] In some embodiments, R b independently, C 1-4 It is alkyl.

[0323] In some embodiments, R b independently, C 3-5 It is cycloalkyl.

[0324] In some embodiments, R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, which ring may contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and may optionally be substituted with one to three identical or different groups selected from the group consisting of F, C alkyl, phenyl, and benzyl.

[0325] In some embodiments, R a and R b together with the nitrogen atom to which they are attached form a saturated heterocyclic ring. In embodiments, the heterocyclic ring is unsubstituted. In embodiments, the heterocyclic ring is substituted with one, two, or three groups independently selected from the group consisting of F, C alkyl, phenyl, and benzyl. In embodiments, the heterocyclic ring does not contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In embodiments, the heterocyclic ring does not contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0326] In some embodiments, R a and R btogether with the nitrogen atom to which they are attached form an unsaturated heterocyclic ring. In embodiments, the heterocyclic ring is unsubstituted. In embodiments, the heterocyclic ring is substituted with one, two, or three groups independently selected from the group consisting of F, C alkyl, phenyl, and benzyl. In embodiments, the heterocyclic ring does not contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In embodiments, the heterocyclic ring contains one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

[0327] In some embodiments, n is 0.

[0328] In some embodiments, n is 1.

[0329] In some embodiments, n is 2.

[0330] In embodiments, m is 0, 1, or 2.

[0331] In some embodiments, R 3a is C 1-4 alkoxy (e.g., OCH), and / or R 3b is a halogen (e.g., F).

[0332] In some embodiments, R 3a is C 1-4 alkoxy (e.g., OCH3), and R 3b is a halogen (e.g., F).

[0333] In some embodiments, R 3c is H and / or R 3e is a halogen (e.g., F).

[0334] In some embodiments, R 3c is H and R 3e is a halogen (e.g., F).

[0335] In some embodiments, R3c is H and / or R 3e is H.

[0336] In some embodiments, R 3c is H and R 3e is H.

[0337] In some embodiments, R 3b is H and / or R 3e is H.

[0338] In some embodiments, R 3b is H and R 3e is H.

[0339] In some embodiments, R 3a is C 1-4 alkoxy (e.g., OCH3), and R 3b is halogen (e.g., F), and / or R 3c is H.

[0340] In some embodiments, R 3a is C 1-4 alkoxy (e.g., OCH3), and R 3b is a halogen (e.g., F), and R 3c is H.

[0341] In some embodiments, R 3a is C 1-4 alkoxy (e.g., OCH3), and R 3b is halogen (e.g., F), and / or R 3c is F.

[0342] In some embodiments, R 3a is C 1-4 alkoxy (e.g., OCH3), and R 3b is a halogen (e.g., F), and R 3c is F.

[0343] In some embodiments, R 3a is C 1-4alkoxy (e.g., OCH3), and R 3b is H and / or R 3c is H.

[0344] In some embodiments, R 3a is C 1-4 alkoxy (e.g., OCH3), and R 3b is H and R 3c is H.

[0345] In some embodiments, R 3b is H and R 3c is H and / or R 3e is H.

[0346] In some embodiments, R 3b is H and R 3c is H and R 3e is H.

[0347] In some embodiments, R 3a is C 1-4 alkoxy (e.g., OCH3), and R 3b is a halogen (e.g., F), and R 3c is H and R 3d is C 1-4 alkyl (e.g., methyl or isopropyl), and optionally 1 to 4 R 6 and / or R 3e is H.

[0348] In some embodiments, R 3a is C 1-4 alkoxy (e.g., OCH3), and R 3b is a halogen (e.g., F), and R 3c is H and R 3d is C 1-4 alkyl (e.g., methyl or isopropyl), and optionally 1 to 4 R 6 is substituted with R 3e is H.

[0349] In some embodiments, R3a is C 1-4 alkoxy (e.g., OCH3), and R 3b is a halogen (e.g., F), and R 3c is F and R 3d is C 1-4 alkyl (e.g., methyl or isopropyl), and optionally 1 to 4 R 6 and / or R 3e is H.

[0350] In some embodiments, R 3a is C 1-4 alkoxy (e.g., OCH3), and R 3b is a halogen (e.g., F), and R 3c is F and R 3d is C 1-4 alkyl (e.g., methyl or isopropyl), and optionally 1 to 4 R 6 is substituted with R 3e is H.

[0351] In some embodiments, R 3a is C 1-4 alkoxy (e.g., OCH3), and R 3b is a halogen (e.g., F), and R 3c is H and R 3d is C 1-4 alkyl (e.g., methyl or isopropyl), and optionally 1 to 4 R 6 and / or R 3e is F.

[0352] In some embodiments, R 3a is C 1-4 alkoxy (e.g., OCH3), and R 3b is a halogen (e.g., F), and R 3c is H and R 3d is C 1-4 alkyl (e.g., methyl or isopropyl), and optionally 1 to 4 R 6 is substituted with R 3e is F.

[0353] Exemplary Compounds Exemplary compounds include those set forth in Table 1 herein, and pharmaceutically acceptable salts thereof.

[0354] In embodiments, the compounds may be used as a mixture of stereoisomers (e.g., a mixture of diastereomers or a mixture of enantiomers). In embodiments, stereochemically enriched compositions comprising the compounds described herein (e.g., a composition of the compound is substantially free of any other stereoisomer of the compound).

[0355] Where the absolute stereochemistry of a stereocenter is not indicated, it is understood that compound embodiments encompass the (R) and (S) configurations in the alternative. Similarly, such compounds may be used in the methods described herein as compositions comprising stereochemical mixtures or as stereochemically enriched compositions (e.g., compositions of the compound that are substantially free of any other stereoisomers of the compound).

[0356] In embodiments, the compound is [ka] (Compound 1A / 1B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 1A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 1B or a pharmaceutically acceptable salt thereof.

[0357] In embodiments, the compound is [ka] (Compound 2A / 2B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 2A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 2B or a pharmaceutically acceptable salt thereof.

[0358] In embodiments, the compound is [ka] (Compound 3A / 3B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 3A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 3B or a pharmaceutically acceptable salt thereof.

[0359] In embodiments, the compound is [ka] (Compound 4A / 4B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 4A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 4B or a pharmaceutically acceptable salt thereof.

[0360] In embodiments, the compound is [ka] (Compound 5A / 5B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 5A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 5B or a pharmaceutically acceptable salt thereof.

[0361] In embodiments, the compound is [ka] (Compound 6A / 6B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 6A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 6B or a pharmaceutically acceptable salt thereof.

[0362] In embodiments, the compound is [ka] (Compound 7A / 7B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 7A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 7B or a pharmaceutically acceptable salt thereof.

[0363] In embodiments, the compound is [ka] (Compound 8A / 8B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 8A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 8B or a pharmaceutically acceptable salt thereof.

[0364] In embodiments, the compound is [ka] (Compound 9A / 9B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 9A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 9B or a pharmaceutically acceptable salt thereof.

[0365] In embodiments, the compound is [ka] (Compound 10A / 10B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 10A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 10B or a pharmaceutically acceptable salt thereof.

[0366] In embodiments, the compound is [ka] (Compound 11A / 11B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 11A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 11B or a pharmaceutically acceptable salt thereof.

[0367] In embodiments, the compound is [ka] (Compound 12A / 12B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 12A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 12B or a pharmaceutically acceptable salt thereof.

[0368] In embodiments, the compound is [ka] (Compound 13A / 13B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 13A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 13B or a pharmaceutically acceptable salt thereof.

[0369] In embodiments, the compound is [ka] (Compound 14A / 14B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 14A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 14B or a pharmaceutically acceptable salt thereof.

[0370] In embodiments, the compound is [ka] (Compound 15A / 15B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 15A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 15B or a pharmaceutically acceptable salt thereof.

[0371] In embodiments, the compound is [ka] (Compound 16A / 16B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 16AB or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 16B or a pharmaceutically acceptable salt thereof.

[0372] In embodiments, the compound is [ka] (Compound 17A / 17B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 17A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 17B or a pharmaceutically acceptable salt thereof.

[0373] In embodiments, the compound is [ka] (Compound 18A / 18B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 18A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 18B or a pharmaceutically acceptable salt thereof.

[0374] In embodiments, the compound is [ka] (Compound 19A / 19B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 19A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 19B or a pharmaceutically acceptable salt thereof.

[0375] In embodiments, the compound is [ka] (Compound 19C / 19D) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 19C or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 19D or a pharmaceutically acceptable salt thereof.

[0376] In embodiments, the compound is [ka] (Compound 20A / 20B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 20D or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 20B or a pharmaceutically acceptable salt thereof.

[0377] In embodiments, the compound is [ka] (Compound 21A / 21B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 21A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 21B or a pharmaceutically acceptable salt thereof.

[0378] In embodiments, the compound is [ka] (Compound 22A / 22B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 22A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 22B or a pharmaceutically acceptable salt thereof.

[0379] In embodiments, the compound is [ka] (Compound 23A / 23B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 23A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 23B or a pharmaceutically acceptable salt thereof.

[0380] In embodiments, the compound is [ka] (Compound 24A / 24B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 24A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 24B or a pharmaceutically acceptable salt thereof.

[0381] In embodiments, the compound is [ka] (Compound 25A / 25B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 25A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 25B or a pharmaceutically acceptable salt thereof.

[0382] In embodiments, the compound is [ka] (Compound 26A / 26B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 26A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 26B or a pharmaceutically acceptable salt thereof.

[0383] In embodiments, the compound is [ka] (Compound 27A / 27B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 27A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 27B or a pharmaceutically acceptable salt thereof.

[0384] In embodiments, the compound is [ka] (Compound 28A / 28B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 28A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 28B or a pharmaceutically acceptable salt thereof.

[0385] In embodiments, the compound is [ka] (Compound 29A / 29B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 29A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 29B or a pharmaceutically acceptable salt thereof.

[0386] In embodiments, the compound is [ka] (Compound 30A / 30B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 30A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 30B or a pharmaceutically acceptable salt thereof.

[0387] In embodiments, the compound is [ka] (Compound 31A / 31B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 31A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 31B or a pharmaceutically acceptable salt thereof.

[0388] In embodiments, the compound is [ka] (Compound 32A / 32B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 32A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 32B or a pharmaceutically acceptable salt thereof.

[0389] In embodiments, the compound is [ka] (Compound 33A / 33B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 33A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 33B or a pharmaceutically acceptable salt thereof.

[0390] In embodiments, the compound is [ka] (Compound 34A / 34B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 34A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 34B or a pharmaceutically acceptable salt thereof.

[0391] In embodiments, the compound is [ka] (Compound 35A / 35B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 35A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 35B or a pharmaceutically acceptable salt thereof.

[0392] In embodiments, the compound is [ka] (Compound 36A / 36B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 36A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 36B or a pharmaceutically acceptable salt thereof.

[0393] In embodiments, the compound is [ka] (Compound 37A / 37B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 37A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 37B or a pharmaceutically acceptable salt thereof.

[0394] In embodiments, the compound is [ka] (Compound 38A / 38B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 38A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 38B or a pharmaceutically acceptable salt thereof.

[0395] In embodiments, the compound is [ka] (Compound 39A / 39B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 39A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 39B or a pharmaceutically acceptable salt thereof.

[0396] In embodiments, the compound is [ka] (Compound 40A / 40B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 40A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 40B or a pharmaceutically acceptable salt thereof.

[0397] In embodiments, the compound is [ka] (Compound 41A / 41B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 41A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 41B or a pharmaceutically acceptable salt thereof.

[0398] In embodiments, the compound is [ka] (Compound 42A / 42B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 42A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 42B or a pharmaceutically acceptable salt thereof.

[0399] In embodiments, the compound is [ka] (Compound 43A / 43B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 43A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 43B or a pharmaceutically acceptable salt thereof.

[0400] In embodiments, the compound is [ka] (Compound 44A / 44B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 44A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 44B or a pharmaceutically acceptable salt thereof.

[0401] In embodiments, the compound is [ka] (Compound 45A / 45B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 45A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 45B or a pharmaceutically acceptable salt thereof.

[0402] In embodiments, the compound is [ka] (Compound 46A / 46B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 46A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 46B or a pharmaceutically acceptable salt thereof.

[0403] In embodiments, the compound is [ka] (Compound 47A / 47B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 47A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 47B or a pharmaceutically acceptable salt thereof.

[0404] In embodiments, the compound is [ka] (Compound 48A / 48B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 48A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 48B or a pharmaceutically acceptable salt thereof.

[0405] In embodiments, the compound is [ka] (Compound 49A / 49B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 49A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 49B or a pharmaceutically acceptable salt thereof.

[0406] In embodiments, the compound is [ka] (Compound 50A / 50B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 50A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 50B or a pharmaceutically acceptable salt thereof.

[0407] In embodiments, the compound is [ka] (Compound 51A / 51B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 51A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 51B or a pharmaceutically acceptable salt thereof.

[0408] In embodiments, the compound is [ka] (Compound 52A / 52B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 52A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 50B or a pharmaceutically acceptable salt thereof.

[0409] In embodiments, the compound is [ka] (Compound 53A / 53B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 53A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 53B or a pharmaceutically acceptable salt thereof.

[0410] In embodiments, the compound is [ka] (Compound 54A / 54B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 54A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 54B or a pharmaceutically acceptable salt thereof.

[0411] In embodiments, the compound is [ka] (Compound 100A / 100B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 100A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 100B or a pharmaceutically acceptable salt thereof.

[0412] In embodiments, the compound is [ka] (Compound 101A / 101B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 101A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 101B or a pharmaceutically acceptable salt thereof.

[0413] In embodiments, the compound is [ka] (Compound 102A / 102B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 102A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 102B or a pharmaceutically acceptable salt thereof.

[0414] In embodiments, the compound is [ka] (Compound 103A / 103B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 103A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 103B or a pharmaceutically acceptable salt thereof.

[0415] In embodiments, the compound is [ka] (Compound 104A / 104B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 104A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 104B or a pharmaceutically acceptable salt thereof.

[0416] In embodiments, the compound is [ka] (Compound 105A / 105B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 105A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 105B or a pharmaceutically acceptable salt thereof.

[0417] In embodiments, the compound is [ka] (Compound 106A / 106B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 106A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 106B or a pharmaceutically acceptable salt thereof.

[0418] In embodiments, the compound is [ka] (Compound 107A / 107B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 107A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 107B or a pharmaceutically acceptable salt thereof.

[0419] In embodiments, the compound is [ka] (Compound 108A / 108B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 108A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 108B or a pharmaceutically acceptable salt thereof.

[0420] In embodiments, the compound is [ka] (Compound 109A / 109B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 109A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 109B or a pharmaceutically acceptable salt thereof.

[0421] In embodiments, the compound is [ka] (Compound 110A / 110B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 110A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 110B or a pharmaceutically acceptable salt thereof.

[0422] In embodiments, the compound is [ka] (Compound 111A / 111B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 111A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 111B or a pharmaceutically acceptable salt thereof.

[0423] In embodiments, the compound is [ka] (Compound 112A / 112B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 112A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 112B or a pharmaceutically acceptable salt thereof.

[0424] In embodiments, the compound is [ka] (Compound 113A / 113B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 113A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 113B or a pharmaceutically acceptable salt thereof.

[0425] In embodiments, the compound is [ka] (Compound 114A / 114B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 114A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 114B or a pharmaceutically acceptable salt thereof.

[0426] In embodiments, the compound is [ka] (Compound 115A / 115B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 115A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 115B or a pharmaceutically acceptable salt thereof.

[0427] In embodiments, the compound is [ka] (Compound 116A / 116B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 116A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 116B or a pharmaceutically acceptable salt thereof.

[0428] In embodiments, the compound is [ka] (Compounds 117A / 117B / 117C / 117D) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 117A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 117B or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 117C or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 117D or a pharmaceutically acceptable salt thereof.

[0429] In embodiments, the compound is [ka] (Compounds 118A / 118B / 118C / 118D) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 118A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 118B or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 118C or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 118D or a pharmaceutically acceptable salt thereof.

[0430] In embodiments, the compound is [ka] (Compound 119A / 119B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 119A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 119B or a pharmaceutically acceptable salt thereof.

[0431] In embodiments, the compound is [ka] (Compounds 120A / 120B / 120C / 120D) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 120A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 120B or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 120C or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 120D or a pharmaceutically acceptable salt thereof.

[0432] In embodiments, the compound is [ka] (Compound 121A / 121B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 121A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 121B or a pharmaceutically acceptable salt thereof.

[0433] In embodiments, the compound is [ka] (Compound 122A / 122B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 122A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 122B or a pharmaceutically acceptable salt thereof.

[0434] In embodiments, the compound is [ka] (Compound 123A / 123B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 123A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 123B or a pharmaceutically acceptable salt thereof.

[0435] In embodiments, the compound is [ka] (Compound 124A / 124B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 124A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 124B or a pharmaceutically acceptable salt thereof.

[0436] In embodiments, the compound is [ka] (Compound 125A / 125B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 125A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 125B or a pharmaceutically acceptable salt thereof.

[0437] In embodiments, the compound is [ka] (Compound 126A / 126B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 126A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 126B or a pharmaceutically acceptable salt thereof.

[0438] In embodiments, the compound is [ka] (Compound 127A / 127B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 127A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 127B or a pharmaceutically acceptable salt thereof.

[0439] In embodiments, the compound is [ka] (Compound 128A / 128B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 128A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 128B or a pharmaceutically acceptable salt thereof.

[0440] In embodiments, the compound is [ka] (Compound 129A / 129B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 129A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 129B or a pharmaceutically acceptable salt thereof.

[0441] In embodiments, the compound is [ka] (Compound 130A / 130B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 130A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 130B or a pharmaceutically acceptable salt thereof.

[0442] In embodiments, the compound is [ka] (Compound 131A / 131B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 131A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 131B or a pharmaceutically acceptable salt thereof.

[0443] In embodiments, the compound is [ka] (Compound 132A / 132B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 132A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 132B or a pharmaceutically acceptable salt thereof.

[0444] In embodiments, the compound is [ka] (Compound 133A / 133B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 133A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 133B or a pharmaceutically acceptable salt thereof.

[0445] In embodiments, the compound is [ka] (Compound 134A / 134B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 134A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 134B or a pharmaceutically acceptable salt thereof.

[0446] In embodiments, the compound is [ka] (Compound 135A / 135B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 135A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 135B or a pharmaceutically acceptable salt thereof.

[0447] In embodiments, the compound is [ka] (Compound 136A / 136B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 136A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 136B or a pharmaceutically acceptable salt thereof.

[0448] In embodiments, the compound is [ka] (Compound 137A / 137B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 137A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 137B or a pharmaceutically acceptable salt thereof.

[0449] In embodiments, the compound is [ka] (Compound 138A / 138B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 138A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 138B or a pharmaceutically acceptable salt thereof.

[0450] In embodiments, the compound is [ka] (Compound 139A / 139B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 139A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 139B or a pharmaceutically acceptable salt thereof.

[0451] In embodiments, the compound is [ka] (Compound 140A / 140B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 140A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 140B or a pharmaceutically acceptable salt thereof.

[0452] In embodiments, the compound is [ka] (Compounds 141A / 141B / 141C / 141D) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 141A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 141B or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 141C or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 141D or a pharmaceutically acceptable salt thereof.

[0453] In embodiments, the compound is [ka] (Compound 142A / 142B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 142A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 142B or a pharmaceutically acceptable salt thereof.

[0454] In embodiments, the compound is [ka] (Compound 143A / 143B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 143A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 143B or a pharmaceutically acceptable salt thereof.

[0455] In embodiments, the compound is [ka] (Compound 144A / 144B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 144A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 144B or a pharmaceutically acceptable salt thereof.

[0456] In embodiments, the compound is [ka] (Compound 145A / 145B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 145A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 145B or a pharmaceutically acceptable salt thereof.

[0457] In embodiments, the compound is [ka] (Compound 146A / 146B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 146A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 146B or a pharmaceutically acceptable salt thereof.

[0458] In embodiments, the compound is [ka] (Compound 147A / 147B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 147A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 147B or a pharmaceutically acceptable salt thereof.

[0459] In embodiments, the compound is [ka] (Compound 148A / 148B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 148A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 148B or a pharmaceutically acceptable salt thereof.

[0460] In embodiments, the compound is [ka] (Compound 149A / 149B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 149A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 149B or a pharmaceutically acceptable salt thereof.

[0461] In embodiments, the compound is [ka] (Compound 150A / 150B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 150A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 150B or a pharmaceutically acceptable salt thereof.

[0462] In embodiments, the compound is [ka] (Compound 151A / 151B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 151A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 151B or a pharmaceutically acceptable salt thereof.

[0463] In embodiments, the compound is [ka] (Compound 152A / 152B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 152A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 152B or a pharmaceutically acceptable salt thereof.

[0464] In embodiments, the compound is [ka] (Compound 153A / 153B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 153A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 153B or a pharmaceutically acceptable salt thereof.

[0465] In embodiments, the compound is [ka] (Compound 154A / 154B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 154A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 154B or a pharmaceutically acceptable salt thereof.

[0466] In embodiments, the compound is [ka] (Compound 155A / 155B) or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 155A or a pharmaceutically acceptable salt thereof. In embodiments, the compound is Compound 155B or a pharmaceutically acceptable salt thereof.

[0467] Deuterium compounds The compounds described herein may contain atoms exhibiting natural isotopic abundance, or one or more of its atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from that predominantly found in nature. The term "isotopologue" refers to a species having the same chemical structure and formula as a specific compound provided herein except for the position of isotopic substitution and / or level of isotopic enrichment at one or more positions, e.g., hydrogen versus deuterium. The present invention is meant to include all suitable isotopic variations of the compounds described herein. For example, different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H), and tritium ( 3 H), as well as compositions enriched for isotopologues of any of the compounds described herein.

[0468] In some embodiments, one or more of the hydrogens of the compounds described herein are replaced with deuterium. When a position is designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. 2 When a position is designated as "H" or "deuterium," the position must be at least 3340 times the natural abundance of deuterium (0.015%) (i.e., "2 H The term "deuterium" or "deuterium" is understood to mean having deuterium (indicating a deuterium incorporation rate of at least 50.1%). Accordingly, the present invention also features compositions enriched in deuterium compounds.

[0469] In embodiments, compositions of any compound described herein may have an isotopic enrichment factor for each deuterium present at a site designated as a deuteration site in the compound of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0470] Exemplary Pharmaceutical Compositions The compounds described herein (e.g., compounds of any one of Formulas (I)-(VII)) or pharmaceutically acceptable salts thereof can be formulated into various 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), as well as pharmaceutically acceptable salts thereof, can be the active ingredient (API) that is combined with one or more other ingredients to form a drug substance (DS) pharmaceutical composition. A drug substance (DS) pharmaceutical composition can include the 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(s), diluent(s), or excipient(s) must be compatible with the other ingredients of the formulation and be suitable, safe, and effective for the intended treatment. The active pharmaceutical ingredient (API) may be selected to be effective. A compound (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof, as described herein, at a desired weight concentration, can be combined with other inactive ingredients to form a drug substance (DS) in a formulation batch. The pharmaceutically acceptable composition can be formulated for administration by an appropriate route, for example, oral delivery in a unit dosage form (including capsules or tablets). Such compositions can be prepared by bringing the active pharmaceutical ingredient (API), including a compound of Formula (I), into association with the carrier(s) or excipient(s).

[0471] In certain embodiments, the present invention provides a pharmaceutical composition formulated for oral delivery of an α4β7 integrin inhibitor, comprising administering 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) as an API formulated for oral therapeutic administration of the α4β7 integrin inhibitor compound and a pharmaceutically acceptable carrier.

[0472] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as the active pharmaceutical ingredient (API).

[0473] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (II), or a pharmaceutically acceptable salt thereof, as an active pharmaceutical ingredient (API).

[0474] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (IIA), or a pharmaceutically acceptable salt thereof, as the active pharmaceutical ingredient (API).

[0475] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (III), or a pharmaceutically acceptable salt thereof, as the active pharmaceutical ingredient (API).

[0476] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (IIIA), or a pharmaceutically acceptable salt thereof, as the active pharmaceutical ingredient (API).

[0477] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (IV), or a pharmaceutically acceptable salt thereof, as the active pharmaceutical ingredient (API).

[0478] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (IVA), or a pharmaceutically acceptable salt thereof, as the active pharmaceutical ingredient (API).

[0479] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (V), or a pharmaceutically acceptable salt thereof, as the active pharmaceutical ingredient (API).

[0480] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (VA), or a pharmaceutically acceptable salt thereof, as the active pharmaceutical ingredient (API).

[0481] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (VI), or a pharmaceutically acceptable salt thereof, as an active pharmaceutical ingredient (API).

[0482] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (VIA), or a pharmaceutically acceptable salt thereof, as the active pharmaceutical ingredient (API).

[0483] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (VII), or a pharmaceutically acceptable salt thereof, as an active pharmaceutical ingredient (API).

[0484] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt thereof, as the active pharmaceutical ingredient (API).

[0485] Pharmaceutically acceptable compositions comprising a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof can be prepared by a variety of procedures. For example, a compound of Formula (I) can be formulated with a suitable excipient, diluent, or carrier, and formed into tablets, or capsules, and other suitable dosage forms.

[0486] Pharmaceutical compositions may be provided in unit dosage forms, containing a predetermined amount of API per unit dose, including a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof. Such units may contain a desired amount of a compound (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof, depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient. As such, such unit doses may be administered at desired administration intervals. The concentration of the active compound in a drug composition depends on various applicable parameters and considerations, such as absorption, inactivation, and excretion rates of the drug, as well as other factors known to those skilled in the art. It should be noted that dosage values ​​also vary depending on the severity of the condition being alleviated. Furthermore, it should be understood that for any particular subject, specific dosage regimens must be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions. The active ingredient can be administered at once or divided into several smaller doses to be administered at varying time intervals.

[0487] In certain embodiments, the mode of administration of the active compound is oral. Oral compositions generally contain an inert diluent or edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be mixed with an excipient and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binders and / or adjuvants can be included as part of the composition. Pharmaceutical compositions containing a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof formulated for oral delivery can be prepared in a unit dosage form, such as a capsule, at the desired dosage strength (e.g., the dosage strength of the compound of Formula (I) or a pharmaceutically acceptable salt thereof). For oral administration in liquid form, the oral drug component can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, or water. For oral administration in tablet or capsule form, the compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof can be combined with an oral, 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 sugars; binders such as cellulose derivatives. Furthermore, if desired or necessary, suitable binders, lubricants, disintegrants, and colorants can also be incorporated into the mixture. Suitable binders include starch, natural sugars, natural and synthetic gums, etc. Lubricants and / or flow agents can be used in these dosage forms.

[0488] Tablets, pills, capsules, troches, and the like may contain any of the following ingredients, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; fillers such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor. When the dosage unit is a capsule, in addition to the above types of materials, it may contain a liquid carrier such as a fatty oil. Furthermore, dosage unit forms may contain various other materials that modify the physical form of the dosage unit, such as sugar or other enteric coatings.

[0489] The compounds can be administered as a component of an elixir, suspension, syrup, wafer, etc. A syrup can contain, in addition to the active compound(s), sucrose or other sweetening agents and certain preservatives, dyes and colorings and flavors.

[0490] The compound can be formulated as a solution suitable for parenteral administration, for example, by intramuscular, subcutaneous or intravenous route.For example, the compound described herein (e.g., the compound of formula (I)) or its pharmaceutically acceptable salt can be dissolved in a suitable buffer solution.The pharmaceutical composition containing the compound described herein (e.g., the compound of formula (I)) or its pharmaceutically acceptable salt at a desired concentration can be formulated as an injectable pharmaceutical solution, which is useful (e.g., in preclinical animal studies).

[0491] Exemplary Treatment Methods The compounds described herein inhibit integrin α v β 8の These compounds may be useful in treating a variety of diseases and disorders that benefit from antagonism. For example, integrin α v Inhibition of β8-driven TGFβ activation has been proposed to reverse tumor tolerance and enhance anti-tumor T / NK cell responses. vb8 inhibition can enhance the outcome of checkpoint inhibitor regimens or reverse checkpoint inhibitor resistance. In embodiments, the compounds described herein can modulate anti-tumor immune responses (e.g., in checkpoint inhibitor-resistant tumors).

[0492] In some embodiments, the present invention provides a method for treating a v The invention features a method for inhibiting b8 integrin, the method comprising administering a therapeutically effective amount of a compound described herein (e.g., any one of the compounds of Formulas (I)-(VII), such as any compound in Table 1), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0493] In embodiments, the invention features a method of treating cancer in a patient, the method including administering to a patient in need thereof 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 embodiments, the method further includes administering a therapeutically effective amount of a second active agent.

[0494] solid tumors In embodiments, administration of a compound described herein (e.g., any one of the compounds of Formulas (I)-(VII), such as any compound in Table 1), or a pharmaceutically acceptable salt thereof, may be useful in treating solid tumors in a patient in need thereof, optionally in combination with one or more additional therapies (e.g., a second active agent).

[0495] In some embodiments, the solid tumor is resistant to one or more previous lines of therapy (e.g., the solid tumor is a therapy-resistant tumor). In some embodiments, the solid tumor is resistant to immune checkpoint therapy.

[0496] In embodiments, the cancer is selected from the group consisting of fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, hemangiosarcoma, lymphangiosarcoma, lymphangiosarcoma, 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, stomach cancer, oral cancer, nasal cancer, pharyngeal cancer, and squamous cell carcinoma. In some embodiments, the solid tumor is a solid tumor such as basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, 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 some embodiments, the solid tumor is an advanced solid tumor (e.g., a locally advanced solid tumor). In some embodiments, the solid tumor is a metastatic solid tumor.

[0497] In embodiments, the cancer (e.g., a solid tumor) is anal 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.

[0498] In embodiments, the cancer (e.g., a 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 cancer.

[0499] In embodiments, the cancer (e.g., a solid tumor) is advanced (e.g., locally advanced).

[0500] In embodiments, the cancer (e.g., a solid tumor) is metastatic.

[0501] In embodiments, the cancer (e.g., a solid tumor) is anal cancer.

[0502] In embodiments, the cancer (e.g., a solid tumor) is cholangiocarcinoma.

[0503] In embodiments, the cancer (e.g., a solid tumor) is bladder cancer.

[0504] In embodiments, the cancer (e.g., a solid tumor) is breast cancer.

[0505] In embodiments, the cancer (e.g., a solid tumor) is cervical cancer.

[0506] In embodiments, the cancer (e.g., a solid tumor) is colorectal cancer.

[0507] In embodiments, the cancer (e.g., a solid tumor) is endometrial cancer.

[0508] In some embodiments, the cancer (e.g., a solid tumor) is esophageal cancer. In some embodiments, the esophageal cancer is adenocarcinoma. In some embodiments, the esophageal cancer is squamous cell carcinoma.

[0509] In embodiments, the cancer (e.g., a solid tumor) is fallopian tube cancer.

[0510] In embodiments, the cancer (e.g., a solid tumor) is gastric cancer.

[0511] In embodiments, the cancer (e.g., a solid tumor) is a glioma.

[0512] In some embodiments, the cancer (e.g., a solid tumor) is liver cancer. In some embodiments, the liver cancer is hepatocellular carcinoma.

[0513] In some embodiments, the cancer (e.g., a solid tumor) is lung cancer. In some embodiments, the lung cancer is lung squamous cell carcinoma. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC).

[0514] In embodiments, the cancer (e.g., a solid tumor) is melanoma.

[0515] In embodiments, the cancer (e.g., a solid tumor) is nasopharyngeal carcinoma.

[0516] In embodiments, the cancer (e.g., a solid tumor) is neuroblastoma.

[0517] In embodiments, the cancer (e.g., a solid tumor) is osteosarcoma.

[0518] In embodiments, the cancer (e.g., a solid tumor) is ovarian cancer.

[0519] In embodiments, the cancer (e.g., a solid tumor) is pancreatic cancer.

[0520] In embodiments, the cancer (e.g., a solid tumor) is a primary peritoneal cancer.

[0521] In embodiments, the cancer (e.g., a solid tumor) is prostate cancer.

[0522] In some embodiments, the cancer (e.g., a solid tumor) is renal cell carcinoma (RCC). In some embodiments, the renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). In some embodiments, the renal cell carcinoma is papillary renal cell carcinoma (PRCC).

[0523] In some embodiments, the cancer (e.g., a solid tumor) is skin cancer. In some embodiments, the skin cancer is cutaneous squamous cell carcinoma (CSCC). In some embodiments, the skin cancer is basal cell carcinoma (BCC).

[0524] In embodiments, the cancer (e.g., a solid tumor) is squamous cell carcinoma of the head and neck (SCCHN).

[0525] In embodiments, the cancer (e.g., a solid tumor) is testicular cancer.

[0526] In embodiments, the cancer (e.g., a solid tumor) is urothelial carcinoma.

[0527] In embodiments, the cancer (e.g., a solid tumor) is uterine cancer.

[0528] In some embodiments, the patient has a therapy-resistant cancer (e.g., a solid tumor as described herein). In some embodiments, the therapy-resistant cancer (e.g., a solid tumor) is checkpoint resistant. In some embodiments, the therapy-resistant cancer (e.g., a solid tumor) is resistant to anti-PD-1 or anti-PD-L1 therapy (collectively, PD-(L)1-resistant cancers).

[0529] Exemplary Combination Therapies and Second Active Agents In embodiments, a compound described herein (e.g., any one of the compounds of Formulas (I)-(VII), such as any compound in Table 1), or a pharmaceutically acceptable salt thereof, can be used in combination therapy. In embodiments, administration of a compound described herein or a pharmaceutically acceptable salt thereof enhances the response to one or more additional therapies (e.g., a second active agent). For example, in embodiments, administration of a compound described herein or a pharmaceutically acceptable salt thereof can improve the response to an additional therapy (e.g., a second active agent).

[0530] For example, the compounds or pharmaceutically acceptable salts described herein can be administered in combination with one or more additional therapies (eg, a second active agent) in the treatment of certain diseases and disorders.

[0531] In some embodiments, the compounds or pharmaceutically acceptable salts described herein may be administered in combination with immunotherapy. In some embodiments, the immunotherapy is cancer immunotherapy. In some embodiments, the cancer immunotherapy is immune checkpoint therapy (e.g., therapy involving the administration of an immune checkpoint inhibitor). In some 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 some embodiments, the cancer immunotherapy is a cancer vaccine. In some embodiments, the cancer immunotherapy is monoclonal antibody therapy (e.g., an antibody useful in immune checkpoint therapy as described herein). In some embodiments, the cancer immunotherapy is cytokine therapy (e.g., interferon or interleukin therapy).

[0532] In embodiments, a compound or pharmaceutically acceptable salt described herein is administered to a patient in need thereof for the treatment of a solid tumor with a second active agent (e.g., as described herein).

[0533] In embodiments, the second active agent is an immune checkpoint inhibitor. In embodiments, the immune checkpoint inhibitor targets PD-1 (e.g., blockade 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., TGFR beta), B7-H1, B7-H4 (VTCN1), OX-40, CD137, CD40, IDO, or CSF-1 / CSF-1R.

[0534] In some embodiments, the checkpoint inhibitor is a small molecule, nucleic acid, polypeptide (e.g., an antibody), carbohydrate, lipid, metal, toxin, or binding agent. In some embodiments, the checkpoint inhibitor is an antibody, antibody conjugate, or antigen-binding fragment thereof.

[0535] In embodiments, the immune checkpoint inhibitor is an agent that inhibits PD-1, TIM-3, CTLA-4, LAG-3, TIGIT, IDO, or CSF-1 / CSF-1R.

[0536] In embodiments, the immune checkpoint inhibitor is selected from pembrolizumab (Keytruda®), nivolumab (Opdivo®), cemiplimab (Libtayo®), dostallimab (Jemperli®), atezolizumab (Tecentriq®), avelumab (Bavencio®), durvalumab (Imfinzi®), ipilimumab (Yervoy®), and leratolimab, and their biosimilars.

[0537] In several embodiments, the second active agent is an anti-PD-1 therapy or an anti-PD-L1 therapy (collectively referred to as anti-PD(L)-1 therapy).

[0538] In embodiments, the anti-PD(L)-1 therapy is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, dostallimab, atezolizumab, avelumab, durvalumab, PDR001, cemiplimab, BGB-A317, LY3300054, BI 754091, IBI308, INCSHR-1210, JNJ-63723283, JS-001, MEDI0680 (AMP-514), MGA-012, PF-06801591, CX-072, FAZ053, and PD-L1 millamolecules, and biosimilars thereof.

[0539] In embodiments, the anti-PD(L)-1 therapy is selected from atezolizumab, avelumab, BGB-A317, BI 754091, CX-072, durvalumab, FAZ053, IBI308, INCSHR-1210, JNJ-63723283, JS-001, MEDI-0680, MGA-012, nivolumab, PDR001, pembrolizumab, PF-06801591, cemiplimab, dostarlimab, any of the antibodies disclosed in WO2014 / 179664, and their biosimilars. In embodiments, the therapeutic agent is selected from the group consisting of BGB-A317, BI 754091, CX-072, FAZ053, IBI308, INCSHR-1210, JNJ-63723283, JS-001, LY3300054, MEDI-0680, MGA-012, nivolumab, PD-L1 millamolecule, PDR001, pembrolizumab, PF-06801591, cemiplimab, and dostarlimab, and biosimilars thereof.

[0540] In embodiments, the anti-PD(L)-1 therapy is selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, dostallimab, PDR-001, tirelizumab (BGB-A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI-754091, IBI-308, and camrelizumab. The PD-1 antibody is selected from the group consisting of genolimuzumab (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, genolimuzumab (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 embodiments, 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.

[0541] In some embodiments, the anti-PD(L)-1 therapy is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, atezolizumab, avelumab, and durvalumab. In some embodiments, the anti-PD(L)-1 therapy is selected from nivolumab, pembrolizumab, cemiplimab, and dostarlimab. In some embodiments, the anti-PD(L)-1 therapy is selected from atezolizumab, avelumab, and durvalumab.

[0542] In some embodiments, the second active agent is an anti-CTLA-4 therapy, hi some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0543] In some embodiments, the second active agent is an anti-LAG-3 therapy selected from LAG525 (IMP701), REGN3767 (R3767), BI 754,091, tebotelimab (MGD013), eftilagimod alpha (IMP321), TSR-033, and FS118.

[0544] In some embodiments, the second active agent is an anti-TIM-3 therapy, hi some embodiments, the anti-TIM-3 therapy is selected from MBG453, Sym023, and TSR-022.

[0545] In some embodiments, the second active agent is an anti-CSF-1 / R therapy, hi some embodiments, the anti-CSF-1 / R therapy is selected from lacnotuzumab (MCS110), LY3022855, SNDX-6352, emactuzumab (RG7155), and pexidartinib (PLX3397).

[0546] In some embodiments, the second active agent is an anti-TIGIT therapy. In some embodiments, the anti-TIGIT therapy is selected from BMS-986207, osipellimab, tiragolumab, vibostolimab, domvanalimab, EOS448, COM902, and AGEN307. In some embodiments, the second active agent is an anti-CEACAM therapy. In some embodiments, the anti-TIGIT therapy is selected from CM24 and NEO-201.

[0547] In some embodiments, the compounds or uses of the present invention may be selected from one or more of the recited embodiments provided below. 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony: The Q ring is [ka] and; L is [ka] and each of these is 1 to 6 R 4 optionally substituted with; X is -CHR 1c -, -O-, or -NR 2 - and; R 1a , R 1b , R 1c , R 1d , R 1e , and R 1f each independently represents H, 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 Alkoxy, CF3, CHF2, CH2F, CN, NO2, NR a R b or C 1-4 Alkyl-NR a R b and Each R 2 are independently H, C 1-4 Alkyl, or C 3-5 is cycloalkyl; R 3a is C 1-4 Alkoxy, C 3-5 cycloalkoxy, CF3, CHF2, CH2F, OCF3, OCHF2 or OCH2F; R 3b is H, halogen, CF3 or CN; R 3c is H, F, CN, or C 1-4 is alkyl; R 3d is C 1-4 Alkyl, C 3-5 cycloalkyl, or 4- to 6-membered heterocycloalkyl, each of which is selected from 1 to 4 R 6 is optionally replaced by; R 3e is H or F; Each R 4 are independently H, C 1-4 alkyl, halogen, CF3, CHF2, or CH2F, cyclopropyl, or two geminal R 4 The groups together can form a spiro-cyclopropyl; Each R 6 independently, 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 membered heteroaryl or NR a R b and; Each R 7 independently, C 1-4 is alkyl or F; R a and R b each independently represents hydrogen, C 1-4 Alkyl, C 3-5 cycloalkyl or R a and R b together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and which may optionally be substituted with one to three identical or different groups selected from the group consisting of F, C1-4 alkyl, phenyl, and benzyl; n is 1 or 2; m is 0, 1, or 2. 2. Q-ring is [ka] 2. The compound of embodiment 1, wherein 3. The compound of embodiment 1 or 2, wherein X is -O-. 4.X is -NR 23. The compound of embodiment 1 or 2, wherein 5.R 2 is methyl. 6. Q ring is [ka] 2. The compound of embodiment 1, wherein 7.R 1d and R 1e The compound of any one of embodiments 1-6, wherein each of is independently H. 8.Each R1c The compound of embodiments 6-7, wherein is independently H. 9.Each R 1a The compound of any one of embodiments 1-8, wherein is independently H. 10.Each R 1b The compound of any one of embodiments 1-9, wherein is independently H. 11.Each R 1b The compound of any one of embodiments 1-9, wherein is independently OMe. 12.Q ring is [ka] 2. The compound of embodiment 1, wherein 13.R 1c and R 1d and n is 0 or 1. The compound of embodiment 12, wherein each of 14.R 1b , R 1b , and R 1f 14. The compound of embodiment 1 or 12-13, wherein each of is independently H. 15.L is, [ka] 15. The compound of any one of embodiments 1-14, wherein 16.L is, [ka] 15. The compound of any one of embodiments 1-14, wherein 17.R 3a C 1-4 The compound of any one of embodiments 1-16, which is alkoxy. 18.R 3a The compound of any one of embodiments 1-16, wherein is OMe, OEt, OCF3, OCHF2, or OCH2F. 19.R 3a The compound of any one of embodiments 1-16, wherein is OMe. 20.R 3b The compound of any one of embodiments 1-19, wherein is F. 21.R 3c The compound of any one of embodiments 1-20, wherein is H. 22.R 3d C 1-4 The compound of any one of embodiments 1-21, wherein is alkyl. 23.R 3d C 3-5 The compound of any one of embodiments 1-21, which is cycloalkyl. 24.R 3d is oxetanyl, tetrahydrofuranyl, or tetrahydro-2H-pyranyl, morpholinyl, or piperazinyl-C 1-4 The compound of any one of embodiments 1-21, wherein is alkyl. 25.R 3d The compound of any one of embodiments 1-21, wherein is isopropyl. 26.R 3e The compound of any one of embodiments 1-25, wherein is H. 27.Each R 4 27. The composition of any one of embodiments 1-26, wherein is independently methyl. 28.Each R 4 is independently F. 29.Each R 4 is independently CF3, CHF2, or CH2F. 30.Each R 4 27. The composition of any one of embodiments 1-26, wherein 31.Each R 6 independently, C 1-4 The composition of any one of embodiments 1-30, wherein the alkyl is alkyl. 32.Each R 6 independently, C 1-4 The composition of any one of embodiments 1-30, wherein the alkyl group is alkenyl. 33.Each R 6 independently, C 3-5 The composition of any one of embodiments 1-30, wherein is cycloalkyl. 34.Each R 6 independently, C 1-4 The composition of any one of embodiments 1-30, wherein the alkoxy group is alkoxy. 35.Each R 6 independently, C 3-5 The composition of any one of embodiments 1-30, which is cycloalkoxy. 36.Each R 6 is independently F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, or OH. 37.Each R 6 The composition of any one of embodiments 1-30, wherein is independently a 5-6 membered heteroaryl. 38.Each R 6 is independently H. 39. The composition of any one of embodiments 1 to 38, wherein n is 0. 40. The composition of any one of embodiments 1 to 38, wherein n is 1. 41. The composition of any one of embodiments 1 to 38, wherein n is 2. 42. The composition of any one of embodiments 1 to 41, wherein m is 0. 43. The compound of embodiment 1, having a structure according to formula (II): [ka] or a pharmaceutically acceptable salt thereof. 44. The compound of embodiment 43, having a structure according to formula (IIA): [ka] or a pharmaceutically acceptable salt thereof. 45. The compound of embodiment 1, having a structure according to formula (III): [ka] or a pharmaceutically acceptable salt thereof. 46. ​​The compound of embodiment 45, having a structure according to formula (IIIA): [ka] or a pharmaceutically acceptable salt thereof. 47. The compound of embodiment 1, having a structure according to formula (IV): [ka] or a pharmaceutically acceptable salt thereof. 48. The compound of embodiment 47, having a structure according to formula (IVA): [ka] or a pharmaceutically acceptable salt thereof. 49. The compound of embodiment 1, having a structure according to formula (V): [ka] or a pharmaceutically acceptable salt thereof. 50. The compound of embodiment 49, having a structure according to formula (VA): [ka] or a pharmaceutically acceptable salt thereof. 51. The compound of embodiment 1, having a structure according to formula (VI): [ka] or a pharmaceutically acceptable salt thereof. 52. The compound of embodiment 51, having a structure according to formula (VIA): [ka] or a pharmaceutically acceptable salt thereof. 53. The compound according to any one of embodiments 49-52, wherein n is 1. 54. The compound of any one of embodiments 49 to 52, wherein n is 2. 55.R 1b The compound of any one of embodiments 43-54, wherein is H, CH3, or OCH3. 56.R 3e The compound of any one of embodiments 43-55, wherein is H or F. 57.R 3d optionally, one R 6 C replaced by 1-4 The compound of any one of embodiments 43-56, wherein is alkyl. 58.R 3d but, [ka] 58. The compound of embodiment 57, wherein 59.R 3d , but optionally one R 6 The compound of any one of embodiments 43-56, wherein R is 4-6 membered heterocycloalkyl substituted with R. 60.R 3d but, [ka] 60. The compound of embodiment 59, wherein 61.R 3d , but optionally one R 6 C replaced by3-5 The compound of any one of embodiments 43-56, which is cycloalkyl. 62.R 3d but, [ka] 62. The compound of embodiment 61, wherein 63. The compound according to any one of embodiments 43-62, wherein the carbon marked by an asterisk (*) has the (R) configuration. 64. The compound according to any one of embodiments 43-62, wherein the carbon marked by an asterisk (*) has the (S) configuration. 65. The compound according to embodiment 1, selected from any compound set forth in Table 1, or a pharmaceutically acceptable salt thereof. 66. The compound of embodiment 1, selected from: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof. 67. The compound according to embodiment 66, wherein the compound is [ka] (Compound 1A / 1B), or a pharmaceutically acceptable salt thereof. 68. The compound according to embodiment 66, wherein the compound is [ka] (Compound 2A / 2B), or a pharmaceutically acceptable salt thereof. 69. The compound according to embodiment 66, wherein the compound is [ka] (Compounds 7A / 7B), or a pharmaceutically acceptable salt thereof. 70. The compound according to embodiment 66, wherein the compound is [ka] (Compounds 11A / 11B), or a pharmaceutically acceptable salt thereof. 71. The compound according to embodiment 66, wherein the compound is [ka] (Compounds 12A / 12B), or a pharmaceutically acceptable salt thereof. 72. The compound according to embodiment 66, wherein the compound is [ka] (Compounds 17A / 17B), or a pharmaceutically acceptable salt thereof. 73. The compound according to embodiment 66, wherein the compound is [ka] (Compounds 20A / 20B), or a pharmaceutically acceptable salt thereof. 74. The compound according to embodiment 66, wherein the compound is [ka] (Compound 24A / B), or a pharmaceutically acceptable salt thereof. 75. The compound according to embodiment 66, wherein the compound is [ka] (Compounds 28A / 28B), or a pharmaceutically acceptable salt thereof. 76. The compound according to embodiment 66, wherein the compound is [ka] (Compounds 35A / 35B), or a pharmaceutically acceptable salt thereof. 77. The compound according to embodiment 66, wherein the compound is [ka] (Compounds 36A / 36B), or a pharmaceutically acceptable salt thereof. 78. The compound according to embodiment 66, wherein the compound is [ka] (Compounds 41A / 41B), or a pharmaceutically acceptable salt thereof. 79. The compound according to embodiment 66, wherein the compound is [ka] (Compounds 42A / 42B), or a pharmaceutically acceptable salt thereof. 80. The compound according to embodiment 66, wherein the compound is [ka] (Compounds 47A / 47B), or a pharmaceutically acceptable salt thereof. 81. The compound according to embodiment 66, wherein the compound is [ka] (Compounds 123A / 123B), or a pharmaceutically acceptable salt thereof. 82. The compound according to embodiment 66, wherein the compound is [ka] (Compounds 125A / 125B), or a pharmaceutically acceptable salt thereof. 83. The compound according to embodiment 66, wherein the compound is [ka] (Compounds 129A / 129B), or a pharmaceutically acceptable salt thereof. 84. The compound according to embodiment 66, wherein the compound is [ka] (Compounds 135A / 136B), or a pharmaceutically acceptable salt thereof. 85. The compound according to embodiment 66, wherein the compound is [ka] (Compounds 136A / 136B), or a pharmaceutically acceptable salt thereof. 86. The compound according to embodiment 66, wherein the compound is [ka] (Compounds 150A / 150B), or a pharmaceutically acceptable salt thereof. 87. The compound according to embodiment 66, wherein the compound is [ka] (Compounds 154A / 154B), or a pharmaceutically acceptable salt thereof. 88. A pharmaceutical composition comprising a compound according to any one of embodiments 1-87, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 89. Alpha in patients v A method for inhibiting β8 integrin, the method comprising administering a therapeutically effective amount of a compound of any one of embodiments 1-87, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. 90. The method according to embodiment 89, wherein the method is for treating a solid tumor in a patient in need thereof. 91. A method of treating a solid tumor in a patient, the method comprising administering to a patient in need thereof: (a) a therapeutically effective amount of a compound of any one of embodiments 1-87, or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a second active agent. 92. The method of embodiment 91, wherein the solid tumor is selected from the following: 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. 93. The method of embodiment 92, wherein the solid tumor is selected from the following: 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. 94. The method of any one of embodiments 91-93, wherein the second active agent is an immune checkpoint inhibitor. 95. The method of embodiment 94, wherein the immune checkpoint inhibitor is an anti-PD-1 or anti-PD-L1 therapy. 96. The method of embodiment 95, wherein the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostallimab, atezolizumab, avelumab, and durvalumab. [Example]

[0548] General Scheme General Scheme 1: [ka] In the formula, Q, L, R 7 , m, R 3e , R 3d , R 3c , R 3b , R 3a is defined as described in formula (I), and B(OR)2 is a boronic acid or boronic ester.

[0549] A general method for preparing compounds of formula (I) is outlined in General Scheme 1. Treatment of 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 sieves in a solvent (i.e., DCM / hexafluoroisopropanol) at elevated temperature (i.e., 60 °C) provides diastereomeric compounds of formula (I), which can be separated by supercritical fluid chromatography (SFC) or preparative HPLC. General Scheme 2: [ka] In the formula, Q, L, R 7 , m, R 3e , R 3d , R 3c , R 3b and R 3a is defined as described in formula (I), and R is an alkyl group.

[0550] Alternatively, compounds of formula (I) may be prepared as outlined in General Scheme 2. Treatment of 2-bromo-2-arylacetic acid salt 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 to slightly elevated temperatures (i.e., 25-50 °C) provides amino ester 2-d. Hydrolysis of 2-d under basic conditions (i.e., LiOH / MeOH when R = CH3) or treatment with an acid (i.e., formic acid or TFA when R = t-Bu) provides diastereomeric compounds of formula (I), which may be separated by supercritical fluid chromatography (SFC) or preparative HPLC. [Table 1-1] [Table 1-2] [Table 1-3]

[0551] Analytical methods, materials, and instrumentation Unless otherwise stated, reagents and solvents were used as received from commercial suppliers. Default methods, materials, and instrumentation are listed below.

[0552] 1 H NMR equipment information: Proton nuclear magnetic resonance (NMR) spectra were obtained at 400 MHz using a Bruker or Varian spectrometer. Spectra are given in ppm (d) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard.

[0553] LCMS equipment information and analysis method: Mass spectrometry data 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 a Chemstation C.01.10, and purity was characterized by UV wavelength 220 nm, ELSD, and ESI.

[0554] Method A: Column: Kinetex C18 2.1 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 a gradient from 5 to 95% B in 2.60 min, then a hold at 95% B for 1.00 min, then 95 to 5% B in 0.01 min.

[0555] Method B: Column: Xbridge C18 2.1 x 50 mm column (5 μm particles); Flow rate: 0.8 mL / min; Mobile phase A: 10 mM NH4HCO3 in water; Mobile phase B: acetonitrile; Gradient: 5% B from 0 to 0.40 min, then a gradient of 5 to 95% B from 0.40 to 3.40 min, then a 0.45 min hold at 95% B, then a 0.01 min gradient from 95 to 5% B.

[0556] SFC Equipment and Analysis Method Information: Instrument: Waters UPCC with PDA detector

[0557] Conditions: Mobile phase A: CO2; Mobile phase B: MeOH with 0.1% isopropylamine (or EtOH with 0.1% isopropylamine, or isopropanol with 0.1% isopropylamine).

[0558] Column:Daicel CHIRALPAK AD-3,50×4.6mm ID,3um;Daicel CHIRALCEL OD-3,50×4.6 mm ID,3um;Daicel CHIRALCEL OJ-3,50×4.6mm ID,3 um;Daicel CHIRALPAK IG-3,50×4.6mm ID,3um;Daicel CHIRALCEL OJ-3,50×4.6mm ID,3um; AS-3,50×4.6mm ID,3um;Daicel CHIRALPAK IC-3,50 x 4.6mm ID,3um;Phenomenex Lux Cellulose-2,50×4.6mm ID,3um;Regis(S,S)-Whelk-O 1,50×4.6mm ID,3.5um

[0559] Column temperature: 35℃

[0560] Gradient: 5% B from 0.0 to 0.2 min, then a gradient of 5 to 50% B from 0.2 to 1.2 min, then a hold at 50% B for 1.0 min, then a gradient of 50 to 5% B from 2.2 to 2.6 min, then a hold at 50% B for 0.4 min.

[0561] Flow rate: 3.4mL / min

[0562] Automatic back pressure regulator (ABPR): 1800psi

[0563] Alternatively, the chiral product is analyzed by chiral SFC using an SFC-80 (Thar, Waters) instrument at a detection wavelength of 214 nm, using one of the following methods for analysis:

[0564] Chiral SFC A: Column: (R,R)-Whelk-O1, 4.6*100mm, 5μm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanolic ammonia), isocratic elution of the text, flow rate: 4 g / min, back pressure: 120 bar.

[0565] Chiral SFC B: Column: AD 4.6*100mm, 5μm (Daicel), Column temperature: 40°C,

[0566] Mobile phase: CO2 / methanol (0.2% methanolic ammonia), isocratic elution of the text, flow rate: 4 g / min, back pressure: 120 bar.

[0567] Chiral SFC H: Column: (S,S)-Whelk-O1, 4.6*100mm, 5μm (Decial), Column temperature: 40 °C, Mobile phase: CO2 / methanol (0.2% methanol ammonia), Isocratic elution of the text, Flow rate: 4g / min, Back pressure: 120 bar.

[0568] Preparative HPLC method Equipment: Gilson 281 semi-preparative HPLC system

[0569] Conditions: Mobile phase A: 0.2% formic acid in water (or 0.1% TFA in water, or 0.05% HCl in water, or 10 mM NH4HCO3 in water, or 0.04% ammonium hydroxide in water); Mobile phase B: acetonitrile

[0570] Column:Phenomenex Luna C18 100 x 30mm x 5um,Phenomenex Gemini C18 100 x 30mm x 5um;Waters Xbridge BEH C18 100 x 30mm x 10um

[0571] Column temperature: ambient temperature

[0572] LC gradient: 5% to 50% B in 10 min, then hold at 50% B for 2 min, then a gradient from 50 to 100% B over 0.1 min, then hold at 100% for 2 min, then a gradient from 100% to 5% B over 0.1 min, then hold at 5% for 2 min

[0573] LC flow rate: 25mL / min

[0574] UV wavelength: 220nm and 254nm

[0575] Alternatively, the crude sample may be dissolved in MeOH and purified by preparative HPLC using a Gilson 215 instrument, detection wavelength 214 nm, using one of the following methods described in the procedure:

[0576] "Prep HPLC A": 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 per text; Flow rate: 20 mL / min.

[0577] "Prep 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 per text; Flow rate: 20 mL / min.

[0578] Preparative Chiral HPLC Method Instrument: Gilson-281 semi-preparative HPLC system; UV: Gilson-156 UV

[0579] Conditions: Mobile phase A: n-heptane; Mobile phase B: ethanol with 0.1% ammonium hydroxide (or 2-propanol with 0.1% ammonium hydroxide, or ethanol with 0.1% TFA, or 2-propanol with 0.1% TFA).

[0580] Column:Daicel CHIRALPAK AD,10um,30mm x 250mm;Daicel CHIRALPAK IH,10um,30mm x 250mm;Daicel CHIRALCEL OD,10um,30mm x 250mm;Daicel CHIRALCEL OJ,10um,30mm x 250mm;Daicel CHIRALPAK IC,10um,30mm x 250mm;Daicel CHIRALPAK IG,10um,30mm x 250mm;Phenomenex Lux Cellulose-2,10um,30mm x 250mm;Regis(S,S)Whelk-O1,10um, 30mm x 250mm

[0581] Column temperature: ambient temperature

[0582] LC gradient: A:B=80:20 or other ratio in isocratic elution mode

[0583] LC flow rate: 25 mL / min. Dual pump

[0584] UV wavelength: 220nm and 254nm

[0585] Preparative Chiral SFC Method Equipment:SFC:Waters 80Q preparative SFC;UV:Waters 2489 UV

[0586] Conditions: Mobile phase A: CO2; Mobile phase B: Methanol with 0.1% ammonium hydroxide (or ethanol with 0.1% ammonium hydroxide, or 2-propanol with 0.1% ammonium hydroxide, or MeCN / EtOH / ammonium hydroxide 50:50:0.1).

[0587] Column:Daicel CHIRALPAK AD,10um,30mm x 250mm;Daicel CHIRALPAK IH,10um,30mm x 250mm;Daicel CHIRALCEL OD,10um,30mm x 250mm;Daicel CHIRALCEL OJ,10um,30mm x 250mm;Daicel CHIRALPAK IC,10um,30mm x 250mm;Daicel CHIRALPAK IG,10um,30mm x 250mm;Phenomenex Lux Cellulose-2,10um,30mm x 250mm;Regis(S,S)Whelk-O1,10um, 30mm x 250mm

[0588] Column temperature: 40℃

[0589] LC gradient: A:B=80:20 or other ratio in isocratic elution mode

[0590] LC flow rate: 70g / min. Dual pump

[0591] Detection wavelength: 220 nm

[0592] System back pressure: 100 bar

[0593] Alternatively, the racemic product is separated into its individual enantiomers by chiral preparative SFC using an SFC-80 (Thar, Waters) instrument at a detection wavelength of 214 nm, using one of the following methods for separation:

[0594] Preparative chiral SFC A: Column: (R,R)-Whelk-O1, 20*250 mm, 5 μm (Decial), Column temperature: 35 °C, Mobile phase: CO2 / methanol (0.2% methanolic ammonia) = 60 / 40, Flow rate: 80 g / min, Back pressure: 100 bar.

[0595] Preparative chiral SFC B: Column: AD 20*250mm, 10μm (Daicel), Column temperature: 35°C,

[0596] Mobile phase: CO2 / methanol (0.2% methanol ammonia) = 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0597] Preparative chiral SFC H: Column: (S,S)-Whelk-O1, 20*250 mm, 5 μm (Decial), Column temperature: 35 °C, Mobile phase: CO2 / methanol (0.2% methanolic ammonia) = 60 / 40, Flow rate: 80 g / min, Back pressure: 100 bar.

[0598] Examples - Left side of exemplary compounds Preparation of (R)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine Step 1: (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate [ka] A mixture of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (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 HO (150 mL) was stirred at 100 °C for 16 h. 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 NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluting with a 0–100% ethyl acetate / petroleum ether gradient at 150 mL / min). (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylic acid (10 g, 39.16 mmol, 76.9% yield) was obtained as a yellow oil.

[0599] Step 2: (R)-tert-butyl 7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [ka] To a solution of (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (10 g, 39.16 mmol) in THF (100 mL) was added 9-BBN (0.5 M in THF, 156.65 mL) at 0° C. The mixture was stirred at 50° C. for 2 h, and then the mixture was added to a mixture of tert-butyl 7-chloro-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (10.52 g, 39.16 mmol), CsCO (25.52 g, 78.32 mmol), and Pd(PPh) (2.26 g, 1.96 mmol) in DMF (200 mL), and the mixture was stirred at 100° C. under N for 14 h. The reaction was 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 NaSO, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® silica flash column, eluting with a 0-100% ethyl acetate / petroleum ether gradient at 200 mL / min). (R)-tert-butyl 7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (8.75 g, 17.87 mmol, 45.63% yield) was obtained as a yellow oil. 1H 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).

[0600] Step 3: (R)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine [ka] A solution of (R)-tert-butyl 7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate in HCl / MeOH (4 M, 50 mL) was stirred at 50° C. for 16 h. The mixture was concentrated in vacuo. 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% to 30%, 20 min; flow rate (25 mL / min). (R)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (3.4 g, 11.75 mmol, 82.18% yield) was obtained as a yellow oil. LCMS (ESI) m / z = 290.3 (M+1).

[0601] Preparation of (R)-5-methoxy-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine hydrochloride Step 1: (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate [ka] To a solution of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (10 g, 53.41 mmol), 5-bromopent-1-ene (23.88 g, 160.23 mmol) in toluene (150 mL) was added TBAB (1.72 g, 5.34 mmol) and a solution of NaOH (10.68 g, 267.04 mmol) in HO (150 mL) with stirring at 25 °C, and the reaction was stirred at 100 °C for 16 h. The mixture was quenched with HO (20 mL), extracted with EtOAc (50 mL x 3), and the organic layer was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g Sepa Flash® silica flash column, eluting with a 20–50% ethyl acetate / petroleum ether gradient at 120 mL / min). (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (6.42 g, 22.88 mmol, 42.84% yield, 91% purity) was obtained as a yellow oil. 1 H NMR (400 MHz, 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).

[0602] Step 2: (R)-tert-butyl 3-((5-(4-methoxy-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate 1 [ka] To a solution of (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (4.42 g, 17.31 mmol) in THF (30 mL) was added 9-BBN (0.5 M in THF, 92.32 mL) at 0 °C. After stirring at 25 °C for 2 h, the solution was added to a suspension of 2-chloro-4-methoxy-1,8-naphthyridine (2.25 g, 11.56 mmol), Pd(OAc) (259.07 mg, 1.15 mmol), tricyclohexylphosphine (323.60 mg, 1.15 mmol), and KCO (3.19 g, 23.08 mmol) in THF (30 mL) and HO (1.3 mL) at 25 °C, and the reaction was stirred at 90 °C for 16 h. After the reaction, water (40 mL) was added, extracted with ethyl acetate (40 mL x 2), and the organic layer was concentrated to give the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 40 g Sepa Flash® silica flash column, eluent of 0-33% ethyl acetate / petroleum ether gradient, 120 mL / min). (R)-tert-butyl 3-((5-(4-methoxy-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (5 g, crude) was obtained as a brown oil. LCMS (ESI) m / z = 416.2 (M+1).

[0603] Step 3: (R)-tert-butyl 3-((5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] To a solution of (R)-tert-butyl 3-((5-(4-methoxy-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (4.2 g, 10.11 mmol) in MeOH (150 mL) was added Pd / C (4 g, 10% purity), and the reaction was stirred under H (50 psi) at 50° C. for 16 h. 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. (R)-tert-butyl 3-((5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (4 g, 9.53 mmol, 94.3% yield) was obtained as a yellow oil. LCMS (ESI) m / z=420.3 (M+1).

[0604] Step 4: Preparation of (R)-5-methoxy-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine hydrochloride [ka] To a solution of (R)-tert-butyl 3-((5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (2 g, 4.77 mmol) in MeOH (10 mL) was added HCl / MeOH (4 M, 20 mL) at 25° C., and the reaction was stirred at 50° C. for 16 h. The solvent was distilled under reduced pressure to give the crude product. (R)-5-methoxy-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine hydrochloride (1.5 g, crude) was obtained as a red oil. 1H NMR (400MHz, methanol-d4) δ ppm=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).

[0605] Preparation of (S)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine Step 1: (S)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate [ka] To a solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (25 g, 133.52 mmol) and 5-bromopent-1-ene (49.74 g, 333.80 mmol) in toluene (375 mL) and HO (375 mL) was added TBAB (4.3 g, 13.36 mmol) and NaOH (26.7 g, 667.60 mmol). The mixture was stirred at 95 °C for 16 h. The reaction was slowly quenched with ice-water (1000 mL) and extracted with ethyl acetate (1000 mL x 2). The combined organic phase was washed with brine (1000 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 330 g Sepa Flash® silica flash column, eluting with a 0-100% ethyl acetate / petroleum ether gradient at 300 mL / min) to give (S)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (23 g, 90.07 mmol, 67.46% yield) as a pale yellow oil. 1 H NMR (400 MHz, methanol-d₄) δ = 5.82 (tdd, J = 6.8, 10.2, 17.1 Hz, 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 = 7.1 Hz, 2H), 2.01-1.89 (m, 2H), 1.69-1.59 (m, 2H), 1.46 (s, 9H).

[0606] Step 2: (S)-tert-butyl 7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [ka] To a solution of (S)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (10 g, 39.16 mmol) in THF (100 mL) was added 9-BBN (0.5 M, 156.64 mL) at 0° C. The mixture was stirred at 20° C. for 2 h, and then the mixture was added to a mixture of tert-butyl 7-chloro-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (10.52 g, 39.16 mmol), CsCO (25.52 g, 78.32 mmol), and Pd(PPh) (2.26 g, 1.96 mmol) in DMF (200 mL), and the resulting mixture was stirred at 100° C. under N for 16 h. The combined organic phases were washed with brine (500 mL x 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 330 g Sepa Flash® silica flash column, eluting with a 0-100% ethyl acetate / petroleum ether gradient at 300 mL / min). (S)-tert-butyl 7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (12.5 g, 25.53 mmol, 65.19% yield) was obtained 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).

[0607] Step 3: (S)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine [ka] A solution of (S)-tert-butyl 7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (5 g, 10.21 mmol) in HCl / MeOH (4 M, 50 mL) was stirred at 50° C. for 16 hours. The mixture was concentrated in vacuo. The racemic product was purified by preparative HPLC (column: Phenomenex Luna 80 x 30 mm x 3 um; mobile phase: A 0.1% TFA in water; B MeCN 1%-30%, 20 min; flow rate 25 mL / min). (S)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (2.3 g, 7.95 mmol, 77.83% yield) was obtained as a yellow oil. LCMS (ESI) m / z=290.2 (M+1).

[0608] Preparation of (R)-7-(2-(2-(pyrrolidin-3-yloxy)ethoxy)ethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine Step 1: (R)-tert-butyl 3-(2-ethoxy-2-oxoethoxy)pyrrolidine-1-carboxylate [ka] t-BuOK (8.99 g, 80.11 mmol) was added portionwise to a solution of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (10 g, 53.41 mmol) in THF (100 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, 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 h. The reaction mixture was quenched with aqueous NH Cl (150 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g Sepa Flash® silica flash column, eluting with a 0-100% ethyl acetate / petroleum ether gradient at 150 mL / min) to give (R)-tert-butyl 3-(2-ethoxy-2-oxoethoxy)pyrrolidine-1-carboxylate (6 g, 21.95 mmol, 41.1% yield) as a yellow oil. 1 H 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=7.1Hz,3H). LCMS (ESI) m / z=218.1 (M-56+1).

[0609] Step 2: (R)-tert-butyl 3-(2-hydroxyethoxy)pyrrolidine-1-carboxylate [ka] DIBAL-H (1 M, 3.66 mL) was added dropwise to a solution of (R)-tert-butyl 3-(2-ethoxy-2-oxoethoxy)pyrrolidine-1-carboxylate (0.5 g, 1.83 mmol) in THF (10 mL) at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched with aqueous NH4Cl (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 a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g Sepa Flash® silica flash column, eluting with a 0-100% ethyl acetate / petroleum ether gradient at 120 mL / min). (R)-tert-butyl 3-(2-hydroxyethoxy)pyrrolidine-1-carboxylate (0.2 g, 864.72 μmol, 47.3% yield) was obtained as a yellow oil. 1 H NMR (400 MHz, 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).

[0610] Step 3: tert-Butyl 7-ethynyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [ka] A mixture of tert-butyl 7-chloro-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (3 g, 11.16 mmol), KCO (3.09 g, 22.33 mmol), Pd(CHCN)Cl (289.61 mg, 1.12 mmol), and X-Phos (532.18 mg, 1.12 mmol) in CHCN (60 mL) was degassed and purged with N three times, and the mixture was stirred at 20 °C for 0.5 h. Ethynyltrimethylsilane (4.39 g, 44.65 mmol, 6.19 mL) was then injected, and the mixture was stirred at 90 °C for 6 h under a N atmosphere. 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 purified by flash silica gel chromatography (ISCO®; 80 g Sepa Flash® silica flash column, eluting with a 0-100% ethyl acetate / petroleum ether gradient at 200 mL / min). tert-Butyl 7-ethynyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (2.1 g, 8.13 mmol, 72.8% yield over two steps) was obtained as a brown solid. 1 H NMR (400MHz, chloroform-d) δ=7.34(d,J=7.70Hz,1H) 7.14(d,J=7.58Hz,1H) 3.73-3.80(m,2H) 3.03(s,1H) 2.76(t,J=6.54Hz,2H) 1.93(quin,J=6.33Hz,2 H) 1.54 (s,9H). LCMS(ESI)m / z=331.2(M+1).

[0611] Step 4: (R,E)-tert-butyl 7-(2-(2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)ethoxy)vinyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [ka] To tert-butyl 7-ethynyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (0.375 g, 1.45 mmol) and (R)-tert-butyl 3-(2-hydroxyethoxy)pyrrolidine-1-carboxylate (470.07 mg, 2.03 mmol) in DMSO (8 mL) was added KOH (81.46 mg, 1.45 mmol). The mixture was stirred at 135° C. for 0.67 h under microwave irradiation. The reaction mixture was quenched at 0° C. by the addition of water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 4 g Sepa Flash® silica flash column, eluting with a 0-33% ethyl acetate / petroleum ether gradient at 120 mL / min). (R,E)-tert-butyl 7-(2-(2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)ethoxy)vinyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (500 mg, 1.02 mmol, 35.2% yield) was obtained as a brown oil. LCMS (ESI) m / z=490.2 (M+1).

[0612] Step 5: (R)-tert-butyl 7-(2-(2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)ethoxy)ethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [ka] To a solution of (R,E)-tert-butyl 7-(2-(2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)ethoxy)vinyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (900 mg, 1.84 mmol) in MeOH (80 mL) was added Pd / C (200 mg, 10% purity), and the reaction was stirred under H (50 psi) at 25° C. for 16 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g Sepa Flash® silica flash column, eluting with a 50-100% ethyl acetate / petroleum ether gradient at 120 mL / min). (R)-tert-Butyl 7-(2-(2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)ethoxy)ethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (645 mg, 1.31 mmol, 71.4% yield) was obtained as a yellow oil. LCMS (ESI) m / z=492.3 (M+1).

[0613] Step 6: (R)-7-(2-(2-(pyrrolidin-3-yloxy)ethoxy)ethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine [ka] To a solution of (R)-tert-butyl 7-(2-(2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)ethoxy)ethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (211 mg, 429.19 μmol) in MeOH (3 mL), HCl / MeOH (4 M, 10 mL) was added to the mixture and the reaction was stirred at 30° C. for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g Sepa Flash® silica flash column, eluting with a 0-50% methanol / ethyl acetate gradient at 120 mL / min). (R)-7-(2-(2-(pyrrolidin-3-yloxy)ethoxy)ethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (180 mg, crude) was obtained as a yellow oil. LCMS (ESI) m / z=292.2 (M+1).

[0614] Preparation of (R)-5-(2-methoxyethoxy)-7-(5-pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine Step 1: (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate [ka] A mixture of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (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 HO (150 mL) was stirred at 100 °C for 16 h. 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 NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g Sepa Flash® silica flash column, eluent of 0-50% ethyl acetate / petroleum ether gradient at 100 mL / min) to give the product (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (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).

[0615] Step 2: (R)-tert-butyl 3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] To a solution of (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (4.7 g, 18.41 mmol) in THF (70 mL) was added 9-BBN (0.5 M, 73.62 mL) at 0 °C under N. The mixture was stirred at 50 °C for 2 h. To the mixture in DMF (50 mL) was added a mixture of 2,4-dichloro-1,8-naphthyridine (5.08 g, 18.89 mmol), CsCO (13.99 g, 42.94 mmol), and Pd(dppf)Cl.CHCl (1.40 g, 1.72 mmol). The mixture was stirred at 100 °C under N for 16 h. The reaction mixture was quenched with HO (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 NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluting with a 0-100% ethyl acetate / petroleum ether gradient at 80 mL / min) to give the product (R)-tert-butyl 3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (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), 3.9 4-4.03(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).

[0616] Step 3: (R)-tert-butyl 3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] To a mixture of 2-methoxyethanol (1.67 g, 21.91 mmol) in THF (16 mL) was added NaH (876.22 mg, 21.91 mmol, 60% purity) at 0 °C. The mixture was stirred at 25 °C for 1 h. To the mixture in THF (46 mL) was added (R)-tert-butyl 3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (4.6 g, 10.95 mmol) at 0 °C. The mixture was stirred at 25 °C for 15 h. The reaction mixture was quenched by the addition of HO (150 mL) at 0 °C and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (300 mL x 3), dried over NaSO, filtered, and concentrated under reduced pressure to provide a residue. The crude product was purified by reverse-phase HPLC (MeOH containing 0.1% formic acid) to give the product (R)-tert-butyl 3-((5-(4-(2-methoxyethoxy)-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (2.4 g, 3.66 mmol, 33.3% yield) as a yellow oil. LCMS (ESI) m / z = 460.2 (M+1).

[0617] Step 4: (R)-tert-butyl 3-((5-(4-methoxyethoxy)-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] To a suspension of Pd / C (1.2 g, 10% purity) in MeOH (80 mL) was added (R)-tert-butyl 3-((5-(4-(2-methoxyethoxy)-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (2.4 g, 5.22 mmol) in MeOH (40 mL) under Ar at 25 °C. The suspension was degassed under reduced pressure and purged with H three times. The mixture was then cooled to 50°C. 2The mixture was stirred at 25° C. for 16 hours under reduced pressure. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, affording the product (R)-tert-butyl 3-((5-(4-(2-methoxyethoxy)-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (3 g, crude) as a yellow oil. LCMS (ESI) m / z=464.4 (M+1).

[0618] Step 5: (R)-5-(2-methoxyethoxy)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine [ka] To a mixture of (R)-tert-butyl 3-((5-(4-methoxyethoxy)-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (3 g, 6.47 mmol) in EtOAc (20 mL) was added HCl / EtOAc (4 M, 30 mL). The mixture was stirred at 25° C. for 2 hours. The mixture was concentrated under reduced pressure to give the crude product. H2 The resulting mixture was dissolved in 0 (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-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (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).

[0619] Preparation of (R)-6-methoxy-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine Step 1: (R)-tert-butyl 3-((5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] BocO (1.81 g, 8.28 mmol, 1.90 mL) was added to a solution of (R)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (2 g, 5.52 mmol, 2HCl) and NaHCO (2.32 g, 27.60 mmol, 1.07 mL) in THF (20 mL) and HO (20 mL) at 20 °C. The mixture was stirred at 20 °C for 2 h. 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 NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 10 g Sepa Flash® silica flash column, eluting with a 0-100% ethyl acetate / petroleum ether gradient at 50 mL / min) to give (R)-tert-butyl 3-((5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (2 g, 5.13 mmol, 93.02% yield) as a yellow oil.

[0620] Step 2: (R)-tert-butyl 3-((5-(3-bromo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] NBS (868.15 mg, 4.88 mmol) was added to a solution of (R)-tert-butyl 3-((5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.9 g, 4.88 mmol) in CHCN (20 mL) at 0° C. The mixture was stirred at 0° C. for 10 min. The mixture was concentrated to give a crude residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g Sepa Flash® silica flash column, eluent of 0-100% THF / petroleum ether gradient, 50 mL / min). (R)-tert-butyl 3-((5-(3-bromo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (2 g, 4.27 mmol, 87.53% yield) was obtained as a yellow oil.

[0621] Step 3: (R)-6-Methoxy-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine [ka] A mixture of 3-((5-(3-bromo-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (0.3 g, 640.44 μmol), NaOMe (0.9 g, 5.00 mmol, 3 mL, 30% purity), CuI (195.16 mg, 1.02 mmol) in DME (6 mL) was stirred at 125° C. for 0.5 h under MW conditions (internal pressure 4 bar). The 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 NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 x 30 mm x 5 μm; mobile phase: A 0.1% TFA in water, B MeCN 5% to 35%, 10 min; flow rate (25 mL / min) to give (R)-6-methoxy-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (0.14 g, 333.69 mmol, 17.37% yield) as a yellow oil. LCMS (ESI) m / z = 320.3 (M+1).

[0622] Preparation of (S)-2-(5-((R)-pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine Step 1: (R)-tert-butyl 3-(4-bromobutoxy)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (13 g, 69.43 mmol) and 1,4-dibromobutane (44.97 g, 208.29 mmol, 25.12 mL) in HO (150 mL) and toluene (150 mL) was added TBAB (2.24 g, 6.94 mmol) and NaOH (13.89 g, 347.16 mmol) at 25 °C. The mixture was stirred at 100 °C for 16 h. Two parallel reactions were performed and worked up together. The mixture was extracted with ethyl acetate (100 mL x 3), washed with brine (100 mL x 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, eluting with a 0-20% ethyl acetate / petroleum ether gradient at 150 mL / min) to afford tert-butyl (3R)-3-(4-bromobutoxy)pyrrolidine-1-carboxylate (32.2 g, 99.93 mmol, 71.96% yield) as a yellow solid. 1 H NMR (400 MHz, 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).

[0623] Step 2: (R)-tert-butyl 3-(but-3-en-1-yloxy)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl (3R)-3-(4-bromobutoxy)pyrrolidine-1-carboxylate (16.1 g, 49.96 mmol) in THF (160 mL) was added t-BuOK (14.02 g, 124.91 mmol) portionwise at 0 °C. The mixture was stirred at 25 °C for 16 h. Two parallel reactions were performed and worked up together. The mixture was quenched with HO (300 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, eluting with a 0–20% ethyl acetate / petroleum ether gradient at 150 mL / min). tert-Butyl (3R)-3-but-3-enoxypyrrolidine-1-carboxylate (18.6 g, 77.07 mmol, 77.13% yield) was obtained as a yellow oil. 1 H NMR (400 MHz, 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 = 6.8 Hz, 2H), 2.00-1.81 (m, 2H), 1.51-1.40 (m, 9H).

[0624] Step 3: Phenyl 2-allyl-1,8-naphthyridine-1(2H)-carboxylate [ka] To a solution of 1,8-naphthyridine (10 g, 76.84 mmol) in CHCN (150 mL) was added phenyl chloroformate (18.05 g, 115.25 mmol, 14.44 mL) and AgOTf (1.97 g, 7.68 mmol) at 20 °C. The mixture was stirred at 20 °C for 0.5 h. To the mixture was added allyltrimethylsilane (13.17 g, 115.25 mmol, 18.39 mL) 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 aqueous NaHCO (100 mL) and brine (100 mL). The organic layer was dried over NaSO, filtered, and the filtrate was concentrated to give the product. The residue was purified by flash silica gel chromatography (ISCO®; 120 g Sepa Flash® silica flash column, eluting with a 0-100% ethyl acetate / petroleum ether gradient at 200 mL / min) to give phenyl 2-allyl-1,8-naphthyridine-1(2H)-carboxylate (14 g, 47.89 mmol, 62.33% yield) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ = 8.24 (dd, J = 1.9, 4.9 Hz, 1H), 7.32 (dd, J = 1.8, 7.5 Hz, 1H), 7.26-7.23 (m, 1H), 7.13-7.07 (m, 3H), 6.96 (dd, J = 4.9, 7.4 Hz, 1H), 6.81-6.7 4(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).

[0625] Step 4: Phenyl 2-((E)-5-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pent-2-en-1-yl)-1,8-naphthyridine-1(2H)-carboxylate [ka] A mixture of phenyl 2-allyl-1,8-naphthyridine-1(2H)-carboxylate (5 g, 17.10 mmol), (R)-tert-butyl 3-(but-3-en-1-yloxy)pyrrolidine-1-carboxylate (6.19 g, 25.66 mmol), and Grubbs catalyst second generation (726.04 mg, 855.19 μmol) in DCM (60 mL) was stirred at 40 °C for 16 h. Two parallel reactions were performed. The mixture was concentrated to give a crude residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g Sepa Flash® silica flash column, eluting with a 0–100% ethyl acetate / petroleum ether gradient at 200 mL / min). Phenyl 2-((E)-5-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pent-2-en-1-yl)-1,8-naphthyridine-1(2H)-carboxylate (5.05 g, 9.95 mmol, 29.08% yield) was obtained as a yellow oil.

[0626] Step 5: Phenyl 2-(5-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [ka] To a solution of Pd / C (3 g, 10% purity) in MeOH (300 mL) was added phenyl 2-((E)-5-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pent-2-en-1-yl)-1,8-naphthyridine-1(2H)-carboxylate (7 g, 13.84 mmol) under an Ar atmosphere. The suspension was degassed and purged with H three times. The mixture was stirred under H (50 psi) at 50 °C for 16 h. The reaction mixture was filtered through a Celite pad and washed with MeOH (100 mL). The filtrate was concentrated in vacuo. A mixture of phenyl 2-(5-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate and methyl 2-(5-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (6.9 g, mixture, crude) was obtained as a yellow oil. LCMS (ESI) m / z=510.3 (M+1).

[0627] Step 6: (3R)-tert-butyl 3-((5-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] To a solution of phenyl 2-(5-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)phenyl-carboxylate (6.9 g, 13.54 mmol) in HO (35 mL) and THF (70 mL), LiOH.HO (1.70 g, 40.62 mmol) was added and the mixture was stirred at 80 °C for 16 h. The reaction was slowly quenched with ice-water (100 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 250 mm x 100 mm x 10 μm; mobile phase: A 0.1% TFA in water; B MeCN 15%-45%, 20 min, flow rate 25 mL / min). (3R)-tert-butyl 3-((5-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.88 g, 4.83 mmol, 35.65% yield) was obtained as a yellow oil. LCMS (ESI) m / z = 390.3 (M+1).

[0628] Step 7: (R)-tert-butyl 3-((5-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] (3R)-tert-Butyl 3-((5-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (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).

[0629] Peak 1, arbitrarily assigned as (R)-tert-butyl 3-((5-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (420 mg, 1.08 mmol, 38.18% 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(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).

[0630] Peak 2, arbitrarily assigned as (R)-tert-butyl 3-((5-((R)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (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).

[0631] Step 8: (S)-2-(5-((R)-pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine [ka] A solution of (R)-tert-butyl 3-((5-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (430 mg, 1.10 mmol) in HCl / MeOH (4 M, 10 mL) was stirred at 50° C. for 16 h. The reaction was concentrated in vacuo to give (S)-2-(5-((R)-pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (450 mg, crude, 2H HCl salt) as a yellow oil. 1 H 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).

[0632] Preparation of (R)-2-(5-((R)-pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine Step 1: (R)-2-(5-((R)-pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine [ka] A solution of (R)-tert-butyl 3-((5-((R)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (400 mg, 1.03 mmol) in HCl / MeOH (4 M, 10 mL) was stirred at 50° C. for 16 h. The reaction was concentrated in vacuo to give (S)-2-(5-((R)-pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (450 mg, crude, 2H HCl salt) 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).

[0633] Preparation of (R)-5-isopropoxy-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine Step 1: (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate [ka] A solution of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (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 HO (130 mL). The mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched by the addition of HO (100 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (80 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g Sepa Flash® silica flash column, eluting with a 0-100% ethyl acetate / petroleum ether gradient at 100 mL / min) to give (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (23 g, 90.07 mmol, 67.46% yield) as a yellow oil. 1H 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).

[0634] Step 2: (R)-tert-butyl 3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] To a solution of (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (5 g, 19.58 mmol) in THF (50 mL) was added 9-BBN (0.5 M, 78.32 mL) at 0 °C. The mixture was stirred at 50 °C for 2 h and then added to a mixture of 2,4-dichloro-1,8-naphthyridine (3.90 g, 19.58 mmol), CsCO (12.76 g, 39.16 mmol), and Pd(PPh) (1.13 g, 979.04 μmol) in DMF (100 mL), and the mixture was stirred at 100 °C under N for 3 h. The two batches of the reaction were combined and worked up. The mixture was quenched with HO (500 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was washed with brine (100 mL x 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by reverse-phase HPLC (water (TFA)-CHCN). (R)-tert-butyl 3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (9 g, 21.43 mmol, 36.48% yield) was obtained as a brown oil. 1H 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).

[0635] Step 3: (R)-tert-butyl 3-((5-(4-isopropoxy-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] To a mixture of (R)-tert-butyl 3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (3 g, 7.14 mmol) in DMF (30 mL) was added CsCO (6.98 g, 21.43 mmol) and i-PrOH (4.29 g, 71.44 mmol, 5.47 mL) at 25 °C. The mixture was stirred at 100 °C for 16 h. The mixture was quenched with HO (50 mL), extracted with ethyl acetate (30 mL x 3), washed with brine (50 mL x 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. (R)-tert-butyl 3-((5-(4-methoxy-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (2 g, 4.51 mmol, 63.11% yield) was obtained as a brown oil. LCMS (ESI) m / z=444.3 (M+1).

[0636] Step 4: (R)-tert-butyl 3-((5-(4-isopropoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] To a suspension of Pd / C (1.9 g, 10% purity) in MeOH (60 mL) was added a solution of (R)-tert-butyl 3-((5-(4-isopropoxy-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.9 g, 4.28 mmol) in MeOH (60 mL) at 25° C. under Ar. The suspension was degassed under reduced pressure and purged with H several times. The mixture was stirred under H (50 psi) at 50° C. for 16 h. The mixture was filtered and concentrated in vacuo to give a residue. The residue was used directly in the next step without further purification. (R)-tert-Butyl 3-((5-(4-isopropoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.55 g, 3.46 mmol, 80.84% ​​yield) was obtained as a yellow oil. LCMS (ESI) m / z=448.3 (M+1).

[0637] Step 5: (R)-tert-butyl 3-((5-(4-isopropoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] To a mixture of (R)-tert-butyl 3-((5-(4-isopropoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.5 g, 3.35 mmol) in MeOH (5 mL) was added HCl / MeOH (4 M, 20 mL) under N at 25 °C. The mixture was stirred at 50 °C for 3 h. The reaction mixture was concentrated to give a residue, which was adjusted to pH = 7-8 with base resin in MeOH (30 mL), and the mixture was stirred at 25 °C for 0.5 h, filtered, and concentrated in vacuo. The residue was used directly in the next step without further purification. (R)-5-isopropoxy-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (1.5 g, crude) was obtained as a yellow oil. LCMS(ESI) m / z=348.3(M+1).

[0638] Preparation of (R)-6-(5-(pyrrolidin-3-yloxy)pentyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine Step 1: (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate [ka] To a solution of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (50 g, 267.04 mmol) in toluene (130 mL) was added 5-bromopent-1-ene (119.39 g, 801.13 mmol), TBAB (8.61 g, 26.70 mmol), and a solution of NaOH (53.40 g, 1.34 mmol) in HO (130 mL). The mixture was stirred at 100 °C for 16 h. Two parallel reactions were performed together. The reaction mixture was quenched by the addition of HO (200 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g Sepa Flash® silica flash column, eluting with a 0-100% ethyl acetate / petroleum ether gradient at 80 mL / min) to give (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (76 g, 297.63 mmol, 55.73% yield) as a yellow oil. 1 H 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).

[0639] Step 2: (R)-tert-butyl 3-((5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] To a solution of (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (12 g, 46.99 mmol) in THF (120 mL) was added 9-BBN (0.5 M, 187.98 mL). The mixture was stirred at 25 °C for 16 h and used directly in the next step. To the mixture was added a solution of 6-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (2 g, 9.30 mmol), CsCO (6.06 g, 18.60 mmol), and Pd(PPh) (537.35 mg, 465.01 μmol) in DMF (20 mL) and HO (1 mL). The mixture was stirred at 100 °C for 3 h. The reaction mixture was quenched by the addition of HO (60 mL) and ethyl acetate (50 mL). The mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give 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 NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g Sepa Flash® silica flash column, eluting with a 0-100% ethyl acetate / petroleum ether gradient at 80 mL / min). (R)-tert-butyl 3-((5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)pentyl)oxy)pyrrolidine-1-carboxylate (5 g, 7.41 mmol, 79.65% yield, 58% purity) was obtained as a yellow oil. 1 H NMR (400 MHz, 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).

[0640] Step 3: (R)-6-(5-(pyrrolidin-3-yloxy)pentyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine [ka] A solution of (R)-tert-butyl 3-((5-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)pentyl)oxy)pyrrolidine-1-carboxylate (3 g, 7.66 mmol) in HCl / MeOH (4 M, 30 mL) was stirred at 50° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The mixture was further purified by preparative HPLC (Column: Phenomenex Luna 80 x 30 mm x 3 um; Mobile phase: A 0.1% TFA in water; B MeCN 0%-22%, 20 min; Flow rate 25 mL / min). (R)-6-(5-(pyrrolidin-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(br s,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).

[0641] Preparation of (R)-1-methyl-6-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine Step 1: Ethyl 2-((6-chloro-3-nitropyridin-2-yl)amino)acetate [ka] To a mixture of 2,6-dichloro-3-nitropyridine (10 g, 51.82 mmol) and EtN (20.97 g, 207.27 mmol, 28.85 mL) in MTBE (100 mL) was added ethyl 2-aminoacetate hydrochloride (7.59 g, 54.41 mmol) 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. HO (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 phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®; 220 g Sepa Flash® silica flash column, eluting with a 0-30% petroleum ether / ethyl acetate gradient at 120 mL / min) to afford ethyl 2-((6-chloro-3-nitropyridin-2-yl)amino)acetate (11 g, 42.37 mmol, 81.8% yield) as a yellow oil. 1 H 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).

[0642] Step 2: Ethyl 2-((tert-butoxycarbonyl)(6-chloro-3-nitropyridin-2-yl)amino)acetate [ka] To a solution of ethyl 2-((6-chloro-3-nitropyridin-2-yl)amino)acetate (11 g, 42.37 mmol), EtN (8.57 g, 84.73 mmol, 11.79 mL), and DMAP (517.57 mg, 4.24 mmol) in THF (120 mL) was added BocO (15.72 g, 72.02 mmol, 16.55 mL) at 20 °C. The mixture was stirred at 60 °C for 12 h. HO (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 phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 3 / 1). Ethyl 2-((tert-butoxycarbonyl)(6-chloro-3-nitropyridin-2-yl)amino)acetate (14 g, 38.91 mmol, 91.8% yield) was obtained as a yellow oil. 1 H 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).

[0643] Step 3: Ethyl 2-((3-amino-6-chloropyridin-2-yl)(tert-butoxycarbonyl)amino)acetate [ka] 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 HO (90 mL) was added Fe (10.87 g, 194.57 mmol) at 20 °C. The mixture was stirred at 90 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated. HO (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 phase was washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Ethyl 2-((3-amino-6-chloropyridin-2-yl)(tert-butoxycarbonyl)amino)acetate (9 g, crude) was obtained as a yellow oil. LCMS (ESI) m / z=330.1 (M+1).

[0644] Step 4: tert-Butyl 6-chloro-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate [ka] 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) was added t-BuOK (3.37 g, 30.02 mmol) at 20 °C. The mixture was stirred at 20 °C for 1 h. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with HO (50 mL) and brine (50 mL x 2), dried over NaSO, and concentrated under reduced pressure. tert-Butyl 6-chloro-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate (3.65 g, crude) was obtained as a yellow solid. LCMS (ESI) m / z = 284.0 (M+1).

[0645] Step 5: tert-Butyl 6-chloro-1-methyl-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate [ka] To a mixture of tert-butyl 6-chloro-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate (3.65 g, 12.87 mmol) in DMF (40 mL) was added NaH (566.02 mg, 14.15 mmol, 60% purity) at 0 °C under N. The mixture was stirred at 0 °C for 0.5 h. MeI (1.83 g, 12.87 mmol, 800.91 uL) was added dropwise at 0 °C under N. The mixture was then stirred at 20 °C for 12 h. The mixture was added to saturated NH Cl (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 phase was washed with brine (200 mL × 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). tert-Butyl 6-chloro-1-methyl-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate (4.2 g, crude) was obtained as a yellow oil. 1 H 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).

[0646] Step 6: (R)-tert-butyl 6-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)-1-methyl-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine 4(1H)-carboxylate [ka] To a solution of (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (2.06 g, 8.06 mmol) in THF (20 mL) was added 9-BBN (0.5 M, 26.87 mL) at 0 °C, and after stirring at 40 °C for 3 h, the formed solution was diluted with tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate in THF (12 mL) and HO (1 mL). A solution of 6-chloro-1-methyl-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate (2 g, 6.72 mmol), tricyclohexylphosphine (188.37 mg, 671.73 μmol), K2CO3 (1.86 g, 13.43 mmol), and Pd(dba)2 (386.25 mg, 671.73 μmol) was added, and the reaction was stirred at 50 °C for 12 h. Two batches were run 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 a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). (R)-tert-Butyl 6-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)-1-methyl-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine 4(1H)-carboxylate (4.2 g, 8.10 mmol, 60.3% yield) was obtained as a yellow oil. LCMS (ESI) m / z = 519.3 (M+1).

[0647] Step 7: (R)-tert-butyl 3-((5-(1-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-6-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] To a solution of (R)-tert-butyl 6-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)-1-methyl-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate (1.93 g, 3.72 mmol) in THF (20 mL) was added BH3 . THF (1 M, 37.21 mL) was added at 0 °C, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with MeOH (10 mL) at 0 °C and concentrated to give the crude product. The residue was purified by preparative HPLC (Column: Waters X bridge BEH C18 250 x 50 mm x 10 μm; Mobile phase: A 10 mmol / L NH4HCO3 in water; B MeCN 40% to 70%, 10 min; Flow rate (25 mL / min)). (R)-tert-butyl 3-((5-(1-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-6-yl)pentyl)oxy)pyrrolidine-1-carboxylate (500 mg, 1.24 mmol, 33.2% yield) was obtained as a yellow oil. LCMS (ESI) m / z = 405.3 (M+1).

[0648] Step 8: (R)-1-methyl-6-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine [ka] A solution of (R)-tert-butyl 3-((5-(1-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-6-yl)pentyl)oxy)pyrrolidine-1-carboxylate (300 mg, 741.57 mmol) in HCl / MeOH (2 mL) was stirred at 25° C. for 12 h. The mixture was concentrated. (R)-1-methyl-6-(5-(pyrrolidin-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).

[0649] Preparation of (R)-N,N-dimethyl-2-(5-(pyrrolidin-3-yloxy)pentyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-4-amine Step 1: (R)-tert-butyl 3-((5-(4-dimethylamino)-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] To a solution of (R)-tert-butyl 3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (3.1 g, 7.38 mmol), dimethylamine (2 M in THF, 13 mL) in NMP (30 mL) was added DIEA (4.60 g, 35.59 mmol, 6.20 mL) and the mixture was stirred at 100° C. for 48 h. The reaction was concentrated in vacuo to give (R)-tert-butyl 3-((5-(4-dimethylamino)-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (3.5 g, crude) as a yellow oil. LCMS (ESI) m / z=429.3 (M+1).

[0650] Step 2: (R)-tert-butyl 3-((5-(4-dimethylamino)-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] To a solution of Pd / C (2 g, 10% purity) in MeOH (60 mL) was added (R)-tert-butyl 3-((5-(4-(dimethylamino)-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (3.5 g, 8.17 mmol) under an Ar atmosphere. The suspension was degassed and purged with H three times. The mixture was stirred under H (50 psi) at 50 °C for 16 h. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo to give (R)-tert-butyl 3-((5-(4-dimethylamino)-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (3.5 g, crude) as a yellow oil. LCMS(ESI) m / z=433.3(M+1).

[0651] Step 3: (R)-N,N-Dimethyl-2-(5-(pyrrolidin-3-yloxy)pentyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-4-amine [ka] A mixture of (R)-tert-butyl 3-((5-(4-(dimethylamino-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (3 g, 6.93 mmol) in HCl / MeOH (4 M, 50 mL) was stirred at 50° C. for 16 hours. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250 x 70 mm, 15 um); mobile phase: A 0.1% TFA in water; B MeCN Purification by HPLC (0% to 30%, 28 min; flow rate 25 mL / min) afforded (R)-N,N-dimethyl-2-(5-(pyrrolidin-3-yloxy)pentyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-4-amine (2.3 g, 5.15 mmol, 74.28% yield, TFA salt) as a yellow oil. 1H NMR(400MHz,METHANOL-d4)δ=6.27(s,1H), 4.24(t,J=4.4Hz,1H), 3.48(t,J=6.5Hz,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).

[0652] Preparation of 7-(5-((trans-4-fluoropyrrolidin-3-yl)oxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine Step 1: tert-Butyl trans-3-fluoro-4-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl trans-3-fluoro-4-hydroxypyrrolidine-1-carboxylate (1.5 g, 8.01 mmol) and 5-bromopent-1-ene (3.58 g, 24.03 mmol) in n-heptane (20 mL) was added 50% aqueous sodium hydroxide (3 mL) and tetrabutylammonium bromide (105 mg, 0.4 mmol). 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 in vacuo, and the residue was purified by silica gel column (petroleum ether: EtOAc = 5:1) to give the desired product, tert-butyl trans-3-fluoro-4-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate, as a pale yellow oil (730 mg, 33% yield). ESI 274 (M+H)+.

[0653] Step 2: tert-Butyl 7-(5-((trans-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [ka] To a solution of tert-butyl trans-3-fluoro-4-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (730 mg, 2.67 mmol) in THF (dry, 10 mL) was added 9-BBN (0.5 M in THF, 10.8 mL, 5.4 mmol) under Ar. The reaction mixture was stirred at 50° C. for 1.5 h, then cooled to room temperature, and 2-chloro-4-methoxy-1,8-naphthyridine (718 mg, 2.67 mmol), Pd(OAc) (29 mg, 0.13 mmol), PCy (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 (petroleum ether: EtOAc = 2:1) to give the desired product tert-butyl 7-(5-((trans-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate as a pale yellow oil (1.2 g, 89% yield). ESI 508 (M+H)+.

[0654] Step 3: 7-(5-((trans-4-fluoropyrrolidin-3-yl)oxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine [ka] To a solution of tert-butyl 7-(5-((trans-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (1.2 g, 2.36 mmol) in dioxane (40 mL) was added HCl / dioxane (4 M, 10 mL). The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed in vacuo to give the desired product, 7-(5-((trans-4-fluoropyrrolidin-3-yl)oxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine, as a yellow oil (0.7 g, 96% yield). ESI 308 (M+H)+.

[0655] Preparation of 7-(5-((cis-4-fluoropyrrolidin-3-yl)oxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine Step 1: tert-Butyl cis-3-fluoro-4-hydroxypyrrolidine-1-carboxylate [ka] To a solution of PPh3 (1.92 g, 7.33 mmol) in THF (20 mL) was added DIAD (1.48 g, 7.33 mmol) under N2 protection at 0 °C. The reaction 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 was quenched with HO (20 mL) and then extracted with EtOAc (20 mL × 3). The combined organic phase was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in a mixture of MeOH (10 mL) and 2 N NaOH (5 mL) and then stirred at room temperature for 3 h. The reaction was extracted with EtOAc (20 mL × 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (Et0Ac / petroleum ether = 20%-30%) to give the desired product, tert-butyl cis-3-fluoro-4-hydroxypyrrolidine-1-carboxylate, as a brown oil (350 mg). Yield 35% ESI 206 (M+H)+.

[0656] Step 2: tert-Butyl cis-3-fluoro-4-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl cis-3-fluoro-4-hydroxypyrrolidine-1-carboxylate (350 mg, 1.71 mmol) in n-heptane (10 mL) was added 50% aqueous sodium hydroxide (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 (petroleum ether: EtOAc 4:1) to give the desired product, tert-butyl cis-3-fluoro-4-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate, as a colorless oil (360 mg), yield 77% (ESI 274 (M+H)+).

[0657] Step 3: tert-Butyl cis-3-fluoro-4-((5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl cis-3-fluoro-4-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (360 mg, 1.32 mmol), 9-BBN (0.5 N in THF, 5.3 mL, 2.65 mmol) was added under a N atmosphere. The mixture was stirred at 60 °C for 1.5 h, cooled to room temperature, and then tert-butyl 7-chloro-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (354 mg, 1.32 mmol), Pd(OAc) (30 mg, 0.13 mmol), PCy (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, tert-butyl cis-3-fluoro-4-((5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate, as a yellow oil (480 mg). Yield 89% (ESI 408 (M+H)+).

[0658] Step 4: 7-(5-((cis-4-fluoropyrrolidin-3-yl)oxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine [ka] Tert-butyl cis-3-fluoro-4-((5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (480 mg, 1.18 mmol) was added to a solution of HCl / dioxane (5 mL, 4N). The mixture was stirred at room temperature for 4 hours and concentrated to give the desired product, 7-(5-((cis-4-fluoropyrrolidin-3-yl)oxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine, as a white solid (320 mg), which was used in the next step without further purification. Yield 88% (ESI 308 (M+H)+).

[0659] Preparation of (R)-5-methyl-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine Step 1: tert-Butyl (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (10.0 g, 53.4 mmol) in n-heptane (120 mL) was added 50% aqueous sodium hydroxide (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 h. 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 NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 4:1) to give the desired product tert-butyl (S)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate as a colorless oil (13 g), yield 95% (ESI 256.2 (M+H)+).

[0660] Step 2: tert-Butyl (R)-3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (2.5 g, 9.8 mmol) in THF (5 mL) was added 9-BBN (35.2 mL, 17.6 mmol, 0.5 N in THF) under a N atmosphere. The mixture was stirred at 60 °C for 1.5 h and cooled to room temperature. tert-Butyl 7-chloro-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (1.95 g, 9.8 mmol), Pd(OAc) (54 mg, 0.5 mmol), PCy (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, tert-butyl (R)-3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate, as a yellow oil (3.1 g). Yield 75% (ESI 420.2 (M+H)+).

[0661] Step 3: tert-Butyl (R)-3-((5-(4-methyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] A mixture of tert-butyl (R)-3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (3.1 mg, 7.4 mmol), methylboronic acid (530 mg, 8.9 mmol), Pd(dppf)Cl (541 mg, 0.74 mmol), and KCO (2.04 g, 14.8 mmol) in 30 mL of dioxane and 3 mL of HO was stirred at 80 °C for 4 h. The mixture was concentrated and purified by silica gel chromatography (EtOAc:petroleum ether = 0% to 70%) to give the desired product, tert-butyl (R)-3-((5-(4-methyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.25 g). Yield 42% (ESI 400.2 (M+H)+).

[0662] Step 4: tert-Butyl (R)-3-((5-(4-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] A mixture of tert-butyl (R)-3-((5-(4-methyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.25 g, 3.13 mmol) and Pd / C (125 mg, 10% on activated carbon) in 10 mL of MeOH was stirred under a hydrogen atmosphere at room temperature for 16 hours. The mixture was filtered, and the filtrate was concentrated to give the desired product, tert-butyl (R)-3-((5-(4-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.15 g). Yield 91% (ESI 404.3 (M+H)+).

[0663] Step 5: (R)-5-methyl-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine [ka] Tert-butyl (R)-3-((5-(4-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.15 g, 2.85 mmol) was added to a solution of HCl / dioxane (10 mL, 4N). The mixture was stirred at room temperature for 16 hours and concentrated to give the desired product, (R)-5-methyl-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine, as a white solid (700 mg), which was used in the next step without further purification. Yield 100% (ESI 304.2 (M+H)+).

[0664] Preparation of (R)-6-methyl-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine Step 1: 3-Methyl-1,8-naphthyridin-2(1H)-one [ka] To a solution of 2-aminonicotinaldehyde (3.0 g, 24.59 mmol) and EtN (4.97 g, 49.18 mmol) in dioxane (20 mL) was added propionyl chloride (3.39 g, 36.89 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h, then quenched with HO (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic phase was washed with saturated aqueous NaHCO, brine, dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was added to a mixture of CsCO (16.13 g, 49.18 mmol) and DMF (20 mL). The reaction mixture was stirred at 70° C. overnight, then concentrated in vacuo, and the residue was purified by silica gel column (petroleum ether: EtOAc 1:1) to give the desired product, 3-methyl-1,8-naphthyridin-2(1H)-one (1.6 g) as a brown solid in 41% yield (ESI 161 [M+H]+).

[0665] Step 2: 2-Chloro-3-methyl-1,8-naphthyridine [ka] A solution of 3-methyl-1,8-naphthyridin-2(1H)-one (1.6 g, 9.94 mmol) in POCl (20 mL) was stirred at 110 °C for 8 h. The reaction was quenched with HO (10 mL) and extracted with EtOAc (30 mL × 3). The combined organic phases were washed with saturated aqueous NaHCO, brine, dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 2:1) to give the desired product, 2-chloro-3-methyl-1,8-naphthyridine (1.1 g), as a yellow solid. Yield 62% (ESI 179 [M+H]).

[0666] Step 3: tert-Butyl (R)-3-((5-(3-methyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (1.57 g, 6.15 mmol) in THF (5 mL) was added 9-BBN (24.6 mL, 12.3 mmol, 0.5 N in THF) under a N atmosphere. The mixture was stirred at 60 °C for 1.5 h and cooled to room temperature. 2-Chloro-3-methyl-1,8-naphthyridine (1.1 g, 6.15 mmol), Pd(OAc) (69 mg, 0.31 mmol), PCy (260 mg, 0.93 mmol), and KOH (517 mg, 9.23 mmol) were 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, tert-butyl (R)-3-((5-(3-methyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate, as a yellow oil (1.6 g). Yield 65% (ESI 400 (M+H)+).

[0667] Step 4: tert-Butyl (R)-3-((5-(3-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] tert-Butyl (R)-3-((5-(3-methyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.6 g, 4 mmol) and Pd / C (160 mg, 20 wt%) in ethyl acetate (20 mL) were stirred at 40 °C under a H balloon for 16 h. The solids were removed by filtration, the filtrate was concentrated in vacuo, and the residue was purified on a silica gel column (DCM:MeOH 30:1) to give the desired product, tert-butyl (R)-3-((5-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate, as a yellow oil (1.5 g). Yield 93% (ESI 404 (M+H)+).

[0668] Step 5: (R)-6-Methyl-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine hydrochloride [ka] Tert-butyl (R)-3-((5-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.5 g, 3.72 mmol) was added to a solution of HCl / dioxane (15 mL, 4N). The mixture was stirred at room temperature for 6 hours and concentrated to give the desired product, (R)-6-methyl-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine hydrochloride, as a white solid (1.1 mg), which was used in the next step without further purification. Yield 87% (ESI 304 (M+H)+).

[0669] Preparation of (R)-N,N-dimethyl-2-(2-(5-(pyrrolidin-3-yloxy)pentyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)ethan-1-amine Step 1: tert-Butyl (R)-3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] A solution of tert-butyl (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (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-naphthyridine (3.9 g, 19.6 mmol), Pd(OAc) (439 mg, 1.96 mmol), PCy (447 mg, 1.96 mmol), and NaOH (1.18 g, 29.4 mmol) were added. The mixture was stirred at 50° C. for 1 hour under an argon atmosphere. The mixture was diluted with EtOAc and filtered. The filtrate was concentrated and purified by silica gel chromatography (EtOAc / petroleum ether=0-50%) to give the desired product, tert-butyl (R)-3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate, as a colorless oil (3.6 g). Yield: 44% (ESI 420.1 (M+H)+).

[0670] Step 2: tert-Butyl (R)-3-((5-(4-vinyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] A mixture of tert-butyl (R)-3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (210 mg, 0.5 mmol), a mixture of potassium vinyltrifluoroborate (87 mg, 0.65 mmol), Pd(dba) (46 mg, 0.05 mmol), Ru-phos (23 mg, 0.05 mmol), and NaCO (160 mg, 1.5 mmol) in toluene (4 mL) and water (0.5 mL) was stirred at 100 °C for 18 h under an argon atmosphere. The mixture was concentrated, and the residue was purified by silica gel chromatography (EtOAc / petroleum ether=0%-20%) to give the desired product, tert-butyl (R)-3-((5-(4-vinyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate, as a colorless oil (100 mg). Yield: 48% (ESI 412.1 (M+H)+).

[0671] Step 3: tert-Butyl (R)-3-((5-(4-(2-(dimethylamino)ethyl)-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] A mixture of tert-butyl (R)-3-((5-(4-vinyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (740 mg, 1.8 mmol) and dimethylamine hydrochloride (438 mg, 5.4 mmol) in MeOH (10 mL) was stirred at 75° C. for 16 h. The mixture was concentrated, and the residue was purified by silica gel chromatography (EtOAc / petroleum ether=0% to 50%) to give the desired product, tert-butyl (R)-3-((5-(4-(2-(dimethylamino)ethyl)-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate, as a yellow solid (450 mg). Yield: 50% (ESI 457.1 (M+H)+).

[0672] Step 4: (R)—N,N-dimethyl-2-(5-(pyrrolidin-3-yloxy)pentyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)ethan-1-amine [ka] A mixture of tert-butyl (R)-3-((5-(4-(2-(dimethylamino)ethyl)-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (456 mg, 1 mmol) and Pd / C (250 mg, 10% on activated carbon) in 10 mL of MeOH was stirred under a hydrogen atmosphere at room temperature for 16 hours. The mixture was filtered, and the filtrate was concentrated. The residue was dissolved in 10 mL of DCM, and then HCl in dioxane (4 N, 5 mL) was added. The mixture was stirred at room temperature for 4 hours and concentrated in vacuo to give the desired product, (R)-N,N-dimethyl-2-(2-(5-(pyrrolidin-3-yloxy)pentyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)ethan-1-amine (340 mg). Yield 94% (ESI 361.2 (M+H)+).

[0673] Preparation of (R)-5-(2-methoxyethyl)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine Step 1: tert-Butyl (R)-3-((5-(2-methoxyethyl)-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl (R)-3-((5-(4-vinyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (411 mg, 1.0 mmol) in 10 mL of MeOH was added MeONa (162 mg, 3.0 mmol). The mixture was stirred at 60° C. for 7 hours, then quenched with water (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were concentrated to give crude product tert-butyl (R)-3-((5-(4-(2-methoxyethyl)-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (376 mg), which was used directly in the next step. (ESI 444.2 (M+H)+).

[0674] Step 2: (R)-5-(2-methoxyethyl)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine [ka] To a solution of tert-butyl (R)-3-((5-(4-(2-methoxyethyl)-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (376 mg, 0.85 mmol) in 15 mL of EtOAc was added Pd / C (10%, 76 mg). The resulting mixture was stirred under a hydrogen atmosphere at 50° C. for 16 hours, then filtered through Celite, and the filtrate was concentrated in vacuo. The residue was dissolved in 5 mL of DCM, and then HCl (4N in 1,4-dioxane, 2 mL) was added. The mixture was stirred at room temperature for 3 hours and then concentrated in vacuo to give the desired product, (R)-5-(2-methoxyethyl)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine, as a pale yellow oil (245 mg). ESI 348.2(M+H)+.

[0675] Preparation of (S)-2-(4-(((R)-pyrrolidin-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine Step 1: tert-Butyl (R)-3-(hex-5-en-1-yloxy)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (20 g, 20 mmol) in n-heptane (250 mL) was added 50% aqueous sodium hydroxide (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 h, 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 NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 4:1) to give the desired product tert-butyl (R)-3-(hex-5-en-1-yloxy)pyrrolidine-1-carboxylate as a colorless oil (26 g), yield 90% (ESI 270 (M+H)+).

[0676] Step 2: tert-Butyl (R)-3-((5-oxopentyl)oxy)pyrrolidine-1-carboxylate [ka] A mixture of tert-butyl (R)-3-(hex-5-en-1-yloxy)pyrrolidine-1-carboxylate (5.0 g, 18.6 mmol), potassium osmate(VI) dihydrate (343 mg, 0.93 mmol), and sodium periodate (9.95 g, 46.5 mmol) in 150 mL of THF and 150 mL of HO 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 NaSO, and concentrated in vacuo to give crude tert-butyl (R)-3-((5-oxopentyl)oxy)pyrrolidine-1-carboxylate (4.9 g) as a colorless oil. Yield 95% (ESI 272 (M+H)+).

[0677] Step 3: tert-Butyl (3R)-3-((5-hydroxyhept-6-en-1-yl)oxy)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl (R)-3-((5-oxopentyl)oxy)pyrrolidine-1-carboxylate (4.9 g, 18 mmol) in THF (50 mL) was added vinylmagnesium bromide (1.0 M in THF, 36 mL, 36 mmol) dropwise over 30 minutes at −10° C. The mixture was stirred at room temperature overnight and then quenched with water (20 mL). The precipitated solid was removed by filtration, and the filtrate was extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with water, dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 5:1) to give the desired product, tert-butyl (3R)-3-((5-hydroxyhept-6-en-1-yl)oxy)pyrrolidine-1-carboxylate (2.01 g), as a pale yellow oil. Yield 37% (ESI 300 [M+H]+).

[0678] Step 4: tert-Butyl (R)-3-((7-(2-chloropyridin-3-yl)-5-oxoheptyl)oxy)pyrrolidine-1-carboxylate [ka] A mixture of tert-butyl (3R)-3-((5-hydroxyhept-6-en-1-yl)oxy)pyrrolidine-1-carboxylate (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) (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 HO (100 mL), and extracted with EtOAc (100 mL × 3). The combined organic layer was concentrated in vacuo, and the residue was purified by silica gel chromatography (EtOAc / petroleum ether=0% to 50%) to give the desired product, tert-butyl (R)-3-((7-(2-chloropyridin-3-yl)-5-oxoheptyl)oxy)pyrrolidine-1-carboxylate (1.5 g) as a colorless oil. Yield 54% (ESI 411 [M+H]+).

[0679] Step 5: tert-Butyl (3R)-3-((5-amino-7-(2-chloropyridin-3-yl)heptyl)oxy)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl (R)-3-((7-(2-chloropyridin-3-yl)-5-oxoheptyl)oxy)pyrrolidine-1-carboxylate (1.5 g, 3.65 mmol) in methanol (20 mL) was added ammonium acetate (2.81 g, 36.5 mmol). The mixture was stirred at room temperature for 10 minutes, and then sodium cyanoborohydride (692 mg, 11 mmol) was added. The mixture was stirred at room temperature for 20 hours, quenched with 1 M NaOH (100 mL), and extracted with DCM (200 mL). The organic layer was concentrated in vacuo to give crude product tert-butyl (3R)-3-((5-amino-7-(2-chloropyridin-3-yl)heptyl)oxy)pyrrolidine-1-carboxylate (1.4 g) as a brown oil. Yield 93% (ESI 412 [M+H]+).

[0680] Step 6: tert-Butyl (3R)-3-(4-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl (3R)-3-((5-amino-7-(2-chloropyridin-3-yl)heptyl)oxy)pyrrolidine-1-carboxylate (1.4 g, 3.4 mmol) in DMF (20 mL) was added cesium carbonate (3.33 g, 10.2 mmol). The mixture was stirred at 130 °C for 20 h. The mixture was cooled to room temperature, diluted with HO (100 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated in vacuo, and the residue was purified by silica gel chromatography (EtOAc / petroleum ether = 0% to 50%) to give the desired product, tert-butyl (3R)-3-(4-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate (810 mg). Yield: 64% (ESI 376 [M+H]+). The racemic products were separated by preparative chiral SFC to give P1 (270 mg arbitrarily assigned as tert-butyl (R)-3-(4-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate) and P2 (250 mg arbitrarily assigned as tert-butyl (R)-3-(4-((R)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate) as pale yellow oils.

[0681] Step 7: (S)-2-(4-(((R)-pyrrolidin-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine [ka] Tert-butyl (R)-3-(4-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate (P1, 1.1 g, 2.93 mmol) was treated with 4 M HCl / dioxane (5 mL) at room temperature for 12 hours. The reaction mixture was concentrated in vacuo to give the desired product, (S)-2-(4-(((R)-pyrrolidin-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (766 mg). Yield: 95% (ESI 276 (M+H)+).

[0682] Preparation of (S)-2-(4-(((R)-pyrrolidin-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine [ka] Tert-butyl (R)-3-(4-((R)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1-carboxylate (P2, 1.1 g, 2.93 mmol) was treated with 4 M HCl / dioxane (5 mL) at room temperature for 12 hours. The reaction mixture was concentrated in vacuo to give the desired product, (R)-2-(4-(((R)-pyrrolidin-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (766 mg). Yield: 95% (ESI 276 (M+H)+).

[0683] Preparation of (S)-2-(6-(((R)-pyrrolidin-3-yl)oxy)hexyl)-1,2,3,4-tetrahydro-1,8-naphthyridine Step 1: tert-Butyl (R)-3-(oct-7-en-1-yloxy)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (20 g, 170 mmol) in n-heptane (250 mL) was added 50% aqueous sodium hydroxide (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 NaSO, filtered, concentrated in vacuo, and the residue was purified by silica gel column (petroleum ether: EtOAc 4:1) to give the desired product tert-butyl (R)-3-(oct-7-en-1-yloxy)pyrrolidine-1-carboxylate as a colorless oil (32 g). Yield 99% (ESI 298 (M+H)+).

[0684] Step 2: tert-Butyl (R)-3-((7-oxoheptyl)oxy)pyrrolidine-1-carboxylate [ka] A mixture of tert-butyl (R)-3-(oct-7-en-1-yloxy)pyrrolidine-1-carboxylate (7.5 g, 25.2 mmol), potassium osmate(VI) dihydrate (464 mg, 1.26 mmol), and sodium periodate (16.2 g, 75.6 mmol) in 150 mL of THF and 150 mL of HO 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 NaSO, filtered, and concentrated in vacuo to give crude tert-butyl (R)-3-((7-oxopentyl)oxy)pyrrolidine-1-carboxylate (7.5 g) as a colorless oil. Yield: 99% (ESI 300 (M+H)+).

[0685] Step 3: tert-Butyl (3R)-3-((7-hydroquinone-8-en-1-yl)oxy)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl (R)-3-((7-oxopentyl)oxy)pyrrolidine-1-carboxylate (7.5 g, 25 mmol) in THF (50 mL) was added vinylmagnesium bromide (1.0 M in THF, 50 mL, 50 mmol) dropwise over 30 minutes at −10° C. The mixture was stirred at room temperature overnight and then quenched with water (20 mL). The precipitated solid was removed by filtration, and the filtrate was extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with water, dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 5:1) to give the desired product, tert-butyl (3R)-3-((7-hydroxynon-8-en-1-yl)oxy)pyrrolidine-1-carboxylate (4.3 g) as a pale yellow oil. Yield 53% (ESI 328 [M+H]+).

[0686] Step 4: tert-Butyl (R)-3-((9-(2-chloropyridin-3-yl)-7-oxononyl)oxy)pyrrolidine-1-carboxylate [ka] A mixture of tert-butyl (3R)-3-((7-hydroxynon-8-en-1-yl)oxy)pyrrolidine-1-carboxylate (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) (634 mg, 2.43 mmol) in DMF (100 mL) was stirred overnight at 70 °C. The mixture was cooled to room temperature, diluted with HO (100 mL), and extracted with EtOAc (100 mL × 3). The combined organic layer was concentrated in vacuo, and the residue was purified by silica gel chromatography (EtOAc / petroleum ether=0% to 50%) to give the desired product, tert-butyl (R)-3-((9-(2-chloropyridin-3-yl)-7-oxononyl)oxy)pyrrolidine-1-carboxylate (2.6 g) as a colorless oil in 45% yield (ESI 438 [M+H]+).

[0687] Step 5: tert-Butyl (3R)-3-((7-amino-9-(2-chloropyridin-3-yl)nonyl)oxy)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl (R)-3-((9-(2-chloropyridin-3-yl)-7-oxononyl)oxy)pyrrolidine-1-carboxylate (2.6 g, 5.9 mmol) in methanol (20 mL) was added ammonium acetate (1.4 g, 18.0 mmol). The mixture was stirred at room temperature for 10 minutes, and then sodium cyanoborohydride (692 mg, 11 mmol) was added. The mixture was stirred at room temperature for 20 hours, quenched with 1 M NaOH (100 mL), and extracted with DCM (200 mL). The organic layer was concentrated in vacuo to give crude product tert-butyl (3R)-3-((7-amino-9-(2-chloropyridin-3-yl)nonyl)oxy)pyrrolidine-1-carboxylate (2.5 g) as a brown oil. Yield 95% (ESI 440 [M+H]+).

[0688] Step 6: tert-Butyl (3R)-3-((6-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)hexyl)oxy)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl (3R)-3-((7-amino-9-(2-chloropyridin-3-yl)nonyl)oxy)pyrrolidine-1-carboxylate (2.5 g, 5.7 mmol) in DMF (20 mL) was added cesium carbonate (5.0 g, 15.3 mmol). The mixture was stirred at 130 °C for 20 h. The mixture was cooled to room temperature, diluted with HO (100 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated in vacuo, and the residue was purified by silica gel chromatography (EtOAc / petroleum ether = 0% to 50%) to give the desired product, tert-butyl (3R)-3-((6-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)hexyl)oxy)pyrrolidine-1-carboxylate (1.3 g). Yield: 57% (ESI 403 [M+H]+). The racemic products were separated by preparative chiral SFC to give P1 (502 mg arbitrarily assigned as tert-butyl (R)-3-((6-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)hexyl)oxy)pyrrolidine-1-carboxylate) and P2 (490 mg arbitrarily assigned as tert-butyl (R)-3-((6-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)hexyl)oxy)pyrrolidine-1-carboxylate) as pale yellow oils.

[0689] Step 7: (S)-2-(6-(((R)-pyrrolidin-3-yl)oxy)hexyl)-1,2,3,4-tetrahydro-1,8-naphthyridine [ka] Tert-butyl (R)-3-((6-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)hexyl)oxy)pyrrolidine-1-carboxylate (P1, 250 mg, 0.62 mmol) was treated with 4 M HCl / dioxane (5 mL) at room temperature for 12 hours. The reaction mixture was concentrated in vacuo to give the desired product, (S)-2-(6-(((R)-pyrrolidin-3-yl)oxy)hexyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (185 mg). Yield: 98% (ESI 304 (M+H)+).

[0690] Preparation of (S)-2-(6-(((R)-pyrrolidin-3-yl)oxy)hexyl)-1,2,3,4-tetrahydro-1,8-naphthyridine [ka] Tert-butyl (R)-3-((6-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)hexyl)oxy)pyrrolidine-1-carboxylate (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 in vacuo to give the desired product, (S)-2-(6-(((R)-pyrrolidin-3-yl)oxy)hexyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (233 mg), which was used in the next step without further purification. Yield 100% (ESI 304.2 (M+H)+).

[0691] Preparation of (R)-5-methyl-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine Step 1: tert-Butyl (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (10.0 g, 53.4 mmol) in n-heptane (120 mL) was added 50% aqueous sodium hydroxide (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 h. 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 organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 4:1) to give the desired product tert-butyl (S)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate as a colorless oil (13 g), yield 95% (ESI 256.2 (M+H)+).

[0692] Step 2: tert-Butyl (R)-3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (2.5 g, 9.8 mmol) in THF (5 mL) was added 9-BBN (35.2 mL, 17.6 mmol, 0.5 N in THF) under a N atmosphere. The mixture was stirred at 60 °C for 1.5 h and cooled to room temperature. tert-Butyl 7-chloro-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (1.95 g, 9.8 mmol), Pd(OAc) (54 mg, 0.5 mmol), PCy (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, tert-butyl (R)-3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate, as a yellow oil (3.1 g). Yield 75% (ESI 420.2 (M+H)+).

[0693] Step 3: tert-Butyl (R)-3-((5-(4-methyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] A mixture of tert-butyl (R)-3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (3.1 mg, 7.4 mmol), methylboronic acid (530 mg, 8.9 mmol), Pd(dppf)Cl (541 mg, 0.74 mmol), and KCO (2.04 g, 14.8 mmol) in 30 mL of dioxane and 3 mL of HO was stirred at 80 °C for 4 h. The mixture was concentrated and purified by silica gel chromatography (EtOAc:petroleum ether = 0% to 70%) to give the desired product, tert-butyl (R)-3-((5-(4-methyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.25 g). Yield: 42% (ESI 400.2 (M+H)+).

[0694] Step 4: tert-Butyl (R)-3-((5-(4-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] A mixture of tert-butyl (R)-3-((5-(4-methyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.25 g, 3.13 mmol) and Pd / C (125 mg, 10% on activated carbon) in 10 mL of MeOH was stirred under a hydrogen atmosphere at room temperature for 16 hours. The mixture was filtered, and the filtrate was concentrated to give the desired product, tert-butyl (R)-3-((5-(4-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.15 g). Yield 91% (ESI 404.3 (M+H)+).

[0695] Step 5: (R)-5-methyl-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine [ka] Tert-butyl (R)-3-((5-(4-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.15 g, 2.85 mmol) was added to a solution of HCl / dioxane (10 mL, 4N). The mixture was stirred at room temperature for 16 hours and concentrated to give the desired product, (R)-5-methyl-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine, as a white solid (700 mg), which was used in the next step without further purification. Yield 100% (ESI 304.2 (M+H)+).

[0696] Preparation of (R)-5-methyl-6-methyl-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine Step 1: 3-Methyl-1,8-naphthyridine-2,4-diol [ka] To a solution of methyl 2-aminonicotinate (5.2 g, 34 mmol) and methyl propionate (39 g, 0.44 mol) in THF (60 mL) was added t-BuOK (9.5 g, 85 mmol). 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 HO, and the aqueous phase was adjusted to pH 6 with 1 N aqueous HCl. A precipitate formed, which was filtered and dried to give the desired product, 3-methyl-1,8-naphthyridine-2,4-diol, as a light brown solid (2.3 g). Yield: 38% (ESI 177.2 (M+H)+).

[0697] Step 2: 2,4-chloro-3-methyl-1,8-naphthyridine [ka] A mixture of 3-methyl-1,8-naphthyridine-2,4-diol (2.3 g, 13 mmol) in POCl (25 mL) was stirred at 120 °C for 2 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with saturated aqueous NaHCO (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic phase was concentrated in vacuo, 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-naphthyridine, as a light brown solid (1.12 g). Yield 41% (ESI 213.1 (M+H)).

[0698] Step 2: tert-Butyl (R)-3-((5-(4-chloro-3-methyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] A solution of tert-butyl (R)-3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (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 for 2 hours under an argon atmosphere. The resulting mixture was cooled to room temperature, and 2,4-dichloro-3-methyl-1,8-naphthyridine (1.42 g, 6.67 mmol), Pd(OAc) (150 mg, 0.67 mmol), PCy (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 tert-butyl (R)-3-((5-(4-chloro-3-methyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate as a yellow oil (1.4 g). Yield 50% (ESI 434.2 (M+H)+).

[0699] Step 3: tert-Butyl (R)-3-((5-(4-methoxy-3-methyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate [ka] A mixture of tert-butyl (R)-3-((5-(4-chloro-3-methyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.7 g, 3.9 mmol) and NaOMe (30% in MeOH, 30 mL) was stirred at 50° C. for 2 hours. The resulting mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phase was concentrated to give tert-butyl (R)-3-((5-(4-methoxy-3-methyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.2 g) as a pale yellow oil. Yield 71% (ESI 430.3 (M+H)+).

[0700] Step 4: (R)-5-Methoxy-6-methyl-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine [ka] To a solution of tert-butyl (R)-3-((5-(4-methoxy-3-methyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (1.2 g, 2.8 mmol) in 40 mL of EtOAc was added Pd / C (10%, 200 mg). The resulting mixture was stirred under a hydrogen atmosphere at 50° C. for 16 hours, then filtered, and the filtrate was concentrated in vacuo. 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 hours and concentrated to give (R)-5-methoxy-6-methyl-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (530 mg), which was used directly in the next step. ESI 334.2 (M+H)+.

[0701] Right side of exemplary compound Preparation of (3-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid Step 1: 1-(3-bromo-5-fluoro-4-hydroxyphenyl)ethanone [ka] To a solution of 1-(3-fluoro-4-hydroxyphenyl)ethanone (25 g, 162.19 mmol) in DMF (250 mL) was added NBS (30 g, 168.55 mmol) in portions. The mixture was stirred at 25 °C for 16 h. Four parallel reactions were performed and worked up 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 NaSO, filtered, and concentrated under reduced pressure to give 1-(3-bromo-5-fluoro-4-hydroxyphenyl)ethanone (151.19 g, crude) as a red oil.

[0702] Step 2: 1-(3-bromo-5-fluoro-4-methoxyphenyl)ethanone [ka] To a solution of 1-(3-bromo-5-fluoro-4-hydroxyphenyl)ethanone (37.5 g, 160.92 mmol) in DMF (450 mL) was added K2CO3 (55.60 g, 402.30 mmol) 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 reaction at 0-5 °C. The mixture was stirred at 25 °C for 15.5 h. Four parallel reactions were performed and worked up 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 a 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)ethanone (130 g, 526.19 mmol, yield 81.1%) as a yellow oil. 1 H NMR (400MHz, chloroform-d) δ=7.92(t,J=1.7Hz,1H), 7.65(dd,J=2.1,11.8Hz,1H), 4.07(d,J=2.8Hz,3H), 2.55(s,3H).

[0703] Step 3: 1-Bromo-3-fluoro-2-methoxy-5-(prop-1-en-2-yl)benzene [ka] To a solution of (methyltriphenyl)phosphanium bromide (48.00 g, 134.38 mmol) in THF (200 mL) was added t-BuOK (18.85 g, 167.97 mmol) 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)ethanone (16.6 g, 67.19 mmol) in THF (50 mL) was added dropwise to the mixture at 0 °C, and the reaction 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 HO (200 mL x 2) and brine (200 mL x 2), dried over NaSO, filtered, and concentrated to give a crude residue. The residue was purified by column chromatography (SiO, 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 H 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).

[0704] Step 4: 1-Bromo-3-fluoro-5-isopropyl-2-methoxybenzene [ka] 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) was added Pd / C (4 g, 10% purity). The suspension was degassed under reduced pressure and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 12 h. The reaction (five parallel reactions) was 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 obtained as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.18 (s, 1H), 6.92 (dd, J = 1.8, 12.0 Hz, 1H), 3.93 (s, 3H), 2.84 (td, J = 6.9, 13.8 Hz, 1H), 1.23 (s, 3H), 1.21 (s, 3H).

[0705] Step 5: (3-Fluoro-5-isopropyl-2-methoxyphenyl)boronic acid [ka] 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 N. The resulting mixture was stirred at −78° C. for 1 h and at 20° C. for 1 h. The reaction mixture was quenched with ice water (100 mL). Then, the pH was adjusted to 5 with aqueous HCl (1 M). The resulting mixture was extracted with ethyl acetate (100 mL × 2), and the combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® silica flash column, eluting with a 0-50% acetone / petroleum ether gradient at 100 mL / min) to give (3-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (1.8 g, 8.49 mmol, 83.91% yield) as a yellow oil. 1 H NMR (400MHz, methanol-d4) δ=7.00(dd,J=1.9,13.4Hz,1H), 6.89(s,1H), 3.94-3.80(m,3H), 2.86(td,J=6.9,13.8Hz,1H), 1.22(d,J=6.9Hz,6H). LCMS(ESI)m / z=213.1(M+1).

[0706] Preparation of ethyl 2-bromo-2-(4-(cyclopropylmethyl)-2-methoxyphenyl)acetate Step 1: 1-Bromo-4-(cyclopropylmethyl)-2-methoxybenzene [ka] A mixture of 4-bromo-3-methoxybenzaldehyde (1.0 g, 4.65 mmol) and 4-methylbenzenesulfonhydrazide (1.04 g, 5.58 mmol) in MeOH (20 mL) was stirred at room temperature for 30 min. The solvent was removed under reduced pressure, diluted with dixoane (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 N for 16 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column (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]+).

[0707] Step 2: Ethyl 2-(4-(cyclopropylmethyl)-2-methoxyphenyl)acetate [ka] To a mixture of 1-bromo-4-(cyclopropylmethyl)-2-methoxybenzene (466 mg, 1.93 mmol), Q-phos (43 mg, 0.06 mmol), and Pd(dba) (55 mg, 0.06 mmol) in THF (10 mL) was added (2-ethoxy-2-oxoethyl)zinc(II) bromide (1 M in THF, 4.8 mL). The reaction mixture was stirred at 50 °C under N for 1 h. The reaction was quenched with aqueous NaHCO and extracted with EtOAc (2 × 20 mL). The combined organic layers were concentrated in vacuo, and the residue was purified by silica gel column (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]+).

[0708] Step 3: Ethyl 2-bromo-2-(4-(cyclopropylmethyl)-2-methoxyphenyl)acetate [ka] To a solution of ethyl 2-(4-(cyclopropylmethyl)-2-methoxyphenyl)acetate (460 mg, 1.85 mmol) in THF (20 mL) at −78° C. was added dropwise a 2.0 M solution of lithium diisopropylamide in THF / hexane (2.30 mL, 4.6 mmol). The reaction was stirred at −78° C. for 30 minutes, then chlorotrimethylsilane (0.49 g, 4.51 mmol) was added and the reaction was stirred at −78° C. for an additional 30 minutes. A solution of NBS (0.80 g, 4.51 mmol) in THF (10 mL) was then added and the reaction was stirred at −78° C. for 30 minutes. The reaction was quenched with HO (10 mL) and then extracted with EtOAc (20 mL × 3). The combined organic phase was washed with saturated aqueous NaHCO, brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether / EtOAc=0%~10%) to give the desired product, ethyl 2-bromo-2-(4-(cyclopropylmethyl)-2-methoxyphenyl)acetate, as a light brown oil (340 mg, yield 56%). ESI 327 / 329 (M+H)+.

[0709] Preparation of ethyl 2-bromo-2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)acetate Step 1: 3-Bromo-5-chloro-4-methoxybenzaldehyde [ka] To a solution of 3-bromo-5-chloro-4-hydroxybenzaldehyde (3.0 g, 12.82 mmol) in DMF (20 mL) was added MeI (2.73 g, 19.23 mmol) and K2CO3 (3.54 g, 25.64 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 5:1) to give the desired product, 3-bromo-5-chloro-4-methoxybenzaldehyde, as a white solid (1.8 g). Yield 57% (ESI 249 (M+H)+).

[0710] Step 2: 1-Bromo-3-chloro-5-(cyclopropylmethyl)-2-methoxybenzene [ka] To a solution of 3-bromo-5-chloro-4-methoxybenzaldehyde (1.8 g, 7.26 mmol) in MeOH (20 mL) was added TsNHNH (1.49 g, 7.986 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was dissolved in 1,4-dioxane (30 mL), and cyclopropylboronic acid (1.25 g, 14.52 mmol) and DBU (2.2 g, 14.52 mmol) were added. The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was quenched with HO (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 10:1) to give the desired product 1-bromo-3-chloro-5-(cyclopropylmethyl)-2-methoxybenzene as a colorless oil (1.1 g), yield 55% (ESI 275 (M+H)+).

[0711] Step 3: Ethyl 2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)acetate [ka] To a mixture of 1-bromo-3-chloro-5-(cyclopropylmethyl)-2-methoxybenzene (1100 mg, 3.99 mmol), Q-phos (89 mg, 0.12 mmol), and Pd(dba) (114 mg, 0.12 mmol) in THF (10 mL) was added (2-ethoxy-2-oxoethyl)zinc(II) bromide (1 M in THF, 10 mL). The reaction mixture was stirred under N at 50 °C for 1 h. The reaction was quenched with aqueous NaHCO and extracted with EtOAc (2 × 20 mL). The combined organic layers were concentrated in vacuo, and the residue was purified by silica gel column (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]+).

[0712] Step 4: Ethyl 2-bromo-2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)acetate [ka] To a solution of ethyl 2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)acetate (282 mg, 1.0 mmol) in THF (20 mL) at −78° C. was added dropwise a 2.0 M solution of lithium diisopropylamide in THF / hexane (2.5 mL, 2.5 mmol). The reaction was stirred at −78° C. for 30 minutes, then chlorotrimethylsilane (272 mg, 2.5 mmol) was added, and the reaction was stirred at −78° C. for an additional 30 minutes. A solution of NBS (445 mg, 2.5 mmol) in THF (5 mL) was then added, and the reaction was stirred at −78° C. for 30 minutes. The reaction was quenched with HO (10 mL) and then extracted with EtOAc (20 mL × 3). The combined organic phase was washed with saturated aqueous NaHCO, brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether / EtOAc=0%~10%) to give the desired product, ethyl 2-bromo-2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)acetate, as a light brown oil (320 mg, yield 88%). ESI 361(M+H)+.

[0713] Preparation of ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-methoxyphenyl)acetate Step 1: 2-Bromo-4-(cyclopropylmethyl)-1-methoxybenzene [ka] To a solution of 3-bromo-4-methoxybenzaldehyde (1.0 g, 4.65 mmol) in MeOH (20 mL) was added TsNHNH (0.96 g, 5.12 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was dissolved in 1,4-dioxane (30 mL), and cyclopropylboronic acid (799 mg, 9.30 mmol) and DBU (1.42 g, 9.30 mmol) were added. The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was quenched with HO (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 10:1) to give the desired product 2-bromo-4-(cyclopropylmethyl)-1-methoxybenzene as a colorless oil (370 mg, 1.53 mmol), yield 33% (ESI 241 (M+H)+).

[0714] Step 2: Ethyl 2-(5-(cyclopropylmethyl)-2-methoxyphenyl)acetate [ka] To a mixture of 2-bromo-4-(cyclopropylmethyl)-1-methoxybenzene (370 mg, 1.53 mmol), Q-phos (34 mg, 0.05 mmol), and Pd(dba) (44 mg, 0.05 mmol) in THF (10 mL) was added (2-ethoxy-2-oxoethyl)zinc(II) bromide (1 M in THF, 3.8 mL). The reaction mixture was stirred at 50 °C under N for 1 h. The reaction was quenched with aqueous NaHCO and extracted with EtOAc (2 × 20 mL). The combined organic layers were concentrated in vacuo, and the residue was purified by silica gel column (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]).

[0715] Step 3: Ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-methoxyphenyl)acetate [ka] To a solution of ethyl 2-(5-(cyclopropylmethyl)-2-methoxyphenyl)acetate (248 mg, 1.0 mmol) in THF (20 mL) at −78° C. was added dropwise a 2.0 M solution of lithium diisopropylamide in THF / hexane (2.5 mL, 2.5 mmol). The reaction was stirred at −78° C. for 30 minutes, then chlorotrimethylsilane (272 mg, 2.5 mmol) was added and the reaction was stirred at −78° C. for an additional 30 minutes. A solution of NBS (445 mg, 2.5 mmol) in THF (5 mL) was then added and the reaction was stirred at −78° C. for 30 minutes. The reaction was quenched with HO (10 mL) and then extracted with EtOAc (20 mL × 3). The combined organic phase was washed with saturated aqueous NaHCO, brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether / EtOAc=0%~10%) to give the desired product, ethyl 2-bromo-2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)acetate, as a light brown oil (287 mg, yield 88%). ESI 327(M+H)+.

[0716] Preparation of ethyl 2-bromo-2-(5-chloro-2-(cyclopropylmethoxy)phenyl)acetate Step 1: 2-Bromo-4-chloro-1-(cyclopropylmethoxy)benzene [ka] To a solution of 2-bromo-4-chlorophenol (1.0 g, 4.85 mmol) in DMF (10 mL) was added (bromomethyl)cyclopropane (976 mg, 7.28 mmol) and K2CO3 (1.34 g, 9.7 mmol). The mixture was stirred at room temperature for 2 h. The reaction was diluted with HO (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether: EtOAc 5:1) to give the desired product, 2-bromo-4-chloro-1-(cyclopropylmethoxy)benzene, as a yellow oil (940 mg). Yield 74% (ESI 261 (M+H)+).

[0717] Step 2: Ethyl 2-(5-chloro-2-(cyclopropylmethoxy)-phenyl)acetate [ka] To a mixture of 2-bromo-4-chloro-1-(cyclopropylmethoxy)benzene (940 mg, 3.59 mmol), Q-phos (80 mg, 0.12 mmol), and Pd(dba) (103 mg, 0.12 mmol) in THF (10 mL) was added (2-ethoxy-2-oxoethyl)zinc(II) bromide (1 M in THF, 8.9 mL). The reaction mixture was stirred at 50 °C under N for 1 h. The reaction was quenched with aqueous NaHCO and extracted with EtOAc (2 × 20 mL). The combined organic layers were concentrated in vacuo, and the residue was purified by silica gel column (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]+).

[0718] Step 3: Ethyl 2-bromo-2-(5-chloro-2-(cyclopropylmethoxy)-phenyl)acetate [ka] To a solution of ethyl 2-(5-chloro-2-(cyclopropylmemethoxy)phenyl)acetate (268 mg, 1.0 mmol) in THF (20 mL) at −78° C. was added dropwise a 2.0 M solution of lithium diisopropylamide in THF / hexane (2.5 mL, 2.5 mmol). The reaction was stirred at −78° C. for 30 minutes, then chlorotrimethylsilane (272 mg, 2.5 mmol) was added and the reaction was stirred at −78° C. for an additional 30 minutes. A solution of NBS (445 mg, 2.5 mmol) in THF (5 mL) was then added and the reaction was stirred at −78° C. for 30 minutes. The reaction was quenched with HO (10 mL) and then extracted with EtOAc (20 mL × 3). The combined organic layers were washed with saturated aqueous NaHCO, brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column (petroleum ether / EtOAc=0%~10%) to give the desired product, ethyl 2-bromo-2-(5-chloro-2-(cyclopropylmethoxy)phenyl)acetate, as a light brown oil (270 mg, yield 78%). ESI 347(M+H)+.

[0719] Preparation of ethyl 2-bromo-2-(2-methoxy-5-((1-methoxycyclopropyl)methyl)phenyl)acetate Step 1: Methyl 2-(3-bromo-4-methoxyphenyl)acetate [ka] 1 mL of H2SO4 (1 mL, concentrated) 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 h. The mixture was concentrated and dissolved in 50 mL of EtOAc. The mixture was washed with water, aqueous 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)+).

[0720] Step 2: 1-(3-bromo-4-methoxybenzyl)cyclopropan-1-ol [ka] EtMgBr (6.5 mL, 13 mmol, 2N 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 adding 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)cyclopropan-1-ol (1.2 g), as a colorless oil. Yield: 90% (ESI 257.1 (M+H)+).

[0721] Step 3: 2-Bromo-1-methoxy-4-((1-methoxycyclopropyl)methyl)benzene [ka] NaH (188 mg, 4.7 mmol, 60% in mineral oil) was added to a stirred solution of 1-(3-bromo-4-methoxybenzyl)cyclopropan-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)+).

[0722] Step 4: Ethyl 2-(2-methoxy-5-((1-methoxycyclopropyl)methyl)phenyl)acetate [ka] (2-(tert-Butoxy)-2-oxoethyl)zinc(II) bromide (6.5 mL, 6.5 mmol, 1N 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 h, concentrated, and purified by silica gel column (EtOAc:petroleum ether = 0% to 10%) to give the desired product, ethyl 2-(2-methoxy-5-((1-methoxycyclopropyl)methyl)phenyl)acetate, as an orange oil (278 mg). Yield 77% (ESI 279.1 (M+H)+).

[0723] Step 5: Ethyl 2-bromo-2-(2-methoxy-5-((1-methoxycyclopropyl)methyl)phenyl)acetate [ka] 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 × 3). The combined organic solvents were concentrated, and the residue was purified by silica gel chromatography (EtOAc:petroleum ether = 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)+).

[0724] Preparation of ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-trifluoromethoxy)phenyl)acetate Step 1: N'-(3-bromo-4-(trifluoromethoxy)benzylidene)-4-methylbenzenesulfonohydrazide [ka] 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 h. The mixture was concentrated in vacuo, 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 h, concentrated, and purified by silica gel chromatography (EtOAc:petroleum ether = 0% to 20%) to give the desired product, N'-(3-bromo-4-(trifluoromethoxy)benzylidene-4-methylbenzenesulfonohydrazide), as a colorless oil (1.03 g). Yield: 47% (ESI 295.1 (M+H)+).

[0725] Step 2: Ethyl 2-(5-(cyclopropylmethyl)-2-trifluoromethoxy)phenyl)acetate [ka] (2-(tert-Butoxy)-2-oxoethyl)zinc(II) bromide (4.5 mL, 4.5 mmol, 1N in THF) was added to a solution 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 h, concentrated, and purified by silica gel column (EtOAc:petroleum ether = 0% to 15%) to give the desired product, ethyl 2-(5-(cyclopropylmethyl)-2-(trifluoromethoxy)phenyl)acetate, as an orange oil (342 mg). Yield 75% (ESI 303.1 (M+H)+).

[0726] Step 3: Ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-trifluoromethoxy)phenyl)acetate [ka] LDA (1.4 mL, 2.8 mmol, 2N in THF) was added to a solution of ethyl 2-(5-(cyclopropylmethoxy)-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 × 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)+).

[0727] Preparation of ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-methoxymethyl)phenyl)acetate Step 1: Methyl 3-bromo-4-(bromomethyl)benzoate [ka] A mixture of 3-bromo-4-methyl-benzoic acid methyl ester (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 to reflux for 4 h. The reaction was cooled to room temperature, and the precipitate was filtered and rinsed with CCl4. The combined filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (5% EtOAc in hexanes) to give 4.7 g of 3-bromo-4-bromomethyl-benzoic acid methyl ester. Yield 76% (ESI 307.2 (M+H)+).

[0728] Step 2: Methyl 3-bromo-4-(methoxymethyl)benzoate [ka] MeONa (2.8 g, 51 mmol) was added to a mixture of methyl 3-bromo-4-(bromomethyl)benzoate (4.5 g, 14.7 mmol) in MeOH (30 mL) at room temperature. The mixture was stirred at 50 °C for 1 h, quenched with water (30 mL), and extracted with EtOAc (30 mL x 3). The combined organic solvent was 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)+).

[0729] Step 3: (3-bromo-4-(methoxymethyl)phenyl)methanol [ka] 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 h. The mixture was quenched with saturated NH 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)+).

[0730] Step 4: 2-Bromo-4-(bromomethyl)-1-(methoxymethyl)benzene [ka] 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. The mixture was stirred at room temperature for 2 h, quenched with water (25 mL), and extracted with DCM (25 mL x 2). The combined organic solvent was concentrated in vacuo, 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)+).

[0731] Step 5: 2-Bromo-4-(cyclopropylmethyl)-1-(methoxymethyl)benzene [ka] 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 added slowly at 0 °C. The mixture was then stirred at room temperature for 4 h, quenched with aqueous NaHCO3, and extracted with EtOAc (20 mL × 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-(cyclopropylmethyl)-1-(methoxymethyl)benzene (940 mg). Yield: 43% (ESI 255.1 (M+H)+).

[0732] Step 6: Ethyl 2-(5-(cyclopropylmethyl)-2-(methoxymethyl)phenyl)acetate [ka] (2-Ethoxy-2-oxoethyl)zinc(II) bromide (4.5 mL, 4.5 mmol, 1N in THF) was added to a solution of 2-bromo-4-(cyclopropylmethyl)-1-(methoxymethyl)benzene (381 g, 1.5 mmol), Pd(dba) (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 h, concentrated, and purified by silica gel column (EtOAc:petroleum ether = 0% to 10%) to give the desired product, 2-(5-(cyclopropylmethyl)-2-(methoxymethyl)phenyl)ethyl acetate, as a yellow oil (304 mg). Yield: 77% (ESI 263.1 (M+H)+).

[0733] Step 7: Ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-(methoxymethyl)phenyl)acetate [ka] LDA (1.1 mL, 2.2 mmol, 2N in THF) was added to a mixture of ethyl 2-(5-(cyclopropylmethoxy)-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 × 3). The combined organic solvents were concentrated, and the residue was purified by silica gel chromatography (EtOAc:petroleum ether = 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)+).

[0734] Preparation of (2,5-difluoro-3-isopropyl-6-methoxyphenyl)boronic acid Step 1: 1-Bromo-2,5-difluoro-4-methoxybenzene [ka] 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 h. 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 in vacuo. The residue was purified by MPLC (Biotage®; 80 g SepaFlash® silica flash column, eluent of 0-3% ethyl acetate / petroleum ether gradient, 150 mL / min) to give 1-bromo-2,5-difluoro-4-methoxybenzene (10.4 g, 46.63 mmol, 97.5% yield) as a white solid. 1 H 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).

[0735] Step 2: 1,4-Difluoro-2-methoxy-5-(prop-1-en-2-yl)benzene [ka] 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-dioxaborolane (15.45 g, 91.92 mmol), KPO (23.41 g, 110.31 mmol), PPh (2.89 g, 11.03 mmol), and Pd(OAc) (825.49 mg, 3.68 mmol) in dioxane (160 mL) and water (16 mL) was stirred at 100 °C for 3 h under a N atmosphere. The mixture was cooled to 25 °C and partitioned between ethyl acetate (150 mL) and water (200 mL). The aqueous phase was extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The mixture was purified by MPLC (Biotage®; 120 g SepaFlash® silica flash column, eluting with a 0-1% ethyl acetate / petroleum ether gradient at 150 mL / min). The crude product was purified by RP-MPLC (neutral, MeOH / HO) to give 1,4-difluoro-2-methoxy-5-(prop-1-en-2-yl)benzene (2.4 g, 13.03 mmol, 28.4% yield) as a pale yellow oil. 1 H NMR (400MHz, chloroform-d) δ=7.04(dd,J=7.2,12.1Hz,1H), 6.68(dd,J=7.2,11.8Hz,1H ), 5.24(d,J=0.7Hz,1H), 5.21(d,J=1.1Hz,1H), 3.88(s,3H), 2.11(d,J=0.7Hz,3H).

[0736] Step 3: 1,4-Difluoro-2-isopropyl-5-methoxybenzene [ka] A suspension of 1,4-difluoro-2-methoxy-5-(prop-1-en-2-yl)benzene (2.2 g, 11.94 mmol) and Pd / C (0.5 g, 10% purity) in MeOH (100 mL) was stirred under H (40 psi) at 25 °C for 3 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by MPLC (Biotage®; 40 g SepaFlash® silica flash column, eluent: 0–1% ethyl acetate / petroleum ether gradient, 120 mL / min) to afford 1,4-difluoro-2-isopropyl-5-methoxybenzene (1.9 g, 10.20 mmol, 78.4% yield) as a colorless oil. 1 H NMR (400MHz, chloroform-d) δ=6.95(dd,J=7.1,12.2Hz,1H), 6.66(dd,J=7.3,11.3Hz,1H), 3.86(s,3H), 3.16(spt,J=6.9Hz,1H), 1.22(d,J=7.0Hz,6H).

[0737] Step 4: (2,5-Difluoro-3-isopropyl-6-methoxyphenyl)boronic acid [ka] To a solution of 1,4-difluoro-2-isopropyl-5-methoxybenzene (1.8 g, 9.67 mmol) in THF (30 mL) was added LDA (2 M, 6.28 mL) under a N atmosphere at −78° C. The reaction was stirred at −78° C. for 0.5 h. Trimethyl borate (3.01 g, 29.00 mmol) in THF (5 mL) was added to the reaction. The reaction was stirred at −78° C. for 2 h. The reaction mixture was quenched with aqueous NH4Cl (40 mL) at 0° C. 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 a residue. The residue was purified by MPLC (Biotage®; 20 g SepaFlash® silica flash column, eluent of 0-33% ethyl acetate / petroleum ether gradient, 120 mL / min) to give (2,5-difluoro-3-isopropyl-6-methoxyphenyl)boronic acid (2.2 g, 9.56 mmol, 98.9% yield) as a white solid. 1 H NMR (400MHz, chloroform-d) δ=7.11(dd,J=7.7,12.5Hz,1H), 6.33(d,J=7.5Hz,2H), 4.04(d,J=2.2Hz,3H), 3.20(td,J=6.9,13.8Hz,1H), 1.23(d,J=7.0Hz,6H).

[0738] Preparation of (3,4-difluoro-5-isopropyl-2-methoxyphenyl)boronic acid Step 1: 2,3-Difluoro-1-methoxy-4-(prop-1-en-2-yl)benzene [ka] A solution of 1-bromo-2,3-difluoro-4-methoxybenzene (25 g, 112.10 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (47.09 g, 280.25 mmol), PPh (8.82 g, 33.63 mmol), KPO (71.39 g, 336.30 mmol), and Pd(OAc) (2.52 g, 11.21 mmol) in dioxane (500 mL) and water (50 mL) was stirred at 100 °C for 10 h under a N atmosphere. The mixture was cooled to 25 °C and partitioned between MTBE (300 mL) and water (500 mL). The mixture was filtered, and the aqueous phase was extracted with MTBE (150 mL × 2). The combined organic phase was washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by MPLC (Biotage®; 220 g SepaFlash® silica flash column, petroleum ether gradient eluent, 150 mL / min). The crude product was purified by RP-MPLC (neutral, MeCN / HO). 2,3-Difluoro-1-methoxy-4-(prop-1-en-2-yl)benzene (14.4 g, 78.18 mmol, 66.4% yield) was obtained as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 6.99 (dt, J = 2.4, 8.4 Hz, 1H), 6.70 (dt, J = 2.0, 8.2 Hz, 1H), 5.24 (br d, J = 0.6 Hz, 1H), 5.22 (br d, J = 1.3 Hz, 1H), 3.91 (s, 3H), 2.13 (d, J = 0.7 Hz, 3H).

[0739] Step 2: 2,3-Difluoro-1-isopropyl-4-methoxybenzene [ka] A suspension of 2,3-difluoro-1-methoxy-4-(prop-1-en-2-yl)benzene (7.2 g, 39.09 mmol) and Pd / C (2 g, 10% purity) in MeOH (150 mL) was stirred under H (40 psi) at 25 °C for 3 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by MPLC (Biotage®; 40 g SepaFlash® silica flash column, petroleum ether gradient eluent, 120 mL / min) to give 2,3-difluoro-1-isopropyl-4-methoxybenzene (6.3 g, 33.83 mmol, 86.6% yield) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ = 6.89 (dt, J = 2.3, 8.3 Hz, 1H), 6.69 (dt, J = 2.0, 8.2 Hz, 1H), 3.89 (s, 3H), 3.25-3.11 (m, 1H), 1.25 (d, J = 7.0 Hz, 6H).

[0740] Step 3: 1-Bromo-3,4-difluoro-5-isopropyl-2-methoxybenzene [ka] A solution of 2,3-difluoro-1-isopropyl-4-methoxybenzene (3 g, 16.11 mmol) and NBS (3.44 g, 19.33 mmol) in AcOH (40 mL) was stirred at 80 °C for 16 h. The reaction was quenched with water (20 mL) and adjusted to pH 7 by adding saturated NaHCO. The aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by MPLC (Biotage®; 80 g SepaFlash® silica flash column, eluent of petroleum ether gradient, 100 mL / min). 1-Bromo-3,4-difluoro-5-isopropyl-2-methoxybenzene (1.3 g, 4.90 mmol, 30.4% yield) was obtained as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ = 7.16 (dd, J = 2.5, 7.1 Hz, 1H), 3.97 (d, J = 1.4 Hz, 3H), 3.19 (spt, J = 6.9 Hz, 1H), 1.25 (d, J = 6.9 Hz, 6H).

[0741] Step 4: (3,4-Difluoro-5-isopropyl-2-methoxyphenyl)boronic acid [ka] To a solution of 1-bromo-3,4-difluoro-5-isopropyl-2-methoxybenzene (1.3 g, 4.90 mmol) and triisopropyl borate (1.38 g, 7.36 mmol) in THF (30 mL) was added n-BuLi (2.5 M, 2.94 mL) at −70° C. under a N atmosphere. The mixture was stirred at −70° C. for 2 hours. The reaction was quenched with saturated NH4Cl (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give (3,4-difluoro-5-isopropyl-2-methoxyphenyl)boronic acid (0.91 g, 3.96 mmol, 80.7% yield) as a pale yellow oil. 1 H NMR (400MHz, chloroform-d) δ=7.45(dd,J=2.1,8.4Hz,1H), 5.82(br s,2H), 4.07(d,J=2.6Hz,3H), 3.19(spt,J=7.0Hz,1H), 1.27(d,J=7.0Hz,6H).

[0742] Preparation of tert-butyl 2-bromo-2-(5-(1,1-difluoroethyl)-3-fluoro-2-methoxyphenyl)acetate Step 1: 1-(3-bromo-5-fluoro-4-hydroxyphenyl)ethanone [ka] To a solution of 1-(3-fluoro-4-hydroxyphenyl)ethanone (25 g, 162.19 mmol) in DMF (250 mL) was added NBS (30 g, 168.55 mmol) in portions. The mixture was stirred at 25 °C for 16 h. Four batches were run in parallel. 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 NaSO, filtered, and concentrated under reduced pressure to give 1-(3-bromo-5-fluoro-4-hydroxyphenyl)ethanone (151.19 g, crude) as a red oil.

[0743] Step 2: 1-(3-bromo-5-fluoro-4-methoxyphenyl)ethanone [ka] To a solution of 1-(3-bromo-5-fluoro-4-hydroxyphenyl)ethanone (37.5 g, 160.92 mmol) in DMF (450 mL) was added K2CO3 (55.60 g, 402.30 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. MeI (45.68 g, 321.84 mmol) was slowly added dropwise to the reaction at 0-5 °C. The mixture was stirred at 25 °C for 15.5 h. Four batches were run in parallel. 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 a 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)ethanone (130 g, 526.19 mmol, yield 81.1%) as a yellow oil. 1 H NMR (400MHz, chloroform-d) δ=7.92(t,J=1.7Hz,1H), 7.65(dd,J=2.1,11.8Hz,1H), 4.07(d,J=2.8Hz,3H), 2.55(s,3H).

[0744] Step 3: 1-Bromo-5-(1,1-difluoroethyl)-3-fluoro-2-methoxybenzene [ka] A solution of 1-(3-bromo-5-fluoro-4-methoxyphenyl)ethanone (2 g, 8.10 mmol) and BAST (10.10 g, 45.65 mmol) was stirred at 60 °C for 16 h. Three batches were run in parallel. The reaction was slowly poured into ice-saturated NaHCO (400 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by column (Biotage®; 80 g SepaFlash® silica flash column, petroleum ether gradient eluent, 120 mL / min) to give 1-bromo-5-(1,1-difluoroethyl)-3-fluoro-2-methoxybenzene (5.3 g, 19.70 mmol, 81.1% yield) as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.48 (s, 1H), 7.22 (dd, J = 1.6, 11.3 Hz, 1H), 4.00 (d, J = 1.8 Hz, 3H), 1.90 (t, J = 18.1 Hz, 3H).

[0745] Step 4: tert-Butyl 2-(5-(1,1-difluoroethyl)-3-fluoro-2-methoxyphenyl)acetate [ka] A suspension of bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (1 M, 27.88 mL), 1-bromo-5-(1,1-difluoroethyl)-3-fluoro-2-methoxybenzene (3 g, 11.15 mmol), and tri-tert-butylphosphane palladium (455.86 mg, 892.00 μmol) in THF (60 mL) was stirred ...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony: The Q ring is 【Chemistry 2】 and L is, 【Transformation 3】 and each of these is 1 to 6 R ４ optionally substituted with; X is -CHR １ｃ -, -O-, or -NR ２ - and; R １ａ , R １ｂ , R １ｃ , R １ｄ , R １ｅ , and R １ｆ each independently represents H, 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 Alkoxy, CF ３ , CHF ２ , C.H. ２ F, CN, NO ２ , N.R. ａ R ｂ or C １－４ Alkyl-NR ａ R ｂ and Each R ２ are independently H, C １－４ Alkyl, or C ３－５ is cycloalkyl; R ３ａ is C １－４ Alkoxy, C ３－５ Cycloalkoxy, CF ３ , CHF ２ , C.H. ２ F, OCF ３ , OCHF ２ or OCH ２ F; R ３ｂ is H, halogen, CF ３ or CN; R ３ｃ is H, F, CN, or C １－４ is alkyl; R ３ｄ is C １－４ Alkyl, C ３－５ cycloalkyl, or 4- to 6-membered heterocycloalkyl, each of which is selected from 1 to 4 R ６ optionally substituted with; R ３ｅ is H or F; Each R ４ are independently H, C １－４ Alkyl, halogen, CF ３ , CHF ２ , or CH ２ F, cyclopropyl, or two geminal R ４ the groups together can form a spiro-cyclopropyl; Each R ６ is independent, C １－４ Alkyl, C １－４ Alkenyl, C ３－５ Cycloalkyl, C １－４ Alkoxy, C ３－５ Cycloalkoxy, F, CF ３ , CHF ２ , C.H. ２ F, OCF ３ , OCHF ２ , OCH ２ F, OH, 5- to 6-membered heteroaryl or NR ａ R ｂ and Each R ７ is independent, C １－４ alkyl or F; R ａ and R ｂ each independently represents hydrogen, C １－４ Alkyl, C ３－５ cycloalkyl or R ａ and R ｂ together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, which ring may optionally contain one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally F, C １－４ may be substituted with 1 to 3 identical or different groups selected from the group consisting of alkyl, phenyl and benzyl; n is 1 or 2; The compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.

2. a.L is 【Chemistry 4】 and b. X is -CHR １ｃ - and; c. The Q ring is 【Transformation 5】 and d. The compound of claim 1, wherein m is 0.

3. a.R １ａ , R １ｃ , R １ｄ , R １ｅ , and R １ｆ each is independently H; b.R １ｂ is 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 3. The compound of claim 2, wherein:

4. The Q ring is 【Transformation 6】 4. The compound of claim 3, wherein:

5. R ３ａ is C １－４ is alkoxy, and R ３ｂ is a halogen, and R ３ｃ The compound according to any one of claims 1 to 4, wherein is H.

6. R ３ａ The compound according to any one of claims 1 to 5, wherein is methoxy.

7. R ３ｂ The compound according to any one of claims 1 to 6, wherein is F.

8. R ３ｄ optionally one R ６ C substituted with １－４ The compound according to any one of claims 1 to 7, which is alkyl.

9. R ３ｄ The compound of any one of claims 1 to 8, wherein is unsubstituted isopropyl.

10. R ３ｄ is C ３－５ cycloalkyl, or 4- to 6-membered heterocycloalkyl, each of which is selected from 1 to 4 R ６ optionally substituted with R ６ is C optionally substituted with halogen １－４ The compound according to any one of claims 1 to 7, wherein the aryl group is alkyl or halogen.

11. R ３ｄ teeth, 【Transformation 7】 is; or R ３ｄ teeth, 【Transformation 8】 is; or R ３ｄ teeth, 【Chemistry 9】 The compound according to any one of claims 1 to 7,

12. R ６ is C ３－５ cycloalkyl, or 5- to 6-membered heteroaryl, and R ６ optionally one or more C １－４ The compound of any one of claims 1 to 11, which is alkyl (optionally substituted with halogen) or substituted with halogen.

13. R ６ is C ３－５ The compound of any one of claims 1 to 12, which is cycloalkyl, or 5- to 6-membered heteroaryl.

14. R ６ is methoxy, hydroxyl, or NR ａ R ｂ and R ａ and R ｂ are each independently H or C １－４ The compound of any one of claims 1 to 12, which is alkyl.

15. The compound according to any one of claims 1 to 14, wherein n is 1.

16. having a structure according to formula (II): 【Chemistry 10】 or having a structure according to formula (IIA): 【Chemistry 11】 or having a structure according to formula (III): 【Chemistry 12】 or having a structure according to formula (IIIA): 【Chemistry 13】 or having a structure according to formula (V): 【Chemistry 14】 or having a structure according to formula (VA): 【Chemistry 15】 or having a structure according to formula (VI): 【Chemistry 16】 having a structure according to formula (VIA): 【Chemistry 17】 or having a structure according to formula (VII): [Chemistry 18] 16. The compound of any one of claims 1 to 15, which is: or a pharmaceutically acceptable salt thereof.

17. having a structure according to formula (IIA): 【Chemistry 19】 In the formula, R １ｂ 17. The compound of claim 16, wherein is H, or a pharmaceutically acceptable salt thereof.

18. 18. The compound of any one of claims 1 to 17, wherein the carbon marked with an asterisk (*) has the (R) configuration.

19. 18. The compound of any one of claims 1 to 17, wherein the carbon marked with an asterisk (*) has the (S) configuration.

20. 2. The compound of claim 1 selected from any compound set forth in Table 1, or a pharmaceutically acceptable salt thereof. 【Request Item 21】 【Chemistry 20-1】 【Chemistry 20-2】 【Chemistry 20-3】 【Chemistry 20-4】 or a pharmaceutically acceptable salt thereof.

22. The compound is 【Chemistry 21】 or a pharmaceutically acceptable salt thereof.

23. The compound is 【Chemistry 22】 or a pharmaceutically acceptable salt thereof.

24. The compound is 【Chemistry 23】 or a pharmaceutically acceptable salt thereof.

25. The compound is 【Chemistry 24】 or a pharmaceutically acceptable salt thereof.

26. The compound is 【Chemistry 25】 or a pharmaceutically acceptable salt thereof.

27. The compound is 【Chemistry 26】 or a pharmaceutically acceptable salt thereof.

28. The compound is 【Chemistry 27】 or a pharmaceutically acceptable salt thereof.

29. The compound is 【Chemistry 28】 or a pharmaceutically acceptable salt thereof.

30. The compound is 【Chemistry 29】 or a pharmaceutically acceptable salt thereof.

31. The compound is 【Transformation 30】 or a pharmaceutically acceptable salt thereof.

32. The compound is 【Chemistry 31】 or a pharmaceutically acceptable salt thereof.

33. The compound is 【Chemistry 32】 or a pharmaceutically acceptable salt thereof.

34. The compound is 【Transformation 33】 or a pharmaceutically acceptable salt thereof.

35. The compound is 【Transformation 34】 or a pharmaceutically acceptable salt thereof.

36. The compound is 【Chemistry 35】 or a pharmaceutically acceptable salt thereof.

37. The compound is 【Transformation 36】 or a pharmaceutically acceptable salt thereof.

38. The compound is 【Chemistry 37】 or a pharmaceutically acceptable salt thereof.

39. The compound is 【Transformation 38】 or a pharmaceutically acceptable salt thereof.

40. The compound is 【Chemistry 39】 or a pharmaceutically acceptable salt thereof.

41. The compound is 【Chemistry 40】 or a pharmaceutically acceptable salt thereof.

42. The compound is 【Chemistry 41】 or a pharmaceutically acceptable salt thereof.

43. A pharmaceutical composition comprising a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

44. α in patients ｖ β ８ 43. A method of inhibiting an integrin, said method comprising administering to said patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

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