Inhibiting alpha v beta 8 integrin

Abstract

This disclosure relates to novel chemical compounds and methods useful for inhibiting αvβ8 integrin, including compounds according to Formula (I) and pharmaceutically acceptable salts thereof.

Description

ATTORNEY DOCKET NO. MORF-010WO1 INHIBITING αvβ8INTEGRIN RELATED APPLICATION

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No.63 / 484,782, filed February 14, 2023, the content of which is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] This disclosure relates to novel chemical compounds and methods useful for inhibiting αvβ8 integrin. BACKGROUND

[0003] In the tumor microenvironment αvβ8is expressed on immune cells, mainly antigen presenting cells (APCs) and regulatory T cells (Tregs) as well as on the tumor cells and cancer associated fibroblast. The major function of αvβ8is activation of growth factor TGF-β1 and 3. The TGF-βs are biosynthesized and stored in tissues as latent forms. The TGF-β homodimer is kept latent by association with its dimeric prodomain (pro-TGF-β). The prodomain-derived homodimer prevents TGF-β from binding TGF-β receptor and is called latency-associated peptide (LAP). The latent TGF-β complex is stored in the extracellular matrix or on the cell surface for subsequent, integrin-dependent activation. The integrin αvβ8heterodimer binds arginine–glycine–aspartic acid motifs (RGD domain) of the latent- TGF-β-1 and 3 to liberate the active TGF-β cytokine from latent complex.

[0004] TGF-β is a pleiotropic cytokine mediating multiple biological process including development and homeostasis. TGF-β is a key player in cell growth, differentiation, and apoptosis. It regulates extracellular matrix (ECM) production contributing to tissue repair processes. In the immune system TGF-β is necessary for the development of distinct immune cell types, as well to promote immunosuppression. Homeostatic role of TGF-β on immunity is critical to prevent excessive inflammatory responses and essential for maintaining tolerance to self- antigens to prevent autoimmunity. As TGF-β is ubiquitously expressed it activity needs to be tightly regulated and when exacerbated lead to disease states. Dysregulation of TGF-β signaling is involved in multiple disorders, especially cancer and fibrosis.

[0005] In cancer, the TGF-β pathway has been implicated in many human neoplastic diseases, including solid and hematopoietic tumors. As a potent inhibitor of cell proliferation,ATTORNEY DOCKET NO. MORF-010WO1 TGF-β acts as a tumor suppressor; however, in tumor cells, TGF-β loses its anti-proliferative response and promotes cancer progression. The TGF-β-promoted tumorigenesis is mainly driven by downregulation of anti-tumor immunity. The immunosuppressive effect leads to tumor immune tolerance. Additionally, TGF-β facilitates epithelial to mesenchymal transition (EMT) and angiogenesis to increase tumor invasiveness. The integrin avb8 expression in cancers correlates with TGF-β activity. It modulates inflammatory phenotype of the APCs and Tregs, the main cell types fundamental for T / NK cell driven anti-tumor activity. The αvβ8integrin locally activates TGF-β to regulate cross-talk between APCs and effector cells to skew immunity from inflammation to tolerance.

[0006] Inhibition of the integrin αvβ8-driven TGF-β activation is proposed to reverse tumor tolerance and enhance anti-tumor T / NK cell responses. In agreement with TGF-β blockage, avb8 inhibition can enhance outcomes in checkpoint inhibitors regimens or reverse checkpoint inhibitor resistance.

[0007] Ubiquitous expression and multifunctionality of TGF-β limits application of strategies based on TGF-β systemic blockage, as those approaches result is unwanted side effects. Blockage of TGF-β activity by antagonizing the integrin αvβ8 increases the safety and has therapeutic advantage over global TGF-β inhibition. It allows for tissue localized and isoform selective TGF- β blockage in specific immunological milieu. Therefore, there remains a need for therapeutic compounds for inhibiting αvβ8integrin. SUMMARY OF THE INVENTION

[0008] This disclosure relates to novel chemical compounds and methods useful for inhibiting αvβ8 integrin.

[0009] In one aspect, the invention features a compound of Formula (I) or a pharmaceutically acceptable salt thereof:wherein:ATTORNEY DOCKET NO. MORF-010WO1is optionally substituted with 1 to 6 R4; X is -CHR1c-, -O-, or -NR2-; each of R1a, R1b, R1c, R1d, R1e, and R1fis independently H, C1-4alkyl, halogen, C1-4alkyoxy, OH, C1-4alkyl-OH, C1-4alkyl-C1-4alkyoxy, C1-4alkyoxy-C1-4alkyoxy, CF3, CHF2, CH2F, CN, NO2, NRaRbor C1-4alkyl-NRaRb, each R2is independently H, C1-4alkyl, or C3-5cycloalkyl; R3ais C1-4alkyoxy, C3-5cycloalkoxy, CF3, CHF2, CH2F, OCF3, OCHF2or OCH2F; R3bis H, halogen, CF3 or CN; R3cis H, F, CN, or C1-4alkyl; R3dis C1-4alkyl, C3-5cycloalkyl, or 4-6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 R6; R3eis H or F; each R4is independently H, C1-4alkyl, halogen, CF3, CHF2 or CH2F, cyclopropyl, or two geminal R4groups together can form a spiro-cyclopropyl; each R6is independently C1-4alkyl, C1-4alkenyl, C3-5cycloalkyl, C1-4alkyoxy, C3- 5cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, 5-6-membered heteroaryl or NRaRb; each R7is independently C1-4alkyl or F; each of Raand Rbis independently hydrogen, C1-4alkyl, C3-5cycloalkyl, or Raand Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of F, C1-4alkyl, phenyl and benzyl; and n is 1 or 2; and m is 0, 1 or 2.ATTORNEY DOCKET NO. MORF-010WO1

[0010] In one aspect, the invention features a compound of Formula (I) or a pharmaceutically acceptable salt thereof:wherein:is optionally substituted with 1 to 6 R4; X is -CHR1c-, -O-, or -NR2-; each of R1a, R1b, R1c, R1d, R1e, and R1fis independently H, C1-4alkyl, halogen, C1-4alkyoxy, OH, C1-4alkyl-OH, C1-4alkyl-C1-4alkyoxy, C1-4alkyoxy-C1-4alkyoxy, CF3, CHF2, CH2F, CN, NO2, NRaRbor C1-4alkyl-NRaRb, each R2is independently H, C1-4alkyl, or C3-5cycloalkyl; R3ais cyano, halogen, C1-4alkyl, C1-4alkyoxy, C3-5cycloalkoxy, CF3, CHF2, CH2F, OCF3, OCHF2 or OCH2F; R3bis H, halogen, CF3 or CN; R3cis H, F, CN, or C1-4alkyl; R3dis C1-4alkyl, C3-5cycloalkyl, or 4-6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 R6; R3eis H or F; each R4is independently H, C1-4alkyl, halogen, CF3, CHF2 or CH2F, cyclopropyl, or two geminal R4groups together can form a spiro-cyclopropyl; each R6is independently C1-4alkyl, C1-4alkenyl, C3-5cycloalkyl, C1-4alkyoxy, C3-5cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, 5-6-membered heteroaryl or NRaRb; each R7is independently C1-4alkyl or F;ATTORNEY DOCKET NO. MORF-010WO1 each of Raand Rbis independently hydrogen, C1-4alkyl, C3-5cycloalkyl, or Raand Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of F, C1-4alkyl, phenyl and benzyl; and n is 1 or 2; and m is 0, 1 or 2.

[0011] In one aspect, the invention features a compound of Formula (I) or a pharmaceutically acceptable salt thereof:wherein:R3ais methoxy; R3bis H, halogen, CF3or CN; R3cis H, F, CN, or C1-4alkyl; R3dis C1-4alkyl, C3-5cycloalkyl, or 4-6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 R6; R3eis H or F; each R6is independently C1-4alkyl, C1-4alkenyl, C3-5cycloalkyl, C1-4alkyoxy, C3-5cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, 5-6-membered heteroaryl or NRaRb; each R7is independently C1-4alkyl or F; each of Ra and Rb is independently hydrogen, C1-4alkyl, C3-5cycloalkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturatedATTORNEY DOCKET NO. MORF-010WO1 heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of F, C1-4alkyl, phenyl and benzyl; and n is 1 or 2; and m is 0, 1 or 2.

[0012] In embodiments, the Q ring, wherein R1c1 and R1c2 are each independently selected from R1c; R1d1and R1d2are each independently selected from R1d; and R1e1and R1e2are each independently selected from R1e.

[0013] In embodiments, the Q ring

[0014] In embodiments, X is -O-.

[0015] In embodiments, X is -NR2-.

[0016] In embodiments, R2is methyl.

[0017] In embodiments, the Q ring

[0018] In embodiments, the Q ring

[0019] In embodiments, each of R1dand R1eis independently H.

[0020] In embodiments, each R1cis independently H.

[0021] In embodiments, each R1ais independently H.

[0022] In embodiments, each R1bis independently H.ATTORNEY DOCKET NO. MORF-010WO1

[0023] In embodiments, each R1bis independently OMe.

[0024] are each independently selected from R1c; and R1d1 and R1d2 are each independently selected from R1d.

[0025] In embodiments, each of R1c1, R1c2, R1d1, and R1d2are each independently H.

[0026] In embodiments, the Q ring

[0027] In embodiments, the Q ring

[0028] In embodiments, the Q ring

[0029] In embodiments, each of R1cand R1dis independently H.

[0030] In embodiments, each of R1a, R1band R1fis independently H.

[0031] In embodiments,

[0032] In embodiments,

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

[0034] In embodiments, L is and n is 2.In embodiments, R3ais C1-4alkyoxy.

[0035] In embodiments, R3ais OMe, OEt, OCF3, OCHF2or OCH2F.

[0036] In embodiments, R3ais OMe.

[0037] In embodiments, R3ais -CN.

[0038] In embodiments, R3ais halogen.ATTORNEY DOCKET NO. MORF-010WO1

[0039] In embodiments, R3ais Cl.

[0040] In embodiments, R3ais C1-4alkyl.

[0041] In embodiments, R3ais methyl.

[0042] In embodiments, R3ais ethyl.

[0043] In embodiments, R3bis F.

[0044] In embodiments, R3cis H.

[0045] In embodiments, R3dis C1-4alkyl.

[0046] In embodiments, R3dis C3-5cycloalkyl.

[0047] In embodiments, R3dis oxetanyl, tetrahydrofuranyl or tetrahydro-2H-pyranyl, morpholinyl or piperazinyl-C1-4alkyl.

[0048] In embodiments, R3dis iso-propyl.

[0049] In embodiments, R3eis H.

[0050] In embodiments, each R4is independently methyl.

[0051] In embodiments, each R4is independently F.

[0052] In embodiments, each R4is independently CF3, CHF2 or CH2F.

[0053] In embodiments, each R4is independently H.

[0054] In embodiments, each R6is independently C1-4alkyl.

[0055] In embodiments, each R6is independently C1-4alkenyl.

[0056] In embodiments, each R6is independently C3-5cycloalkyl.

[0057] In embodiments, each R6is independently C1-4alkyoxy.

[0058] In embodiments, each R6is independently C3-5cycloalkoxy.

[0059] In embodiments, each R6is independently F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F or OH.

[0060] In embodiments, each R6is independently a 5-6-membered heteroaryl.

[0061] In embodiments, each R6is independently H.

[0062] In embodiments, each R7is independently F.ATTORNEY DOCKET NO. MORF-010WO1

[0063] In embodiments, n is 0.

[0064] In embodiments, n is 1.

[0065] In embodiments, n is 2.

[0066] In embodiments, m is 0.

[0067] In embodiments, m is 1.

[0068] In embodiments, m is 2.

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

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

[0071] In embodiments, a compound has a structure according to Formula (III),or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0075] In embodiments, a compound has a structure according to Formula (V),or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0079] In one aspect, the invention features a compound of Formula (VII) or a pharmaceutically acceptable salt thereof:  wherein each of L, Q, R7, R3a, R3b, R3c, R3d, R3eis independently according to any embodiment described herein. .ATTORNEY DOCKET NO. MORF-010WO1

[0080] In one aspect, the invention features a compound of Formula (VII) or a pharmaceutically acceptable salt thereof:n is 1 or 2; R3ais methoxy; R7 is H or F; R3a is methoxy; and R3b, R3c, R3d, R3eare as disclosed herein above with respect to Formula (I).

[0081] In embodiments, n is 1.

[0082] In embodiments, n is 2.

[0083] In embodiments, R1bis H, CH3, or OCH3.

[0084] In embodiments, R3eis H or F.

[0085] In embodiments, R3dis C1-4alkyl optionally substituted with 1 R6.

[0087] In embodiments, R3dis 4-6-membered heterocycloalkyl optionally substituted with 1 R6.

[0088] In embodiments,

[0089] In embodiments, R3dis C3-5cycloalkyl optionally substituted with 1 R6.ATTORNEY DOCKET NO. MORF-010WO1

[0090] In embodiments,

[0091] In embodiments, the carbon marked by the asterisk (*) has the (R)-configuation.

[0092] In embodiments, the carbon marked by the asterisk (*) has the (S)-configuation.

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

[0094] In embodiments, a compound of Formula (I) is selected from the group consisting of:ATTORNEY DOCKET NO. MORF-010WO1ATTORNEY DOCKET NO. MORF-010WO1ATTORNEY DOCKET NO. MORF-010WO1or a pharmaceutically acceptable salt thereof.

[0095] In embodiments, a compound of Formula (I) isacceptable salt thereof. In embodiments, a compound is Compound 1A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound aB, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1acceptable salt thereof. In embodiments, a compound is Compound 2A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 2B, or a pharmaceutically acceptable salt thereof.acceptable salt thereof. In embodiments, a compound is Compound 7A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 7B, or a pharmaceutically acceptable salt thereof.salt thereof. In embodiments, a compound is Compound 11A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 11B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

[0101] In embodiments, a compound of Formula (I) is(Compound 20A / 20B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 20A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 20B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

[0104] In embodiments, a compound of Formula (I) is(Compound 35A / 35B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 35A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 35B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0108] In embodiments, a compound of Formula (I) is(Compound 47A / 47B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 47A, or a pharmaceuticallyATTORNEY DOCKET NO. MORF-010WO1 acceptable salt thereof. In embodiments, a compound is Compound 47B, or a pharmaceutically acceptable salt thereof.

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

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

[0111] In embodiments, a compound of Formula (I) is(Compound 129A / 129B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 129A, or a pharmaceuticallyATTORNEY DOCKET NO. MORF-010WO1 acceptable salt thereof. In embodiments, a compound is Compound 129B, or a pharmaceutically acceptable salt thereof.

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

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

[0114] In embodiments, a compound of Formula (I) is(Compound 150A / 150B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 150A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 150B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

[0116] In another aspect, the invention features a pharmaceutical composition, comprising 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 comprising administering to the 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 solid tumor in a patient, the method comprising administering to the 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 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 carcinoma, 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 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.ATTORNEY DOCKET NO. MORF-010WO1

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

[0122] 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 understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

[0123] In order for the present invention to be more readily understood, 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 phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to 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 herein in the specification and in 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 interpreted as being inclusive, i.e., the inclusion of at least one, butATTORNEY DOCKET NO. MORF-010WO1 also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted 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.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0127] As used herein in the specification and in the 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 each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0128] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0129] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of” and “consisting essentially of” shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0130] Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention mayATTORNEY DOCKET NO. MORF-010WO1 also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0131] If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed 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, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a13C- or14C-enriched carbon are within the scope of this invention.

[0133] The terms “αvβ8”, “avB8”, “avb8”, “alpha-v beta-8” and “alpha v beta 8” and the like as used herein all refer to αvβ8.

[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, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body. 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 which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) 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 ethylATTORNEY DOCKET NO. MORF-010WO1 oleate and ethyl laurate; (13) agar; (14) buffering agents, 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 solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient.

[0135] The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the 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 laurylsulphonate salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19.)

[0136] In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a 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 its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).

[0137] A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment, refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinicallyATTORNEY DOCKET NO. MORF-010WO1 acceptable standards for the disorder or condition to be treated or the cosmetic purpose, 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 to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0139] The term “patient” refers to a mammal in need of a particular treatment. In certain embodiments, a patient is a primate, canine, feline, or equine. In certain embodiments, a patient is a human.

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

[0141] An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group.

[0142] “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or 1 up to 30 carbon atoms if no specification is made. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties. Alkyl of 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 chain or branchedATTORNEY DOCKET NO. MORF-010WO1 chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30for straight chains, C3-C30for branched chains), and more preferably 20 or fewer. Alkyl goups may 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 the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH2)-, ethylene -(CH2CH2)-, n-propylene -(CH2CH2CH2)-, isopropylene -(CH2CH(CH3))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.

[0144] "Cycloalkyl" means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may 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 carbons is otherwise specified, “lower alkyl,” as used herein, means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl.

[0146] The term “aryl” as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (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 adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-ATTORNEY DOCKET NO. MORF-010WO1 membered rings, whose ring structures include one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.

[0147] The term “halo”, “halide”, or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, 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, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, 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 such substituents as described above, as 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, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like.

[0149] The term “heterocycloalkyl” as used herein, is a non-aromatic heterocyclyl wherein 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 are 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-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H- pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-ATTORNEY DOCKET NO. MORF-010WO1 azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. The heterocycloalkyl group can be substituted or unsubstituted as recited, e.g., for heterocyclyls as described herein.

[0150] The term “carbonyl” is art-recognized and includes such moieties as can be represented by the formula:

[0151] wherein X’ is a bond or represents an oxygen or a sulfur, and R15 represents a hydrogen, an alkyl, an alkenyl, -(CH2)m-R10or a pharmaceutically acceptable salt, R16represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-R10, where m and R10are as defined above. Where X’ is an oxygen and R15or R16is not hydrogen, the formula represents an “ester.” Where X’ is an oxygen, and R15 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R15 is a hydrogen, the formula represents a “carboxylic acid”. Where X’ is an oxygen, and R16 is a hydrogen, the formula represents a “formate.” On the other hand, where X’ is a bond, and R15is not hydrogen, the above formula represents a “ketone” group. Where X’ is a bond, and R15is a 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. Illustrative substituents include, for example, those described herein above, and for example substituted with one or more substituents selected from alkyl, cycloalkyl, heterocyclylakyl, halogen, OH, OMe, C(H)F2, C(F)H2, CF3, C(H)2CF3, SF5, CHFCH2amine, CH2amine, and CN. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.ATTORNEY DOCKET NO. MORF-010WO1

[0153] As used herein, the term “nitro” means -NO2; the term “halogen” designates - F, -Cl, -Br, or -I; the term “hydroxyl” means -OH; and the term “cyano” means –CN;.

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

[0155] The term “prodrug” as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. Accordingly, prodrugs include compounds that are transformed in vivo to yield a disclosed compound or any other pharmaceutically acceptable form of the compound. In embodiments, a prodrug may be inactive when administered to a subject but may be converted in vivo to an active compound, 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., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol.14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. 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, which release the active compound in vivo when such prodrug is administered to a subject.

[0156] Prodrugs of compounds described herein may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to provide a compound described herein (i.e., the parent active compound). Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like. Other examples of prodrugs include compounds that comprise —NO, — NO2, —ONO, or —ONO2moieties.ATTORNEY DOCKET NO. MORF-010WO1

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

[0158] This disclosure relates to novel chemical compounds and methods useful for inhibiting αvβ8integrin.

[0159] Exemplary formulas and compounds are described herein. Also provided herein are exemplary embodiments of structural features which may be present in any formula described herein. Any exemplary embodiment of a structural feature may occur in combination with any other exemplary structural feature described herein. Further, and unless otherwise indicated herein, any description of a formula or compound also includes any pharmaceutically acceptable forms of the compound, including but not limited to any pharmaceutically acceptable salts, hydrates, solvates, isomers, polymorphs, prodrugs, and isotopically labeled derivatives of disclosed formulas and compounds.

[0160] In embodiments, a compound described herein is a selective inhibitor of αvβ8 integrin. In embodiments, a compound described herein selectively inhibits αvβ8 integrin over, e.g., αvβ6 integrin (e.g., a selectivity of at least about 10×, 20×, 50×, 100×, 500×, or 1000× as measured according to an assay (e.g., fluorescence polarization assay)).

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

[0162] In one aspect, the invention features a compound of Formula (I), or a pharmaceutically acceptable salt thereof:wherein:ATTORNEY DOCKET NO. MORF-010WO1is optionally substituted with 1 to 6 R4; X is -CHR1c-, -O-, or -NR2-; each of R1a, R1b, R1c, R1d, R1e, and R1fis independently H, C1-4alkyl, halogen, C1-4alkyoxy, OH, C1-4alkyl-OH, C1-4alkyl-C1-4alkyoxy, C1-4alkyoxy-C1-4alkyoxy, CF3, CHF2, CH2F, CN, NO2, NRaRbor C1-4alkyl-NRaRb, each R2is independently H, C1-4alkyl, or C3-5cycloalkyl; R3ais C1-4alkyoxy, C3-5cycloalkoxy, CF3, CHF2, CH2F, OCF3, OCHF2or OCH2F; R3bis H, halogen, CF3 or CN; R3cis H, F, CN, or C1-4alkyl; R3dis C1-4alkyl, C3-5cycloalkyl, or 4-6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 R6; R3eis H or F; each R4is independently H, C1-4alkyl, halogen, CF3, CHF2 or CH2F, cyclopropyl, or two geminal R4groups together can form a spiro-cyclopropyl; each R6is independently C1-4alkyl, C1-4alkenyl, C3-5cycloalkyl, C1-4alkyoxy, C3- 5cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, 5-6-membered heteroaryl or NRaRb; each R7is independently C1-4alkyl or F; each of Raand Rbis independently hydrogen, C1-4alkyl, C3-5cycloalkyl, or Raand Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of F, C1-4alkyl, phenyl and benzyl; and n is 1 or 2; and m is 0, 1 or 2.

[0163] In one aspect, the invention features a compound of Formula (I) or a pharmaceutically acceptable salt thereof:ATTORNEY DOCKET NO. MORF-010WO1wherein:is optionally substituted with 1 to 6 R4; X is -CHR1c-, -O-, or -NR2-; each of R1a, R1b, R1c, R1d, R1e, and R1fis independently H, C1-4alkyl, halogen, C1-4alkyoxy, OH, C1-4alkyl-OH, C1-4alkyl-C1-4alkyoxy, C1-4alkyoxy-C1-4alkyoxy, CF3, CHF2, CH2F, CN, NO2, NRaRb or C1-4alkyl-NRaRb, each R2is independently H, C1-4alkyl, or C3-5cycloalkyl; R3ais cyano, halogen, C1-4alkyl, C1-4alkyoxy, C3-5cycloalkoxy, CF3, CHF2, CH2F, OCF3, OCHF2or OCH2F; R3bis H, halogen, CF3 or CN; R3cis H, F, CN, or C1-4alkyl; R3dis C1-4alkyl, C3-5cycloalkyl, or 4-6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 R6; R3eis H or F; each R4is independently H, C1-4alkyl, halogen, CF3, CHF2or CH2F, cyclopropyl, or two geminal R4groups together can form a spiro-cyclopropyl; each R6is independently C1-4alkyl, C1-4alkenyl, C3-5cycloalkyl, C1-4alkyoxy, C3- 5cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, 5-6-membered heteroaryl or NRaRb; each R7is independently C1-4alkyl or F; each of Raand Rbis independently hydrogen, C1-4alkyl, C3-5cycloalkyl, or Raand Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally containATTORNEY DOCKET NO. MORF-010WO1 additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of F, C1-4alkyl, phenyl and benzyl; and n is 1 or 2; and m is 0, 1 or 2.

[0164] In one aspect, the invention features a compound of Formula (I) or a pharmaceutically acceptable salt thereof:wherein:R3ais methoxy; R3bis H, halogen, CF3 or CN; R3cis H, F, CN, or C1-4alkyl; R3dis C1-4alkyl, C3-5cycloalkyl, or 4-6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 R6; R3eis H or F; each R6is independently C1-4alkyl, C1-4alkenyl, C3-5cycloalkyl, C1-4alkyoxy, C3- 5cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, 5-6-membered heteroaryl or NRaRb; each R7is independently C1-4alkyl or F; each of Raand Rbis independently hydrogen, C1-4alkyl, C3-5cycloalkyl, or Raand Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen andATTORNEY DOCKET NO. MORF-010WO1 sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of F, C1-4alkyl, phenyl and benzyl; and n is 1 or 2; and m is 0, 1 or 2.

[0165] In embodiments, the Q ring, wherein R1c1 and R1c2 are each independently selected from R1c; R1d1 and R1d2 are each independently selected from R1d; and R1e1 and R1e2 are each independently selected from R1e.

[0166] In embodiments, the Q ring

[0167] In embodiments, X is -O-.

[0168] In embodiments, X is -NR2-.

[0169] In embodiments, R2is methyl.

[0170] In embodiments, the Q ring

[0171] are each independently selected from R1c; and R1d1 and R1d2 are each independently selected from R1d.

[0172] In embodiments, each of R1c1, R1c2, R1d1, and R1d2 are each independently H.

[0173] In embodiments, the Q ringATTORNEY DOCKET NO. MORF-010WO1

[0174] In embodiments, the Q ring

[0175] In embodiments, the Q ring

[0176] In embodiments, each of R1dand R1eis independently H.

[0177] In embodiments, each R1cis independently H.

[0178] In embodiments, each R1ais independently H.

[0179] In embodiments, each R1bis independently H.

[0180] In embodiments, each R1bis independently OMe.

[0181] In embodiments, the Q ring

[0182] In embodiments, each of R1cand R1dis independently H.

[0183] In embodiments, each of R1a, R1band R1fis independently H.

[0184] In embodiments,

[0185] In embodiments,

[0186] In embodiments, L is .

[0187] In embodiments,

[0188] In embodiments, R3ais C1-4alkyoxy.

[0189] In embodiments, R3ais OMe, OEt, OCF3, OCHF2or OCH2F.

[0190] In embodiments, R3ais OMe.

[0191] In embodiments, R3ais -CN.

[0192] In embodiments, R3ais halogen.

[0193] In embodiments, R3ais Cl.ATTORNEY DOCKET NO. MORF-010WO1

[0194] In embodiments, R3ais C1-4alkyl.

[0195] In embodiments, R3ais methyl.

[0196] In embodiments, R3ais ethyl.

[0197] In embodiments, R3bis F.

[0198] In embodiments, R3cis H.

[0199] In embodiments, R3dis C1-4alkyl.

[0200] In embodiments, R3dis C3-5cycloalkyl.

[0201] In embodiments, R3dis oxetanyl, tetrahydrofuranyl or tetrahydro-2H-pyranyl, morpholinyl or piperazinyl-C1-4alkyl.

[0202] In embodiments, R3dis iso-propyl.

[0203] In embodiments, R3eis H.

[0204] In embodiments, each R4is independently methyl.

[0205] In embodiments, each R4is independently F.

[0206] In embodiments, each R4is independently CF3, CHF2or CH2F.

[0207] In embodiments, each R4is independently H.

[0208] In embodiments, each R6is independently C1-4alkyl.

[0209] In embodiments, each R6is independently C1-4alkenyl.

[0210] In embodiments, each R6is independently C3-5cycloalkyl.

[0211] In embodiments, each R6is independently C1-4alkyoxy.

[0212] In embodiments, each R6is independently C3-5cycloalkoxy.

[0213] In embodiments, each R6is independently F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F or OH.

[0214] In embodiments, each R6is independently a 5-6-membered heteroaryl.

[0215] In embodiments, each R6is independently H.

[0216] In embodiments, each R7is independently F.

[0217] In embodiments, each R7is independently F and m is 0 or 1.ATTORNEY DOCKET NO. MORF-010WO1

[0218] In embodiments, each R7is independently methyl.

[0219] In embodiments, each R7is independently methyl and m is 0 or 1.

[0220] In embodiments, n is 0.

[0221] In embodiments, n is 1.

[0222] In embodiments, n is 2.

[0223] In embodiments, m is 0. Formulas (II)-(VII)

[0224] In embodiments, a compound has a structure according to Formula (II),or a pharmaceutically acceptable salt thereof, wherein each of R1b, R3a, R3b, R3c, R3d, R3eis independently according to any embodiment described herein.

[0225] In embodiments, a compound has a structure according to Formula (IIA),or a pharmaceutically acceptable salt thereof, wherein each of R1b, R3d, and R3eis independently according to any embodiment described herein.

[0226] In embodiments, a compound has a structure according to Formula (III),ATTORNEY DOCKET NO. MORF-010WO1 or a pharmaceutically acceptable salt thereof, wherein each of R1b, R3a, R3b, R3c, R3d, R3eis independently according to any embodiment described herein.

[0227] In embodiments, a compound has a structure according to Formula (IIIA),or a pharmaceutically acceptable salt thereof, wherein each of R1b, R3d, and R3eis independently according to any embodiment described herein.

[0228] In embodiments, a compound has a structure according to Formula (IV),or a pharmaceutically acceptable salt thereof, wherein each of R1b, R3a, R3b, R3c, R3d, R3eis independently according to any embodiment described herein.

[0229] In embodiments, a compound has a structure according to Formula (IVA),or a pharmaceutically acceptable salt thereof, wherein each of R1b, R3d, and R3eis independently according to any embodiment described herein.

[0230] In embodiments, a compound has a structure according to Formula (V),ATTORNEY DOCKET NO. MORF-010WO1 or a pharmaceutically acceptable salt thereof, wherein each of n, R1b, R3a, R3b, R3c, R3d, R3eis independently according to any embodiment described herein.

[0231] In embodiments, a compound has a structure according to Formula (VA),or a pharmaceutically acceptable salt thereof, wherein each of n, R1b, R3d, and R3eis independently according to any embodiment described herein.

[0232] In embodiments, a compound has a structure according to Formula (VI),or a pharmaceutically acceptable salt thereof, wherein each of n, R1b, R3a, R3b, R3c, R3d, R3eis independently according to any embodiment described herein.

[0233] In embodiments, a compound has a structure according to Formula (VIA),or a pharmaceutically acceptable salt thereof, wherein each of n, R1b, R3d, and R3eis 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:ATTORNEY DOCKET NO. MORF-010WO1  wherein each of L, Q, R7, R3a, R3b, R3c, R3d, R3e is 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:n is 1 or 2; R3ais methoxy; R7is H or F; R3a is methoxy; and R3b, R3c, R3d, R3e are as disclosed herein above with respect to Formula (I).

[0236] In embodiments, n is 1.

[0237] In embodiments, n is 2.

[0238] In embodiments, R1bis H, CH3, or OCH3.

[0239] In embodiments, R3eis H or F.

[0240] In embodiments, R3dis C1-4alkyl optionally substituted with 1 R6.ATTORNEY DOCKET NO. MORF-010WO1

[0242] In embodiments, R3dis 4-6-membered heterocycloalkyl optionally substituted with 1 R6.

[0243] In embodiments,

[0244] In embodiments, R3dis C3-5cycloalkyl optionally substituted with 1 R6.

[0245] In embodiments,

[0246] In embodiments, the carbon marked by the asterisk (*) has the (R)-configuation.

[0247] In embodiments, the carbon marked by the asterisk (*) has the (S)-configuation.

[0248] In embodiments, the compound is selected from any compound described in Table 1, or a pharmaceutically acceptable salt thereof. Additional Exemplary Embodiments

[0249] Still further exemplary embodiments of variables in the exemplary Formulas (I)-(VII) which may be present in any combination as valency permits are described herein.

[0250] In embodiments, the Q ringembodiments, X is -CHR1c-. In embodiments, X is -O-. In embodiments, X is -NR2-.

[0251] In embodiments, the Q ring is. In embodiments, the Q ring isATTORNEY DOCKET NO. MORF-010WO1embodiments, the Q ring isembodiments, the Q ring embodiments, the Q ring is. In embodiments, the Q ring embodiments, the Q ringembodiments, the Q ring isembodiments, the Q ring

[0252] In embodiments, the Q ringembodiments, X is -CHR1c-. In embodiments, X is -O-. In embodiments, X is -NR2-.

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

[0254] In embodiments, L isoptionally substituted with 1 to 6 R4. In embodiments, L is unsubstituted. In embodiments, L is substituted with 1 to 6 R4. In embodiments, L is substituted with 1, 2, or 3 R4. In embodiments, L is substituted with 1 R4. In embodiments, L is substituted with 2 R4. In embodiments, L is substituted with 3 R4. InATTORNEY DOCKET NO. MORF-010WO1 embodiments, L is substituted with 4 R4. In embodiments, L is substituted with 5 R4. In embodiments, L is substituted with 6 R4.

[0255] In embodiments, L isoptionally substituted with 1 to 6 R4. In embodiments, L is unsubstituted. In embodiments, L is substituted with 1 to 6 R4. In embodiments, L is substituted with 1, 2, or 3 R4. In embodiments, L is substituted with 1 R4. In embodiments, L is substituted with 2 R4. In embodiments, L is substituted with 3 R4. In embodiments, L is substituted with 4 R4. In embodiments, L is substituted with 5 R4. In embodiments, L is substituted with 6 R4.

[0256] In embodiments, R1ais H. In embodiments, R1ais C1-4alkyl. In embodiments, R1ais halogen (e.g., F). In embodiments, R1ais C1-4alkyoxy. In embodiments, R1ais OH. In embodiments, R1ais C1-4alkyl-OH. In embodiments, R1ais C1-4alkyl-C1-4alkyoxy. In embodiments, R1ais C1-4alkyoxy-C1-4alkyoxy. In embodiments, R1ais CF3. In embodiments, R1ais CHF2. In embodiments, R1ais CH2F. In embodiments, R1ais CN. In embodiments, R1ais NO2. In embodiments, R1ais NRaRb. In embodiments, R1ais C1-4alkyl-NRaRb.

[0257] In embodiments, R1bis H. In embodiments, R1bis C1-4alkyl. In embodiments, R1bis halogen (e.g., F). In embodiments, R1bis C1-4alkyoxy. In embodiments, R1bis OH. In embodiments, R1bis C1-4alkyl-OH. In embodiments, R1bis C1-4alkyl-C1-4alkyoxy. In embodiments, R1bis C1-4alkyoxy-C1-4alkyoxy. In embodiments, R1bis CF3. In embodiments, R1bis CHF2. In embodiments, R1bis CH2F. In embodiments, R1bis CN. In embodiments, R1bis NO2. In embodiments, R1bis NRaRb. In embodiments, R1bis C1-4alkyl-NRaRb.

[0258] In embodiments, R1cis H. In embodiments, R1cis C1-4alkyl. In embodiments, R1cis halogen (e.g., F). In embodiments, R1cis C1-4alkyoxy. In embodiments, R1cis OH. In embodiments, R1cis C1-4alkyl-OH. In embodiments, R1cis C1-4alkyl-C1-4alkyoxy. In embodiments, R1cis C1-4alkyoxy-C1-4alkyoxy. In embodiments, R1cis CF3. In embodiments, R1cis CHF2. In embodiments, R1cis CH2F. In embodiments, R1cis CN. In embodiments, R1bis NO2. In embodiments, R1cis NRaRb. In embodiments, R1cis C1-4alkyl-NRaRb.

[0259] In embodiments, R1dis H. In embodiments, R1dis C1-4alkyl. In embodiments, R1dis halogen (e.g., F). In embodiments, R1dis C1-4alkyoxy. In embodiments, R1dis OH. In embodiments, R1dis C1-4alkyl-OH. In embodiments, R1dis C1-4alkyl-C1-4alkyoxy. In embodiments, R1dis C1-4alkyoxy-C1-4alkyoxy. In embodiments, R1dis CF3. In embodiments, R1dis CHF2. In embodiments, R1dis CH2F. In embodiments, R1dis CN. In embodiments, R1dis NO2. In embodiments, R1dis NRaRb. In embodiments, R1dis C1-4alkyl-NRaRb.ATTORNEY DOCKET NO. MORF-010WO1

[0260] In embodiments, R1eis H. In embodiments, R1eis C1-4alkyl. In embodiments, R1eis halogen (e.g., F). In embodiments, R1eis C1-4alkyoxy. In embodiments, R1eis OH. In embodiments, R1eis C1-4alkyl-OH. In embodiments, R1eis C1-4alkyl-C1-4alkyoxy. In embodiments, R1eis C1-4alkyoxy-C1-4alkyoxy. In embodiments, R1eis CF3. In embodiments, R1eis CHF2. In embodiments, R1eis CH2F. In embodiments, R1eis CN. In embodiments, R1eis NO2. In embodiments, R1eis NRaRb. In embodiments, R1eis C1-4alkyl-NRaRb.

[0261] In embodiments, R1fis H. In embodiments, R1fis C1-4alkyl. In embodiments, R1fis halogen (e.g., F). In embodiments, R1fis C1-4alkyoxy. In embodiments, R1fis OH. In embodiments, R1fis C1-4alkyl-OH. In embodiments, R1fis C1-4alkyl-C1-4alkyoxy. In embodiments, R1fis C1-4alkyoxy-C1-4alkyoxy. In embodiments, R1fis CF3. In embodiments, R1fis CHF2. In embodiments, R1fis CH2F. In embodiments, R1fis CN. In embodiments, R1fis NO2. In embodiments, R1fR1eis NRaRb. In embodiments, R1fis C1-4alkyl-NRaRb.

[0262] In embodiments, R2is H.

[0263] In embodiments, R2is C1-4alkyl.

[0264] In embodiments, R2is C3-5cycloalkyl.

[0265] In embodiments, R3ais C1-4alkyoxy.

[0266] In embodiments, R3ais C3-5cycloalkoxy.

[0267] In embodiments, R3ais CF3.

[0268] In embodiments, R3ais CHF2.

[0269] In embodiments, R3ais CH2F.

[0270] In embodiments, R3ais OCF3.

[0271] In embodiments, R3ais OCHF2.

[0272] In embodiments, R3ais OCH2F.

[0273] In embodiments, R3ais -CN.

[0274] In embodiments, R3ais halogen.

[0275] In embodiments, R3ais Cl.

[0276] In embodiments, R3ais C1-4alkyl.

[0277] In embodiments, R3ais methyl.ATTORNEY DOCKET NO. MORF-010WO1

[0278] In embodiments, R3ais ethyl.

[0279] In embodiments, R3bis H.

[0280] In embodiments, R3bis halogen.

[0281] In embodiments, R3bis CF3.

[0282] In embodiments, R3bis CN.

[0283] In embodiments, R3cis H.

[0284] In embodiments, R3cis F.

[0285] In embodiments, R3cis CN.

[0286] In embodiments, R3cis C1-4alkyl.

[0287] In embodiments, R3dis C1-4alkyl optionally substituted with 1 to 4 R6. In embodiments, R3dis unsubstituted C1-4alkyl (e.g., methyl, ethyl, isopropyl, or tert-butyl). In embodiments, R3dis C1-4alkyl substituted with 1 R6(e.g., a methyl, ethyl, propyl, isopropyl, or n- butyl group substituted by methyl, ethyl, cyclopropyl, OH, oxazolyl, isoxazolyl, thiazolyl, methoxy, ethoxy, isopropyloxy, dimethylamino, pyrrolidinyl, morpholinyl, piperidinyl; or a methyl, ethyl, propyl, isopropyl, or n-butyl group substituted by NRaRb wherein Ra and Rb together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring (e.g., azanorbornyl or piperidnyl) optionally comprising 1 or 2 substituents selected from methyl, fluoro, cyclopropyl, and methoxy). In embodiments, R3dis C1-4alkyl substituted with 2 R6. In embodiments, R3dis C1-4alkyl substituted with 3 R6. In embodiments, R3dis C1-4alkyl substituted with 4 R6.

[0288] In embodiments, R3dis C3-5cycloalkyl optionally substituted with 1 to 4 R6. In embodiments, R3dis unsubstituted C3-5cycloalkyl (e.g., cyclopropyl). In embodiments, R3dis C3- 5cycloalkyl optionally substituted with 1 R6(e.g., a cyclopropyl substituted by methyl, ethyl, methoxy, or trifluoromethyl). In embodiments, R3dis C3-5cycloalkyl optionally substituted with 2 R6. In embodiments, R3dis C3-5cycloalkyl optionally substituted with 3 R6. In embodiments, R3dis C3-5cycloalkyl optionally substituted with 4 R6.

[0289] In embodiments, R3dis 4-6-membered heterocycloalkyl optionally substituted with 1 to 4 R6. In embodiments, R3dis unsubstituted 4-6-membered heterocycloalkyl (e.g., tetrayhydrofuranyl, tetrahydropyranyl, oxetanyl, isoxazolyl, morpholinyl, pyrrolidinyl, or piperidinyl). In embodiments, R3dis 4-6-membered heterocycloalkyl substituted with 1 R6(e.g.,ATTORNEY DOCKET NO. MORF-010WO1 tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, isoxazolyl, morpholinyl, pyrrolidinyl, or piperidinyl, substituted by methyl, methoxy or fluoro). In embodiments, R3dis 4-6-membered heterocycloalkyl substituted with 2 R6(e.g., tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, isoxazolyl, morpholinyl, pyrrolidinyl, piperidinyl, comprising two substituents independently selected from methyl and fluoro). In embodiments, R3dis 4-6-membered heterocycloalkyl substituted with 3 R6. In embodiments, R3dis 4-6-membered heterocycloalkyl substituted with 4 R6.

[0290] In embodiments, R3eis H.

[0291] In embodiments, R3eis F.

[0292] In embodiments, R4is H.

[0293] In embodiments, R4is C1-4alkyl.

[0294] In embodiments, R4is halogen (e.g., F).

[0295] In embodiments, R4is CF3.

[0296] In embodiments, R4is CHF2.

[0297] In embodiments, R4is CH2F.

[0298] In embodiments, R4is cyclopropyl.

[0299] In embodiments, two geminal R4groups together can form a spiro-cyclopropyl.

[0300] In embodiments, R6is C1-4alkyl.

[0301] In embodiments, R6is C1-4alkenyl.

[0302] In embodiments, R6is C3-5cycloalkyl.

[0303] In embodiments, R6is C1-4alkyoxy.

[0304] In embodiments, R6is C3-5cycloalkoxy.

[0305] In embodiments, R6is F.

[0306] In embodiments, R6is CF3.

[0307] In embodiments, R6is CHF2.

[0308] In embodiments, R6is CH2F.

[0309] In embodiments, R6is OCF3.ATTORNEY DOCKET NO. MORF-010WO1

[0310] In embodiments, R6is OCHF2.

[0311] In embodiments, R6is OCH2F.

[0312] In embodiments, R6is OH.

[0313] In embodiments, R6is 5-6-membered heteroaryl.

[0314] In embodiments, R6is NRaRb.

[0315] In embodiments, R7is independently C1-4alkyl.

[0316] In embodiments, R7is F.

[0317] In embodiments, R7is CH3or F.

[0318] In embodiments, Ra is independently hydrogen.

[0319] In embodiments, Ra is independently C1-4alkyl.

[0320] In embodiments, Ra is independently C3-5cycloalkyl.

[0321] In embodiments, Rbis independently hydrogen.

[0322] In embodiments, Rbis independently C1-4alkyl.

[0323] In embodiments, Rbis independently C3-5cycloalkyl.

[0324] In embodiments, Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, wherein said ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of F, C1-4alkyl, phenyl and benzyl.

[0325] In embodiments, Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated heterocyclic ring. In embodiments, said heterocyclic ring is unsubstituted. In embodiments, said heterocyclic ring is substituted by 1, 2 or 3 groups independently selected from the group consisting of F, C1-4alkyl, phenyl and benzyl. In embodiments, said heterocyclic ring does not contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In embodiments, said heterocyclic ring contains additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.ATTORNEY DOCKET NO. MORF-010WO1

[0326] In embodiments, Raand Rb, together with the nitrogen atom to which they are attached, form an unsaturated heterocyclic ring. In embodiments, said heterocyclic ring is unsubstituted. In embodiments, said heterocyclic ring is substituted by 1, 2 or 3 groups independently selected from the group consisting of F, C1-4alkyl, phenyl and benzyl. In embodiments, said heterocyclic ring does not contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In embodiments, said heterocyclic ring contains additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

[0327] In embodiments, n is 0.

[0328] In embodiments, n is 1.

[0329] In embodiments, n is 2.

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

[0331] In embodiments, R3ais C1-4alkyoxy (e.g., OCH3) and / or R3bis halogen (e.g., F).

[0332] In embodiments, R3ais C1-4alkyoxy (e.g., OCH3) and R3bis halogen (e.g., F).

[0333] In embodiments, R3cis H and / or R3eis halogen (e.g., F).

[0334] In embodiments, R3cis H and R3eis halogen (e.g., F).

[0335] In embodiments, R3cis H and / or R3eis H.

[0336] In embodiments, R3cis H and R3eis H.

[0337] In embodiments, R3bis H and / or R3eis H.

[0338] In embodiments, R3bis H and R3eis H.

[0339] In embodiments, R3ais C1-4alkyoxy (e.g., OCH3), R3bis halogen (e.g., F), and / or R3cis H.

[0340] In embodiments, R3ais C1-4alkyoxy (e.g., OCH3), R3bis halogen (e.g., F), and R3cis H.

[0341] In embodiments, R3ais C1-4alkyoxy (e.g., OCH3), R3bis halogen (e.g., F), and / or R3cis F.

[0342] In embodiments, R3ais C1-4alkyoxy (e.g., OCH3), R3bis halogen (e.g., F), and R3cis F.

[0343] In embodiments, R3ais C1-4alkyoxy (e.g., OCH3), R3bis H, and / or R3cis H.ATTORNEY DOCKET NO. MORF-010WO1

[0344] In embodiments, R3ais C1-4alkyoxy (e.g., OCH3), R3bis H, and R3cis H.

[0345] In embodiments, R3bis H, R3cis H, and / or R3eis H.

[0346] In embodiments, R3bis H, R3cis H, and R3eis H.

[0347] In embodiments, R3ais C1-4alkyoxy (e.g., OCH3), R3bis halogen (e.g., F), R3cis H, R3dis C1-4alkyl (e.g., methyl or isopropyl) optionally substituted with 1 to 4 R6, and / or R3eis H.

[0348] In embodiments, R3ais C1-4alkyoxy (e.g., OCH3), R3bis halogen (e.g., F), R3cis H, R3dis C1-4alkyl (e.g., methyl or isopropyl) optionally substituted with 1 to 4 R6, and R3eis H.

[0349] In embodiments, R3ais C1-4alkyoxy (e.g., OCH3), R3bis halogen (e.g., F), R3cis F, R3dis C1-4alkyl (e.g., methyl or isopropyl) optionally substituted with 1 to 4 R6, and / or R3eis H.

[0350] In embodiments, R3ais C1-4alkyoxy (e.g., OCH3), R3bis halogen (e.g., F), R3cis F R3dis C1-4alkyl (e.g., methyl or isopropyl) optionally substituted with 1 to 4 R6, and R3eis H.

[0351] In embodiments, R3ais C1-4alkyoxy (e.g., OCH3), R3bis halogen (e.g., F), R3cis H, R3dis C1-4alkyl (e.g., methyl or isopropyl) optionally substituted with 1 to 4 R6, and / or R3eis F.

[0352] In embodiments, R3ais C1-4alkyoxy (e.g., OCH3), R3bis halogen (e.g., F), R3cis H, R3dis C1-4alkyl (e.g., methyl or isopropyl) optionally substituted with 1 to 4 R6, and R3eis F. Exemplary Compounds

[0353] Exemplary compounds include those described in Table 1 herein and pharmaceutically acceptable salts thereof.

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

[0355] Where the absolute stereochemistry of a stereocenter is not indicated, it is understood that embodiments of the compound encompass (R)- and (S)- configurations in the alternative. Likewise, such compounds may be used in methods described herein as compositions comprising stereochemical mixtures or as stereochemically-enriched compositions (e.g., compositions of a compound substantially free of any other stereoisomer of that compound).ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0359] In embodiments, a compound(Compound 4A / 4B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 4A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 4B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0363] In embodiments, a compound(Compound 8A / 8B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 8A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 8B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0367] In embodiments, a compound(Compound 12A / 12B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 12A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 12B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0371] In embodiments, a compound(Compound 16A / 16B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 16A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 16B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0375] In embodiments, a compound(Compound 19C / 19D), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 19C, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 19D, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0379] In embodiments, a compound(Compound 23A / 23B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 23A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 23B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0383] In embodiments, a compound(Compound 27A / 27B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 27A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 27B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0387] In embodiments, a compound(Compound 31A / 31B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 31A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 31B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0391] In embodiments, a compound(Compound 35A / 35B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 35A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 35B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0395] In embodiments, a compound(Compound 39A / 39B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 39A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 39B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0399] In embodiments, a compound(Compound 43A / 43B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 43A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 43B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0403] In embodiments, a compound(Compound 47A / 47B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 47A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 47B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0407] In embodiments, a compound(Compound 51A / 51B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 51A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 51B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0411] In embodiments, a compound(Compound 100A / 100B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 100A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 100B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 101A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 101B, or a pharmaceutically acceptable salt thereof.

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

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

[0415] In embodiments, a compound is(Compound 104A / 104B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 104A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 104B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 105A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 105B, or a pharmaceutically acceptable salt thereof.

[0417] In embodiments, a compound(Compound 106A / 106B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 106A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 106B, or a pharmaceutically acceptable salt thereof.(Compound 107A / 107B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 107A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 107B, or a pharmaceutically acceptable salt thereof.

[0419] In embodiments, a compound(Compound 108A / 108B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 108A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 108B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0423] In embodiments, a compound(Compound 112A / 112B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 112A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 112B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0427] In embodiments, a compound(Compound 116A / 116B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 116A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 116B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

[0430] In embodiments, a compound is(Compound 119A / 119B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 119A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 119B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

[0432] In embodiments, a compound(Compound 121A / 121B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 121A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 121B, or a pharmaceutically acceptable salt thereof.(Compound 122A / 122B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 122A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 122B, or a pharmaceutically acceptable salt thereof.

[0434] In embodiments, a compound(Compound 123A / 123B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 123A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 123B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

[0435] In embodiments, a compound(Compound 124A / 124B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 124A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 124B, or a pharmaceutically acceptable salt thereof.compound is Compound 125A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 125B, or a pharmaceutically acceptable salt thereof.

[0437] (Compound 126A / 126B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 126A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 126B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1compound is Compound 127A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 127B, or a pharmaceutically acceptable salt thereof.

[0439] In embodiments, a compound(Compound 128A / 128B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 128A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 128B, or a pharmaceutically acceptable salt thereof.compound is Compound 129A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 129B, or a pharmaceutically acceptable salt thereof.

[0441] In embodiments, a compound is(Compound 130A / 130B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 130A, or aATTORNEY DOCKET NO. MORF-010WO1 pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 130B, or a pharmaceutically acceptable salt thereof.

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

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

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

[0445] In embodiments, a compound(Compound 134A / 134B), or a pharmaceutically acceptable salt thereof. In embodiments, aATTORNEY DOCKET NO. MORF-010WO1 compound is Compound 134A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 134B, or a pharmaceutically acceptable salt thereof.

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

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

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

[0449] In embodiments, a compound(Compound 138A / 138B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 138A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 138B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

[0452] In embodiments, a compound is(Compound 141A / 141B / 141C / 141D), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 141A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 141B, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 141C, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 141D, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

[0454] In embodiments, a compound is(Compound 143A / 143B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 143A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 143B, or a pharmaceutically acceptable salt thereof.(Compound 144A / 144B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 144A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 144B, or a pharmaceutically acceptable salt thereof.(Compound 145A / 145B), or a pharmaceutically acceptable salt thereof. In embodiments, aATTORNEY DOCKET NO. MORF-010WO1 compound is Compound 145A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 145B, or a pharmaceutically acceptable salt thereof.

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

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

[0459] In embodiments, a compound(Compound 148A / 148B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 148A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 148B, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

[0463] In embodiments, a compound(Compound 152A / 152B), or a pharmaceutically acceptable salt thereof. In embodiments, aATTORNEY DOCKET NO. MORF-010WO1 compound is Compound 152A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 152B, or a pharmaceutically acceptable salt thereof.

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

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

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

[0467] Compounds described herein can comprise atoms that exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotopeATTORNEY DOCKET NO. MORF-010WO1 having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominately found in nature. The term “isotopologue” refers to a species that has the same chemical structure and formula as a specific compound provided herein, with the exception of the positions of isotopic substitution and / or level of isotopic enrichment at one or more positions, e.g., hydrogen vs. deuterium. The present invention is meant to include all suitable isotopic variations of the compounds of the compounds described herein. For example, different isotopic forms of hydrogen (H) include protium (1H), deuterium (2H), and tritium (3H), as well as compositions enriched in isotopologues of any compound described herein.

[0468] In embodiments, one or more of the hydrogens of the compounds described herein is replaced by a deuterium. When a position is designated as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. When a position is designated as “2H” or “deuterium”, the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., the term “2H” or “deuterium” indicates at least 50.1% incorporation of deuterium). Accordingly, the invention also features compositions enriched in deuterated compounds.

[0469] In embodiments, compositions of any compound provided herein may have an isotopic enrichment factor for each deuterium present at a site designated as a potential site of deuteration on 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). Exemplary Pharmaceutical Compositions

[0470] Compounds described herein (e.g., compounds of any one of Formulas (I)-(VII)) or pharmaceutically acceptable salts thereof can be formulated in various pharmaceutical compositions. A compound described herein (e.g., a compound of Formula (I) (including compounds of Formulas (II)-(VI) and any compound of Table 1 as provided herein), as well as pharmaceutically acceptable salts thereof, may be the active pharmaceutical ingredient (API) combined with one or more other ingredients to form a drug substance pharmaceutical composition. The drug substance (DS) pharmaceutical composition can comprise the API (e.g., aATTORNEY DOCKET NO. MORF-010WO1 compound of Formula (I) or pharmaceutically acceptable salt thereof) and one or more pharmaceutically acceptable carriers, diluents, and / or excipients. The carrier(s), diluent(s) or excipient(s) can be selected to be compatible with the other ingredients of the formulation and appropriately safe and effective for an intended therapy. A desired weight concentration of a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API) can be combined with the other inactive ingredients to form a drug substance (DS) in a formulation batch. Pharmaceutically acceptable compositions can be formulated for administration by an appropriate route, for example by the oral delivery (including as a capsule or tablet) in unit dosage forms. Such compositions may be prepared by bringing into association the active pharmaceutical ingredient (API) comprising a compound of Formula (I) with the carrier(s) or excipient(s).

[0471] In certain embodiments, the invention provides a pharmaceutical composition formulated for oral delivery of an ^4^7integrin integrin inhibitor, the composition comprising the ^4^7integrin inhibitor compound described herein (e.g., a compound of any one of Formulas (I)- (VII) such as any compound of Table 1, or a pharmaceutically acceptable salt thereof) as an API and a pharmaceutically acceptable carrier formulated for oral therapeutic administration of the ^4 ^7 integrin inhibitor compound.

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

[0474] In certain embodiments, the 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 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 invention provides a pharmaceutical composition comprising a compound of Formula (IIIA), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).ATTORNEY DOCKET NO. MORF-010WO1

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

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

[0484] In certain embodiments, the 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 various procedures. For example, the compounds of Formula (I) can be formulated with suitable excipients, diluents, or carriers, and formed into tablets, or capsules, and other suitable dosage forms.

[0486] Pharmaceutical compositions can be provided in unit dose forms containing a predetermined amount of API comprising a compound described herein (e.g., a compound ofATTORNEY DOCKET NO. MORF-010WO1 Formula (I)) or a pharmaceutically acceptable salt thereof per unit dose. Such a unit may contain, a desired amount of a compound (e.g., a compound of the Formula (I)) or pharmaceutically acceptable salt thereof, depending on the condition being treated, the route of administration and the age, weight and condition of the patient. Such unit doses may therefore be administered at a desired dose interval. The concentration of active compound in the drug composition will depend on various applicable parameters and considerations such as the absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should 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 exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient can be administered at once, or can be divided into a number of smaller doses to be administered at varying intervals of time.

[0487] In certain embodiments, the mode of administration of the active compound is oral. Oral compositions will generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. Pharmaceutical compositions comprising 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 a desired dosage strength (e.g., of the compound of Formula (I) or a pharmaceutically acceptable salt thereof). For oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. For oral administration in the form of a tablet or capsule, a 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 that are suitable for such formulations include the following: fillers and extenders such as starch, and sugars; and binding agents such as cellulose derivatives. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. SuitableATTORNEY DOCKET NO. MORF-010WO1 binders include starch, natural sugars, natural and synthetic gums, and the like. Lubricants and / or glidants can be used in these dosage forms.

[0488] The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, unit dosage forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, or other enteric agents.

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

[0490] The compounds can be formulated as solutions appropriate for parenteral administration, for example, by intramuscular, subcutaneous or intravenous routes. For example, a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof can be dissolved in a suitable buffer. A pharmaceutical composition comprising a desired concentration of a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof can be formulated as an injectable drug solution in (useful, e.g., in preclinical animal studies). Exemplary Therapeutic Methods

[0491] Compounds described herein can be useful for the treatment of various diseases and disorders that benefit from antagonizing the integrin αvβ8. For example, inhibiting the integrin αvβ8-driven TGFβ activation is proposed to reverse tumor tolerance and enhance anti-tumor T / NK cell responses. For example, αvβ8 inhibition can enhance outcomes in checkpoint inhibitors regimens or reverse checkpoint inhibitor resistance. In embodiments, a compound described herein can modulate an anti-tumor immune response (e.g., in checkpoint-inhibitor resistant tumors).

[0492] In embodiments, the invention features a method of inhibiting αvβ8integrin in a patient, said method comprising administering to a patient in need thereof a therapeuticallyATTORNEY DOCKET NO. MORF-010WO1 effective amount of a compound described herein (e.g., a compound of any one of Formulas (I)- (VII) such as any compound of Table 1) or a pharmaceutically acceptable salt thereof.

[0493] In embodiments, the invention features a method of treating a cancer (e.g., a solid tumor) in a patient, said method comprising 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 of Table 1) or a pharmaceutically acceptable salt thereof. In embodiments, a method further comprises administration of a therapeutically effective amount of a second active agent. Solid Tumors

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

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

[0496] In embodiments, a cancer is a solid tumor such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, 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, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, uterine cancer, testicular cancer, non small cell lung cancer (NSCLC), small cell lung carcinoma, bladder carcinoma, lung cancer, epithelial carcinoma, skin cancer, melanoma, neuroblastoma (NB), or retinoblastoma. In embodiments, a solid tumor is an advanced stage solid tumor (e.g., a locally advanced solid tumor). In embodiments, a solid tumor is a metastatic solid tumor.ATTORNEY DOCKET NO. MORF-010WO1

[0497] In embodiments, a cancer (e.g., solid tumor) is anal cancer, bile duct cancer (cholangiocarcinoma), bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, fallopian tube cancer, gastric cancer, glioma liver cancer, lung cancer, melanoma, nasopharyngeal carcinoma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, primary peritoneal carcinoma, 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, a cancer (e.g., solid tumor) is breast cancer, squamous cell carcinoma of the head and neck (SCCHN), renal cell carcinoma, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, pancreatic cancer, bile duct cancer, endometrial cancer, melanoma, or urothelial carcinoma.

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

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

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

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

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

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

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

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

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

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

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

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

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

[0512] In embodiments, a cancer (e.g., solid tumor) is liver cancer. In embodiments, a liver cancer is hepatocellular carcinoma.ATTORNEY DOCKET NO. MORF-010WO1

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0528] In embodiments, a patient has a cancer (e.g., a solid tumor such as those described herein) that is therapy resistant. In embodiments, a therapy resistant cancer (e.g., a solid tumor) is checkpoint resistant. In embodiments, a therapy resistant cancer (e.g., a solid tumor) is resistant to an anti-PD-1 or anti-PD-L1 therapy (collectively, a PD-(L)1 resistant cancer).ATTORNEY DOCKET NO. MORF-010WO1 Exemplary Combination Therapies and Second Active Agents

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

[0530] For example, a compound or pharmaceutically acceptable salt described herein may be administered in combination with one or more additional therapies (e.g., a second active agent) in the treatment of certain diseases and disorders.

[0531] In embodiments, a compound or pharmaceutically acceptable salt described herein may be administered in combination with an immunotherapy. In embodiments, an immunotherapy is a cancer immunotherapy. In embodiments, a cancer immunotherapy is an immune checkpoint therapy (e.g., therapy comprising administration of an immune checkpoint inihbitor). In embodiments, a cancer immunotherapy is a cellular immunotherapy such as adoptive T cell transfer therapy (e.g., Chimeric Antigen Receptor (CAR) T cell therapy, CAR natural killer (NK) cell therapy, tumor infiltrating lymphocyte (TIL) therapy, or endogenous T cell (ETC) therapy). In embodiments, a cancer immunotherapy is a cancer vaccine. In embodiments, a cancer immunotherapy is monoclonal antibody therapy (e.g., an antibody useful for immune checkpoint therapy such as those described herein). In embodiments, a cancer immunotherapy is cytokine therapy (e.g., interferon or interleukin therapy).

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

[0533] In embodiments, a second active agent is an immune checkpoint inhibitor. In embodiments, an immune checkpoint inhibitor targets PD-1 (e.g., inhibition via anti-PD-1, anti- PD-L1, or anti-PD-L2 therapies), CTLA-4, TIM-3, TIGIT, LAGs (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.ATTORNEY DOCKET NO. MORF-010WO1

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

[0535] In embodiments, an 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, an immune checkpoint inhibitor is selected from: pembrolizumab (Keytruda®), nivolumab (Opdivo®), cemiplimab (Libtayo®), dostarlimab (Jemperli®), atezolizumab (Tecentriq®), avelumab (Bavencio®), durvalumab (Imfinzi®), ipilimumab (Yervoy®), and relatlimab, as well as biosimilars thereof.

[0537] In embodiments, a 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, an anti-PD(L)-1 therapy is selected from the group consisting of: pembrolizumab, nivolumab, cemiplimab, dostarlimab, 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 millamolecule, as well as biosimilars thereof.

[0539] In embodiments, an 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, as well as biosimilarsthereof. In embodiments, an anti-PD(L)-1 therapy 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, as well as biosimilars thereof.

[0540] In embodiments, an anti-PD(L)-1 therapy is selected from pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, dostarlimab, PDR-001, tislelizumab (BGB- A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI-754091, IBI-308, camrelizumab (HR-301210), BCD-100, JS-001, CX-072, BGB-A333, AMP-514 (MEDI-0680), AGEN-2034, CS1001, Sym-021, SHR-1316, PF-06801591, LZM009, KN-035, AB122, genolimzumab (CBT-501), FAZ-053, CK-301, AK 104, GLS-010, JTX-4014, SHR-1210, AMP- 224, AUN-P12, CA-170, BMS-986189, and any of the PD-1 antibodies disclosed inATTORNEY DOCKET NO. MORF-010WO1 WO2014 / 179664. In embodiments, an 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 embodiments, an anti-PD(L)-1 therapy is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, atezolizumab, avelumab, and durvalumab. In embodiments, an anti-PD(L)-1 therapy is selected from nivolumab, pembrolizumab, cemiplimab, and dostarlimab. In embodiments, an anti-PD(L)-1 therapy is selected from atezolizumab, avelumab, and durvalumab.

[0542] In embodiments, a second active agent is an anti-CTLA-4 therapy. In embodiments, an anti-CTLA-4 therapy is ipilimumab.

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

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

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

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

[0547] In some embodiments, a compound or use of the present invention can be selected from one or more of the enumerated embodiments provided below.ATTORNEY DOCKET NO. MORF-010WO1 1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:wherein: the Q ringL is each o4f which is optionally substituted with 1 to 6 R ; X is -CHR1c-, -O-, or -NR2-; each of R1a, R1b, R1c, R1d, R1e, and R1fis independently H, C1-4alkyl, halogen, C1-4alkyoxy, OH, C1-4alkyl-OH, C1-4alkyl-C1-4alkyoxy, C1-4alkyoxy-C1-4alkyoxy, CF3, CHF2, CH2F, CN, NO2, NRaRbor C1-4alkyl-NRaRb, each R2is independently H, C1-4alkyl, or C3-5cycloalkyl; R3ais C1-4alkyoxy, C3-5cycloalkoxy, CF3, CHF2, CH2F, OCF3, OCHF2 or OCH2F; R3bis H, halogen, CF3 or CN; R3cis H, F, CN, or C1-4alkyl; R3dis C1-4alkyl, C3-5cycloalkyl, or 4-6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 R6; R3eis H or F; each R4is independently H, C1-4alkyl, halogen, CF3, CHF2 or CH2F, cyclopropyl, or two geminal R4groups together can form a spiro-cyclopropyl; each R6is independently C1-4alkyl, C1-4alkenyl, C3-5cycloalkyl, C1-4alkyoxy, C3-5cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, 5-6-membered heteroaryl or NRaRb; each R7is independently C1-4alkyl or F; each of Ra and Rb is independently hydrogen, C1-4alkyl, C3-5cycloalkyl, or Ra and Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may beATTORNEY DOCKET NO. MORF-010WO1 optionally substituted by from one to three groups which may be the same or different selected from the group consisting of F, C1-4alkyl, phenyl and benzyl; and n is 1 or 2; and m is 0, 1 or 2. 2. The compound of Embodiment 1, wherein the Q ring3. The compound of Embodiment 1 or 2, wherein X is -O-. 4. The compound of Embodiment 1 or 2, wherein X is -NR2-. 5. The compound of Embodiment 4, wherein R2is methyl. 6. The compound of Embodiment 1, wherein the Q ring is . 7. The compound of any one of Embodiments 1-6, wherein each of R1dand R1eis independently H. 8. The compound of Embodiment 6-7, wherein each R1cis independently H. 9. The compound of any one of Embodiments 1-8, wherein each R1ais independently H. 10. The compound of any one of Embodiments 1-9, wherein each R1bis independently H. 11. The compound of any one of Embodiments 1-9, wherein each R1bis independently OMe. 12. The compound of Embodiment 1, wherein the Q ring13. The compound of Embodiment 12, wherein each of R1cand R1dis independently H.ATTORNEY DOCKET NO. MORF-010WO1 The compound of Embodiment 1 or 12-13, wherein each of R1a, R1band R1fis independently H. The compound of any one of Embodiments 1-14, wherein L is. The compound of any one of Embodiments 1-14, wherein L is. The compound of any one of Embodiments 1-16, wherein R3ais C1-4alkyoxy. The compound of any one of Embodiments 1-16, wherein R3ais OMe, OEt, OCF3, OCHF2or OCH2F. The compound of any one of Embodiments 1-16, wherein R3ais OMe. The compound of any one of Embodiments 1-19, wherein R3bis F. The compound of any one of Embodiments 1-20, wherein R3cis H. The compound of any one of Embodiments 1-21, wherein R3dis C1-4alkyl. The compound of any one of Embodiments 1-21, wherein R3dis C3-5cycloalkyl. The compound of any one of Embodiments 1-21, wherein R3dis oxetanyl, tetrahydrofuranyl or tetrahydro-2H-pyranyl, morpholinyl or piperazinyl-C1-4alkyl. The compound of any one of Embodiments 1-21, wherein R3dis iso-propyl. The compound of any one of Embodiments 1-25, wherein R3eis H. The compound of any one of Embodiments 1-26, wherein each R4is independently methyl. The compound of any one of Embodiments 1-26, wherein each R4is independently F. The compound of any one of Embodiments 1-26, wherein each R4is independently CF3, CHF2or CH2F. The compound of any one of Embodiments 1-26, wherein each R4is independently H. The compound of any one of Embodiments 1-30, wherein each R6is independently C1-4alkyl.ATTORNEY DOCKET NO. MORF-010WO1 The compound of any one of Embodiments 1-30, wherein each R6is independently C1- 4alkenyl. The compound of any one of Embodiments 1-30, wherein each R6is independently C3- 5cycloalkyl. The compound of any one of Embodiments 1-30, wherein each R6is independently C1- 4alkyoxy. The compound of any one of Embodiments 1-30, wherein each R6is independently C3-5cycloalkoxy. The compound of any one of Embodiments 1-30, wherein each R6is independently F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F or OH. The compound of any one of Embodiments 1-30, wherein each R6is independently a 5-6- membered heteroaryl. The compound of any one of Embodiments 1-30, wherein each R6is independently H. The compound of any one of Embodiments 1-38, wherein n is 0. The compound of any one of Embodiments 1-38, wherein n is 1. The compound of any one of Embodiments 1-38, wherein n is 2. The compound of any one of Embodiments 1-41, wherein m is 0. The compound of Embodiment 1, having a structure according to Formula (II),or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1 compound of Embodiment 43, having a structure according to Formula (IIA),or a pharmaceutically acceptable salt thereof. compound of Embodiment 1, having a structure according to Formula (III),or a pharmaceutically acceptable salt thereof. compound of Embodiment 45, having a structure according to Formula (IIIA),or a pharmaceutically acceptable salt thereof. compound of Embodiment 1, having a structure according to Formula (IV),or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1 compound of Embodiment 47, having a structure according to Formula (IVA),or a pharmaceutically acceptable salt thereof. compound of Embodiment 1, having a structure according to Formula (V),or a pharmaceutically acceptable salt thereof. compound of Embodiment 49, having a structure according to Formula (VA),or a pharmaceutically acceptable salt thereof. compound of Embodiment 1, having a structure according to Formula (VI),or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1 The compound of Embodiment 51, having a structure according to Formula (VIA),or a pharmaceutically acceptable salt thereof. The compound of any one of Embodiments 49-52, wherein n is 1. The compound of any one of Embodiments 49-52, wherein n is 2. The compound of any one of Embodiments 43-54, wherein R1bis H, CH3, or OCH3. The compound of any one of Embodiments 43-55, wherein R3eis H or F. The compound of any one of Embodiments 43-56, wherein R3dis C1-4alkyl optionally substituted with 1 R6. The compound of Embodiment 57, wherein R3dis,The compound of any one of Embodiments 43-56, wherein R3dis 4-6-membered heterocycloalkyl optionally substituted with 1 R6. The compound of Embodiment 59, wherein R3dis. The compound of any one of Embodiments 43-56, wherein R3dis C3-5cycloalkyl optionally substituted with 1 R6. The compound of Embodiment 61, wherein R3dis. The compound of any one of Embodiments 43-62, wherein the carbon marked by the asterisk (*) has the (R)-configuation.ATTORNEY DOCKET NO. MORF-010WO1 The compound of any one of Embodiments 43-62, wherein the carbon marked by the asterisk (*) has the (S)-configuation. The compound of Embodiment 1, selected from any compound described in Table 1, or a pharmaceutically acceptable salt thereof. The compound of Embodiment 1, selected from:ATTORNEY DOCKET NO. MORF-010WO1ATTORNEY DOCKET NO. MORF-010WO1ATTORNEY DOCKET NO. MORF-010WO1or a pharmaceutically acceptable salt thereof. pound of embodiment 66, wherein the compound isATTORNEY DOCKET NO. MORF-010WO1 The compound of embodiment 66, wherein the compound is(Compound 2A / 2B), or a pharmaceutically acceptable salt thereof. The compound of embodiment 66, wherein the compound is(Compound 7A / 7B), or a pharmaceutically acceptable salt thereof. The compound of embodiment 66, wherein the compound is(Compound 11A / 11B), or a pharmaceutically acceptable salt thereof. The compound of embodiment 66, wherein the compound is(Compound 12A / 12B), or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1 The compound of embodiment 66, wherein the compound is(Compound 17A / 17B), or a pharmaceutically acceptable salt thereof. The compound of embodiment 66, wherein the compound is(Compound 20A / 20B), or a pharmaceutically acceptable salt thereof. The compound of embodiment 66, wherein the compound is(Compound 24A / B), or a pharmaceutically acceptable salt thereof. The compound of embodiment 66, wherein the compound is(Compound 28A / 28B), or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1 The compound of embodiment 66, wherein the compound is(Compound 35A / 35B), or a pharmaceutically acceptable salt thereof. The compound of embodiment 66, wherein the compound is(Compound 36A / 36B), or a pharmaceutically acceptable salt thereof. The compound of embodiment 66, wherein the compound is(Compound 41A / 41B), or a pharmaceutically acceptable salt thereof. The compound of embodiment 66, wherein the compound is(Compound 42A / 42B), or a pharmaceutically acceptable salt thereof. The compound of embodiment 66, wherein the compound is(Compound 47A / 47B), or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1 The compound of embodiment 66, wherein the compound ispharmaceutically acceptable salt thereof. The compound of embodiment 66, wherein the compound ispharmaceutically acceptable salt thereof. The compound of embodiment 66, wherein the compound ispharmaceutically acceptable salt thereof. The compound of embodiment 66, wherein the compound ispharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1 The compound of embodiment 66, wherein the compound is(Compound 136A / 136B), or a pharmaceutically acceptable salt thereof. The compound of embodiment 66, wherein the compound ispharmaceutically acceptable salt thereof. The compound of embodiment 66, wherein the compound is(Compound 154A / 154B), or a pharmaceutically acceptable salt thereof. A pharmaceutical composition, comprising a compound of any one of Embodiments 1-87, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. A method of inhibiting αvβ8 integrin in a patient, the method comprising administering to the patient in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-87, or a pharmaceutically acceptable salt thereof. The method of embodiment 89, wherein the method is for treating a solid tumor in a patient in need thereof. A method of treating solid tumor in a patient, the method comprising administering to the patient in need thereof (a) a therapeutically effective amount of a compound of any one ofATTORNEY DOCKET NO. MORF-010WO1 embodiments 1-87, or a pharmaceutically acceptable salt thereof, and (b) a therapeutically effective amount of a second active agent. The method of Embodiment 91, wherein the solid tumor is selected from: anal cancer, bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, fallopian tube cancer, gastric cancer, glioma liver cancer, lung cancer, melanoma, nasopharyngeal carcinoma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, primary peritoneal carcinoma, prostate cancer, renal cell carcinoma, skin cancer, squamous cell carcinoma of the head and neck (SCCHN), testicular cancer, urothelial carcinoma, and uterine cancer. The method of embodiment 92, wherein the solid tumor is selected from: breast cancer, squamous cell carcinoma of the head and neck (SCCHN), renal cell carcinoma, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, pancreatic cancer, bile duct cancer, endometrial cancer, melanoma, and urothelial carcinoma. The method of any one of Embodiments 91-93, wherein the second active agent is an immune checkpoint inhibitor. The method of embodiment 94, wherein the immune checkpoint inhibitor is an anti-PD-1 or an anti-PD-L1 therapy. The method of embodiment 95, wherein the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, atezolizumab, avelumab, and durvalumab.ATTORNEY DOCKET NO. MORF-010WO1 Examples General Schemes General Scheme 1:wherein Q, L, R7, m, R3e, R3d, R3c, R3b, R3aare defined as in Formula (I) and B(OR)2 is a boronic acid or boronic ester

[0548] A general method of preparing compounds of Formula (I) is outlined in General Scheme 1. Treatment of a pyrrolidine (or pyrrolidine-HCl salt) 2-a, an aryl boronic 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 an elevated temperature (i.e., 60 °C) provides diastereomeric compounds of Formula (I) which could be separated by supercritical fluid chromatography (SFC) or prep-HPLC. General Scheme 2:wherein Q, L, R7, m, R3e, R3d, R3c, R3band R3aare defined as in Formula (I) and R is an alkyl group

[0549] Alternatively, compounds of Formula (I) can be prepared as outlined in General Scheme 2. Treatment of a 2-bromo-2-arylacetate 2-c (i.e., R= Et or t-Bu) and a pyrrolidine (or pyrrolidine-HCl salt) 2-a in a solvent (i.e., acetonitrile) in the presence of base (i.e., DIEA) at ambient to slightly elevated temperatures (i.e., 25-50 °C) yields an amino ester 2-d. Hydrolysis ofATTORNEY DOCKET NO. MORF-010WO1 2-d under basic conditions (i.e., LiOH / MeOH for R=CH3) or treatment with acid (i.e., formic acid or TFA for R=t-Bu) yields diastereomeric compounds of Formula (I), which could be separated by supercritical fluid chromatography (SFC) or prep-HPLC. Abbreviations Abbreviation Chemical Name 4A MS Molecular sieves, 4A, powder 9-BBN 9-Borabicyclo[3.3.1]nonane dimer AcOH acetic acid AgOTf silver trifluoromethanesulfonate AIBN 2,2-Azobis(2-methylpropionitrile) B(O-iPr)3triisopropyl borate BBr3tribromoborane BH3 ^THF borane tetrahydrofuran complex Cs2CO3 cesium carbonate CuI copper(I) iodide DBU 1，8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DIEA N,N-diisopropylethylamine DMF dimethyl formamide DMSO dimethyl sulfoxide EtOAc ethyl acetate EtOH ethanol H2hydrogen H2O2hydrogen peroxide H2SO4 sulfuric acid HCl hydrochloric acid HFIP 1,1,1,3,3,3-hexafluoropropan-2-ol i-PrMgBr isopropylmagnesium bromide i-PrMgCl ^LiCl isopropylmagnesium chloride-lithium chloride complexATTORNEY DOCKET NO. MORF-010WO1 K2CO3potassium carbonate K3PO4potassium phosphate KF potassium fluoride KI potassium iodide KOAc potassium acetate LDA lithium diisopropyl amide LiHMDS lithium bis(trimethylsilyl)azanide Lindlar catalyst palladiumoncalciumcarbonate LiOH lithium hydroxide MeCN acetonitrile MeI iodomethane MeOH methanol Mg magnesium MTBE tert-butyl methyl Ether Na2SO3 disodium sulfite Na2SO4sodium sulfate NaH sodium hydride NaHCO3 sodium bicarbonate NaI sodium iodide NaOAc sodium acetate NaOH sodium hydroxide NBS N-bromosuccinimide NH3.H2O ammonium hydroxide NH4Cl ammonium chloride NH4HCO3 ammoniumhydrogencarbonate NIS N-iodosuccinimide PCy3tricyclohexylphosphine Pd(dba)2bis(dibenzylideneacetone)palladium Pd(dppf)Cl2 1,1-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) Pd(OAc)2 palladium (II) acetateATTORNEY DOCKET NO. MORF-010WO1 Pd(t-Bu3P)2bis(tri-tert-butylphosphine)palladium(0) Pd / C palladium on activated charcoal Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) PPh3 triphenylphosphane prep-HPLC preparative high performance liquid chromatography Phos pentaphenyl(di-tert-butylphosphino)ferrocene Selectfluor 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane;ditetrafluoroborateSFC supercritical fluid chromatography SiO2 silicon dioxide TBAB tetrabutylazanium bromide TBAF tetrabutylazanium fluoride t-BuOK potassium tert-butoxide TEA triethylamine TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofuran TMSCF3 trimethyl(trifluoromethyl)silane TMSCl chloro(trimethyl)silane ZnCl2zinc chloride Analytical Methods, Materials, and Instrumentation

[0550] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Default methods, materials and instrumentation are listed below.1H NMR instrumental information:

[0551] Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker or Varian spectrometers at 400 MHz. Spectra are given in ppm (d) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. LCMS instrumental information and analysis method:ATTORNEY DOCKET NO. MORF-010WO1

[0552] Mass spectra were collected using an Agilent 6120 Single Quad Mass Spectrometer (ESI). Purity and low resolution mass spectral data were measured using Agilent 1260 Infinity II high-performance liquid chromatography (HPLC) system with Photo Diode Array Detector, Agilent 1260 Infinity II Evaporative Light Scattering Detector (ELSD) and Agilent 6120 Mass Spectrometer. Data was acquired using Chemstation C.01.10 and purity characterized by UV wavelength 220 nm, ELSD and ESI.

[0553] Method A: Column: Kinetex C182.1 x 50 mm, 5 um; Flow rate 1.0 mL / min; Mobile phase A: water with 0.04% TFA, Mobile phase B: acetonitrile with 0.02% trifluoroacetic acid; Gradient: 5% B from 0-0.40 min, then a gradient of 5-95% B over 2.60 min, then hold on 95% B for 1.00 min, then 95-5% B over 0.01 min.

[0554] Method B: Column: Xbridge C182.1 x 50 mm column (5 um particles); Flow rate 0.8 mL / min; Mobile phase A: water with 10 mM NH4HCO3; Mobile phase B: acetonitrile; Gradient: 5% B from 0-0.40 min, then a gradient of 5-95% B from 0.40-3.40 min, then hold 95% B for 0.45 min, then 95-5% B over 0.01 min. SFC instrumental and analytical methods information:

[0555] Instrument: Waters UPCC with PDA detector

[0556] 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).

[0557] Columns: Daicel CHIRALPAK AD-3, 50 × 4.6 mm I.D., 3 um; Daicel CHIRALCEL OD-3, 50 × 4.6 mm I.D., 3 um; Daicel CHIRALCEL OJ-3, 50 × 4.6 mm I.D., 3 um; Daicel CHIRALPAK IG-3, 50 × 4.6 mm I.D., 3 um; Daicel CHIRALPAK AS-3, 50 × 4.6 mm I.D., 3 um; Daicel CHIRALPAK IC-3, 50 x 4.6 mm I.D., 3 um; Phenomenex Lux Cellulose-2, 50 × 4.6 mm I.D., 3 um; Regis (S,S)-Whelk-O 1, 50 × 4.6 mm I.D., 3.5 um

[0558] Column temperature: 35°C

[0559] Gradient: 5% B from 0.0-0.2 min, then a gradient of 5-50% B from 0.2-1.2 min, then hold 50% B for 1.0 min, then a gradient of 50-5% B from 2.2-2.6 min, then hold 50% B for 0.4 min.

[0560] Flow rate: 3.4 mL / min

[0561] Automated back pressure regulator (ABPR): 1800 psiATTORNEY DOCKET NO. MORF-010WO1

[0562] Alternatively, chiral products were analyzed by chiral SFC using an SFC-80 (Thar, Waters) instrument, detection wavelength 214 nm using one of the following methods:

[0563] Chiral SFC A: column: (R,R)-Whelk-O1, 4.6*100mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.

[0564] Chiral SFC B: column: AD 4.6*100mm, 5 µm (Daicel), column temperature: 40 °C,

[0565] mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar.

[0566] Chiral SFC H: column: (S,S)-Whelk-O1, 4.6*100mm, 5 µm (Daicel), column temperature: 40 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia), isocratic elution as in text, flow rate: 4 g / min, back pressure: 120 bar. Preparative HPLC Method

[0567] Instruments: Gilson 281 semi-preparative HPLC system

[0568] Conditions: Mobile Phase A: water with 0.2% formic acid (or water with 0.1% TFA, or water with 0.05% HCl, or water with 10 mM NH4HCO3or water with 0.04% ammonium hydroxide); Mobile Phase B: acetonitrile

[0569] Columns: Phenomenex Luna C18100 x 30 mm x 5um, Phenomenex Gemini C18100 x 30 mm x 5 um; Waters Xbridge BEH C18100 x 30 mm x 10 um

[0570] Column temperature: ambient

[0571] LC gradient: gradient of 5% to 50% B over 10 min, then hold 50% B for 2 min, then a gradient of 50-100% Bover 0.1 min, then hold at 100% for 2 min, then a gradient of 100% to 5% over 0.1 min, then hold at 5% for 2 min

[0572] LC flow rate: 25 mL / min

[0573] UV wavelength: 220 nm and 254 nm

[0574] Alternatively, crude samples may be dissolved in MeOH and purified by prep HPLC using a Gilson 215 instrument, detection wavelength 214 nm, using one of the following methods noted in the procedures:

[0575] “Prep-HPLC A”: column: XBridge C18, 21.2 x 250 mm, 10 µm; Mobile phase A: water (10 mM ammonium hydrogen carbonate), Mobile phase B: acetonitrile; gradient elution as in text; flow rate: 20 mL / min.ATTORNEY DOCKET NO. MORF-010WO1

[0576] “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 in text; flow rate: 20 mL / min. Preparative Chiral HPLC method

[0577] Instruments: Gilson-281 semi preparative HPLC system; UV: Gilson-156 UV

[0578] 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).

[0579] Columns: Daicel CHIRALPAK AD, 10 um, 30 mm x 250 mm; Daicel CHIRALPAK IH, 10 um, 30 mm x 250 mm; Daicel CHIRALCEL OD, 10 um, 30 mm x 250 mm; Daicel CHIRALCEL OJ, 10 um, 30 mm x 250 mm; Daicel CHIRALPAK IC, 10 um, 30 mm x 250 mm; Daicel CHIRALPAK IG, 10 um, 30 mm x 250 mm; Phenomenex Lux Cellulose-2, 10 um, 30 mm x 250 mm; Regis (S,S) Whelk-O1, 10 um, 30 mm x 250 mm

[0580] Column temperature: ambient

[0581] LC gradient: A:B = 80:20 or other ratio of isocratic elution mode

[0582] LC flow rate: 25 mL / min binary pump

[0583] UV wavelength: 220 nm and 254 nm Preparative Chiral SFC methods

[0584] Instruments: SFC: Waters 80Q preparative SFC; UV: Waters 2489 UV

[0585] 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)

[0586] Columns: Daicel CHIRALPAK AD, 10 um, 30 mm x 250 mm; Daicel CHIRALPAK IH, 10 um, 30 mm x 250 mm; Daicel CHIRALCEL OD, 10 um, 30 mm x 250 mm; Daicel CHIRALCEL OJ, 10 um, 30 mm x 250 mm; Daicel CHIRALPAK IC, 10 um, 30 mm x 250 mm; Daicel CHIRALPAK IG, 10 um, 30 mm x 250 mm; Phenomenex Lux Cellulose-2, 10 um, 30 mm x 250 mm; Regis (S, S) Whelk-O1, 10 um, 30 mm x 250 mm;

[0587] Column temperature: 40 °C

[0588] LC gradient: A:B = 80:20 or other ratios of isocratic elution modeATTORNEY DOCKET NO. MORF-010WO1

[0589] LC flow rate: 70 g / min binary pump

[0590] UV wavelength: 220 nm

[0591] System back pressure: 100 bar

[0592] Alternatively, racemic products could be separated to individual enantiomers by chiral Prep SFC using an SFC-80 (Thar, Waters) instrument, detection wavelength 214 nm using one of the following methods.

[0593] Prep chiral SFC A: column: (R,R)-Whelk-O1, 20*250mm, 5 µm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0594] Prep chiral SFC B: column: AD 20*250mm, 10 µm (Daicel), column temperature: 35 °C,

[0595] mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar.

[0596] Prep chiral SFC H: column: (S,S)-Whelk-O1, 20*250mm, 5 µm (Daicel), column temperature: 35 °C, mobile phase: CO2 / methanol (0.2% methanol ammonia)= 60 / 40, flow rate: 80 g / min, back pressure: 100 bar. Examples – Left Hand 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

[0597] 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), NaOH (10.68 g, 267.04 mmol) in toluene (150 mL) and H2O (150 mL) was stirred for 16 h at 100 °C. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~100% EthylATTORNEY DOCKET NO. MORF-010WO1 acetate / Petroleum ether gradient @ 150 mL / min). (R)-tert-butyl 3-(pent-4-en-1- yloxy)pyrrolidine-1-carboxylate (10 g, 39.16 mmol, 76.9% yield) was obtained as a yellow oil. Step 2: (R)-tert-butyl 7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)-3,4-dihydro- 1,8-naphthyridine-1(2H)-carboxylate

[0598] 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, 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), Cs2CO3 (25.52 g, 78.32 mmol) and Pd(PPh3)4 (2.26 g, 1.96 mmol) in DMF (200 mL), the mixture was stirred at 100 °C for 14 h under N2 The reaction was quenched by ice water (500 mL) slowly, stirred at 0 °C for 30 min, extracted with ethyl acetate (400 mL x 2). The combined organic phase was washed with brine (400 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 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 yellow oil.1H NMR (400MHz, METHANOL-d4) δ = 7.47 (d, J = 7.7 Hz, 1H), 6.96 (d, J = 7.7 Hz, 1H), 4.03 (br d, J = 2.8 Hz, 2H), 3.76-3.72 (m, 2H), 3.55 (t, J = 6.5 Hz, 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 = 7.1 Hz, 2H), 1.51 (s, 9H), 1.46 (s, 9H), 1.42-1.39 (m, 2H). LCMS (ESI) m / z = 490.3 (M+1). Step 3: (R)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine

[0599] 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 (4M, 50 mL) was stirred at 50 °C for 16 h. The mixture was concentrated in vacuum. The racemic product was purified by prep-HPLC (column: Phenomenex luna C18 (250 x 70 mm, 15 um); mobile phase: A water (TFA 0.1%), B MeCN 1%-30%, 20 min; Flow Rate (25 mL / min). (R)-7-(5-(pyrrolidin-3-ATTORNEY DOCKET NO. MORF-010WO1 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). 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

[0600] 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 H2O (150 mL) with stirring at 25 °C, the reaction was stirred at 100 °C for 16 h. The mixture was quenched by H2O (20 mL), extracted with EtOAc (50 mL x 3), 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, Eluent of 20~50% Ethyl acetate / Petroleum ether gradient @ 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 yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 5.74-5.88 (m, 1 H), 4.91-5.10 (m, 2 H), 4.00 (br s, 1 H), 3.43 (br s, 6 H), 2.12 (q, J = 6.97 Hz, 2 H), 1.67 (quin, J = 6.94 Hz, 2 H), 1.47 (s, 9 H) LCMS (ESI) m / z = 256.3 (M+1). Step 2: (R)-tert-butyl 3-((5-(4-methoxy-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1- carboxylate1

[0601] 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 into a suspension of 2-chloro-4-methoxy-1,8- naphthyridine (2.25 g, 11.56 mmol), Pd(OAc)2(259.07 mg, 1.15 mmol) and tricyclohexylphosphine (323.60 mg, 1.15 mmol) and K2CO3 (3.19 g, 23.08 mmol) in THF (30 mL) and H2O (1.3 mL) at 25 °C, 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), the organic layer wasATTORNEY DOCKET NO. MORF-010WO1 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 brown oil. LCMS (ESI) m / z = 416.2 (M+1). Step 3: (R)-tert-butyl 3-((5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate

[0602] 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), the reaction was stirred at 50 °C for 16 h under H2(50 psi). The mixture was filtered and the filtrate was concentrated to give the crude product. The residue was used the next step directly 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 yellow oil. LCMS (ESI) m / z = 420.3 (M+1). Step 4: (R)-5-methoxy-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8- naphthyridine hydrochloride

[0603] 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 (4M, 20 mL) at 25 °C, the reaction was stirred at 50 °C for 16 h. The solvent was distilled out under vacuum 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 red oil.1H NMR (400 MHz, METHANOL-d4) δ ppm = 6.61 (s, 1 H) 4.23-4.28 (m, 1 H), 3.99- 4.04 (m, 3 H), 3.50 (t, J = 6.32 Hz, 2 H), 3.42 (br d, J = 5.75 Hz, 2 H), 3.35-3.39 (m, 2 H), 3.31 (s, 2 H), 2.71-2.76 (m, 2 H), 2.63 (t, J = 6.32 Hz, 2 H), 2.15-2.23 (m, 2 H), 2.06 (qd, J = 9.42, 5.00 Hz, 1 H), 1.88-1.91 (m, 2 H), 1.76 (br d, J = 7.75 Hz, 2 H), 1.63 (br d, J = 7.75 Hz, 2 H), 1.48 (br d, J = 7.13 Hz, 2 H), 1.33-1.40 (m, 2 H). LCMS (ESI) m / z = 320.2 (M+1).ATTORNEY DOCKET NO. MORF-010WO1 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

[0604] 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 H2O (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 quenched by ice water (1000 mL) slowly, extracted with ethyl acetate (1000 mL x 2). The combined organic phase was washed with brine (1000 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO ®; 330 g Sepa Flash ® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 300 mL / min). (S)-tert-butyl 3-(pent- 4-en-1-yloxy)pyrrolidine-1-carboxylate (23 g, 90.07 mmol, 67.46% yield) was obtained as light yellow oil.1H NMR (400MHz, 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). Step 2: (S)-tert-butyl 7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)-3,4-dihydro- 1,8-naphthyridine-1(2H)-carboxylate

[0605] 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, then added to a mixture of tert-butyl 7-chloro-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate (10.52 g, 39.16 mmol), Cs2CO3(25.52 g, 78.32 mmol) and Pd(PPh3)4(2.26 g, 1.95 mmol) in DMF (200 mL), the resulting mixture was stirred at 100 °C for 16 h under N2. The combined organic phase was washed with brine (500 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO ®; 330 g Sepa Flash ® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 300 mL / min). (S)-tert-butyl 7-(5-((1-(tert- butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylateATTORNEY DOCKET NO. MORF-010WO1 (12.5 g, 25.53 mmol, 65.19% yield) was obtained as yellow oil.1H NMR (400MHz, METHANOL-d4) δ = 7.46 (d, J = 7.5 Hz, 1H), 6.96 (d, J = 7.7 Hz, 1H), 4.03 (br d, J = 2.9 Hz, 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 = 7.7 Hz, 2H), 1.63-1.54 (m, 3H), 1.50 (s, 9H), 1.45 (s, 11H). LCMS (ESI) m / z = 490.3 (M+1). Step 3: (S)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine

[0606] 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 (4M, 50 mL) was stirred at 50 °C for 16 h. The mixture was concentrated in vacuum. The racemic product was purified by prep-HPLC (column: Phenomenex Luna 80 x 30 mm x 3 um; mobile phase: A water with 0.1% TFA; 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 yellow oil. LCMS (ESI) m / z = 290.2 (M+1) 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

[0607] t-BuOK (8.99 g, 80.11 mmol) was added portion wise to a solution of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (10 g, 53.41 mmo) in THF (100 mL) at 0 °C. The mixture was stirred for 1 h at 0 °C, then ethyl 2-bromoacetate (13.38 g, 80.11 mmol, 8.86 mL) was added dropwise to the mixture. The resulting mixture was stirred for 15 h at 20 °C. The reaction mixture was quenched with aqueous NH4Cl (150 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO ®; 80 g Sepa Flash ® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 150 mL / min). (R)-tert-butyl 3-(2-ethoxy-2- oxoethoxy)pyrrolidine-1-carboxylate (6 g, 21.95 mmol, 41.1% yield) was obtained as a yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 4.25-4.18 (m, 2H), 4.18-4.13 (m, 1H), 4.13-ATTORNEY DOCKET NO. MORF-010WO1 4.04 (m, 2H), 3.50-3.38 (m, 4H), 2.11-1.90 (m, 2H), 1.45 (s, 9H), 1.28 (t, J = 7.1 Hz, 3H). LCMS (ESI) m / z = 218.1 (M-56+1). Step 2: (R)-tert-butyl 3-(2-hydroxyethoxy)pyrrolidine-1-carboxylate

[0608] 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 for 2 h at 20 °C. 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, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 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.1H 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). Step 3: tert-butyl 7-ethynyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate

[0609] A mixture of tert-butyl 7-chloro-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (3 g, 11.16 mmol), K2CO3(3.09 g, 22.33 mmol), Pd(CH3CN)2Cl2(289.61 mg, 1.12 mmol) and X- Phos (532.18 mg, 1.12 mmol,) in CH3CN (60 mL) was degassed and purged with N2for 3 times, the mixture was stirred at 20oC for 0.5 h. Then ethynyltrimethylsilane (4.39 g, 44.65 mmol, 6.19 mL) was injected, and then the mixture was stirred at 90oC for 6 h under N2 atmosphere. After cooled to 20 °C, TBAF (1 M in THF, 5.58 mL) was added, 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, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 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.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.34 (d,ATTORNEY DOCKET NO. MORF-010WO1 J = 7.70 Hz, 1 H) 7.14 (d, J = 7.58 Hz, 1 H) 3.73-3.80 (m, 2 H) 3.03 (s, 1 H) 2.76 (t, J = 6.54 Hz, 2 H) 1.93 (quin, J = 6.33 Hz, 2 H) 1.54 (s, 9 H). LCMS (ESI) m / z = 331.2 (M+1). 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

[0610] To the solution of 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. The reaction mixture was quenched by addition water (20 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 the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 4 g Sepa Flash ® Silica Flash Column, Eluent of 0~33% Ethyl acetate / Petroleum ether gradient @ 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 brown oil. LCMS (ESI) m / z = 490.2 (M+1). 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

[0611] 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), the reaction was stirred at 25 °C under H2(50 psi) for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue. The residue was purified by flash silica gel chromatography (ISCO ®; 12 g Sepa Flash® Silica Flash Column, Eluent of 50~100% Ethyl acetate / Petroleum ether gradient @ 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 yellow oil. LCMS (ESI) m / z = 492.3 (M+1).ATTORNEY DOCKET NO. MORF-010WO1 Step 6: (R)-7-(2-(2-(pyrrolidin-3-yloxy)ethoxy)ethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine

[0612] 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) was added HCl / MeOH (4 M, 10 mL) in the mixture, the reaction was stirred at 30 °C for 12 h. The mixture was concentrated under reduced pressure to get a residue. The residue was purified by flash silica gel chromatography (ISCO ®; 4 g Sepa Flash® Silica Flash Column, Eluent of 0~50% Methanol / Ethyl acetate gradient @ 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 yellow oil. LCMS (ESI) m / z = 292.2 (M+1). 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

[0613] The 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 H2O (150 mL) was stirred at 100oC 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 Na2SO4, 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 @ 100 mL / min) to afford the product (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1- carboxylate (11.9 g, 46.60 mmol, 79.3% yield) as yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 5.69-5.86 (m, 1 H), 4.90-5.04 (m, 2 H), 3.98 (br s, 1 H), 3.32-3.42 (m, 2 H), 3.28 (br dd, J = 11.74, 4.52 Hz, 2 H), 3.22 (br d, J = 11.49 Hz, 2 H), 2.00-2.08 (m, 2 H), 1.86 (br d, J = 3.55 Hz, 2 H), 1.52-1.60 (m, 2 H), 1.39 (s, 9 H). Step 2: (R)-tert-butyl 3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1- carboxylateATTORNEY DOCKET NO. MORF-010WO1

[0614] 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 N2. The mixture was stirred at 50 °C for 2 h. To the mixture was added a mixture of 2,4-dichloro-1,8- naphthyridine (5.08 g, 18.89 mmol), Cs2CO3(13.99 g, 42.94 mmol) and Pd(dppf)Cl2.CH2Cl2(1.40 g, 1.72 mmol) in DMF (50 mL). The mixture was stirred at 100 °C for 16 h under N2. The reaction mixture was quenched by H2O (200 mL). The reaction mixture was filtered and the filtrate was extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (500 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ethergradient @ 80 mL / min) to afford 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 yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 9.14 (dd, J = 4.28, 1.83 Hz, 1 H), 8.58 (dd, J = 8.31, 1.83 Hz, 1 H), 7.56 (dd, J = 8.31, 4.28 Hz, 1 H), 7.50 (s, 1 H), 3.94-4.03 (m, 1 H), 3.34- 3.47 (m, 6 H), 2.99-3.09 (m, 2 H), 1.92 (dt, J = 14.95, 7.50 Hz, 4 H), 1.60-1.67 (m, 2 H), 1.47- 1.55 (m, 2 H), 1.46 (s, 9 H). LCMS (ESI) m / z = 420.3 (M+1). Step 3: (R)-tert-butyl 3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1- carboxylate

[0615] To the 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 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) in THF (46 mL) at 0 °C. The mixture was stirred at 25 °C for 15 h. The reaction mixture was quenched by addition H2O (150 mL) at 0 °C and extracted with ethyl acetate (100 mL x 3). The combined organic layers wereATTORNEY DOCKET NO. MORF-010WO1 washed with brine (300 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (MeOH with 0.1% formic acid condition) to afford 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 yellow oil. LCMS (ESI) m / z = 460.2 (M+1). Step 4: (R)-tert-butyl 3-((5-(4-(2-methoxyethoxy)-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate

[0616] 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 25oC. The suspension was degassed under vacuum and purged with H2for three times. The mixture was stirred at 25oC for 16 h under H2(50 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuum to get a residue to afford 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 yellow oil. LCMS (ESI) m / z = 464.4 (M+1). Step 5: (R)-5-(2-methoxyethoxy)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8- naphthyridine

[0617] To the mixture of (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, 6.47 mmol) in EtOAc (20 mL) was added HCl / EtOAc (4 M, 30 mL). The mixture was stirred at 25oC for 2 h. The mixture was concentrated under reduced pressure to afford the crude product. The crude product was dissolved in H2O (80 mL) and extracted with EtOAc (80 mL x 3). The aqueous phase was lyophilized to afford the product (R)-5-(2-methoxyethoxy)-7-(5-(pyrrolidin-3-yloxy)pentyl)-ATTORNEY DOCKET NO. MORF-010WO1 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.1H NMR (400 MHz, DEUTERIUM OXIDE) δ = 6.43 (br s, 1 H), 4.29 (br s, 2 H), 3.81 (br s, 2 H), 3.18-3.58 (m, 12 H), 2.48-2.73 (m, 4 H), 2.02-2.13 (m, 2 H), 1.80 (br s, 2 H), 1.58-1.68 (m, 2 H), 1.54 (br d, J = 6.25 Hz, 2 H), 1.26-1.37 (m, 2 H). LCMS (ESI) m / z = 364.3 (M+1). 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

[0618] Boc2O (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, 2 HCl) and NaHCO3(2.32 g, 27.60 mmol, 1.07 mL) in THF (20 mL) and H2O (20 mL) at 20 °C. The mixture was stirred for 2 h at 20 °C. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO ®; 10 g Sepa Flash ® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 50 mL / min). (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) was obtained as yellow oil. Step 2: (R)-tert-butyl 3-((5-(3-bromo-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate

[0619] 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 CH3CN (20 mL) at 0 °C. The mixture was stirred for 10 min at 0 °C. The mixture was concentrated to give 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-ATTORNEY DOCKET NO. MORF-010WO1 yl)pentyl)oxy)pyrrolidine-1-carboxylate (2 g, 4.27 mmol, 87.53% yield) was obtained as yellow oil. Step 3: (R)-6-methoxy-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8- naphthyridine

[0620] 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 for 0.5 h at 125 °C under MW condition (inner pressure 4 bar). The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18100 x 30 mm x 5 um; mobile phase: A water with 0.1% TFA; B MeCN 5%-35%, 10 min; Flow Rate (25 mL / min). (R)- 6-methoxy-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (0.14 g, 333.69 μmol, 17.37% yield) was obtained as yellow oil. LCMS (ESI) m / z = 320.3 (M+1). 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

[0621] 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 H2O (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 paralleled reactions were carried out and worked up together. The mixture was extracted with ethyl acetate (100 mL x 3), washed with brine (100 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ether gradient @ 150 mL / min). tert-butyl (3R)-3-(4-bromobutoxy)pyrrolidine-1-carboxylate (32.2 g, 99.93 mmol, 71.96% yield) was obtained as yellow.1H NMR (400MHz, CHLOROFORM-d) δ = 3.98 (br s, 1H), 3.49-3.28 (m, 8H), 2.00-1.84 (m, 4H), 1.76-1.63 (m, 2H), 1.45 (s, 9H).ATTORNEY DOCKET NO. MORF-010WO1 Step 2: (R)-tert-butyl 3-(but-3-en-1-yloxy)pyrrolidine-1-carboxylate

[0622] 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) in portions at 0°C. The mixture was stirred at 25 °C for 16 h. Two paralleled reactions were carried out and worked up together. The mixture was quenched with H2O (300 mL), extracted with ethyl acetate (100 mL x 3), the combined organic layers were washed with brine (100 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ethergradient @ 150 mL / min). tert-butyl (3R)-3-but-3-enoxypyrrolidine-1- carboxylate (18.6 g, 77.07 mmol, 77.13% yield) was obtained as yellow oil.1H NMR (400MHz, CHLOROFORM-d) δ = 5.88-5.70 (m, 1H), 5.14-4.97 (m, 2H), 4.00 (br s, 1H), 3.53-3.25 (m, 6H), 2.31 (q, J = 6.8 Hz, 2H), 2.00-1.81 (m, 2H), 1.51-1.40 (m, 9H). Step 3: phenyl 2-allyl-1,8-naphthyridine-1(2H)-carboxylate

[0623] To a solution of 1,8-naphthyridine (10 g, 76.84 mmol) in CH3CN (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 for 0.5 h at 20 °C. To the mixture was added allyltrimethylsilane (13.17 g, 115.25 mmol, 18.39 mL) at 0 °C and the mixture was stirred for 16 h at 20 °C. The mixture was diluted with MTBE (100 mL) and filtered. The filtrate was washed with aqueous NaHCO3 (100 mL) and brine (100 mL). The organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give product. The residue was purified by flash silica gel chromatography (ISCO ®; 120 g Sepa Flash ® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 200 mL / min). phenyl 2-allyl-1,8- naphthyridine-1(2H)-carboxylate (14 g, 47.89 mmol, 62.33% yield) was obtained as a yellow solid.1H 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), 6.81-6.74 (m, 1H), 6.73-6.68 (m, 1H), 6.41 (d, J = 9.5 Hz, 1H), 6.06 (dd, J = 5.8, 9.5 Hz, 1H), 5.78-5.62 (m, 1H), 5.11 (q, J = 6.8 Hz, 1H), 5.01-4.90 (m, 2H), 2.36-2.13 (m, 2H). LCMS (ESI) m / z = 209.1 (M+1).ATTORNEY DOCKET NO. MORF-010WO1 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

[0624] 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), Grubbs catalyst 2ndgeneration (726.04 mg, 855.19μmol) in DCM (60 mL) was stirred for 16 h at 40 °C. Two paralleled reactions were carried out. The mixture was concentrated to give crude residue. The residue was purified by flash silica gel chromatography (ISCO ®; 80 g Sepa Flash ® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 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 yellow oil. Step 5: phenyl 2-(5-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)pentyl)-3,4-dihydro- 1,8-naphthyridine-1(2H)-carboxylate

[0625] 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 Ar atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 psi) at 50 °C for 16 h. The reaction mixture was filtered through a celite pad and washed by MeOH (100 mL). The filtrate was concentrated in vacuum. 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 yellow oil. LCMS (ESI) m / z = 510.3 (M+1). Step 6: (3R)-tert-butyl 3-((5-(1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate

[0626] To a solution of phenyl 2-(5-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-3- yl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (6.9 g, 13.54 mmol) in H2O (35ATTORNEY DOCKET NO. MORF-010WO1 mL) and THF (70 mL) was added LiOH.H2O (1.70 g, 40.62 mmol) and the mixture was stirred at 80 °C for 16 h. The reaction was quenched by ice water (100 mL) slowly, extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18250 mm x 100 mm x 10 um; mobile phase: A water with 0.1% TFA; 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 yellow oil. LCMS (ESI) m / z = 390.3 (M+1). Step 7: (R)-tert-butyl 3-((5-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate

[0627] (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 um); mobile phase: EtOH with 0.1% ammonium hydroxide; B%: 35%-35%, 10 min).

[0628] 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) which was obtained as a white solid.1H NMR (400 MHz, METHANOL-d4) δ = 7.69 (dd, J = 1.6, 5.1 Hz, 1H), 7.22 (d, J = 7.0 Hz, 1H), 6.49 (dd, J = 5.2, 7.2 Hz, 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).

[0629] 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) which was obtained as a white solid.1H NMR (400 MHz, METHANOL-d4) δ = 7.69 (dd, J = 1.6, 5.1 Hz, 1H), 7.22 (dd, J = 1.5, 7.1 Hz, 1H), 6.49 (dd, J = 5.1, 7.1 Hz, 1H), 4.04 (br d, J = 3.0 Hz, 1H), 3.53-3.36 (m, 7H), 2.74 (dd, J = 5.9, 7.0 Hz, 2H), 2.02-1.91 (m, 3H), 1.67-1.48 (m, 7H), 1.46 (s, 11H). Step 8: (S)-2-(5-((R)-pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridineATTORNEY DOCKET NO. MORF-010WO1

[0630] 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 vacuum. (S)-2-(5-((R)-pyrrolidin-3- yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (450 mg, crude, 2 HCl salt) was obtained as yellow oil.1H NMR (400 MHz, METHANOL-d4) δ = 7.78-7.65 (m, 2H), 6.80 (t, J = 6.8 Hz, 1H), 4.26 (br s, 1H), 3.64-3.57 (m, 1H), 3.50 (t, J = 6.4 Hz, 2H), 3.41-3.37 (m, 1H), 3.41-3.37 (m, 1H), 3.27 (br d, J = 3.9 Hz, 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). 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

[0631] 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 vacuum. (R)-2-(5-((R)-pyrrolidin-3- yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (450 mg, crude, 2 HCl salt) was obtained as yellow oil.1H NMR (400 MHz, METHANOL-d4) δ = 7.75-7.69 (m, 2H), 6.82 (t, J = 6.8 Hz, 1H), 4.28 (br s, 1H), 3.66-3.60 (m, 1H), 3.52 (t, J = 6.4 Hz, 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). 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

[0632] To a solution of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (12.5 g, 66.76 mmol) in toluene (130 mL) was added 5-bromopent-1-ene (29.85 g, 200.28 mmol), TBAB (2.15 g, 6.68 mmol) and a solution of NaOH (13.35 g, 333.80 mmol) in H2O (130 mL). The mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched by addition H2O (100 mL), and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give aATTORNEY DOCKET NO. MORF-010WO1 residue. The residue was purified by flash silica gel chromatography (ISCO ®; 220 g Sepa Flash ® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 100 mL / min). (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylate (23 g, 90.07 mmol, 67.46% yield) was obtained as yellow oil.1H NMR (400 MHz, 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 = 3.4 Hz, 9H). Step 2: (R)-tert-butyl 3-((5-(4-chloro-1, 8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1- carboxylate

[0633] 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, then added to a mixture of 2,4-dichloro-1,8-naphthyridine (3.90 g, 19.58 mmol), Cs2CO3 (12.76 g, 39.16 mmol) and Pd(PPh3)4 (1.13 g, 979.04 μmol) in DMF (100 mL), the mixture was stirred at 100 °C for 3 h under N2. Two batches reactions were worked up together. The mixture was quenched with H2O (500 mL), extracted with ethyl acetate (100 mL x 3), the organic layers were washed with brine (100 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by reversed-phase HPLC (water (TFA)-CH3CN). (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 brown oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 8.87-8.93 (m, 1H), 8.34 (dd, J = 8.4, 1.6 Hz, 1H), 7.32 (dd, J = 8.3, 4.3 Hz, 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 = 7.8 Hz, 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). Step 3: (R)-tert-butyl 3-((5-(4-isopropoxy-1, 8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1- carboxylateATTORNEY DOCKET NO. MORF-010WO1

[0634] To the 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 Cs2CO3(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 H2O (50 mL), extracted with ethyl acetate (30 mL x 3), washed with brine (50 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum.. (R)-tert-butyl 3-((5-(4-isopropoxy-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate (2 g, 4.51 mmol, 63.11% yield) was obtained as brown oil. LCMS (ESI) m / z = 444.3 (M+1). Step 4: (R)-tert-butyl 3-((5-(4-isopropoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate

[0635] 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 vacuum and purged with H2several times. The mixture was stirred under H2(50 psi) at 50 °C for 16 h. The mixture was filtered and concentrated in vacuum to give a residue. The residue was used the next step directly 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 yellow oil. LCMS (ESI) m / z = 448.3 (M+1). Step 5: (R)-tert-butyl 3-((5-(4-isopropoxy-5, 6, 7, 8-tetrahydro-1, 8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate

[0636] 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) at 25 °C under N2. The mixture was stirred at 50 °C for 3 h. The reaction mixture was concentrated to give the residue which was regulated to pH = 7~8 with the base resin in MeOH (30 mL), the mixture was stirred at 25 °C for 0.5 h, filtered andATTORNEY DOCKET NO. MORF-010WO1 concentrated in vacuum. The residue was used the next step directly 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 yellow oil. LCMS (ESI) m / z = 348.3 (M+1). 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

[0637] 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 mol) in H2O (130 mL). The mixture was stirred at 100 °C for 16 h. Two paralleled reactions were carried out together. The reaction mixture was quenched by addition H2O (200 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO ®; 330 g Sepa Flash ® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 80 mL / min). (R)-tert-butyl 3-(pent-4-en-1-yloxy)pyrrolidine- 1-carboxylate (76 g, 297.63 mmol, 55.73% yield) was obtained as yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 5.80 (tdd, J = 6.7, 10.3, 17.1 Hz, 1H), 5.06-4.92 (m, 2H), 3.99 (br s, 1H), 3.49-3.35 (m, 6H), 2.11 (q, J = 7.1 Hz, 2H), 1.95 (br d, J = 3.6 Hz, 2H), 1.69-1.61 (m, 2H), 1.46 (s, 9H). 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

[0638] 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 to next step directly. 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) in DMF (20 mL) and H2O (1 mL) and Cs2CO3 (6.06 g, 18.60 mmol), Pd(PPh3)4 (537.35 mg, 465.01 μmol). The mixture was stirredATTORNEY DOCKET NO. MORF-010WO1 at 100 °C for 3 h. The reaction mixture was quenched by addition H2O (60 mL) and ethyl acetate (50 mL), the mixture was filtered with celite pad and the filtrate was concentrated in vacuum to get a residue. The filtrate was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO ®; 40 g Sepa Flash ® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 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 yellow oil.1H 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). Step 3: (R)-6-(5-(pyrrolidin-3-yloxy)pentyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

[0639] 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 (4M, 30 mL) was stirred at 50 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The mixture was further purification by pre-HPLC (column: Phenomenex Luna 80 x 30 mm x 3 um; mobile phase: A water with 0.1% TFA; 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 yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 8.97 (br s, 2H), 7.37 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 7.9 Hz, 1H), 4.22 (t, J = 4.5 Hz, 2H), 4.14 (td, J = 2.1, 3.9 Hz, 1H), 3.57 (br t, J = 4.6 Hz, 2H), 3.37 (t, J = 6.5 Hz, 2H), 3.23-3.11 (m, 4H), 2.63 (t, J = 7.6 Hz, 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). 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)acetateATTORNEY DOCKET NO. MORF-010WO1

[0640] To a mixture of 2,6-dichloro-3-nitropyridine (10 g, 51.82 mmol) and Et3N (20.97 g, 207.27 mmol, 28.85 mL) in MTBE (100 mL) 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. Then the mixture was stirred at 20 °C for 12 h. H2O (100 mL) and ethyl acetate (100 mL) were added to the mixture. The layers were separated and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO ®; 220 g Sepa Flash ® Silica Flash Column, Eluent of 0~30% Petroleum ether / Ethyl acetate gradient @ 120 mL / min). ethyl 2-((6-chloro-3-nitropyridin-2- yl)amino)acetate (11 g, 42.37 mmol, 81.8% yield) was obtained as yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 8.63 (br s, 1H), 8.38 (d, J = 8.5 Hz, 1H), 6.70 (d, J = 8.6 Hz, 1H), 4.37 (d, J = 5.3 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). LCMS (ESI) m / z = 260.0 (M+1). Step 2: ethyl 2-((tert-butoxycarbonyl)(6-chloro-3-nitropyridin-2-yl)amino)acetate

[0641] To a mixture of ethyl 2-((6-chloro-3-nitropyridin-2-yl)amino)acetate (11 g, 42.37 mmol), Et3N (8.57 g, 84.73 mmol, 11.79 mL) and DMAP (517.57 mg, 4.24 mmol) in THF (120 mL) was added Boc2O (15.72 g, 72.02 mmol, 16.55 mL) at 20 °C. The mixture was stirred at 60 °C for 12 h. H2O (100 mL) and ethyl acetate (100 mL) were added 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 Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 3 / 1). ethyl 2-((tert-butoxycarbonyl)(6-chloro-3- nitropyridin-2-yl)amino)acetate (14 g, 38.91 mmol, 91.8% yield) was obtained as yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 8.22 (br d, J = 8.3 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 4.64 (br s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.54-1.39 (m, 9H), 1.31 (t, J = 7.1 Hz, 3H). LCMS (ESI) m / z = 360.0 (M+1). Step 3: ethyl 2-((3-amino-6-chloropyridin-2-yl)(tert-butoxycarbonyl)amino)acetateATTORNEY DOCKET NO. MORF-010WO1

[0642] To a mixture of ethyl 2-((tert-butoxycarbonyl)(6-chloro-3-nitropyridin-2- yl)amino)acetate (14 g, 38.91 mmol) and NH4Cl (10.41 g, 194.57 mmol) in EtOH (280 mL) and H2O (90 mL) 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. H2O (100 mL) and ethyl acetate (200 mL) were added 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 vacuum. ethyl 2-((3- amino-6-chloropyridin-2-yl)(tert-butoxycarbonyl)amino)acetate (9 g, crude) was obtained as yellow oil. LCMS (ESI) m / z = 330.1 (M+1). Step 4: tert-butyl 6-chloro-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate

[0643] 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, the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with H2O (50 mL) and brine (50 mL x 2), dried over Na2SO4, concentrated under reduced pressure. tert-butyl 6-chloro-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate (3.65 g, crude) obtained as a yellow solid. LCMS (ESI) m / z = 284.0 (M+1). Step 5: tert-butyl 6-chloro-1-methyl-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)- carboxylate

[0644] 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 N2. The mixture was stirred at 0 °C for 0.5 h. MeI (1.83 g, 12.87ATTORNEY DOCKET NO. MORF-010WO1 mmol, 800.91 uL) was added dropwise at 0 °C under N2. Then the mixture was stirred at 20 °C for 12 h. The mixture was added into sat. NH4Cl (100 mL) at 0 °C. Ethyl acetate (100 mL) was added to the mixture. The layers were separated and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (200 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, 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 yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 7.66 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.5 Hz, 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). 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

[0645] 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, after stirred at 40 °C for 3 h, this formed solution was added into a solution of tert-butyl 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), Pd(dba)2 (386.25 mg, 671.73 μmol) in THF (12 mL) and H2O (1 mL), the reaction was stirred at 50 °C for 12 h. Two batches were carried out in parallel. Water (50 mL) was added, 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, 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 yellow oil. LCMS (ESI) m / z = 519.3 (M+1). Step 7: (R)-tert-butyl 3-((5-(1-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-6- yl)pentyl)oxy)pyrrolidine-1-carboxylateATTORNEY DOCKET NO. MORF-010WO1

[0646] 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) at 0 °C, 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 crude product. The residue was purified by prep-HPLC (column: Waters X bridge BEH C18250 x 50 mm x 10 um; mobile phase: A water with 10 mmol / L NH4HCO3; B MeCN 40%-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 yellow oil. LCMS (ESI) m / z = 405.3 (M+1). Step 8: (R)-1-methyl-6-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazine

[0647] 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 μmol) 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 yellow oil. LCMS (ESI) m / z = 305.2 (M+1). 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

[0648] 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 atATTORNEY DOCKET NO. MORF-010WO1 100 °C for 48 h. The reaction was concentrated in vacuo. (R)-tert-butyl 3-((5-(4- (dimethylamino)-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1-carboxylate (3.5 g, crude) was obtained as yellow oil. LCMS (ESI) m / z = 429.3 (M+1). Step 2: (R)-tert-butyl 3-((5-(4-(dimethylamino)-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate

[0649] 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 Ar atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (50 psi) at 50 °C for 16 h. The reaction mixture was filtered through a celite pad. The filtrate was concentrated in vacuo. (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) was obtained as yellow oil. LCMS (ESI) m / z = 433.3 (M+1). Step 3: (R)-N,N-dimethyl-2-(5-(pyrrolidin-3-yloxy)pentyl)-5,6,7,8-tetrahydro-1,8- naphthyridin-4-amine

[0650] 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 h. The reaction was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250 x 70 mm, 15 um); mobile phase: A water with 0.1% TFA; B MeCN 0%-30%, 28 min; Flow Rate 25 mL / min). (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) was obtained as yellow oil.1H NMR (400 MHz, METHANOL-d4) δ = 6.27 (s, 1H), 4.24 (t, J = 4.4 Hz, 1H), 3.48 (t, J = 6.5 Hz, 2H), 3.42-3.35 (m, 4H), 3.34 (br d, J = 3.0 Hz, 1H), 3.24 (dd, J = 4.1, 12.4 Hz, 1H), 3.05 (s, 6H), 2.71 (t, J = 6.2 Hz, 2H), 2.64-2.57 (m, 2H), 2.19 (dddd, J = 1.9, 3.6, 6.9, 12.2 Hz, 1H), 2.09-1.98 (m, 1H), 1.82 (td, J = 5.9, 11.6 Hz, 2H), 1.75-1.57 (m, 4H), 1.51-1.38 (m, 2H). LCMS (ESI) m / z = 333.3 (M+1).ATTORNEY DOCKET NO. MORF-010WO1 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

[0651] 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 sodium hydroxide 50% solution in water (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 rt, diluted with EtOAc (30 mL) and water (20 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (30 mL x2). The combined organic layer was dried over Na2SO4, filtered, concentrated in vacuo and the residue was purified by silica gel column (pet 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) +. 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

[0652] 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) under Ar, was added 9-BBN (0.5 M in THF, 10.8 mL, 5.4 mmol). The reaction mixture was stirred at 50°C for 1.5 hours, then cooled to rt, added 2-chloro-4-methoxy-1,8-naphthyridine (718 mg, 2.67 mmol), Pd(OAc)2 (29 mg, 0.13 mmol), PCy3 (73 mg, 0.26 mmol) and KOH (146 mg, 2.6 mmol). The reaction mixture was stirred at 80°C for 15 hours. Solvent was removed in vacuo, and the residue was purified by silica gel column (pet 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) +. Step 3: 7-(5-((trans-4-fluoropyrrolidin-3-yl)oxy)pentyl)-1,2,3,4-tetrahydro-1,8- naphthyridineATTORNEY DOCKET NO. MORF-010WO1

[0653] 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 (4M, 10 mL). The reaction mixture was stirred at rt 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) +. 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

[0654] To a solution of PPh3 (1.92 g, 7.33 mmol) in THF (20 mL) was added DIAD (1.48 g, 7.33 mmol) at 0 °C under N2protection. The reaction was stirred at 0 °C for 30 min, 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 rt for 6 h. The reaction was quenched with H2O (20 mL), then extracted with EtOAc (20 mL × 3). The combined organic phase was washed with sat. NaHCO3 solution, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in a mixture of MeOH (10 mL) and 2N NaOH (5 mL), then stirred at rt 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 (EtOAc / pet 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) +. Step 2: tert-butyl cis-3-fluoro-4-(pent-4-en-1-yloxy)pyrrolidine-1-carboxylateATTORNEY DOCKET NO. MORF-010WO1

[0655] 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 sodium hydroxide 50% solution in water (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 rt, diluted with EtOAc (30 mL) and water (30 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (30 mL x2). The combined organic layer was dried over Na2SO4 and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column (pet 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) +). Step 3: tert-butyl cis-3-fluoro-4-((5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate

[0656] To a solution of tert-butyl cis-3-fluoro-4-(pent-4-en-1-yloxy)pyrrolidine-1- carboxylate (360 mg, 1.32 mmol) was added 9-BBN (0.5 N in THF, 5.3 mL, 2.65 mmol) under N2 atmosphere. The mixture was stirred at 60 °C for 1.5 h and cooled to rt, then tert-butyl 7- chloro-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (354 mg, 1.32 mmol), Pd(OAc)2 (30 mg, 0.13 mmol), PCy3 (73 mg, 0.26 mmol) and KOH (107 mg, 1.98 mmol) were added. The mixture was stirred at 70 °C for 12 hours, concentrated and purified by silica gel chromatography (EtOAc: pet ether = 0%~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) +). Step 4: 7-(5-((cis-4-fluoropyrrolidin-3-yl)oxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine

[0657] 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 h and concentrated to give the desired product 7-(5-((cis-4-fluoropyrrolidin-3-yl)oxy)pentyl)-1,2,3,4-tetrahydro-1,8-ATTORNEY DOCKET NO. MORF-010WO1 naphthyridine as white solid (320 mg), which was used to the next step without further purification. Yield 88% (ESI 308 (M+H) +). 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

[0658] To a solution of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (10.0 g, 53.4 mmol) in n-heptane (120 mL) was added sodium hydroxide 50% solution in water (11 mL, 267 mmol), tetrabutylammonium bromide (861 mg, 2.67 mmol) and 5-bromopent-1-ene (11.9 g, 80.1 mmol). The mixture was stirred at 80 °C for 2 hours. Then the reaction mixture was cooled to rt, EtOAc (100 mL) and water (100 mL) were added. The organic phase was separated and the aqueous phase was extracted with EtOAc (50 mL x2). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet 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) +). Step 2: tert-butyl (R)-3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1- carboxylate

[0659] 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 N2 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)2(54 mg, 0.5 mmol), PCy3 (135 mg, 0.5 mmol) and KOH (825 mg, 14.7 mmol) were added. The mixture was stirred at 70 °C for 16 hours, then concentrated and purified by silica gel chromatography (EtOAc: pet ether = 0%~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) +).ATTORNEY DOCKET NO. MORF-010WO1 Step 3: tert-butyl (R)-3-((5-(4-methyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1- carboxylate

[0660] 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)Cl2(541 mg, 0.74 mmol) and K2CO3 (2.04 g, 14.8 mmol) in 30 mL of dioxane and 3 mL of H2O was stirred at 80 °C for 4 hours. The mixture was concentrated and purified by silica gel chromatography (EtOAc:pet ether = 0%~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) +). Step 4: tert-butyl (R)-3-((5-(4-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate

[0661] 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 at room temperature under hydrogen atmosphere 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) +). Step 5: (R)-5-methyl-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine

[0662] 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 andATTORNEY DOCKET NO. MORF-010WO1 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 to the next step without further purification. Yield 100% (ESI 304.2 (M+H) +). 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

[0663] To a solution of 2-aminonicotinaldehyde (3.0 g, 24.59 mmol) and Et3N (4.97g, 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 hours, then quenched with H2O (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic phase was washed with sat. NaHCO3 solution, brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was added to a mixture of Cs2CO3 (16.13 g, 49.18mmol) 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 (pet ether: EtOAc 1 : 1) to give the desired product 3-methyl-1,8-naphthyridin-2(1H)- one (1.6 g) as a brown solid. Yield 41% (ESI 161 [M+H] +). Step 2: 2-chloro-3-methyl-1,8-naphthyridine

[0664] A solution of 3-methyl-1,8-naphthyridin-2(1H)-one (1.6 g, 9.94 mmol) in POCl3 (20 mL) was stirred at 110 °C for 8 hours. The reaction was quenched with H2O (10 mL), then extracted with EtOAc (30 mL × 3). The combined organic phase was washed with sat. NaHCO3 solution, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet 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] +). Step 3: tert-butyl (R)-3-((5-(3-methyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1- carboxylateATTORNEY DOCKET NO. MORF-010WO1

[0665] 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 N2 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)2(69 mg, 0.31 mmol), PCy3(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: pet ether = 0%~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) +). Step 4: tert-butyl (R)-3-((5-(3-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate

[0666] A mixture of 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 (160mg, 20wt%) in ethyl acetate (20 mL) was stirred under H2 balloon at 40°C for 16 hours. The solid was removed by filtration, the filtrate was concentrated in vacuo and the residue was purified by 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) +). Step 5: (R)-6-methyl-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridine hydrochloride

[0667] 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-ATTORNEY DOCKET NO. MORF-010WO1 tetrahydro-1,8-naphthyridine hydrochloride as white solid (1.1 g), which was used to the next step without further purification. Yield 87% (ESI 304 (M+H) +). 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

[0668] 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℃ for 2 hours. After cooling to room temperature, 2,4-dichloro-1,8-naphthyridine (3.9 g, 19.6 mmol), Pd(OAc)2 (439 mg, 1.96 mmol), PCy3 (447 mg, 1.96 mmol) and NaOH (1.18 g, 29.4 mmol) were added. The mixture was stirred at 50℃ under argon atmosphere for 1 h. The mixture was diluted with EtOAc and filtered. The filtrate was concentrated and purified by silica gel chromatography (EtOAc / petrol 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) +). Step 2: tert-butyl (R)-3-((5-(4-vinyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1- carboxylate

[0669] 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), potassium vinyltrifluoroborate (87 mg, 0.65 mmol), Pd2(dba)3(46 mg, 0.05 mmol), Ru-phos (23 mg, 0.05 mmol) and Na2CO3(160 mg, 1.5 mmol) in toluene (4 mL) and water (0.5 mL) was stirred at 100 ℃ under argon atmosphere for 18 hours. The mxiture was concentrated and the residue was purified by silica gel chromatography (EtOAc / petrol ether = 0%~20%) to give the desired product tert-butyl (R)-3-ATTORNEY DOCKET NO. MORF-010WO1 ((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) +). Step 3: tert-butyl (R)-3-((5-(4-(2-(dimethylamino)ethyl)-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate

[0670] 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℃ for 16 hours. The mixture was concentrated and the residue was purified by silica gel chromatography (EtOAc / petrol ether = 0%~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) +). Step 4: (R)-N,N-dimethyl-2-(2-(5-(pyrrolidin-3-yloxy)pentyl)-5,6,7,8-tetrahydro-1,8- naphthyridin-4-yl)ethan-1-amine

[0671] 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 at room temperature under hydrogen atmosphere for 16 hours. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in 10 mL of DCM, then added HCl in dioxane (4 N, 5 mL). 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) +).ATTORNEY DOCKET NO. MORF-010WO1 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-(4-(2-methoxyethyl)-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate

[0672] 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 extraced with EtOAc (20 mL x2). The combined organic phase was concetrated 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 to the next step. (ESI 444.2 (M+H) +). Step 2: (R)-5-(2-methoxyethyl)-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8- naphthyridine

[0673] 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 at 50 °C under hydrogen atmosphere for 16 hours, then filtered through celite and the filtrate was concentrated in vacuo. The residue was dissolved in 5 mL of DCM, then added HCl (4N in 1,4-dioxane, 2 mL). The mixture was stirred at room temperature for 3 hours, 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 solid (245 mg). ESI 348.2 (M+H) +. 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-carboxylateATTORNEY DOCKET NO. MORF-010WO1

[0674] To a solution of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (20 g, 107 mmol) in n-heptane (250 mL) was added sodium hydroxide 50% solution in water (86 mL, 1070 mmol), tetrabutylammonium bromide (3.45 g, 10.7 mmol) and 6-bromohex-1-ene (52 g, 321 mmol). The mixture was stirred at 80 °C for 2 hours, then cooled to rt, diluted with EtOAc (500 mL) and water (300 mL). The organic phase was separated and the aqueous phase was extracted with EtOAc (200 mL x2). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet 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) +). Step 2: tert-butyl (R)-3-((5-oxopentyl)oxy)pyrrolidine-1-carboxylate

[0675] 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 H2O was stirred at rt for 12 hours. The mixture was extracted with EtOAc (200 mL x2). The combined organic layer was washed with water (200 mL), dry over Na2SO4 and concentrated in vacuo to give crude product tert-butyl (R)-3-((5- oxopentyl)oxy)pyrrolidine-1-carboxylate (4.9 g) as a colorless oil. Yield 95% (ESI 272 (M+H) +). Step 3: tert-butyl (3R)-3-((5-hydroxyhept-6-en-1-yl)oxy)pyrrolidine-1-carboxylate

[0676] 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 min at -10°C. The mixture was stirred at rt overnight, then quenched with water (20 mL). The precipitated solid was removed by filtration and the filtrate was extracted with ethyl acetate (200 mL x2). The combined organic layer was washed with water, dried over Na2SO4, concentrated in vacuo and the residue was purified by silica gel column (petATTORNEY DOCKET NO. MORF-010WO1 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 light yellow oil. Yield 37% (ESI 300 [M+H] +). Step 4: tert-butyl (R)-3-((7-(2-chloropyridin-3-yl)-5-oxoheptyl)oxy)pyrrolidine-1- carboxylate

[0677] 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)2 (0.32 g, 1.41 mmol) in DMF (50 mL) was stirred at 70 °C overnight. The mixture was cooled to rt, diluted with H2O (100 mL) and extracted with EtOAc (100 mL x3). The combined organic lay was concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / petrol ether = 0%~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] +). Step 5: tert-butyl (3R)-3-((5-amino-7-(2-chloropyridin-3-yl)heptyl)oxy)pyrrolidine-1- carboxylate

[0678] 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 rt for 10 min, then added sodium cyanoborohydride (692 mg, 11 mmol). The mixture was stirred at rt for 20 hours, quenched with 1M NaOH (100 mL) and extracted with DCM (200 mL). The organic layer was concentrated in vacuo to give the 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] +). Step 6: tert-butyl (3R)-3-(4-(1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)butoxy)pyrrolidine-1- carboxylateATTORNEY DOCKET NO. MORF-010WO1

[0679] 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 caesium carbonate (3.33 g, 10.2 mmol). The mixture was stirred at 130 °C for 20 hours. The mixture was cooled to rt, diluted with H2O (100 mL) and extracted with EtOAc (100 mL x3). The combined organic lay was concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / petrol ether = 0%~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 product was separated by Prep 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. Step 7: (S)-2-(4-(((R)-pyrrolidin-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine

[0680] 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 4M HCl / dioxane (5 mL) at rt 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) +). Preparation of (R)-2-(4-(((R)-pyrrolidin-3-yl)oxy)butyl)-1,2,3,4-tetrahydro-1,8-naphthyridine

[0681] 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 4M HCl / dioxane (5 mL) at rt for 12 hours.ATTORNEY DOCKET NO. MORF-010WO1 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) +). 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

[0682] To a solution of tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate (20 g, 107 mmol) in n-heptane (250 mL) was added sodium hydroxide 50% solution in water (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 rt, 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 x2). The combined organic layer was dried over Na2SO4, filtered, concentrated in vacuo and the residue was purified by silica gel column (pet 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) +). Step 2: tert-butyl (R)-3-((7-oxoheptyl)oxy)pyrrolidine-1-carboxylate

[0683] 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 H2O was stirred at rt for 12 hours. The mixture was extracted ethyl acetate (200 mL x2). The combined organic layer was washed with water (200 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product tert- butyl (R)-3-((7-oxoheptyl)oxy)pyrrolidine-1-carboxylate (7.5 g) as a colorless oil . Yield 99% (ESI 300 (M+H) +). Step 3: tert-butyl (3R)-3-((7-hydroxynon-8-en-1-yl)oxy)pyrrolidine-1-carboxylateATTORNEY DOCKET NO. MORF-010WO1

[0684] To a solution of tert-butyl (R)-3-((7-oxoheptyl)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 min at -10°C. The mixture was stirred at rt overnight, then quenched with water (20 mL). The precipitated solid was removed by filtration and the filtrate was extracted with ethyl acetate (200 mL x2). The combined organic layer was washed with water, dried over Na2SO4, concentrated in vacuo and the residue was purified by silica gel column (pet 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 light yellow oil. Yield 53% (ESI 328 [M+H] +). Step 4: tert-butyl (R)-3-((9-(2-chloropyridin-3-yl)-7-oxononyl)oxy)pyrrolidine-1-carboxylate

[0685] 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)2 (634 mg, 2.43 mmol) in DMF (100 mL) was stirred at 70 °C overnight. The mixture was cooled to rt, diluted with H2O (100 mL) and extracted with EtOAc (100 mL x3). The combined organic lay was concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / petrol ether = 0%~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. Yield 45% (ESI 438[M+H] +). Step 5: tert-butyl (3R)-3-((7-amino-9-(2-chloropyridin-3-yl)nonyl)oxy)pyrrolidine-1- carboxylate

[0686] 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 addedATTORNEY DOCKET NO. MORF-010WO1 ammonium acetate (1.4 g, 18.0 mmol). The mixture was stirred at rt for 10 min, then added sodium cyanoborohydride (692 mg, 11 mmol). The mixture was stirred at rt for 20 hours, quenched with 1M NaOH (100 mL) and extracted with DCM (200 mL). The organic layer was concentrated in vacuo to give the 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] +). Step 6: tert-butyl (3R)-3-((6-(1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)hexyl)oxy)pyrrolidine-1-carboxylate

[0687] 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 caesium carbonate (5.0 g, 15.3 mmol). The mixture was stirred at 130 °C for 20 hours. The mixture was cooled to rt, diluted with H2O (100 mL) and extracted with EtOAc (100 mL x3). The combined organic lay was concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc / petrol ether = 0%~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 product was separated by Prep 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. Step 7: (S)-2-(6-(((R)-pyrrolidin-3-yl)oxy)hexyl)-1,2,3,4-tetrahydro-1,8-naphthyridine

[0688] 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 4M HCl / dioxane (5 mL) at rt 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) +).ATTORNEY DOCKET NO. MORF-010WO1 Preparation of (S)-2-(6-(((R)-pyrrolidin-3-yl)oxy)hexyl)-1,2,3,4-tetrahydro-1,8-naphthyridine

[0689] 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 (4N, 3 mL) at rt 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 to the next step without further purification. Yield 100% (ESI 304.2 (M+H) +). 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

[0690] To a solution of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (10.0 g, 53.4 mmol) in n-heptane (120 mL) was added sodium hydroxide 50% solution in water (11 mL, 267 mmol), tetrabutylammonium bromide (861 mg, 2.67 mmol) and 5-bromopent-1-ene (11.9 g, 80.1 mmol). The mixture was stirred at 80 °C for 2 hours. Then the reaction mixture was cooled to rt, EtOAc (100 mL) and water (100 mL) were added. The organic phase was separated and the aqueous phase was extracted with EtOAc (50 mL x2). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet 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) +). Step 2: tert-butyl (R)-3-((5-(4-chloro-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1- carboxylate

[0691] 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 N2ATTORNEY DOCKET NO. MORF-010WO1 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)2(54 mg, 0.5 mmol), PCy3 (135 mg, 0.5 mmol) and KOH (825 mg, 14.7 mmol) were added. The mixture was stirred at 70 °C for 16 hours, then concentrated and purified by silica gel chromatography (EtOAc: pet ether = 0%~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) +). Step 3: tert-butyl (R)-3-((5-(4-methyl-1,8-naphthyridin-2-yl)pentyl)oxy)pyrrolidine-1- carboxylate

[0692] 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)Cl2(541 mg, 0.74 mmol) and K2CO3 (2.04 g, 14.8 mmol) in 30 mL of dioxane and 3 mL of H2O was stirred at 80 °C for 4 hours. The mixture was concentrated and purified by silica gel chromatography (EtOAc:pet ether = 0%~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) +). Step 4: tert-butyl (R)-3-((5-(4-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate

[0693] 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 at room temperature under hydrogen atmosphere 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) +). Step 5: (R)-5-methyl-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8-naphthyridineATTORNEY DOCKET NO. MORF-010WO1

[0694] 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 to the next step without further purification. Yield 100% (ESI 304.2 (M+H) +). Preparation of (R)-5-methoxy-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

[0695] 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, then heated at 100 °C for 4 h. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved with H2O, and the aqueous phase was adjusted to PH ~6 with 1 N HCl aqueous solution. The precipitate was formed, filtered and dried to give the desired product 3-methyl-1,8-naphthyridine-2,4-diol as a pale brown solid (2.3 g). Yield 38% (ESI 177.2 (M+H) +). Step 2: 2,4-dichloro-3-methyl-1,8-naphthyridine

[0696] A mixture of 3-methyl-1,8-naphthyridine-2,4-diol (2.3 g, 13 mmol) in POCl3 (25 mL) was stirred at 120 °C for 2 h. The reaction mixture was concentrated in vacuo and the residue was diluted with aq. sat. NaHCO3 (30 mL) and extrated with EtOAc (30 mL x 2). The combinedATTORNEY DOCKET NO. MORF-010WO1 organic phase was concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc:petroleum ether = 0%~15%) to give the desired product 2,4-dichloro-3- methyl-1,8-naphthyridine as a pale brown solid (1.12 g). Yield 41% (ESI 213.1 (M+H) +). Step 2: tert-butyl (R)-3-((5-(4-chloro-3-methyl-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate

[0697] 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 h under argon atmosphere. The resulting mixture was cooled to room temperature, added 2,4-dichloro-3- methyl-1,8-naphthyridine (1.42 g, 6.67 mmol), Pd(OAc)2 (150 mg, 0.67 mmol), PCy3 (153 mg, 0.67 mmol) and NaOH (400 mg, 10.0 mmol). The reaction mixture was stirred at 60 °C for 4 h then concentrated. The residue was purified by Prep-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) +). Step 3: tert-butyl (R)-3-((5-(4-methoxy-3-methyl-1,8-naphthyridin-2- yl)pentyl)oxy)pyrrolidine-1-carboxylate

[0698] 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 h. The resulting mixture was quenched with aq. sat. NH4Cl (50 mL), and extracted with EtOAc (50 mL x3). 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) +). Step 4: (R)-5-methoxy-6-methyl-7-(5-(pyrrolidin-3-yloxy)pentyl)-1,2,3,4-tetrahydro-1,8- naphthyridineATTORNEY DOCKET NO. MORF-010WO1

[0699] 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 at 50 °C for 16 h under hydrogen atmosphere, then filtered and the filtrate was concentrated in vacuo. The residue was dissolved with DCM (20 mL), then added TFA (4 mL). The resulting mixture was stirred at room temperature for 16 h, 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 for the next step. ESI 334.2 (M+H) +. Right Hand Side of Exemplary Compounds Preparation of (3-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid Step 1: 1-(3-bromo-5-fluoro-4-hydroxyphenyl)ethanone

[0700] 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 paralleled reactions were carried out and worked up together. The reaction mixture was quenched by water (1 L), extracted with EtOAc (1 L x 3). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-(3-bromo-5-fluoro-4-hydroxyphenyl)ethanone (151.19 g, crude) as red oil. Step 2: 1-(3-bromo-5-fluoro-4-methoxyphenyl)ethanoneATTORNEY DOCKET NO. MORF-010WO1

[0701] 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 slow dropwise added into the reaction at 0~5 °C. The mixture was stirred at 25 °C for 15.5 h. Four paralleled reactions were carried out and worked up together. The reaction mixture was quenched by water (2 L), 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, 81.1% yield) as yellow oil.1H NMR (400MHz, CHLOROFORM-d) δ = 7.92 (t, J = 1.7 Hz, 1H), 7.65 (dd, J = 2.1, 11.8 Hz, 1H), 4.07 (d, J = 2.8 Hz, 3H), 2.55 (s, 3H). Step 3: 1-bromo-3-fluoro-2-methoxy-5-(prop-1-en-2-yl)benzene

[0702] To a solution of methyl triphenyl)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, 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 in the mixture at 0 °C, the reaction was stirred at 25 °C for 15.5 h. Water (500 mL) was added, the mixture was extracted with ethyl acetate (300 mL x 2). The combined organic layers were washed with H2O (200 mL x 2) and brine (200 mL x 2), dried over Na2SO4, filtered, concentrated to give crude residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 100 / 1 to 0 / 1). 1-bromo-3-fluoro- 2-methoxy-5-(prop-1-en-2-yl)benzene (43 g, 175.45 mmol, 87.4% yield) was obtained as yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.42 (t, J = 1.8 Hz, 1H), 7.19-7.13 (m, 1H), 5.33 (s, 1H), 5.12 (s, 1H), 3.97 (d, J = 1.4 Hz, 3H), 2.10 (s, 3H). Step 4: 1-bromo-3-fluoro-5-isopropyl-2-methoxybenzene

[0703] 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 degassedATTORNEY DOCKET NO. MORF-010WO1 under vacuum and purged with H2several times. The mixture was stirred under H2(15 psi) at 25 °C for 12 h. The reactions (Five paralleled 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 colorless oil.1H 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). Step 5: (3-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid

[0704] n-BuLi (2.5 M, 6.07 mL) was added dropwise to a solution of 1-bromo-3-fluoro-5- isopropyl-2-methoxybenzene (2.5 g, 10.12 mmol) and triisopropyl borate (2.85 g, 15.18 mmol, 3.49 mL) in THF (50 mL) at -78 °C under N2. The resulting mixture was stirred for 1 h at -78 °C and 1 h at 20 °C. The reaction mixture was quenched with ice water (100 mL). Then adjusted to pH = 5 with aqueous HCl (1M). The resulting mixture was extracted with ethyl acetate (100 mL x 2), the combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0~50% Acetone / Petroleum ether gradient @ 100 mL / min). (3-fluoro-5-isopropyl-2- methoxyphenyl)boronic acid (1.8 g, 8.49 mmol, 83.91% yield) was obtained as a yellow oil.1H NMR (400 MHz, METHANOL-d4) δ = 7.00 (dd, J = 1.9, 13.4 Hz, 1H), 6.89 (s, 1H), 3.94-3.80 (m, 3H), 2.86 (td, J = 6.9, 13.8 Hz, 1H), 1.22 (d, J = 6.9 Hz, 6H). LCMS (ESI) m / z = 213.1 (M+1). Preparation of ethyl 2-bromo-2-(4-(cyclopropylmethyl)-2-methoxyphenyl)acetate Step 1: 1-bromo-4-(cyclopropylmethyl)-2-methoxybenzeneATTORNEY DOCKET NO. MORF-010WO1

[0705] A mixture of 4-bromo-3-methoxybenzaldehyde (1.0 g, 4.65 mmol) and 4- methylbenzenesulfonhydrazide (1.04g, 5.58mmol) in MeOH (20 mL) was stirred at room temperature for 30 min. The solvent was removed under vacuum, diluted with dixoane (20 mL), then cyclopropylboronic acid (600 mg, 7.0 mmol) and DBU (1.41 g, 9.3 mmol) was added. The mixture was stirred at 100 °C under N2 for 16 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel column (pet ether: 100%) to give the desired product 1- bromo-4-(cyclopropylmethyl)-2-methoxybenzene (466 mg, 1.93mmol) as a colorless oil. Yield 42% (ESI 241 [M+H] +). Step 2: ethyl 2-(4-(cyclopropylmethyl)-2-methoxyphenyl)acetate

[0706] To a mixture of 1-bromo-4-(cyclopropylmethyl)-2-methoxybenzene (466 mg, 1.93 mmol), Q-phos(43 mg, 0.06 mmol) and Pd2(dba)3 (55 mg, 0.06 mmol) in THF (10 mL), 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 N2 for 1 hour. The reaction was quenched with NaHCO3 (aq) and extracted with EtOAc (2 x 20 mL). The combined organic layer was concentrated in vacuo and the residue was purified by silica gel column (pet 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] +). Step 3: ethyl 2-bromo-2-(4-(cyclopropylmethyl)-2-methoxyphenyl)acetate

[0707] 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 lithium diisopropylamide solution 2.0 M in THF / hexanes (2.3 mL, 4.6 mmol) dropwise. The reaction was stirred at -78°C for 30 min, thenATTORNEY DOCKET NO. MORF-010WO1 chlorotrimethylsilane (0.49 g, 4.51 mmol) was added and the reaction was stirred at -78°C for another 30 min. Then a solution of NBS (0.80 g, 4.51 mmol) in THF (10 mL) was added and the reaction was stirred at -78°C for 30 min. The reaction was quenched with H2O (10 mL), then extracted with EtOAc (20 mL × 3). The combined organic phase was washed with Sat. NaHCO3 solution, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether / EtOAc = 0%~10%) to give the desired product ethyl 2-bromo-2- (4-(cyclopropylmethyl)-2-methoxyphenyl)acetate as a pale brown oil (340 mg, 56% yield) ESI 327 / 329 (M+H) +. Preparation of ethyl 2-bromo-2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)acetate Step 1: 3-bromo-5-chloro-4-methoxybenzaldehyde

[0708] To a solution of 3-bromo-5-chloro-4-hydroxybenzaldehyde (3.0 g, 12.82 mmol) in DMF (20 mL) were added MeI (2.73 g, 19.23 mmol) and K2CO3 (3.54 g, 25.64 mmol). The mixture was stirred at rt overnight. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3x 100 mL). The combined organic layer was washed with saturated NaCl (aq.), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet 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) +). Step 2: 1-bromo-3-chloro-5-(cyclopropylmethyl)-2-methoxybenzene

[0709] To a solution of 3-bromo-5-chloro-4-methoxybenzaldehyde (1.8 g, 7.26 mmol) in MeOH (20 mL) was added TsNHNH2 (1.49 g, 7.986 mmol). The reaction mixture was stirred at rt overnight. The solvent was removed in vacuo and the residue was dissolved in 1,4-dioxane (30 mL), added cyclopropylboronic acid (1.25 g, 14.52 mmol) and DBU (2.2 g, 14.52 mmol). TheATTORNEY DOCKET NO. MORF-010WO1 reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (3x 100 mL). The combined organic layer was washed with saturated NaCl (aq.), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product 1-bromo-3- chloro-5-(cyclopropylmethyl)-2-methoxybenzene as a colourless oil (1.1 g). Yield 55% (ESI 275 (M+H) +). Step 3: ethyl 2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)acetate

[0710] 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 Pd2(dba)3 (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 at 50 °C under N2 for 1 hour. The reaction was quenched with NaHCO3 (aq) and extracted with EtOAc (2 x 20 mL). The combined organic layer was concentrated in vacuo and the residue was purified by silica gel column (pet 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] +). Step 4: ethyl 2-bromo-2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)acetate

[0711] 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 lithium diisopropylamide solution 2.0 M in THF / hexanes (2.5 mL, 2.5 mmol) dropwise. The reaction was stirred at -78°C for 30 min, then chlorotrimethylsilane (272 mg, 2.5 mmol) was added and the reaction was stirred at -ATTORNEY DOCKET NO. MORF-010WO1 78°C for another 30 min. Then a solution of NBS (445 mg, 2.5 mmol) in THF (5 mL) was added and the reaction was stirred at -78°C for 30 min. The reaction was quenched with H2O (10 mL), then extracted with EtOAc (20 mL × 3). The combined organic phase was washed with Sat. NaHCO3 solution, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether / EtOAc = 0%~10%) to give the desired product ethyl 2- bromo-2-(3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)acetate as a pale yellow oil (320 mg, 88% yield) ESI 361 (M+H) +. Preparation of ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-methoxyphenyl)acetate Step 1: 2-bromo-4-(cyclopropylmethyl)-1-methoxybenzene

[0712] To a solution of 3-bromo-4-methoxybenzaldehyde (1.0 g, 4.65 mmol) in MeOH (20 mL) was added TsNHNH2 (0.96 g, 5.12 mmol). The reaction mixture was stirred at rt overnight. The solvent was removed in vacuo and the residue was dissolved in 1,4-dioxane (30 mL), added cyclopropylboronic acid (799 mg, 9.30 mmol) and DBU (1.42 g, 9.30 mmol). The reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (3x 100 mL). The combined organic layer was washed with saturated NaCl (aq.), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether: EtOAc 10:1) to give the desired product 2-bromo-4- (cyclopropylmethyl)-1-methoxybenzene as a colourless oil (370 mg, 1.53 mmol). Yield 33% (ESI 241 (M+H) +). Step 2: ethyl 2-(5-(cyclopropylmethyl)-2-methoxyphenyl)acetate

[0713] To a mixture of 2-bromo-4-(cyclopropylmethyl)-1-methoxybenzene (370 mg, 1.53 mmol), Q-phos(34 mg, 0.05 mmol) and Pd2(dba)3 (44 mg, 0.05 mmol) in THF (10 mL), was added (2-ethoxy-2-oxoethyl)zinc(II) bromide ( 1 M in THF, 3.8 mL). The reaction mixture wasATTORNEY DOCKET NO. MORF-010WO1 stirred at 50 °C under N2 for 1 hour. The reaction was quenched with NaHCO3 (aq) and extracted with EtOAc (2 x 20 mL). The combined organic layer was concentrated in vacuo and the residue was purified by silica gel column (pet 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] +). Step 3: ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-methoxyphenyl)acetate

[0714] 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 lithium diisopropylamide solution 2.0 M in THF / hexanes (2.5 mL, 2.5 mmol) dropwise. The reaction was stirred at -78°C for 30 min, then chlorotrimethylsilane (272 mg, 2.5 mmol) was added and the reaction was stirred at -78°C for another 30 min. Then a solution of NBS (445 mg, 2.5 mmol) in THF (5 mL) was added and the reaction was stirred at -78°C for 30 min. The reaction was quenched with H2O (10 mL), then extracted with EtOAc (20 mL × 3). The combined organic phase was washed with Sat. NaHCO3 solution, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether / EtOAc = 0%~10%) to give the desired product ethyl 2-bromo-2- (3-chloro-5-(cyclopropylmethyl)-2-methoxyphenyl)acetate as a pale yellow oil (287 mg, 88% yield) ESI 327 (M+H) +. Preparation of ethyl 2-bromo-2-(5-chloro-2-(cyclopropylmethoxy)phenyl)acetate Step 1: 2-bromo-4-chloro-1-(cyclopropylmethoxy)benzene

[0715] To a solution of 2-bromo-4-chlorophenol (1.0 g, 4.85 mmol) in DMF (10 mL) were added (bromomethyl)cyclopropane (976 mg, 7.28 mmol) and K2CO3 (1.34 g, 9.7 mmol). The mixture was stirred at rt for 2 hours. The reaction was diluted with H2O ( 50 mL) and extracted with EtOAc (3x 50 mL). The combined organic layer was washed with saturated NaCl (aq.), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gelATTORNEY DOCKET NO. MORF-010WO1 column (pet 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) +). Step 2: ethyl 2-(5-chloro-2-(cyclopropylmethoxy)phenyl)acetate

[0716] To a mixture of 2-bromo-4-chloro-1-(cyclopropylmethoxy)benzene (940 mg, 3.59 mmol), Q-phos(80 mg, 0.12 mmol) and Pd2(dba)3 (103 mg, 0.12 mmol) in THF (10 mL), 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 N2 for 1 hour. The reaction was quenched with NaHCO3 (aq) and extracted with EtOAc (2 x 20 mL). The combined organic layer was concentrated in vacuo and the residue was purified by silica gel column (pet 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] +). Step 3: ethyl 2-bromo-2-(5-chloro-2-(cyclopropylmethoxy)phenyl)acetate

[0717] To a solution of ethyl 2-(5-chloro-2-(cyclopropylmethoxy)phenyl)acetate (268 mg, 1.0 mmol) in THF (20 mL) at -78°C, was added lithium diisopropylamide solution 2.0 M in THF / hexanes (2.5 mL, 2.5 mmol) dropwise. The reaction was stirred at -78°C for 30 min, then chlorotrimethylsilane (272 mg, 2.5 mmol) was added and the reaction was stirred at -78°C for another 30 min. Then a solution of NBS (445 mg, 2.5 mmol) in THF (5 mL) was added and the reaction was stirred at -78°C for 30 min. The reaction was quenched with H2O (10 mL), then extracted with EtOAc (20 mL × 3). The combined organic phase was washed with sat. NaHCO3 solution, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (pet ether / EtOAc = 0%~10%) to give the desired product ethyl 2-bromo-2- (5-chloro-2-(cyclopropylmethoxy)phenyl)acetate as a pale yellow oil (270 mg, 78% yield) ESI 347 (M+H) +.ATTORNEY DOCKET NO. MORF-010WO1 Preparation of ethyl 2-bromo-2-(2-methoxy-5-((1-methoxycyclopropyl)methyl)phenyl)acetate Step 1: methyl 2-(3-bromo-4-methoxyphenyl)acetate

[0718] 1 mL of H2SO4(1 mL, conc.) 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, NaHCO3 aqueous solution, dried over anhydrous Na2SO4 and concentrated to give methyl 2-(3-bromo-4-methoxyphenyl)acetate (1.92 g) as colorless oil. Yield 91% (ESI 259.2 (M+H) +). Step 2: 1-(3-bromo-4-methoxybenzyl)cyclopropan-1-ol

[0719] 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 at 0 °C. The mixture was stirred at room temperature for 12 h, quenched by adding 1 M sulfuric acid solution and extraced with EtOAc (20 mL x 2). The combined organic solvents were concentrated and the residue was purified by silica gel chromatography (EtOAc:pet ether = 0%~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) +). Step 3: 2-bromo-1-methoxy-4-((1-methoxycyclopropyl)methyl)benzene

[0720] 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 extraced with EtOAc (20 mL x 2). The combined organic solvents were concentrated and the residue was purified by silica gel chromatography (EtOAc:pet ether = 0%~5%) to give the desired product 2-bromo-1-methoxy-4-((1-ATTORNEY DOCKET NO. MORF-010WO1 methoxycyclopropyl)methyl)benzene (331 mg) as a colorless oil. Yield 39% (ESI 271.2 (M+H) +). Step 4: ethyl 2-(2-methoxy-5-((1-methoxycyclopropyl)methyl)phenyl)acetate

[0721] (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (6.5 mL, 6.5 mmol, 1 N in THF) was added to a solution of 2-bromo-1-methoxy-4-((1-methoxycyclopropyl)methyl)benzene (330 mg, 1.3 mmol), Pd2(dba)3 (65 mg, 0.067 mmol) and Q-phos (50 mg, 0.07 mmol) in 6 mL of THF under argon atmosphere. The mixture was stirred at 60 °C for 18 h, concentrated and purified by silica gel column (EtOAc:pet ether = 0%~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) +). Step 5: ethyl 2-bromo-2-(2-methoxy-5-((1-methoxycyclopropyl)methyl)phenyl)acetate

[0722] 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 additional 30 min, NBS (470 mg, 2.5 mmol) was added. The mixture was stirred at -78 °C for 1 h, quenched with water (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic solvents were concentrated and the residue was purified by silica gel chromatography (EtOAc: PE = 0%~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) +). Preparation of ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-(trifluoromethoxy)phenyl)acetate Step 1: N'-(3-bromo-4-(trifluoromethoxy)benzylidene)-4-methylbenzenesulfonohydrazideATTORNEY DOCKET NO. MORF-010WO1

[0723] 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 with 20 mL of dioxane, added cyclopropylboronic acid (963 mg, 11 mmol) and DBU (2.3 g, 15 mmol). The resulting mixture was stirred at 100 °C for 16 h, concentrated and purified by silica gel chromatography (EtOAc:pet ether = 0%~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) +). Step 2: ethyl 2-(5-(cyclopropylmethyl)-2-(trifluoromethoxy)phenyl)acetate

[0724] (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (4.5 mL, 4.5 mmol, 1 N in THF) was added to a mixture of 2-bromo-4-(cyclopropylmethyl)-1-(trifluoromethoxy)benzene (441 mg, 1.5 mmol), Pd2(dba)3(55 mg, 0.05 mmol) and Q-phos (69 mg, 0.05 mmol) in 8 mL of THF under argon atmosphere. The mixture was stirred at 60 °C for 4 h, concentrated and purified by silica gel column (EtOAc:pet ether = 0%~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) +). Step 3: ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-(trifluoromethoxy)phenyl)acetateATTORNEY DOCKET NO. MORF-010WO1

[0725] LDA (1.4 mL, 2.8 mmol, 2N in THF) was added to a solution of ethyl 2-(5- (cyclopropylmethyl)-2-(trifluoromethoxy)phenyl)acetate (342 mg, 1.1 mmol) in 8 mL of THF at - 78 °C. After stirring for 30 min, TMSCl (304 mg, 2.8 mmol) was added at -78 °C. After stirring for additional 30 min, NBS (501 mg, 2.8 mmol) was added. The mixture was stirred for 1 h at - 78 °C, quenched with water (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic solvents were concentrated to give the crude product ethyl 2-bromo-2-(5- (cyclopropylmethyl)-2-(trifluoromethoxy)phenyl)acetate (342 mg). Yield 79% (ESI 381.0 (M+H) +). Preparation of ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-(methoxymethyl)phenyl)acetate Step 1: methyl 3-bromo-4-(bromomethyl)benzoate

[0726] 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 at reflux for 4 h. The reaction was cooled to room temperature, 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 provide 4.7 g of 3-bromo-4- bromomethyl-benzoic acid methyl ester. Yield 76% (ESI 307.2 (M+H) +). Step 2: methyl 3-bromo-4-(methoxymethyl)benzoate

[0727] 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 mixtureATTORNEY DOCKET NO. MORF-010WO1 was stirred at 50 °C for 1 h, quenched with water ( 30 mL) and extracted with EtOAc (30 mL x 3). The combined organic solvents were concentrated and the residue was purified by silica gel chromatography (EtOAc:pet ether = 0%~10%) to give the desired product methyl 3-bromo-4- (methoxymethyl)benzoate (1.9 g). Yield 50% (ESI 259.2 (M+H) +). Step 3: (3-bromo-4-(methoxymethyl)phenyl)methanol

[0728] DIBAL-H (1M 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 NH4Cl aqueous solution and extracted with EtOAc (25 mL x 2). The combined organic solvents were concentrated and the residue was purified by silica gel chromatography (EtOAc:pet ether = 0%~25%) to give the desired product (3-bromo-4-(methoxymethyl)phenyl)methanol (1.3 g). Yield 76% (ESI 231.2 (M+H) +). Step 4: 2-bromo-4-(bromomethyl)-1-(methoxymethyl)benzene

[0729] 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 solvents were concentrated in vacuo and the residue was purified by silica gel chromatography (EtOAc:pet ether = 0%~15%) to give the desired product 2-bromo-4-(bromomethyl)-1-(methoxymethyl)benzene (1.9 g). Yield 93% (ESI 293.2 (M+H) +). Step 5: 2-bromo-4-(cyclopropylmethyl)-1-(methoxymethyl)benzeneATTORNEY DOCKET NO. MORF-010WO1

[0730] 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, 1 N in THF) was added slowly at 0 °C. The mixture was then stirred at room temperature for 4 h, quenched with NaHCO3 aqueous solution and extraced with EtOAc (20 mL X 2). The combined organic solvents were concentrated and the residue was purified by silica gel chromatography (EtOAc:pet ether = 0%~15%) to give the desired product 2-bromo-4-(cyclopropylmethyl)-1- (methoxymethyl)benzene (940 mg). Yield 43% (ESI 255.1 (M+H) +). Step 6: ethyl 2-(5-(cyclopropylmethyl)-2-(methoxymethyl)phenyl)acetate

[0731] (2-ethoxy-2-oxoethyl)zinc(II) bromide (4.5 mL, 4.5 mmol, 1 N in THF) was added to a solution of 2-bromo-4-(cyclopropylmethyl)-1-(methoxymethyl)benzene (381 g, 1.5 mmol), Pd2(dba)3 (55 mg, 0.07 mmol) and Q-phos (69 mg, 0.07 mmol) in 8 mL of THF under argon atmosphere. The mixture was stirred at 60 °C for 18 h, concentrated and purified by silica gel column (EtOAc:pet ether = 0%~10%) to give the desired product ethyl 2-(5-(cyclopropylmethyl)- 2-(methoxymethyl)phenyl)acetate as a yellow oil (304 mg). Yield 77% (ESI 263.1 (M+H) +). Step 7: ethyl 2-bromo-2-(5-(cyclopropylmethyl)-2-(methoxymethyl)phenyl)acetateATTORNEY DOCKET NO. MORF-010WO1

[0732] LDA (1.1 mL, 2.2 mmol, 2N in THF) was added to a mixture of ethyl 2-(5- (cyclopropylmethyl)-2-(methoxymethyl)phenyl)acetate (304 mg, 1.16 mmol) in 10 mL of THF at -78 °C. After stirring for 30 min, TMSCl (241 mg, 2.2 mmol) was added at -78 °C. After stirring for additional 30 min, NBS (398 mg, 2.2 mmol) was added. The mixture was stirred for 1 h at - 78 °C, quenched with water and extracted with EtOAc (15 mL x 3). The combined organic solvents were concentrated and the residue was purified by silica gel chromatography (EtOAc: PE = 0%~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) +). Preparation of (2,5-difluoro-3-isopropyl-6-methoxyphenyl)boronic acid Step 1: 1-bromo-2,5-difluoro-4-methoxybenzene

[0733] 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 phase was washed with brine (200 Ml x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. 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.1H NMR (400MHz, 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). Step 2: 1,4-difluoro-2-methoxy-5-(prop-1-en-2-yl)benzene

[0734] 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), K3PO4 (23.41 g, 110.31 mmol), PPh3 (2.89 g, 11.03 mmol) and Pd(OAc)2 (825.49 mg, 3.68 mmol) in dioxane (160ATTORNEY DOCKET NO. MORF-010WO1 mL) and water (16 mL) was stirred at 100 °C for 3 h under N2atmosphere. 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 phase was washed with brine (150 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The mixture was purified by MPLC (Biotage®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~1% ethyl acetate / petroleum ether gradient @ 150 mL / min). The crude product was purified by RP-MPLC (neutral, MeOH / H2O) to give 1,4-difluoro-2-methoxy-5-(prop-1-en-2-yl)benzene (2.4 g, 13.03 mmol, 28.4% yield) as light yellow oil.1H NMR (400MHz, CHLOROFORM-d) δ = 7.04 (dd, J = 7.2, 12.1 Hz, 1H), 6.68 (dd, J = 7.2, 11.8 Hz, 1H), 5.24 (d, J = 0.7 Hz, 1H), 5.21 (d, J = 1.1 Hz, 1H), 3.88 (s, 3H), 2.11 (d, J = 0.7 Hz, 3H). Step 3: 1,4-difluoro-2-isopropyl-5-methoxybenzene

[0735] 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 at 25 °C for 3 h under H2 (40 psi). 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 of 0~1% ethyl acetate / petroleum ether gradient @ 120 mL / min) to give 1,4-difluoro-2-isopropyl-5- methoxybenzene (1.9 g, 10.20 mmol, 78.4% yield) as colorless oil.1H NMR (400MHz, CHLOROFORM-d) δ = 6.95 (dd, J = 7.1, 12.2 Hz, 1H), 6.66 (dd, J = 7.3, 11.3 Hz, 1H), 3.86 (s, 3H), 3.16 (spt, J = 6.9 Hz, 1H), 1.22 (d, J = 7.0 Hz, 6H). Step 4: (2,5-difluoro-3-isopropyl-6-methoxyphenyl)boronic acid

[0736] 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) at -78 °C under N2 atmosphere. 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 intoATTORNEY DOCKET NO. MORF-010WO1 the reaction. The reaction was stirred at -78 °C for 2 h. The reaction mixture was quenched by aq.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.1H NMR (400MHz, CHLOROFORM-d) δ = 7.11 (dd, J = 7.7, 12.5 Hz, 1H), 6.33 (d, J = 7.5 Hz, 2H), 4.04 (d, J = 2.2 Hz, 3H), 3.20 (td, J = 6.9, 13.8 Hz, 1H), 1.23 (d, J = 7.0 Hz, 6H). 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

[0737] 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), PPh3(8.82 g, 33.63 mmol), K3PO4 (71.39 g, 336.30 mmol) and Pd(OAc)2 (2.52 g, 11.21 mmol) in dioxane (500 mL) and water (50 mL) was stirred at 100 °C for 10 h under N2 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 x 2). The combined organic phase was washed with brine (200 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by MPLC (Biotage®, 220 g SepaFlash® Silica Flash Column, Eluent of petroleum ether gradient @ 150 mL / min). The crude product was purified by RP- MPLC (neutral, MeCN / H2O). 2,3-difluoro-1-methoxy-4-(prop-1-en-2-yl)benzene (14.4 g, 78.18 mmol, 66.4% yield) was obtained as yellow oil.1H NMR (400MHz, 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). Step 2: 2,3-difluoro-1-isopropyl-4-methoxybenzeneATTORNEY DOCKET NO. MORF-010WO1

[0738] 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 at 25 °C for 3 h under H2(40 psi). 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 of petroleum ether gradient @ 120 mL / min) to give 2,3-difluoro-1-isopropyl-4-methoxybenzene (6.3 g, 33.83 mmol, 86.6% yield) as colorless oil.1H NMR (400MHz, 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). Step 3: 1-bromo-3,4-difluoro-5-isopropyl-2-methoxybenzene

[0739] 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 by water (20 mL) and adjusted to pH ~7 by adding sat.NaHCO3. The aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, 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 colorless oil.1H NMR (400MHz, 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). Step 4: (3,4-difluoro-5-isopropyl-2-methoxyphenyl)boronic acidATTORNEY DOCKET NO. MORF-010WO1

[0740] 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 N2 atmosphere. The mixture was stirred at -70 °C for 2 h. The reaction was quenched with sat.NH4Cl (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. 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 light yellow oil.1H NMR (400MHz, CHLOROFORM-d) δ = 7.45 (dd, J = 2.1, 8.4 Hz, 1H), 5.82 (br s, 2H), 4.07 (d, J = 2.6 Hz, 3H), 3.19 (spt, J = 7.0 Hz, 1H), 1.27 (d, J = 7.0 Hz, 6H). 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

[0741] 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 carried out in parallel. The reaction mixture was quenched by water (1 L), extracted with EtOAc (1 L x 3). The combined organic layers were washed with brine (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-(3-bromo-5-fluoro- 4-hydroxyphenyl)ethanone (151.19 g, crude) as red oil. Step 2: 1-(3-bromo-5-fluoro-4-methoxyphenyl)ethanone

[0742] 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 slow dropwise added into the reaction at 0~5 °C. The mixture was stirred at 25 °C for 15.5 h. Four batches were carried out in parallel. The reaction mixture was quenched by water (2 L), 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 columnATTORNEY DOCKET NO. MORF-010WO1 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, 81.1% yield) as yellow oil.1H NMR (400MHz, CHLOROFORM-d) δ = 7.92 (t, J = 1.7 Hz, 1H), 7.65 (dd, J = 2.1, 11.8 Hz, 1H), 4.07 (d, J = 2.8 Hz, 3H), 2.55 (s, 3H). Step 3: 1-bromo-5-(1,1-difluoroethyl)-3-fluoro-2-methoxybenzene

[0743] 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 carried out in parallel. The reactions were poured into ice sat.NaHCO3 (400 mL) slowly and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column (Biotage®; 80 g SepaFlash® Silica Flash Column, Eluent of petroleum ether gradient @ 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 colorless oil.1H NMR (400MHz, 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). Step 4: tert-butyl 2-(5-(1,1-difluoroethyl)-3-fluoro-2-methoxyphenyl)acetate

[0744] 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 palladium tritert- butylphosphane (455.86 mg, 892.00 μmol) in THF (60 mL) was stirred at 70 °C for 2 h under N2 atmosphere. The mixture was quenched with water (50 mL) and filtered. The filtrate was extracted with ethyl acetate (80 mL x 3). The combined organic phase was washed with brine (80 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by MPLC (Biotage®; 20 g SepaFlash® Silica Flash Column, Eluent of Petroleum ether gradient @ 100 mL / min) to give tert-butyl 2-(5-(1,1-difluoroethyl)-3-fluoro-2- methoxyphenyl)acetate (2.6 g, 8.54 mmol, 76.6% yield) as light yellow oil.1H NMR (400MHz, CHLOROFORM-d) δ = 7.20-7.14 (m, 1H), 7.12 (s, 1H), 3.96 (d, J = 2.3 Hz, 3H), 3.59 (s, 2H), 1.90 (t, J = 18.1 Hz, 3H), 1.47 (s, 9H).ATTORNEY DOCKET NO. MORF-010WO1 Step 5: tert-butyl 2-bromo-2-(5-(1,1-difluoroethyl)-3-fluoro-2-methoxyphenyl)acetate

[0745] To a solution of tert-butyl 2-(5-(1,1-difluoroethyl)-3-fluoro-2-methoxyphenyl)acetate (1.5 g, 4.93 mmol) in THF (30 mL) was added LiHMDS (1 M, 7.39 mL) dropwise at -70 °C under N2 atmosphere. The mixture was stirred at -70 °C for 0.5 h. Then TMSCl (803.29 mg, 7.39 mmol) was added. After stirred at -70 °C for 0.5 h, NBS (2.63 g, 14.79 mmol) in THF (30 mL) was added dropwise. The reaction was stirred at -70 °C for 1 h. The residue was quenched with sat.NH4Cl (20 mL) and extracted with ethyl acetate (20 mLx 2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by MPLC (Biotage®; 20 g SepaFlash® Silica Flash Column, Eluent of Petroleum ether gradient @ 100 mL / min) to give tert-butyl 2-bromo-2-(5-(1,1- difluoroethyl)-3-fluoro-2-methoxyphenyl)acetate (1.5 g, 3.91 mmol, 79.4% yield) as yellow oil.1H NMR (400MHz, CHLOROFORM-d) δ = 7.54 (s, 1H), 7.27-7.21 (m, 1H), 5.71 (s, 1H), 4.05 (d, J = 2.4 Hz, 3H), 1.91 (t, J = 18.1 Hz, 3H), 1.48 (s, 9H). Preparation of (5-(2-cyclopropylpropan-2-yl)-2-methoxyphenyl)boronic acid Step 1: (3-bromo-4-methoxyphenyl)(cyclopropyl)methanone

[0746] TFAA (5.39 g, 25.66 mmol, 3.57 mL) was added dropwise to a solution of 1-bromo- 2-methoxybenzene (2 g, 10.69 mmol, 1.33 mL), cyclopropanecarboxylic acid (1.10 g, 12.83 mmol, 1.01 mL) in TFA (10 mL) at 25 °C. The mixture was stirred for 4 h at 25 °C. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with aqueous NaHCO3 (50 mL), 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®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate / Petroleum ether gradient @ 100 mL / min). (3-bromo-4- methoxyphenyl)(cyclopropyl)methanone (1.8 g, 7.06 mmol, 65.98% yield) was obtained as a yellow solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 8.25 (d, J = 2.1 Hz, 1H), 7.99 (dd, JATTORNEY DOCKET NO. MORF-010WO1 = 2.1, 8.6 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 3.98 (s, 3H), 2.66-2.54 (m, 1H), 1.25-1.20 (m, 2H), 1.04 (qd, J = 3.6, 7.6 Hz, 2H). LCMS (ESI) m / z = 254.9 (M+1). Step 2: 2-bromo-4-(2-cyclopropylpropan-2-yl)-1-methoxybenzene

[0747] TiCl4 (5.80 g, 30.58 mmol) was added dropwise to DCM (50 mL) at -40 °C under N2, then the mixture was cooled to -50 °C and treated with ZnMe2 (1 M in toluene, 30.58 mL) dropwise, the temperature was kept at -40~-50 °C. After stirred for 10 min, a solution of (3- bromo-4-methoxyphenyl)(cyclopropyl)methanone (1.3 g, 5.10 mmol) in DCM (5 mL) was added dropwise to the mixture at -40 °C. The resulting mixture was stirred for 0.5 h at -40 °C and 16 h at 20 °C. The mixture was added dropwise to ice water (200 mL) with stirring slowly and the aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated NaHCO3 (100 mL), water (100 mL) and brine (100 mL), dried and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ether gradient @ 60 mL / min). 2-bromo-4-(2-cyclopropylpropan-2-yl)-1-methoxybenzene (1.1 g, 4.09 mmol, 80.19% yield) was obtained as yellow oil.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.66 (d, J = 2.32 Hz, 1H), 7.40 (dd, J = 8.56, 2.32 Hz, 1H), 6.88 (d, J = 8.68 Hz, 1H), 3.92 (s, 3H), 2.36 (s, 1H), 2.02 (s, 1H), 1.24-1.40 (m, 1H), 1.19 (s, 6H), 0.88-1.09 (m, 1H), 0.43-0.49 (m, 2H), 0.28- 0.33 (m, 2H). Step 3. (5-(2-cyclopropylpropan-2-yl)-2-methoxyphenyl)boronic acid

[0748] To the mixture of 2-bromo-4-(2-cyclopropylpropan-2-yl)-1-methoxybenzene (300 mg, 1.11 mmol) and 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (755.25 mg, 3.34 mmol) in dioxane (5 mL) was added KOAc (218.76 mg, 2.23 mmol) and Pd(dppf)Cl2.CH2Cl2 (91.02 mg, 111.45 μmol). The mixture was stirred at 90 °C for 16 h under N2. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether / Acetone = 100 / 1 to 0 / 100) and pre-HPLC (column:ATTORNEY DOCKET NO. MORF-010WO1 Phenomenex Luna 80 x 30 mm x 3 um; mobile phase: A water with 0.1% TFA; B acetonitrile 30%-60%, 8 min; Flow Rate 25 mL / min). (5-(2-cyclopropylpropan-2-yl)-2- methoxyphenyl)boronic acid (180 mg, 768.91 μmol, 68.99% yield) was obtained as a white solid. LCMS (ESI) m / z = 235.1 (M+1). Preparation of (5-(cyclopropylmethyl)-2-methoxyphenyl)boronic acid Step 1: N'-(3-bromo-4-methoxybenzylidene)-4-methylbenzenesulfonohydrazide

[0749] To a solution of 4-methylbenzenesulfonohydrazide (8.83 g, 47.43 mmol) in MeOH (200 mL) was added 3-bromo-4-methoxybenzaldehyde (10 g, 46.50 mmol), the reaction was stirred at 25 °C for 2 h. The solvent was distilled out under vacuum at 45 °C to give the crude product. N'-(3-bromo-4-methoxybenzylidene)-4-methylbenzenesulfonohydrazide (27.6 g, crude) was obtained as white solid. Step 2: 2-bromo-4-(cyclopropylmethyl)-1-methoxybenzene

[0750] To a solution of N'-(3-bromo-4-methoxybenzylidene)-4- methylbenzenesulfonohydrazide (5 g, 13.05 mmol) and cyclopropylboronic acid (1.68 g, 19.57 mmol) in dioxane (100 mL) was added Cs2CO3 (7.65 g, 23.48 mmol) at 25 °C, the reaction was stirred at 100 °C for 16 h. The mixture was quenched by H2O (80 mL), extracted by EtOAc (80 mL x 3), the organic layer was 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, Eluent of 0~33% Ethyl acetate / Petroleum ether gradient @ 120 mL / min). 2-bromo-4- (cyclopropylmethyl)-1-methoxybenzene (1.88 g, 7.80 mmol, 43.0% yield) was obtained as yellow oil. Step 3: (5-(cyclopropylmethyl)-2-methoxyphenyl)boronic acidATTORNEY DOCKET NO. MORF-010WO1

[0751] To a solution of 2-bromo-4-(cyclopropylmethyl)-1-methoxybenzene (0.5 g, 2.07 mmol) in THF (7 mL) was added n-BuLi (2.5 M, 1.08 mL) at -78 °C, the reaction was stirried at - 78 °C for 0.5 h. Then trimethyl borate (646.43 mg, 6.22 mmol) was added in the reaction at - 78 °C, the reaction was stirred at -78 °C for 0.5 h. The mixture was quenched by H2O (10 mL), extracted by EtOAc (10 mL x 3), the organic layer was concentrated in vacuum to get a residue. The residue was purified by flash silica gel chromatography (ISCO ®; 4 g Sepa Flash ® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 120 mL / min). (5- (cyclopropylmethyl)-2-methoxyphenyl)boronic acid (0.17 g, 0.83 mmol, 38.0% yield) was obtained as white solid. LCMS (ESI) m / z = 207.2 (M+1). Preparation of (2-fluoro-3-isopropyl-6-methoxyphenyl)boronic acid Step 1: 2-fluoro-1-isopropyl-4-methoxybenzene

[0752] To a mixture of Pd / C (2 g, 10% purity) in MeOH (50 mL) was added a solution of 1- bromo-4-fluoro-5-isopropyl-2-methoxybenzene (2 g, 8.09 mmol) in MeOH (50 mL) at 25 °C under N2, the suspension was degassed under vacuum and purged with H2 several times, and the mixture was stirred under H2(15 psi) at 25 °C for 16 h. The reaction was 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 1 / 1) to give 2-fluoro-1-isopropyl- 4-methoxybenzene (650 mg, 3.86 mmol, 47.7% yield) as white oil.1H NMR (400MHz, CHLOROFORM-d) δ = 7.06 (t, J = 8.7 Hz, 1H), 6.59-6.48 (m, 2H), 3.70 (s, 3H), 3.09 (td, J = 6.9, 13.9 Hz, 1H), 1.16 (d, J = 6.9 Hz, 6H). Step 2: (2-fluoro-3-isopropyl-6-methoxyphenyl)boronic acid

[0753] To a solution of 2-fluoro-1-isopropyl-4-methoxybenzene (590 mg, 3.51 mmol) in THF (6 mL) was added LDA (2 M, 2.63 mL) at -78 °C. The reaction was stirred at -78 °C for 0.5ATTORNEY DOCKET NO. MORF-010WO1 h. A solution of trimethyl borate (1.09 g, 10.52 mmol, 1.19 mL) in THF (2 mL) was added into the reaction. The reaction was stirred at -78 °C for 0.5 h. The mixture was stirred at -78 °C for 2 h under N2 atmosphere. The reaction mixture was quenched by aqueous NH4Cl (10 mL) at 0 °C, extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: Phenomenex luna C18250 x 50mm x 10 um; mobile phase: A water with 0.1% TFA, B acetonitrile 40%-60%, 10 min; Flow Rate 25 mL / min) to give (2-fluoro-3-isopropyl-6-methoxyphenyl)boronic acid (370 mg, 1.75 mmol, 49.7% yield) as yellow solid.1H NMR (400MHz, CHLOROFORM-d) δ = 7.33 (t, J = 9.0 Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H), 6.36 (br d, J = 7.7 Hz, 2H), 3.92 (s, 3H), 3.20 (spt, J = 6.9 Hz, 1H), 1.24 (d, J = 6.8 Hz, 6H) LCMS (ESI) m / z = 213.1 (M+1). Preparation of methyl 2-bromo-2-(2-methoxy-5-(2-methoxypropan-2-yl)phenyl)acetate Step 1: 2-(3-bromo-4-methoxyphenyl)propan-2-ol

[0754] To a solution of methyl 3-bromo-4-methoxybenzoate (5 g, 20.40 mmol) in THF (100 mL) was added MeMgBr (3 M in THF, 20.40 mL) at 0 °C, then the reaction was stirred at 25 °C for 3 h. Water (80 mL) was added, the mixture was extracted with ethyl acetate (80 mL x 2). The combined organic layers were washed with H2O mL (40 mL x 2) and brine (40 mL x2), dried over Na2SO4, 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, Eluent of 0~30% Ethyl acetate / Petroleum ether gradient @ 120 mL / min). 2-(3-bromo-4- methoxyphenyl)propan-2-ol (5.17 g, crude) was obtained as a yellow oil. LCMS (ESI) m / z = 245.0 (M+1) Step 2: 2-bromo-1-methoxy-4-(2-methoxypropan-2-yl)benzene

[0755] To a solution of NaH (611.91 mg, 15.30 mmol, 60% purity) in DMF (10mL) was added 2-(3-bromo-4-methoxyphenyl)propan-2-ol (2.5 g, 10.20 mmol) in DMF (25 mL) at 0 °C, the reaction was stirred for 0.5 h, then MeI (2.90 g, 20.40 mmol, 1.27 mL) was added in the mixture at 0 °C, the reaction was stirred at 25 °C for 0.5 h. The reaction mixture was quenchedATTORNEY DOCKET NO. MORF-010WO1 by H2O (30 mL) at 0 °C, extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, 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, Eluent of 10~30% Ethyl acetate / Petroleum ether gradient @ 120 mL / min). 2-bromo-1-methoxy-4-(2-methoxypropan-2-yl)benzene (1.73 g, 6.68 mmol, 65.5% yield) was obtained as a yellow oil.1H NMR (400MHz, CHLOROFORM-d) δ = 7.58 (d, J = 2.3 Hz, 1H), 7.31 (dd, J = 2.3, 8.6 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 3.90 (s, 3H), 3.06 (s, 3H), 1.50 (s, 6H). LCMS (ESI) m / z = 259.0 (M+1). Step 3: methyl 2-(2-methoxy-5-(2-methoxypropan-2-yl)phenyl)acetate

[0756] To a solution of (2-methoxy-2-oxoethyl)zinc(II) bromide (1 M, 7.72 mL) in THF (3 mL) was added Pd(t-Bu3P)2 (118.33 mg, 231.54 μmol) and 2-bromo-1-methoxy-4-(2- methoxypropan-2-yl)benzene (0.4 g, 1.54 mmol), the reaction was stirr...

Claims

ATTORNEY DOCKET NO. MORF-010WO1 CLAIMS WE CLAIM:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:X is -CHR1c-, -O-, or -NR2-; each of R1a, R1b, R1c, R1d, R1e, and R1fis independently H, C1-4alkyl, halogen, C1-4alkyoxy, OH, C1-4alkyl-OH, C1-4alkyl-C1-4alkyoxy, C1-4alkyoxy-C1-4alkyoxy, CF3, CHF2, CH2F, CN, NO2, NRaRbor C1-4alkyl-NRaRb, each R2is independently H, C1-4alkyl, or C3-5cycloalkyl; R3ais C1-4alkyoxy, C3-5cycloalkoxy, CF3, CHF2, CH2F, OCF3, OCHF2or OCH2F; R3bis H, halogen, CF3 or CN; R3cis H, F, CN, or C1-4alkyl; R3dis C1-4alkyl, C3-5cycloalkyl, or 4-6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 R6; R3eis H or F; each R4is independently H, C1-4alkyl, halogen, CF3, CHF2or CH2F, cyclopropyl, or two geminal R4groups together can form a spiro-cyclopropyl; each R6is independently C1-4alkyl, C1-4alkenyl, C3-5cycloalkyl, C1-4alkyoxy, C3-5cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, 5-6-membered heteroaryl or NRaRb; each R7is independently C1-4alkyl or F;ATTORNEY DOCKET NO. MORF-010WO1 each of Raand Rbis independently hydrogen, C1-4alkyl, C3-5cycloalkyl, or Raand Rb, together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, which ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of F, C1-4alkyl, phenyl and benzyl; and n is 1 or 2; and m is 0, 1 or 2.

2. The compound of claim 1, whereind. m is 0.

3. The compound of claim 2, wherein a. each of R1a, R1c, R1d, R1e, and R1fis independently H; and b. R1bis H, C1-4alkyl, C1-4alkyoxy, C1-4alkyl-C1-4alkyoxy, C1-4alkyoxy-C1-4alkyoxy, NRaRb or C1-4alkyl-NRaRb.

4. The compound of claim 3, wherein the Q ring5. The compound of any one of claims 1-4, wherein R3ais C1-4alkyoxy, R3bis halogen and R3cis H.

6. The compound of any one of claims 1-5, wherein wherein R3ais methoxy.

7. The compound of any one of claims 1-6, wherein R3bis F.ATTORNEY DOCKET NO. MORF-010WO1 8. The compound of any one of claims 1-7, wherein R3dis C1-4alkyl, optionally substituted with 1 R6.

9. The compound of any one of claims 1-8, wherein R3dis unsubstituted isopropyl.

10. The compound of any one of claims 1-7, wherein R3dis C3-5cycloalkyl, or 4-6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 R6; and R6is C1- 4alkyl optionally substituted with halogen, or halogen.

11. The compound of any one of claims 1-7, wherein12. The compound of any one of claims 1-11, wherein R6is C3-5cycloalkyl, or 5-6-membered heteroaryl, wherein R6is optionally substituted with one or more C1-4alkyl optionally substituted with halogen, or halogen.

13. The compound of any one of claims 1-12, wherein R6is C3-5cycloalkyl, or 5-6-membered heteroaryl.

14. The compound of any one of claims 1-12, wherein R6is methoxy, hydroxyl, or NRaRbwherein Raand Rbare each independently H or C1-4alkyl.

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

16. The compound of any one of claims 1-15, having a structure according to Formula (II),ATTORNEY DOCKET NO. MORF-010WO1 having a structure according to Formula (IIA),having a structure according to Formula (III),having a structure according to Formula (IIIA),having a structure according to Formula (V),having a structure according to Formula (VA),ATTORNEY DOCKET NO. MORF-010WO1 having a structure according to Formula (VI),having a structure according to Formula (VIA),having a structure according to Formula (VII),or a pharmaceutically acceptable salt thereof.

17. The compound of claim 16, having a structure according to Formula (IIA), wher1bein R is H, or a pharmaceutically acceptable salt thereof.

18. The compound of any one of claims 1-17, wherein the carbon marked by the asterisk (*) has the (R)-configuation.

19. The compound of any one of claims 1-17, wherein the carbon marked by the asterisk (*) has the (S)-configuation.

20. The compound of claim 1, selected from any compound described in Table 1, or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1, selected from:ATTORNEY DOCKET NO. MORF-010WO1ATTORNEY DOCKET NO. MORF-010WO1ATTORNEY DOCKET NO. MORF-010WO1;ATTORNEY DOCKET NO. MORF-010WO1or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

23. The compound of claim 1 wherein the compound ispharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1 24. The compound of claim 1, wherein the compound is(Compound 7A / 7B), or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1, wherein the compound is(Compound 11A / 11B), or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1 wherein the compound is(Compound 12A / 12B), or a pharmaceutically acceptable salt thereof.

27. The compound of claim 1, wherein the compound is(Compound 17A / 17B), or a pharmaceutically acceptable salt thereof.

28. The compound of claim 1, wherein the compound is(Compound 20A / 20B), or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1 29. The compound of claim 1, wherein the compound is(Compound 24A / B), or a pharmaceutically acceptable salt thereof.

30. The compound of claim 1, wherein the compound is(Compound 28A / 28B), or a pharmaceutically acceptable salt thereof.

31. The compound of claim 1, wherein the compound is(Compound 35A / 35B), or a pharmaceutically acceptable salt thereof.

32. The compound of claim 1, wherein the compound is(Compound 36A / 36B), or a pharmaceutically acceptable salt thereof.

33. The compound of claim 1, wherein the compound is(Compound 41A / 41B), or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1 34. The compound of claim 1, wherein the compound is(Compound 42A / 42B), or a pharmaceutically acceptable salt thereof.

35. The compound of claim 1, wherein the compound is(Compound 47A / 47B), or a pharmaceutically acceptable salt thereof.

36. The compound of claim 1, wherein the compound is(Compound 123A / 123B), or a pharmaceutically acceptable salt thereof.

37. The compound of claim 1, wherein the compound is(Compound 125A / 125B);, or a pharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1 38. The compound of claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

39. The compound of claim 1, wherein the compound is(Compound 135A / 136B), or a pharmaceutically acceptable salt thereof.

40. The compound of claim 1, wherein the compound ispharmaceutically acceptable salt thereof.

41. The compound of claim 1, wherein the compound ispharmaceutically acceptable salt thereof.ATTORNEY DOCKET NO. MORF-010WO1 42. The compound of claim 1, wherein the compound is(Compound 154A / 154B), or a pharmaceutically acceptable salt thereof.

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

44. A method of inhibiting αvβ8integrin in a patient, the method comprising administering to the patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof.

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