Inhibition of human integrin α5β1

Abstract

A compound of formula (I) is disclosed that can be used in a method of treating or preventing a disease or condition that responds to inhibition of human α5β1 integrin by administering the compound of formula (I) to a patient in need. Many diseases and conditions can be treated by administering the compound of formula (I). [Formula 1] JPEG2026534170000398.jpg45128

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority and benefits of U.S. Provisional Patent Application No. 63 / 687,186, filed on 26 August 2024, and U.S. Provisional Patent Application No. 63 / 584,383, filed on 21 September 2023, the contents of which, respectively, are incorporated herein by reference in their entirety.

[0002] (Field of invention) This application discloses a method for treating diseases and conditions by inhibiting α5β1 integrin. Diseases and conditions that respond to α5β1 integrin inhibition include, for example, hypertension such as pulmonary hypertension (PAH). [Background technology]

[0003] Fibronectin (Fn) is an extracellular matrix protein that integrates complex cell adhesion and signaling via cell surface integrin receptors (fibronectin-binding integrins (e.g., a5b1)) during tissue development, remodeling, and diseases such as hypertension and heart failure. Heart failure (HF) is a debilitating disease in which abnormal functioning of the heart leads to insufficient hypoperfusion of the body's tissues and organs. Hypertension is the cause of various adverse effects, including heart failure, with high morbidity and mortality. One form of hypertension is pulmonary hypertension (PAH). PAH is a rare but destructive disease in which normally low pulmonary artery pressure rises due to vasoconstriction and remodeling of the pulmonary blood vessels. Vasoconstriction and vascular remodeling increase the workload on the right side of the heart, leading to right ventricular hypertrophy, fibrosis, and ultimately heart failure.

[0004] Integrins are a family of glycoprotein transmembrane receptors that mediate cell-cell and cell-matrix interactions. Integrins are heterodimers with two distinct chains, alpha and beta subunits. In mammals, 18 alpha subunits and 8 beta subunits have been described. The integrin superfamily of cell surface receptors is formed from several structurally and functionally related surface glycoproteins, with each receptor existing as a heterodimer of non-covalently linked α and β subunits. At least 18 distinct α subunits and 8 β subunits have been identified in mammals, and these are known to form more than 24 distinct receptors. Each integrin specifically interacts with defined extracellular ligands, including extracellular matrix proteins such as fibronectin, vitronectin, and collagen, as well as cell surface molecules such as VCAM, ICAM, and PECAM, via a linear adhesion motif.

[0005] Integrin α5β1 is composed of the subunits ITGA5 (integrin α5) and integrin β1. Some integrins bind to fibronectin. Integrin α5β1 is selective for fibronectin because it requires both the 9th and 10th type II repeat sequences (FNIII-9 and FNIII-10) of fibronectin for interaction. α5β1 integrin expression is primarily found in the vascular system and connective tissue. Expression is significantly enhanced in tumor blood vessels, but also in tumor cells themselves in many types of cancer (including colon, breast, ovarian, lung, and brain tumors). It is further expressed to varying degrees in many cell types, including fibroblasts, hematopoietic cells, immune cells, smooth muscle cells, and epithelial cells. High expression of α5β1 integrin has also been observed in fibrotic tissues, such as pulmonary fibrosis.

[0006] Integrin α5β1 (a5b1 or alpha-5-beta-1) is composed of α5 (a5 or alpha-5) and β1 (b1 or beta-1) subunits. The a5 subunit forms a specific dimer with the beta-1 subunit and is widely expressed in most tissues. Integrin a5b1 almost exclusively mediates cell adhesion through interaction with fibronectin, which binds via a short arginine-glycine-aspartate (RGD) adhesion motif. However, endothelial cells and platelets can bind to fibrin via a5b1. The interaction of a5b1 with fibronectin plays a crucial role in physiological and pathological angiogenesis and vascular integrity. Endothelial cells express various integrins, but a5b1 is important for endothelial cell survival in vitro on a provisional matrix, suppressing apoptosis and promoting proliferation. a5b1 expression is upregulated in tumor vascular systems and patients with pulmonary hypertension. Consistent with the crucial functional role of receptor-ligand pairing, the a5b1 ligand fibronectin is also upregulated in tumor tissue and during wound healing.

[0007] Current treatments include vasodilators targeting Ca channels or endothelin receptors. New approaches are needed in the treatment of pulmonary hypertension, PAH, heart failure, and related diseases. Due to the limitations of current treatments for pulmonary hypertension, there remains great interest in and need for additional or alternative therapies to treat, stabilize, prevent, and / or delay pulmonary hypertension. Various methods have been developed to obtain more effective and / or less toxic drugs for the treatment of pulmonary hypertension. However, these methods still exhibit serious side effects, and the resulting drugs often have short half-lives and low bioavailability.

[0008] As an important addition to the therapeutic options for α5β1 integrin-mediated conditions, there remains a medical need for effective and safe oral α5β1 integrin inhibitors. In particular, there remains an unmet need for small molecules designed to inhibit integrin α5β1, including the need for such small molecules for oral administration, which would avoid the need for regular therapeutic infusions and the complications associated with this form of drug administration. [Overview of the project] [Means for solving the problem]

[0009] The present invention provides, in particular, methods and compositions for treating diseases associated with increased expression or activity of integrin α5β1. Many normal physiological and disease processes require cells to come into contact with other cells and / or the extracellular matrix. Cell-matrix and cell-cell adhesion are mediated through several protein families, including integrins, selectins, cadherins, and immunoglobulins, which promote various normal cellular functions such as proliferation, migration, differentiation, or survival. Cell adhesion is also important for a range of pathological conditions, and therefore pharmacological disruption of cell adhesion interactions can provide a mechanism for therapeutic intervention. Members of the integrin superfamily adhesion molecules play important roles in acute and chronic disease conditions such as cancer, inflammatory diseases, stroke, and neurodegenerative disorders. Thus, integrins represent complex biological regions.

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

[0011] [ka] During the ceremony,

[0012] [ka] is a 6-12 membered aryl ring structure (e.g., phenyl) or a 3-19 membered heterocyclyl ring structure (e.g., a 3-15 membered heterocyclyl ring structure such as 6-membered heteroaryl),

[0013]

Chemical formula

[0014] In some embodiments, the present invention features a compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0015]

Chemical formula

[0016]

Chemical formula

[0017]

Chemical formula

[0018] In some embodiments, the present invention is characterized by a compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0019] [ka] During the ceremony,

[0020] [ka] This is a 3-19 member heterocyclyl ring structure (for example, a 3-15 member heterocyclyl ring structure such as a 6 member heteroaryl),

[0021] [ka] is halogen, C 1~6 Alkyl, C 1~6 It is optionally substituted with alkyloxy, 3-8 membered heterocyclyl ring structure, aryl, or 5-6 membered heteroaryl, C 1~6 Alkyl, C 1~6 Alkyloxy, 3-8 membered heterocyclyl ring structure, aryl, or 5-6 membered heteroaryl may contain one or more halogens, C 1~4 C is optionally substituted with alkyloxy or one or more halogens. 1~6 It is optionally substituted with alkyl groups; a is 1, 2, 3, 4, 5, 6, 7, or 8; R a C 1~6 It is alkyl.

[0022] In some embodiments, the compound of formula (I) is the compound of formula (IA) or a pharmaceutically acceptable salt thereof:

[0023] [ka]

[0024] In some embodiments,

[0025] [ka] However, the compound of formula (I), which is phenyl or a six-membered heteroaryl, is, for example, the compound of formula (IA), or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments,

[0027] [ka] but,

[0028] [ka] The compound is of formula (I), for example, a compound of formula (IA), or a pharmaceutically acceptable salt thereof. During the ceremony, R1 is C 1~4 It is an alkoxy; R2 is a C that is optionally substituted with one or more halogens. 1~4 Alkyl or

[0029] [ka] When R1 and R2 combine to form a condensed 5-8 member heterocycloalkyl ring, a condensed 5-6 member heteroaryl ring, or a condensed 7-15 member spirocyclic heterocycloalkyl ring system, it is a 9-19 member heterocyclyl, and the condensed ring is a halogen, C 1~4 Alkyl, C 3~6 It is optionally substituted with a cycloalkyl or a 4- to 8-membered heterocycloalkyl ring, C 1~4 Alkyl, C 3~6 A cycloalkyl or 4- to 8-membered heterocycloalkyl ring is optionally substituted with one or more halogens. 1~4 It is optionally substituted with alkyl; R3 is C, optionally substituted with one or more halogens. 1-4 It is alkyl. In some embodiments, R1 is methoxy; R2 is fluoro; and R3 is C, optionally substituted with one or more fluoros. 1~4 It is alkyl.

[0030] In some embodiments,

[0031] [ka] but,

[0032] [ka] The compound is of formula (I), for example, a compound of formula (IA), or a pharmaceutically acceptable salt thereof. During the ceremony, R4 and R 14 Each of these is independently substituted with H, a halogen, or one or more halogens, and C is optionally substituted with them. 1~4 It is alkyl; X1 is CR 5a R 5b or NR 5c and R 5a C is optionally substituted with H or one or more halogens. 1~4 It is alkyl, R 5b C1~4 Alkyl or C 3~6 It is a cycloalkyl, C 1~4 Alkyl or C 3~6 The cycloalkyl group is optionally substituted with one or more halogens; or R 5a and R 5b Together they form a spirocyclic 3-8 membered heterocycloalkyl or spirocyclic C 3~6 Forms a cycloalkyl group, and a 3- to 8-membered heterocycloalkyl group or C 3~6 Cycloalkyls are C molecules optionally substituted with one or more halogens. 1~4 C is optionally substituted with alkyl, 4-6 membered spirocyclic heterocycloalkyl, or one or more halogens. 1~4 C optionally substituted with alkyl 3~6 It is optionally substituted with a spirocyclic cycloalkyl group; R 5c C 1~4 Alkyl, or C 3~6 It is a cycloalkyl, C 1~4 Alkyl or C 3~6 The cycloalkyl group is optionally substituted with one or more halogens; X2 is CR 6a R 6b -CH2CR 6a R 6b , C=O, O or NR 6c and; R 6a and R 6b These are H and C, which are independent of each other. 1~4 Alkyl, 5-6 member heteroaryl, 6 member aryl, C 3~7 It is a cycloalkyl or a 4- to 7-membered heterocycloalkyl, C 1~4 Alkyl, 5-6 member heteroaryl, 6 member aryl, C 3~8 Each cycloalkyl or 4- to 7-membered heterocycloalkyl contains one or more halogens or C 1~4 It is optionally substituted with alkyl groups; R 6c C is optionally substituted with one or more halogens. 1~4 It is alkyl, X3 is a direct bond, CR 7a R 7b , O or NR 7c ; R 7a and R 7b are each independently H or C optionally substituted with one or more halogens 1~4 alkyl; R 7c is C optionally substituted with one or more halogens 1~4 alkyl; X4 is CR 8a R 8b or NR 8c R 8a is H, and R 8b is halogen or C optionally substituted with one or more halogens 1~4 alkyl; R 8a and R 8b are taken together to form a spirocyclic 3-8 membered heterocycloalkyl or C 3~6 cycloalkyl, and the 3-8 membered heterocycloalkyl or C 3~6 cycloalkyl is optionally substituted with C optionally substituted with one or more halogens 1~4 alkyl, 4-8 membered spirocyclic heterocycloalkyl, or C optionally substituted with C alkyl that is optionally substituted with one or more halogens 1~4 alkyl optionally substituted C 3~7 spirocyclic cycloalkyl; R 8c is H, C 1~4 alkyl, 4-8 membered heterocycloalkyl, or C 3~6 cycloalkyl, and the C 1~4 alkyl, 4-8 membered heterocycloalkyl, or C 3~6 cycloalkyl is optionally substituted with one or more halogens; provided that two of both X2 and X3 do not contain O or N heteroatoms, and two of X3 and X4 do not contain O or N heteroatoms.

[0033] In some embodiments,​

[0034] [ka] but,

[0035] [ka] The compound is of formula (I), for example, a compound of formula (IA), or a pharmaceutically acceptable salt thereof. R4 and R 14 Each of these is independently substituted with H, a halogen, or one or more halogens, and C is optionally substituted with them. 1~4 It is alkyl; X1 is CR 5a R 5b or NR 5c and R 5a C is optionally substituted with H or one or more halogens. 1~4 It is alkyl, R 5b C 1~4 Alkyl or C 3~6 It is a cycloalkyl, C 1~4 Alkyl or C 3~6 The cycloalkyl group is optionally substituted with one or more halogens; or R 5a and R 5b Together they form a spirocyclic 3-8 membered heterocycloalkyl or spirocyclic C 3~6 Forms a cycloalkyl group, and a 3- to 8-membered heterocycloalkyl group or C 3~6 Cycloalkyls are C molecules optionally substituted with one or more halogens. 1~4 C is optionally substituted with alkyl, 4-6 membered spirocyclic heterocycloalkyl, or one or more halogens. 1~4 C optionally substituted with alkyl 3~6 It is optionally substituted with a spirocyclic cycloalkyl group; R 5c C 1~4 Alkyl, or C 3~6 It is a cycloalkyl, C 1~4 Alkyl or C3~6 The cycloalkyl group is optionally substituted with one or more halogens; X2 is CR 6a R 6b -CH2CR 6a R 6b , C=O, O or NR 6c and; R 6a and R 6b These are H and C, which are independent of each other. 1~4 Alkyl, 5-6 member heteroaryl, 6 member aryl, C 3~7 It is a cycloalkyl or a 4- to 7-membered heterocycloalkyl, C 1~4 Alkyl, 5-6 member heteroaryl, 6 member aryl, C 3~8 Each cycloalkyl or 4- to 7-membered heterocycloalkyl contains one or more halogens or C 1~4 It is optionally substituted with alkyl groups; R 6c C is optionally substituted with one or more halogens. 1~4 It is alkyl, X3 is a direct join, CR 7a R 7b , O or NR 7c and; R 7a and R 7b Each of these is independently and optionally substituted with H or one or more halogens. 1~4 It is alkyl; R 7c C is optionally substituted with one or more halogens. 1~4 It is alkyl; X4 is CR 8a R 8b or NR 8c and R 8a H is R 8b C is a halogen or a C atom optionally substituted with one or more halogens. 1~4 It is alkyl; R 8a and R 8b Together they form a spirocyclic 3-8 membered heterocycloalkyl or C 3~6Forms a cycloalkyl group, and a 3- to 8-membered heterocycloalkyl group or C 3~6 Cycloalkyls are C molecules optionally substituted with one or more halogens. 1~4 C is optionally substituted with alkyl, 4-8 membered spirocyclic heterocycloalkyl, or one or more halogens. 1~4 C optionally substituted with alkyl 3~7 It is optionally substituted with a spirocyclic cycloalkyl group; R 8c H, C 1~4 Alkyl, 4-8 member heterocycloalkyl, or C 3~6 It is a cycloalkyl, C 1~4 Alkyl, 4-8 member heterocycloalkyl, or C 3~6 The cycloalkyl group is optionally substituted with one or more halogens; However, two of both X2 and X3 do not contain O or N heteroatoms, and two of X3 and X4 do not contain O or N heteroatoms.

[0036] In some embodiments, R1 is methoxy; R2 is fluoro; and R3 is C, which is optionally substituted with one or more fluoros. 1~4 It is alkyl. In some embodiments, R 14 is H, and X1 is CR 5a R 5b And R 5a H is R 5b is methyl or cyclopropyl. In some embodiments, R4 is H, fluoro, or methyl; X1 is CR 5a R 5b And R 5a H is R 5b X2 is methyl; X2 is O, and X3 is CR. 7a R 7b And R 7a and R 7b Each of these is independently and optionally substituted with H or one or more halogens. 1~4 It is alkyl; or X3 is O and X2 is CR 6a R 7b And R6a and R 6b Each is independently H; X4 is CR 8a R 8b And R 8a R 8b Each of these is independently and optionally substituted with H or one or more halogens. 1~4 Alkyl or R 8a and R 8b Together they form a 4-7 membered heterocycloalkyl ring or C 3~7 Forms a cycloalkyl ring, and is a 4-7 membered heterocycloalkyl or C 3~7 Cycloalkyls are C molecules optionally substituted with halogens, or one or more halogens. 1~4 C is optionally substituted with alkyl, 4- to 7-membered spirocyclic heterocycloalkyl, or one or more halogens. 1~4 C optionally substituted with alkyl 3~7 It is optionally substituted with a spirocyclic cycloalkyl group.

[0037] In some embodiments,

[0038] [ka] teeth,

[0039] [ka] The compound is of formula (I), for example, a compound of formula (IA), or a pharmaceutically acceptable salt thereof. During the ceremony, R 10a and R 10b Each of these is independently substituted with H, a halogen, or one or more halogens, and C is optionally substituted with them. 1~4 It is alkyl; R 10a and R 10b They come together, forming a spirocyclic C 3~6 Forming a cycloalkyl or spirocyclic 6-membered heterocycloalkyl; R 11a and R 11bEach of these is independently substituted with H, a halogen, or one or more halogens, and C is optionally substituted with them. 1~4 It is alkyl; R 12a and R 12b Each of these is independently substituted with H, a halogen, or one or more halogens, and C is optionally substituted with them. 1~4 It is alkyl; R 13a These are methyl, ethyl, or cyclopropyl; R 13b H is; R 14 C is optionally substituted with H, a halogen, or one or more halogens. 1~4 It is alkyl.

[0040] In some embodiments, R 10a and R 10b Each is independently either hydrogen or methyl; R 11a and R 11b Each of these is independently H, methyl, or ethyl; R 12a and R 12b Each is independently either H or methyl; R 13a is methyl, ethyl, or cyclopropyl; R 13b H is; R 14 R4 is H, fluoro, or methyl. In some embodiments, R4 is H or fluoro; R 13a is methyl, ethyl, or cyclopropyl; R 14 is H. In some embodiments, X2 is NR 6c And R 6c C 1~4 It is alkyl.

[0041] In some embodiments,

[0042] [ka] but,

[0043] [ka] The compound is of formula (I), for example, a compound of formula (IA), or a pharmaceutically acceptable salt thereof, where R 13a R4 is either H or methyl, and R4 is either H, F, or methyl.

[0044] In some embodiments,

[0045] [ka] but,

[0046] [ka] The compound is of formula (I), for example, a compound of formula (IA), or a pharmaceutically acceptable salt thereof, where R4 is H, fluoro, or methyl. In some embodiments, R 10a , R 10b , and R 11a Each is either H or methyl. In some embodiments, R 11b It is H, methyl, or ethyl.

[0047] In some embodiments,

[0048] [ka] but,

[0049] [ka] The compound of formula (I), for example, the compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein R4 is H, a halogen, or a methyl optionally substituted with one or more halogens; R 9a and R 9b Each is independently H, a halogen, or a methyl atom optionally substituted with one or more halogens. In some embodiments, R4 is H, a fluoro, or a methyl atom; R 9a and R 9bEach of these is independently a methyl atom optionally substituted with H, fluoro, chloro, or one or more fluoro atoms.

[0050] In some embodiments,

[0051] [ka] but,

[0052] [ka] The compound is of formula (I), for example, a compound of formula (IA), or a pharmaceutically acceptable salt thereof. During the ceremony, R 20 H, halogen, C 1~4 Alkyl or C 1~4 It is an alkoxy, C 1~4 Alkyl or C 1~4 Each alkoxy is optionally substituted with one or more halogens; X5 is CR 25a R 25b or NR 25c and; R 25a and R 25b Each of these is independently a C that is optionally substituted with H or one or more halogens or alkoxys. 1~4 Is it alkyl; or R 25a and R 25b They come together, and each one is halogen, C 1~4 Alkyl, spirocyclic C 3~6 C is optionally substituted with a cycloalkyl or a spirocyclic 4-6 membered heterocyclyl ring. 3~6 Forming a cycloalkyl ring or a 4-6 membered heterocyclyl ring, C 1~4 Alkyl, spirocyclic C 3~6 A cycloalkyl or spirocyclic 4-6 membered heterocycline ring contains one or more halogens or C 1~4 It is optionally substituted with alkyl groups; R 25c C 1~4Alkyl, 5-6 membered heteroaryl, or C6 aryl, C 1~4 Alkyl, 5-6 membered heteroaryl, or C6aryl compounds may contain one or more halogens or C 1~4 It is optionally substituted with an alkoxy; X6 is CR 26a R 26b Or C=O; R 26a and R 26b Each of these independently comprises H or one or more halogens or C 1~4 C optionally substituted with alkyl 1~4 It is alkyl; X7 is CR 27a R 27b or NR 27c and; R 27a and R 27b Each of these is independently a C that is optionally substituted with H or one or more halogens or alkoxys. 1~4 Is it alkyl; or R 27a and R 27b They came together, C 3~6 Forming a cycloalkyl ring or a 4-6 membered heterocyclyl ring, C 3~6 The cycloalkyl ring or 4-6 membered heterocyclyl ring contains one or more halogens and one or more carbon atoms. 1~4 Alkyl, spirocyclic C 3~6 It is optionally substituted with a cycloalkyl or spirocyclic 4-6 membered heterocyclyl ring, C 1~4 Alkyl, spirocyclic C 3~6 A cycloalkyl or spirocyclic 4-6 membered heterocyclyl ring contains one or more halogens or C 1~4 It is optionally substituted with alkyl groups; R 27c H, C 1~4 Alkyl, C 3~6 The C6 aryl is a cycloalkyl, a 4-7 member heterocycloalkyl, or a 5-11 member spirocyclic heterocycloalkyl, a 5-6 member heteroaryl, or a C6 aryl. 1~4 Alkyl, C 3~6Cycloalkyl, 4-6 membered heterocycloalkyl, 5-11 membered spirocyclic heterocycloalkyl, 5-6 membered heteroaryl, or C6 aryl is a C6 aryl molecule that is optionally substituted with one or more halogens. 1~4 It is optionally substituted with alkyl groups; However, only one of X5 and X7 contains an N heteroatom.

[0053] In some embodiments, R 20 H, halogen, C 1~4 Alkyl, or C 1~4 It is an alkoxy, C 1~4 Alkyl and C 1~4 The alkoxy is optionally substituted with one or more halogens; X5 is CR 25a R 25b And R 25a and R 25b Each is independently methyl; R 25a and R 25b They combine to form a cyclopropyl group; X6 is C=O; R 26a and R 26b Each of these independently comprises H or one or more halogens or C 1~4 C optionally substituted with alkyl 1~4 It is alkyl; X7 is NR 27c And; R 27c C 1~4 Alkyl, C 3~6 The C6 aryl is a cycloalkyl, a 4-7 member heterocycloalkyl, or a 5-11 member spirocyclic heterocycloalkyl, a 5-6 member heteroaryl, or a C6 aryl. 1~4 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-11 membered spirocyclic heterocycloalkyl, 5-6 membered heteroaryl, or C6 aryl is a C6 aryl molecule that is optionally substituted with one or more halogens. 1~4 It is optionally substituted with alkyl. In some embodiments, R 27c C 1~4 It is alkyl. In some embodiments, R 27cR is a 5-membered heteroaryl. In some embodiments, R 27c C is optionally substituted with one or more halogens. 3~6 C is optionally substituted with a cycloalkyl group or one or more halogens. 1~4 It is alkyl. In some embodiments, R 27c C 1~4 Alkyl, 4-7 member heterocycloalkyl, or 5-11 member spirocyclic heterocycloalkyl, C 1~4 Alkyl, 4-7 membered heterocycloalkyl, and 5-11 membered spirocyclic heterocycloalkyl groups are C12C 1~4 It is optionally substituted with alkyl groups.

[0054] In some embodiments,

[0055] [ka] but,

[0056] [ka] The compound is of formula (I), for example, a compound of formula (IA), or a pharmaceutically acceptable salt thereof. In the formula, R 20 The group is H, fluoro, methyl, ethyl, methoxy, -CH2-O-CH3, or -CF3.

[0057] In some embodiments, R 27c R is a tetrahydropyran optionally substituted with one or more methyl or fluoro groups. In some embodiments, R 27c teeth,

[0058] [ka] And in the formula, R 32a , R 32b , R 33aand R 33 b is independently H, methyl, or fluoro; or R 32a and R 32b Or R 33a and R 33b One of them combines to form a spirocyclic C 3~6 It forms a cycloalkyl or spirocyclic 3-6 membered heterocycle. In some embodiments, R 27c teeth,

[0059] [ka] That is the case.

[0060] In some embodiments,

[0061] [ka] but,

[0062] [ka] The compound of formula (I), for example, the compound of formula (IA), or a pharmaceutically acceptable salt thereof, wherein, R 30a , R 30b , R 31a , and R 31b Each of these is independently H, fluoro, or methyl; R 20 is H, fluoro, methyl, ethyl, methoxy, -CH2-O-CH3, or -CF3; R 27c is methyl. In some embodiments, the compound is R 27c C 1~4 It is an alkyl compound of formula (I).

[0063] In some embodiments,

[0064] [ka] but,

[0065] [ka] The compound is of formula (I), for example, of formula (IA), or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments,

[0067] [ka] but,

[0068] [ka] The compound is of formula (I), for example, a compound of formula (IA), or a pharmaceutically acceptable salt thereof. In the formula, R 20 H, halogen, C 1~4 C is optionally substituted with an alkoxy. 1~4 C is optionally substituted with an alkoxy, a 4-6 membered heterocycline, or one or more halogens. 1~4 It is alkyl. In some embodiments, R 25c C 1~4 It is alkyl; R 27c is one or more halogens or C 1~4 C is optionally substituted with an alkoxy. 1~4 Alkyl, C 3~6 It is a cycloalkyl or 4-6 member heterocycloalkyl, C 3~6 Cycloalkyl or 4-6 member heterocycloalkyl groups are C123 1~4 It is optionally substituted with alkyl. In some embodiments, R 27c C 1~4 It is alkyl; R 25c is one or more halogens or C 1~4 C is optionally substituted with an alkoxy. 1~4 Alkyl, C 3~6 It is a cycloalkyl or 4-6 member heterocycloalkyl, C3~6 Cycloalkyl or 4-6 member heterocycloalkyl groups are C123 1~4 It is optionally substituted with alkyl. In some embodiments, R 20 is either H or methyl.

[0069] In some embodiments,

[0070] [ka] but,

[0071] [ka] is a compound of formula (I), for example, a compound of formula (IA), or a pharmaceutically acceptable salt thereof; in the formula, R 20 H, halogen, C 1~4 C is optionally substituted with an alkoxy. 1~4 C is optionally substituted with an alkoxy, a 4-6 membered heterocycline, or one or more halogens. 1~4 It is alkyl; R 25c C 1~4 It is alkyl; R 27c These are 4-6 member heterocyclyl or C 3~6 It is a cycloalkyl group, and is a 4-6 membered heterocycline or C 3~6 Cycloalkyl is C 1~4 It is optionally substituted with alkyl groups.

[0072] In some embodiments, the compound of formula (I) is

[0073] [ka]

[0074] [ka] Alternatively, it is a compound selected from the group consisting of pharmaceutically acceptable salts thereof. [Brief explanation of the drawing]

[0075] [Figure 1-1] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-2] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-3] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-4] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-5] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-6] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-7] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-8] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-9] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-10] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-11] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-12] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-13] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-14] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-15] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-16]Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-17] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-18] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-19] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-20] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-21] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-22] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-23] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-24] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-25] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-26] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-27] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-28] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-29] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-30] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-31] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-32] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-33] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-34] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-35] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-36] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-37] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-38] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-39] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-40] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-41] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-42] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-43] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-44] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-45] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-46] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-47] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-48] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-49] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-50] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-51]Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-52] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-53] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-54] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-55] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-56] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-57] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-58] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-59] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-60] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-61] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-62] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-63] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-64] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-65] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-66] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-67] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-68] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-69] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-70] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-71] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-72] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-73] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-74] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-75] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-76] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-77] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-78] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-79] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Figure 1-80] Figures 1-1 to 1-80 are tables of compounds disclosed herein. [Modes for carrying out the invention]

[0076] The compound of formula (I) is an α5β1-targeting small molecule integrin therapeutic that can be administered to treat patients with diseases and conditions that respond to α5β1 integrin inhibition.

[0077] The present invention provides methods and compositions for treating diseases associated with increased expression or activity of integrin α5β1, comprising administering an integrin α5β1 inhibitor. In some embodiments, the diseases are characterized by World Health Organization (WHO) groups. In some embodiments, the diseases are pulmonary hypertension, WHO Group 1 pulmonary hypertension or pulmonary arterial hypertension (PAH), WHO Group 2 pulmonary hypertension, WHO Group 3 pulmonary hypertension, WHO Group 4 pulmonary hypertension, and WHO Group 5 pulmonary hypertension. In some embodiments, the diseases are characterized by the World Health Organization (WHO) classification system. In some embodiments, the diseases are characterized by the WHO functional classification based on cardiac function. In some embodiments, the diseases are pulmonary hypertension, WHO Class I pulmonary hypertension or pulmonary arterial hypertension (PAH), WHO Class II pulmonary hypertension, WHO Class III pulmonary hypertension, and WHO Class IV pulmonary hypertension. In some embodiments, the diseases associated with increased expression or activity of integrin α5β1 are heart failure or right ventricular failure.

[0078] Inhibition of integrin α5β1 or inhibition of α5β1 fibronectin binding by blocking the activity of α5β1 is effective in the prevention and treatment of pulmonary hypertension, PAH, heart failure, and right ventricular failure. The present invention provides various compounds (e.g., small molecule compounds and antibodies) that inhibit this interaction. These compounds are generally referred to as "integrin α5β1 inhibitors" in this specification.

[0079] Exemplary compounds of the present invention This disclosure relates to novel chemical compounds and methods useful for inhibiting α5β1 integrin.

[0080] Exemplary formulas and compounds are described herein. Exemplary embodiments of structural features that may be present in any formula described herein are also provided herein. Any exemplary embodiment of a structural feature may arise in combination with any other exemplary structural features described herein. Furthermore, unless otherwise indicated herein, any description of a formula or compound includes any pharmaceutically acceptable form of the compound, including but not limited to any pharmaceutically acceptable salts, hydrates, solvates, isomers, polymorphs, prodrugs, and isotopically labeled derivatives of any disclosed formula and compound.

[0081] Compound of formula (I) In some embodiments, the integrin α5β1 inhibitor is a small molecule compound that binds to integrin α5β1. In some embodiments, the integrin α5β1 inhibitor is a small molecule compound that specifically binds to integrin α5. In some embodiments, the integrin α5β1 inhibitor is a small molecule compound that specifically binds to integrin β1. In some embodiments, the integrin α5β1 inhibitor is a small molecule compound that specifically binds to integrin α5β1. In some embodiments, the integrin α5β1 inhibitor is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0082] In one embodiment, the present invention is characterized by a compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0083] [ka] During the ceremony,

[0084] [ka] This is a 6-12 member aryl ring structure (e.g., phenyl) or a 3-19 member heterocyclyl ring structure (e.g., a 3-15 member heterocyclyl ring structure such as a 6-member heteroaryl).

[0085] [ka] is halogen, C 1~6 Alkyl, C 1~6 It is optionally substituted with alkyloxy, 3-8 membered heterocyclyl ring structure, aryl, or 5-6 membered heteroaryl, C 1~6 Alkyl, C 1~6 Alkyloxy, 3-8 membered heterocyclyl ring structure, aryl, or 5-6 membered heteroaryl may contain one or more halogens, C 1~4 C is optionally substituted with alkyloxy or one or more halogens. 1~6 It is optionally substituted with alkyl groups; a is 1, 2, 3, 4, 5, 6, 7, or 8; R a C 1~6 It is alkyl.

[0086] In some embodiments, the present invention is characterized by a compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0087] [ka] During the ceremony,

[0088] [ka] It has a 6-12 membered aryl ring structure (e.g., phenyl),

[0089] [ka] is halogen, C 1~6 Alkyl, C 1~6 It is optionally substituted with alkyloxy, 3-8 membered heterocyclyl ring structure, aryl, or 5-6 membered heteroaryl, C 1~6 Alkyl, C 1~6 Alkyloxy, 3-8 membered heterocyclyl ring structure, aryl, or 5-6 membered heteroaryl may contain one or more halogens, C 1~4C is optionally substituted with alkyloxy or one or more halogens. 1~6 It is optionally substituted with alkyl groups; a is 1, 2, 3, 4, 5, 6, 7, or 8; R a C 1~6 It is alkyl.

[0090] In some embodiments, the present invention is characterized by a compound of formula (I), or a pharmaceutically acceptable salt thereof:

[0091] [ka] During the ceremony,

[0092] [ka] This is a 3-19 member heterocyclyl ring structure (for example, a 3-15 member heterocyclyl ring structure such as a 6 member heteroaryl),

[0093] [ka] is halogen, C 1~6 Alkyl, C 1~6 It is optionally substituted with alkyloxy, 3-8 membered heterocyclyl ring structure, aryl, or 5-6 membered heteroaryl, C 1~6 Alkyl, C 1~6 Alkyloxy, 3-8 membered heterocyclyl ring structure, aryl, or 5-6 membered heteroaryl may contain one or more halogens, C 1~4 C is optionally substituted with alkyloxy or one or more halogens. 1~6 It is optionally substituted with alkyl groups; a is 1, 2, 3, 4, 5, 6, 7, or 8; R a C 1~6 It is alkyl.

[0094] In some embodiments,

[0095] [ka] It has a 3- to 15-membered heterocyclic structure.

[0096] In some embodiments, the compound is the compound of formula (IA) or a pharmaceutically acceptable salt thereof.

[0097] [ka]

[0098] In some embodiments, the compound is a compound of formula (I), where,

[0099] [ka] It is phenyl or a 6-membered heteroaryl compound.

[0100] In some embodiments, the compound is a compound of formula (I),

[0101] [ka] teeth,

[0102] [ka] And, During the ceremony, R1 is C 1~4 It is an alkoxy, and R2 is a C that is optionally substituted with one or more halogens. 1~4 Is it alkyl; or

[0103] [ka] When R1 and R2 combine to form a condensed 5-8 member heterocycloalkyl ring, a condensed 5-6 member heteroaryl ring, or a condensed 7-15 member spirocyclic heterocycloalkyl ring system, it is a 9-19 member heterocyclyl, and the condensed ring is a halogen, C 1~4 Alkyl, C 3~6 It is optionally substituted with a cycloalkyl or a 4- to 8-membered heterocycloalkyl ring, C 1~4 Alkyl, C 3~6 A cycloalkyl or 4- to 8-membered heterocycloalkyl ring is optionally substituted with one or more halogens. 1~4 It is optionally substituted with alkyl; R3 is C, optionally substituted with one or more halogens. 1~4 It is alkyl.

[0104] In some embodiments, the compound is a compound of formula (I), where R1 is methoxy, R2 is fluoro; and R3 is a C compound optionally substituted with one or more fluoro compounds. 1~4 It is alkyl.

[0105] In some embodiments, the compound is a compound of formula (I), where,

[0106] [ka] teeth,

[0107] [ka] R4 and R 14 Each of these is independently substituted with H, a halogen, or one or more halogens, and C is optionally substituted with them. 1~4 It is alkyl; X1 is CR 5a R 5b or NR 5c And; R 5a C is optionally substituted with H or one or more halogens. 1~4 It is alkyl, R 5b C 1~4 Alkyl or C3~6 It is a cycloalkyl, C 1~4 Alkyl or C 3~6 The cycloalkyl group is optionally substituted with one or more halogens; or R 5a and R 5b Together they form a spirocyclic 3-8 membered heterocycloalkyl or spirocyclic C 3~6 Forms a cycloalkyl group, and a 3- to 8-membered heterocycloalkyl group or C 3~6 Cycloalkyls are C molecules optionally substituted with one or more halogens. 1~4 C is optionally substituted with alkyl, 4-6 membered spirocyclic heterocycloalkyl, or one or more halogens. 1~4 C optionally substituted with alkyl 3~6 It is optionally substituted with a spirocyclic cycloalkyl group; R 5c C 1~4 Alkyl or C 3~6 It is a cycloalkyl, C 1~4 Alkyl or C 3~6 The cycloalkyl group is optionally substituted with one or more halogens; X2 is CR 6a R 6b -CH2CR 6a R 6b , C=O, O or NR 6c And; R 6a and R 6b These are H and C, which are independent of each other. 1~4 Alkyl, 5-6 member heteroaryl, 6 member aryl, C 3~7 It is a cycloalkyl or a 4- to 7-membered heterocycloalkyl, C 1~4 Alkyl, 5-6 member heteroaryl, 6 member aryl, C 3~8 Each cycloalkyl or 4- to 7-membered heterocycloalkyl contains one or more halogens or C 1~4 It is optionally substituted with alkyl; R 6c C is optionally substituted with one or more halogens. 1~4 It is alkyl; X3 is directly bonded, CR 7a R 7b , O or NR 7c And; R 7a and R 7bEach of these is independently and optionally substituted with H or one or more halogens. 1~4 It is alkyl; R 7c C is optionally substituted with one or more halogens. 1~4 It is alkyl; X4 is CR 8a R 8b or NR 8c And; R 8a H is R 8b C is a halogen or a C atom optionally substituted with one or more halogens. 1~4 It is alkyl; R 8a and R 8b Together they form a spirocyclic 3-8 membered heterocycloalkyl or C 3~6 Forms a cycloalkyl group, and a 3- to 8-membered heterocycloalkyl group or C 3~6 Cycloalkyls are C molecules optionally substituted with one or more halogens. 1~4 C is optionally substituted with alkyl, 4- to 8-membered spirocyclic heterocycloalkyl, or one or more halogens. 1~4 C optionally substituted with alkyl 3~7 It is optionally substituted with a spirocyclic cycloalkyl group; R 8c H, C 1~4 Alkyl, 4-8 member heterocycloalkyl, or C 3~6 It is a cycloalkyl, C 1~4 Alkyl, 4-8 member heterocycloalkyl, or C 3~6 The cycloalkyl group is optionally substituted with one or more halogens; however, two of both X2 and X3 do not contain O or N heteroatoms, and two of X3 and X4 do not contain O or N heteroatoms.

[0108] In some embodiments, the compound is a compound of formula (I), where R 14 is H; X1 is CR 5a R 5b And; R 5a H is R 5b It is methyl or cyclopropyl.

[0109] In some embodiments, the compound is a compound of formula (I), where R4 is H, fluoro, or methyl; X1 is CR 5a R 5b And; R 5a H is R 5b X2 is methyl; X2 is O, and X3 is CR. 7a R 7b And R 7a and R 7b Each of these is independently and optionally substituted with H or one or more halogens. 1~4 It is alkyl; or X3 is O and X2 is CR 6a R 7b And R 6a and R 6b Each is independently H; X4 is CR 8a R 8b And R 8a and R 8b Each of these is independently and optionally substituted with H or one or more halogens. 1~4 Alkyl or R 8a and R 8b Together they form a 4-7 membered heterocycloalkyl ring or C 3~7 Forms a cycloalkyl ring, and is a 4-7 membered heterocycloalkyl or C 3~7 Cycloalkyls are C molecules optionally substituted with halogens, or one or more halogens. 1~4 C is optionally substituted with alkyl, 4- to 7-membered spirocyclic heterocycloalkyl, or one or more halogens. 1~4 C optionally substituted with alkyl 3~7 It is optionally substituted with a spirocyclic cycloalkyl group.

[0110] In some embodiments, the compound is a compound of formula (I), where,

[0111] [ka] teeth,

[0112] [ka] And R 10a and R 10b Each of these is independently substituted with H, a halogen, or one or more halogens, and C 1~4 Is it alkyl; or R 10a and R 10b They come together, forming a spirocyclic C 3~6 Forms a cycloalkyl or spirocyclic 6-membered heterocycloalkyl; R 11a and R 11b Each of these is independently substituted with H, a halogen, or one or more halogens, and C is optionally substituted with them. 1~4 It is alkyl; R 12a and R 12b Each of these is independently substituted with H, a halogen, or one or more halogens, and C is optionally substituted with them. 1~4 It is alkyl; R 13a is methyl, ethyl, or cyclopropyl; R 13b H is; R 14 C is optionally substituted with H, a halogen, or one or more halogens. 1~4 It is alkyl.

[0113] In some embodiments, the compound is a compound of formula (I), where R 10a and R 10b Each is independently either H or methyl; R 11a and R 11b Each of these is independently H, methyl, or ethyl; R 12a and R 12b Each is independently either H or methyl; R 13a is methyl, ethyl, or cyclopropyl; R 13b H is; R 14 is H, fluoro, or methyl.

[0114] In some embodiments, the compound is a compound of formula (I), where R4 is H or fluoro; R 13a is methyl, ethyl, or cyclopropyl; R 14 H is H.

[0115] In some embodiments, the compound is a compound of formula (I), where X2 is NR 6c And R 6c C 1~4 It is alkyl.

[0116] In some embodiments, the compound is a compound of formula (I), where,

[0117] [ka] teeth,

[0118] [ka] And R 13a R4 is either H or methyl, and R4 is either H, F, or methyl.

[0119] In some embodiments, the compound is a compound of formula (I),

[0120] [ka] teeth,

[0121] [ka] In this formula, R4 is H, fluoro, or methyl.

[0122] In some embodiments, the compound is a compound of formula (I), where R 10a , R 10b , and R 11a Each of these is either H or methyl.

[0123] In some embodiments, the compound is a compound of formula (I), and R 11b It is H, methyl, or ethyl.

[0124] In some embodiments, the compound is a compound of formula (I), where,

[0125] [ka] teeth,

[0126] [ka] In the formula, R4 is H, a halogen, or a methyl atom optionally substituted with one or more halogens; R 9a and R 9b Each of these is independently a methyl molecule substituted with H, a halogen, or one or more halogens in an optional manner.

[0127] In some embodiments, the compound is a compound of formula (I), where R4 is H, fluoro, or methyl; R 9a and R 9b Each of these is independently a methyl atom optionally substituted with H, fluoro, chloro, or one or more fluoro atoms.

[0128] In some embodiments, the compound is a compound of formula (I), where,

[0129] [ka] teeth,

[0130] [ka] And R 20 H, halogen, C 1~4 Alkyl, or C 1~4 It is an alkoxy, C 1~4 Alkyl and C 1~4 Each alkoxy is optionally substituted with one or more halogens; X5 is CR 25a R 25b or NR 25c And; R 25a and R 25bEach of these is independently a C that is optionally substituted with H or one or more halogens or alkoxys. 1~4 Is it alkyl; or R 25a and R 25b They come together, and each one is halogen, C 1~4 Alkyl, spirocyclic C 3~6 C is optionally substituted with a cycloalkyl or spirocyclic 4-6 membered heterocyclyl ring. 3~6 Forming a cycloalkyl ring or a 4-6 membered heterocyclyl ring, C 1~4 Alkyl, spirocyclic C 3~6 A cycloalkyl or spirocyclic 4-6 membered heterocycline ring contains one or more halogens or C 1~4 Optionally substituted with alkyl; R 25c C 1~4 Alkyl, 5-6 membered heteroaryl, or C6 aryl, C 1~4 Alkyl, 5-6 membered heteroaryl, or C6aryl compounds may contain one or more halogens or C 1~4 It is optionally substituted with an alkoxy; X6 is CR 26a R 26b Or C=O; R 26a and R 26b Each of these independently comprises H or one or more halogens or C 1~4 C optionally substituted with alkyl 1~4 It is alkyl; X7 is CR 27a R 27b or NR 27c And; R 27a and R 27b Each of these is independently a C that is optionally substituted with H or one or more halogens or alkoxys. 1~4 It is alkyl; R 27a and R 27b They came together, C 3~6 Forming a cycloalkyl ring or a 4-6 membered heterocyclyl ring, C 3~6 The cycloalkyl ring or 4-6 membered heterocyclyl ring contains one or more halogens and one or more carbon atoms. 1~4 Alkyl, spirocyclic C 3~6It is optionally substituted with a cycloalkyl or a spirocyclic 4-6 membered heterocyclyl ring, C 1~4 Alkyl, spirocyclic C 3~6 A cycloalkyl or spirocyclic 4-6 membered heterocyclyl ring contains one or more halogens or C 1~4 It is optionally substituted with alkyl; R 27c H, C 1~4 Alkyl, C 3~6 The C6 aryl is a cycloalkyl, a 4-7 member heterocycloalkyl, or a 5-11 member spirocyclic heterocycloalkyl, a 5-6 member heteroaryl, or a C6 aryl. 1~4 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-11 membered spirocyclic heterocycloalkyl, 5-6 membered heteroaryl, or C6 aryl is a C6 aryl molecule that is optionally substituted with one or more halogens. 1~4 The atoms are optionally substituted with alkyl groups; however, only one of X5 and X7 contains an N heteroatom.

[0131] In some embodiments, the compound is a compound of formula (I), where R 20 H, halogen, C 1~4 Alkyl, or C 1~4 It is an alkoxy, C 1~4 Alkyl and C 1~4 The alkoxy is optionally substituted with one or more halogens; X5 is CR 25a R 25b And R 25a and R 25b Each is independently methyl; R 25a and R 25b They combine to form a cyclopropyl group; X6 is C=O; R 26a and R 26b Each of these independently comprises H or one or more halogens or C 1~4 C optionally substituted with alkyl 1~4 It is alkyl; X7 is NR 27c And; R 27c C 1~4 Alkyl, C 3~6The C6 aryl is a cycloalkyl, 4-7 member heterocycloalkyl, 5-11 member spirocyclic heterocycloalkyl, 5-6 member heteroaryl, or C6 aryl. 1~4 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, 5-11 membered spirocyclic heterocycloalkyl, 5-6 membered heteroaryl, or C6 aryl is a C6 aryl molecule that is optionally substituted with one or more halogens. 1~4 It is optionally substituted with alkyl groups.

[0132] In some embodiments, the compound is a compound of formula (I), and R 27c C 1~4 It is alkyl. In some embodiments, the compound is a compound of formula (I), where R 27c is a 5-membered heteroaryl compound. In some embodiments, the compound is a compound of formula (I), where R 27c C is optionally substituted with one or more halogens. 3~6 C is optionally substituted with a cycloalkyl group or one or more halogens. 1~4 It is alkyl. In some embodiments, the compound is a compound of formula (I), where R 27c C 1~4 Alkyl, 4-7 member heterocycloalkyl, or 5-11 member spirocyclic heterocycloalkyl, C 1~4 Alkyl, 4-7 membered heterocycloalkyl, and 5-11 membered spirocyclic heterocycloalkyl are C12C 1~4 It is optionally substituted with alkyl groups.

[0133] In some embodiments, the compound is a compound of formula (I), where,

[0134] [ka] teeth,

[0135] [ka] And in the formula, R 20 is H, fluoro, methyl, ethyl, methoxy, -CH2-O-CH3, or -CF3. In some embodiments, the compound is a compound of formula (I), where R 27c is a tetrahydropyran optionally substituted with one or more methyl or fluoro groups. In some embodiments, the compound is a compound of formula (I), where R 27c teeth,

[0136] [ka] And R 32a , R 32b , R 33a and R 33 b is independently H, methyl, or fluoro; or R 32a and R 32b Or R 33a and R 33b One of them combines to form a spirocyclic C 3~6 It forms a cycloalkyl or spirocyclic 3-6 membered heterocycle.

[0137] In some embodiments, the compound is a compound of formula (I), and R 27c teeth,

[0138] [ka] In some embodiments, the compound is a compound of formula (I), where,

[0139] [ka] teeth,

[0140] [ka] And in the formula, R 30a , R 30b , R 31a, and R 31b Each of these is independently H, fluoro, or methyl; R 20 is H, fluoro, methyl, ethyl, methoxy, -CH2-O-CH3, or -CF3; R 27c R is methyl. In some embodiments, the compound is the compound of formula (I), where R is methyl. 27c C 1~4 It is alkyl.

[0141] In some embodiments, the compound is a compound of formula (I), where,

[0142] [ka] teeth,

[0143] [ka] In some embodiments, the compound is a compound of formula (I), where,

[0144] [ka] teeth,

[0145] [ka] And R 20 H, halogen, C 1~4 C is optionally substituted with an alkoxy. 1~4 C is optionally substituted with an alkoxy, a 4-6 membered heterocycline, or one or more halogens. 1~4 It is alkyl.

[0146] In some embodiments, the compound is a compound of formula (I), where R 25c C 1~4 It is alkyl; R 27c is one or more halogens or C 1~4 C is optionally substituted with an alkoxy.1~4 Alkyl, C 3~6 It is a cycloalkyl or 4-6 member heterocycloalkyl, C 3~6 Cycloalkyl or 4-6 member heterocycloalkyl groups are C123 1~4 It is optionally substituted with alkyl groups.

[0147] In some embodiments, the compound is a compound of formula (I), where R 27c C 1~4 It is alkyl; R 25c is one or more halogens or C 1~4 C is optionally substituted with an alkoxy. 1~4 Alkyl, C 3~6 It is a cycloalkyl or a 4-6 member heterocycloalkyl, C 3~6 Cycloalkyl or 4-6 member heterocycloalkyl groups are C123 1~4 It is optionally substituted with alkyl groups.

[0148] In some embodiments, the compound is a compound of formula (I), where R 20 is H or methyl. In some embodiments, the compound is a compound of formula (I), where,

[0149] [ka] teeth,

[0150] [ka] And; in the formula, R 20 H, halogen, C 1~4 C is optionally substituted with an alkoxy. 1~4 C is optionally substituted with an alkoxy, a 4-6 membered heterocycline, or one or more halogens. 1~4 It is alkyl; R 25c C 1~4 It is alkyl; R 27c These are 4-6 member heterocyclyl or C3~6 It is a cycloalkyl group, and is a 4-6 membered heterocycline or C 3~6 Cycloalkyl is C 1~4 It is optionally substituted with alkyl groups.

[0151] In some embodiments, the compound is chemical formula

[0152] [ka] The compound is a compound of or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of the chemical formula

[0153] [ka] The compound is a compound of or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of the chemical formula

[0154] [ka] The compound is a compound of or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of the chemical formula

[0155] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, the compound is chemical formula

[0157] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, the compound is chemical formula

[0159] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, the compound is chemical formula

[0161] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments, the compound is chemical formula

[0163] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, the compound is chemical formula

[0165] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, the compound is chemical formula

[0167] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments, the compound is chemical formula

[0169] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, the compound is chemical formula

[0171] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0172] In some embodiments, the compound is chemical formula

[0173] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0174] In some embodiments, the compound is chemical formula

[0175] [ka] It is a compound of or a pharmaceutically acceptable salt thereof.

[0176] In some embodiments, the compound is a compound selected from the group consisting of the compounds in Figure 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound selected from the group consisting of the compounds in Table 3, or a pharmaceutically acceptable salt thereof.

[0177] definition For convenience, prior to further description of the present invention, the specific terms used in this specification, the examples, and the appended claims are summarized here. These definitions should be read in light of the remainder of this disclosure and understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0178] To facilitate understanding of the present invention, certain terms and phrases are defined below and throughout this specification.

[0179] The articles “a” and “an” are used herein to refer to one or more (i.e., at least one) of the grammatical objects of the article. For example, “an element” means one or more elements.

[0180] As used herein and in the claims, the phrase “and / or” should be understood to mean “either or both” of the elements thus combined, i.e., elements that exist as a combination in some cases and separately in others. Multiple elements listed using “and / or” must be interpreted in the same way, i.e., “one or more” of the elements thus combined. Other elements other than those specifically identified by the “and / or” clause may exist optionally, whether related to those specifically identified elements or not. Thus, as a non-restrictive example, a reference to “A and / or B” when used in conjunction with open-ended language such as “comprising” may, in one embodiment, refer to A only (optionally including elements other than B), in another embodiment, refer to B only (optionally including elements other than A), in yet another embodiment, refer to both A and B (optionally including other elements), and so on.

[0181] Where used herein 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” should be interpreted as inclusive; that is, it should be interpreted as including not just one but two or more of a group of elements or a list of elements, and optionally including any additional items not listed. Only terms that are explicitly indicated in the opposite way, such as “only one of” or “exactly one of,” or, where used in the claims, “consisting of,” should be interpreted as including exactly one element of a group of elements or a list of elements. In general, where used herein, the term “or” should be interpreted as indicating only an exclusive choice (i.e., “one or the other but not both”) when followed by an exclusive term such as “either,” “one of,” “only one of,” or “exactly one of.” When used in patent claims, "consisting essentially of" shall have the ordinary meaning as it has in the field of patent law.

[0182] When used in the specification and claims herein, the phrase “at least one” relating to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, and not necessarily including at least one of each element or all elements specifically listed in the list of elements, nor excluding any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements referred to by the phrase “at least one,” whether related to or unrelated to those specifically identified elements. Therefore, as a non-restrictive 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”) could, in one embodiment, refer to at least one A that is absent (and optionally includes elements other than B) and optionally includes two or more elements; in another embodiment, refer to at least one B that is absent (and optionally includes elements other than A) and optionally includes two or more elements; and in yet another embodiment, refer to at least one optionally two or more A's and at least one optionally two or more B's (and optionally include other elements), and so on.

[0183] Furthermore, unless explicitly stated otherwise, in any method claimed herein that includes two or more steps or actions, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are enumerated.

[0184] In the claims and in the above specification, all transitional clauses such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and “composed of” should be understood to be non-restrictive, meaning they include but are not restrictive. Only the transitional clauses “consisting of” and “consisting essentially of” are closed or semi-closed transitional clauses, respectively, as described in Section 2111.03 of the U.S. Patent and Trademark Office Manual of Patent Examination Procedures.

[0185] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. In addition, the polymers of the present invention may also be optically active. The present invention envisions all such compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof, and other mixtures thereof, and they are within the scope of the invention. Additional chiral carbon atoms may be present in substituents, such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention.

[0186] For example, if a specific enantiomer of the compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with chiral auxiliaries, and the resulting diastereomer mixture is separated and the auxiliary groups are cleaved to yield the pure enantiomer of the choice. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, a diastereomer salt can be formed using a suitable optically active acid or base, and then the formed diastereomer can be separated by fractional crystallization or by chromatographic means well known in the art to recover the pure enantiomer.

[0187] The structures shown herein also mean that they may include different compounds based solely on the presence of one or more isotopically enriched atoms. For example, compounds produced by replacing hydrogen with deuterium or tritium, or by replacing carbon with 13C or 14C-rich carbon, are within the scope of the present invention.

[0188] As used herein, the terms “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” mean a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in transporting or carrying the chemical substance in question from one organ or part of the body to another. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation, is not harmful to the patient, and is substantially non-pyrogenic. Some examples of substances that 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) celluloses such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate, and their derivatives; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter; (9) peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and oats. (10) Oils such as soybean oil; glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) 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 solution; and (21) other non-toxic, suitable substances used in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce a significant temperature increase when administered to a patient.

[0189] In this regard, the term “pharmaceutically acceptable salt” refers to relatively non-toxic inorganic and organic acid addition salts of a compound. These salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J.Pharm.Sci.66:1-19.)

[0190] In other cases, compounds useful in the methods of the present invention may contain one or more acidic functional groups, and thus can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these examples, the term “pharmaceutically acceptable salt” refers to relatively non-toxic inorganic and organic base addition salts of the compound. These salts can also be prepared in situ during the final isolation and purification of the compound, or separately from the purified compound in its free acid form, by reacting it with a suitable base such as a pharmaceutically acceptable metal cation hydroxide, carbonate, or bicarbonate, ammonia, or a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Typical alkali salts or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Typical organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine (see, for example, Berge et al. above).

[0191] With regard to therapeutic use, the “therapeutic effective dose” (or “effective dose”) of a compound means the amount of the compound in a preparation that, when administered (to mammals, preferably humans) as part of a desired drug regimen, alleviates symptoms, improves a condition, or delays the onset of a disease condition, for example, in a reasonable benefit / risk ratio applicable to any medical treatment, according to clinically acceptable criteria for the disorder or condition being treated or for cosmetic purposes.

[0192] The terms “preventive or therapeutic” treatments are recognized in the art and involve the administration of one or more subject compositions to a host. If administered before the onset of clinical symptoms of an undesirable condition (e.g., a disease or other undesirable condition in a host animal), the treatment is preventive (i.e., protects the host from the onset of the undesirable condition), whereas if administered after the onset of symptoms of an undesirable condition, the treatment is therapeutic (i.e., intended to reduce, improve or stabilize an existing undesirable condition or its side effects).

[0193] The term "patient" refers to a mammal requiring specific treatment. In certain embodiments, the patient may be a primate, dog, cat, or horse. In certain embodiments, the patient may be a human.

[0194] Whenever a term (e.g., alkyl or aryl) or the root of its prefix (e.g., alk- or ar-) appears in the name of a substituted compound, that name should be interpreted as including those limitations provided herein. For example, adding the suffix "-ene" to a group indicates that the group is a divalent part; for example, arylene is the divalent part of aryl, heteroarylene is the divalent part of heteroaryl, and heterocycloalkylene is the divalent part of heterocycloalkyl. Similarly, adding the suffix "-oxy" to a group indicates that the group is bonded to the parent molecule structure via an oxygen atom (-O-), for example, "alkyloxy," "alkoxy," or "cycloalkoxy" as used herein.

[0195] Aliphatic chains include the classifications of alkyl, alkenyl, and alkynyl as defined below. Straight aliphatic chains are limited to the unbranched carbon chain portion. As used herein, the term “aliphatic group” refers to a straight, branched, or cyclic aliphatic hydrocarbon group, and includes saturated and unsaturated aliphatic groups such as alkyl, alkenyl, or alkynyl groups.

[0196] "Alkyl" refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain portion having a specified number of carbon atoms, or 1 to 30 carbon atoms if not specified. For example, alkyls with 1 to 8 carbon atoms refer to portions such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as positional isomers of these portions. Alkyls with 10 to 30 carbon atoms include decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, and tetracosyl. In certain embodiments, linear or branched alkyls have 30 or fewer carbon atoms in their backbone (for example, C1 to C1 for a linear chain). 30 Regarding the branching chain, C3~C 30 ), more preferably having 20 or fewer carbon atoms. The alkyl group may be substituted or unsubstituted. As used herein, both "Me" and -CH3 refer to methyl.

[0197] As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbon atoms, e.g., 2 to 12 carbon atoms, with two bonding sites 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)-, and isopropylene-(CH2CH(CH3))-. The alkylene group may be a cyclic or acyclic, branched or unbranched carbon chain portion and may be optionally substituted with one or more substituents.

[0198] "Cycloalkyl" refers to a monocyclic, bicyclic, bridged, spirocyclic, or polycyclic saturated carbocyclic ring, each having 3 to 12 carbon atoms. Similarly, preferred cycloalkyls have 3 to 10 carbon atoms in their ring structure, and more preferably 3 to 6 carbon atoms in their ring structure. Cycloalkyls may be substituted or unsubstituted. Exemplary cycloalkyls include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cycloheptyl (C7), and cyclooctyl (C8).

[0199] Unless otherwise specified, “lower alkyl” as used herein means alkyl groups as defined above, but having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, in their skeletal structure, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout this application, preferred alkyl groups are lower alkyl groups. In certain embodiments, substituents designated as alkyl herein are lower alkyl groups.

[0200] As used herein, the term “aryl” includes 3- to 12-membered substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, the aryl group includes a 5- to 12-membered ring, more preferably a 6- to 10-membered ring. The term “aryl” also includes polycyclic ring systems having two or more rings in which two or more carbons are common to two adjacent rings, and at least one of the rings is aromatic, for example, the other ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Examples of carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, and aniline. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, the ring structure containing 1 to 4 heteroatoms. Examples of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. The aryl and heteroaryl groups may be monocyclic, bicyclic, or polycyclic.

[0201] As used herein, the terms “halo,” “halide,” or “halogen” mean halogen, and include, for example, fluoro, chloro, bromo, iodine, and both radioactive and non-radioactive forms. In preferred embodiments, the halo is selected from the group consisting of fluoro, chloro, and bromo.

[0202] The term "heterocyclyl" or "heterocyclic group" refers to a 3- to 12-membered ring structure, more preferably a 5- to 12-membered ring, and more preferably a 5- to 10-membered ring, the ring structure containing 1 to 4 heteroatoms. The heterocycle may be monocyclic, bicyclic, spirocyclic, or polycyclic. Examples of heterocyclyl groups include thiophene, thiantrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxatiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indidine, isoindole, indole, indazole, purine, quinoridine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, sinnoline, pteridine, carbazole, carborin, phenanthidine, acridine, pyrimidine, phenanthroline, phenazine, phenalzazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolan, oxazole, piperidine, piperazine, morpholine, lactone, lactam (e.g., azetidinone and pyrrolidinone), sultam, and sultone. The heterocycle may be substituted at one or more positions with substituents such as halogens, alkyls, aralkyls, alkenyls, alkynyls, cycloalkyls, hydroxyls, aminos, nitros, sulfhydryls, iminos, amides, phosphates, phosphonates, phosphinates, carbonyls, carboxyls, silyls, sulfamoyls, sulfinyls, ethers, alkylthios, sulfonyls, ketones, aldehydes, esters, heterocyclyls, aromatic or heteroaromatic moieties, -CF3, -CN, and others as listed above.

[0203] As used herein, the term "heterocycloalkyl" refers to a non-aromatic heterocyclyl in which at least one atom is a heteroatom, such as nitrogen, oxygen, sulfur, or phosphorus, and the remaining atoms are carbon. Examples of heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, and 1,2,3,6-tetrahydro These include pyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, and quinolidinyl. The heterocycloalkyl groups may be substituted or unsubstituted, for example, as enumerated for the heterocyclyls described herein.

[0204] The term "carbonyl" is recognized in the art, and the formula is:

[0205] [ka] It includes parts that can be represented by, In the formula, X' represents a bond, or oxygen or sulfur, and R 15 is hydrogen, alkyl, alkenyl, -(CH2) m -R 10 Alternatively, it represents a pharmaceutically acceptable salt, where R16 is hydrogen, alkyl, alkenyl or -(CH2) m -R 10 Represents m and R 10 This is as defined above. X' is oxygen, and R 15 or R 16If X' is not hydrogen, the formula represents an "ester". X' is oxygen, and R 15 If it is as defined above, that part is referred to herein as a carboxyl group, and in particular R 15 If X' is hydrogen, the formula represents a "carboxylic acid". 16 If X' is hydrogen, the formula represents "formate". On the other hand, if X' is a bond, R 15 If X' is not hydrogen, the above formula represents a "ketone" group. X' is a bond, and R 15 When the group is hydrogen, the above formula represents an "aldehyde" group.

[0206] As used herein, the term “substituted” is intended to include all acceptable substituents of an organic compound. In a broad view, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Exemplary substituents include, for example, those listed above herein, which are substituted with one or more substituents selected from alkyl, cycloalkyl, heterocyclylalkyl, halogen, OH, OMe, C(H)F2, C(F)H2, CF3, C(H)2CF3, SF5, CHFCH2 amine, CH2 amine, and CN. There may be one or more acceptable substituents, which may be the same or different for a given organic compound. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or substituents of any acceptable organic compound described herein that satisfy the valence of the heteroatom. The present invention is not intended to be limited in any way by the substituents of the acceptable organic compound. The terms "substitution" or "substituted by" imply that such substitutions are subject to the allowable values ​​of the substituted atom and substituent, and that the substitutions result in stable compounds that do not undergo spontaneous transformation, such as rearrangement, cyclization, or exclusion.

[0207] As used herein, the term "nitro" means -NO2, the term "halogen" means -F, -Cl, -Br, or -I, the term "hydroxyl" means -OH, and the term "cyano" means -CN.

[0208] When used herein, each expression, such as alkyl, m, n, etc., is intended to be independent of its definition elsewhere in any given structure if it appears more than once in that structure.

[0209] As used herein, the term “prodrug” encompasses compounds that are converted into therapeutically active agents under physiological conditions. One method for producing a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to exhibit a desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of a host animal. Thus, a prodrug includes a compound that is converted in vivo to produce the disclosed compound or any other pharmaceutically acceptable form of the compound. In embodiments, the prodrug may be inactive when administered to a subject but may be converted in vivo to an active compound, for example, by hydrolysis. See, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). Discussions of prodrugs are provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” ACSSymposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety. 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” also means that such a prodrug contains any covalent carrier that releases an active compound in vivo when administered to a subject.

[0210] Prodrugs of the compounds described herein may be prepared by modifying functional groups present in the active compound so that the modifications are cleaved either in a routine operation or in vivo, thereby providing the compounds described herein (i.e., the parental active compounds). Prodrugs include compounds in which a hydroxy, amino, or mercapto group is attached to any group that, when the prodrug of the active compound is administered to a subject, is cleaved 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 alcohols, or acetamide, formamide, and benzamide derivatives of amine functional groups in the active compound. Other examples of prodrugs include compounds containing -NO, -NO2, -ONO, or -ONO2 moieties.

[0211] For the purposes of this invention, chemical elements are identified according to the periodic table of elements as described on the back cover of the CAS edition of Handbook of Chemistry and Physics, 67th Ed., 1986-87.

[0212] In some embodiments, the compound is a compound selected from Figure 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound selected from Table 3, or a pharmaceutically acceptable salt thereof.

[0213] [Table 1-1]

[0214] [Table 1-2]

[0215] [Table 1-3]

[0216] Therapeutic use of compounds of formula (I) In tissues, normal fibroblasts are present in a low population of only 4-5%. However, during fibrosis, they proliferate and can account for up to 80-90% of the organ's mass. Myofibroblasts in fibrotic tissue produce large amounts of extracellular matrix proteins that scar and render the tissue dysfunctional. Inhibition of myofibroblasts can counteract these processes. Integrins promote cell proliferation, survival, hypertrophic growth, and fibrosis. As described herein, integrin inhibition can modulate these key elements that lead to the progression of pulmonary hypertension (e.g., PAH).

[0217] The present invention provides a method for treating a disease associated with increased expression or activity of integrin α5β1, comprising administering an integrin α5β1 inhibitor. In one embodiment, the present invention provides an integrin α5β1 inhibitor for use in treating a subject requiring treatment for a disease associated with increased expression or activity of integrin α5β1, comprising administering the integrin α5β1 inhibitor and a pharmaceutical excipient to the subject.

[0218] In some embodiments, the disease is heart failure or right ventricular failure. In one embodiment, the present invention provides a method for treating pulmonary hypertension (PAH) in a subject, comprising administering an integrin α5β1 inhibitor. In some embodiments, the integrin α5β1 inhibitor is administered orally, intravenously, subcutaneously, intranasally, transdermally, intraperitoneally, intramuscularly, or intrapulmonaryly. Also provided is a method for treating a subject suffering from fibrosis or fibrosis-related disorder, comprising administering a therapeutically effective dose of the integrin α5β1 inhibitor according to the present invention to the subject. As used herein, the term “fibrosis” refers to a condition characterized by the deposition of extracellular matrix components in the skin or organs including the lungs, kidneys, heart, liver, and joints, resulting in scar tissue. The term also refers to the process of scar tissue formation.

[0219] In some embodiments, fibrosis-related disorders are disorders or conditions that may result from or are associated with fibrosis. In some embodiments, fibrosis and / or fibrosis-related disorders are diseases or conditions selected from the group consisting of renal fibrosis, hepatic fibrosis, cirrhosis, pulmonary fibrosis, cutaneous fibrosis, cholangiofibrosis, peritoneal fibrosis, myocardial fibrosis, pancreatic fibrosis, myelofibrosis and / or myelofibrosis, reperfusion injury after liver or kidney transplantation, interstitial lung disease (ILD), cystic fibrosis (CF), atherosclerosis, systemic sclerosis, osteosclerosis, herniated disc and other spinal cord injuries, fibromatosis, fibromyalgia, arthropathy, and restenosis. Pulmonary fibrosis includes idiopathic pulmonary fibrosis and scleroderma pulmonary fibrosis.

[0220] The methods described herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living organism, such as an animal or a human. In this context, the methods described herein may be used therapeutically in an organism. “Ex vivo” means outside a living organism. Examples of ex vivo cell populations include biological samples, including in vitro cell cultures and bodily fluid or tissue samples obtained from organisms.

[0221] Information gathered from such use may be used for experimental purposes or to establish protocols for in vivo treatment in a clinical setting. Selected compounds may be further characterized to investigate safety or tolerable dosages in human or non-human subjects. Such properties can be investigated using methods generally known to those skilled in the art.

[0222] In some embodiments, the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, tautomers, or deuterated analogs thereof, may be used to treat subjects having, or suspected to have, disease conditions, disorders, and conditions (collectively referred to as “indications”) that respond to, or are thought to respond to, inhibition of α5β1 integrin activity. In some embodiments, the compounds described herein may be used to inhibit the activity of α5β1 integrin. In some embodiments, the disclosure provides compounds described herein that are useful as inhibitors of α5β1 integrin. In some embodiments, the disclosure provides a method for treating or preventing an inflammatory disease or condition, which includes administering a compound described herein to a patient. In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier. In some embodiments, compounds described herein are provided that are useful for treating an inflammatory disease or condition in a patient that is at least partially mediated by α5β1 integrin.

[0223] Concurrent administration may also involve administering component drugs, for example, one or more compounds described herein and one or more additional (e.g., second, third, fourth, or fifth) therapeutic agents. Such combinations of one or more compounds described herein and one or more additional therapeutic agents may be administered simultaneously or sequentially (one after the other) within a reasonable timeframe of each administration (e.g., about 1 minute to 24 hours), depending on the pharmacokinetic and / or pharmacodynamic properties of each drug or combination. Concurrent administration may also involve treatment in fixed combinations, where the drugs of the treatment regimen can be combined in fixed dosages or in combined delivery media (e.g., solid, liquid, or aerosol).

[0224] Treatment with a second, third, fourth, or fifth active agent may be performed before, concurrently with, or after treatment with the compounds described herein. In some embodiments, the compounds described herein are combined with another active agent in a single dosage form.

[0225] In this embodiment, the target is an adult.

[0226] Dosage and frequency of medication In some embodiments, a compound of formula (I) described herein or any pharmaceutically acceptable salt thereof is administered in an effective amount to a human patient in need.

[0227] In some embodiments, a method for treating a disease associated with increased expression or activity of integrin α5β1 comprises administering an integrin α5β1 inhibitor in doses of 1 mg / kg to 1000 mg / kg. In some embodiments, the dose is at least 2 mg / kg, at least 4 mg / kg, at least 6 mg / kg, or at least 8 mg / kg. In some embodiments, the dose is at least 10 mg / kg, at least 20 mg / kg, at least 30 mg / kg, at least 40 mg / kg, at least 50 mg / kg, at least 60 mg / kg, at least 70 mg / kg, at least 80 mg / kg, at least 90 mg / kg, or at least 100 mg / kg. In some embodiments, the dose is at least 200 mg / kg, at least 300 mg / kg, at least 400 mg / kg, at least 500 mg / kg, at least 600 mg / kg, at least 700 mg / kg, at least 800 mg / kg, at least 900 mg / kg, or at least 1000 mg / kg.

[0228] In one embodiment, the subject receives a dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof once daily. In another embodiment, the subject receives a dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof twice daily.

[0229] Cardiac function parameters To determine the efficacy of the treatment of the present invention, various endpoint parameters can be evaluated, such as α5β1 levels, pulmonary vascular resistance (PVR), mean pulmonary artery pressure (PAP), cardiac index (CI), mean pulmonary artery wedge pressure (PCWP), right atrial pressure (RAP), 6-minute walk distance (6MWD), brain natriuretic peptide (BNP) levels, lung volume diffusion (DLCO), and mortality or survival. See Chung et al. Chest (2010), 138(6):1383-1394.

[0230] PVR is commonly used as an endpoint parameter to determine the effectiveness of PAH treatment. A PVR greater than 240 dyn·sec / cm5 in subjects is an indicator of mild PAH. A PVR of 600-800 dyn·sec / cm5 in subjects indicates moderate to severe PAH. A decrease in PVR of 130 dyn·sec / cm5 or more in subjects after treatment using the method and composition of the present invention indicates effective treatment. For example, administration of an A5B1 inhibitor to subjects with PAH resulting in a PVR decrease of 180-350 dyn·sec / cm5 indicates effective treatment.

[0231] Mean pulmonary artery pressure (PAP) is also used as an endpoint parameter to determine the effectiveness of PAH treatment. Subjects without PAH have a mean PAP in the range of approximately 15–24 mmHg. Subjects with mild PAH have a mean PAP of approximately 25–30 mmHg (e.g., >25 mmHg at rest or 30 mmHg during exercise). Subjects with severe PAH have a PAP greater than 30 mmHg, e.g., 40–70 mmHg or 60–70 mmHg. A decrease in PAP of more than 1.5 mmHg after treatment indicates effective treatment. In some embodiments, treatment results in a decrease in PAP of more than 5, 10, 20, 40, or 50 mmHg, which indicates effective treatment.

[0232] Cardiac index (CI) is also used as an endpoint parameter to determine the effectiveness of PAH treatment. A low or decreased CI indicates heart failure. For example, a CI of 2.5 L / min / m2 or less indicates PAH or heart failure. An increase in CI of more than 0.3 L / min / m2 after treatment indicates effective treatment.

[0233] Mean pulmonary artery wedge pressure (PCWP) can be used as an endpoint parameter to determine the effectiveness of PAH treatment. A mean PCWP of ≤18 mmHg (e.g., ≤10 mmHg) indicates that the subject has PAH. An increase in mean PCWP of more than 0.5 mmHg after treatment indicates effective treatment.

[0234] Right atrial pressure (RAP) is also used as an endpoint parameter to determine the effectiveness of PAH treatment. Subjects without PAH have a normal RAP of 0–8 mmHg. RAP of 8 mmHg or higher indicates PAH. Subjects with severe PAH have an RAP of approximately 20 mmHg. A decrease of more than 0.5 mmHg after treatment indicates effective treatment.

[0235] The 6-minute walk distance (6MWD) is used as an endpoint parameter to determine the effectiveness of PAH treatment. The average 6MWD for patients with CTD-PAH is approximately 300m. An increase of 25m or more in 6MWD after treatment, or an increase of more than 10%, indicates effective treatment. For example, a 6MWD of 1000m or more after treatment indicates effective treatment.

[0236] Brain natriuretic peptide (BNP) is used as an endpoint parameter to determine the effectiveness of treatment for postoperative heart disease (PAH). BNP is a highly sensitive marker of worsening heart failure and a predictor of mortality in PAH patients. Normal BNP levels are <100 pg / mL, e.g., 30–90 pg / mL. Higher BNP levels indicate worsening heart failure. BNP levels of approximately 100–200 pg / mL, e.g., above 160 pg / mL, indicate early heart failure. BNP levels of approximately 200–1000 pg / mL indicate actual heart failure. The mean BNP level in patients with CTDPAH is approximately 430 pg / mL. Any decrease in BNP levels after treatment indicates effective treatment.

[0237] N-terminal pro-brain natriuretic peptide (NT-proBNP): A reproducible, non-invasive parameter useful for tracking patients with PAH. BNP is produced in the ventricles and is elevated in PPH / IPAH. BNP levels have recently been shown to be closely associated with functional impairment in PPH / IPAH patients and to parallel pulmonary hemodynamic changes and the degree of right heart failure. BNP levels correlate long-term with functional assessments performed throughout the course of the study. Plasma NT-pro-BNP is measured by a sandwich immunoassay using a polyclonal antibody that recognizes the epitope located in the N-terminal segment (1-76) of pro-BNP (Elecsys analyzer, Roche Diagnostics, Manheim, Germany).

[0238] Lung capacity diffusion (DLCO), or CO diffusion capacity, is also used as an endpoint parameter to determine the effectiveness of PAH treatment. DLCO measures the ability of carbon monoxide (CO) to diffuse across membranes. Subjects without PAH have a normal DLCO greater than 80%. Subjects with PAH have an abnormal DLCO of less than 80%, less than 65%, or less than 45%. Any increase in %DLCO after treatment indicates effective treatment.

[0239] In some embodiments, administration of an integrin α5β1 inhibitor modulates the levels of a biomarker in the subject, and the biomarker is selected from the group consisting of Survivin, PCNA, Ki67, and Annexin V.

[0240] Pulmonary hypertension Pulmonary hypertension (PH) is a syndrome characterized by increased pulmonary artery pressure. PH is hemodynamically defined as a systolic pulmonary artery pressure higher than 30 mmHg or a mean pulmonary artery pressure (MAP) higher than 25 mmHg. See Zaiman et al., Am.J.Respir.Cell Mol.Biol.33:425-31(2005). Furthermore, PH damages both the great and small pulmonary arteries as a result of the increased pressure. The walls of the smallest vessels thicken, making it impossible for oxygen and carbon dioxide to move normally between the blood and the lungs. Eventually, pulmonary hypertension leads to thickening of the pulmonary arteries and narrowing of the passages through which blood flows. When pulmonary hypertension develops, the right side of the heart works harder to compensate. However, the increased workload causes it to enlarge and thicken. The proliferation of smooth muscle and endothelial cells, which are normally present in a resting state, leads to vascular remodeling with obstruction of the lumen of the pulmonary vascular system. This causes a gradual increase in pulmonary artery pressure as blood is pumped through the reduced lumen area. Because blood tends to pool in the ventricles and legs, an enlarged right ventricle puts a person at risk of pulmonary embolism. If a blood clot forms in the pooled blood, the clot may eventually travel to and remain in the lungs. The gradual increase in pressure also places an additional workload on the right ventricle, which eventually fails and leads to premature death in these patients.

[0241] As a result of pulmonary hypertension (PH), various pathological changes occur in the pulmonary arteries. Persistent vasoconstriction and structural remodeling of pulmonary vessels are major features of PH. Pulmonary vascular smooth muscle cells undergo a phenotypic shift from a normal contractile phenotype to a synthetic phenotype, leading to cell proliferation and matrix deposition. Histological examination of tissue samples from patients with pulmonary hypertension shows intimal thickening and smooth muscle cell hypertrophy, particularly in vessels less than 100 mm in diameter. Furthermore, abnormal smooth muscle cells often overexpress endothelin and serotonin transporters, which appear to play a role in the development of PH.

[0242] The most common symptom of pulmonary hypertension is initially shortness of breath on exertion. Some people feel lightheaded or fatigued on exertion, and angina-like chest pain is common. General weakness is another issue because body tissues are not receiving enough oxygen. Other symptoms, such as cough and wheezing, may be caused by an underlying lung disease. Swelling of the legs, in particular, can occur because fluid may leak from the veins into the tissues, signaling the development of cor pulmonale. Some people with pulmonary hypertension also have connective tissue disorders, especially scleroderma. When people have both pulmonary hypertension and connective tissue disorders, Raynaud's phenomenon often develops before the symptoms of pulmonary hypertension appear, sometimes years earlier.

[0243] Treatment for some types of pulmonary hypertension is often directed towards the underlying lung disease. Currently, treatment options available to patients with PH target cellular dysfunction that leads to vascular stenosis. Therapies such as prostanoids, phosphodiesterase-5 inhibitors, and endothelin receptor antagonists primarily work by causing dilation of pulmonary blood vessels. Vasodilators such as calcium channel blockers, nitric oxide, and prostacyclin are often helpful for pulmonary hypertension associated with scleroderma, chronic liver disease, and HIV infection. In contrast, these drugs have not proven effective in people with pulmonary hypertension due to underlying lung disease. For most people with pulmonary hypertension of unknown cause, vasodilators such as prostacyclin dramatically lower blood pressure in the pulmonary arteries. Prostacyclin administered intravenously via a surgically implanted catheter in the skin improves quality of life, increases survival, and reduces the likelihood of lung transplantation. Unfortunately, many patients either respond poorly to these therapies or stop responding to them over time. At that point, the only remaining option is a single or double lung transplant to treat PH. Although there is some evidence that available therapies have a secondary effect on vascular remodeling, there are currently no therapies that target the abnormal cell proliferation in PAH.

[0244] In some embodiments, pulmonary hypertension is pulmonary venous hypertension (PVH). In some embodiments, PVH is left-sided heart failure. In some embodiments, pulmonary hypertension is pulmonary hypertension associated with respiratory disorders and / or hypoxia. In some embodiments, pulmonary hypertension is pulmonary hypertension resulting from chronic thrombotic and / or embolic disease. In some embodiments, pulmonary hypertension is miscellaneous pulmonary hypertension. In some embodiments, miscellaneous pulmonary hypertension is associated with sarcoidosis, eosinophilic granuloma, type X erythrocyte, lymphangiomatosis, or compression of pulmonary vessels (e.g., glandular pathways, tumors, or fibrotic mediastinitis). In some embodiments, pulmonary hypertension is associated with chronic obstructive pulmonary disease (COPD). In some embodiments, pulmonary hypertension is associated with pulmonary fibrosis. In some embodiments, pulmonary hypertension is associated with cardiac fibrosis. In some embodiments, pulmonary hypertension is early pulmonary hypertension or advanced pulmonary hypertension.

[0245] In some embodiments, one or more symptoms of pulmonary hypertension are improved. In some embodiments, pulmonary hypertension is delayed. In some embodiments, pulmonary hypertension is prevented. In some embodiments, the therapeutic method provided herein reduces pulmonary artery pressure. In some embodiments, the therapeutic method provided herein inhibits and / or reduces abnormal cell proliferation in the pulmonary arteries.

[0246] In some embodiments, pulmonary hypertension is characterized by World Health Organization (WHO) groups. In some embodiments, pulmonary hypertension is WHO Group 1 pulmonary hypertension or pulmonary arterial hypertension (PAH), WHO Group 2 pulmonary hypertension, WHO Group 3 pulmonary hypertension, WHO Group 4 pulmonary hypertension, and WHO Group 5 pulmonary hypertension. In some embodiments, pulmonary hypertension is characterized by the World Health Organization (WHO) classification system. In some embodiments, pulmonary hypertension is characterized by the WHO functional classification based on cardiac function. In some embodiments, pulmonary hypertension is WHO Class I pulmonary hypertension or pulmonary arterial hypertension (PAH), WHO Class II pulmonary hypertension, WHO Class III pulmonary hypertension, and WHO Class IV pulmonary hypertension.

[0247] In some embodiments, pulmonary hypertension is associated with pulmonary capillary hemangioma. In some embodiments, the disease is heart failure or right ventricular failure. In one aspect, the present invention provides a method for treating pulmonary arterial hypertension (PAH) in a subject, comprising administering an integrin α5β1 inhibitor.

[0248] Pulmonary arterial hypertension (PAH) In one embodiment, the present invention provides a method for treating pulmonary artery hypertension (PAH), comprising administering an integrin α5β1 inhibitor (e.g., small molecule compounds and antibodies disclosed herein). PAH is characterized by a progressive increase in pulmonary vascular resistance, leading to right ventricular overload and ultimately heart failure. PAH results in progressive obstruction and decreased compliance of the pulmonary arteries (PA), leading to right ventricular (RV) failure and premature death. Similar to cancer cells, PA smooth muscle cells (PASMCs) and endothelial cells (PA ECs) exhibit excessive proliferation and resistance to apoptosis in response to increased PA rigidity caused by extracellular matrix (ECM) remodeling. Integrin signaling can contribute to PA vascular remodeling by promoting PAH-PASMC and PAH-PA EC proliferation and resistance to apoptosis, but in the RV, it can promote maladaptive hypertrophy and fibrosis, leading to RV failure in PAH. This invention is partly based on the discovery that inhibition of α5b1 integrin can reverse PA vascular remodeling and prevent RV dysfunction in PAH.

[0249] PAH is a chronic disorder affecting all layers of the pulmonary blood vessels. Vasoconstriction, structural changes in the pulmonary vascular wall (vascular remodeling), and thrombosis contribute to increased pulmonary vascular resistance in PAH. Structural and functional changes in the endothelium lead to endothelial dysfunction. Increased vasoconstrictive factors (e.g., endothelin) and decreased vasodilatory capacity (e.g., decreased prostacyclin) lead to increased vasoconstriction and pulmonary vascular resistance. Current treatments that attempt to address vasoconstriction can slow the progression of PAH or improve clinical symptoms for a limited time, but they have not been proven to substantially reduce the overall morbidity and mortality of PAH. Underlying structural changes in the pulmonary blood vessels—vascular remodeling—are not affected by these treatments.

[0250] Vascular remodeling in PAH is characterized by proliferative and occlusive changes involving many cell types, including endothelial cells, smooth muscle cells, and fibroblasts. Vascular remodeling can manifest, for example, as thickening of the pulmonary vessels due to smooth muscle cell hyperplasia and hypertrophy, formation of neointima composed of smooth muscle cells and / or myofibroblasts, and / or formation of reticular lesions consisting of local proliferation of endothelial cells, smooth muscle cells, lymphocytes, and mast cells. Vascular remodeling leads to occlusion of the vascular lumen and results in pulmonary hypertension. Therapies addressing the proliferative aspect of PAH are needed.

[0251] In some embodiments, pulmonary hypertension is pulmonary arterial hypertension (PAH). In some variants, PAH is idiopathic PAH. In some variants, PAH is familial PAH. In some variants, PAH is associated with persistent pulmonary hypertension in neonates. In some variations, the above PAH is associated with pulmonary veno-occlusive disease.

[0252] In some embodiments, pulmonary hypertension is associated with lung disease. In some embodiments, the lung disease is idiopathic pulmonary fibrosis (IPF) or interstitial pneumonia (IIP). IPF is a type of idiopathic interstitial pneumonia (IIP), which is then a type of interstitial lung disease (also known as diffuse parenchymal lung disease (DPLD)). Interstitial lung disease involves the alveolar epithelium, pulmonary capillary endothelium, basement membrane, perivascular and perilymphatic tissues. Other forms of idiopathic interstitial pneumonia include nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), and acute interstitial pneumonia (AIP). Examples of known causes of interstitial lung disease include sarcoidosis, hypersensitivity pneumonitis, pulmonary Langerhans cell histiocytosis, asbestosis, and collagenous vascular diseases (e.g., scleroderma and rheumatoid arthritis).

[0253] Pulmonary fibrosis is the formation or development of excessive fibrous connective tissue in the lungs.

[0254] heart failure (HF) In one embodiment, the present invention provides a method for treating heart failure (HF), comprising administering an integrin α5β1 inhibitor (e.g., small molecule compounds and antibodies disclosed herein). Heart failure refers to any condition characterized by the heart's inability to supply sufficient blood to the body. It is a physiological condition in which cardiac output is insufficient to meet the body's needs, or can only do so at higher filling pressures. There are many underlying causes of HF, including myocardial infarction, coronary artery disease, valvular heart disease, hypertension, and myocarditis. Chronic heart failure is associated with neurohormone activation and alterations in autonomic nervous system regulation. While these compensatory neurohormone mechanisms provide valuable support to the heart under normal physiological conditions, they also play a fundamental role in the onset and subsequent progression of HF.

[0255] For example, one of the body's primary compensatory mechanisms for reduced blood flow in HF is to increase the amount of salt and water retained by the kidneys. Retaining salt and water instead of excreting them through urine increases the volume of blood in the bloodstream and helps maintain blood pressure. However, with more blood, the heart muscle, especially the ventricles, hypertrophies. As the heart chambers enlarge, the thickness of the walls decreases, weakening the heart's contraction and causing a downward spiral in cardiac function. Another compensatory mechanism is vasoconstriction of the arterial system, which increases blood pressure to help maintain adequate perfusion and thus increases the load that the heart has to pump.

[0256] In low ejection fraction (EF) heart failure, cardiac hypertension arises from the body's attempt to maintain the high pressure necessary for adequate peripheral perfusion. However, the condition worsens when the heart weakens due to such high pressure. Left atrial pressure can exceed 25 mmHg, at which point blood flowing through the pulmonary circulation leaks or flows out from the pulmonary capillaries into the interstitial space and alveoli, causing pulmonary congestion, which, if left untreated, leads to acute pulmonary edema and a fatal syndrome.

[0257] Standard treatment (SoC) and combination therapy As described herein, a method for treating a disease associated with increased expression or activity of integrin α5β1, comprising administering an integrin α5β1 inhibitor, may include combination therapy in which the integrin α5β1 inhibitor is administered to a patient in need of treatment in combination with one or more drugs approved for the treatment of PH, PAH, heart failure, or right ventricular failure.

[0258] Approved medications currently used in the United States and the European Union (EU) for the treatment of PH, PAH, heart failure, and right ventricular failure include orally administered PDE-5 inhibitors: sildenafil (Revatio) and tadalafil (Adeirca); and dual endothelin-1A receptor antagonists (ERAs): bosentan (Tracleer) and ambrisentan (Letairis in the US; Volibris internationally). Patients with more advanced disease are often treated with prostacyclins or prostacyclin analogs, such as iloprost (Ventavis) or treprostinil (Tyvaso) administered as multiple daily inhalations, epoprostenol (Flolan / Veletri) or treprostinil (Remodulin) administered as continuous intravenous infusions, or treprostinil also used as continuous subcutaneous infusions. Intravenous sildenafil is currently prescribed but approved for patients who are temporarily unable to take oral sildenafil. Inhaled nitric oxide (INOmax) is approved for the neonatal form of persistent pulmonary hypertension (PPHN) in newborns. Therefore, according to the present invention, combination therapy of any of these drugs with an integrin α5b1 inhibitor is useful for the treatment of PAH or the disorders disclosed herein.

[0259] In some embodiments, the second therapy is selected from the group consisting of anticoagulants, diuretics, digitalis glycosideglycosides, calcium channel blockers, endothelin receptor antagonists, phosphodiesterase 5 (PDE5) inhibitors, prostanoids, prostanoid receptor agonists, soluble guanylate cyclase stimulants, and / or surgery.

[0260] In some embodiments, the second therapy is oxygen administration, warfarin, furosemide, bumetanide, bendroflumethiazide, metrazone, spironolactone, amiloride, digoxin, nifedipine, diltiazem, nicardipine, amlodipine, ambrisentan, bosentan, macitentan, sildenafil, tadalafil, epoprostenol, iloprost, treprostinil, riociguat, selexipag, surgery, pulmonary valve resection, and / or atrial septal defect creation. In some embodiments, the second therapy is macitentan and / or tadalafil. Floran (a prostacyclin analog) is an approved therapy for PAH, but its use (intravenously) is extremely cumbersome and inconvenient, and it has unique safety concerns. As a result, Floran is usually reserved for patients with a severe functional state or rapidly progressive PAH. Patients must administer the drug several times a day under sterile conditions. The drug is available as a lyophilized preparation that needs to be dissolved in an alkaline buffer. Because floran has a short half-life (3-5 minutes) and is stable (8 hours at room temperature), it must be kept refrigerated while administered by continuous infusion through a central venous catheter via a portable pump (CADD pump, Smith Medical MD, St. Paul, Minnesota) worn in a bag around the waist. In 2008, the FDA also approved a new continuous intravenous formulation of epoprostenol (GeneraMedix, Liberty Corner, NJ) that is stable for up to 24 hours at room temperature after dilution and can be stored for up to 5 days at refrigerated temperatures before use. In 2009, GeneraMedix marketed this formulation to Actelion, which began selling the drug (under the brand name Veletri) in April 2010. In the latter half of 2010, the Veletri label was expanded to allow for drug preparation at refrigerated temperatures for up to 7 days or at room temperature for up to 48 hours before use. Therefore, in one embodiment of the present invention, an integrin α5b1 inhibitor is administered in combination with epoprostenol in any of its approved forms to treat PAH.

[0261] Remodulin (a serial subcutaneous infusion form of a prostacyclin analog) was generally not used as an initial treatment due to its cost, delivery route, and limited efficacy. In 2004, the FDA and Health Canada approved an intravenous formulation of Remodulin for patients with PAH class II–IV disease who could not tolerate the subcutaneous form. In early 2006, the FDA expanded the label of Remodulin to include patients requiring a transition from Flolan. In 2009, United Therapeutics received FDA approval for an inhaled formulation of treprostinil (Tyvaso). Thus, in one embodiment of the present invention, an integrin α5b1 inhibitor is administered in combination with treprostinil to treat PAH.

[0262] Ventavis (iloprost), a prostacyclin analog administered by inhalation, is also marketed as Ilomedine as an intravenous formulation in several EU member states. In the EU, the labeling of inhaled iloprost is limited to patients with idiopathic PAH and functional class III symptoms. In contrast, the US labeling is broader, covering patients with PAH (regardless of etiology) and class III or IV symptoms. It requires administration 6 to 9 times daily. Therefore, in one embodiment of the present invention, an integrin α5b1 inhibitor is administered in combination with iloprost in any of its approved forms to treat PAH.

[0263] In 2001, non-selective ERA Tracleer (bosentan) became the first oral PAH treatment, and due to its significant risks of (reversible) liver damage, teratogenicity, testicular atrophy, and male infertility, it was only available in the United States through a special intensive access program. Treatment with Tracleer consists of an initial dose of 62.5 mg twice daily for 4 weeks, followed by a maintenance dose of 125 mg twice daily. Tracleer was initially prescribed for patients with PAH and moderate or severe functional status (WHO classification III, IV). In 2008 (EU) and 2009 (US), the label was expanded to include patients with mild symptoms (functional classification II). Therefore, in one embodiment of the present invention, an integrin α5b1 inhibitor is administered in combination with bosentan in any of its approved forms to treat PAH.

[0264] Ambrisentan is an orally selective ERA receptor antagonist marketed by Gilead Sciences (Letairis) in the United States and GlaxoSmithKline (Volibris) in other regions for once-daily treatment of patients with WHO Class II or III symptoms to improve motor function and delay clinical progression. Similar to bosentan, ambrisentan has teratogenic, testicular trauma, male fertility impairment, and anemia classification effects. Therefore, in one embodiment of the present invention, an integrin α5b1 inhibitor is administered in combination with ambrisentan in any of its approved forms to treat PAH.

[0265] The oral PDE-5 inhibitor Revatio (sildenafil) was approved in the United States for the treatment of PAH (WHO Group I) at a dose of 20 mg three times daily to improve motor function and delay clinical progression, regardless of functional classification or etiology. The EU label is limited to the improvement of motor function in patients with PAH that is idiopathic or associated with collagen vascular disease and functional classification III status. In 2009, the FDA approved an intravenous form of Revatio, administered as an injection (10 mg three times daily) for patients unable to take the oral formulation. In May 2010, the EU approved Revatio as an oral suspension (composed from a 20 mg tablet) for the treatment of pediatric patients aged 1–17 years with PAH. Therefore, in one embodiment of the present invention, an integrin a5b1 inhibitor is administered in combination with sildenafil in one of its approved forms to treat PAH.

[0266] The oral PDE-5 inhibitor Adeirca (tadalafil) 40 mg once daily has been shown in the United States to improve motor function in patients with PAH (WHO Group I), regardless of etiology or functional classification (packet insert). The EU label is limited to patients with functional classification II and III states. Tadalafil has a long half-life (35 hours) in PAH patients (US Packet Insert) and has also been shown to be beneficial in combination with bosentan in PAH patients.

[0267] Therefore, methods of treating patients may include administering at least one additional active agent, i.e., an integrin a5b1 inhibitor. The additional active agent may be, for example, vasodilators such as prostacyclin, epoprostenol, and sildenafil; endothelin receptor antagonists such as bosentan; calcium channel blockers such as amlodipine, diltiazem, and nifedipine; anticoagulants such as warfarin; diuretics, prostanoids (e.g., prostacyclin or PGI2), drugs for treating diseases associated with hyperactive or dysfunctional B cells such as rituximab, and / or phosphodiesterase type V (PDE5) inhibitors.

[0268] When the method of the present invention includes combination therapy, that is, when a secondary agent such as a vasodilator is administered simultaneously with an integrin A5B1 inhibitor, the agents may be administered separately on the same day, at the same time, or at different times, or they may be administered as a single composition. Accordingly, the present invention provides novel pharmaceutical formulations in which an integrin A5B1 inhibitor is combined with one of the above-mentioned active agents, and unit dosage forms of these formulations.

[0269] In the combination therapy of the present invention, each agent may be administered in an "immediate-release" or "controlled-release" manner. If the additional active agent is a vasodilator, for example, any dosage form containing both active agents, i.e., both an integrin A5B1 inhibitor and a vasodilator, can provide either immediate-release or controlled-release of the vasodilator, and immediate-release or controlled-release of the integrin A5B1 inhibitor.

[0270] As a general example, a combination dosage form of the present invention for once-daily administration may contain an integrin A5B1 inhibitor in the range of about 1 mg to about 1000 mg in controlled-release (e.g., sustained-release) or immediate-release form, and sildenafil in either immediate-release or controlled-release form, together with an additional active agent present in an amount that provides the weight ratio of integrin A5B1 inhibitor to sildenafil, or as specified above. In other formulations of the present invention, two or more additional active agents, which may or may not be drugs of the same classification (e.g., vasodilators), may be present in combination with the integrin A5B1 inhibitor. In such cases, the effective amount of any or each of the individual additional active agents present is generally reduced compared to the amount required when only a single additional agent is used.

[0271] The additional active agent may also be a type V phosphodiesterase inhibitor administered together with the integrin A5B1 inhibitor, or together with both the integrin A5B1 inhibitor and a vasodilator, as described above. Examples of type V phosphodiesterase inhibitors include, but are not limited to, avanafil, sildenafil, tadalafil, zaprinast, dipyridamole, vardenafil and acid adducts or other pharmaceutically acceptable salts thereof. Sildenafil is an excellent example. In exemplary embodiments, the integrin A5B1 inhibitor is administered co-administered with a type V phosphodiesterase inhibitor selected from the group consisting of avanafil, tadalafil, and sildenafil, and the daily dose of the integrin A5B1 inhibitor compound is shown above for monotherapy regimens.

[0272] In one embodiment, the vasodilator is selected from sildenafil, avanafil, tadalafil, zaprinast, dipyridamole, vardenafil, bosentan, and pharmaceutically acceptable salts thereof. Additional active agents may also be endothelin receptor antagonists, such as bosentan, citaxsentan, or ambrisentan, as discussed above, with bosentan being an exemplary active agent.

[0273] The pharmaceutical compositions of the present invention are pharmaceutical formulations containing an active agent formulated in a manner suitable for its intended route of administration. Various routes are intended, including but not limited to oral, pulmonary, inhalation, sublingual, intranasal, parenteral, intradermal, transdermal, topical, transmucosal, subcutaneous, intravenous, intramuscular, intraperitoneal, oral cavity, and rectal administration. As used herein, the term "parenteral" is intended to include subcutaneous, intravenous, and intramuscular injection.

[0274] Generally, the pharmaceutical formulations of the present invention are prepared for oral administration in an immediate-release form suitable for once-daily (QD) administration. Certain formulations are suitable for intranasal administration to patients.

[0275] Certain pharmaceutical formulations of the present invention comprise an integrin A5B1 inhibitor or a salt thereof and one or more pharmaceutically acceptable excipients or carriers (approved by a state or federal regulatory authority for use in humans, or listed in the United States Pharmacopeia or the European Pharmacopoeia). As used herein, the term excipient or carrier broadly refers to a biologically inert substance used in combination with the active agent of the formulation. Excipients can be used, for example, as solubilizers, stabilizers, diluents, inert carriers, preservatives, binders, disintegrants, coatings, flavorings, or colorants. Preferably, at least one excipient is selected to provide the formulation with one or more beneficial physical properties, such as increased stability and / or solubility of the active agent. The integrin A5B1 inhibitors or salts thereof described herein are exemplary active agents suitable for use in the formulations of the present invention.

[0276] Examples of suitable excipients include certain inactive proteins such as albumin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as aspartic acid (also known as aspartate), glutamic acid (also known as glutamate), lysine, arginine, glycine, and histidine; fatty acids and phospholipids such as alkyl sulfonates and caprylates; surfactants such as sodium dodecyl sulfate and polysorbate; nonionic surfactants, e.g., TWEEN®, PLURONICS®, or polyethylene glycol (PEG); carbohydrates, e.g., glucose, sucrose, mannose, maltose, trehalose, and dextrins including cyclodextrin; polyols such as mannitol and sorbitol; chelating agents, e.g., EDTA; and salt-forming counterions, e.g., sodium.

[0277] The solutions or suspensions used for delivery may contain the following components: sterile diluents, such as water for injection, physiological saline, non-volatile oils, polyethylene glycol, glycerin, propylene glycol, polysorbate, tocopherol polyethylene glycol succinate (TPGS), or other synthetic solvents; antimicrobial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffering agents such as acetates, citrates, or phosphates; and agents for adjusting tonicity such as sodium chloride or dextrose. The pH may be adjusted with an acid or base such as hydrochloric acid or sodium hydroxide. These preparations may be sealed in ampoules, disposable syringes, or glass or plastic multi-dose vials.

[0278] In some embodiments, the pharmaceutical formulation of the present invention contains multiple liposomes or microparticles comprising an integrin A5B1 inhibitor active agent. In various embodiments, the pharmaceutical formulation of the integrin A5B1 inhibitor is a powder comprising solid particles (e.g., liposomes or microparticles) suitable for administration by inhalation. The solid particles comprise the active agent, a carrier, optionally a surfactant, and optionally additional recipients. The powder can be prepared by any convenient method. An example of a preparation method is to spray-dry a solution containing the active agent (and other components) onto a powder containing a carrier compound. Another example is to freeze-dry a solution containing all the components of the final powder.

[0279] Suitable liposomes for use in the formulations of the present invention are known in the art. For example, suitable liposomes comprise cholesterol, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and PEG-DSPE in a weight ratio of approximately 5:10:1. In some embodiments, the liposomal formulation comprises about 0.1–25%, e.g., 0.1%, 1%, 5%, 10%, or 20% (w / w) of phospholipids, e.g., dipalmitoylphosphatidylcholine (DPPC) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC). In some embodiments, the liposomal formulation comprises about 0.5–20%, e.g., 1%, 5%, or 10% (w / w) of a hydrophilic polymer such as polyvinylpyrrolidone (PVP). In some embodiments, the liposomal formulation comprises about 10–35% of amino acids, e.g., L-leucine.

[0280] Suitable microparticles for use in the formulations of the present invention are known in the art. For example, the microparticles are formed from one or more hydrophilic polymers such as polyvinylpyrrolidone (e.g., PVP-10), polyvinyl alcohol (e.g., PVA-30), polyvinyl acetate, or poloxamer (e.g., poloxamer-188). In some embodiments, the microparticle formulation contains about 70-85 wt% polyvinyl alcohol (e.g., PVA-30), about 5-15% PVP (e.g., PVP-10), 1-5% poloxamer (e.g., poloxamer-188), 0-10% L-leucine, and about 0.5-10% integrin a5b1 inhibitor compound (e.g., 5%). In some embodiments, the formulation is suitable for administration via the airway.

[0281] Pharmaceutical formulations of integrin A5B1 inhibitors useful in the method of the present invention can be prepared as liquids or in solid forms such as powders, tablets, pills, or capsules for oral administration. Specific pharmaceutical compositions for injection are suspensions, solutions, or emulsions in an oily or aqueous vehicle and may contain formulations such as suspending agents, stabilizers, and / or dispersants. In one embodiment, the formulation is an aqueous solution. In another embodiment, the final formulation is lyophilized. In some embodiments, the integrin A5B1 inhibitor is formulated for inhalation.

[0282] In various embodiments, the formulations of the present invention contain an integrin A5B1 inhibitor at concentrations of 0.25 wt% to 100 wt%, or 0.25 wt% in 50 wt%, or 0.8 wt% to 25 wt%, or 1 wt% to 10%, or 1.5 wt% to 5 wt%. In certain embodiments, the integrin A5B1 inhibitor compound is formulated at a concentration of about 0.5 wt% to about 5 wt%. In certain embodiments, the integrin A5B1 inhibitor compound is formulated at a concentration of about 0.25 wt% to about 10 wt%.

[0283] The present invention also provides a pharmaceutical pack or kit comprising one or more containers filled with a solid or liquid formulation of an integrin A5B1 inhibitor. In certain embodiments, the formulation is a powder formulation of the integrin A5B1 inhibitor. In various embodiments, the integrin A5B1 inhibitor is formulated at a concentration of at least about 0.5 wt%, and the formulation is suitable for delivery to humans via inhalation.

[0284] The present invention also provides the use of integrin α5B1 inhibitor formulations in the manufacture of pharmaceuticals for the treatment of PAH or other disorders disclosed herein. Generally, pharmaceutical formulations are sterile.

[0285] Generally, dosage forms, such as inhalable dosage forms, provide sustained release, or sustained release, of the compound of the present invention, e.g., an integrin A5B1 inhibitor, from the dosage form to the patient's body over a long period, typically providing substantially constant blood levels of the drug over a period of time ranging from about 4 to about 12 hours, and typically from about 6 to about 10 hours. In a particularly preferred embodiment, after intranasal administration of a dosage form containing the compound of the present invention, e.g., an integrin A5B1 inhibitor, the blood concentration of the drug increases very gradually, and as a result, the peak blood concentration is not reached until at least 4 to 6 hours have elapsed, and the rate of increase in the blood concentration of the drug is almost linear. In addition, in a preferred embodiment, the blood levels decrease equally at the end of the sustained release period.

[0286] The pharmaceutical composition of the present invention is preferably formulated for inhalation, for example, as a solution in physiological saline, as a dry powder, or as an aerosol, but other modes of administration are equally suitable. For example, administration may be sublingual, oral, parenteral, transdermal, via implant depot, or transmucosal, for example, rectally or vaginally, and preferably, suppositories containing excipients such as suppository wax added to the active drug are used. Transmucosal administration also includes transurethral administration.

[0287] Depending on the intended mode of administration, the pharmaceutical formulation may be solid, semi-solid, or liquid, such as tablets, capsules, caplets, solutions, suspensions, emulsions, suppositories, granules, pellets, beads, or powders, and preferably a unit dosage form suitable for a single dose of a precise amount. Suitable pharmaceutical compositions and dosage forms are known to those skilled in the art of pharmaceutical formulation and can be prepared using conventional methods described in relevant texts and literature, such as Remington: The Science and Practice of Pharmacy (Easton, Pa.: Mack Publishing Co., 1995). For orally active compounds, oral dosage forms are generally preferred, including tablets, capsules, caplets, solutions, suspensions, and syrups, and may also include multiple granules, beads, powders, or pellets, which may or may not be encapsulated. Preferred oral dosage forms are tablets and capsules.

[0288] In embodiments, it may be particularly advantageous to formulate the compositions of the present invention in unit dosage forms for ease of administration and uniformity of dosage. As used herein, the term “unit dosage form” refers to a physically distinct unit suitable as a unit dosage for the target to be treated. That is, the composition is formulated into individual dosage units, each containing a predetermined “unit dosage” of the active agent, calculated to produce the desired therapeutic effect together with the necessary pharmaceutical carrier. The specification of the unit dosage forms of the present invention depends on the unique characteristics of the active agent to be delivered. The dosage can further be determined by referring to the usual doses and modes of administration of the components. It should be noted that in some cases, two or more combined individual dosage units may provide a therapeutically effective dose of the active agent, for example, two combined tablets or capsules may provide a therapeutically effective dose of an integrin A5B1 inhibitor such that the unit dosage in each tablet or capsule is about 50% of the therapeutically effective dose.

[0289] Tablets can be manufactured using standard tablet processing procedures and equipment. Direct compression and granulation techniques are preferred. In addition to the active agent, tablets generally contain inert, pharmaceutically acceptable carrier materials, such as binders, lubricants, disintegrants, fillers, stabilizers, surfactants, and colorants.

[0290] Capsules are another oral dosage form for the orally active compounds of the present invention, such as integrin A5B1 inhibitors, in which case the active drug-containing composition may be encapsulated in liquid or solid form (including fine particles such as granules, beads, powders, or pellets). Preferred capsules may be rigid or flexible and are generally made from gelatin, starch, or cellulose material, with gelatin capsules being preferred. Two rigid gelatin capsules are preferably sealed, for example, with a gelatin band. See, for example, Remington: The Science and Practice of Pharmacy, cited herein earlier, which describes materials and methods for preparing encapsulated pharmaceuticals.

[0291] The oral dosage form may be a tablet, capsule, caplet, or particulate, and may be formulated to provide controlled release of the compound of the present invention, for example, an integrin A5B1 inhibitor, if desired. In a preferred embodiment, the formulation is a controlled-release oral dosage form.

[0292] Generally, as those skilled in the art will understand, sustained-release formulations are formulated by dispersing an active agent in a matrix of a gradually hydrolyzable material such as a hydrophilic polymer, or by coating a solid drug-containing formulation with such a material. Examples of hydrophilic polymers useful for providing sustained-release coatings or matrices include cellulosic polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetate, and sodium carboxymethylcellulose; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, alkyl acrylates, alkyl methacrylates, etc., e.g., copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate; and vinyl polymers and copolymers, e.g., polyvinylpyrrolidone, polyvinyl acetate, and ethylene-vinyl acetate copolymers.

[0293] Preparations according to the present invention for parenteral administration include sterile aqueous and non-aqueous solutions, suspensions, and emulsions. Aqueous solutions for injection contain the active agent in a water-soluble form. Examples of non-aqueous solvents or vehicles include fatty oils such as olive oil and corn oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, low molecular weight alcohols such as propylene glycol, synthetic hydrophilic polymers such as polyethylene glycol, and liposomes. Parenteral formulations may also contain adjuvants such as solubilizers, preservatives, wetting agents, emulsifiers, dispersants, and stabilizers, and aqueous suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, and dextran. Injectable formulations are sterilized by incorporating a sterilizing agent, filtration through a bacterial-retaining filter, irradiation, or heat. They may also be manufactured using a sterile injection medium. The active agent may also be in a dry form, such as lyophilized form, which can be rehydrated with a suitable vehicle immediately before administration by injection.

[0294] The active agent may also be administered through the skin using a conventional transdermal drug delivery system, in which case the active agent is contained within a laminated structure that functions as a drug delivery device that adheres to the skin. In such a structure, the drug composition is contained in a layer or “reservoir” beneath the upper backing layer. The laminated structure may contain a single reservoir or multiple reservoirs. In one embodiment, the reservoir contains a polymer matrix of a pharmaceutically acceptable contact adhesive material that functions to adhere the system to the skin during drug delivery. Alternatively, the drug-containing reservoir and the skin contact adhesive may exist as separate layers, with the adhesive beneath the reservoir, in which case the reservoir may be the polymer matrix described above, or a liquid or hydrogel reservoir, or may take several other forms. The transdermal drug delivery system may further contain a skin penetration enhancer.

[0295] In addition to the formulations described above, the active agent may be formulated as a depot preparation for controlled release of the active agent, preferably for sustained release over a long period. These sustained-release formulations are generally administered by implantation (e.g., subcutaneous, intramuscular, or intramuscular injection).

[0296] Certain compounds or active agents of the present invention can further form salts. All of these forms are also intended within the scope of the claimed invention. The compounds of the present invention can also be prepared as esters, for example, pharmaceutically acceptable esters. For example, carboxylic acid functional groups in the compounds can be converted to their corresponding esters, such as methyl, ethyl, or other esters. Alcohol groups in the compounds can also be converted to their corresponding esters, such as acetate, propionate, or other esters.

[0297] The compounds of the present invention may also be prepared as prodrugs, for example, pharmaceutically acceptable prodrugs. The terms “pro-drug” and “prodrug” are used interchangeably herein and refer to any compound that releases an active parent drug in vivo. Since prodrugs are known to enhance many desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacture, etc.), the compounds of the present invention may be delivered in the form of prodrugs. Accordingly, the present invention is intended to encompass prodrugs of the currently claimed compounds, methods for delivering them, and compositions containing them. “Prodrug” is to be easily defined as any covalent carrier that releases the active parent drug of the present invention in vivo when such a prodrug is administered to a subject. Prodrugs of the present invention are prepared by modifying functional groups present in the compound such that the modifications cleave into the parent compound either in a routine operation or in vivo. The prodrugs include the compounds of the present invention, wherein a hydroxyl, amino, sulfhydryl, carboxyl, or carbonyl group is cleaved in vivo and bonded to any group that can form a free hydroxyl, free amino, free sulfhydryl, free carboxyl, or free carbonyl group.

[0298] Examples of prodrugs in the compounds of the present invention include, but are not limited to, esters of hydroxyl functional groups (e.g., acetates, dialkylaminoacetates, formates, phosphates, sulfates, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl), esters of carboxyl functional groups (e.g., ethyl esters, morpholinoethanol esters), N-acyl derivatives of amino functional groups (e.g., N-acetyl), N-Mannich bases, Schiff bases, and enaminones, oximes, acetals, ketals, and enol esters of ketone and aldehyde functional groups. See Bundegaard, H., Design of Prodrugs, p192, Elesevier, New York-Oxford (1985).

[0299] A drug regimen utilizing a compound is selected according to various factors, including the patient's type, breed, age, weight, sex, and medical condition; the severity of the condition being treated; the route of administration; the patient's renal and hepatic function; and the specific compound or salt thereof used. A physician or veterinarian skilled in the art can easily determine and prescribe the effective dose of the drug necessary to prevent, counteract, or halt the progression of the condition.

[0300] In some embodiments, the composition is suitable for topical administration. In one embodiment, the composition is an inhalable formulation used to treat PAH or any of the disorders disclosed herein.

[0301] In yet another embodiment, the Disclosure provides a pharmaceutical composition comprising an integrin a5b1 inhibitor and a plurality of particles, wherein the plurality of particles are a plurality of liposomes or a plurality of microparticles comprising a hydrophilic polymer containing 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)] (PEG-DSPE). In one embodiment, the composition is suitable for inhalation, and in one embodiment, the composition is an inhalable formulation used to treat PAH or a disorder disclosed herein.

[0302] Pharmaceutical composition The pharmaceutical compositions described herein can be administered in a variety of different ways. For example, a pharmaceutical composition comprising a peptide or polymer according to the present invention, preferably the peptide according to the present invention, and a pharmaceutically acceptable carrier, can be administered orally, intranasally, rectally, topically, intraperitoneally, intravenously, intramuscularly, subcutaneously, subdermally, transdermally, intrathecally, and intracranially. For oral administration, the active ingredient can be administered in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions.

[0303] The pharmaceutical composition of the present invention comprises at least one pharmaceutically acceptable carrier, diluent, or excipient. Examples of suitable carriers include, for example, keyhole limpet hemocyanin (KLH), serum albumin (e.g., BSA or RSA), and ovalbumin. In some embodiments, the suitable carrier is a solution, such as physiological saline. Examples of excipients that can be incorporated into tablets, capsules, etc., include: binders such as tragacanth gum, acacia, corn starch, or gelatin; excipients such as microcrystalline cellulose; disintegrants such as corn starch, pregelatinized starch, or alginic acid; lubricants such as magnesium stearate; sweeteners such as sucrose, lactose, or saccharin; and flavorings such as peppermint, wintergreen oil, or cherry. If the dosage unit form is a capsule, it may contain a liquid carrier such as fatty oil, added to the above types of substances. Various other substances may be present as a coating or otherwise to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. Syrups or elixirs may contain active compounds, sucrose as a sweetener, methyl and propylparabens as preservatives, colorants, and flavoring agents such as cherry or orange flavor. The pharmaceutical compositions according to the present invention are preferably suitable for use in humans.

[0304] Sterile compositions for injection can be formulated according to conventional pharmaceutical practices by dissolving or suspending the integrin A5B1 inhibitor of the present invention in an injection vehicle, such as water, or a naturally occurring vegetable oil such as sesame oil, coconut oil, peanut oil, or cottonseed oil, or a synthetic fatty vehicle such as ethyl oleate. Buffers, preservatives, antioxidants, etc., may also be incorporated.

[0305] Compositions for topical administration can also be formulated according to conventional pharmaceutical practices. As used herein, “topical administration” refers to application to a body surface, such as the skin or mucous membrane, for the local treatment of a condition resulting from a microbial or parasitic infection. Examples of formulations suitable for topical administration include, but are not limited to, creams, gels, ointments, lotions, foams, suspensions, sprays, aerosols, and powder aerosols. Topical agents can be present on the skin, meaning they are applied directly to the skin. Topical agents may be inhaled for application to the mucous membrane epithelium of the respiratory tract, for example, or applied to the surface of tissues other than the skin, such as eye drops applied to the conjunctiva or ear drops placed in the ear. The pharmaceutical composition formulated for topical administration preferably comprises at least one pharmaceutical excipient suitable for topical application, such as an emulsifier, diluent, humectant, preservative, pH adjuster, and / or water.

[0306] Exemplary Embodiments The following examples are provided to aid in understanding the present invention and should not be construed as specifically limiting the invention as described herein and claimed. Such modifications of the invention, including the substitution of all currently known or subsequently developed equivalents, and changes in formulation or experimental design, which are within the scope of those skilled in the art, should be considered to be within the scope of the invention as incorporated herein.

[0307] The following specific examples relate to a method for treating or preventing α5β1 integrin inhibitor-responsive diseases by administering a compound of formula (I) to a person requiring such treatment. [Examples]

[0308] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. In addition, the polymers of the present invention may also be optically active. The present invention envisions all such compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, and they are within the scope of the invention. Additional chiral carbon atoms may be present in substituents, such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention.

[0309] For example, if a specific enantiomer of the compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with chiral auxiliaries, and the resulting diastereomer mixture is separated and the auxiliary groups are cleaved to yield the pure enantiomer of the choice. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, a diastereomer salt can be formed using a suitable optically active acid or base, and then the formed diastereomer can be separated by fractional crystallization or by chromatographic means well known in the art to recover the pure enantiomer.

[0310] Abbreviation

[0311] [Table 2]

[0312] Analytical methods, materials, and equipment Unless otherwise noted, reagents and solvents were used as received from their commercial suppliers.

[0313] Left-hand intermediate Preparation of (1S,3S)-N-methyl-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)cyclopentan-1-amine

[0314] [ka] Step 1: (1S,3S)-3-(methylamino)cyclopentan-1-ol

[0315] [ka] In the 500 mL THF (in this embodiment), 1 / 3 of the solution of tert-butyl ((1S,3S)-3-hydroxycyclopentyl)carbamate (50 g, 248.43 mmol, 1 equivalent) in THF (500 mL) was slowly added dropwise at 20°C under N2, and the solution was stirred at 80°C. Then, 2 / 3 of the tert-butyl ((1S,3S)-3-hydroxycyclopentyl)carbamate solution was slowly added to the solution under N2 at 80°C, and the solution was stirred at 80°C for 2 hours. TLC (petroleum ether / ethyl acetate = 1 / 1) showed that the starting material was completely consumed and one new spot was formed. The reaction mixture was quenched by slowly adding H2O (20 mL), NaOH aqueous solution (15%, 20 mL), and H2O (60 mL) dropwise under N2 at 10°C. The mixture was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. (1S,3S)-3-(methylamino)cyclopentan-1-ol (28.61 g, crude) was obtained as a yellow oily substance. The residue was used directly without further purification.

[0316] Step 2: tert-butyl((1S,3S)-3-hydroxycyclopentyl)(methyl)carbamate

[0317] [ka] To a solution of (1S,3S)-3-(methylamino)cyclopentan-1-ol (56 g, 486.23 mmol, 1 equivalent) in 600 mL of THF, NaHCO3 (81.69 g, 972.45 mmol, 37.82 mL, 2 equivalents) and (Boc)2O (137.95 g, 632.09 mmol, 145.21 mL, 1.3 equivalents) in H2O (90 mL) were added under N2 at 25°C, and the solution was stirred at 25°C for 16 hours. TLC (petroleum ether / ethyl acetate = 1 / 1, R f A reading of 0.4 indicated that the starting material had been completely consumed and one new spot had formed. H2O (200 mL) was added to the reactants and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~1 / 1). Tert-butyl ((1S,3S)-3-hydroxycyclopentyl)(methyl)carbamate (yield 82.16%) was obtained as a yellow oil. 1 ¹H NMR (400MHz, chloroform-d): δ = 4.74 (brs, 1H), 4.39 (brs, 1H), 2.73 (s, 3H), 2.03-1.97 (m, 2H), 1.88-1.72 (m, 2H), 1.66-1.54 (m, 2H), 1.47 (s, 9H).

[0318] Step 3: tert-butyl((1S,3S)-3-(4-bromobutoxy)cyclopentyl)(methyl)carbamate

[0319] [ka] To a solution of tert-butyl((1S,3S)-3-hydroxycyclopentyl)(methyl)carbamate (85 g, 394.82 mmol, 1 equivalent) and NaOH (247.09 g, 6.18 mol, 500 mL, 15.65 equivalents) in toluene (1000 mL), 1,4-dibromobutane (170.49 g, 789.64 mmol, 95.25 mL, 2 equivalents) and TBAI (218.75 g, 592.23 mmol, 1.5 equivalents) were added at 25°C, and the solution was stirred at 50°C for 16 hours. TLC (petroleum ether / ethyl acetate = 5 / 1, R f A reading of 0.6) indicated that the starting material remained and one new spot was formed. The reaction mixture was quenched by adding H2O (1000 mL) at 0°C and extracted with ethyl acetate (300 mL x 3). The combined organic layer was washed with brine (300 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~5 / 1). Tert-butyl ((1S,3S)-3-(4-bromobutoxy)cyclopentyl)(methyl)carbamate (yield 28.92%) was obtained as a yellow oil. 1 H NMR (400MHz, chloroform-d) δ = 4.61 (brs, 1H), 3.91 (brd, J = 2.9Hz, 1H), 3.47-3.37 (m, 4H), 2.72 (s, 3H), 2.00-1.82 (m, 6H), 1.72-1.62 (m, 4H), 1.46 (s, 9H).

[0320] Step 4: tert-butyl((1S,3S)-3-(buta-3-en-1-yloxy)cyclopentyl)(methyl)carbamate

[0321] [ka] To a solution of tert-butyl((1S,3S)-3-(4-bromobutoxy)cyclopentyl)(methyl)carbamate (33 g, 94.21 mmol, 1 equivalent) in THF (400 mL), t-BuOK (26.43 g, 235.52 mmol, 2.5 equivalents) was added at 0°C, and the mixture was stirred at 20°C for 16 hours. TLC (petroleum ether / ethyl acetate = 5 / 1, R f =0.61) indicated that the starting material was completely consumed and one new spot was formed. The reaction mixture was then converted to H2O (100 mL) 0 ℃ The mixture was quenched by adding [a specific substance] and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). Tert-butyl((1S,3S)-3-(buta-3-en-1-yloxy)cyclopentyl)(methyl)carbamate (yield 90.63%) was obtained as a yellow oil. 1 H NMR(400MHz,chloroform-d)δ=5.82(tdd,J=6.7,10.3,17.1Hz,1H),5.14-4.99(m,2H),4.61(brs,1H),3.94-3.89( m,1H),3.43-3.37(m,2H),2.72(s,3H),2.32-2.27(m,2H),1.99-1.84(m,4H),1.69-1.61(m,2H),1.46(s,9H).

[0322] Step 5: tert-butyl7-(4-(((1S,3S)-3-((tert-butoxycarbonyl)(methyl)amino)-cyclopentyl)oxy)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate

[0323] [ka] To a solution of tert-butyl((1S,3S)-3-(buta-3-en-1-yloxy)cyclopentyl)(methyl)carbamate (23 g, 85.38 mmol, 1 equivalent) in THF (50 mL), 9-BBN (0.5 M, 341.53 mL, 2 equivalents) was added, and the mixture was stirred at 25°C for 2 hours. TLC (petroleum ether / ethyl acetate = 5 / 1, R f A reading of 0.53 indicated that the starting material was completely consumed and one new spot was formed. To the above solution (34.87 g, 89.09 mmol, 1 equivalent) in tAmylOH (400 mL), tert-butyl 7-chloro-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (21.55 g, 80.18 mmol, 0.9 equivalents), APhos Pd G3 (5.66 g, 8.91 mmol, 0.1 equivalent), and Cs2CO3 (58.06 g, 178.18 mmol, 2 equivalents) were added at 25°C. The mixture was stirred further at 80°C under N2 for 14 hours. LCMS showed that the starting material was completely consumed and one main peak with the desired mass was detected. The reaction mixture was quenched by adding H2O (500 mL) at 0°C and extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with brine (200 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~1 / 1). Tert-butyl 7-(4-(((1S,3S)-3-((tert-butoxycarbonyl)(methyl)amino)-cyclopentyl)oxy)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylic acid (yield 62.40%) was obtained as a red oil. 1 H NMR(400MHz,chloroform-d)δ=7.23(brd,J=7.6Hz,1H),6.75(d,J=7.6Hz,1H),3.90-3.77(m,1H),3.70-3.66(m,2H),3 .31(t,J=6.6Hz,2H),2.65(brs,3H),2.64(s,3H),1.92-1.74(m,6H),1.73-1.50(m,8H),1.45(s,9H),1.38(s,9H).

[0324] Step 6: (1S,3S)-N-methyl-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)cyclopentan-1-amine

[0325] [ka] To a solution of tert-butyl 7-(4-(((1S,3S)-3-((tert-butoxycarbonyl)(methyl)amino)-cyclopentyl)oxy)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (28 g, 55.59 mmol, 1 equivalent) in DCM (300 mL), TFA (153.50 g, 1.35 mol, 100.00 mL, 24.22 equivalents) was added under N2 at 25°C, and the solution was stirred at 25°C for 16 hours. LCMS showed that the starting material was completely consumed and a single main peak with the desired mass was detected. The residue was adjusted to approximately pH 7 with aqueous NaHCO3, extracted with DCM (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250×100mm×10um, mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 0%~50%, 35 min) to obtain (1S,3S)-N-methyl-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyridine-2-yl)butoxy)cyclopentan-1-amine (yield 54.54%) as a yellow oily substance.

[0326] LCMS:[M+1]=304.2;SFC:R t =2.070 minutes; 1H NMR (400MHz, methanol-d4) δ=7.11(d,J=7.4Hz,1H),6.35(d,J=7.4Hz,1H),4.07-3.82(m,1H),3.41-3.34(m,4H),3.10(quin,J=7.1Hz,1H),2.68(t, J=6.3Hz,2H),2.51(t,J=7.6Hz,2H),2.32(s,3H),2.03-1.91(m,3H),1.9 0-1.83(m,2H),1.71-1.59(m,3H),1.57-1.46(m,3H),1.38-1.28(m,1H).

[0327] Preparation of rac-(1S,4R)-N,3,3-trimethyl-4-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)cyclopentan-1-amine hydrochloride

[0328] [ka] Step 1: 5-Bromo-2,2-dimethylcyclopentan-1-one

[0329] [ka] To a solution of 2,2-dimethylcyclopentan-1-one (250 g, 2.23 mol, 279.64 mL, 1 equivalent) in DCM (2000 mL), add a solution of Br2 (391.8 g, 2.45 mol, 126.31 mL, 1.1 equivalent) in DCM (500 mL), 0 ℃ The mixture was added. The mixture was stirred at 20°C for 16 hours. The reaction was quenched by adding H2O (2000 mL) and saturated NaS2O3 at 25°C until the solution became colorless. The pH of the solution was adjusted to pH=7 by adding saturated NaHCO3. The mixture was diluted with DCM (2000 mL) and extracted with DCM (1000 mL x 3). The organic solutions were combined, washed with brine (1000 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 5-bromo-2,2-dimethylcyclopentan-1-one (350 g, crude) as a brown solid.

[0330] Step 2: 5,5-bromo-2-difluoroindoline-1-one

[0331] [ka] A mixture of 5-bromo-2,2-dimethylcyclopentan-1-one (350 g, 1.83 mol, 1 equivalent) and DBU (334.65 g, 2.20 mol, 331.34 mL, 1.2 equivalents) in MTBE (2000 mL) was degassed and purged three times with nitrogen. The mixture was stirred under N2 at 25°C for 16 hours. The mixture was distilled under vacuum (62°C, -0.08 MPa / water pump). 5,5-dimethylcyclopenta-2-en-1-one (110 g, 798.89 mmol, 44.81% yield in 2 steps) was obtained as a pale yellow oil.

[0332] Step 3: 4-(benzyl(methyl)amino)-2,2-dimethylcyclopentan-1-one

[0333] [ka] BnMeNH (114.96 g, 948.68 mmol, 122.43 mL, 0.95 equivalents) was added dropwise to 5,5-dimethylcyclopenta-2-en-1-one (110 g, 998.61 mmol, 1 equivalent) at 25°C, and the mixture was stirred at 50°C for 2 hours. The reaction mixture was cooled to 0°C, and a solid was formed. The mixture was filtered, and the filtered cake was dried under vacuum. 4-(benzyl(methyl)amino)-2,2-dimethylcyclopentan-1-one (yield 51.95%) was obtained as a yellow solid.

[0334] Step 4: tert-butyl(3,3-dimethyl-4-oxocyclopentyl)(methyl)carbamate

[0335] [ka] To a solution of Pd / C (5g, 10% purity) in MeOH (1000mL), Boc2O (84.91g, 389.05 mmol, 89.38mL, 1.5 equivalents) and 4-(benzyl(methyl)amino)-2,2-dimethylcyclopentan-1-one (60g, 259.37 mL, 1 equivalent) were added under Ar at 25°C. The suspension was degassed under vacuum and purged three times with H2. The mixture was stirred under H2 (30 psi) at 25°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~3 / 1). Tert-butyl(3,3-dimethyl-4-oxocyclopentyl)(methyl)carbamate (yield 51.92%) was obtained as a pale yellow oil. 1 H NMR(400MHz, CDCl3)δ=4.81(brd,J=1.0Hz,1H),2.77(s,3H),2.61-2.48(m,1H),2.39-2. 25(m,1H),2.02-1.93(m,1H),1.89-1.77(m,1H),1.47(s,9H),1.13(s,3H),1.06(s,3H).

[0336] Step 6: rac-tert-butyl((1S,4R)-4-hydroxy-3,3-dimethylcyclopentyl)(methyl)carbamate

[0337] [ka] To a solution of tert-butyl(3,3-dimethyl-4-oxocyclopentyl)(methyl)carbamate (130 g, 538.69 mmol, 1 equivalent) in THF (1000 mL), DIBAL-H (1 M, 538.69 mL, 1 equivalent) was added at 0°C under an N2 atmosphere. The reaction mixture was then heated to 20°C and stirred at 20°C under an N2 atmosphere for 16 hours. The mixture was quenched by adding Na2SO4.10 H2O (100 g). The mixture was then dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~3 / 1). Rac-tert-butyl((1S,4R)-4-hydroxy-3,3-dimethylcyclopentyl)(methyl)carbamate (yield 41.96%) was obtained as a colorless oil. 1 H NMR(400MHz,CDCl3)δ=4.72(m,1H),3.83(t,J=7.8Hz,1H),2.73(s,3H),2.06-1.96(m,2H),1.88 (brdd,J=7.7,10.4Hz,1H),1.75(dd,J=8.6,12.9Hz,1H),1.46(s,9H),1.06(s,3H),0.94(s,3H).

[0338] Final step: rac-(1S,4R)-N,3,3-trimethyl-4-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)cyclopentan-1-amine hydrochloride

[0339] [ka] rac-tert-butyl((1S,4R)-4-hydroxy-3,3-dimethylcyclopentyl)(methyl)carbamate was converted to rac-(1S,3S)-N-methyl-3-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)cyclopentan-1-amine hydrochloride by the same method as described above in steps 3-6 of the synthesis of rac-(1S,4R)-N,3,3-trimethyl-4-(4-(5,6,7,8-tetrahydro-1,8-naphthyrizin-2-yl)butoxy)cyclopentan-1-amine hydrochloride. LCMS[M+1] = 332.2%, 96.78% 1 H NMR(400MHz,CD3OD)δ=7.58(d,J=7.3Hz,1H),6.60(d,J=7.4Hz,1H),3.64(brdd,J=6.8,8.5Hz,1H),3.57(s,5H),2.82(t,J=6.1Hz,2H),2.73(t,J=7. 7Hz,2H),2.65(s,3H),2.13-1.93(m,5H),1.82-1.73(m,2H),1.62(brdd,J =6.2,8.7Hz,2H),1.45(dd,J=8.8,13.1Hz,1H),1.11(s,3H),0.94(s,3H).

[0340] right intermediate Preparation of 1-bromo-3-fluoro-4-methyl-2-nitrobenzene

[0341] [ka] Step 1: 3-Fluoro-4-methyl-2-nitroaniline Two reactions were carried out in parallel. To a mixture of 4-bromo-3-fluoro-2-nitroaniline (25 g, 106.38 mmol, 1 equivalent) and methylboronic acid (31.84 g, 531.89 mmol, 5 equivalents) in dioxane (250 mL) and H2O (62.5 mL), Pd(dppf)Cl2 (3.89 g, 5.32 mmol, 0.05 equivalents) and K2CO3 (44.11 g, 319.13 mmol, 3 equivalents) were added at 25 °C. The mixture was stirred at 90 °C for 16 hours under an N2 atmosphere. The mixture was quenched by adding H2O (300 mL) and filtered. The mixture was extracted with ethyl acetate (200 mL x 3). The organic solutions were combined, washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). 3-Fluoro-4-methyl-2-nitroaniline (yield 55.25%) was obtained as a yellow oil. LCMS:R t =0.557 min, [M+1]=171.1, 55.30%. 1 H NMR (400MHz, CDCl3) δ=7.11(t,J=8.1Hz,1H),6.50(dd,J=1.6,8.6Hz,1H),2.19(d,J=2.5Hz,3H).

[0342] Step 2: 1-Bromo-3-fluoro-4-methyl-2-nitrobenzene To a solution of HBr (111.75 g, 455.77 mmol, 75.00 mL, 33% purity, 15.51 equivalents) in H2O (500 mL), 3-fluoro-4-methyl-2-nitroaniline was added, and the mixture was stirred at 70°C for 30 minutes. The mixture was cooled to -5°C, and NaNO2 (12.57 g, 182.20 mmol, 6.2 equivalents) dissolved in H2O (62.5 mL) was slowly added. The mixture was stirred at -5°C for 30 minutes. A solution of CuBr (52.70 g, 367.34 mmol, 11.19 mL, 12.5 equivalents) in an aqueous HBr solution (260.75 g, 1.06 mol, 175.00 mL, 33% purity, 36.19 equivalents) was added dropwise at 0°C. The mixture was stirred at 70°C for 30 minutes. The reaction mixture was quenched by adding water (200 mL) and extracted with DCM (200 mL x 3). The organic layers were combined, washed with aqueous NaOH solution (4 M, 150 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). 1-Bromo-3-fluoro-4-methyl-2-nitrobenzene (yield 79.97%) was obtained as a yellow oil. 1 H NMR (400MHz, CDCl3) δ=7.36(dd,J=1.4,8.3Hz,1H),7.26-7.20(m,1H),2.33(d,J=2.1Hz,3H).

[0343] Preparation of tert-butyl 2-bromo-2-(1-(tert-butyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl) acetate

[0344] [ka] Step 1: 3-Bromo-N-(tert-butyl)-2-nitroaniline

[0345] [ka] To a solution of 1-bromo-3-fluoro-2-nitrobenzene (50 g, 227.28 mmol, 1 equivalent) in DMSO (100 mL), Cs2CO3 (148.10 g, 454.55 mmol, 2 equivalents) and t-BuNH2 (16.62 g, 227.28 mmol, 23.88 mL, 1 equivalent) were added at 25°C. The mixture was stirred at 60°C for 12 hours. TLC (petroleum ether:ethyl acetate = 5:1, R) f A value of 0.63 indicated that the starting material had been completely consumed and new spots with lower polarity had been detected. The mixture was quenched with H2O (300 mL) and ethyl acetate (150 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 (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 3-bromo-N-(tert-butyl)-2-nitroaniline (yield 64.4%) as a red oil. 1 ¹H NMR (400MHz, methanol-d4): δ = 7.21-7.16 (m, 2H), 6.98 (dd, J = 2.4, 6.5Hz, 1H), 1.39 (s, 9H)

[0346] Process 2: 3-Bromo-N 1 -(tert-butyl)benzene-1,2-diamine

[0347] [ka] To a solution of 3-bromo-N-(tert-butyl)-2-nitroaniline (30 g, 109.84 mmol, 1 equivalent) in CH3COOH (75 mL) and siRNA (225 mL), H2O (25 mL) was added at 25 °C. The mixture was heated to 50 °C. Then, Fe (30.67 g, 549.20 mmol, 5 equivalents) was added little by little at 50 °C, and the mixture was then heated to 80 °C and stirred for 16 hours. TLC (petroleum ether:ethyl acetate = 5:1, R fA value of 0.61 indicated that the starting material had been completely consumed and several new spots with greater polarity were detected. The reaction mixture was filtered at 80°C and then concentrated to obtain the residue. The residue was dissolved in toluene (200 mL) and the pH was adjusted to 7-8 with saturated NaHCO3. The organic phase was separated and washed with brine (100 mL x 3). The organic phase was dried over Na2SO4, filtered, and concentrated to obtain the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 200 g SepaFlash® silica flash column, ethyl acetate / petroleum gradient of 0-50% eluent @ 150 mL / min). 3-Bromo-N 1 -(tert-butyl)benzene-1,2-diamine (yield 74.9%) was obtained as a yellow oily substance. 1 H NMR (400MHz, methanol-d4) δ = 7.00 (dd, J = 1.3, 8.0 Hz, 1H), 6.88 (dd, J = 1.3, 7.9 Hz, 1H), 6.52 (t, J = 7.9 Hz, 1H), 1.27 (s, 9H).

[0348] Step 3: 4-bromo-1-(tert-butyl)-1,3-dihydro-2H-benzo[d]imidazole-2-one

[0349] [ka] 3-bromo-N in THF (200 mL) 1 To a solution of -(tert-butyl)benzene-1,2-diamine (20 g, 82.26 mmol, 1 equivalent), TEA (24.97 g, 246.77 mmol, 34.35 mL, 3 equivalents) and bis(trichloromethyl) carbonate (24.41 g, 82.26 mmol, 1 equivalent) were added. The mixture was stirred at 20°C for 16 hours. LCMS(R tThe reaction time (0.675 min) indicated that the starting material was completely consumed and a single main peak with the desired mass was detected. The reaction mixture was slowly quenched with ice water (200 mL) to adjust the pH to 7 and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 200 g SepaFlash® silica flash column, ethyl acetate / petroleum gradient of 0-50% eluent @ 150 mL / min). 4-bromo-1-(tert-butyl)-1,3-dihydro-2H-benzo[d]imidazole-2-one (yield 84.0%) was obtained as a yellow oil. LCMS:[M+1]=270.9. 1 ¹H NMR (400MHz, methanol-d4): δ = 7.45 (d, J=8.3Hz, 1H), 7.15 (d, J=8.2Hz, 1H), 6.91 (t, J=8.3Hz, 1H), 1.77 (s, 9H).

[0350] Step 4: 4-Bromo-1-(tert-butyl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-one

[0351] [ka] To a solution of 4-bromo-1-(tert-butyl)-1,3-dihydro-2H-benzo[d]imidazole-2-one (18.6 g, 69.11 mmol, 1 equivalent) in DMF (190 mL), NaH (5.53 g, 138.22 mmol, 60% purity, 2 equivalents) was added. The mixture was stirred at 0°C for 0.5 hours. Then, MeI (19.62 g, 138.22 mmol, 62.42 mL, 2 equivalents) was added to the mixture, and the mixture was stirred at 20°C for 1 hour. LCMS(R tThe reaction time (1.661 min) indicated that the starting material was completely consumed and a single main peak with the desired mass was detected. The reaction mixture was quenched by adding NH4Cl (200 mL) at 0°C and extracted with siRNA (150 mL x 3). The combined organic layer was washed with 450 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 200 g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum gradient @ 150 mL / min). 4-Bromo-1-(tert-butyl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-one (yield 97.09%) was obtained as a yellow oil. LCMS:[M+1]=283.1. 1 ¹H NMR (400MHz, methanol-d4): δ = 7.52 (d, J=8.3Hz, 1H), 7.21 (d, J=8.1Hz, 1H), 6.92 (t, J=8.3Hz, 1H), 3.70 (s, 3H), 1.77 (s, 9H).

[0352] Step 5: tert-butyl 2-(1-(tert-butyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl)acetate

[0353] [ka] Pd(t-Bu3P)2 (1.71g, 6.71mmol, 0.05 equivalents) was added to a solution of 4-bromo-1-(tert-butyl)-3-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-one (19g, 67.10mmol, 1 equivalent) and bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (1M, 167.75mL, 2.5 equivalents) in THF (200mL). The mixture was stirred at 80°C for 2 hours. TLC (petroleum ether:ethyl acetate = 5:1, R fA value of 0.43 indicated that the starting material had been completely consumed and new spots with greater polarity had been detected. The reaction mixture was slowly quenched with ice water (200 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 200 g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum gradient @ 120 mL / min). Tert-butyl 2-(1-(tert-butyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl) acetate (yield 93.61%) was obtained as a yellow oil. 1 ¹H NMR (400MHz, methanol-d4): δ=7.47 (dd, J=0.7, 8.2Hz, 1H), 7.02-6.94 (m, 1H), 6.89 (d, J=7.5Hz, 1H), 3.91 (s, 2H), 3.57 (s, 3H), 1.79 (s, 9H), 1.44 (s, 9H).

[0354] Step 6: tert-butyl 2-bromo-2-(1-(tert-butyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl) acetate

[0355] [ka] To a solution of tert-butyl 2-(1-(tert-butyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl) acetate (3g, 9.42 mmol, 1 equivalent) in THF (30 mL), LDA (2M, 14.13 mL, 3 equivalents) was added at -70°C, and the mixture was stirred at -70°C for 45 minutes. TMSCl (3.07 g, 28.27 mmol, 3.59 mL, 3 equivalents) was added. After 15 minutes, a solution of NBS (5.03 g, 28.27 mmol, 3 equivalents) in THF (15 mL) was added, and the mixture was stirred at -70°C for 1 hour. TLC (petroleum ether:ethyl acetate = 5:1, R fA value of 0.69 indicated that the starting material had been completely consumed and new spots with lower polarity had been detected. The reaction mixture was slowly quenched with ice water (30 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0-50% ethyl acetate / petroleum gradient @ 80 mL / min). Tert-butyl 2-bromo-2-(1-(tert-butyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl) acetate (yield 90.83%) was obtained as a yellow oil.

[0356] The intermediates in the following table were prepared from the indicated starting materials, using appropriate reagents instead, following a procedure similar to that described for tert-butyl 2-bromo-2-(1-(tert-butyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl) acetate, and purified under appropriate conditions:

[0357] [Table 3]

[0358] Preparation of tert-butyl 2-bromo-2-(3,6-dimethyl-1-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl)acetate

[0359] [ka] Step 1: tert-butyl 2-(3-methyl-1-(1-methylcyclopropyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-benzo[d]imidazole-4-yl) acetate

[0360] [ka] To a solution of tert-butyl 2-(3-methyl-1-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl) acetate (2 g, 6.32 mmol, 1 equivalent) in dioxane (40 mL), dtbpy (101.80 mg, 379.27 umol, 0.06 equivalents), [Ir(OMe)(cod)]2 (251.41 mg, 379.27 umol, 0.06 equivalents) and Pin2B2 (3.21 g, 12.64 mmol, 2 equivalents) were added under N2 at 20°C. The mixture was heated to 80°C and stirred under N2 at 80°C for 16 hours. TLC (petroleum ether / ethyl acetate = 5 / 1, R f A value of 0.52 indicated that the starting material had been completely consumed and that one major new spot with lower polarity had been detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue and crude product. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). Tert-butyl 2-(3-methyl-1-(1-methylcyclopropyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-benzo[d]imidazole-4-yl)acetic acid (4.5 g, crude) was obtained as a yellow oily substance.

[0361] Step 2: tert-butyl 2-(3,6-dimethyl-1-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl) acetate

[0362] [ka] To a solution of tert-butyl 2-(3-methyl-1-(1-methylcyclopropyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-benzo[d]imidazole-4-yl) acetate (3.5 g, 7.91 mmol, 1 equivalent) in toluene (35 mL), EtOH (14 mL), and H2O (14 mL), K2CO3 (3.28 g, 23.74 mmol, 3 equivalents), Pd(PPh3)4 (457.15 mg, 395.61 mmol, 0.05 equivalents), and MeI (5.62 g, 39.56 mmol, 2.46 mL, 5 equivalents) were sequentially added under N2 conditions at 20°C. Next, the reaction mixture was heated to 100°C and stirred under N2 at 100°C for 16 hours. LCMS(R t =0.797, [M+1]=331.1, 56.55%) indicated that compound 2 was completely consumed and 56.55% of the desired MS was detected. The reaction mixture was diluted with water (150 mL) for 20 minutes. ℃ The mixture was quenched and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine (30 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0~80 / 20). Tert-butyl 2-(3,6-dimethyl-1-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl) acetate (yield 42.08%) was obtained as a yellow oil.

[0363] Step 3: tert-butyl 2-bromo-2-(3,6-dimethyl-1-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl) acetate

[0364] [ka] To a solution of tert-butyl 2-(3,6-dimethyl-1-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl) acetate (550 mg, 1.66 mmol, 1 equivalent) in THF (10 mL), LDA (2 M, 2.50 mL, 3 equivalents) was added under N2 at -70°C. The mixture was then stirred under N2 at -70°C for 0.5 hours. Next, TMSCl (542.52 mg, 4.99 mmol, 633.78 μL, 3 equivalents) was added to the reaction mixture under N2 at -70°C. ℃ The mixture was then stirred under N2 at -70°C for 0.5 hours. Next, a solution of NBS (888.79 mg, 4.99 mmol, 3 equivalents) in THF solution (10 mL) was added to the reaction mixture under N2 at -70°C. The mixture was then stirred under N2 at -70°C for 1 hour. LC-MS showed that the starting material was completely consumed and 87.45% of the desired MS was detected. The reaction mixture was quenched with saturated NH4Cl aqueous solution (100 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). Tert-butyl 2-bromo-2-(3,6-dimethyl-1-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl) acetate (yield 77.79%) was obtained as a yellow oily substance. LCMS:[M+1]=411.1. 1 H NMR(400MHz,CDCl3)δ=7.15(s,1H),6.99(d,J=0.8Hz,1H),5.94(s,1H),3.71(s,3H),2.41( s, 3H), 2.05 (s, 2H), 1.49 (s, 9H), 1.15-1.12 (m, 2H), 1.00-0.96 (m, 2H), 0.21-0.13 (m, 1H).

[0365] The intermediates in the following table were prepared from the indicated starting materials, using appropriate reagents instead, following a procedure similar to that described for tert-butyl 2-bromo-2-(3,6-dimethyl-1-(1-methylcyclopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl) acetate, and purified under appropriate conditions:

[0366] [Table 4]

[0367] Preparation of 4-bromo-6-methylindorin-2-one

[0368] [ka] Step 1: Methyl 2-(2-bromo-6-fluoro-4-methylphenyl)-2-oxoacetate

[0369] [ka] To a solution of 1-bromo-3-fluoro-5-methylbenzene (100g, 529.03 mmol, 1 equivalent) in THF (500 mL), LDA (2M, 317.42 mL, 1.2 equivalents) was added dropwise under N2 at -70°C. The reaction mixture was then stirred at -70°C for 0.5 hours. Next, a solution of dimethyl oxalate (81.21g, 687.74 mmol, 1.3 equivalents) in THF (500 mL) was added to the reaction mixture under N2 at -70°C. The reaction mixture was then stirred at N2 at -70°C for 1 hour. TLC (petroleum ether / ethyl acetate = 5 / 1, R) fA reading of 0.43 indicated that the starting material had been completely consumed and one new spot had formed. The residue was quenched with NH4Cl aqueous solution (1000 mL) and extracted with siRNA (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~5 / 1). Methyl 2-(2-bromo-6-fluoro-4-methylphenyl)-2-oxoacetate (yield 65.28%) was obtained as a red oil. 1 ¹H NMR (400MHz, chloroform-d): δ = 7.29 (s, 1H), 6.96 (d, J = 10.3Hz, 1H), 3.95 (s, 3H), 2.40 (s, 3H).

[0370] Step 2: 4-Bromo-1-(tert-butyl)-6-methylindoline-2,3-dione

[0371] [ka] To a solution of t-BuNH2 (5.85 g, 79.98 mmol, 8.40 mL, 2.2 equivalents) in THF (100 mL), n-BuLi (2.5 M, 30.54 mL, 2.1 equivalents) was added under N2 at -70°C. The mixture was stirred at -70°C for 0.5 hours. Methyl 2-(2-bromo-6-fluoro-4-methylphenyl)-2-oxoacetate (10 g, 36.35 mmol, 1 equivalent) was added to THF (100 mL) under N2 at -70°C. The mixture was stirred at 20°C for 2 hours. LCMS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The reaction mixture was quenched with ice HCl aqueous solution (200 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was ground in PE:EA = 3:1 at 20°C for 30 minutes. 4-Bromo-1-(tert-butyl)-6-methylindoline-2,3-dione (yield 63.47%) was obtained as a red solid. LCMS:[M+1] = 296.0.1 ¹H NMR (400 MHz, chloroform-d): δ = 7.07 (s, 2H), 2.42 (s, 3H), 1.74 (s, 9H)

[0372] Step 3: 4-Bromo-1-(tert-butyl)-6-methylindoline-2-one

[0373] [ka] To a solution of 4-bromo-1-(tert-butyl)-6-methylindoline-2,3-dione (39 g, 131.69 mmol, 1 equivalent) in glycol (400 mL), NH2NH2·H2O (82.56 g, 1.62 mol, 80 mL, 98% purity, 12.27 equivalents) was added under N2 at 25°C. The mixture was stirred at 130°C for 3 hours. LC-MS showed that the starting material was completely consumed and a single main peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure, quenched by adding H2O (200 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was used directly without further purification. 4-Bromo-1-(tert-butyl)-6-methylindorin-2-one (yield 94.19%) was obtained as a red solid. LCMS:[M+1]=284.0. 1 ¹H NMR (400MHz, chloroform-d): δ=6.99 (d, J=9.7Hz, 2H), 3.38 (s, 2H), 2.36 (s, 3H), 1.71 (s, 9H)

[0374] Step 4: 4'-Bromo-1'-(tert-butyl)-6'-methylspiro[cyclopropane-1,3'-indoline]-2'-one

[0375] [ka] To a solution of 4-bromo-1-(tert-butyl)-6-methylindorin-2-one (42 g, 148.84 mmol, 1 equivalent) in DMF (400 mL), NaH (17.86 g, 446.53 mmol, 60% purity, 3 equivalents) was added under N2 at 0°C, and the solution was stirred at 0°C for 0.5 hours. Then, 1,2-dibromoethane (83.89 g, 446.53 mmol, 33.69 mL, 3 equivalents) was added to the solution at 0°C, and the solution was stirred at 25°C for 1 hour. LC-MS showed that the starting material was completely consumed and a single main peak with the desired mass was detected. The reaction mixture was quenched with saturated NH4Cl (400 mL) and extracted with siRNA (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). 4'-bromo-1'-(tert-butyl)-6'-methylspiro[cyclopropan-1,3'-indoline]-2'-one (yield 47.96%) was obtained as a yellow oil. LCMS:[M+1]=310.1. 1 ¹H NMR (400MHz, chloroform-d): δ = 7.03 (s, 1H), 6.85 (s, 1H), 2.28 (s, 3H), 2.15 (q, J=3.7Hz, 2H), 1.67 (s, 9H), 1.35 (q, J=3.7Hz, 2H), 1.31 (s, 3H).

[0376] Step 5: 4-Bromo-6-methylindoline-2-one

[0377] [ka] Under N2 conditions, a solution of 4'-bromo-1'-(tert-butyl)-6'-methylspiro[cyclopropan-1,3'-indoline]-2'-one (22 g, 71.38 mmol, 1 equivalent) in TFA (100 mL) was stirred at 25°C for 0.5 hours. LC-MS showed that the starting material was completely consumed and a single main peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The crude product was ground in MeCN at 20°C for 30 minutes. 4-bromo-6-methylindoline-2-one (yield 77.80%) was obtained as a yellow solid. LC-MS: [M+1] = 253.9. 1 ¹H NMR (400MHz, chloroform-d): δ = 6.94 (s, 1H), 6.76 (s, 1H), 2.33 (s, 3H), 2.28 (d, J=3.9Hz, 2H), 1.56 (d, J=3.9Hz, 2H).

[0378] Preparation of 5-bromo-4-methyl-5',6'-dihydro-2'H,4'H-spiro[isochroman-1,3'-pyran]

[0379] [ka] Step 1: 2-(2,6-dibromophenyl)oxirane

[0380] [ka] 2,6-dibromobenzaldehyde (30g, 113.67 mmol, 1 equivalent) and Me3S in THF (500mL) and DMSO (100mL) + I -To a solution of (69.59 g, 341.02 mmol, 3 equivalents), NaH (13.64 g, 341.02 mmol, 60% purity, 3 equivalents) was added under N2 at -10°C. The mixture was stirred at 20°C for 1 hour. TLC (petroleum ether / ethyl acetate = 10 / 1, Rf = 0.6) showed that 2,6-dibromobenzaldehyde had been consumed and one major new spot with greater polarity was detected. The mixture was quenched with aqueous NH4Cl solution (1.5 L) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (1000 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was ground over EtOH at 20°C for 10 minutes to obtain 2-(2,6-dibromophenyl)oxirane (yield 66.47%) as a white solid. 1 ¹H NMR (400MHz, chloroform-d): δ=7.55 (d, J=8.1Hz, 2H), 7.06 (t, J=8.1Hz, 1H), 3.94-3.85 (m, 1H), 3.33 (dd, J=4.3, 5.0Hz, 1H), 2.98 (dd, J=2.8, 5.1Hz, 1H).

[0381] Step 2: 2-(2,6-dibromophenyl)propan-1-ol

[0382] [ka] A solution of AlMe3 (2.0 M, 82.75 mL, 1 equivalent) in toluene (500 mL) was added dropwise to a solution of 2-(2,6-dibromophenyl)oxirane (46 g, 165.50 mmol, 1 equivalent) in toluene (300 mL) under N2 at -60°C. The mixture was stirred at 0°C for 1 hour. TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.3) showed that the 2-(2,6-dibromophenyl)oxirane had been consumed and one major new spot with greater polarity was detected. The mixture was quenched by adding Na2SO4·10H2O (100 g) and THF (500 mL). The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to obtain 2-(2,6-dibromophenyl)propan-1-ol (yield 61.66%) as a colorless oil.

[0383] Step 3: 1,3-Dibromo-2-(1-(methoxymethoxy)propan-2-yl)benzene

[0384] [ka] To a solution of 2-(2,6-dibromophenyl)propan-1-ol (28 g, 95.24 mmol, 1 equivalent) and DIEA (49.24 g, 380.97 mmol, 66.36 mL, 4 equivalents) in DCM (200 mL), MOMBr (23.80 g, 190.49 mmol, 15.55 mL, 2 equivalents) was added at 0°C, and the mixture was stirred at 20°C for 16 hours. TLC (petroleum ether / ethyl acetate = 1 / 1, Rf = 0.59) showed that 2-(2,6-dibromophenyl)propan-1-ol had been consumed, and one major new spot with lower polarity was detected. The reaction mixture was quenched by adding saturated NaHCO3 aqueous solution (300 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain 1,3-dibromo-2-(1-(methoxymethoxy)propan-2-yl)benzene (yield 86.97%) as a colorless oil. 1 H NMR (400MHz, chloroform-d) δ=7.57(d,J=8.0Hz,1H),7.51(d,J=8.0Hz,1H),6.90(t,J=8.0Hz,1H),4.6 7-4.56(m,2H),4.17-4.05(m,2H),3.93(dd,J=6.8,8.9Hz,1H),3.31(s,3H),1.44(d,J=7.0Hz,3H).

[0385] Step 4: 3-(3-bromo-2-(1-(methoxymethoxy)propan-2-yl)phenyl)tetrahydro-2H-pyran-3-ol

[0386] [ka] To a solution of 1,3-dibromo-2-(1-(methoxymethoxy)propan-2-yl)benzene (5.2 g, 15.38 mmol, 1 equivalent) and TMEDA (1.97 g, 16.92 mmol, 2.55 mL, 1.1 equivalent) in THF (60 mL), n-BuLi (2.5 M, 6.15 mL, 1 equivalent) was added dropwise under N2 at -60°C. The mixture was stirred at -60°C for 0.5 hours. Then, dihydro-2H-pyran-3(4H)-one (4.62 g, 46.15 mmol, 3 equivalents) was added dropwise at -60°C, and the mixture was stirred at 0°C for 0.5 hours. TLC (petroleum ether / ethyl acetate = 10 / 1, Rf = 0.4) showed that 1,3-dibromo-2-(1-(methoxymethoxy)propan-2-yl)benzene was consumed and one major new spot with greater polarity was detected. The mixture was quenched with NH4Cl aqueous solution (300 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layer was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1~2 / 1) to obtain 3-(3-bromo-2-(1-(methoxymethoxy)propan-2-yl)phenyl)tetrahydro-2H-pyran-3-ol (yield 37.09%) as a colorless oil.

[0387] Step 5: 3-(3-bromo-2-(1-hydroxypropan-2-yl)phenyl)tetrahydro-2H-pyran-3-ol

[0388] [ka] To a solution of 3-(3-bromo-2-(1-(methoxymethoxy)propan-2-yl)phenyl)tetrahydro-2H-pyran-3-ol (14 g, 38.97 mmol, 1 equivalent) in MeCN (50 mL), HCl (100 mL) was added at 20°C, and the mixture was stirred at 20°C for 12 hours. TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.42) showed that 3-(3-bromo-2-(1-(methoxymethoxy)propan-2-yl)phenyl)tetrahydro-2H-pyran-3-ol had been consumed, and one major new spot with greater polarity was detected. The mixture was quenched with H2O (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain 3-(3-bromo-2-(1-hydroxypropan-2-yl)phenyl)tetrahydro-2H-pyran-3-ol (10.7 g, 23.76 mmol, yield 60.98%, purity 70%) as a yellow oily substance. LCMS:[M+1]=296.9.

[0389] Step 6: 5-bromo-4-methyl-5',6'-dihydro-2'H,4'H-spiro[isochroman-1,3'-pyran]

[0390] [ka] To a solution of 3-(3-bromo-2-(1-hydroxypropan-2-yl)phenyl)tetrahydro-2H-pyran-3-ol (10.7 g, 23.76 mmol, 1 equivalent) in toluene (100 mL), CMBP (8.60 g, 35.64 mmol, 1.5 equivalents) was added at 20°C. The mixture was stirred at 80°C for 16 hours. LC-MS showed that 3-(3-bromo-2-(1-hydroxypropan-2-yl)phenyl)tetrahydro-2H-pyran-3-ol was consumed and approximately 53% of the desired compound was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1), and then purified by preparative HPLC (column: Phenomenex lunac18 250mm*100mm*10um; mobile phase: [H2O(0.1%TFA)-ACN]; gradient: 30% to 65% over 24.0 minutes B) to obtain 5-bromo-4-methyl-5',6'-dihydro-2'H,4'H-spiro[isochroman-1,3'-pyran] (yield 67.97%) as a yellow oily substance.

[0391] Step 7: Stereoisomers of 5-bromo-4-methyl-5',6'-dihydro-2'H,4'H-spiro[isochroman-1,3'-pyran]

[0392] [ka] 5-Bromo-4-methyl-5',6'-dihydro-2'H,4'H-spiro[isochroman-1,3'-pyran] (4.8g, 16.15 mmol, 1 equivalent) was separated by SFC (column: DAIEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [CO2-MeOH]; B%: 15%, fixed composition elution mode) to obtain four isomers.

[0393] Peak 1, arbitrarily assigned (1S,4S)-5-bromo-4-methyl-5',6'-dihydro-2'H,4'H-spiro[isochroman-1,3'-pyran] (yield 20.83%), was obtained as a white solid. LCMS: [M+1] = 297.2. SFC: Rt = 1.656. 1 H NMR (400MHz, chloroform-d) δ=7.46(d,J=7.5Hz,1H),7.13-7.06(m,2H),4.08(brdd ,J=4.2,11.2Hz,1H),4.01(brd,J=12.4Hz,1H),3.96-3.91(m,1H),3.87-3.82( m,1H),3.56-3.49(m,1H),3.39(d,J=12.5Hz,1H),3.00(q,J=6.2Hz,1H),2.30- 2.19(m,1H),2.06-1.97(m,2H),1.57(brd,J=9.3Hz,1H),1.39(d,J=6.9Hz,3H).

[0394] Peak 2, arbitrarily assigned (1S,4R)-5-bromo-4-methyl-5',6'-dihydro-2'H,4'H-spiro[isochroman-1,3'-pyran] (yield 16.88%), was obtained as a white solid. LCMS: [M+1] = 297.2. SFC: Rt = 1.848. 1 H NMR(400MHz,chloroform-d)δ=7.46(dd,J=2.3,6.6Hz,1H),7.11-7.06(m,2H),4.08(brdd,J=3.0,12.4Hz,1H),3.91-3.85(m,2H),3.76-3.74(m,1H),3.7 1-3.67(m,1H),3.54(brt,J=11.8Hz,1H),3.05-2.98(m,1H),2.24-2.14(m ,2H),1.79-1.71(m,1H),1.51(brd,J=13.5Hz,1H),1.39(d,J=6.9Hz,3H).

[0395] Peak 3, arbitrarily assigned (1R,4R)-5-bromo-4-methyl-5',6'-dihydro-2'H,4'H-spiro[isochroman-1,3'-pyran] (yield 22.92%), was obtained as a white solid. LCMS: [M+1] = 297.2. SFC: Rt = 2.441.1 H NMR(400MHz,chloroform-d)δ=7.46(dd,J=1.6,7.4Hz,1H),7.12-7.05(m,2H),4.08(brdd,J=4.4,11.2Hz,1H),4.02(brd,J=12.4Hz,1H),3.96-3.92(m,1H),3. 87-3.83(m,1H),3.56-3.49(m,1H),3.39(d,J=12.4Hz,1H),3.03-2.97(m,1H) ,2.29-2.19(m,1H),2.06-1.98(m,2H),1.56(brs,1H),1.39(d,J=6.9Hz,3H).

[0396] Peak 4, arbitrarily assigned (1R,4S)-5-bromo-4-methyl-5',6'-dihydro-2'H,4'H-spiro[isochroman-1,3'-pyran] (yield 22.92%), was obtained as a white solid. LCMS: [M+1] = 297.2. SFC: Rt = 2.441. 1 H NMR(400MHz,chloroform-d)δ=7.46(dd,J=2.2,6.7Hz,1H),7.11-7.06(m,2H),4.11-4.06(m,1H),3.90-3.85(m,2H),3.74(brd,J=2.0Hz,1H),3 .71-3.67(m,1H),3.57-3.51(m,1H),3.01(q,J=6.8Hz,1H),2.24-2.14(m,2H),1.79-1.71(m,1H),1.56-1.49(m,1H),1.39(d,J=6.9Hz,3H).

[0397] Preparation of 5-bromo-4-methyl-2',3',5',6'-tetrahydrospiro[isochroman-1,4'-pyran]

[0398] [ka] Isomers of 5-bromo-4-methyl-2',3',5',6'-tetrahydrospiro[isochroman-1,4'-pyran] were prepared using the same method as described above for the preparation of 5-bromo-4-methyl-5',6'-dihydro-2'H,4'H-spiro[isochroman-1,3'-pyran], and separated by SFC (column: DAIEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [CO2-EtOH]; B%: 15%, fixed composition elution mode).

[0399] Peak 1, arbitrarily assigned (S)-5-bromo-4-methyl-2',3',5',6'-tetrahydrospiro-[isochroman-1,4'-pyran], was obtained as a white solid. SFCR t =1.638 minutes. 1 H NMR(400MHz,CDCl3)δ=7.44(dd,J=1.6,7.4Hz,1H),7.14-7.07(m,2H),3.99-3.92(m,1H),3.90-3.86(m,2H),3.85-3.82(m, 2H),3.80(s,1H),3.04-2.96(m,1H),2.23-2.16(m,1H),1.93-1.87(m,2H),1.65(brd,J=13.5Hz,1H),1.38(d,J=6.9Hz,3H).

[0400] Peak 2, the arbitrarily assigned (R)-5-bromo-4-methyl-2',3',5',6'-tetrahydrospiro-[isochroman-1,4'-pyran], was obtained as a white solid. SFCR t =1.873 minutes. 1 H NMR(400MHz,CDCl3)δ=7.44(dd,J=1.6,7.4Hz,1H),7.15-7.08(m,2H),3.99-3.92(m,1H),3.87(dd,J=4.7,7.1Hz,2H),3.85-3.8 3(m,2H),3.80(s,1H),3.02-2.96(m,1H),2.25-2.17(m,1H),1.92-1.87(m,2H),1.65(brd,J=13.6Hz,1H),1.38(d,J=6.9Hz,3H).

[0401] Preparation of methyl 2-bromo-2-((S)-4-methyl-2',3',5',6'-tetrahydrospiro[isochroman-1,4'-pyran]-5-yl) acetate

[0402] [ka] Step 1: (S)-5-allyl-4-methyl-2',3',5',6'-tetrahydrospiro[isochroman-1,4'-pyran]

[0403] [ka] To a solution of (S)-5-bromo-4-methyl-2',3',5',6'-tetrahydrospiro[isochroman-1,4'-pyran] (0.7 g, 2.36 mmol, 1 equivalent) in dioxane (10 mL), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (791.61 mg, 4.71 mmol, 2 equivalents), Pd(dppf)Cl2 (172.35 mg, 235.54 μmol, 0.1 equivalent), and Cs2CO3 (1.53 g, 4.71 mmol, 2 equivalents) were added at 20°C. The mixture was stirred under N2 at 80°C for 16 hours. The reaction product was quenched by adding H2O (50 mL) and extracted with ethyl acetate (10 mL x 3). The organic solutions were combined, washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain (S)-5-allyl-4-methyl-2',3',5',6'-tetrahydrospiro[isochroman-1,4'-pyran] (0.62 g, 1.20 mmol, yield 50.94%, purity 50%) as a white solid.

[0404] Step 2: (S)-2-(4-methyl-2',3',5',6'-tetrahydrospiro[isochroman-1,4'-pyran]-5-yl)acetic acid

[0405] [ka] To a solution of (S)-5-allyl-4-methyl-2',3',5',6'-tetrahydrospiro[isochroman-1,4'-pyran] (0.6 g, 1.16 mmol, 1 equivalent) in MeCN (5 mL), hexane (5 mL), and H2O (10 mL), RuCl3 (24.09 mg, 116.12 μmol, 7.74 μL, 0.1 equivalent) and NaIO4 (993.47 mg, 4.64 mmol, 257.38 μL, 4 equivalents) were gradually added at -10°C. The mixture was stirred at -10°C for 1 hour. The reaction product was quenched by slowly adding an aqueous solution of Na2SO3 (100 mL) to adjust the pH to 5, and extracted with ethyl acetate (50 mL x 2). The organic solutions were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain (S)-2-(4-methyl-2',3',5',6'-tetrahydrospiro[isochroman-1,4'-pyran]-5-yl)acetic acid (0.5 g, 904.73 μmol, yield 77.91%, purity 50%) as a white solid.

[0406] Step 3: Methyl(S)-2-(4-methyl-2',3',5',6'-tetrahydrospiro[isochroman-1,4'-pyran]-5-yl)acetate

[0407] [ka] To a solution of (S)-2-(4-methyl-2',3',5',6'-tetrahydrospiro[isochroman-1,4'-pyran]-5-yl)acetic acid (0.5 g, 904.73 μmol, 1 equivalent) in MeOH (10 mL), H2SO4 (460.00 mg, 4.69 mmol, 250.00 μL, 5.18 equivalents) was added at 20°C. The mixture was stirred at 70°C for 16 hours. The reaction product was quenched by adding NaHCO3 (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic solutions were combined, washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain methyl(S)-2-(4-methyl-2',3',5',6'-tetrahydrospiro[isochroman-1,4'-pyran]-5-yl) acetate (yield 95.17%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ=7.23-7.18(m,1H),7.16-7.09(m,2H),3.99-3.91(m,1H),3.90-3.81(m,4H),3.78(d,J=8.2Hz,1H),3.76-3.72(m,1H),3.71 (s,3H),3.65-3.59(m,1H),2.87(q,J=6.6Hz,1H),2.22(dt,J=5.3,13.1H z,1H),1.95-1.89(m,2H),1.66(brd,J=13.6Hz,1H),1.33(d,J=6.9Hz,3H)

[0408] Step 4: Methyl 2-bromo-2-((S)-4-methyl-2',3',5',6'-tetrahydrospiro[isochroman-1,4'-pyran]-5-yl) acetate

[0409] [ka] To a solution of methyl(S)-2-(4-methyl-2',3',5',6'-tetrahydrospiro[isochroman-1,4'-pyran]-5-yl) acetate (0.25 g, 861.02 μmol, 1 equivalent) in THF (3 mL), LDA (2 M, 861.02 μL, 2 equivalents) was added at -60°C, and the mixture was stirred at -60°C for 30 minutes. TMSCl (205.79 mg, 1.89 mmol, 240.41 μL, 2.2 equivalents) was added at -60°C, and the mixture was stirred at -60°C for 0.5 hours. A solution of NBS (199.22 mg, 1.12 mmol, 1.3 equivalents) in THF (3 mL) was added at -60°C. The mixture was stirred at -60°C for 1 hour. The mixture was diluted with NH4Cl (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic solutions were combined, washed with brine (50 mL), dried over 2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain methyl 2-bromo-2-((S)-4-methyl-2',3',5',6'-tetrahydrospiro-[isochroman-1,4'-pyran]-5-yl) acetate (yield 78.63%) as a yellow solid. 1 H NMR(400MHz, CDCl3)δ=7.59(d,J=7.8Hz,1H),7.31-7.28(m,1H),7.18(d,J=8 .0Hz,1H),5.69(s,1H),3.94(brd,J=12.3Hz,1H),3.86(brdd,J=3.0,10.6Hz, 4H),3.83(s,3H),3.80-3.78(m,1H),2.93-2.87(m,1H),2.19(dt,J=5.4,12. 9Hz, 1H), 1.95-1.91 (m, 2H), 1.65 (brd, J=14.0Hz, 1H), 1.45 (d, J=7.0Hz, 3H).

[0410] Methyl 2-bromo-2-((R)-4-methyl-2',3',5',6'-tetrahydrospiro[isochroman-1,4'-pyran]-5-yl) acetate was prepared from (R)-5-bromo-4-methyl-2',3',5',6'-tetrahydrospiro[isochroman-1,4'-pyran] using a similar procedure.

[0411] Preparation of methyl 2-bromo-2-(2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl) acetate

[0412] [ka] Step 1: 4'-bromospiro[cyclopropane-1,3'-indoline]-2'-one

[0413] [ka] To a solution of 4'-bromospiro[cyclopropan-1,3'-indoline]-2'-one (6 g, 28.30 mmol, 1 equivalent) in DMF (250 mL), (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (18.82 g, 42.44 mmol, 1.5 equivalents) was added under N2 at 25°C, and the solution was stirred at 25°C for 6 minutes. Then, TEA (8.59 g, 84.89 mmol, 11.82 mL, 3 equivalents) was added to the solution at 25°C, and the solution was stirred at 25°C for 6 hours. LCMS showed that the starting material was completely consumed and one peak with the desired mass was detected. The reaction mixture was quenched by adding H2O (750 mL) at 0°C and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 3 / 1). 4'-bromospiro[cyclopropan-1,3'-indoline]-2'-one (yield 62.34%) was obtained as a yellow oil. 1 H NMR (400MHz, methanol-d4) δ = 7.12-7.06 (m, 2H), 6.96 (dd, J = 2.3, 6.4Hz, 1H), 2.29 (q, J = 3.9Hz, 2H), 1.47 (q, J = 3.9Hz, 2H).

[0414] Step 2: 4'-bromo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-2'-one

[0415] [ka] To a solution of 4'-bromospiro[cyclopropan-1,3'-indoline]-2'-one (3.4 g, 14.28 mmol, 1 equivalent) in toluene (10 mL), CMBP (6.89 g, 28.56 mmol, 2 equivalents) and tetrahydro-2H-pyran-4-ol (5.83 g, 57.12 mmol, 5.72 mL, 4 equivalents) were added under N2 at 25°C, and the solution was stirred at 120°C for 16 hours. LC-MS showed that the starting material remained and two peaks with the desired mass were detected. The reaction mixture was quenched by adding H2O (50 mL) at 0°C and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. Separation of residue by HPLC (column: Welch Xtimate C18 250*70mm #10um; mobile phase: [water (TFA)-ACN]; B%: 25%~55%, 20 min. HPLC: R t The product was further purified by (3.332 mins) to obtain the product. 4'-bromo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropan-1,3'-indoline]-2'-one (yield 34.77%) was obtained as a yellow solid.

[0416] Step 3: Methyl 2-(2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl)acetate

[0417] [ka] To a solution of 4'-bromo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropan-1,3'-indoline]-2'-one (1.6g, 4.97 mmol, 1 equivalent) in THF (15 mL), Pd(t-Bu3P)2 (126.89 mg, 248.30 umol, 0.05 equivalent) and BrZnCH2COOMe (1 M, 14.90 mL, 3 equivalents) were added. 2 The solution was added at 25°C and stirred at 80°C for 2 hours. LC-MS(R t The reaction time (0.602 min) indicated that the starting material remained and two peaks with the desired mass were detected. The reaction mixture was quenched by adding H2O (50 mL) at 0°C and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~3 / 1). Methyl 2-(2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl) acetate (1.6 g, crude) was obtained as a yellow solid.

[0418] Step 4: Methyl 2-bromo-2-(2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl)acetate

[0419] [ka] To a solution of methyl 2-(2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl) acetate (600 mg, 1.90 mmol, 1 equivalent) in THF (4 mL), LDA (2 M, 1.71 mL, 1.8 equivalents) was added dropwise under N2 at -70°C, and the solution was stirred at -78°C for 0.5 hours. Then, TMSCl (413.40 mg, 3.81 mmol, 482.94 μL, 2 equivalents) was added to the solution at -78°C, and the solution was stirred at -78°C for 0.5 hours. Next, NBS (677.24 mg, 3.81 mmol, 2 equivalents) in THF (2 mL) was added to the solution at -78°C, and the solution was stirred at -78°C for 1 hour. LC-MS indicated that the starting material remained and that one peak with the desired mass was detected. The reaction mixture was quenched by adding NH4Cl (10 mL) at 0°C and extracted with ethyl acetate (5 mL x 3). The combined organic layer was washed with brine (5 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~3 / 1). Methyl 2-bromo-2-(2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl) acetate (yield 79.99%) was obtained as a yellow oil.

[0420] The intermediates in the following table were prepared from the listed starting materials, using appropriate reagents instead, following a procedure similar to that described for methyl 2-bromo-2-(2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl)acetate, and purified under appropriate conditions:

[0421] [Table 5]

[0422] Preparation of methyl 2-(6'-methoxy-2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl)acetate

[0423] [ka] Step 1: Methyl 2-(2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl)acetate

[0424] [ka] To a solution of methyl 2-(2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl) acetate (300 mg, 951.29 μmol, 1 equivalent) in dioxane (6 mL), Pin2B2 (483.14 mg, 1.90 mmol, 2 equivalents), [Ir(OMe)(cod)]2 (51.06 mg, 190.26 μmol, 0.2 equivalents) and dtbpy (50.00 mg, 75.43 μmol, 7.93 e-2 equivalents) were added under N2 at 25°C. The mixture was heated to 60°C and stirred under N2 at 60°C for 2 hours. LCMS showed that the starting material was completely consumed and 77.62% with the desired Ms was detected. The reaction mixture was added to H2O (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~3 / 1). Methyl 2-(2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl) acetate (2.3 g, crude) was obtained as a yellow solid. LCMS:[M+1]=442.3. 1H NMR (400MHz, methanol-d4)δ=7.47(s,1H),7.34(s,1H),4.47(ddd,J=4.2,8.0,12.3Hz,1H),4.09(brdd,J=4.2,11.5Hz,2H),3.68(s,3H),3.59 (brt,J=11.4Hz,2H),3.47(s,2H),2.66-2.55(m,2H),2.06-1.99(m,2H),1.68(brdd,J=2.0,12.3Hz,2H),1.60-1.54(m,2H),1.37(s,12H).

[0425] Step 2: Methyl 2-(6'-hydroxy-2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl)acetate

[0426] [ka] To a solution of methyl 2-(2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl) acetate (2.3 g, 3.65 mmol, 1 equivalent) in acetone (100 mL), oxone (3.36 g, 5.47 mmol, 1.5 equivalents) in H2O (50 mL) at 0°C was added. The mixture was heated to 25°C and stirred at 25°C for 1 hour. LC-MS showed that the starting material was completely consumed and 86.72% with the desired Ms was detected. The mixture was quenched with Na2SO3 (100 mL) and 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 (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~1 / 1). Methyl 2-(6'-hydroxy-2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl)acetate (yield 64.52%) was obtained as a yellow solid. LCMS:[M+1]=332.1. 1 H NMR(400MHz,chloroform-d)δ=6.74(d,J=2.1Hz,1H),6.42(d,J=2.0Hz,1H),4.56(tt,J=4.1,12.4Hz,1H),4.14(brdd,J=4.4,11.5Hz,2H), 3.71(s,3H),3.58-3.51(m,2H),3.31(s,2H),2.60-2.49(m,2H),1.87-1.80(m,2H),1.69(brdd,J=2.3,12.8Hz,2H),1.64-1.59(m,3H).

[0427] Step 3: Methyl 2-bromo-2-(6'-methoxy-2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl)acetate

[0428] [ka] A mixture of methyl 2-(6'-hydroxy-2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl) acetate (680 mg, 2.05 mmol, 1 equivalent) and K2CO3 (425.42 mg, 3.08 mmol, 1.5 equivalents) in DMF (10 mL) was gradually mixed with MeI (1.75 g, 12.31 mmol, 766.52 μL, 6 equivalents) under N2 at 25°C. The mixture was stirred at 25°C for 2 hours. LC-MS showed that approximately 8% of the starting material remained, and 87.09% with the desired mass was detected. The reaction mixture was added to H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~1 / 1). Methyl 2-bromo-2-(6'-methoxy-2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl) acetate (yield 73.37%) was obtained as a yellow solid. LCMS:[M+1]=346.1. 1 H NMR(400MHz,chloroform-d)δ=6.71(d,J=2.1Hz,1H),6.46(d,J=2.1Hz,1H),4.52(tt,J=4.3,12.4Hz,1H),4.12(dd,J=4.6,11.5Hz,2H),3.83(s,3H), 3.71(s,3H),3.53(dt,J=1.9,12.0Hz,2H),3.35(s,2H),2.60-2.49(m,2H ),1.86-1.81(m,2H),1.68(brdd,J=2.6,12.5Hz,2H),1.63-1.59(m,2H).

[0429] Step 4: Methyl 2-(6'-methoxy-2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl)acetate

[0430] [ka] A mixture of methyl 2-bromo-2-(6'-methoxy-2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl) acetate (570 mg, 1.65 mmol, 1 equivalent) in THF (20 mL) was stirred at 25°C under N2. The mixture was cooled to -70°C under N2. Then, LDA (2 M, 2.48 mL, 3 equivalents) was added at -70°C, and the mixture was stirred at -70°C under N2 for 30 minutes. Then, TMSCl (537.88 mg, 4.95 mmol, 628.36 μL, 3 equivalents) was added, and the mixture was stirred at -70°C under N2 for 30 minutes. A solution of NBS (881.19 mg, 4.95 mmol, 3 equivalents) in THF (10 mL) was added to the mixture at -70°C and stirred under N2 at -70°C for 1 hour. LC-MS showed that 33.57% of the starting material remained and 62.09% of the desired mass was detected. The mixture was quenched with NH4Cl (10 mL) and ethyl acetate (10 × 3 mL) was added to the mixture. The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~3 / 1). Methyl 2-(6'-methoxy-2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl) acetate (yield 58.55%) was obtained as a yellow oily substance. LCMS:[M+1]=426.4. 1 H NMR (400MHz, chloroform-d) δ=6.88(d,J=2.1Hz,1H),6.75(d,J=2.1Hz,1H),4.96(s,1H),4.56-4.47(m,1H),4.13(brdd,J=2.0,9.4H z,2H),3.85(s,3H),3.80(s,3H),3.56-3.49(m,2H),2.56-2.47(m,2H),1.96-1.90(m,1H),1.89-1.84(m,1H),1.75-1.65(m,4H).

[0431] Using the same procedure as described above in steps 1, 2, and 3, 7-bromo-5-methoxy-1,3-dimethyl-1H-indazole was prepared as a white solid, starting from 7-bromo-1,3-dimethyl-1H-indazole. 1 H NMR (400MHz, CD3OD) δ=7.24(d,J=2.1Hz,1H),7.04(d,J=2.1Hz,1H),4.23(s,3H),3.83(s,3H),2.46(s,3H).

[0432] Using the same procedure as described above in steps 1, 2, and 3, 7-bromo-5-(2-methoxyethoxy)-1,3-dimethyl-1H-indazole was prepared as a yellow solid, starting from 7-bromo-1,3-dimethyl-1H-indazole. 1 H NMR (400MHz, CDCl3) δ=7.31(d,J=2.1Hz,1H),6.93(d,J=2.1Hz,1H),4.29(s,3H),4.18-4.12(m,2H),3.82-3.74(m,2H),3.48(s,3H),2.49(s,3H).

[0433] Preparation of methyl 2-bromo-2-((S)-6-fluoro-1-methylisochroman-8-yl) acetate and methyl 2-bromo-2-((R)-6-fluoro-1-methylisochroman-8-yl) acetate

[0434] [ka] Step 1: 7-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-inden-1-ol

[0435] [ka] To a solution of MeMgBr (3M, 145.53 mL, 5 equivalents), 7-bromo-5-fluoro-2,3-dihydro-1H-inden-1-one (20 g, 87.32 mmol, 1 equivalent) in THF (200 mL) was added at 0°C under an N2 atmosphere. The mixture was stirred at 0°C for 2 hours. TLC (petroleum ether / ethyl acetate = 5 / 1, R f A value of 0.47 indicated that the starting material had been completely consumed and a new spot with lower polarity had formed. The reaction mixture was quenched with 500 mL of aqueous NH4Cl solution and extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with 500 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 7-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-inden-1-ol (22.2 g, crude) as a white solid. The crude product was used directly in the next step without purification. 1 ¹H NMR (400MHz, chloroform-d): δ=7.11 (dd, J=1.9, 8.4Hz, 1H), 6.87 (dd, J=0.9, 8.1Hz, 1H), 2.97-2.86 (m, 1H), 2.84-2.76 (m, 1H), 2.29 (dd, J=5.6, 8.6Hz, 2H), 1.63 (s, 3H).

[0436] Step 2: 4-bromo-6-fluoro-3-methyl-1H-indene

[0437] [ka] To a solution of 7-bromo-5-fluoro-1-methyl-2,3-dihydro-1H-inden-1-ol (22.2 g, 90.58 mmol, 1 equivalent) in THF (200 mL), HCl (12 M, 200 mL, 26.50 equivalents) was added at 0°C under an N2 atmosphere. The mixture was stirred at 20°C for 2 hours. TLC (petroleum ether / ethyl acetate = 5 / 1, R) fA value of 0.69 indicated that the starting material remained and a new spot with lower polarity was formed. The reaction mixture was quenched with H2O (400 mL) and extracted with MTBE (200 mL x 4). The combined organic layer was washed with brine (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® silica flash column, 0-5% ethyl acetate / petroleum ether gradient @ 90 mL / min). 4-bromo-6-fluoro-3-methyl-1H-indene (yield 97.24%) was obtained as a white solid. 1 H NMR (400MHz, chloroform-d) δ=7.19(dd,J=2.3,8.8Hz,1H),7.10(dd,J=2.3,8.0Hz,1H),6.26-6.22(m,1H),3.29(t,J=2.0Hz,2H),2.40(q,J=2.0Hz,3H).

[0438] Step 3: 1-(2-bromo-4-fluoro-6-(2-hydroxyethyl)phenyl)ethane-1-ol

[0439] [ka] A solution of 4-bromo-6-fluoro-3-methyl-1H-indene (20 g, 88.08 mmol, 1 equivalent) in DCM (200 mL) and MeOH (40 mL) was bubbling with O3 (21.14 g, 440.39 mmol, 5 equivalents) for 2 hours at -70°C. Then, NaBH4 (11.30 g, 298.58 mmol, 3.39 equivalents) was added at 0°C, and the mixture was stirred at 25°C for 16 hours. TLC (petroleum ether / ethyl acetate = 3 / 1, R fA value of 0.41 indicated that the starting material had been completely consumed and a new spot with higher polarity had formed. The reaction mixture was quenched with H2O (300 mL) and extracted with DCM (100 mL x 3). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 1-(2-bromo-4-fluoro-6-(2-hydroxyethyl)phenyl)ethane-1-ol (20 g, crude) as a white solid. The crude product was used directly in the next step without purification. 1 H NMR (400MHz, chloroform-d) δ=7.21(dd,J=2.6,7.7Hz,1H),6.95(dd,J=2.6,9.2Hz,1H),5.59(q,J=6.7Hz,1H),3.99(td,J= 5.1,10.2Hz,1H),3.84(dt,J=5.1,9.7Hz,1H),3.64-3.52(m,1H),2.84(td,J=4.7,13.7Hz,1H),1.55(d,J=6.8Hz,3H).

[0440] Step 4: 8-bromo-6-fluoro-1-methylisochromane

[0441] [ka] To a solution of 1-(2-bromo-4-fluoro-6-(2-hydroxyethyl)phenyl)ethane-1-ol (20 g, 76.02 mmol, 1 equivalent) in THF (300 mL), PPh3 (29.91 g, 114.02 mmol, 1.5 equivalents) and DIAD (26.13 g, 129.23 mmol, 25.05 mL, 1.7 equivalents) were added at 0°C, and the mixture was stirred at 25°C for 16 hours under an N2 atmosphere. TLC (petroleum ether / ethyl acetate = 10 / 1, R fA value of 0.57) indicated that the starting material was completely consumed and two new spots with lower polarity were formed. The highest point was desired. The reaction mixture was quenched with H2O (500 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® silica flash column, ethyl acetate / petroleum ether gradient of 0-22% eluent @ 80 mL / min). 8-Bromo-6-fluoro-1-methylisochromane (yield 40.79%) was obtained as a purple oil. 1 ¹H NMR (400MHz, chloroform-d): δ=7.15 (dd, J=2.5, 8.1Hz, 1H), 6.83 (dd, J=2.5, 8.7Hz, 1H), 5.02 (q, J=6.4Hz, 1H), 4.08 (ddd, J=4.3, 9.6, 11.7Hz, 1H), 3.85 (ddd, J=3.5, 6.0, 11.7Hz, 1H), 2.97-2.85 (m, 1H), 2.78-2.67 (m, 1H), 1.57 (d, J=6.4Hz, 3H).

[0442] Step 5: Methyl 2-(6-fluoro-1-methylisochroman-8-yl)acetate

[0443] [ka] To a solution of 8-bromo-6-fluoro-1-methylisochroman (7.5 g, 30.60 mmol, 1 equivalent) in THF (80 mL), Pd(t-Bu3P)2 (1.56 g, 3.06 mmol, 0.1 equivalent) and MeOOCCH2ZnBr (1 M, 45.90 mL, 1.5 equivalent) were added at 25°C. The mixture was stirred at 80°C for 2 hours under an N2 atmosphere. TLC (petroleum ether / ethyl acetate = 5 / 1, R) fA value of 0.36 indicated that the starting material had been completely consumed and three new spots with greater polarity had formed. The reaction mixture was quenched with H2O (150 mL). The mixture was filtered and the filtrate was extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® silica flash column, ethyl acetate / petroleum ether gradient of 0-28% eluent @ 80 mL / min). Methyl 2-(6-fluoro-1-methylisochroman-8-yl)acetate (yield 96.01%) was obtained as a yellow oil. 1 H NMR (400MHz, chloroform-d) δ=6.85(dd,J=2.6,9.4Hz,1H),6.77(dd,J=2.3,8.8Hz,1H),5.06(q,J=6.5Hz,1H),4.13-4.05(m,1H) ,3.82(td,J=5.4,10.8Hz,1H),3.72(s,3H),3.64-3.46(m,2H),2.99-2.88(m,1H),2.81-2.72(m,1H),1.46(d,J=6.5Hz,3H).

[0444] Step 6: Methyl(S)-2-(6-fluoro-1-methylisochroman-8-yl)acetate and Methyl(R)-2-(6-fluoro-1-methylisochroman-8-yl)acetate

[0445] [ka] Methyl 2-(6-fluoro-1-methylisochroman-8-yl)acetate (7g) was separated by SFC separation (column: ChiralPak IH, 250*50mm, 10um; mobile phase: [CO2-IPA (0.1% NH3H2O)]; B%: 11%, fixed composition elution mode).

[0446] Peak 1 (yield 44.29%) was obtained as a yellow oily substance and arbitrarily assigned the name methyl(S)-2-(6-fluoro-1-methylisochroman-8-yl).1 ¹H NMR (400MHz, chloroform-d): δ=6.85 (dd, J=2.5, 9.5Hz, 1H), 6.77 (dd, J=2.3, 8.9Hz, 1H), 5.06 (q, J=6.5Hz, 1H), 4.08 (ddd, J=4.4, 8.7, 11.5Hz, 1H), 3.88-3.78 (m, 1H), 3.72 (s, 3H), 3.65-3.47 (m, 2H), 2.97-2.85 (m, 1H), 2.81-2.72 (m, 1H), 1.46 (d, J=6.5Hz, 3H)

[0447] Peak 2 (yield 45.71%) was obtained as a yellow oily substance and arbitrarily assigned as methyl(R)-2-(6-fluoro-1-methylisochroman-8-yl)acetate. 1 ¹H NMR (400MHz, chloroform-d): δ=6.85 (dd, J=2.5, 9.4Hz, 1H), 6.77 (dd, J=2.3, 8.9Hz, 1H), 5.06 (q, J=6.5Hz, 1H), 4.08 (ddd, J=4.5, 8.8, 11.5Hz, 1H), 3.87-3.78 (m, 1H), 3.72 (s, 3H), 3.65-3.45 (m, 2H), 2.99-2.87 (m, 1H), 2.82-2.70 (m, 1H), 1.46 (d, J=6.5Hz, 3H)

[0448] Step 7: Methyl 2-bromo-2-((S)-6-fluoro-1-methylisochroman-8-yl)acetate

[0449] [ka] To a solution of arbitrarily assigned methyl(S)-2-(6-fluoro-1-methylisochroman-8-yl) (1 g, 4.20 mmol, 1 equivalent) in THF (20 mL), LDA (2 M, 6.30 mL, 3 equivalents) was added at -78°C under an N2 atmosphere. The mixture was stirred at -78°C for 30 minutes. TMSCl (1.37 g, 12.59 mmol, 1.60 mL, 3 equivalents) was added at -78°C. After stirring the reaction mixture at -78°C for 30 minutes, NBS (2.24 g, 12.59 mmol, 3 equivalents) in THF (40 mL) was added. The mixture was stirred at -78°C for 1 hour. TLC (petroleum ether / ethyl acetate = 5 / 1, R f The values ​​(=0.45, 0.51) indicated that the starting material was completely consumed and two new, less polar spots were formed. The reaction mixture was quenched by adding NH4Cl aqueous solution (40 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layer was washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, ethyl acetate / petroleum ether gradient of 0-22% eluent @ 80 mL / min). Optionally assigned methyl 2-bromo-2-((S)-6-fluoro-1-methylisochroman-8-yl) acetate (yield 97.66%) was obtained as a yellow oil. 1 ¹H NMR (400MHz, chloroform-d): δ=7.36 (ddd, J=2.6, 9.7, 16.4Hz, 1H), 6.83 (brd, J=8.6Hz, 1H), 5.45-5.35 (m, 1H), 5.23-5.10 (m, 1H), 4.09-4.04 (m, 1H), 3.87-3.77 (m, 4H), 3.01-2.88 (m, 1H), 2.81-2.71 (m, 1H), 1.56 (dd, J=6.6, 12.1Hz, 3H).

[0450] Starting from the arbitrarily assigned methyl(R)-2-(6-fluoro-1-methylisochroman-8-yl)acetate, the arbitrarily assigned methyl 2-bromo-2-((R)-6-fluoro-1-methylisochroman-8-yl)acetate was prepared using the same procedure as described in step 7 above. 1 ¹H NMR (400MHz, chloroform-d): δ=7.36 (ddd, J=2.6, 9.7, 16.3Hz, 1H), 6.83 (brd, J=8.6Hz, 1H), 5.46-5.35 (m, 1H), 5.22-5.06 (m, 1H), 4.09-4.03 (m, 1H), 3.86-3.77 (m, 4H), 2.99-2.88 (m, 1H), 2.79-2.72 (m, 1H), 1.56 (dd, J=6.6, 12.0Hz, 3H).

[0451] Starting from the arbitrarily assigned methyl(R)-2-(1-methylisochroman-8-yl)acetate, the arbitrarily assigned methyl 2-bromo-2-((R)-1-methylisochroman-8-yl)acetate was prepared using the same procedure as described in step 7 above. 1 ¹H NMR (400MHz, chloroform-d): δ = 7.68-7.51 (m,1H), 7.26-7.20 (m,1H), 5.66-5.34 (m,1H), 4.18-4.05 (m,2H), 3.76 (s,3H), 3.05-2.87 (m,2H), 2.87-2.64 (m,2H), 1.57 (s,3H).

[0452] Following the same procedure as described in step 7 above, starting with the arbitrarily assigned methyl(S)-2-(6-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[isochroman-4,4'-pyran]-8-yl) acetate, the arbitrarily assigned methyl 2-bromo-2-((S)-6-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[isochroman-4,4'-pyran]-8-yl) acetate (yield 79.6%) was prepared as a yellow solid.

[0453] Starting from the arbitrarily assigned methyl(R)-2-(6-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[isochroman-4,4'-pyran]-8-yl) acetate, the arbitrarily assigned methyl 2-bromo-2-((R)-6-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[isochroman-4,4'-pyran]-8-yl) acetate was prepared using the same procedure as described in step 7 above.

[0454] Using the same procedure as described in step 6 above, methyl 2-(1'-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-4'-yl) acetate is processed (SFC(column:DAICEL CHIRALPAK) Separation was performed using an IG (250mm*30mm, 10um); mobile phase: [CO2-MeOH]; B%: 20%, fixed composition elution mode) to obtain arbitrarily assigned methyl(S)-2-(1'-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-4'-yl) acetate and arbitrarily assigned methyl(R)-2-(1'-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-4'-yl) acetate.

[0455] Starting from the arbitrarily assigned methyl(R)-2-(1'-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-4'-yl) acetate, the arbitrarily assigned methyl 2-bromo-2-(1'-((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-4'-yl) acetate (yield 78.26%) was prepared as a yellow oil. 1H NMR(400MHz,CDCl3)δ=7.38(d,J=8.0Hz,1H),7.30-7.28(m,1H),7.14(d,J=8.1Hz,1H),5.00(s,1H),4.83-4.69(m,1H),3.96-3.90(m,1H),3.86 -3.81(m,1H),3.80(s,3H),2.52-2.43(m,1H),2.35-2.28(m,1H),1.98- 1.91(m,1H),1.78(s,2H),1.71-1.60(m,3H),1.36(s,3H),1.32(s,3H).

[0456] Starting from an arbitrarily assigned methyl(S)-2-(1'-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-4'-yl) acetate, methyl 2-bromo-2-(1'-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-4'-yl) acetate was prepared using the same procedure as described in step 7 above.

[0457] Following the same procedure as described in step 6 above, methyl 2-(4-methylchroman-5-yl)acetate was separated by SFC (column: DAIEL CHIRALPAK IC (250mm*30mm, 10um); mobile phase: [CO2-IPA (0.1%NH3H2O)]; B%:B%:25%, fixed composition elution mode) to obtain two compounds. Peak 1, arbitrarily assigned methyl(S)-2-(4-methylchroman-5-yl)acetate was obtained as a yellow oily substance. SFCR t =0.900 minutes. 1¹H NMR (400MHz, CD3OD) δ=7.00 (t, J=7.9Hz, 1H), 6.73 (dd, J=0.8, 7.4Hz, 1H), 6.65 (d, J=8.3Hz, 1H), 4.23-4.15 (m, 2H), 3.75-3.57 (m, 5H), 3.14-3.01 (m, 1H), 2.16-1.94 (m, 1H), 1.75 (qd, J=2.2, 13.8Hz, 1H), 1.24 (d, J=7.0Hz, 3H). Peak 2, arbitrarily assigned methyl(R)-2-(4-methylchroman-5-yl)acetate was obtained as a yellow oily substance. SFCR t =1.170 minutes. 1 H NMR(400MHz,CD3OD)δ=7.00(t,J=7.9Hz,1H),6.73(dd,J=0.7,7.4Hz,1H),6.66(d,J=8.3Hz,1H),4.28-4.12(m,2H),3.76-3 .69(m,1H),3.67(s,3H),3.65-3.58(m,1H),3.12-3.01(m,1H),2.11-1.95(m,1H),1.82-1.67(m,1H),1.24(d,J=7.1Hz,3H).

[0458] Following the same procedure as described in step 7 above, starting with arbitrarily assigned methyl(S)-2-(4-methylchroman-5-yl)acetate, arbitrarily assigned methyl 2-bromo-2-((S)-4-methylchroman-5-yl)acetate was prepared as a yellow oily substance. LCMS[M+1] = 299.0. 1 H NMR(400MHz,CDCl3)δ=7.33-7.21(m,1H),7.14(dt,J=2.7,8.0Hz,1H),6.80(ddd,J=0.8,3.5,8.0Hz,1H),5.67(d,J=1.8Hz,1H),4.33-4. 19(m,2H),3.80(d,J=19.9Hz,3H),3.26-3.10(m,1H),2.21-2.08(m,1H),1.78(qdd,J=2.2,4.5,13.8Hz,1H),1.39(dd,J=2.3,7.1Hz,3H).

[0459] Following the same procedure as described in step 7 above, an arbitrarily assigned methyl(R)-2-(4-methylchroman-5-yl)acetate was used to prepare an arbitrarily assigned methyl 2-bromo-2-((R)-4-methylchroman-5-yl)acetate as a yellow oil. LCMS[M+1] = 219.1.

[0460] Following the same procedure as described in step 7 above, methyl (S)-2-(1-methylisochroman-8-yl)acetate was used to prepare methyl 2-bromo-2-((S)-1-methylisochroman-8-yl)acetate (yield 92.03%) as a yellow oil. LCMS[M+1] = 300.9.

[0461] Two compounds were prepared starting from 8-bromo-1-methylisochroman (SFC separation conditions: (Column: ChiralPakIH, 250 × 50 mm, 10 μm; Mobile phase: [CO2-heptane: IPA = 1:1 (0.1% NH3H2O)]; B%: 11%, fixed composition elution mode)) using the same procedure as described in steps 5 and 6. Peak 1, optionally assigned (R)-2-(1-methylisochroman-8-yl)acetate was obtained as a yellow oil. Peak 2, optionally assigned methyl(S)-2-(1-methylisochroman-8-yl)acetate was obtained as a yellow oil. 1 H NMR(400MHz,CDCl3)δ=7.19-7.14(m,1H),7.13-7.09(m,1H),7.05(d,J=7.2Hz,1H),5.11(q,J=6.6Hz,1H),4.13-4.06(m,1H),3. 86-3.80(m,1H),3.71(s,3H),3.67-3.60(m,1H),3.58-3.51(m,1H),2.97-2.90(m,1H),2.84-2.76(m,1H),1.49(d,J=6.6Hz,3H).

[0462] Two compounds were prepared starting from (3R,4S)-5-bromo-3,4,7-trimethylisochroman-5-yl) (SFC separation conditions: column: DAIEL CHIRALPAK AD (250 mm * 50 mm, 10 μm); mobile phase: [CO2-i-PrOH (0.1% NH3·H2O)]; B%: 11%-11%, 2 min) using the same procedure as described in steps 5, 6, and 7. Peak 1, optionally assigned tert-butyl 2-bromo-2-((3R,4S)-3,4,7-trimethylisochroman-5-yl) acetate was obtained as a yellow oil. Peak 2, optionally assigned tert-butyl 2-bromo-2-((3S,4R)-3,4,7-trimethylisochroman-5-yl) acetate was obtained as a yellow oil.

[0463] Two compounds were prepared starting from 5-bromo-7-fluoro-4-methylisochroman (SFC separation conditions: column: DAIEL CHIRALPAK IC (250 mm * 30 mm, 10 μm); mobile phase: [CO2-i-PrOH (0.1% NH3H2O)]; 18% B fixed composition elution mode) using the same procedure as described in steps 5, 6, and 7. Peak 1, optionally assigned methyl 2-bromo-2-((S)-7-fluoro-4-methylisochroman-5-yl) acetate was obtained as a yellow oil. Peak 2, optionally assigned methyl 2-bromo-2-((R)-7-fluoro-4-methylisochroman-5-yl) acetate was obtained as a yellow oil.

[0464] Preparation of methyl(S)-2-(1-methylisochroman-8-yl)acetate and methyl(R)-2-(1-methylisochroman-8-yl)acetate

[0465] [ka] Step 1: 7-bromo-1-methyl-2,3-dihydro-1H-inden-1-ol

[0466] [ka] To a solution of MeMgBr (3M, 157.94 mL, 5 equivalents), 7-bromo-2,3-dihydro-1H-inden-1-one (20 g, 94.76 mmol, 1 equivalent) in THF (200 mL) was added under N2 conditions at 0°C. The mixture was stirred at 0°C for 2 hours. TLC (petroleum ether / ethyl acetate = 5 / 1, R f A value of 0.35 indicated the formation of a new spot, signifying the complete consumption of 7-bromo-2,3-dihydro-1H-inden-1-ol. The reaction mixture was quenched with 500 mL of NH4Cl aqueous solution and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (400 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~0 / 1). 7-bromo-1-methyl-2,3-dihydro-1H-inden-1-ol (yield 88.29%) was obtained as a yellow oil. 1 H NMR(400MHz,CDCl3)δ=7.35(d,J=7.8Hz,1H),7.19-7.14(m,1H),7.11-7.06(m,1H), 2.97-2.91(m,1H),2.82(t,J=8.8Hz,1H),2.27(dd,J=5.4,8.7Hz,2H),1.64(s,3H).

[0467] Step 2: 4-bromo-3-methyl-1H-iddene

[0468] [ka] To a solution of 7-bromo-1-methyl-2,3-dihydro-1H-inden-1-ol (19 g, 83.66 mmol, 1 equivalent) in toluene (150 mL), TsOH (288.14 mg, 1.67 mmol, 0.02 equivalents) was added at 20°C. The mixture was stirred at 135°C for 2 hours. TLC (petroleum ether / ethyl acetate = 3 / 1, R) fA concentration of 0.85 (=0.85) indicated the formation of one new spot, signifying the complete consumption of 7-bromo-1-methyl-2,3-dihydro-1H-inden-1-ol. The reaction mixture was quenched with H2O (300 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (200 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~0 / 1). 4-bromo-3-methyl-1H-inden (yield 97.18%) was obtained as a colorless solid. 1 H NMR (400MHz, CDCl3)δ=7.47-7.35(m,2H),7.02(t,J=7.6Hz,1H),6.33-6.20(m,1H),3.30(t,J=2.2Hz,2H),2.43(q,J=2.2Hz,3H).

[0469] Step 3: 2-(3-bromo-2-(1-hydroxyethyl)phenyl)ethane-1-ol

[0470] [ka] To a solution of 4-bromo-3-methyl-1H-indene (10 g, 47.83 mmol, 1 equivalent) in DCM (100 mL) and MeOH (20 mL), O3 (11.48 g, 239.14 mmol, 5 equivalents) was added at -70°C. The mixture was stirred at -70°C for 0.5 hours. NaBH4 (2.35 g, 62.18 mmol, 1.3 equivalents) was added at -70°C. The mixture was stirred at 15°C for 2 hours. TLC (petroleum ether / ethyl acetate = 5 / 1, R fA value of 0.25 indicated the formation of a new spot, signifying the complete consumption of 4-bromo-3-methyl-1H-indene. The reaction mixture was quenched with NH4Cl (200 mL) and extracted with CH2Cl2 (100 mL x 3). The combined organic layer was washed with brine (200 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was used in the next step without purification. 2-(3-bromo-2-(1-hydroxyethyl)phenyl)ethane-1-ol (6.4 g, crude) was obtained as a white solid.

[0471] Step 4: 8-bromo-1-methylisochromane

[0472] [ka] To a solution of 2-(3-bromo-2-(1-hydroxyethyl)phenyl)ethane-1-ol (6.2 g, 25.29 mmol, 1 equivalent) in CH3CN (60 mL), H3PO4 (26.04 g, 265.73 mmol, 15.50 mL, 10.51 equivalents) was added under N2 at 20°C. The mixture was stirred at 80°C for 12 hours. TLC (petroleum ether / ethyl acetate = 3 / 1, R f The reaction (=0.5) showed the formation of one new spot, indicating the presence of 2-(3-bromo-2-(1-hydroxyethyl)phenyl)ethane-1-ol. The reaction mixture was quenched with H2O (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (200 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~0 / 1). 8-bromo-1-methylisochromane (yield 52.23%) was obtained as a colorless oil.

[0473] Step 5: Methyl 2-(1-methylisochroman-8-yl)acetate

[0474] [ka] To a mixture of Zn (15.39 g, 235.33 mmol, 1.2 equivalents) in THF (196.11 mL), TMSCl (2.13 g, 19.61 mmol, 2.49 mL, 0.1 equivalent) was added at 20°C, and the mixture was then stirred at 20°C for 0.5 hours. BrCH2COOt-Bu (30 g, 196.11 mmol, 18.52 mL, 1 equivalent) was added dropwise at 20°C, and the mixture was then stirred at 20°C for 12 hours. To a solution of 8-bromo-1-methylisochroman (3 g, 13.21 mmol, 1 equivalent) in THF (25 mL), (Pd t-Bu3P)2 (675.11 mg, 1.32 mmol, 0.1 equivalent) and the above mixture (1 M, 39.63 mL, 3 equivalents) were added under N2 at 25°C. The mixture was stirred at 80°C for 1 hour. TLC (petroleum ether / ethyl acetate = 2 / 1, R f A value of 0.26 indicated that 8-bromo-1-methylisochroman was completely consumed and one new spot was formed. The reaction mixture was filtered, and the filtered cake was washed with ethyl acetate. The reaction mixture was then quenched by adding H2O (20 mL) at 20°C and extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~0 / 1). Methyl 2-(1-methylisochroman-8-yl)acetate (yield 68.73%) was obtained as a white solid. 1 H NMR(400MHz,CDCl3)δ=7.19-7.13(m,1H),7.13-7.09(m,1H),7.05(d,J=7.4Hz,1H),5.11(q,J=6.6Hz,1H),4.12-4.07(m,1H),3. 86-3.80(m,1H),3.70(s,3H),3.66-3.60(m,1H),3.57-3.51(m,1H),3.00-2.89(m,1H),2.82-2.73(m,1H),1.49(d,J=6.5Hz,3H).

[0475] Step 6: Methyl(S)-2-(1-methylisochroman-8-yl)acetate and methyl(R)-2-(1-methylisochroman-8-yl)acetate

[0476] [ka] Methyl 2-(1-methylisochroman-8-yl)acetate was separated by SFC (column: DAIEL CHIRALCEL OJ (250mm*50mm, 10um); mobile phase: [heptane-EtOH]; B%: 20%, fixed composition elution mode) and two peaks were obtained (R t1 =2.93min&R t2 =3.44 minutes).

[0477] Peak 1 (yield 40.00%) was obtained as a yellow oily substance and arbitrarily assigned as methyl(S)-2-(1-methylisochroman-8-yl)acetate. 1 ¹H NMR (400MHz, chloroform-d): δ = 7.19-7.14 (m, 1H), 7.13-7.09 (m, 1H), 7.05 (d, J=7.3Hz, 1H), 5.11 (q, J=6.5Hz, 1H), 4.11 (dd, J=4.4, 8.6, 11.4Hz, 1H), 3.87-3.80 (m, 1H), 3.71 (s, 3H), 3.66-3.60 (m, 1H), 3.58-3.51 (m, 1H), 2.99-2.90 (m, 1H), 2.83-2.75 (m, 1H), 1.49 (d, J=6.5Hz, 3H).

[0478] Peak 2 (yield 40.00%) was obtained as a yellow oily substance and arbitrarily assigned as methyl(R)-2-(1-methylisochroman-8-yl)acetate. 1¹H NMR (400MHz, chloroform-d): δ = 7.19-7.14 (m, 1H), 7.13-7.08 (m, 1H), 7.05 (d, J=7.4Hz, 1H), 5.11 (q, J=6.5Hz, 1H), 4.11 (ddd, J=4.5, 8.6, 11.4Hz, 1H), 3.83 (td, J=5.0, 11.3Hz, 1H), 3.71 (s, 3H), 3.66-3.61 (m, 1H), 3.58-3.50 (m, 1H), 2.99-2.89 (m, 1H), 2.84-2.75 (m, 1H), 1.49 (d, J=6.5Hz, 3H).

[0479] Preparation of methyl 2-(6-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[isochroman-4,4'-pyran]-8-yl) acetate

[0480] [ka] Step 1: 2-(2-acetyl-3-bromo-5-fluorophenyl)acetic acid

[0481] [ka] A mixture of 1-(2-bromo-4-fluorophenyl)ethane-1-one (8.50 g, 39.16 mmol, 1 equivalent), 5-diazo-2,2-dimethyl-1,3-dioxan-4,6-dione (9.99 g, 58.75 mmol, 1.5 equivalents), [Ir(Cp)Cl2]2 (315.97 mg, 391.64 μmol, 0.01 equivalents), AgNTf2 (258.33 mg, 665.79 μmol, 0.017 equivalents), and PhB(OH)2 (4.78 g, 39.16 mmol, 1 equivalent) in H2O (170 mL) was stirred at 80°C for 16 hours. LCMS showed that 66% of the starting material remained, and approximately 16% with the desired mass was detected. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 2). The combined organic layer was washed with brine (20 mL x 2), dried over Na2SO4, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (Biotage®; 40 g SepaFlash® silica flash column, eluent 0-10% ethyl acetate / petroleum ether gradient @ 80 mL / min) to obtain 2-(2-acetyl-3-bromo-5-fluorophenyl)acetic acid (yield 9.3%) as a white solid. LCMS: [M+1] = 275.0. 1 H NMR (400MHz, chloroform-d) δ = 7.27 (dd, J = 2.3, 7.8 Hz, 1H), 7.00 (dd, J = 2.3, 8.8 Hz, 1H), 3.62 (s, 2H), 2.59 (s, 3H).

[0482] Step 2: 2-(2-acetyl-3-bromo-5-fluorophenyl)-N,N-dimethylacetamide

[0483] [ka] To a solution of 2-(2-acetyl-3-bromo-5-fluorophenyl)acetic acid (1.91 g, 6.96 mmol, 1 equivalent) in DCM (25 mL), N-methylmethanamine hydrochloride (1.30 g, 16.00 mmol, 2.3 equivalents), DIEA (3.15 g, 24.35 mmol, 4.24 mL, 3.5 equivalents), DMAP (1.44 g, 11.83 mmol, 1.7 equivalents), and HATU (4.76 g, 12.52 mmol, 1.8 equivalents) were added, and the mixture was stirred at 25°C for 16 hours. LCMS showed the desired mass of approximately 30.9%. Water (30 mL) was added, and the mixture was extracted with DCM (30 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over Na₂SO₄, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, 20g SepaFlash® silica flash column, eluent 0-30% petroleum ether gradient / ethyl acetate @ 120 mL / min) to obtain product 2-(2-acetyl-3-bromo-5-fluorophenyl)-N,N-dimethylacetamide (yield 66.6%) as a yellow oil. LCMS:[M+1]=302.0.

[0484] Step 3: 2-(3-bromo-5-fluoro-2-(1-hydroxyethyl)phenyl)-N,N-dimethylacetamide

[0485] [ka] To a solution of 2-(2-acetyl-3-bromo-5-fluorophenyl)-N,N-dimethylacetamide (1.4 g, 4.63 mmol, 1 equivalent) in THF (20 mL), LiBH4 (2 M, 4.63 mL, 2 equivalents) was added at 0°C, and the mixture was stirred at 25°C for 12 hours. LCMS showed approximately 66% of the desired mass. The mixture was poured into ice water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, and concentrated under reduced pressure to obtain a residue, from which 2-(3-bromo-5-fluoro-2-(1-hydroxyethyl)phenyl)-N,N-dimethylacetamide (1.1 g, crude) was obtained as a yellow oil. LCMS:[M+1]=286.0.

[0486] Step 4: 8-bromo-6-fluoro-1-methylisochroman-3-one

[0487] [ka] To a solution of 2-(3-bromo-5-fluoro-2-(1-hydroxyethyl)phenyl)-N,N-dimethylacetamide (1.1 g, 3.62 mmol, 1 equivalent) in THF (12 mL), HCl (3 M, 1.21 mL, 1 equivalent) was added, and the mixture was stirred at 90°C for 2 hours. LC-MS showed approximately 54% of the desired mass. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 2). The combined organic layers were washed with brine (15 mL × 2), dried over Na₂SO₄, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO₂, 20 g SepaFlash® silica flash column, eluent 0-30% petroleum ether gradient / ethyl acetate @ 120 mL / min) to obtain 8-bromo-6-fluoro-1-methylisochroman-3-one (yield 59.7%) as a yellow oil. LCMS:[M+1]=259.0. 1H NMR (400MHz, chloroform-d): δ=7.20-7.18(m,1H), 6.84(brd,J=8.1Hz,1H), 5.73(q,J=6.9Hz,1H), 3.71-3.61(m,2H), 1.55(d,J=6.9Hz,3H).

[0488] Step 5: 8-bromo-6-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[isochroman-4,4'-pyran]-3-one

[0489] [ka] To a solution of Cs2CO3 (6.41 g, 19.69 mmol, 3 equivalents) in DMF (10 mL), 8-bromo-6-fluoro-1-methylisochroman-3-one (1.7 g, 6.56 mmol, 1 equivalent) in DMF (10 mL) was added and stirred under N2 at 20°C. The mixture was stirred at 20°C for 0.5 hours. 1-bromo-2-(2-bromoethoxy)ethane (6.09 g, 26.25 mmol, 3.30 mL, 4 equivalents) was added under N2 at 20°C. The mixture was stirred at 20°C for 12 hours. LC-MS showed the detection of one peak with the desired mass. The reaction mixture was quenched with H2O (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~0 / 1) to obtain 8-bromo-6-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro-[isochroman-4,4'-pyran]-3-one (yield 69.4%) as a colorless oil. LCMS:[M+1]=329.1. 1 H NMR(400MHz,chloroform-d)δ=7.31(dd,J=2.4,7.5Hz,1H),7.24(dd,J=2.3,10.1Hz,1H),5.76(q,J=6.6Hz,1H),4.50(dt, J=2.5,11.6Hz,1H),4.05-3.86(m,3H),2.34(ddd,J=5.6,11.6,13.9Hz,1H),2.04-1.90(m,3H),1.72(d,J=6.8Hz,3H).

[0490] Step 6: 8-bromo-6-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[isochroman-4,4'-pyran]-3-ol

[0491] [ka] To a solution of 8-bromo-6-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[isochroman-4,4'-pyran]-3-one (1.5 g, 4.56 mmol, 1 equivalent) in CH2Cl2 (20 mL), DIBAL-H (1 M, 5.92 mL, 1.3 equivalents) was added under N2 at 0°C. The mixture was stirred at 0°C for 1 hour. TLC (petroleum ether / ethyl acetate = 3 / 1, Rf = 0.25) showed the formation of one new spot. HCl aqueous solution (1 M, 50 mL) was added to the reaction mixture and stirred for 30 minutes, then extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain 8-bromo-6-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[isochroman-4,4'-pyran]-3-ol (800 mg, 2.42 mmol, 53.0%) as a white solid. 1 ¹H NMR (400MHz, chloroform-d): δ = 7.25-7.15 (m, 2H), 5.77-5.46 (m, 1H), 5.11 (q, J = 6.4Hz, 1H), 4.01-3.77 (m, 4H), 2.29-2.06 (m, 2H), 1.82-1.59 (m, 5H).

[0492] Step 7: 8-bromo-6-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[isochroman-4,4'-pyran]

[0493] [ka] To a solution of 8-bromo-6-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[isochroman-4,4'-pyran]-3-ol (700 mg, 2.11 mmol, 1 equivalent) in DCM (14 mL), Et3SiH (1.47 g, 12.68 mmol, 2.03 mL, 6 equivalents) and TFA (2.17 g, 19.02 mmol, 1.41 mL, 9 equivalents) were added under N2 at 20°C. The mixture was stirred at 50°C for 24 hours. TLC (Plate 1, petroleum ether / ethyl acetate = 3 / 1, Rf = 0.5) showed the formation of one new spot. The reaction mixture was quenched with H2O (30 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~0 / 1) to obtain 8-bromo-6-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[isochroman-4,4'-pyran] (1.1 g, crude) as a white solid. 1 ¹H NMR (400MHz, chloroform-d): δ=7.20-7.13 (m, 2H), 5.04 (q, J=6.4Hz, 1H), 4.10 (d, J=12.1Hz, 1H), 3.97-3.87 (m, 3H), 3.75-3.67 (m, 1H), 3.58 (dt, J=2.1, 12.4Hz, 1H), 2.23 (dt, J=5.1, 13.3Hz, 1H), 1.90-1.81 (m, 1H), 1.77-1.70 (m, 1H), 1.60 (d, J=6.4Hz, 3H), 1.56 (brd, J=4.8Hz, 1H).

[0494] Step 8: Methyl 2-(6-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[isochroman-4,4'-pyran]-8-yl) acetate

[0495] [ka] A mixture of 8-bromo-6-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[isochroman-4,4'-pyran] (1.0 g, 3.17 mmol, 1 equivalent) obtained in THF (5 mL) was added to Pd(t-Bu3P)2 (162.15 mg, 317.28 μmol, 0.1 equivalent) at 25 °C. BrZnCH2COOMe (1 M, 6.98 mL, 2.2 equivalents) was added to the reaction mixture. The reaction mixture was stirred at 80 °C for 3 hours. TLC (petroleum ether:ethyl acetate = 2:1) was performed using the starting materials (R f =0.50) consumes a new spot (R f The presence of (=0.30) was observed. The mixture was filtered and H2O was added to the filtrate. The mixture was filtered, the layers were separated, and the aqueous phase was extracted with siRNA (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1). The product was further separated by SFC (conditions: column: DAIEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [CO2-EtOH]; B%: 15%, constant composition elution mode).

[0496] Peak 1 (yield 15.3%) was obtained as a yellow oily substance and arbitrarily assigned as methyl(S)-2-(6-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[isochroman-4,4'-pyran]-8-yl)acetate. 1 H NMR(400MHz,chloroform-d)δ=7.10(dd,J=2.6,10.3Hz,1H),6.87(dd,J=2.6,9.1Hz,1H),5.07(q,J=6.5Hz,1H),4.06-3.95(m,2H),3.93-3.83(m,2H),3.7 3(s,3H),3.75-3.66(m,1H),3.64-3.48(m,3H),2.21(dt,J=5.1,13.3Hz,1 H),1.92(dt,J=5.1,13.3Hz,1H),1.76-1.50(m,4H),1.49(d,J=6.5Hz,3H).

[0497] Peak 2 (yield 15.3%) was obtained as a yellow oily substance and arbitrarily assigned as methyl(R)-2-(6-fluoro-1-methyl-2',3',5',6'-tetrahydrospiro[isochroman-4,4'-pyran]-8-yl)acetate. 1 H NMR (400MHz, chloroform-d) δ=7.09(dd,J=2.6,10.3Hz,1H),6.87(dd,J=2.5,9.1Hz,1H),5.07(q,J=6.5Hz,1H),4.00(q,J=12.0Hz,2H),3.95-3.84(m ,2H),3.80-3.67(m,4H),3.64-3.47(m,3H),2.21(dt,J=5.2,13.4Hz,1H) ,1.92(dt,J=5.1,13.2Hz,1H),1.74-1.59(m,2H),1.48(d,J=6.5Hz,3H).

[0498] Separation of isomers of methyl 2-(6'-methyl-1'-(2-methyltetrahydro-2H-pyran-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-4'-yl) acetate

[0499] [ka] Methyl 2-(6'-methyl-1'-(2-methyltetrahydro-2H-pyran-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-4'-yl) acetate (4.8 g, 16.15 mmol, 1 equivalent) was separated by SFC (column: DAIEL CHIRALPAK IC (250 mm * 50 mm, 10 μm); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 35%, fixed composition elution mode and column: REGIS(s,s)WHELK-O1 (250 mm * 50 mm, 10 μm); mobile phase: [CO2-IPA]; B%: B%: 25%, fixed composition elution mode) to obtain four isomers.

[0500] Peak 1 yielded methyl 2-(6'-methyl-1'-((2S,4S)-2-methyltetrahydro-2H-pyran-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-4'-yl) acetate (yield 13.00%) as a yellow oil. SFC: Rt = 2.228 mins. 1 H NMR (400MHz, chloroform-d) δ=6.92(s,1H),6.74(s,1H),4.66-4.45(m,1H),4.15(dd ,J=3.8,11.9Hz,1H),3.71(s,3H),3.65-3.52(m,2H),3.35(s,2H),2.50(dq,J=4 .7,12.6Hz,1H),2.38(s,3H),2.25-2.11(m,1H),1.89-1.85(m,2H),1.75(td,J= 2.0,12.6Hz,1H),1.68(brd,J=2.4Hz,1H),1.61(brs,2H),1.28(d,J=6.2Hz,3H).

[0501] Peak 2 yielded methyl 2-(6'-methyl-1'-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-4'-yl) acetate (yield 13.00%) as a yellow oil. SFC: Rt = 2.450 min. 1 ¹H NMR (400MHz, chloroform-d) δ=6.92(s,1H),6.74(s,1H),4.57(tdd,J=4.3,8.3,12.6Hz,1H),4.15(dd,J=4.5,11.1Hz,1H),3.71(s,3H),3.65-3.55(m,2H),3.35(s,2H),2.50(d q,J=4.8,12.6Hz,1H),2.38(s,3H),2.26-2.11(m,1H),1.91-1.82(m,2H),1.75(td,J =2.0,12.7Hz,1H),1.68(brd,J=2.0Hz,1H),1.65-1.61(m,2H),1.28(d,J=6.2Hz,3H).

[0502] Peak 3 yielded methyl 2-(6'-methyl-1'-((2R,4S)-2-methyltetrahydro-2H-pyran-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-4'-yl) acetate (yield 31.7%) as a yellow oil. SFC: Rt = 2.794 mins. 1 H NMR (400MHz, chloroform-d) δ=6.91(s,1H),6.75(s,1H),4.79-4.68(m,1H),4.40-4.32(m,1H),3.92-3.86(m,2H),3.71(s,3H),3.35(s,2H) ),2.70-2.61(m,1H),2.56-2.45(m,1H),2.38(s,3H),1.89-1.83(m,2H),1.77-1.70(m,1H),1.65-1.57(m,3H),1.39(d,J=6.9Hz,3H).

[0503] Peak 4 yielded methyl 2-(6'-methyl-1'-((2S,4R)-2-methyltetrahydro-2H-pyran-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-4'-yl) acetate (yield 33.33%) as a yellow oil. SFC: Rt = 3.106 mins. 1 H NMR (400MHz, chloroform-d) δ=6.91(s,1H),6.75(s,1H),4.87-4.61(m,1H),4.44-4.28(m,1H),3.93-3.82(m,2H),3.71(s,3H),3.35(s,2H) ),2.70-2.60(m,1H),2.56-2.44(m,1H),2.38(s,3H),1.88-1.82(m,2H),1.77-1.68(m,1H),1.65-1.57(m,3H),1.39(d,J=6.8Hz,3H).

[0504] Preparation of methyl 2-bromo-2-(7'-fluoro-2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl) acetate

[0505] [ka] Step 1: Methyl 2-(6-bromo-2,3-difluorophenyl)-2-oxoacetate

[0506] [ka] To a solution of 4-bromo-1,2-difluorobenzene (10 g, 51.82 mmol, 1 equivalent) in THF (100 mL), LDA (2 M, 25.91 mL, 1 equivalent) was added dropwise at -70°C under an N2 atmosphere. The reaction mixture was stirred at -70°C for 0.5 hours. To this mixture, a solution of dimethyl oxalate (6.12 g, 51.82 mmol, 1 equivalent) in THF (50 mL) was added at -70°C. The reaction mixture was stirred at -70°C for 1 hour. The reaction mixture was quenched by adding aqueous NH4Cl solution (200 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. Methyl 2-(6-bromo-2,3-difluorophenyl)-2-oxoacetate (8.7 g, crude) was obtained as a yellow oily substance. 1 H NMR (400MHz, CDCl3) δ=7.40(ddd,J=1.8,3.9,8.9Hz,1H),7.27-7.20(m,1H),3.98(s,3H).

[0507] Step 2: 2-(6-bromo-2,3-difluorophenyl)-2-oxo-N-(tetrahydro-2H-pyran-4-yl)acetamide

[0508] [ka] Methyl 2-(6-bromo-2,3-difluorophenyl)-2-oxoacetate (8.7 g, 31.18 mmol, 1 equivalent) in MeOH (100 mL) was mixed with tetrahydro-2H-pyran-4-amine (4.73 g, 46.77 mmol, 1.5 equivalents) at 25°C under a N2 atmosphere. The reaction mixture was stirred at 25°C for 16 hours under a N2 atmosphere. The mixture was concentrated under reduced pressure. The crude product was ground using petroleum ether / ethyl acetate (5 / 1). 2-(6-bromo-2,3-difluorophenyl)-2-oxo-N-(tetrahydro-2H-pyran-4-yl)acetamide (yield 73.70%) was obtained as a yellow oil. LCMS[M+1] = 348.0. 1 H NMR(400MHz,CDCl3)δ=7.36(ddd,J=1.8,3.9,8.9Hz,1H),7.26-7.14(m,1H),6.88(brd,J =6.4Hz,1H),4.05-3.94(m,3H),3.56-3.49(m,2H),2.05-1.92(m,2H),1.67-1.58(m,2H)

[0509] Step 3: 4-Bromo-7-fluoro-1-(tetrahydro-2H-pyran-4-yl)indoline-2,3-dione

[0510] [ka] To a solution of 2-(6-bromo-2,3-difluorophenyl)-2-oxo-N-(tetrahydro-2H-pyran-4-yl)acetamide (8 g, 22.98 mmol, 1 equivalent) in toluene (100 mL), potassium 2-methylbutane-2-oleate (1 M, 34.47 mL, 1.5 equivalents) was added at 0°C under a N2 atmosphere. The mixture was stirred at 25°C for 1 hour. The reaction product was quenched by adding cold aqueous HCl (1 M, 100 mL) and extracted with ethyl acetate (100 mL x 2). The organic solutions were combined, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 4-bromo-7-fluoro-1-(tetrahydro-2H-pyran-4-yl)indoline-2,3-dione (yield 66.31%) as a yellow solid. LCMS[M+1] = 328.0. 1 H NMR(400MHz,CDCl3)δ=7.25(s,1H),7.23(d,J=2.5Hz,1H),4.63-4.54(m,1H),4.13(dd,J =4.8,11.7Hz,2H),3.54-3.49(m,2H),2.55-2.46(m,2H),1.75(brdd,J=2.4,12.3Hz,2H).

[0511] Step 4: 4-Bromo-7-fluoro-1-(tetrahydro-2H-pyran-4-yl)indoline-2-one

[0512] [ka] Two batches were carried out in parallel. To a mixture of Zn (1.4 g, 21.41 mmol, 4.68 equivalents) in THF (20 mL), TiCl4 (2.60 g, 13.71 mmol, 1.5 mL, 3 equivalents) was added dropwise at 0°C under an N2 atmosphere. The mixture was stirred at 80°C for 2 hours. A solution of 4-bromo-7-fluoro-1-(tetrahydro-2H-pyran-4-yl)indorin-2,3-dione (1.5 g, 4.57 mmol, 1 equivalent) in THF (20 mL) was added at 20°C, and the mixture was stirred at 20°C for 2 hours. The reaction product was quenched by adding saturated NaHCO3 aqueous solution (100 mL). The mixture was filtered, and the filtrate was extracted with ethyl acetate (100 mL x 3). The organic solutions were combined, washed with brine (100 mL), dried over anhydrous 2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1). 4-Bromo-7-fluoro-1-(tetrahydro-2H-pyran-4-yl)indorin-2-one (yield 69.63%) was obtained from the combined batch as a yellow oily substance. LCMS[M+1] = 314.0. 1 H NMR(400MHz,CDCl3)δ=7.13(dd,J=3.7,8.9Hz,1H),6.97(dd,J=8.9,11.8Hz,1H),4.73-4.62(m,1H), 4.11(dd,J=4.9,11.6Hz,2H),3.55-3.48(m,4H),2.50-2.39(m,2H),1.66(brdd,J=2.4,12.3Hz,2H).

[0513] Step 5: 4'-bromo-7'-fluoro-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-2'-one

[0514] [ka] To a solution of 4-bromo-7-fluoro-1-(tetrahydro-2H-pyran-4-yl)indorin-2-one (2.1 g, 6.68 mmol, 1 equivalent) in DMF (30 mL), Cs2CO3 (6.53 g, 20.05 mmol, 3 equivalents) and 1,2-dibromoethane (6.28 g, 33.42 mmol, 2.52 mL, 5 equivalents) were added. The mixture was stirred at 35°C for 12 hours. The reaction product was quenched by adding H2O (100 mL) at 0°C and extracted with ethyl acetate (50 mL x 3). The organic solutions were combined, washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~3 / 1). 4'-bromo-7'-fluoro-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropan-1,3'-indoline]-2'-one (yield 87.95%) was obtained as a yellow solid. LCMS[M+1]=340.0.1H NMR(400MHz,CDCl3)δ=7.07(dd,J=4.0,8.9Hz,1H),6.90(dd,J=8.9,11.8Hz,1H),4.81-4.69(m,1H),4.11(dd,J=4.8,1 1.5Hz,2H), 3.52(brt,J=11.9Hz,2H),2.58-2.46(m,2H),2.41(q,J=3.9Hz,2H),1.72-1.65(m,2H),1.61-1.58(m,2H).

[0515] Step 6: Methyl 2-(7'-fluoro-2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl)acetate

[0516] [ka] To a solution of 4'-bromo-7'-fluoro-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropan-1,3'-indoline]-2'-one (1.2 g, 3.53 mmol, 1 equivalent) in THF (10 mL), Pd(t-Bu3P)2 (90.14 mg, 176.37 μmol, 0.05 equivalent) and BrZnCH2COOMe (1 M, 10.58 mL, 3 equivalents) were added at 20°C, and the reaction mixture was stirred at 80°C for 2 hours under an N2 atmosphere. The reaction mixture was quenched by adding H2O (30 mL) at 0°C and filtered. The mixture was extracted with ethyl acetate (30 mL x 3). The organic solutions were combined, washed with brine (30 mL x 3), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1). Methyl 2-(7'-fluoro-2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl)acetate (yield 19.56%) was obtained as a yellow oily substance. LCMS Rt=0.445min, [M+1]=334.3.1H NMR(400MHz,CDCl3)δ=6.99(dd,J=8.6,12.0Hz,1H),6.94-6.86(m,1H),4.86-4.63(m,1H),4.13-4.08(m,2 H),3.71(s,3H),3.56-3.50(m,2H),3.35(s,2H),2.60-2.46(m,2H),2.00-1.89(m,2H),1.72-1.65(m,4H).

[0517] Step 7: Methyl 2-bromo-2-(7'-fluoro-2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl)acetate

[0518] [ka] To a solution of methyl 2-(7'-fluoro-2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl) acetate (180 mg, 539.97 μmol, 1 equivalent) in THF (5 mL), LDA (2 M, 269.98 μL, 1 equivalent) was added at -70°C under an N2 atmosphere. After 0.5 hours, TMSCl (70.40 mg, 647.96 μmol, 82.24 μL, 1.2 equivalents) was added, and the mixture was stirred at -70°C for 0.5 hours. NBS (288.32 mg, 1.62 mmol, 3 equivalents) in THF (5 mL) was added. The mixture was stirred at -70°C for 0.5 hours. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (30 mL) and extracted with ethyl acetate (30 mL x 2). The organic solutions were combined, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1). Methyl 2-bromo-2-(7'-fluoro-2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl) acetate (yield 8.40%) was obtained as a yellow oil. LCMS[M+1] = 412.0. 1 H NMR(400MHz,CDCl3)δ=7.40(dd,J=4.2,8.9Hz,1H),7.07(dd,J=8.9,11.9Hz,1H),4.95(s,1H),4.77-4.72(m,1H) ),4.11-4.08(m,2H),3.80(s,3H),3.52(s,2H),2.52(brd,J=7.9Hz,2H),2.02-1.91(m,2H),1.73-1.67(m,4H).

[0519] Methyl 2-bromo-2-(6'-fluoro-2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl) acetate was prepared from 4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-4-yl)indoline-2,3-dione by following the same procedure as steps 4, 5, 6, and 7 described above in the synthesis of methyl 2-bromo-2-(7'-fluoro-2'-oxo-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropane-1,3'-indoline]-4'-yl) acetate. 1 H NMR(400MHz,CDCl3)δ=7.11(dd,J=2.3,10.3Hz,1H),6.89(dd,J=2.1,9.0Hz,1H),4.94(d,J=1.4Hz,1H),4.51(tt,J=4.4,12.6Hz,1H),4.13(d ,J=7.1Hz,2H),3.81(s,3H),3.53(dt,J=1.8,12.0Hz,2H),2.56-2.45(m,2H),1.78(brd,J=2.3Hz,2H),1.72-1.67(m,2H),1.29-1.25(m,2H).

[0520] Preparation of 4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-4-yl)indoline-2,3-dione

[0521] [ka] Step 1: Methyl 2-(2-bromo-4,6-difluorophenyl)-2-oxoacetate

[0522] [ka] To a solution of 1-bromo-3,5-difluoro-2-iodobenzene (26 g, 81.53 mmol, 1 equivalent) in toluene (400 mL), n-BuLi (2.5 M, 24.46 mL, 0.75 equivalents) was added dropwise at -70°C under an N2 atmosphere. The reaction mixture was stirred at -70°C for 0.5 hours. Next, a solution of dimethyl oxalate (19.26 g, 163.07 mmol, 2 equivalents) in toluene (500 mL) was added to the reaction mixture at -70°C. The reaction mixture was stirred at -70°C for 1 hour. The reaction product was quenched by adding aqueous NH4Cl solution (400 mL), and the mixture was extracted with ethyl acetate (100 mL x 2). The organic solutions were combined, washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 2 / 1). Three batches were carried out in parallel. Methyl 2-(2-bromo-4,6-difluorophenyl)-2-oxoacetate (yield 70.33%) was obtained as a yellow oil. 1 H NMR (400MHz, CDCl3) δ=7.25(td,J=1.9,7.8Hz,1H),6.92(ddd,J=2.3,8.4,9.6Hz,1H),3.96(s,3H).

[0523] Step 2: 4-Bromo-6-fluoro-1-(tetrahydro-2H-pyran-4-yl)indoline-2,3-dione

[0524] [ka] To a solution of tetrahydro-2H-pyran-4-amine (3.99 g, 39.42 mmol, 1.1 equivalents) in THF (50 mL), n-BuLi (2.5 M, 14.34 mL, 1 equivalent) was added at 0°C under an N2 atmosphere. The reaction mixture was stirred at 0°C for 0.5 hours. The reaction mixture was added to a solution of methyl 2-(2-bromo-4,6-difluorophenyl)-2-oxoacetate (10 g, 35.84 mmol, 1 equivalent) in THF (50 mL) under an N2 atmosphere at 0°C. The mixture was stirred at 25°C for 0.5 hours. The reaction mixture was quenched with 2 M aqueous HCl (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic solutions were combined, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was pulverized using petroleum ether / ethyl acetate (3 / 1). 4-bromo-6-fluoro-1-(tetrahydro-2H-pyran-4-yl)indoline-2,3-dione (yield 42.52%) was obtained as a yellow solid. 1 H NMR(400MHz,CDCl3)δ=7.00(dd,J=1.2,8.6Hz,1H),6.83(dd,J=1.2,8.9Hz,1H),4.36(tt,J=4.3,12.3Hz,1H),4.15 (brdd,J=4.4,11.7Hz,2H),3.52(brt,J=11.5Hz,2H),2.45(dq,J=4.6,12.5Hz,2H),1.74(brdd,J=2.2,12.5Hz,2H)

[0525] Preparation of methyl 2-bromo-2-((R)-4-methylisochroman-5-yl)acetate

[0526] [ka] Step 1: Methyl 2-(2-bromophenyl)propanoate

[0527] [ka] To a solution of methyl 2-(2-bromophenyl)acetate (50 g, 218.27 mmol, 1 equivalent) in THF (100 mL), LiHMDS (1 M, 240.10 mL, 1.1 equivalents) was added dropwise at 0°C under an N2 atmosphere, and the reaction mixture was stirred at 0°C for 1 hour. MeI (30.98 g, 218.27 mmol, 13.59 mL, 1 equivalent) was added dropwise at 0°C under an N2 atmosphere. The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was quenched by adding saturated NH4Cl (500 mL) and extracted with ethyl acetate (200 mL x 3). The organic solutions were combined, washed with brine (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. Methyl 2-(2-bromophenyl)propanoate (60 g, crude) was obtained as a yellow oily substance. 1 H NMR(400MHz,CDCl3)δ=7.57(d,J=8.2Hz,1H),7.35-7.27(m,2H),7.16-7.10(m,1H),4.24(q,J=7.2Hz,1H),3.69(s,3H),1.50(d,J=7.2Hz,3H)

[0528] Step 2: 2-(2-bromophenyl)propan-1-ol

[0529] [ka] Two reactions were carried out in parallel. To a solution of LiBH4 (8.04 g, 368.86 mmol, 2.99 equivalents) in THF (100 mL), a solution of methyl 2-(2-bromophenyl-)propanoate (30 g, 123.41 mmol, 1 equivalent) in THF (100 mL) was added at 0°C. The mixture was stirred at 20°C for 12 hours. The mixture was diluted with H2O (500 mL) and extracted with ethyl acetate (200 mL x 3). The organic solutions were combined, washed with brine (200 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). 2-(2-bromophenyl)propan-1-ol (37g, 172.02 mmol, 78.72% yield in 2 steps) was obtained as a colorless oil. LCMSRt = 0.869, [M-18+1] = 197.1. 1 H NMR(400MHz,CDCl3)δ=7.56(d,J=7.9Hz,1H),7.32-7.27(m,1H),7.26(d,J=6.8Hz,1H),7.10- 7.04(m,1H),3.82-3.75(m,1H),3.72-3.66(m,1H),3.54-3.46(m,1H),1.28(d,J=7.0Hz,3H).

[0530] Step 3: 5-bromo-4-methylisochromane

[0531] [ka] 2-(2-bromophenyl)propan-1-ol (17g, 79.04 mmol, 1 equivalent) and (HCHO) in TFA (100mL) nA solution of (7.83 g, 86.94 mmol, 1.1 equivalents) was stirred at 100°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic solutions were combined, washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The mixture was further purified by preparative HPLC (column: Phenomenex luna C18 250*150 mm*15 μm; mobile phase: [water (TFA)-ACN]; B%: 30%~60%, 20 min). 5-bromo-4-methylisochromane (yield 44.57%) was obtained as a yellow oil. LCMSRt = 1.031, [M-18+1] = 209.0. 1 H NMR(400MHz,CDCl3)δ=7.43(d,J=7.9Hz,1H),7.05(t,J=7.8Hz,1H),6.98-6.92(m,1H),4.87-4.79(m,1H),4 .76-4.67(m,1H),4.00-3.93(m,1H),3.80(dd,J=2.8,11.3Hz,1H),3.02-2.92(m,1H),1.39(d,J=6.9Hz,3H).

[0532] Step 4: Methyl(R)-2-(4-methylisochroman-5-yl)acetate and methyl(S)-2-(4-methylisochroman-5-yl)acetate

[0533] [ka] To a solution of 5-bromo-4-methylisochromane (6 g, 26.42 mmol, 1 equivalent) and Pd(t-Bu3P)2 (1.35 g, 2.64 mmol, 0.1 equivalent) in THF (60 mL), BrZnCH2COOt-Bu (1.0 M, 60 mL, 2.27 equivalents) was added at 20°C under an N2 atmosphere. The mixture was stirred at 80°C for 2 hours. The reaction mixture was diluted with H2O (200 mL) and extracted with ethyl acetate (100 mL x 2). The organic solutions were combined, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was poured into HCl / MeOH (100 mL) at 20°C. The mixture was stirred at 50°C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H2O (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic solutions were combined, washed with brine (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). A racemic mixture (5 g) was obtained as a yellow oily substance. The racemic mixture was separated by SFC (column: DAIEL CHIRALPAK AD (250 mm x 50 mm, 10 μm); mobile phase: [0.1% NH3H2O ​​IPA]; B%: 11% to 11%, 1.6 min).

[0534] Peak 1, arbitrarily assigned methyl(S)-2-(4-methylisochroman-5-yl)acetate (yield 30.93%), was obtained as a colorless oil. LCMS[M-18+1] = 203.1. SFC Rt = 1.134. 1 H NMR(400MHz,CDCl3)δ=7.20-7.12(m,2H),6.95-6.89(m,1H),4.89-4.74(m,2H),3.97-3.91(m,1H),3.85- 3.80(m,1H),3.76-3.72(m,1H),3.71(s,3H),3.65-3.60(m,1H),2.93-2.85(m,1H),1.33(d,J=7.0Hz,3H).

[0535] Peak 2 yielded methyl(R)-2-(4-methylisochroman-5-yl)acetate (yield 25.78%) as a colorless oil. LCMS[M-18+1] = 203.1. SFC Rt = 1.330. 1 H NMR(400MHz,CDCl3)δ=7.18-7.11(m,2H),6.94-6.89(m,1H),4.89-4.73(m,2H),3.97-3.91(m,1H),3.87- 3.79(m,1H),3.76-3.72(m,1H),3.71(s,3H),3.66-3.59(m,1H),2.94-2.84(m,1H),1.33(d,J=7.0Hz,3H).

[0536] Step 5: Methyl 2-bromo-2-((S)-4-methylisochroman-5-yl)acetate

[0537] [ka] To a solution of methyl(S)-2-(4-methylisochroman-5-yl)acetate (500.00 mg, 2.27 mmol, 1 equivalent) in THF (10 mL), LDA (2 M, 1.70 mL, 1.5 equivalents) was added at -60°C, and the mixture was stirred at -60°C for 30 minutes. TMSCl (394.58 mg, 3.63 mmol, 460.96 μL, 1.6 equivalents) was added at -60°C, and the mixture was stirred at -60°C for 0.5 hours. A solution of NBS (484.82 mg, 2.72 mmol, 1.2 equivalents) in THF (5 mL) was added at -60°C. The mixture was stirred at -60°C for 1 hour. The residue was diluted with NH4Cl (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic solutions were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 20 / 1). Methyl 2-bromo-2-((S)-4-methylisochroman-5-yl)acetate (yield 29.45%) was obtained as a yellow oil.

[0538] Starting with arbitrarily assigned methyl(R)-2-(4-methylisochroman-5-yl)acetate, methyl 2-bromo-2-((S)-4-methylisochroman-5-yl)acetate was prepared by a similar procedure.

[0539] Preparation of methyl 2-((methylsulfonyl)oxy)-2-(2-(2-oxopyrrolidine-1-yl)-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)acetate

[0540] [ka] Step 1: 4-(3-bromo-2-nitrophenoxy)tetrahydro-2H-pyran

[0541] [ka] To a solution of 3-bromo-2-nitrophenol (13 g, 59.63 mmol, 1 equivalent) in toluene (200 mL), DIAD (18.09 g, 89.45 mmol, 17.34 mL, 1.5 equivalents), tetrahydro-2H-pyran-4-ol (7.31 g, 71.56 mmol, 7.15 mL, 1.2 equivalents) and PPh3 (18.77 g, 71.56 mmol, 1.2 equivalents) were added. The mixture was stirred at 100 °C for 2 hours. The reaction product was quenched by adding H2O (20 mL) at 20 °C and extracted with ethyl acetate (10 mL x 3). The organic solutions were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). 4-(3-bromo-2-nitrophenoxy)tetrahydro-2H-pyran (23 g, 53.29 mmol, yield 89.37%, purity 70%) was obtained as a colorless oil. 1H NMR(400MHz,CDCl3)δ=7.30-7.27(m,1H),7.25-7.20(m,1H),7.00(dd,J=1.3,8.3Hz,1H),4.64(tt,J=3.5,7.0Hz, 1H), 3.90(ddd,J=3.5,7.6,11.5Hz,2H),3.64-3.56(m,2H),2.05-1.99(m,2H),1.83(ddd,J=3.6,6.9,13.5Hz,2H).

[0542] Step 2: 2-Bromo-6-((tetrahydro-2H-pyran-4-yl)oxy)aniline

[0543] [ka] To a solution of 4-(3-bromo-2-nitrophenoxy)tetrahydro-2H-pyran (20 g, 66.20 mmol, 1 equivalent) in ethyl acetate (180 mL) and H2O (20 mL), AcOH (48.14 g, 801.67 mmol, 45.89 mL, 12.11 equivalents) was added at 25 °C. The mixture was stirred at 50 °C. Fe (18.48 g, 330.99 mmol, 5 equivalents) was added at 50 °C. The mixture was stirred at 80 °C for 2 hours. The reaction product was quenched by adding NaOH (10 mL) at 20 °C, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic solutions were combined, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). 2-Bromo-6-((tetrahydro-2H-pyran-4-yl)oxy)aniline (18g, 49.61 mmol, yield 74.94%, purity 75%) was obtained as a yellow oily substance. 1H NMR(400MHz,CDCl3)δ=7.06(dd,J=0.8,8.2Hz,1H),6.76(d,J=8.0Hz,1H),6.60-6.53(m,1H),6.39(brs,2H),4.49(tt,J=3. 9,8.0Hz,1H),4.02-3.96(m,2H),3.59(ddd,J=3.2,8.6,11.7Hz,2H),2.08-2.04(m,2H),1.83(tdd,J=4.2,8.6,12.9Hz,2H).

[0544] Step 3: N-(2-bromo-6-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-chlorobutanamide

[0545] [ka] To a solution of 2-bromo-6-((tetrahydro-2H-pyran-4-yl)oxy)aniline (9 g, 33.07 mmol, 1 equivalent) and Na2HPO4 (9.39 g, 66.14 mmol, 9.39 mL, 2 equivalents) in CHCl3 (90 mL), 4-chlorobutanoyl chloride (5.60 g, 39.69 mmol, 4.44 mL, 1.2 equivalents) was added at 25°C, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. N-(2-bromo-6-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-chlorobutanamide (12 g, crude) was obtained as a yellow oily substance. 1 H NMR(400MHz,CDCl3)δ=7.24(brd,J=9.5Hz,1H),7.12(brt,J=6.4Hz,1H),6.90(brd,J=8.1Hz,1H),6.37(brs,2H),4.51 (dt,J=3.9,7.6Hz,1H),3.99-3.90(m,2H),3.60-3.54(m,2H),2.16-2.06(m,4H),2.04-1.98(m,2H),1.85-1.75(m,2H).

[0546] Step 4: 1-(2-bromo-6-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)pyrrolidine-2-one

[0547] [ka] To a solution of NaH (1.17 g, 29.20 mmol, 60% purity, 1.1 equivalent) in DMF (50 mL), a solution of N-(2-bromo-6-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-4-chlorobutanamide (10 g, 26.55 mmol, 1 equivalent) in DMF (50 mL) was added at 0°C, and the mixture was stirred at 25°C for 12 hours. The reaction product was quenched by adding saturated NH4Cl (50 mL), and the mixture was extracted with ethyl acetate (50 mL x 2). The organic solutions were combined, washed with brine (30 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~0 / 1). 1-(2-bromo-6-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)pyrrolidine-2-one (7g, 16.46 mmol, yield 62.00%, purity 80%) was obtained as a yellow oily substance. 1H NMR(400MHz,CDCl3)δ=7.25-7.19(m,1H),7.13(t,J=8.2Hz,1H),6.89(d,J=8.2Hz,1H),4.99-4.95(m,1H),4.52(tt,J=3.5,7.0Hz,1H),4.35(s,1H), 3.96-3.87(m,2H),3.59(dddd,J=3.8,7.5,11.4,18.5Hz,2H),2.63-2.51( m,2H),2.27-2.23(m,2H),2.00(td,J=3.4,6.9Hz,2H),1.82-1.75(m,2H).

[0548] Step 5: 1-(2-((tetrahydro-2H-pyran-4-yl)oxy)-6-vinylphenyl)pyrrolidine-2-one

[0549] [ka] To a solution of 1-(2-bromo-6-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)pyrrolidine-2-one (3.5 g, 10.29 mmol, 1 equivalent) in dioxane (40 mL) and H2O (4 mL), K2CO3 (4.27 g, 30.86 mmol, 3 equivalents), Pd(dppf)Cl2 (1.51 g, 2.06 mmol, 0.2 equivalents), and trifluoro(vinyl)-λ4-borane, potassium salt (4.13 g, 30.86 mmol, 3 equivalents) were added. The mixture was stirred at 100°C for 12 hours. The reaction product was quenched by adding H2O (30 mL) at 20°C and extracted with ethyl acetate (15 mL x 3). The organic solutions were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). 1-(2-((tetrahydro-2H-pyran-4-yl)oxy)-6-vinylphenyl)pyrrolidine-2-one (yield 47.36%) was obtained as a brown oily substance. LCMS[M+1] = 288.1. 1 H NMR(400MHz,CDCl3)δ=7.26-7.20(m,2H),6.87(d,J=7.8Hz,1H),6.71(dd,J=1 1.1,17.6Hz,1H),5.76(d,J=17.5Hz,1H),5.34(d,J=11.0Hz,1H),4.53(tt,J=3 .5,7.0Hz,1H),3.96-3.89(m,2H),3.83-3.76(m,1H),3.65-3.50(m,3H),2.61 -2.54(m,2H),2.24(quin,J=7.5Hz,2H),2.05-1.95(m,2H),1.84-1.76(m,2H).

[0550] Step 6: 2-(2-oxopyrrolidine-1-yl)-3-((tetrahydro-2H-pyran-4-yl)oxy)benzaldehyde

[0551] [ka] To a solution of 1-(2-((tetrahydro-2H-pyran-4-yl)oxy)-6-vinylphenyl)pyrrolidine-2-one (1.4 g, 4.87 mmol, 1 equivalent) and 2,6-lutidine (1.04 g, 9.74 mmol, 1.13 mL, 2 equivalents) in THF (20 mL) and H2O (10 mL), K2OsO4.2H2O (179.51 mg, 487.21 μmol, 0.1 equivalent) and NaIO4 (4.17 g, 19.49 mmol, 1.08 mL, 4 equivalents) were added at 0°C. The reaction mixture was stirred at 25°C for 0.5 hours. The reaction mixture was filtered, the filtrate was diluted with saturated Na2SO3 (20 mL), and extracted with ethyl acetate (10 mL x 3). The organic solutions were combined, washed with brine (15 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). 2-(2-oxopyrrolidine-1-yl)-3-((tetrahydro-2H-pyran-4-yl)oxy)benzaldehyde (950 mg, 2.63 mmol, yield 53.92%, 80% purity) was obtained as a yellow oil. 1 H NMR(400MHz,CDCl3)δ=10.03(s,1H),7.54(dd,J=1.1,7.7Hz,1H),7.43(t,J=7.9Hz,1H),7.26-7.20(m,1H),4.61-4.55(m,1 H),4.03-3.91(m,3H),3.67-3.57(m,3H),2.66-2.53(m,2H),2.34-2.25(m,2H),2.12-2.04(m,2H),1.83(brd,J=7.6Hz,2H).

[0552] Step 7: 2-Hydroxy-2-(2-(2-oxopyrrolidine-1-yl)-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)acetonitrile

[0553] [ka] To a solution of 2-(2-oxopyrrolidine-1-yl)-3-((tetrahydro-2H-pyran-4-yl)oxy)benzaldehyde (950 mg, 3.28 mmol, 1 equivalent) in DCM (10 mL), TMSCN (488.62 mg, 4.93 mmol, 616.16 μL, 1.5 equivalents) and ZnCl2 (104.81 mg, 328.35 μmol, 0.1 equivalent) were added. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic solutions were combined, washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-hydroxy-2-(2-(2-oxopyrrolidine-1-yl)-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)acetonitrile (1.5 g, crude) as a yellow oily substance. LCMS[M+1] = 389.2.

[0554] Step 8: Methyl 2-hydroxy-2-(2-(2-oxopyrrolidine-1-yl)-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)acetate

[0555] [ka] A solution of 2-hydroxy-2-(2-(2-oxopyrrolidine-1-yl)-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)acetonitrile (1.3 g, 2.01 mmol, 1 equivalent) in HCl / MeOH solution (6 M, 334.59 μL, 1 equivalent) was stirred at 30°C for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm, mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 20%~40% over 8.0 mins) to obtain methyl 2-hydroxy-2-(2-(2-oxopyrrolidine-1-yl)-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)acetate (yield 57.03%) as a yellow oil. LCMS[M+1] = 350.1. 1H NMR(400MHz,CDCl3)δ=7.36(t,J=8.1Hz,1H),7.08(d,J=7.0Hz,1H),6.97(d,J=8.2Hz,1H),5.16(s,1H),4.60-4.53(m ,1H),3.95-3.69(m,9H),2.72-2.61(m,2H),2.33-2.22(m,2H),2.13-1.98(m,2H),1.80(ddd,J=3.5,7.3,13.6Hz,2H).

[0556] Step 9: Methyl 2-((methylsulfonyl)oxy)-2-(2-(2-oxopyrrolidine-1-yl)-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)acetate

[0557] [ka] To a solution of methyl 2-hydroxy-2-(2-(2-oxopyrrolidine-1-yl)-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl) acetate (150 mg, 429.34 μmol, 1 equivalent) in DCM (3 mL), TEA (130.33 mg, 1.29 mmol, 179.27 μL, 3 equivalents) and Ms2O (224.37 mg, 1.29 mmol, 3 equivalents) were added at 0°C. The mixture was stirred at 0°C for 15 minutes. The reaction product was quenched by adding NaHCO3(aq) (2 mL) at 20°C and extracted with DCM (2 mL x 3). The organic solutions were combined, washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Methyl 2-((methylsulfonyl)oxy)-2-(2-(2-oxopyrrolidine-1-yl)-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl) acetate (170 mg, crude) was obtained as a yellow oily substance. LCMS[M+1] = 428.1.

[0558] Preparation of tert-butyl 2-bromo-2-(5-(methoxymethyl)-1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-7-yl) acetate

[0559] [ka] Step 1: 7-Bromo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one

[0560] [ka] Three parallel reactions were carried out. A solution of 7-bromoindorin-2-one (15 g, 70.74 mmol, 1 equivalent) in DMF (450 mL) was added to a mixture of NaH (14.15 g, 353.70 mmol, 60% purity, 5 equivalents) in DMF (450 mL) under an N2 atmosphere at 0°C. The reaction mixture was stirred at 0°C for 1 hour. 1-bromo-2-(2-bromoethoxy)ethane (24.61 g, 106.11 mmol, 13.30 mL, 1.5 equivalents) was added at 0°C. The reaction mixture was warmed to 25°C and stirred at 25°C for 15 hours. The three parallel reactions were combined. The reaction mixture was quenched by adding H2O (3000 mL). The filtered cake was washed with water (600 mL x 3) and dried in vacuum to obtain 7-bromo-2',3',5',6'-tetrahydrospiro[indorin-3,4'-pyran]-2-one (50 g, 120.46 mmol, yield 56.76%, crude) as a red solid. LCMS[M+1] = 282.1.

[0561] Step 2: 7-Bromo-1-methyl-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one

[0562] [ka] Two parallel reactions were carried out. To a solution of 7-bromo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one (12 g, 42.53 mmol, 1 equivalent) in DMF (160 mL), NaH (3.40 g, 85.07 mmol, 60% purity, 2 equivalents) was added at 0°C under an N2 atmosphere. The reaction mixture was stirred at 0°C for 0.5 hours under an N2 atmosphere. MeI (12.07 g, 85.07 mmol, 5.30 mL, 2 equivalents) was added dropwise to the reaction mixture at 0°C. The reaction mixture was warmed to 25°C and stirred for 2 hours. The two reaction mixtures were combined and quenched by adding saturated NH4Cl (500 mL) at 0°C. The mixture was extracted with ethyl acetate (50 mL x 3). The organic solutions were combined, washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~3 / 1). 7-Bromo-1-methyl-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one (yield 35.72%) was obtained as a white solid. LCMS[M+1] = 675.4. 1 H NMR(400MHz,CDCl3)δ=7.40(dd,J=0.8,8.3Hz,1H),7.23(dd,J=0.8,7.4Hz,1H),6.93(t,J=7.8Hz,1 H),4.32-4.26(m,2H),3.93-3.88(m,2H),3.60(s,3H),1.95-1.88(m,2H),1.76(brd,J=13.9Hz,2H).

[0563] Step 3: 7-Bromo-5-iodo-1-methyl-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one

[0564] [ka] Two parallel reactions were carried out. To a solution of 7-bromo-1-methyl-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one (5 g, 16.88 mmol, 1 equivalent) in AcOH (50 mL), NIS (9.5 g, 42.21 mmol, 2.5 equivalents) was added at 25°C under an N2 atmosphere. The reaction mixture was heated to 50°C and stirred for 16 hours. The two reaction mixtures were combined, quenched by adding saturated NaHCO3 (200 mL), and extracted with ethyl acetate (30 mL x 3). The organic solutions were combined, washed with brine (30 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0~90 / 10). 7-Bromo-5-iodo-1-methyl-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one (yield 70.17%) was obtained as a white solid. LCMS[M+1] = 421.7. 1 H NMR(400MHz,CDCl3)δ=7.73(d,J=1.5Hz,1H),7.47(d,J=1.5Hz,1H),4.29-4.23 (m,2H),3.91-3.86(m,2H),3.56(s,3H),1.93-1.86(m,2H),1.76-1.71(m,2H).

[0565] Step 4: 7-bromo-1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-5-carbaldehyde

[0566] [ka] Two parallel reactions were carried out. To a solution of 7-bromo-5-iodo-1-methyl-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one (5g, 11.85 mmol, 1 equivalent) in THF (50 mL), i-PrMgBr (1M, 17.77 mL, 1.5 equivalents) was added dropwise at 0°C under an N2 atmosphere. The reaction mixture was stirred at 0°C for 0.5 hours. DMF (8.66 g, 118.47 mmol, 9.12 mL, 10 equivalents) was added to the reaction mixture at 0°C. The reaction mixture was warmed to 25°C and stirred at 25°C for 2 hours. The two reaction mixtures were combined and quenched by adding saturated NaHCONH4Cl (200 mL) at 20°C, and extracted with ethyl acetate (50 mL x 3). The organic solutions were combined, washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0~80 / 20). 7-Bromo-1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-5-carbaldehyde (yield 78.12%) was obtained as a yellow solid. LCMS[M+1] = 323.8. 1 H NMR(400MHz,CDCl3)δ=9.86(s,1H),7.93(d,J=1.3Hz,1H),7.75(d,J=1.3Hz,1H),4.27(t,J =9.8Hz,2H),3.95-3.91(m,2H),3.65(s,3H),1.99-1.94(m,2H),1.77(brd,J=13.9Hz,2H).

[0567] Step 5: 7-Bromo-5-(hydroxymethyl)-1-methyl-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one

[0568] [ka] Two parallel reactions were carried out. To a solution of 7-bromo-1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-5-carbaldehyde (3 g, 9.25 mmol, 1 equivalent) in THF (30 mL), NaBH4 (350.12 mg, 9.25 mmol, 1 equivalent) was added at 0°C under an N2 atmosphere. The reaction mixture was warmed to 25°C and stirred for 2 hours. The two reaction mixtures were combined and quenched by adding 250 mL of water at 25°C, and extracted with ethyl acetate (50 mL x 3). The organic solutions were combined, washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0~70 / 30). 7-Bromo-5-(hydroxymethyl)-1-methyl-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one (yield 82.82%) was obtained as a yellow solid. LCMS[M+1] = 325.9. 1 H NMR(400MHz,CDCl3)δ=7.36(s,1H),7.21(s,1H),4.57(s,2H),4.26-4.20(m,2H ),3.88-3.84(m,2H),3.53(s,3H),1.90-1.84(m,2H),1.70(brd,J=13.9Hz,2H).

[0569] Step 6: 7-Bromo-5-(methoxymethyl)-1-methyl-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one

[0570] [ka] To a solution of 7-bromo-5-(hydroxymethyl)-1-methyl-2',3',5',6'-tetrahydrospiro[indorin-3,4'-pyran]-2-one (5g, 15.33 mmol, 1 equivalent) in THF (100 mL), add NaH (919.64 mg, 22.99 mmol, 60% purity, 1.5 equivalents), 2 The mixture was added under controlled conditions at 0°C. The reaction mixture was 0°C. ℃The mixture was stirred for 0.5 hours. MeI (3.26 g, 22.99 mmol, 1.43 mL, 1.5 equivalents) was added to the reaction mixture at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched by adding saturated NH4Cl (200 mL) at 25°C and extracted with ethyl acetate (50 mL x 3). The organic solutions were combined, washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0~80 / 20). 7-Bromo-5-(methoxymethyl)-1-methyl-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one (yield 92.04%) was obtained as a yellow solid. LCMS[M+1] = 340.0.

[0571] Step 7: tert-butyl 2-(5-(methoxymethyl)-1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-7-yl) acetate

[0572] [ka] To a solution of 7-bromo-5-(methoxymethyl)-1-methyl-2',3',5',6'-tetrahydrospiro[indolin-3,4'-pyran]-2-one (4.8 g, 14.11 mmol, 1 equivalent) in THF (50 mL), Pd(t-Bu3P)3 (721.04 mg, 1.41 mmol, 0.1 equivalent) and ZnBrCH2COOt-Bu (1 M, 28.22 mL, 2 equivalents) were added at 25°C under an N2 atmosphere. The reaction mixture was heated to 80°C and stirred at 80°C for 2 hours. The reaction mixture was quenched by adding water (150 mL) at 25°C and filtered. The filtered cake was washed with ethyl acetate (20 mL x 3) and then with 1N HCl (500 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The organic solutions were combined, washed with brine (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0~80 / 20). Tert-butyl 2-(5-(methoxymethyl)-1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-7-yl) acetate (yield 84.95%) was obtained as a yellow solid. LCMS[M+1] = 376.3. 1 H NMR(400MHz,CDCl3)δ=7.22(s,1H),7.04(s,1H),4.41(s,2H),4.32-4.26(m,2H),3.94-3.89(m,2H) ),3.80(s,2H),3.44(s,3H),3.40(s,3H),1.96-1.90(m,2H),1.75(brd,J=13.9Hz,2H),1.45(s,9H)

[0573] Step 8: tert-butyl 2-bromo-2-(5-(methoxymethyl)-1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-7-yl) acetate

[0574] [ka] To a solution of tert-butyl 2-(5-(methoxymethyl)-1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-7-yl) acetate (1 g, 2.66 mmol, 1 equivalent) in THF (10 mL), LDA (2 M, 1.60 mL, 1.2 equivalents) was added dropwise at -70°C under an N2 atmosphere. The reaction mixture was stirred at -70°C for 0.5 hours. TMSCl (434.04 mg, 4.00 mmol, 507.05 μL, 1.5 equivalents) was added to the reaction mixture at -70°C. The reaction mixture was stirred at -70°C for 0.5 hours. A solution of NBS (711.07 mg, 4.00 mmol, 1.5 equivalents) in THF (8 mL) was added to the reaction mixture at -70°C. The reaction mixture was stirred at -70°C for 1 hour. The reaction mixture was quenched by adding saturated NH4Cl (50 mL) at 25°C and extracted with ethyl acetate (10 mL x 3). The organic solutions were combined, washed with brine (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0~75 / 25). Tert-butyl 2-bromo-2-(5-(methoxymethyl)-1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-7-yl) acetate (yield 24.79%) was obtained as a yellow oil. LCMS[M+1] = 454.0. 1 H NMR(400MHz,CDCl3)δ=7.53(s,1H),7.28(brs,1H),6.00(s,1H),4.42(s,2H),4.30-4.27(m,2H), 3.93-3.90(m,2H),3.59(s,3H),3.40(s,3H),1.96-1.92(m,2H),1.78-1.75(m,2H),1.49(s,9H).

[0575] Preparation of methyl 2-(4-methylchroman-5-yl)acetate

[0576] [ka] Step 1: Methyl(E)-3-(2-bromo-6-fluorophenyl)buta-2-enoate

[0577] [ka] To a solution of methyl 2-(dimethoxyphosphoryl)acetate (15.10 g, 82.94 mmol, 11.95 mL, 1.2 equivalents) in THF (150 mL), t-BuOK (1 M, 82.94 mL, 1.2 equivalents) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours. 1-(2-bromo-6-fluorophenyl)ethane-1-one (15 g, 69.11 mmol, 1 equivalent) was added to THF (150 mL) at 0°C, and the mixture was stirred at 0°C for 1.5 hours, then at 50°C for 14 hours. The reaction product was quenched by adding H2O (300 mL), and ethyl acetate (50 mL) was added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The organic solutions were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was subjected to column chromatography: SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1, TLC: petroleum ether / ethyl acetate = 10 / 1, R f It was purified using (=0.56). Methyl(E)-3-(2-bromo-6-fluorophenyl)buta-2-enoate (20g, crude) was obtained as a yellow oily substance. 1 H NMR (400MHz, CDCl3)δ=7.17-7.14(m,1H),7.09-7.05(m,1H),6.98-6.96(m,1H),6.01(d,J=1.5Hz,1H),3.66(s,3H),2.47(d,J=1.1Hz,3H).

[0578] Step 2: (E)-3-(2-bromo-6-fluorophenyl)buta-2-en-1-ol

[0579] [ka] Two reactions were carried out in parallel. To a solution of methyl(E)-3-(2-bromo-6-fluorophenyl)buta-2-enoate (11 g, 40.28 mmol, 1 equivalent) in THF (120 mL), LiAlH4 (2.5 M, 24.17 mL, 1.5 equivalents) was added under a nitrogen atmosphere at 0°C. The reaction mixture was stirred at 20°C for 2 hours. H2O (2.5 mL) and NaOH (15%, 2.5 mL) were added to the reaction mixture. The mixture was further diluted with H2O (500 mL) and extracted with ethyl acetate (100 mL x 3). The organic solutions were combined, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. (E)-3-(2-bromo-6-fluorophenyl)buta-2-en-1-ol (yield 50.65%) was obtained as a yellow oil.

[0580] Step 3: 5-bromo-4-methyl-2H-chromene

[0581] [ka] To a solution of (E)-3-(2-bromo-6-fluorophenyl)buta-2-en-1-ol (15 g, 61.20 mmol, 1 equivalent) in DMF (180 mL), Cs2CO3 (59.82 g, 183.61 mmol, 3 equivalents) was added at 20 °C. The mixture was stirred at 80 °C for 16 hours. The reaction product was quenched by adding H2O (400 mL), and ethyl acetate (200 mL) was added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (200 mL x 3). The organic solutions were combined, washed with brine (400 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). 5-bromo-4-methyl-2H-chromene (yield 19.54%) was obtained as a yellow oily substance. 1H NMR(400MHz,CDCl3)δ=7.20(dd,J=1.3,7.9Hz,1H),6.97(t,J=8.0Hz,1H),6.87(dd,J=1.3,8.1 Hz,1H), 5.82(ddd,J=1.5,3.1,6.0Hz,1H),4.48(qd,J=1.4,4.5Hz,2H),2.37(q,J=1.5Hz,3H).

[0582] Step 4: Methyl 2-(4-methyl-2H-chromen-5-yl)acetate

[0583] [ka] A suspension of 5-bromo-4-methyl-2H-chromene (200 mg, 888.57 μmol, 1 equivalent), BrZnCH2COOMe (1 M, 4.44 mL, 5 equivalents), and Pd(t-Bu3P)2 (22.71 mg, 44.43 μmol, 0.05 equivalents) in THF (250 mL) was stirred at 70°C for 2 hours under an N2 atmosphere. Water (5 mL) was added, and the mixture was filtered. The filtrate was extracted with ethyl acetate (5 mL x 2). The organic solutions were combined, washed with brine (5 mL x 2), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 25 g Sepa Flash® silica flash column, eluent 0-20% petroleum ether gradient / ethyl acetate @ 120 mL / min). Methyl 2-(4-methyl-2H-chromen-5-yl)acetate (yield 85.94%) was obtained as a yellow oily substance. LCMS[M+1] = 219.1. 1 H NMR(400MHz,CDCl3)δ=7.10(t,J=7.8Hz,1H),6.87(dd,J=1.1,8.1Hz,1H),6.80(dd,J=0.8,7.6Hz,1H),5.76( ddd,J=1.4,3.2,5.9Hz,1H),4.48-4.44(m,2H),3.87-3.85(m,2H),3.73-3.70(m,3H),2.16(d,J=1.4Hz,3H).

[0584] Step 5: Methyl 2-(4-methylchroman-5-yl)acetate

[0585] [ka] A solution of methyl 2-(4-methyl-2H-chromen-5-yl)acetate (2 g, 9.16 mmol, 1 equivalent) and Pd / C (20.00 g, 18.79 mmol, 1.88 mL, 10% purity, 2.05 equivalents) in MeOH (30 mL) was stirred under H2 (15 psi) at 30°C for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain methyl 2-(4-methylchroman-5-yl)acetate (1.7 g, 84.22%) as a yellow oily substance. LCMS[M+1] = 221.2.

[0586] Preparation of 8-bromo-1-methylisochromane

[0587] [ka] Step 1: 1-(2,6-dibromophenyl)ethane-1-ol

[0588] [ka] MeMgBr (3M, 142.09 mL, 1.5 equivalents) was added dropwise at 0°C to a solution of 2,6-dibromobenzaldehyde (75 g, 284.18 mmol, 1 equivalent) in THF (1000 mL). The mixture was stirred at 0-10°C for 2 hours. The reaction mixture was added dropwise at 0°C under an atmosphere of N2 to saturated NH4Cl (1000 mL), and the mixture was extracted with ethyl acetate (200 mL x 2). The organic solutions were combined, washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 1-(2,6-dibromophenyl)ethane-1-ol (yield 94.97%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ=7.55(d,J=8.0Hz,2H),6.97(t,J=8.0Hz,1H),5.57(q,J=6.8Hz,1H),1.64(d,J=6.8Hz,3H).

[0589] Step 2: 2-(1-(2,6-dibromophenyl)ethoxy)acetic acid

[0590] [ka] To a solution of 1-(2,6-dibromophenyl)ethane-1-ol (36 g, 128.59 mmol, 1 equivalent) in THF (400 mL), NaH (10.29 g, 257.18 mmol, 60% purity, 2 equivalents) was added at 0°C under an N2 atmosphere. The mixture was stirred at 0°C for 0.5 hours. BrCH2COOMe (39.34 g, 257.18 mmol, 24.35 mL, 2 equivalents) was added at 0°C, and the solution was stirred at 20°C for 1 hour. H2O (200 mL) and NaOH (10.29 g, 257.18 mmol, 2 equivalents) were added to the reaction mixture, and the mixture was stirred at 20°C for 2 hours. The mixture was extracted with ELISA (200 mL x 3). The aqueous phase was adjusted to pH=3 by adding HCl (1M) and extracted with DCM (200 mL x 3). The organic solutions were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(1-(2,6-dibromophenyl)ethoxy)acetic acid (yield 98.93%) as a white solid. 1 H NMR(400MHz,CD3OD)δ=7.63(d,J=8.0Hz,2H),7.09(t,J=8.0Hz,1H),5.51-5.42 (m,1H),3.94(d,J=16.5Hz,1H),3.70(d,J=16.6Hz,1H),1.60(d,J=6.8Hz,3H).

[0591] Step 3: 2-(1-(2,6-dibromophenyl)ethoxy)-N-methoxy-N-methylacetamide

[0592] [ka] A mixture of 2-(1-(2,6-dibromophenyl)ethoxy)acetic acid (96 g, 284.03 mmol, 1 equivalent) and HATU (118.80 g, 312.43 mmol, 1.1 equivalents) in DCM (1000 mL) was stirred at 20°C for 1 hour. DIEA (110.13 g, 852.09 mmol, 148.42 mL, 3 equivalents) and N,O-dimethylhydroxylamine hydrochloride (33.25 g, 340.84 mmol, 1.2 equivalents) were added to the mixture. The reaction mixture was stirred at 20°C for 15 hours. The reaction mixture was quenched by adding H2O (1000 mL) and extracted with ethyl acetate (200 mL x 3). The organic solutions were combined, washed with brine (200 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1). 2-(1-(2,6-dibromophenyl)ethoxy)-N-methoxy-N-methylacetamide (yield 85.93%) was obtained as a yellow oil. 1 H NMR(400MHz,CDCl3)δ=7.57(d,J=8.1Hz,2H),6.99(t,J=7.9Hz,1H),5.45(q,J=6.7Hz,1H),4.2 0(brd,J=15.6Hz,1H),3.94(d,J=15.8Hz,1H),3.59(s,3H),3.19(s,3H),1.68(d,J=6.7Hz,3H).

[0593] Step 4: 8-bromo-1-methylisochroman-4-one

[0594] [ka] To a solution of 2-(1-(2,6-dibromophenyl)ethoxy)-N-methoxy-N-methylacetamide (51 g, 133.84 mmol, 1 equivalent) in THF (300 mL), n-BuLi (2.5 M, 53.53 mL, 1 equivalent) was added at -70°C, and the solution was stirred at -70°C for 2 hours under an N2 atmosphere. The reaction mixture was quenched by adding saturated NH4Cl (300 mL) at 0°C and extracted with ethyl acetate (50 mL x 3). The organic solutions were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1). 8-bromo-1-methylisochroman-4-one (yield 74.38%) was obtained as a white solid. 1 H NMR(400MHz,CDCl3)δ=8.02(dd,J=0.9,7.8Hz,1H),7.77(dd,J=1.2,7.9Hz,1H),7.30(t,J=7.9H z,1H),5.34-5.30(m,1H),4.64(d,J=18.3Hz,1H),4.37(d,J=18.1Hz,1H),1.67(d,J=6.8Hz,3H).

[0595] Step 5: 8-bromo-1-methylisochromane

[0596] [ka] To a solution of 8-bromo-1-methylisochroman-4-one (38.5 g, 159.70 mmol, 1 equivalent) in TFA (300 mL), Et3SiH (92.85 g, 798.49 mmol, 127.54 mL, 5 equivalents) was added at 20°C under an N2 atmosphere, and the solution was stirred at 50°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned into ethyl acetate (20 mL) and saturated NaHCO3 (100 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic solutions were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain 8-bromo-1-methylisochroman (yield 82.72%) as a white solid. 1H NMR(400MHz,CDCl3)δ=7.39(dd,J=0.6,7.6Hz,1H),7.05(td,J=7.2,14.9Hz,2H),5.06(q,J=6.5Hz,1H),4.11(ddd,J=4 .3,9.4,11.5Hz,1H),3.86(ddd,J=3.8,5.9,11.5Hz,1H),2.99-2.90(m,1H),2.78-2.72(m,1H),1.59(d,J=6.5Hz,3H).

[0597] Preparation of methyl 2-bromo-2-((S)-1,6-dimethylisochroman-8-yl)acetate

[0598] [ka] Step 1: Methyl(S)-2-(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-8-yl)acetate

[0599] [ka] To a solution of arbitrarily assigned methyl(S)-2-(1-methylisochroman-8-yl)acetate (1.5 g, 6.81 mmol, 1 equivalent) in dioxane (20 mL), Pin2B2 (3.46 g, 13.62 mmol, 2 equivalents), dtbpy (109.67 mg, 408.60 μmol, 0.06 equivalents), and [Ir(OMe)(cod)]2 (135.42 mg, 204.30 μmol, 0.03 equivalents) were added at 20°C under an N2 atmosphere. The mixture was stirred at 100°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain methyl(S)-2-(1,6-dimethylisochroman-8-yl)acetate (3g, crude) as a yellow oily substance. LCMS[M+1] = 235.1. 1H NMR(400MHz,CDCl3)δ=7.51(s,2H),5.15-5.08(m,1H),4.15-4.06(m,1H),3.83(dd,J=5.0,10.9Hz,1H),3.71-3.69(m,3H),3 .65-3.61(m,1H),3.60-3.55(m,1H),2.93(brdd,J=5.8,7.8Hz,1H),2.85-2.76(m,1H),1.47(d,J=6.5Hz,3H),1.34(s,12H).

[0600] Step 2: Methyl(S)-2-(1,6-dimethylisochroman-8-yl)acetate

[0601] [ka] To a solution of methyl(S)-2-(1,6-dimethylisochroman-8-yl)acetate (3 g, 8.66 mmol, 1 equivalent) in toluene (50 mL), EtOH (20 mL), and H2O (20 mL), Pd(PPh3)4 (500.64 mg, 433.24 μmol, 0.05 equivalent), K2CO3 (3.59 g, 25.99 mmol, 3 equivalents), and MeI (6.15 g, 43.32 mmol, 2.70 mL, 5 equivalents) were sequentially added at 20°C under an N2 atmosphere. The reaction mixture was heated to 100°C and stirred at 100°C for 16 hours. The reaction mixture was quenched with water (200 mL) at 20°C and extracted with ethyl acetate (100 mL x 3). The organic solutions were combined, washed with brine (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain methyl(S)-2-(1,6-dimethylisochroman-8-yl)acetate (1 g, 3.41 mmol, yield 39.41%, purity 80%) as a yellow oil. LCMS[M+1] = 235.1 1H NMR(400MHz,CDCl3)δ=6.93(brs,1H),6.87(s,1H),5.08(q,J=6.5Hz,1H),4.13-4.05(m,1H),3.81(td,J=5.1,10.8Hz,1H),3. 71(s,3H),3.63-3.57(m,1H),3.53-3.48(m,1H),2.94-2.84(m,1H),2.79-2.70(m,1H),2.30(s,3H),1.47(brd,J=6.5Hz,3H).

[0602] Step 3: Methyl 2-bromo-2-((S)-1,6-dimethylisochroman-8-yl)acetate

[0603] [ka] To a solution of methyl(S)-2-(1,6-dimethylisochroman-8-yl)acetate (0.5 g, 2.13 mmol, 1 equivalent) in THF (5 mL), LDA (2 M, 3.20 mL, 3 equivalents) was added at -60°C, and the mixture was stirred at -60°C for 30 minutes. TMSCl (765.10 mg, 7.04 mmol, 893.81 μL, 3.3 equivalents) was added at -60°C, and the mixture was stirred at -60°C for 0.5 hours. A solution of NBS (569.74 mg, 3.20 mmol, 1.5 equivalents) in THF (5 mL) was added at -60°C. The mixture was stirred at 60°C for 1 hour. The reaction product was diluted with saturated NH4Cl (50 mL) and extracted with ethyl acetate (20 mL x 3). The organic solutions were combined, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain methyl 2-bromo-2-((S)-1,6-dimethylisochroman-8-yl) acetate (0.46 g, 734.39 μmol, yield 34.41%, purity 50%) as a yellow oil.

[0604] Starting from arbitrarily assigned methyl(R)-2-(1-methylisochroman-8-yl)acetate, arbitrarily assigned methyl 2-bromo-2-((R)-1,6-dimethylisochroman-8-yl)acetate was prepared by the same method.

[0605] Preparation of tert-butyl 2-(1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-7-yl) acetate

[0606] [ka] Step 1: 7-Bromo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one

[0607] [ka] Four parallel reactions were carried out. To a solution of 7-bromoindolin-2-one (5 g, 23.58 mmol, 1 equivalent) in THF (100 mL), LiHMDS (1 M, 117.90 mL, 5 equivalents) was added at -70°C, and the mixture was stirred at -70°C for 0.5 hours. Next, 1-bromo-2-(2-bromoethoxy)ethane (8.20 g, 35.37 mmol, 4.43 mL, 1.5 equivalents) was added at -70°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched by adding H2O (500 mL), and ethyl acetate (200 mL) was added. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (200 mL x 3). The organic solutions were combined, washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 3 / 1). 7-bromo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one (yield 29.69%) was obtained as a yellow solid. 1H NMR(400MHz,CDCl3)δ=7.37(d,J=8.3Hz,1H),7.29(s,1H),6.97(t,J=7.9Hz,1H) ,4.24(td,J=6.2,11.9Hz,2H),3.92(td,J=4.7,11.8Hz,2H),1.96-1.86(m,4H).

[0608] Step 2: 7-Bromo-1-methyl-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one

[0609] [ka] To a solution of 7-bromo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one (5.4 g, 19.14 mmol, 1 equivalent) in DMF (55 mL), NaH (765.52 mg, 19.14 mmol, 60% purity, 1 equivalent) was added at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, and then MeI (5.43 g, 38.28 mmol, 2.38 mL, 2 equivalents) was added at 0°C. The mixture was stirred at 20°C for 16 hours. The mixture was quenched by adding saturated NH4Cl (200 mL), and ethyl acetate (100 mL) was added. The organic and aqueous phases were separated, and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic solutions were combined, washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). 7-Bromo-1-methyl-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one (yield 89.97%) was obtained as a yellow solid. 1 H NMR(400MHz,CDCl3)δ=7.39(dd,J=1.1,8.2Hz,1H),7.22(dd,J=1.0,7.4Hz,1H),6.96-6.89(m,1H),4.29(ddd ,J=2.9,10.4,11.6Hz,2H),3.90(td,J=4.3,11.8Hz,2H),3.59(s,3H),1.97-1.88(m,2H),1.80-1.72(m,2H).

[0610] Step 3: tert-butyl 2-(1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-7-yl) acetate

[0611] [ka] To a solution of 7-bromo-1-methyl-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one (6.5 g, 21.95 mmol, 1 equivalent) in THF (65 mL), BrZnCH2COOt-Bu (1 M, 43.90 mL, 2 equivalents) and Pd(t-Bu3P)2 (1.12 g, 2.19 mmol, 0.1 equivalent) were added at 20°C. The mixture was stirred at 80°C for 2 hours. The mixture was quenched by adding H2O and filtered. The filtrate was extracted with ethyl acetate (100 mL x 3). The organic solutions were combined, washed with brine (100 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1~5 / 1). Tert-butyl 2-(1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-7-yl) acetate (yield 89.36%) was obtained as a yellow solid. 1 H NMR(400MHz,CDCl3)δ=7.23(dd,J=1.4,7.1Hz,1H),7.09-7.01(m,2H),4.38-4.21(m,2H),3.92(td,J=4.3,11.7 Hz,2H), 3.81(s,2H),3.46(s,3H),1.94(ddd,J=4.4,10.0,14.1Hz,2H),1.77(brd,J=13.9Hz,2H),1.45(s,9H).

[0612] Preparation of 4'-bromo-6'-methyl-1'-(tetrahydro-2H-pyran-4-yl)spiro[cyclopropan-1,3'-indoline]-2'-one

[0613] [ka] Step 1: Methyl 2-(2-bromo-6-fluoro-4-methylphenyl)-2-oxoacetate

[0614] [ka] To a solution of 1-bromo-3-fluoro-5-methylbenzene (50 g, 264.52 mmol, 1 equivalent) in THF (500 mL), LDA (2 M, 158.71 mL, 1.2 equivalents) was added dropwise at -70°C under an N2 atmosphere. The reaction mixture was stirred at -70°C for 0.5 hours. To the reaction mixture, a solution of dimethyl oxalate (40.61 g, 343.87 mmol, 1.3 equivalents) in THF (500 mL) was added under an N2 atmosphere at -70°C. The reaction mixture was stirred at -70°C under N2 for 2 hours. The reaction product was quenched by adding NH4Cl (500 mL) and extracted with ...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 During the ceremony, 【Chemistry 2】 However, it has a 6-12 membered aryl ring structure or a 3-19 membered heterocyclyl ring structure. 【Transformation 3】 However, halogen, C １～６ Alkyl, C １～６ The C may be substituted with an alkyloxy, a 3- to 8-membered heterocyclyl ring structure, an aryl, or a 5- to 6-membered heteroaryl. １～６ alkyl, the C １～６ Alkyloxy, the 3-8 membered heterocyclyl ring structure, the aryl, or the 5-6 membered heteroaryl may contain one or more halogens, C １～４ C is optionally substituted with alkyloxy or one or more halogens. １～６ It may also be substituted with alkyl; a is 1, 2, 3, 4, 5, 6, 7, or 8; R ａ However, C １～６ A compound of formula (I) that is alkyl, or a pharmaceutically acceptable salt thereof.

2. A compound of formula (I-A), or a pharmaceutically acceptable salt thereof, 【Chemistry 4】 The compound according to claim 1. 【Request Item 3】 【Chemistry 5】 The compound according to any one of claims 1 to 2, wherein the compound is phenyl or a six-membered heteroaryl. 【Request Item 4】 【Chemistry 6】 but, 【Transformation 7】 And in the formula, R １ is C １～４ alkoxy; R ２ is C optionally substituted with one or more halogens １～４ alkyl, or 【Transformation 8】 However, R １ and R ２ When these combine to form a condensed 5-8 member heterocycloalkyl ring, a condensed 5-6 member heteroaryl ring, or a condensed 7-15 member spirocyclic heterocycloalkyl ring system, it is a 9-19 member heterocyclil, and the condensed ring is a halogen, C １～４ Alkyl, C ３～６ The C may be substituted with a cycloalkyl or a 4- to 8-membered heterocycloalkyl ring. １～４ alkyl, the C ３～６ The cycloalkyl or the 4- to 8-membered heterocycloalkyl ring may be substituted with one or more halogens or one or more halogens. １～４ It may also be substituted with alkyl; R ３ However, C may be substituted with one or more halogens. １～４ A compound according to any one of claims 1 to 3, wherein it is alkyl.

5. R １ However, it is methoxy; R ２ However, it is fluoro; R ３ However, C may be substituted with one or more fluoropolymers. １～４ The compound according to claim 4, wherein it is alkyl. 【Request Item 6】 【Chemistry 9】 but, 【Chemistry 10】 And, During the ceremony, R ４ and R １４ However, each C may be independently substituted with H, a halogen, or one or more halogens. １～４ It is alkyl; X １ However, CR ５ａ R ５ｂ Or NR ５ｃ and R ５ａ However, C may be substituted with H or one or more halogens. １～４ It is alkyl, R ５ｂ However, C １～４ Alkyl or C ３～６ It is a cycloalkyl, and the C １～４ Alkyl or the aforementioned C ３～６ The cycloalkyl group is optionally substituted with one or more halogens; or R ５ａ and R ５ｂ These combine to form a spirocyclic 3- to 8-membered heterocycloalkyl or spirocyclic C ３～６ Forms a cycloalkyl group, and the 3-8 membered heterocycloalkyl group or the C ３～６ The cycloalkyl group may be substituted with one or more halogens. １～４ C may be substituted with alkyl, 4-6 membered spirocyclic heterocycloalkyl, or one or more halogens. １～４ C may be substituted with alkyl. ３～６ It may also be substituted with a spirocyclic cycloalkyl group; R ５ｃ However, C １～４ Alkyl, or C ３～６ It is a cycloalkyl, and the C １～４ Alkyl or the C ３～６ The cycloalkyl group may be substituted with one or more halogens; X ２ However, CR ６ａ R ６ｂ ien-CH ２ CR ６ａ R ６ｂ , C=O, O or NR ６ｃ And; R ６ａ and R ６ｂ However, H and C are independent of each other. １～４ Alkyl, 5-6 member heteroaryl, 6 member aryl, C ３～７ The C is a cycloalkyl or a 4- to 7-membered heterocycloalkyl, and １～４ alkyl, the 5-6 member heteroaryl, the 6 member aryl, the C ３～８ Each of the cycloalkyl group or the 4- to 7-membered heterocycloalkyl group contains one or more halogens or C １～４ It may also be substituted with alkyl; R ６ｃ However, C may be substituted with one or more halogens. １～４ It is alkyl, X ３ However, direct bonding, CR ７ａ R ７ｂ , O or NR ７ｃ And; R ７ａ and R ７ｂ However, each C may be independently substituted with H or one or more halogens. １～４ It is alkyl; R ７ｃ However, C may be substituted with one or more halogens. １～４ It is alkyl; X ４ However, CR ８ａ R ８ｂ Or NR ８ｃ and R ８ａ However, H is R ８ｂ However, C may be substituted with a halogen or one or more halogens. １～４ It is alkyl; R ８ａ and R ８ｂ are taken together to form a spirocyclic 3- to 8-membered heterocycloalkyl or C ３～６ cycloalkyl, wherein said 3- to 8-membered heterocycloalkyl or said C ３～６ cycloalkyl is optionally substituted with one or more halogen C １～４ alkyl, 4- to 8-membered spirocyclic heterocycloalkyl, or C optionally substituted with one or more halogen １～４ alkyl optionally substituted C ３～７ spirocyclic cycloalkyl, which may be optionally substituted; R ８ｃ However, H, C １～４ Alkyl, 4-8 membered heterocycloalkyl, or C ３～６ It is a cycloalkyl, and the C １～４ Alkyl, the 4-8 membered heterocycloalkyl, or the C ３～６ The cycloalkyl group may be substituted with one or more halogens; with the proviso that X ２ and X ３ two of both do not contain an O or N heteroatom, and X ３ and X ４ two of which do not contain an O or N heteroatom, the compound according to any one of claims 1 to 3.

7. R １４ However, it is H; X １ However, CR ５ａ R ５ｂ And R ５ａ However, H is R ５ｂ The compound according to claim 6, wherein the compound is methyl or cyclopropyl.

8. R ４ However, it is H, fluoro, or methyl; X １ However, CR ５ａ R ５ｂ And R ５ａ However, H is R ５ｂ is methyl; X ２ However, O and X ３ However, CR ７ａ R ７ｂ And R ７ａ and R ７ｂ However, each C may be independently substituted with H or one or more halogens. １～４ It is alkyl; or X ３ However, O and X ２ However, CR ６ａ R ７ｂ And R ６ａ and R ６ｂ Each of these is independently H; X ４ However, CR ８ａ R ８ｂ And, R ８ａ and R ８ｂ However, each C may be independently substituted with H or one or more halogens. １～４ Alkyl or R ８ａ and R ８ｂ Together, they form a 4-7 member heterocycloalkyl ring or C ３～７ A cycloalkyl ring is formed, and the 4- to 7-membered heterocycloalkyl or the C ３～７ The cycloalkyl group may be substituted with a halogen, or one or more halogens. １～４ C may be substituted with alkyl, 4- to 7-membered spirocyclic heterocycloalkyl, or one or more halogens. １～４ C may be substituted with alkyl. ３～７ The compound according to any one of claims 6 to 7, wherein it is optionally substituted with a spirocyclic cycloalkyl group. 【Request Item 9】 【Chemistry 11】 but, 【Chemistry 12】 And, During the ceremony, R １０ａ and R １０ｂ However, each C may be independently substituted with H, a halogen, or one or more halogens. １～４ It is alkyl; R １０ａ and R １０ｂ Together, they form a spirocyclic C ３～６ Forming a cycloalkyl or spirocyclic 6-membered heterocycloalkyl; R １１ａ and R １１ｂ However, each C may be independently substituted with H, a halogen, or one or more halogens. １～４ It is alkyl; R １２ａ and R １２ｂ However, each C may be independently substituted with H, a halogen, or one or more halogens. １～４ It is alkyl; R １３ａ However, it is methyl, ethyl, or cyclopropyl; R １３ｂ However, it is H; R １４ However, C may be substituted with H, a halogen, or one or more halogens. １～４ The compound according to claim 6, which is alkyl, or a pharmaceutically acceptable salt thereof.

10. R １０ａ and R １０ｂ However, each is independently either H or methyl; R １１ａ and R １１ｂ However, each is independently H, methyl, or ethyl; R １２ａ and R １２ｂ However, each is independently either H or methyl; R １３ａ However, it is methyl, ethyl, or cyclopropyl; R １３ｂ However, it is H; R １４ The compound according to claim 9, wherein the compound is H, fluoro, or methyl.

11. R ４ However, it is either H or fluoro; R １３ａ However, it is methyl, ethyl, or cyclopropyl; R １４ The compound according to claim 10, wherein H is present.

12. X ２ However, NR ６ｃ And R ６ｃ However, C １～４ The compound according to claim 6, wherein it is alkyl. 【Request Item 13】 【Chemistry 13】 but, 【Chemistry 14】 And R １３ａ However, it is H or methyl, and R ４ The compound according to claim 6, wherein the compound is H, F, or methyl. 【Request Item 14】 【Chemistry 15】 but, 【Chemistry 16】 And in the formula, R ４ The compound according to claim 6, wherein the compound is H, fluoro, or methyl.

15. R １０ａ , R １０ｂ , and R １１ａ The compound according to claim 14, wherein each of them is H or methyl.

16. R １１ｂ The compound according to claim 14, wherein the compound is H, methyl, or ethyl. 【Request Item 17】 【Chemistry 17】 but, [Chemistry 18] And in the formula, R ４ However, it is H, a halogen, or a methyl atom which may be substituted with one or more halogens; R ９ａ and R ９ｂ The compound according to claim 6, wherein each is independently H, a halogen, or a methyl atom which may be substituted with one or more halogens.

18. R ４ However, it is H, fluoro, or methyl; R ９ａ and R ９ｂ The compound according to claim 17, wherein each is independently H, fluoro, chloro, or methyl which may be substituted with one or more fluoros. 【Request Item 19】 【Chemistry 19】 but, 【Chemistry 20】 And, R ２０ However, H, halogen, C １～４ Alkyl or C １～４ It is an alkoxy, and the C １～４ Alkyl or the C １～４ Each alkoxy may be substituted with one or more halogens; X ５ However, CR ２５ａ R ２５ｂ Or NR ２５ｃ and R ２５ａ and R ２５ｂ However, each C may be independently substituted with H or one or more halogens or alkoxys. １～４ It is alkyl; or R ２５ａ and R ２５ｂ Together, they each produce halogen, C １～４ Alkyl, spirocyclic C ３～６ C may be substituted with a cycloalkyl or a spirocyclic 4-6 membered heterocycline ring. ３～６ A cycloalkyl ring or a 4-6 membered heterocyclyl ring is formed, and the C １～４ Alkyl, the aforementioned spirocyclic C ３～６ A cycloalkyl group, or the aforementioned 4-6 membered spirocyclic heterocycline ring, contains one or more halogens or C １～４ It may also be substituted with alkyl; R ２５ｃ However, C １～４ Alkyl, 5-6 member heteroaryl, or C ６ It is aryl, and the C １～４ Alkyl, the 5-6 member heteroaryl, or the C ６ The aryl is one or more halogens or C １～４ It is also acceptable if it is substituted with an alkoxy; X ６ However, CR ２６ａ R ２６ｂ Or C = O; R ２６ａ and R ２６ｂ However, each independently contains H or one or more halogens or C １～４ C may be substituted with alkyl. １～４ It is alkyl; X ７ However, CR ２７ａ R ２７ｂ Or NR ２７ｃ And; R ２７ａ and R ２７ｂ However, each C may be independently substituted with H or one or more halogens or alkoxys. １～４ It is alkyl; R ２７ａ and R ２７ｂ Together, C ３～６ A cycloalkyl ring or a 4-6 membered heterocyclyl ring is formed, and the C ３～６ The cycloalkyl ring or the 4-6 membered heterocyclyl ring contains one or more halogens and one or more C １～４ Alkyl, spirocyclic C ３～６ The C may be substituted with a cycloalkyl or a spirocyclic 4-6 membered heterocyclyl ring. １～４ Alkyl, the aforementioned spirocyclic C ３～６ The cycloalkyl or the 4-6 membered spirocyclic heterocyclyl ring contains one or more halogens or C １～４ It may also be substituted with alkyl; R ２７ｃ However, H, C １～４ Alkyl, C ３～６ Cycloalkyl, 4-7 membered heterocycloalkyl, or 5-11 membered spirocyclic heterocycloalkyl, 5-6 membered heteroaryl, or C ６ It is aryl, and the C １～４ alkyl, the C ３～６ Cycloalkyl, the 4-6 member heterocycloalkyl, the 5-11 member spirocyclic heterocycloalkyl, the 5-6 member heteroaryl, or the C ６ The aryl group may be substituted with one or more halogens or one or more halogens. １～４ It may also be substituted with alkyl; However, X ５ and X ７ The compound according to any one of claims 1 to 4, wherein only one of the elements contains an N heteroatom.

20. R ２０ However, H, halogen, C １～４ Alkyl, or C １～４ It is an alkoxy, and the C １～４ Alkyl and the C １～４ The alkoxy may be substituted with one or more halogens; X ５ However, CR ２５ａ R ２５ｂ and R ２５ａ and R ２５ｂ However, each is independently methyl; or R ２５ａ and R ２５ｂ They come together to form a cyclopropyl; X ６ However, C = O; R ２６ａ and R ２６ｂ However, each independently contains H or one or more halogens or C １～４ C may be substituted with alkyl. １～４ It is alkyl; X ７ However, NR ２７ｃ And; R ２７ｃ However, C １～４ Alkyl, C ３～６ Cycloalkyl, 4-7 membered heterocycloalkyl, or 5-11 membered spirocyclic heterocycloalkyl, 5-6 membered heteroaryl, or C ６ It is aryl, and the C １～４ alkyl, the C ３～６ Cycloalkyl, the 4-6 member heterocycloalkyl, the 5-11 member spirocyclic heterocycloalkyl, the 5-6 member heteroaryl, or the C ６ The aryl group may be substituted with one or more halogens or one or more halogens. １～４ The compound according to claim 19, which is optionally substituted with an alkyl group.

21. R ２７ｃ However, C １～４ The compound according to claim 20, wherein it is alkyl.

22. R ２７ｃ The compound according to claim 20, wherein it is a five-membered heteroaryl compound.

23. R ２７ｃ However, C may be substituted with one or more halogens. ３～６ C may be substituted with a cycloalkyl group or one or more halogens. １～４ The compound according to claim 20, wherein it is alkyl.

24. R ２７ｃ However, C １～４ The C is an alkyl, a 4-7 member heterocycloalkyl, or a 5-11 member spirocyclic heterocycloalkyl, １～４ The alkyl, the 4-7 membered heterocycloalkyl, and the 5-11 membered spirocyclic heterocycloalkyl may be substituted with one or more halogens, or C １～４ The compound according to claim 20, which is optionally substituted with an alkyl group. 【Request Item 25】 【Chemistry 21】 but, 【Chemistry 22】 And, In the formula, R ２０ However, H, fluoro, methyl, ethyl, methoxy, -CH ２ -O-CH ３ , or -CF ３ The compound according to claim 24.

26. R ２７ｃ The compound according to claim 25, wherein the compound is a tetrahydropyran which may be substituted with one or more methyl or fluoro groups.

27. R ２７ｃ but, 【Chemistry 23】 And in the formula, R ３２ａ , R ３２ｂ , R ３３ａ and R ３３ b is independently H, methyl, or fluoro; or R ３２ａ and R ３２ｂ Or R ３３ａ and R ３３ｂ One of them combines to form a spirocyclic C ３～６ The compound according to claim 25, which forms a cycloalkyl or spirocyclic 3-6 membered heterocycle.

28. R ２７ｃ but, 【Chemistry 24】 The compound according to claim 25. 【Request Item 29】 【Chemistry 25】 but, 【Chemistry 26】 And in the formula, R ３０ａ , R ３０ｂ , R ３１ａ , and R ３１ｂ However, each is independently H, fluoro, or methyl; R ２０ However, H, fluoro, methyl, ethyl, methoxy, -CH ２ -O-CH ３ , or -CF ３ And; R ２７ｃ The compound according to claim 19, wherein the compound is methyl.

30. R ２７ｃ However, C １～４ The compound according to claim 25, wherein it is alkyl. 【Request Item 31】 【Chemistry 27】 but, 【Chemistry 28】 The compound according to claim 19. 【Request Item 32】 【Chemistry 29】 but, 【Transformation 30】 And, During the ceremony, R ２０ However, H, halogen, C １～４ C may be substituted with an alkoxy group. １～４ C may be substituted with an alkoxy, a 4- to 6-membered heterocycline, or one or more halogens. １～４ A compound according to any one of claims 1 to 4, wherein it is alkyl.

33. R ２５ｃ However, C １～４ It is alkyl; R ２７ｃ However, one or more halogens or C １～４ C may be substituted with an alkoxy group. １～４ Alkyl, C ３～６ The C is a cycloalkyl or a 4-6 member heterocycloalkyl, ３～６ The cycloalkyl or the 4-6 membered heterocycloalkyl may be substituted with one or more halogens. １～４ The compound according to claim 32, which is optionally substituted with an alkyl group.

34. R ２７ｃ However, C １～４ It is alkyl; R ２５ｃ However, one or more halogens or C １～４ C may be substituted with an alkoxy group. １～４ Alkyl, C ３～６ The C is a cycloalkyl or a 4-6 member heterocycloalkyl, ３～６ The cycloalkyl or the 4-6 membered heterocycloalkyl may be substituted with one or more halogens. １～４ The compound according to claim 32, which is optionally substituted with an alkyl group.

35. R ２０ The compound according to any one of claims 32 to 34, wherein the compound is H or methyl. 【Request Item 36】 【Chemistry 31】 but, 【Chemistry 32】 And; in the formula, R ２０ However, H, halogen, C １～４ C may be substituted with an alkoxy group. １～４ C may be substituted with an alkoxy, a 4- to 6-membered heterocycline, or one or more halogens. １～４ It is alkyl; R ２５ｃ However, C １～４ It is alkyl; R ２７ｃ However, 4-6 member heterocyclyl or C ３～６ It is a cycloalkyl, and is the 4-6 membered heterocycline or the C ３～６ Cycloalkyl, C １～４ The compound according to claim 19, which is optionally substituted with an alkyl group.

37. chemical formula 【Transformation 33】 Compounds thereof, or pharmaceutically acceptable salts thereof.

38. chemical formula 【Transformation 34】 Compounds thereof, or pharmaceutically acceptable salts thereof.

39. chemical formula 【Chemistry 35】 Compounds thereof, or pharmaceutically acceptable salts thereof.

40. chemical formula 【Transformation 36】 Compounds thereof, or pharmaceutically acceptable salts thereof.

41. chemical formula 【Chemistry 37】 Compounds thereof, or pharmaceutically acceptable salts thereof.

42. chemical formula 【Transformation 38】 Compounds thereof, or pharmaceutically acceptable salts thereof.

43. chemical formula 【Chemistry 39】 Compounds thereof, or pharmaceutically acceptable salts thereof.

44. chemical formula 【Chemistry 40】 Compounds thereof, or pharmaceutically acceptable salts thereof.

45. chemical formula 【Chemistry 41】 Compounds thereof, or pharmaceutically acceptable salts thereof.

46. chemical formula 【Chemistry 42】 Compounds thereof, or pharmaceutically acceptable salts thereof.

47. chemical formula 【Chemistry 43】 Compounds thereof, or pharmaceutically acceptable salts thereof.

48. chemical formula 【Chemistry 44】 Compounds thereof, or pharmaceutically acceptable salts thereof.

49. chemical formula 【Chemistry 45】 Compounds thereof, or pharmaceutically acceptable salts thereof.

50. chemical formula 【Chemistry 46】 Compounds thereof, or pharmaceutically acceptable salts thereof.

51. A compound selected from the group consisting of the compounds in Figure 1, or a pharmaceutically acceptable salt thereof.

52. A compound selected from the group consisting of the compounds in Table 3, or a pharmaceutically acceptable salt thereof.

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