Map4k1 inhibitors, pharmaceutical composition, and use thereof

TWI935138BActive Publication Date: 2026-08-11BLUEPRINT MEDICINES CORP
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Patent Information

Application Number
TW111126358
Authority / Receiving Office
TW · TW
Patent Type
Patents
Current Assignee / Owner
Priority Date
2021-07-14
Filing Date
2022-07-13
Publication Date
2026-08-11
Estimated Expiration
2042-07-12

AI Technical Summary

Technical Problem

There is a need for novel compounds that can selectively modulate MAP4K1 activity to treat MAP4K1-dependent diseases such as cancer and viral infections, as existing treatments are inadequate.

Method used

Development of compounds represented by specific chemical formulas that inhibit MAP4K1 activity, enhancing the immune response and providing therapeutic benefits for conditions like cancer and viral infections.

Benefits of technology

The developed compounds effectively inhibit MAP4K1, potentially boosting the immune response and offering treatment options for MAP4K1-dependent disorders, including cancer and viral infections.

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Abstract

One embodiment of the present invention is a compound represented by Formula I or a pharmaceutically acceptable salt thereof. The variables in Formula I are defined herein. Compound I is a MAP4K1 inhibitor, which can be used to treat diseases or conditions in individuals that benefit from the control of MAP4K1 activity.
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Description

[Technical Field]

[0001] This application relates to MAP4K1 inhibitors and methods of use thereof, such as for controlling the activity of MAP4K1 in an individual. [Previous Technology]

[0002] MAP4K1, also known as hematopoietic progenitor kinase 1 (HPK1), was originally selected from hematopoietic progenitor cells (Hu, MC et al., Genes Dev, 1996. 10(18): pp. 2251-64). MAP4K1 has attracted much attention as a target because it is mainly expressed in hematopoietic cells, such as T cells, B cells, macrophages, dendritic cells, neutrophils and mast cells (Hu, MC et al., Genes Dev, 1996. 10(18): pp. 2251-64; Kiefer, F. et al., EMBO J, 1996. 15(24): pp. 7013-25). MAP4K1 kinase activity has been shown to be induced by activation of T cell receptor (TCR) (Liou, J. et al., Immunity, 2000. 12(4): 399-408), B cell receptor (BCR) (Liou, J. et al., Immunity, 2000. 12(4): 399-408), transforming growth factor receptor (TGF-R) (Wang, W. et al., J Biol Chem, 1997. 272(36): 22771-5; Zhou, G. et al., J Biol Chem, 1999. 274(19): 13133-8) or Gs-coupled PGE2 receptors (EP2 and EP4) (Ikegami, R et al., J Immunol, 2001. 166(7): 4689-96). Therefore, MAP4K1 regulates a wide variety of functions of various immune cells.

[0003] MAP4K1 plays a crucial role in regulating the function of various immune cells and has been involved in autoimmune diseases and antitumor immunity (Shui, JW et al., Nat Immunol, 2007. 8(1): 84-91; Wang, X. et al., J Biol Chem, 2012. 287(14): 11037-48). These observations suggest that reduced MAP4K1 activity may contribute to autoimmunity in patients. In addition, MAP4K1 can also control antitumor immunity through a T-cell-dependent mechanism. In a Lewis lung cancer tumor model that produces PGE2, tumors develop more slowly in MAP4K1 knockout mice compared to wild-type mice (see US 2007 / 0087988). Furthermore, it has been shown that MAP4K1-deficient T cells more effectively control tumor growth and metastasis than wild-type T cells (Alzabin, S. et al., Cancer Immunol Immunother, 2010. 59(3): 419-29). Similarly, bone marrow-derived dendritic cells (BMDCs) from MAP4K1 knockout mice more effectively initiate T cell responses to eradicate Lewis lung cancer than wild-type BMDCs (Alzabin, S. et al., J Immunol, 2009. 182(10): 6187-94). Data from MAP4K1 kinase-dead mice confirm that MAP4K1 kinase activity is crucial in conferring inhibitory function on MAP4K1 in a wide range of immune cells, including CD4+, CD8+, DCs, NK cells, and T regulatory cells (Tregs), and that inactivation of the kinase domain is sufficient to elicit a robust anti-tumor immune response. Liu et al., PLoS ONE 14(3):e0212670 https: / / doi.org / 10.1371 / jourNal.pone.0212670. Furthermore, loss of MAP4K1 kinase function inhibited tumor growth in preclinical tumor models, and therapeutic co-blockade of MAP4K1 kinase and PD-L1 enhanced the antitumor response. HerNandez S. et al., Cell Reports 2018 25: pp. 80-94. Recent results demonstrate tumor growth inhibition in CT-26 syngeneic mouse models using small molecule MAP4K1 inhibitors (Seungmook, L., Cancer research. AACR Journal, 2019, Abstract 4150). These data confirm MAP4K1 as a novel drug target for enhancing antitumor immunity.

[0004] Therefore, there is a need for novel compounds that modulate MAP4K1 activity to treat MAP4K1-dependent diseases or conditions (such as cancer, viral infections, and other diseases and conditions). Of particular importance are novel compounds that selectively modulate MAP4K1 activity. [Summary of the Invention]

[0005] This document provides compounds, or pharmaceutically acceptable salts and compositions thereof, that inhibit MAP4K1 to enhance an individual's immune response. For example, the IC50 values ​​for MAP4K1 inhibition provided in Table 3 indicate that these compounds are potent inhibitors of MAP4K1. Methods for treating cancer and viral infections using the compounds and compositions described herein are also disclosed.

[0006] A first embodiment of the present invention is a compound represented by formula I: , or a pharmaceutically acceptable salt thereof, wherein: T is selected from and contains 4-5 member heterocycles, wherein the heterocycle is substituted by 1-2 R6 radicals as appropriate; Z is absent, is O or NH; ring A is a C4-6 cycloalkyl or a nitrogen-containing 4-6 member heterocycle, wherein the cycloalkyl or heterocycle is substituted by 1-2 R6 radicals as appropriate; L1 is selected from C1-C3 alkyl groups, wherein the alkyl group is substituted by 1-2 R11 radicals as appropriate; L2 is selected from C1-C3 alkyl groups; B is O or NH; Q is N or CH; x is 0, 1 or 2; n is 0, 1, 2, 3 or 4; R1 and R2 are each independently selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl and 4 to 6 member heterocycles, wherein the alkyl group is substituted by 1-2 R3 radicals as appropriate; each R 3 is independently selected from halogens, hydroxyl groups, and OR 4; each R 4 is independently selected from C1-3 alkyl groups, CF 3, CH 2F, and CHF 2; each R 5 is independently selected from C1-2 alkyl groups, CF 3, CH 2F, and CHF 2, or two R 5s attached to the same carbon atom together with the carbon atom to which they are attached form a C3-5 cycloalkyl group; or two R 5s attached to two adjacent carbon atoms together with the two adjacent carbon atoms to which they are attached form a C4-6 cycloalkyl group; each R 6 is independently selected from CH 3, methoxy, CF 3, CH 2F, and CHF 2; R 7 is selected from C1-3 alkyl groups, C3-6 cycloalkyl groups, C1-4 alkyl groups, NR 9R 10, and 3-5 member heterocycles containing nitrogen or oxygen, wherein the alkyl group, the cycloalkyl group, or the heterocycle is substituted by 1-3 R 8s as appropriate; each R 8 is independently selected from halogens, C 1-3 alkyl, hydroxyl and OC 1-3 alkyl, wherein the alkyl is substituted by 1-3 R 12 as appropriate; R 9 is selected from C 1-2 alkyl; R 10 is selected from C 1-2 alkyl; each R 11 is independently selected from halogen, methoxy, C 1-2 alkyl, CH 2F, CHF 2 and CF 3, or two R 11 together with the two adjacent carbon atoms to which they are attached form a cyclopropyl group; and each R 12 is a halogen.

[0007] Another embodiment of the present invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0008] Another embodiment of the present invention is a method for inhibiting MAP4K1 in an individual in need, comprising contacting MAP4K1 with an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0009] Another embodiment of the present invention is a method of treating MAP4K1-dependent symptoms or diseases (e.g., cancer) in an individual in need, comprising administering to the individual an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound(e.g.)

[0010] Another embodiment of the present invention is the use of the compounds disclosed herein or their pharmaceutically acceptable salts or pharmaceutical compositions containing the compounds thereof for the preparation of medicaments for the treatment of MAP4K1-dependent conditions or diseases (e.g., cancer) in individuals in need.

[0011] Another embodiment of the present invention is a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such compound(s), for the treatment of MAP4K1-dependent conditions or diseases (e.g., cancer) in an individual in need.

Implementation Method

[0012] Related Application This application claims priority to U.S. Provisional Application No. 63 / 221,825, filed July 14, 2021, the entire teachings of which are incorporated herein by reference.

[0013] The disclosed compound or its pharmaceutically acceptable salt is a MAP4K1 inhibitor, which can be used to treat MAP4K1-dependent conditions or diseases. Such conditions or diseases include cancer and viral infections.

[0014] Exemplary examples of compounds include: First example: a compound represented by formula I, or a pharmaceutically acceptable salt thereof. The variables in formula I are described in the above description of the invention.

[0015] Second embodiment: a compound represented by formula II: , or a pharmaceutically acceptable salt thereof, wherein the other variables in formula II are defined as defined in the first embodiment.

[0016] Third embodiment: a compound represented by formula III, or a pharmaceutically acceptable salt thereof, wherein the other variables in formula III are defined as defined in the first embodiment.

[0017] Fourth embodiment: a compound represented by formula IV: , or a pharmaceutically acceptable salt thereof, wherein the other variables in formula IV are defined as defined in the first embodiment.

[0018] Fifth embodiment: A compound represented by formula V: , or a pharmaceutically acceptable salt thereof, wherein other variables in formula V are defined as defined in the first embodiment.

[0019] Sixth embodiment: a compound represented by formula VI: , or a pharmaceutically acceptable salt thereof, wherein the other variables in formula VI are defined as defined in the first embodiment.

[0020] Seventh embodiment: a compound represented by formula VII: , or a pharmaceutically acceptable salt thereof, wherein the other variables in formula VII are defined as defined in the first embodiment.

[0021] Eighth embodiment: a compound or a pharmaceutically acceptable salt thereof represented by formula I, II, III, IV, V, VI or VII, wherein L1 is a bond; T is a bond; and L2 is a bond or a methylene group, wherein the other variables in formula I, II, III, IV, V, VI and VII are defined as defined in the first embodiment.

[0022] Ninth embodiment: a compound represented by formula I, II, III, IV, V, VI or VII or a pharmaceutically acceptable salt thereof, wherein ring A is selected from azahexacyclobutyl, azacyclobutyl, azacyclopentyl and azapyridine, and the azahexacyclobutyl, azacyclobutyl, azacyclopentyl and azapyridine are substituted with 1 to 2 R 6, wherein the other variables in formula I, II, III, IV, V, VI and VII are defined as defined in the first and / or eighth embodiments.

[0023] Tenth embodiment: a compound or a pharmaceutically acceptable salt thereof represented by formula I, II, III, IV, V, VI or VII, wherein ring A is an extended cyclobutyl group substituted with 1-2 R 6, and the other variables in formula I, II, III, IV, V, VI and VII are defined as defined in the first and / or eighth embodiments.

[0024] Eleventh embodiment: a compound or a pharmaceutically acceptable salt thereof represented by formula I, II, III, IV, V, VI or VII, wherein L1 is a C1-C3 alkyl group substituted with 1-2 R11 as appropriate; and T is, wherein the other variables in formula I, II, III, IV, V, VI and VII are defined as defined in the first embodiment.

[0025] Twelfth embodiment: a compound or a pharmaceutically acceptable salt thereof represented by formula I, II, III, IV, V, VI or VII, wherein L1 is an enylpropyl group substituted with 1-2 R11 as appropriate, and the other variables in formula I, II, III, IV, V, VI and VII are defined as defined in the first and / or eleventh embodiments.

[0026] Thirteenth embodiment: a compound or a pharmaceutically acceptable salt thereof represented by formula I, II, III, IV, V, VI or VII, wherein L1 is selected from formulas L-1, L-2, L-3, L-4, L-5, L-6 and L-7, wherein ⁎ represents a bond to B; and ⁎ represents a bond to T, and wherein the other variables in formulas I, II, III, IV, V, VI and VII are defined as defined in the first, eleventh and / or twelfth embodiments.

[0027] Fourteenth embodiment: a compound or a pharmaceutically acceptable salt thereof represented by formula I, II, III, IV, V, VI or VII, wherein Z is 0, and the other variables in formula I, II, III, IV, V, VI and VII are defined as defined in the first, eleventh, twelfth and / or thirteenth embodiments.

[0028] Fifteenth embodiment: a compound or a pharmaceutically acceptable salt thereof represented by formula I, II, III, IV, V, VI or VII, wherein Z is NH, and the other variables in formula I, II, III, IV, V, VI and VII are defined as defined in the first, eleventh, twelfth and / or thirteenth embodiments.

[0029] Sixteenth embodiment: a compound or a pharmaceutically acceptable salt thereof represented by formula I, II, III, IV, V, VI or VII, wherein Z is absent, and the other variables in formula I, II, III, IV, V, VI and VII are defined as defined in the first, eleventh, twelfth and / or thirteenth embodiments.

[0030] Seventeenth embodiment: a compound or a pharmaceutically acceptable salt thereof represented by formula I, II, III, IV, V, VI or VII, wherein T is a 4-5 member heterocycle containing monoxide, and the heterocycle is substituted with 1-2 R6 groups as appropriate; and L1 is selected from methyl, methylene and ethyl groups, and wherein the other variables in formulas I, II, III, IV, V, VI and VII are defined as defined in the first embodiment.

[0031] Eighteenth embodiment: a compound or a pharmaceutically acceptable salt thereof represented by formula I, II, III, IV, V, VI or VII, wherein T is a 4-membered heterocycle containing monoxide, wherein the heterocycle is substituted with 1-2 R6 radicals as appropriate, and wherein the other variables in formula I, II, III, IV, V, VI and VII are defined as defined in the first and / or seventeenth embodiments.

[0032] Nineteenth Example: A compound or a pharmaceutically acceptable salt thereof represented by formula I, II, III, IV, V, VI or VII, wherein R1 and R2 are each independently selected from hydrogen, C1-6 alkyl and C3-6 cycloalkyl, wherein the alkyl group is substituted with OR3 as appropriate; each R3 is independently selected from halogen, hydroxyl and OR4; and each R4 is independently selected from C1-3 alkyl, wherein the other variables in formula I, II, III, IV, V, VI and VII are defined as defined in examples I, VIII, IX, X, XI, XII, XIII, XIV, XVI and / or XVIII.

[0033] Twentieth Example: A compound represented by formula I, II, III, IV, V, VI or VII or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each independently selected from hydrogen, CH3, CH2CH3, CH2CH2CH3, CH2-OCH3 and cyclopropyl, and wherein the other variables in formula I, II, III, IV, V, VI and VII are defined as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth and / or eighteenth examples. In alternative embodiments, for compounds represented by formulas I, II, III, IV, V, VI, or VII, or their pharmaceutically acceptable salts: R1 and R2 are each CH3; or R1 is hydrogen and R2 is CH2CH3; or R1 is CH3 and R2 is CH2CH3; or R1 is CH3 and R2 is CH2-OCH3; or R1 is hydrogen and R2 is CH2CH2CH3; or R1 is CH3 and R2 is CH2CH2CH3; or R1 is hydrogen and R2 is cyclopropyl; or R1 is CH3 and R2 is cyclopropyl, and wherein the other variables in formulas I, II, III, IV, V, VI, and VII are defined as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, and / or eighteenth embodiments.

[0034] Twenty-first embodiment: a compound or a pharmaceutically acceptable salt thereof represented by formula I, II, III, IV, V, VI or VII, wherein R5 is CH3, or two R5s attached to the same carbon atom together with the carbon atom to which they are attached form a cyclopropyl group; and n is 1, 2, 3 or 4, and wherein the other variables in formula I, II, III, IV, V, VI and VII are defined as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth and / or twentieth embodiments. In alternative embodiments: for compounds represented by formulas I, II, III, IV, V, VI, or VII, or their pharmaceutically acceptable salts: n is 0; or n is 1 and R5 is CH3; or n is 2 and each R5 is CH3; or n is 3 and each R5 is CH3; or n is 3, where two R5s attached to the same carbon atom form a cyclopropyl group with the carbon atom to which they are attached, and one R5 is CH3; or n is 4, where two R5s attached to the same carbon atom form a cyclopropyl group with the carbon atom to which they are attached, and both R5s are CH3, and wherein the other variables in formulas I, II, III, IV, V, VI, and VII are defined as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, and / or twentieth embodiments.

[0035] Twenty-second embodiment: a compound or a pharmaceutically acceptable salt thereof represented by formula I, II, III, IV, V, VI or VII, wherein each R 6 is CH 3, and wherein the other variables in formula I, II, III, IV, V, VI and VII are defined as defined in the first, eighth, ninth, tenth, seventeenth, eighteenth, nineteenth, twentieth and / or twenty-first embodiments.

[0036] Twenty-third embodiment: a compound or a pharmaceutically acceptable salt thereof represented by formula I, II, III, IV, V, VI or VII, wherein R7 is selected from C1-3 alkyl, CH2F, CHF2, CF3, C3-6 cycloalkyl and NR9R10; R9 is selected from C1-2 alkyl; and R10 is selected from C1-2 alkyl, and wherein the other variables in formula I, II, III, IV, V, VI and VII are defined as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, nineteenth, twentieth, twenty-first and / or twenty-second embodiments.

[0037] Twenty-fourth embodiment: a compound or a pharmaceutically acceptable salt thereof represented by formula I, II, III, IV, V, VI or VII, wherein R7 is selected from CH3, CF3, CH2CH3, CH(CH3)2, cyclopropyl and N(CH3)2, and wherein the other variables in formula I, II, III, IV, V, VI and VII are defined as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, nineteenth, twentieth, twenty-first and / or twenty-second embodiments.

[0038] Twenty-fifth embodiment: a compound or a pharmaceutically acceptable salt thereof represented by formula I, II, III, IV, V, VI or VII, wherein each R 11 is independently selected from CH 3, CF 3 and CH 2CH 3, and wherein the other variables in formula I, II, III, IV, V, VI and VII are defined as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third and / or twenty-fourth embodiments.

[0039] Twenty-sixth embodiment: a compound or a pharmaceutically acceptable salt thereof represented by formula I, II, III, IV, V, VI or VII, wherein each R 11 is CH 3, and wherein the other variables in formula I, II, III, IV, V, VI and VII are defined as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third and / or twenty-fourth embodiments.

[0040] In an alternative embodiment, for a compound represented by formula I, II or V or a pharmaceutically acceptable salt thereof, B is NH, and the other variables in formula I, II and V are defined as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth and / or twenty-sixth embodiments.

[0041] This invention also includes the compounds depicted in Table 1 and, in the examples, prepared in their neutral and pharmaceutically acceptable salt forms. Synthetic schemes for preparing the compounds in Table 1 are listed in the last row of Table 1, and complete details of each synthetic scheme are described in procedures 1 and 2 of the General Synthetic Methods and Intermediates section. Table 1 Compound numbering structure LCMS (M+1) NMR Synthesis scheme 1 498 1 H-NMR (400 MHz, 6d-DMSO): δ ppm 10.73 (s, 1H), 9.47 (s, 1H), 9.40 (s, 1H), 8.18 (s, 1H), 8.09 (d,J= 8.8 Hz, 1H), 7.38 (d,J= 8.8 Hz, 1H), 5.72-5.66 (m, 1H), 4.83 (dd,J= 7.6, 15.6 Hz, 2H), 4.61 (q,J= 6.0 Hz, 1H), 4.48 (dd,J= 3.2, 15.6 Hz, 2H), 3.03-2.96 (m, 1H), 1.66 (d,J= 2.0 Hz, 6H), 1.44 (d,J= 7.2 Hz, 3H), 1.38 (d,J= 6.4 Hz, 3H). Process 1, intermediate 1 and intermediates twenty one 2 498 1 H-NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1H), 9.33 (s, 1H), 8.19-8.09 (m, 2H), 7.15 (d,J= 8.4 Hz, 1H), 5.45-5.37 (m, 1H), 4.66-4.62 (m, 2H), 3.88-3.77 (m, 1H), 3.24-3.18 (m, 2H), 3.00-2.95 (m, 2H), 2.93 (s, 3H), 2.72-2.62 (m, 2H), 1.81 (s, 6H). Process 1, intermediate 7 and intermediates twenty two 3 512 1H NMR (400 MHz, CD3OD): δ ppm 9.45 (s, 1H), 9.39 (s, 1H), 8.19 (s, 1H), 8.15 (d,J=8.8 Hz, 1H), 7.24 (d,J=8.8 Hz, 1H), 5.79-5.75 (m, 1H), 4.80 (dd,J=8.0 Hz,J=3.6 Hz, 2H), 4.42 (dd,J=8.0 Hz,J=3.6 Hz, 2H), 3.07-3.02 (m, 1H), 1.84 (d,J=8.0 Hz, 6H), 1.55 (s, 3H), 1.46 (s, 3H), 1.41 (d,J=7.6 Hz, 3H). Process 1, intermediate 3 and intermediates twenty one 4 512 1 H-NMR (400 MHz, 6d-DMSO): δ ppm 10.99 (s, 1H), 9.68 (s, 1H), 9.34 (s, 1H), 8.19 (s, 1H), 8.03 (d,J= 8.4 Hz, 1H), 7.34 (d,J= 8.4 Hz, 1H), 5.43-5.29 (m, 1H), 3.91-3.77 (m, 1H), 2.95 (s, 3H), 2.90-2.80 (m, 2H), 2.11-1.98 (m, 2H), 1.69 (s, 12H). Process 1, intermediate 6 and intermediate products twenty two 5 512 1H-NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 9.24 (s, 1H), 8.17 (d,J= 8.8 Hz, 1H), 8.05 (s, 1H), 7.26 (d,J= 8.8 Hz, 1H), 5.57-5.32 (m, 1H), 4.75-4.66 (m, 1H), 4.43 (dd,J= 2.8, 11.4 Hz, 1H), 3.83 (t,J= 8.4 Hz, 1H), 3.23-3.11 (m, 1H), 3.03-2.95 (m, 2H), 2.93 (s, 3H), 2.77-2.61 (m, 2H), 1.95 (d,J= 7.4 Hz, 6H), 1.49 (d,J= 7.2 Hz, 3H). Process 1, intermediate 8 and intermediates twenty two Second dissolution isomer from chiral HPLC Tube Column: Chiralpak IC-3 50×4.6 mm ID, 3 µm; Moving phase: A2 = Heptane (0.05% DEA); B1 = IPA + ACN (0.05% DEA); Gradient dissolution: 40% IPA+ ACN (0.05% DEA) 6 512 1H-NMR (400 MHz, CD3OD): δ ppm 9.39 (s, 1H), 9.28 (s, 1H), 8.16 (d,J= 8.8 Hz, 1H), 8.10 (s, 1H), 7.25 (d,J= 8.4 Hz, 1H), 5.44 (q,J= 7.2 Hz, 1H), 4.70 (dd,J= 3.6, 11.6 Hz, 1H), 4.43 (dd,J= 2.6, 11.4 Hz, 1H), 3.83 (t,J= 8.4 Hz, 1H), 3.24-3.11 (m, 1H), 3.01-2.95 (m, 2H), 2.93 (s, 3H), 2.75-2.65 (m, 2H), 1.89 (d,J= 7.0 Hz, 6H), 1.49 (d,J= 7.2 Hz, 3H). Process 1, intermediate 8 and intermediates twenty two The first dissolution isomer from chiral HPLC Tube Column: Daicel Chiralpak IC (250 mm × 30 mm, 10 µm); Moving phase: 35% Hexane-IPA (0.1% NH3 in CO2) 7 514 1 H-NMR (400 MHz, CD3OD): δ ppm 9.47 (s, 1H), 8.94 (s, 1H), 8.46 (s, 1H), 8.17 (d,J= 8.8 Hz, 1H), 8.04-7.92 (m, 1H), 7.39 (d,J= 8.8 Hz, 1H), 4.75-4.64 (m, 3H), 3.45-3.37 (m, 2H), 3.04 (s, 3H), 3.02-2.98 (m, 1H), 2.49-2.38 (m, 2H), 2.02 (d,J= 6.8 Hz, 6H), 1.51 (d,J= 6.8 Hz, 3H), 1.46 (d,J= 6.0 Hz, 3H). Process 1, intermediate 1 and intermediates twenty three 8 526 1 H-NMR (400 MHz, CD3OD): δ ppm 9.37 (s, 1H), 9.21 (s, 1H), 8.13 (d,J= 8.6 Hz, 1H), 8.05 (s, 1H), 7.23 (d,J= 8.6 Hz, 1H), 5.44 (t,J= 7.2 Hz, 1H), 4.70 (dd,J= 3.6, 11.2 Hz, 1H), 4.43 (dd,J= 3.2, 11.2 Hz, 1H), 3.90-3.74 (m, 1H), 3.16 (td,J= 3.6, 7.2 Hz, 1H), 3.02-2.96 (m, 2H), 2.93 (s, 3H), 2.74-2.65 (m, 2H), 2.55 (qd,J= 7.3, 14.6 Hz, 1H), 2.24 (qd,J= 7.4, 14.6 Hz, 1H), 1.89-1.81 (m, 3H), 1.47 (d,J= 7.2 Hz, 3H), 0.77 (t,J= 7.4 Hz, 3H). Process 1, intermediate 8 and intermediate items twenty four The second dissolution isomer from SFC Tube Column: Daicel Chiralpak AD-H (250 mm × 30 mm, 5 µm); Moving phase: [0.1%NH3H2O ​​IPA]; B%: 40%-40% 9 526 1H-NMR (400 MHz, CD3OD): δ ppm 9.39 (s, 1H), 9.22-9.14 (m, 1H), 8.15 (d,J= 8.6 Hz, 1H), 8.02 (s, 1H), 7.25 (d,J= 8.8 Hz, 1H), 5.45 (t,J= 7.2 Hz, 1H), 4.70 (dd,J= 3.6, 11.2 Hz, 1H), 4.43 (dd,J= 2.9, 11.3Hz, 1H), 3.83 (q,J= 8.4 Hz, 1H), 3.19-3.10 (m, 1H), 3.03-2.95 (m, 2H), 2.93 (s, 3H), 2.77-2.64 (m, 2H), 2.63-2.54 (m, 1H), 2.22 (qd,J= 7.2, 14.6 Hz, 1H), 1.92 (s, 3H), 1.48 (d,J= 7.2 Hz, 3H), 0.79 (t,J= 7.4 Hz, 3H). Process 1, intermediate 8 and intermediates twenty four The first dissolution isomer from SFC Tube Column: Daicel Chiralpak AD-H (250 mm × 30 mm, 5 µm); Moving phase: [0.1%NH3H2O ​​IPA]; B%: 40%-40% 10 526 1 H NMR (400 MHz, MeOD-d4) δ ppm 9.39 (d,J= 9.2 Hz, 2H), 8.22 (s, 1H), 8.14 (d,J= 8.8 Hz, 1H), 7.22 (d,J= 8.8 Hz, 1H), 4.81 - 4.77 (m, 2H), 4.55 - 4.48 (m, 2H), 3.05 (q,J= 7.2 Hz, 1H), 2.10 (s, 3H), 1.80 (d,J= 7.6 Hz, 6H), 1.54 (s, 3H), 1.45 (s, 3H), 1.40 (d,J= 7.2 Hz, 3H). Process 1, intermediate 3 and intermediates 25 11 526 1 H NMR (400 MHz, MeOD): δ ppm 9.40 (s, 1H), 8.76 (s, 1H), 8.17 (s, 1H), 7.49 (d,J= 8.8 Hz, 1H), 7.50 (J= 8.8 Hz, 1H), 5.45-5.41 (m, 1H), 4.32 (s, 2H), 3.82-3.80 (m, 1H), 3.02-2.95 (m, 2H), 2.93 (s, 3H), 2.69-2.66 (m, 2H), 1.78 (s, 6H), 1.47 (s, 6H). Process 1, intermediate 14 and intermediate products twenty two 12 526 1 H-NMR (400 MHz, CDCl3): δ ppm 9.39 (s, 2H), 8.23 ​​(d,J= 8.8 Hz, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 7.18 (d,J= 8.8 Hz, 1H), 4.74 (d,J= 6.4 Hz, 2H), 4.39-4.33 (m, 2H), 4.21-4.16 (m, 2H), 3.22-3.17 (m, 1H), 3.02-2.96 (m, 1H), 1.77 (s, 6H), 1.51 (s, 3H), 1.48 (s, 3H), 1.43 (d,J= 7.2 Hz, 3H). Process 1, intermediate 3 and intermediates 26 13 526 1H-NMR (400 MHz, 6d-DMSO): δ ppm 10.69 (s, 1H), 9.44 (s, 1H), 9.32 (s, 1H), 8.15 (s, 1H), 8.08 (d,J= 8.8 Hz, 1H), 7.37 (d,J= 8.8 Hz, 1H), 5.39-5.32 (m, 1H), 4.64-4.57 (m, 1H), 3.89-3.79 (m, 1H), 3.52-3.42 (m, 1H), 3.28 (s, 1H), 3.03-2.97 (m, 1H), 2.94 (s, 3H), 2.90-2.79 (m, 2H), 2.08-1.93 (m, 2H), 1.65 (d,J= 2.0 Hz, 6H), 1.44 (d,J= 7.2 Hz, 3H), 1.38 (d,J= 6.4 Hz, 3H). Process 1, intermediate 1 and intermediates twenty two 14 526 1 H-NMR (400 MHz, 6d-DMSO): 10.7 (s, 1H), 9.45-9.34 (m, 2H), 8.29 (s, 1H), 8.16 (s, 1H), 8.10 (d,J= 8.8 Hz, 1H), 8.09-8.08 (m, 1H), 7.40 (d,J= 8.8 Hz, 1H), 5.52 (m, 1H), 4.62 (m, 1H), 4.11-3.98 (m, 2H), 3.03 (s, 3H), 3.01-2.89 (m, 3H), 2.77-2.66 (m, 2H), 1.68 (m, 6H), 1.45 (d,J= 7.2 Hz, 3H), 1.39 (d,J= 6.4 Hz, 3H). Process 1, intermediate 1 and intermediates 27 15 527 1H-NMR (400 MHz, CD3OD): δ ppm 9.48 (s, 1H), 9.03 (s, 1H), 8.17 (d,J= 8.8 Hz, 1H), 8.04 (s, 1H), 7.38 (d,J= 8.8 Hz, 1H), 5.70-5.57 (m, 1H), 4.72-4.61 (m, 1H), 4.45 (dd,J= 6.8, 10.0 Hz, 2H), 4.19 (dd,J= 4.8, 9.6 Hz, 2H), 3.05 (s, 3H), 3.04-2.98 (m, 1H), 1.98 (d,J= 6.6 Hz, 6H), 1.53 (d,J= 7.2 Hz, 3H), 1.48 (d,J= 6.4 Hz, 3H). Process 1, intermediate 1 and intermediates 20 16 528 1 H NMR (400 MHz, CD3OD): δ ppm 9.42 (s, 1H), 9.19 (s, 1H), 8.56 (s, 1H), 8.20-8.12 (m, 1H), 8.06 (s, 1H), 7.30-7.24 (m, 1H), 5.75-5.61 (m, 1H), 4.75-4.68 (m, 1H), 4.48-4.40 (m, 1H), 3.44-3.34 (m, 2H), 3.22-3.11 (m, 1H), 3.03 (s, 3H), 2.69-2.55 (m, 1H), 2.44-2.33 (m, 2H), 2.33-2.22 (m, 1H), 1.94 (s, 3H), 1.56-1.51 (m, 3H), 1.50-1.46 (m, 3H), 0.86-0.77 (m, 3H). Process 1, intermediate 8 and intermediates 31 Second dissolution isomer from chiral HPLC Tube Column: Phenomenex Gemini-NX C18 75×30mm ×3 µm; Moving phase: [Water (0.225%FA)-ACN]; B%: 10%-40%) 17 528 1 H-NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 9.34 (s, 1H), 8.17 (s, 1H), 8.13 (d,J= 8.8 Hz, 1H), 7.22 (d,J= 8.8 Hz, 1H), 4.67 (t,J= 6.2 Hz, 2H), 3.46-3.37 (m, 2H), 3.10-2.98 (m, 4H), 2.51-2.34 (m, 2H), 1.82 (d,J= 7.6 Hz, 6H), 1.54 (s, 3H), 1.45 (s, 3H), 1.40 (d,J= 16 Hz, 3H). Process 1, intermediate 3 and intermediates twenty three 18 528 1 H-NMR (400 MHz, 6d-DMSO): δ ppm 10.64 (s, 1H), 9.38 (s, 1H), 9.35 (s, 1H), 8.18 (s, 1H), 8.08 (d,J= 8.8 Hz, 1H), 7.42 (d,J= 8.4 Hz, 1H), 5.54-5.50 (m, 1H), 4.60 (m, 1H), 3.31 (s, 2H), 3.02-2.93 (m, 4 H), 2.23-2.19 (m, 2H), 2.00 (s, 2H), 1.66 (d,J= 2.0 Hz, 6H), 1.44 (m, 6H), 1.39 (d,J= 6.4 Hz, 3H). Process 1, intermediate 1 and intermediates 29 19 528 1H-NMR (400 MHz, 6d-DMSO): δ ppm 10.64 (s, 1H), 9.36-9.22 (m, 2H), 8.17 (s, 1H), 8.09 (d,J= 8.8 Hz, 1H), 7.43 (d,J= 8.8 Hz, 1H), 5.54-5.49 (m, 1H), 4.60 (m, 1H), 3.32-3.23 (m, 3H), 3.02 (s, 3H), 2.20-2.10(m, 2H), 2.01 (s, 2H), 1.66 (s, 6H), 1.42-1.45 (m, 6H), 1.38 (d,J= 6.4 Hz, 3H). Process 1, intermediate 1 and intermediates 28 20 528 1 H-NMR (400 MHz, CD3OD): δ ppm 9.47 (s, 1H), 8.94 (s, 1H), 8.17 (d,J= 8.8 Hz, 1H), 8.00 (s, 1H), 7.38 (d,J= 8.8 Hz, 1H), 4.71 (t,J= 6.2 Hz, 2H), 4.68-4.62 (m, 1H), 3.46-3.37 (m, 2H), 3.04 (s, 3H), 3.02-2.95 (m, 1H), 2.62 (m, 1H), 2.51-2.39 (m, 2H), 2.30 (m, 1H), 1.95 (s, 3H), 1.48 (m, 6H), 0.82 (t, J = 7.6 Hz, 3H). Process 1, intermediate 1 and intermediate 100 twenty one 528 1H-NMR (400 MHz, CD3OD): δ ppm 9.44 (s, 1H), 9.32 (s, 1H), 8.51 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 8.04 (s, 1H), 7.19 (d,J= 8.8 Hz, 1H), 4.91 (m, 1H), 4.70 (t,J= 6.2 Hz, 2H), 3.45-3.37 (m, 2H), 3.04 (s, 3H), 3.02-2.95 (m, 1H), 2.66-2.55 (m, 1H), 2.48-2.39 (m, 2H), 2.30 (m, 1H), 1.91 (s, 3H), 1.52 (d,J= 6.4 Hz, 3H), 1.32 (d,J= 7.2 Hz, 3H), 0.81 (t,J= 7.4 Hz, 3H). Process 1, intermediate 93 and intermediate 100 twenty two 528 1 H NMR (400MHz, CD3OD): δ ppm 9.50-9.47 (m, 1H), 8.60-8.50 (m, 1H), 8.35-7.99 (m, 2H), 7.60-7.50 (m, 1H), 4.70-4.62 (m, 2H), 4.40-4.30 (m, 2H), 3.50-3.40 (m, 2H), 3.05-2.95 (m, 3H), 2.55-2.40 (m, 3H), 2.25-2.05 (m, 1H), 1.90-1.78 (m, 3H), 1.52-1.40 (m, 6H), 0.77-0.72 (m, 3H). Process 1, intermediate 14 and intermediates 100 twenty three 528 1H-NMR (400 MHz, CD3OD): δ ppm 10.68 (s, 1H), 9.42 (s, 1H), 9.38 (s, 1H), 8.35 (s, 1H), 8.16 (s, 1H), 8.08 (d,J= 8.8 Hz, 1H), 7.35 (d,J= 8.8 Hz, 1H), 4.57 (t,J= 6.2 Hz, 2H), 3.43 (s, 2H), 3.15 (s, 2H), 3.04 (s, 3H), 2.35-2.21 (m, 2H), 2.18-1.98 (m, 2H), 1.63 (s, 3H), 1.45 (s, 6H), 0.66 (t, J = 7.4 Hz, 3H). Process 1, intermediate 5 and intermediates 100 twenty four 538 1H NMR (400 MHz, CD3OD): δ ppm 9.43 (s, 1 H), 8.36 (s, 1 H), 8.18 (d,J= 8.8 Hz, 1 H), 8.04 (s, 1 H), 7.59 (d,J= 8.8 Hz, 1 H), 5.50-5.35 (m, 1 H), 4.74-4.58 (m, 1 H), 3.91-3.72 (m, 1 H), 3.02-2.95 (m, 2 H), 2.93 (s, 3 H), 2.74-2.64 (m, 2 H) ,1.88 (s, 6 H), 1.63-1.47 (m, 2 H), 1.41-1.35 (m, 3 H), 1.29-1.23 (m, 2 H)。 Process 1, intermediate 12 and intermediates 22 25 538 1 H-NMR (400 MHz, CD3OD): δ ppm 9.38 (s, 1H), 9.25 (s, 1H), 8.14 (d,J= 8.8 Hz, 1H), 8.10 (s, 1H), 7.23 (d,J= 8.8 Hz, 1H), 5.48-5.40 (m, 1H), 4.72-4.65 (m, 1H), 4.45-4.40 (m, 1H), 3.90-3.82 (m, 1H), 3.20-3.10 (m, 1H), 3.05-2.91 (m, 2H), 2.75-2.62 (m, 2H), 2.60-2.52 (m, 1H), 1.89 (d,J= 7.2 Hz, 6H), 1.48 (d,J= 7.2 Hz, 3H), 1.14-1.07 (m, 4H). Process 1, intermediate 8 and intermediates 32 Second dissolution isomer from chiral HPLC Tube Column: Shim-pack C18 150×25×10 µm; Moving phase: [Water (0.225% FA)-ACN]; B%: 12%-42%) 26 538 1 H-NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1H), 9.25 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 8.08 (s, 1H), 7.25 (d,J= 8.8 Hz, 1H), 5.45-5.40 (m, 1H), 4.72-4.65 (m, 1H), 4.45-4.40 (m, 1H), 3.93-3.89 (m, 1H), 3.25-3.12 (m, 1H), 3.00-2.91 (m, 2H), 2.75-2.63 (m, 2H), 2.60-2.52 (m, 1H), 1.91 (d,J= 7.2 Hz, 6H), 1.48 (d,J= 7.2 Hz, 3H), 1.14-1.07 (m, 4H). Process 1, intermediate 8 and intermediates 32 The first dissolution isomer from chiral HPLC Tube Column: Shim-pack C18 150×25×10 µm; Moving phase: [Water (0.225% FA)-ACN]; B%: 12%-42%) 27 539 1H-NMR (400 MHz, CD3OD): δ ppm 9.42 (s, 1H), 9.38 (s, 1H), 8.08 (d,J= 8.8 Hz, 1H), 7.72 (d,J= 8.4 Hz, 1H), 7.14 (d,J= 8.8 Hz, 1H), 6.69 (d,J= 8.4 Hz, 1H), 4.98 (t,J= 7.2 Hz, 1H), 3.89-3.75 (m, 1H), 3.07-2.96 (m, 3H), 2.94 (s, 3H), 2.73-2.62 (m, 2H), 1.81 (d,J= 8.4 Hz, 6H), 1.54 (s, 3H), 1.44 (s, 3H), 1.38 (d,J= 7.2 Hz, 3H). Process 1, intermediate 3 and intermediates 35 28 539 1 H-NMR (400 MHz, CD3OD): δ ppm 9.34 (s, 1H), 9.19 (s, 1H), 8.13 (d,J= 8.8 Hz, 1H), 8.02 (s, 1H), 7.23 (d,J= 8.8 Hz, 1H), 4.68-4.64 (m, 1H), 3.91-3.74 (m, 1H), 3.06-2.98 (m, 1H), 2.92 (s, 3H), 2.89-2.80 (m, 2H), 2.66 (s, 1H), 2.59-2.49 (m, 2H), 1.83 (d,J= 8.4 Hz, 6H), 1.54 (s, 3H), 1.44 (s, 3H), 1.41-1.37 (m, 3H). Process 1, intermediate 3 and intermediates 36 29 540 1H NMR (400 MHz, CD3OD): δ ppm 9.39 (s, 1H), 8.53 (s, 1H), 8.17 (s, 1H), 8.14 (d,J=8.8 Hz, 1H), 7.50 (d,J=8.8 Hz, 1H), 5.67-5.55 (m, 1H), 4.67-4.57 (m, 1H), 3.41-3.32 (m, 2H), 3.00 (s, 3H), 2.40-2.26 (m, 2H), 1.75 (s, 6H), 1.68-1.61 (m, 1H), 1.57-1.53​​ (m, 1H), 1.50 (d,J=6.4 Hz, 3H), 1.37 (d,J=6.4 Hz, 3H), 1.27-1.16 (m, 2H). Process 1, intermediate 12 and intermediates 55 30 540 1H-NMR (400 MHz, CD3OD): δ ppm 9.42 (s, 1H), 9.02 (s, 1H), 8.17 (d,J= 8.8 Hz, 1H), 8.04 (s, 1H), 7.36 (d,J= 8.8 Hz, 1H), 5.20-5.16 (m, 1H), 4.72-4.64 (m, 1H), 3.50-3.40 (m, 1H), 3.09-2.89 (m, 6H), 2.49-2.41 (m, 1H), 1.96 (d,J= 6.0 Hz, 6H), 1.53-1.43 (m, 9H)。 Process 1, intermediate 1 and intermediates 39 31 540 1H-NMR (400 MHz, CD3OD): δ ppm 9.38 (s, 1H), 9.06 (s, 1H), 8.14 (d,J= 8.8 Hz, 1H), 8.10 (s, 1H), 7.33 (d,J= 8.8 Hz, 1H), 5.18-5.12 (m, 1H), 4.72-4.64 (m, 1H), 3.48-3.39 (m, 1H), 3.08-2.88 (m, 6H), 2.49-2.36 (m, 1H), 1.88 (d,J= 6.0 Hz, 6H), 1.52-1.41 (m, 9H)。 Process 1, intermediate 1 and intermediates 40 32 540 1H-NMR (400 MHz, CD3OD): δ ppm 9.38 (s, 1H), 9.25 (s, 1H), 8.54 (br s, 1H), 8.14 (d,J= 8.8 Hz, 1H), 8.04 (s, 1H), 7.21 (d,J= 8.6 Hz, 1H), 5.45 (q,J= 7.2 Hz, 1H), 3.83 (q,J= 8.4 Hz, 1H), 3.20 (s, 2H), 3.03 - 2.95 (m, 2H), 2.93 (s, 3H), 2.75 - 2.65 (m, 2H), 2.51 (br dd,J= 7.3, 14.4 Hz, 1H), 2.27 (qd,J= 7.2, 14.4 Hz, 1H), 1.88 (s, 3H), 1.53 (s, 6H), 0.80 (br t,J= 7.2 Hz, 3H). Process 1, intermediate 5 and intermediate products twenty four 33 540 1 H-NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 8.53 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 8.06 (s, 1H), 7.58 (d,J= 8.6 Hz, 1H), 5.45 (t,J= 7.2 Hz, 1H), 4.31 (s, 2H), 3.83 (br t,J= 8.4 Hz, 1H), 3.03-2.96 (m, 2H), 2.94 (s, 3H), 2.76-2.64 (m, 2H), 2.49 (br dd,J= 7.4, 14.4 Hz, 1H), 2.17 (qd,J= 7.2, 14.4 Hz, 1H), 1.83 (s, 3H), 1.45 (s, 6H), 0.77 (t,J= 7.4 Hz, 3H). Process 1, intermediate 14 and intermediate products twenty four 34 540 1H-NMR (400 MHz, CD3OD): δ ppm 9.34 (s, 1H), 9.19 (s, 1H), 8.20 (s, 1H), 8.13 (d,J= 8.8 Hz, 1H), 7.30 (d,J= 8.8 Hz, 1H), 5.80 (s, 1H), 4.67-4.64 (m, 1H), 3.99-3.95 (m, 1H), 3.02-3.00 (m, 1H), 2.98 (s, 3H), 2.49-2.45 (m, 2H), 2.27-2.22 (m, 4H), 1.77 (d,J= 4.8 Hz, 6H), 1.51 (d,J= 6.4 Hz, 3H), 1.45 (d,J= 6.4 Hz, 3H). Process 1, intermediate 1 and intermediates 42 The second dissolution isomer from chiral SFC Tube Column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 µm); Moving phase: [0.1%NH3H2O ​​IPA]; B%: 40%-40%) 35 540 1 H-NMR (400 MHz, CD3OD): δ ppm 9.39 (s, 1H), 9.04 (s, 1H), 8.51 (s, 1H), 8.17 (d,J= 8.8 Hz, 1H), 8.07 (s, 1H), 7.34 (d,J= 8.8 Hz, 1H), 5.82 (s, 1H), 4.70-4.60 (m, 1H), 4.02-3.92 (m, 1H), 3.04-3.00 (m, 1H), 2.98 (s, 3H), 2.50-2.47 (m, 2H), 2.40-2.15 (m, 4H), 1.91 (d,J= 6.8 Hz, 6H), 1.51 (d,J= 7.2 Hz, 3H), 1.45 (d,J= 6.8 Hz, 3H). Process 1, intermediate 1 and intermediates 42 The first dissolution isomer from chiral SFC Tube Column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 µm); Moving phase: [0.1%NH3H2O ​​IPA]; B%: 40%-40%) 36 540 1 H-NMR (400 MHz, CD3OD): δ ppm 9.43 (s, 1H), 9.40 (s, 1H), 8.21 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 7.24 (d,J= 8.8 Hz, 1H), 4.67-4.61 (m, 2H), 3.48-3.41 (m, 1H), 3.31-3.27 (m, 1H), 3.24-3.18 (m, 1H), 3.17-3.12 (m, 2H), 3.08-3.03 (m, 1H), 2.58-2.47 (m, 1H), 2.27-2.15 (m, 1H), 1.82 (d,J= 7.2 Hz, 6H), 1.56 (s, 3H), 1.47 (s, 3H), 1.42 (d,J= 7.2 Hz, 3H). Process 1, intermediate 3 and intermediates 43 The second dissolution isomer from chiral SFC Tube Column: Phenomenex-Cellulose-2 (250 mm×30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​MEOH];B%:50%-50%) 37 540 1H-NMR (400 MHz, CD3OD): δ ppm 9.43 (s, 1H), 9.40 (s, 1H), 8.21 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 7.24 (d,J= 8.8 Hz, 1H), 4.68-4.59 (m, 2H), 3.46-3.38 (m, 1H), 3.32-3.27 (m, 1H), 3.24-3.17 (m, 1H), 3.17-3.10 (m, 2H), 3.09-3.03 (m, 1H), 2.57-2.48 (m, 1H), 2.27-2.15 (m, 1H), 1.82 (d,J= 7.2 Hz, 6H), 1.56 (s, 3H), 1.47 (s, 3H), 1.42 (d,J= 7.2 Hz, 3H). Process 1, intermediate 3 and intermediates 43 The first dissolution isomer from chiral SFC Tube Column: Phenomenex-Cellulose-2 (250 mm×30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​MEOH];B%:50%-50%) 38 540 1H-NMR (400 MHz, CD3OD): δ ppm 9.39 (s, 1H), 9.08 (d,J= 7.6 Hz, 1H), 8.15 (d,J= 8.8 Hz, 1H), 8.07 (s, 1H), 7.32 (d,J= 8.4 Hz, 1H), 5.48-5.41 (m, 1H), 4.70-4.64 (m, 1H), 3.87-3.79 (m, 1H), 3.03-2.95 (m, 3H), 2.93 (s, 3H), 2.72-2.66 (m, 2H), 2.52-2.46 (m, 1H), 2.26-2.15 (m, 1H), 1.83 (d,J= 12.8 Hz, 3H), 1.51-1.49 (m, 3H), 1.47-1.45 (m, 3H), 0.78-0.75 (m, 3H). Process 1, intermediate 1 and intermediates twenty four 39 540 1 H-NMR (400 MHz, d6-DMSO): δ ppm 10.70 (s, 1H), 9.42 (s, 1H), 9.32 (s, 1H), 8.14 (s, 1H), 8.08 (d,J= 8.63Hz, 1H) 7.37 (d,J= 8.8 Hz, 1H), 5.42-5.30 (m, 1H), 4.67-4.49 (m, 1H), 3.99-3.77 (m, 1H), 3.10-3.04 (m, 2H), 3.02-2.95 (m, 1H), 2.89-2.82 (m, 2H), 2.57-2.53 (m, 1H), 1.65 (d,J= 2.4 Hz, 6H), 1.44 (d,J= 7.2 Hz, 3H), 1.37 (d,J= 6.4 Hz, 3H), 1.21 (t,J= 7.4 Hz, 3H). Process 1, intermediate 1 and intermediates 44 40 540 1 H-NMR (400 MHz, CD3OD): δ ppm 9.31 (s, 1H), 9.07 (s, 1H), 8.09 (s, 1H), 8.04 (d,J= 8.4 Hz, 1H), 7.21 (d,J= 8.8 Hz, 1H), 5.62-5.06 (m, 1H), 4.60-4.50 (m, 1H), 3.75-3.70 (m, 1H), 3.00-2.95 (m, 1H), 2.87 (s, 3H), 2.60-2.50 (m, 1H), 2.40-2.30 (m, 2H), 2.35-2.20 (m, 2H), 2.20-1.90 (m, 1H), 1.70 (d,J= 4.4 Hz, 6H), 1.41 (d,J= 7.2 Hz, 3H), 1.36 (d,J= 6.8 Hz, 3H). Process 1, intermediate 1 and intermediates 41, The second dissolution isomer from chiral SFC Tube Column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​MEOH];B%:50%-50%) 41 540 1H-NMR (400 MHz, CD3OD): δ ppm 9.31 (s, 1H), 9.07 (s, 1H), 8.09 (s, 1H), 8.04 (d,J= 8.4 Hz, 1H), 7.21 (d,J= 8.8 Hz, 1H), 5.62-5.06 (m, 1H), 4.60-4.50 (m, 1H), 3.75-3.70 (m, 1H), 3.00-2.95 (m, 1H), 2.87 (s, 3H), 2.60-2.50 (m, 1H), 2.40-2.30 (m, 2H), 2.35-2.20 (m, 2H), 2.20-1.90 (m, 1H), 1.70 (d,J= 4.4 Hz, 6H), 1.41 (d,J= 7.2 Hz, 3H), 1.36 (d,J= 6.8 Hz, 3H). Process 1, intermediate 1 and intermediates 41 The first dissolution isomer from chiral SFC Tube Column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​MEOH];B%:50%-50%) 42 540 1 H-NMR (400 MHz, CD3OD): δ ppm 9.39 (s, 1H), 9.21 (s, 1H), 8.54 (s, 1H), 8.14 (d,J= 8.8 Hz, 1H), 8.07-8.03 (m, 1H), 7.25 (d,J= 8.8 Hz, 1H), 5.51-5.36 (m, 1H), 3.92-3.75 (m, 1H), 3.05-2.95 (m, 3H), 2.93 (s, 3H), 2.76-2.63 (m, 2H), 1.94 (d,J= 11.2 Hz, 6H), 1.53 (s, 3H), 1.45 (s, 3H), 1.40 (d, J = 7.2 Hz, 3H). Process 1, intermediate 3 and intermediates twenty two 43 540 1 H NMR (400 M Hz, CD3OD): δ ppm 9.47 (s, 1H), 8.52 (s, 1H), 8.26 (s, 1H), 8.17 (d,J= 8.8 Hz, 1H), 8.02 (s, 1H), 7.64 (d,J= 8.8 Hz, 1H), 4.69 (t,J= 6.2 Hz, 2H), 4.67-4.61 (m, 1H), 3.46-3.38 (m, 2H), 3.04 (s, 3H), 2.51-2.39 (m, 3H), 2.20 (m, 1H), 1.85 (s, 3H), 1.64-1.56 (m, 1H), 1.53-1.44 (m, 1H), 1.38 (d,J= 6.4 Hz, 3H), 1.28-1.17 (m, 2H), 0.80 (t,J= 7.4 Hz, 3H). Process 1, intermediate 12 and intermediate 100 44 554 1 H NMR (400 M Hz, CD3OD): δ ppm 9.49 (s, 1H), 8.50 (s, 1H), 8.18 (d,J= 8.8 Hz, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.71 (d,J= 8.4 Hz, 1H), 4.70 (t,J= 6.0 Hz, 2H), 3.46-3.38 (m, 2H), 3.04 (s, 3H), 2.57-2.38 (m, 3H), 2.28-2.16 (m, 1H), 1.89 (s, 3H), 1.52 (s, 2H), 1.42 (s, 6H), 1.29 (s, 2H), 0.81 (t, J = 7.0 Hz, 3H). Process 1, intermediate 15 and intermediates 100 45 541 1 H NMR (400 MHz, CD3OD): δ ppm 9.38 (s, 2H), 8.08 (d,J= 8.4 Hz, 1H), 7.73 (d,J= 8.0 Hz, 1H), 7.14 (d,J= 8.8 Hz, 1H), 6.87 (d,J= 8.8 Hz, 1H), 4.95-4.90 (m, 2H), 3.45-3.35(m, 1H), 3.06-3.01 (m, 1H), 3.00 (s, 3H), 2.40-2.28 (m, 2H), 1.82 (d,J= 8.0 Hz, 6H), 1.54 (s, 3H), 1.48 (d,J= 6.0 Hz, 3H), 1.44 (s, 3H), 1.37(d,J= 7.2 Hz, 3H). Process 1, intermediate 3 and intermediates 34 The second dissolution isomer from chiral SFC Tube Column: Chiralpak AD-3 50×4.6 mm ID, 3 µm; Moving phase: 40% IPA (0.05% DEA) in CO2 46 541.2 1H NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 2H), 8.07 (d,J= 8.8 Hz, 1H), 7.73 (d,J= 8.0 Hz, 1H), 7.14 (d,J= 8.8 Hz, 1H), 6.87 (d,J= 8.4 Hz, 1H), 4.95-4.90 (m, 2H), 3.45-3.35(m, 1H), 3.06-3.01 (m, 1H), 3.00 (s, 3H), 2.36-2.29 (m, 2H), 1.82 (d,J= 9.8 Hz, 6H), 1.54 (s, 3H), 1.48 (d,J= 6.0 Hz, 3H), 1.44 (s, 3H), 1.37(d,J= 7.2 Hz, 3H). Process 1, intermediate 3 and intermediates 34 The first dissolution isomer from chiral SFC Tube Column: Chiralpak AD-3 50×4.6 mm ID, 3 µm; Moving phase: 40% IPA (0.05% DEA) in CO2 47 542 1 H-NMR (400 MHz, CD3OD): δ ppm 9.44 (s, 1H), 9.13 (s, 1H), 8.17 (d,J= 8.8 Hz, 1H), 7.98 (s, 1H), 7.30 (d,J= 8.4 Hz, 1H), 5.76-5.71 (m, 1H), 4.74-4.70 (m, 1H), 4.47-4.43 (m, 1H), 3.41-3.36 (m, 1H), 3.19-3.15 (m, 1H), 2.94 (s, 3H), 2.79-2.74 (m, 1H), 2.46-2.36 (m, 2H), 2.22-2.11 (m, 1H), 2.04 (s, 3H), 1.52-1.47 (m, 9H), 0.86-0.82 (m, 3H). Process 1, intermediate 8 and intermediates 53 The second dissolution isomer from chiral SFC Tube Column: DAICEL CHIRALCEL OJ-H (250 mm × 30 mm, 5 µm); Moving phase: [0.1% NH3H2O ​​MEOH];B%:20%-20%) 48 542 1 H-NMR (400 MHz, CD3OD): δ ppm 9.38 (s, 1H), 9.26 (s, 1H), 8.16-8.14 (m, 2H), 7.23 (d,J= 8.8 Hz, 1H), 5.72-5.67 (m, 1H), 4.71-4.68 (m, 1H), 4.45-4.41 (m, 1H), 3.39-3.34 (m, 1H), 3.18-3.14 (m, 1H), 2.93 (s, 3H), 2.54-2.39 (m, 2H), 2.19-2.09 (m, 2H), 1.81 (s, 3H), 1.51-1.48 (m, 9H), 0.77-0.73 (m, 3H). Process 1, intermediate 8 and intermediates 53 The first dissolution isomer from chiral SFC Tube Column: DAICEL CHIRALCEL OJ-H (250 mm × 30 mm, 5 µm); Moving phase: [0.1% NH3H2O ​​MEOH];B%:20%-20% 49 542 1H-NMR (400 MHz, CD3OD): δ ppm 9.39 (s, 1H), 9.25 (s, 1H), 8.13 (d,J= 8.8 Hz, 1H), 8.07 (s, 1H), 7.20 (d,J= 8.8 Hz, 1H), 5.68-5.59 (m, 1H), 3.43-3.32 (m, 2H), 3.19 (s, 2H), 3.01 (s, 3H), 2.55-2.44 (m, 1H), 2.40-2.30 (m, 2H), 2.30-2.21 (m, 1H), 1.86 (s, 3H), 1.55-1.48 (m, 9H), 0.79 (t,J= 7.4 Hz, 3H). Process 1, intermediate 5 and intermediate products 31 50 542 1 H-NMR (400 MHz, CD3OD): δ ppm 9.46 (s, 1H), 8.44 (s, 1H), 8.17 (d,J= 8.8 Hz, 1H), 8.02 (s, 1H), 7.63 (d,J= 8.8 Hz, 1H), 5.69-5.60 (m, 1H), 4.38-4.25 (m, 2H), 3.43-3.32 (m, 2H), 3.01 (s, 3H), 2.64-2.52 (m, 1H), 2.41-2.29 (m, 2H), 2.26-2.16 (m, 1H), 1.89 (s, 3H), 1.52 (d,J= 6.2 Hz, 3H), 1.45 (s, 6H), 0.79 (t,J= 7.4 Hz, 3H). Process 1, intermediate 14 and intermediate products 31 51 542 1H-NMR (400 MHz, CD3OD): δ ppm 9.43 (s, 1H), 8.99 (s, 1H), 8.52 (s, 1H), 8.18 (d,J= 8.8 Hz, 1H), 8.04 (s, 1H), 7.38 (d,J= 8.4 Hz, 1H), 5.74-5.71 (m, 1H), 4.70-4.64 (m, 1H), 3.40-3.35 (m, 1H), 3.05-3.01 (m, 1H), 2.94 (s, 3H), 2.46-2.35 (m, 1H), 2.20-2.11 (m, 1H), 1.99 (d,J= 5.2 Hz, 6H), 1.52-1.46 (m, 12H). Process 1, intermediate 1 and intermediates 52 52 542 1 H NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1H), 9.14 (s, 1H), 8.20-8.11 (m, 2H), 7.31 (d,J= 8.8 Hz, 1H), 5.71-5.53 (m, 1H), 4.73-4.63 (m, 1H), 3.42-3.32 (m, 2H), 3.07-2.97 (m, 4H), 2.50-2.39 (m, 1H), 2.37-2.29 (m, 2H), 2.24-2.11 (m, 1H), 1.78 (s, 3H), 1.54-1.48 (m, 6H), 1.46 (d,J= 6.8 Hz, 3H), 0.75 (t,J= 7.4 Hz, 3H). Process 1, intermediate 1 and intermediates 31 53 542 1H-NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 9.09 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 8.10 (s, 1H), 7.32 (d,J= 8.8 Hz, 1H), 5.68-5.58 (m, 1H), 4.75-4.63 (m, 1H), 3.41-3.32 (m, 2H), 3.04-2.98 (m, 4H), 2.53-2.42 (m, 1H), 2.39-2.29 (m, 2H), 2.27-2.15 (m, 1H), 1.82 (s, 3H), 1.50 (t,J= 6.6 Hz, 6H), 1.46 (d,J= 6.8 Hz, 3H), 0.77 (t,J= 7.4 Hz, 3H). Process 1, intermediate 1 and intermediates 54 54 542 1 H-NMR (400 MHz, CD3OD): δ ppm 9.44 (s, 1H), 9.23 (s, 1H), 8.17(d,J= 8.8 Hz, 1H), 8.10 (s, 1H), 7.28 (d,J= 8.8 Hz, 1H), 5.69-5.65 (m, 1H), 3.40-3.34 (m, 2H), 3.07-3.04 (m, 1H), 3.02 (s, 3H), 2.38-2.33(m, 2H), 2.06-1.97 (s, 6H), 1.56 (s, 3H), 1.54 (s, 3H), 1.47 (s, 3H), 1.43 (d,J= 7.2 Hz, 3H). Process 1, intermediate 3 and intermediates 28 55 542 1H-NMR (400 MHz, CD3OD): δ ppm 9.41 (m, 1H), 9.38 (s, 1H), 8.22 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 7.24 (d,J= 8.80 Hz, 1H), 5.67-5.60 (m, 1H), 3.39-3.35 (m, 2H), 3.07 (m, 1H), 3.02 (s, 3H), 2.38-2.34 (m, 2H), 1.82 (d,J= 6.8 Hz, 6H), 1.56 (s, 3H), 1.52 (d,J= 6.4 Hz, 3H), 1.47 (s, 3H), 1.42 (d, J = 7.6 Hz, 3H). Process 1, intermediate 3 and intermediates 29 56 542 1 H NMR (400 MHz, CD3OD): δ ppm 9.50 (s, 1H), 8.31 (s, 1H), 8.18 (d,J= 8.8 Hz, 1H), 7.97 (s, 1H), 7.72 (d,J= 8.8 Hz, 1H), 4.71 (t,J= 6.0 Hz, 2H), 4.65-4.55 (m, 1H), 3.43 (t,J= 6.0 Hz, 2H), 3.05 (s, 3H), 2.70-2.60 (m, 1H), 2.50-2.40 (m, 2H), 2.30-2.20 (m, 1H), 1.95 (s, 3H), 1.55-1.45 (m, 6H), 1.30 (s, 3H), 0.85-0.78 (m, 3H). Process 1, intermediate 97 and intermediate 100 57 544 1H NMR (400 MHz, CD3OD): δ ppm 9.43 (s, 1H), 9.05 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 8.07 (s, 1H), 7.35 (d,J= 8.8 Hz, 1H), 4.71-4.65 (m, 3H), 4.00-3.99 (m, 2H), 3.44-3.38 (m, 5H), 3.04-3.00 (m, 4H), 2.47-2.40 (m, 2H), 1.87 (s, 3H), 1.51-1.42 (m, 6H). Process 1, intermediate 1 and intermediates 99 58 552 1 H NMR (400 MHz, CD3OD): δ ppm 9.39 (s, 1 H), 8.39 (s, 1 H), 8.15 (d,J= 8.4 Hz, 1 H), 8.08 (s, 1 H), 7.56 (d,J= 8.8 Hz, 1 H), 5.47-5.38 (m, 1 H), 4.66-4.60 (m, 1 H), 3.72-3.95 (m, 1 H), 3.01-2.95 (m, 2 H), 2.93 (s, 3 H), 2.73-2.64 (m, 2 H), 2.40-2.29 (m, 1 H), 2.16-2.06 (m, 1 H), 1.75 (s, 3 H), 1.65-1.47 (m, 2 H), 1.37 (d,J= 6.60 Hz, 3 H), 1.25-1.17 (m, 2 H), 0.77-0.71 (m, 3 H). Process 1, intermediate 12 and intermediates twenty four 59 552 1H NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1 H), 8.37 (s, 1 H), 8.16 (d,J= 8.8 Hz, 1 H), 8.08 (s, 1 H), 7.59 (d,J= 8.8 Hz, 1 H), 5.5-5.36 (m, 1 H), 3.90-3.75 (m, 1 H), 3.01-2.95 (m, 2 H), 2.93 (s, 3 H), 2.75-2.60 (m, 2 H), 1.83 (s, 6 H), 1.58-1.53​​ (m, 2 H), 1.42 (s, 6 H), 1.31-1.28 (m, 2H). Process 1, intermediate 15 and intermediate products twenty two 60 552 1 H-NMR (400 MHz, 6d-DMSO): δ ppm 10.67 (s, 1H), 9.54 (s, 1H), 9.32 (s, 1H), 8.31 (s, 1H), 8.08 (d,J= 8.8 Hz, 1H), 7.38 (d,J= 8.8 Hz, 1H), 5.42-5.31 (m, 1H), 4.64-4.56 (m, 1H), 3.90-3.80 (m, 1H), 3.00-2.92 (m, 4H), 2.89-2.82 (m, 2H), 2.56-2.53 (m, 1H), 1.61-1.52 (m, 5H), 1.44 (d,J= 7.2 Hz, 3H), 1.37 (d,J= 6.0 Hz, 3H), 0.61-0.54 (m, 1H), 0.48-0.37 (m, 3H). Process 1, intermediate 1 and intermediates 56 61 552 1H-NMR (400 MHz, CD3OD): δ ppm 9.38 (s, 1H), 9.14 (s, 1H), 8.16-8.12 (m, 2H), 7.31 (d,J= 8.8 Hz, 1H), 5.49-5.39 (m, 1H), 4.67-4.60 (m, 1H), 3.88-3.84 (m, 1H), 3.05-2.95 (m, 3H), 2.80-2.64 (m, 2H), 2.60-2.50 (m, 1H), 1.83 (d,J= 5.2 Hz, 6H), 1.55-1.43 (m, 6H), 1.14-1.07 (m, 4H). Process 1, intermediate 1 and intermediates 32 62 552 1 H-NMR (400 MHz, CD3OD): δ ppm 9.39-9.23 (m, 1H), 8.97-8.83 (m, 1H), 8.20 (s, 1H), 8.15-8.07 (m, 1H), 7.19 (d,J= 8.8 Hz, 1H), 5.61-5.27 (m, 2H), 3.83 (d,J= 6.4 Hz, 2H), 3.67-3.56 (m, 1H), 3.22-3.11 (m, 1H), 2.93 (s, 4 H), 2.68 (d,J= 5.2 Hz, 2H), 1.54-1.43 (m, 9H), 0.73-0.34 (m, 4H). Step 2, intermediate 3 and intermediates 58 The penultimate intermediate from preparative HPLC is the second dissolution isomer. Tube Column: Phenomenex Gemini-NX C18 75×30mm× 3 µm; Moving phase: [Water (0.05% ammonia v / v) - ACN]; B%: 26%-56%, 10 minutes 63 553 1 H-NMR (400 MHz, CD3OD): δ ppm 9.42 (s, 1H), 9.33 (s, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 5.01 (d, J = 6.8 Hz, 1H), 3.87 - 3.78 (m, 1H), 3.07 (q, J = 7.2 Hz, 2H), 3.04 - 2.96 (m, 3H), 2.74 - 2.64 (m, 2H), 1.93 (d, J = 10.4 Hz, 6H), 1.54 (s, 3H), 1.45 (s, 3H), 1.39 (d, J = 7.2 Hz, 3H), 1.36 (t, J = 7.6 Hz, 3H). Process 1, intermediate 3 and intermediates 59 64 553 1 H-NMR (400 MHz, CD3OD): δ ppm 9.37 (s, 1H), 9.01 (s, 1H), 8.51 (s, 1H), 8.13 (d,J= 8.8 Hz, 1H), 7.88 (s, 1H), 7.26 (d,J= 8.8 Hz, 1H), 4.74-5.62 (m, 1H), 3.85-3.81 (m, 1H), 3.06-2.96 (m, 3H), 2.81-2.78 (m, 2H), 2.59-2.51 (m, 2H), 1.94 (d,J= 11.2 Hz, 6H), 1.52 (s, 3H), 1.43 (s, 3H), 1.38 (d,J= 7.2 Hz, 3H), 1.34 (t,J= 7.6 Hz, 3H). Process 1, intermediate 3 and intermediates 60 65 554 1 H NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1H), 8.47 (s, 1H), 8.15 (d,J= 8.4 Hz, 1H), 8.13 (s, 1H), 7.54 (d,J= 8.4 Hz, 1H), 5.74-5.65 (m, 1H), 4.68-4.60 (m, 1H), 3.41-3.33 (m, 1H), 2.93 (s, 3H), 2.45-2.37 (m, 1H), 2.17-2.08 (m, 1H), 1.80 (s, 6H), 1.68-1.61 (m, 1H), 1.54-1.52 (m, 1H), 1.51-1.47 (m, 6H), 1.38 (d,J= 6.4 Hz, 3H), 1.26-1.18 (m, 2H). Process 1, intermediate 12 and intermediates 52 66 554 1 H NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 8.44 (s, 1H), 8.16 (d,J= 8.8 Hz, 1H), 8.12 (s, 1H), 7.56 (d,J= 8.8 Hz, 1H), 5.67-5.57 (m, 1H), 4.67-4.59 m, 1H), 3.41-3.32 (m, 2H), 3.00 (s, 3H), 2.40-2.24 (m, 3H), 2.16-2.03 (m, 1H), 1.73 (s, 3H), 1.69-1.62 (m, 1H), 1.51 (d,J= 6.0 Hz, 4H), 1.38 (d,J= 6.4 Hz, 3H), 1.27-1.14 (m, 2H), 0.74 (t,J= 7.4 Hz, 3H)。 Process 1, intermediate 12 and intermediates 31 67 554 1 H NMR (400 MHz, CD3OD): δ ppm 9.66 (s, 1H), 8.77 (s, 1H), 8.45 (s, 1H), 8.40 (d,J=8.4 Hz, 1H), 7.78 (d,J=8.8 Hz, 1H), 5.93-5.86 (m, 1H), 3.72-3.63 (m, 2H), 3.63-3.58 (m, 2H), 2.68-2.57 (m, 2H), 2.02 (s, 6H), 1.87-1.82 (m, 3H), 1.80-1.78 (d, 3H), 1.69 (s, 6H), 1.57-1.53​​ (m, 2H). Process 1, intermediate 15 and intermediate products 55 68 554 1 H-NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1H), 9.26 (s, 1H), 8.14 (d,J= 8.8 Hz, 1H), 8.10 (s, 1H), 7.25 (d,J= 8.8 Hz, 1H), 5.20-5.10 (m, 1H), 3.48-3.40 (m, 1H), 3.10-2.90 (m, 6H), 2.48-2.40 (m, 1H), 1.90 (d,J= 9.2 Hz, 6H), 1.54 (s, 3H), 1.46-1.38 (m, 9H). Process 1, intermediate 3 and intermediates 38 The second dissolution isomer from chiral SFC Tube Column: Daicel Chiralpak AD (250 mm × 30 mm, 10 µm); Moving phase: [0.1%NH3H2O ​​IPA]; B%: 40%-40% 69 554 1 H-NMR (400 MHz, CD3OD): δ ppm 9.42 (s, 1H), 9.20 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 8.05 (s, 1H), 7.27 (d,J= 8.8 Hz, 1H), 5.20-5.13 (m, 1H), 3.45-3.40 (m, 1H), 3.10-2.90 (m, 6H), 2.50-2.40 (m, 1H), 1.95 (d,J= 11.2 Hz, 6H), 1.53 (s, 3H), 1.45-1.35 (m, 9H). Process 1, intermediate 3 and intermediates 38 The first dissolution isomer from chiral SFC Tube Column: Daicel Chiralpak AD (250 mm × 30 mm, 10 µm); Moving phase: [0.1%NH3H2O ​​IPA]; B%: 40%-40% 70 554 1 H-NMR (400 MHz, CD3OD): δ ppm 9.38 (s, 1H), 9.31 (s, 1H), 8.14-8.10 (m, 2H), 7.23 (d,J= 8.4 Hz, 1H), 5.52-5.45 (m, 1H), 3.97-3.92 (m, 1H), 3.27-3.25 (m, 1H), 3.05-2.95 (m, 5H), 2.62-2.54 (m, 1H), 1.85 (d,J= 8.4 Hz, 6H), 1.56-1.53​​ (m, 6H), 1.45-1.38 (m, 6H). Process 1, intermediate 3 and intermediates 37 The second dissolution isomer from chiral SFC Tube Column: Daicel Chiralpak AD (250 mm × 30 mm, 10 µm); Moving phase: [0.1%NH3H2O_ETOH] 71 554 1 H-NMR (400 MHz, CD3OD): δ ppm 9.38 (s, 1H), 9.31 (s, 1H), 8.14-8.10 (m, 2H), 7.23 (d,J= 8.4 Hz, 1H), 5.52-5.45 (m, 1H), 3.97-3.92 (m, 1H), 3.27-3.25 (m, 1H), 3.05-2.95 (m, 5H), 2.62-2.54 (m, 1H), 1.85 (d,J= 8.4 Hz, 6H), 1.56-1.53​​ (m, 6H), 1.45-1.38 (m, 6H). Process 1, intermediate 3 and intermediates 37 The first dissolution isomer from chiral SFC (column: Daicel Chiralpak AD (250 mm × 30 mm, 10 µm); Moving phase: [0.1%NH3H2O_ETOH] 72 554 1 H-NMR (400 MHz, CDCl3): δ ppm 9.42 (s, 1H), 9.21 (s, 1H), 8.24 (d,J= 9.6 Hz, 1H), 8.08 (s, 1H), 7.89 (s, 1H), 5.60-5.50 (m, 1H), 4.59-4.52 (m, 1H), 3.31 (d,J= 7.6 Hz, 2H), 3.19-3.11 (m, 1H), 3.04-2.97 (m, 1H), 2.93 (s, 3H), 2.76-2.64 (m, 2H), 2.64-2.56 (m, 2H), 2.23-2.13 (m, 1H), 2.09-2.01 (m, 1H), 1.69 (s, 3H), 1.61 (s, 3H,), 1.52 (s, 3H), 0.83-0.70 (m, 3H). Process 1, intermediate 1 and intermediates 49 73 554 1H-NMR (400 MHz, 6d-DMSO): δ ppm 10.7 (s, 1H), 9.33 (s, 1H), 9.31 (s, 1H), 8.14 (s, 1H), 8.08 (d,J= 8.4 Hz, 1H), 7.38 (d,J= 8.4 Hz, 1H), 5.33-5.24 (m, 1H), 4.69-4.48 (m, 1H), 3.37 (s, 2H), 3.02-2.96 (m, 1H), 2.94 (s, 3H), 2.82-2.74 (m, 2H), 2.55-2.51 (m, 1H), 2.47 (s, 1H), 2.21-1.98 (m, 5H), 1.59 (s, 3H), 1.42 (d,J= 7.2 Hz, 3H), 1.37 (d,J= 6.4 Hz, 3H), 0.66-0.60 (m, 3H). Process 1, intermediate 1 and intermediates 48 74 554 1 H-NMR (400 MHz, CD3OD): δ ppm 9.38 (s, 1H), 8.73 (s, 1H), 8.20 (s, 1H), 8.13 (d,J= 8.7 Hz, 1H), 7.31 (d,J= 8.7 Hz, 1H), 5.47 (br t,J= 7.3 Hz, 1H), 4.73 (br t,J= 7.0 Hz, 1H), 3.89-3.75 (m, 1H), 3.19 (q,J= 7.1 Hz, 1H), 3.07 (q,J= 7.5 Hz, 2H), 2.97 (td,J= 7.4, 12.0 Hz, 2H), 2.76-2.64 (m, 2H), 2.17 (quin,J= 7.2 Hz, 2H), 1.57-1.49 (m, 6H), 1.43 (s, 3H), 1.36 (t,J= 7.5 Hz, 3H), 1.04 (t,J= 7.4 Hz, 3H). Step 2, intermediate 3 and intermediates 46 The penultimate intermediate from preparative HPLC was the first dissolution isomer. Tube Column: Phenomenex Luna C18 75×30 mm×3 µm; Moving phase: [Water (0.05% HCl) - ACN]; B%: 42%-62% 75 554 1 H-NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1H), 9.37 (s, 1H), 8.18 -8.10 (m, 2H), 7.21 (d,J= 8.8 Hz, 1H), 5.57-5.49 (m, 1H), 3.43 (d,J= 7.6 Hz, 2H), 3.13-3.01 (m, 2H), 2.97 (s, 3H), 2.64-2.56 (m, 4H), 1.79 (d,J= 7.6 Hz, 6H), 1.54 (s, 3H), 1.45 (s, 3H), 1.40 (d,J= 7.2 Hz, 3H). Process 1, intermediate 3 and intermediates 47 The first dissolution isomer from chiral SFC Tube Column: DAICEL CHIRALPAK ID (250 mm×30 mm, 10 µm); Moving phase: [0.1%NH3H2O ​​ETOH]; B%: 60%-60%) 76 554 1H-NMR (400 MHz, CD3OD): δ ppm 9.46-9.29 (m, 2H), 8.24-8.08 (m, 2H), 7.29-7.13 (m, 1H), 5.45-5.30 (m, 1H), 3.37 (d,J= 6.8 Hz, 2H), 3.10-3.00 (m, 1H), 2.96 (s, 3H), 2.94-2.84 (m, 2H), 2.68-2.54 (m, 1H), 2.25-2.11 (m, 2H), 1.79 (d,J= 5.6 Hz, 6H), 1.54 (s, 3H), 1.45 (s, 3H), 1.39 (d,J= 5.6 Hz, 3H). Process 1, intermediate 3 and intermediates 47 The second dissolution isomer from chiral SFC Tube Column: DAICEL CHIRALPAK ID (250 mm × 30 mm, 10 µm); Moving phase: [0.1% [NH3 H2O ETOH]; B%: 60%-60% 77 554 1 H-NMR (400 MHz, CD3OD): δ ppm 9.35 (s, 1H), 9.16 (d,J= 10.8 Hz, 1H), 8.16-8.11 (m, 2H), 7.30-7.27 (m, 1H), 5.47-5.40 (m, 1H), 4.69-4.63 (m, 1H), 3.87-3.78 (m, 1H), 3.09-3.06 (m, 2H), 3.02-2.93 (m, 3H), 2.73-2.65 (m, 2H), 2.41-2.31 (m, 1H), 2.19-2.04 (m, 1H), 1.73 (s, 3H), 1.51-1.45 (m, 6H), 1.37-1.34 (m, 3H), 0.74-0.70 (m, 3H). Process 1, intermediate 1 and intermediates 45 78 554 1 H-NMR (400 MHz, CD3OD): δ ppm 9.37 (s, 1H), 9.28 (d,J= 15.6 Hz, 1H), 8.31 (d,J= 8.4 Hz, 1H), 8.09 (s, 1H), 7.22 (d,J= 8.8 Hz, 1H), 5.48-5.40 (m, 1H), 3.87-3.79 (m, 1H), 3.04-2.95 (m, 3H), 2.93 (s, 3H), 2.73-2.65 (m, 2H), 2.50-2.41 (m, 1H), 2.28-2.16 (m, 1H), 1.81 (d,J= 8.4 Hz, 3H), 1.54 (s, 3H), 1.45 (s, 3H), 1.40-1.38 (m, 3H), 0.78-0.74 (m, 3H). Process 1, intermediate 3 and intermediates twenty four 79 554 1H-NMR (400 MHz, CD3OD): δ ppm 9.33 (s, 1H), 8.85 (s, 1H), 8.21-8.04 (m, 2H), 7.23 (d,J= 8.8 Hz, 1H), 5.47-5.39 (m, 1H), 4.52-4.46 (m, 1H), 3.90-3.73 (m, 1H), 3.18-3.1 (m, 1H), 2.96 (s, 2H), 2.93 (s, 3H), 2.74-2.62 (m, 2H), 2.02-1.81 (m, 2H), 1.52-1.48 (m, 6H), 1.45 (s, 3H), 1.44-1.27 (m, 2H), 0.99-0.93(m, 3H)。 Step 2, intermediate 3 and intermediates 61 80 554 1H-NMR (400 MHz, CD3OD): δ ppm 9.37 (s, 1H), 9.35 (s, 1H), 8.16 (s, 1H), 8.13 (d,J= 8.4 Hz, 1H), 7.22 (d,J= 8.8 Hz, 1H), 5.52-5.37 (m, 1H), 3.91-3.75 (m, 1H), 3.10-3.02 (m, 3H), 3.02-2.92 (m, 2H), 2.75-2.61 (m, 2H), 1.82 (d,J= 8.0 Hz, 6H), 1.54 (s, 3H), 1.45 (s, 3H), 1.40 (d,J= 7.2 Hz, 3H), 1.35 (t,J= 7.4 Hz, 3H). Process 1, intermediate 3 and intermediates 44 81 555 1 H-NMR (400 MHz, CD3OD): δ ppm 9.43 (s, 1H), 9.05 (s, 1H), 8.49 (s, 1H), 8.18 (d,J= 8.4 Hz, 1H), 7.37 (d,J= 8.8 Hz, 1H), 5.44-5.40 (m, 1H), 4.67-4.66 (m, 1H), 3.84-3.80 (m, 1H), 3.01-2.90 (m, 3H), 2.90 (s, 6H), 2.75-2.70 (m, 2H), 1.95 (d,J= 6.0 Hz, 6H), 1.52 (d,J= 7.2 Hz, 3H), 1.47 (d,J= 6.8 Hz, 3H). Process 1, intermediate 1 and intermediates 64 82 555 1H-NMR (400 MHz, CD3OD): δ ppm 9.41 (d,J= 5.6 Hz, 1H), 9.11 (s, 1H), 8.52 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 8.09 (s, 1H), 7.32 (d,J= 8.8 Hz, 1H), 5.66-5.61 (m, 1H), 4.70-4.62 (m, 1H), 4.15-4.05 (m, 1H), 3.07-3.00 (m, 3H), 2.79-2.72 (m, 2H), 1.85 (d,J= 5.6 Hz, 6H), 1.51 (d,J= 7.2 Hz, 3H), 1.45 (d, J = 6.4 Hz, 3H). Process 1, intermediate 1 and intermediates 63 83 556 1 H-NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 9.14 (s, 1H), 8.18-8.1 (m, 2H), 7.31 (d,J= 8.8 Hz, 1H), 5.59-5.50 (m, 1H), 4.72-4.63 (m, 1H), 3.35-3.32 (m, 1H), 3.29-3.25 (m, 1H), 3.07-3.00 (m, 1H), 2.99 (s, 3H), 2.49-2.38 (m, 1H), 2.38-2.28 (m, 2H), 2.23-2.12 (m, 1H), 1.96-1.84 (m, 2H), 1.78 (s, 3H), 1.50 (d,J= 7.2 Hz, 3H), 1.46 (d,J= 6.8 Hz, 3H), 1.04 (t,J= 7.4 Hz, 3H), 0.75 (t,J= 7.2 Hz, 3H). Process 1, intermediate 1 and intermediates 65 The second dissolution isomer from chiral SFC Tube Column: DAICEL CHIRALPAK AS (250 mm × 30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​MEOH]; B%: 50%-50%) 84 556 1 H-NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 9.14 (s, 1H), 8.18-8.11 (m, 2H), 7.31 (d,J= 8.8 Hz, 1H), 5.59-5.50 (m, 1H), 4.72-4.62 (m, 1H), 3.35 (s, 1H), 3.29 (s, 1H), 3.07-3.01 (m, 1H), 2.99 (s, 3H), 2.48-2.26 (m, 3H), 2.23-2.11 (m, 1H), 1.98-1.83 (m, 2H), 1.77 (s, 3H), 1.50 (d,J= 7.2 Hz, 3H), 1.46 (d,J= 6.8 Hz, 3H), 1.04 (t,J= 7.4 Hz, 3H), 0.75 (t,J= 7.2 Hz, 3H). Process 1, intermediate 1 and intermediates 65 The first dissolution isomer from chiral SFC Tube Column: DAICEL CHIRALPAK AS (250 mm × 30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​MEOH]; B%: 50%-50%) 85 556 1H-NMR (400 MHz, CD3OD): δ ppm 9.45 (s, 1H), 9.17 (s, 1H), 8.19-8.17 (m, 1H), 7.95 (s, 1H), 7.27-7.25 (m, 1H), 5.67 (s, 1H), 3.36 (s, 1H), 3.22 (s, 2H), 3.01 (s, 3H), 2.68-2.61 (m, 1H), 2.35-2.67 (m, 3H), 2.02 (s, 3H), 1.53 (s, 9H), 1.37-0.98 (m, 3H), 0.90 (s, 3H). Process 1, intermediate 5 and intermediate products 69 86 556 1 H-NMR (400 MHz, CD3OD): δ ppm 9.47 (s, 1H), 8.95 (s, 1H), 8.20-8.18 (m, 1H), 7.93 (s, 1H), 7.41-7.39 (m, 1H), 5.67 (s, 1H), 4.71 (s, 1H), 3.36 (s, 1H), 3.01 (s, 4H), 2.72-2.66 (m, 1H), 2.36 (s, 2H), 2.25-2.19 (m, 1H), 2.00 (s, 3H), 1.52 (s, 6H), 1.46 (s, 3H), 1.41-1.29 (m, 2H), 1.03-0.98 (m, 1H), 0.89 (s, 3H). Process 1, intermediate 1 and intermediates 69 87 556 1H-NMR (400 MHz, CD3OD): δ ppm 9.35 (d,J= 8.8 Hz, 2H), 8.15-8.12 (m, 2H), 7.19 (d,J= 8.4 Hz, 1H), 5.73-5.65 (m, 1H), 3.41-3.34 (m, 1H), 3.21 (s, 2H), 2.93 (s, 3H), 2.45-2.33 (m, 2H), 2.23-2.08 (m, 2H), 1.76 (s, 3H), 1.53 (s, 6H), 1.51-1.49 (m, 6H), 0.77-0.74 (m, 3H). Process 1, intermediate 5 and intermediate products 53 88 556 1 H-NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 8.66 (s, 1H), 8.17-8.15 (m, 2H), 7.53 (d,J= 8.4 Hz, 1H), 5.71-5.66 (m, 1H), 4.31 (s, 2H), 3.39-3.33 (m, 1H), 2.93 (s, 3H), 2.45-2.34 (m, 2H), 2.16-2.08 (m, 2H), 1.74 (s, 3H), 1.51-1.49 (m, 6H), 1.46 (s, 6H), 0.75-0.71 (m, 3H). Process 1, intermediate 14 and intermediate products 53 89 556 1H-NMR (400 MHz, CD3OD): δ ppm 9.37 (s, 1H), 9.18 (s, 1H), 8.26-8.06 (m, 2H), 7.31 (d,J= 8.4 Hz, 1H), 5.78-5.61 (m, 1H), 4.71-4.60 (m, 1H), 3.43-3.36 (m, 1H), 3.17-2.99 (m, 3H), 2.47-2.35 (m, 1H), 2.18-2.05 (m, 1H), 1.80 (d,J= 4.8 Hz, 6H), 1.54-1.43 (m, 12H), 1.34-1.28 (m, 3H). Process 1, intermediate 1 and intermediates 70 90 556 1 H-NMR (400 MHz, CD3OD): δ ppm 9.38 (s, 1H), 9.17 (s, 1H), 8.19-8.12 (m, 2H), 7.30 (d,J= 8.4 Hz, 1H), 5.74-5.66 (m, 1H), 4.71-4.64 (m, 1H), 3.41-3.33 (m, 1H), 3.08-3.00 (m, 1H), 2.93 (s, 3H), 2.47-2.34 (m, 2H), 2.21-2.07 (m, 2H), 1.74 (s, 3H), 1.54-1.48 (m, 9H), 1.46 (d,J= 6.8 Hz, 3H), 0.74 (t, J = 7.2 Hz, 3H). Process 1, intermediate 1 and intermediates 53 91 556 1H-NMR (400 MHz, CD3OD): δ ppm 9.39 (s, 1H), 9.28 (s, 1H), 8.17-8.12 (m, 2H), 7.25 (d,J= 8.8 Hz, 1H), 5.75-5.67 (m, 1H), 3.40-3.33 (m, 1H), 3.07-3.00 (m, 1H), 2.93 (s, 3H), 2.44-2.37 (m, 1H), 2.18-2.08 (m, 1H), 1.88 (d,J= 8.8 Hz, 6H), 1.54 (s, 3H), 1.52-1.48 (m, 6H), 1.45 (s, 3H), 1.40 (d, J = 7.2 Hz, 3H). Process 1, intermediate 3 and intermediates 52 92 556 1 H NMR (400 M Hz, CD3OD): δ ppm 9.43 (s, 1H), 9.02 (s, 1H), 8.16 (d,J= 8.4 Hz, 1H), 8.04 (s, 1H), 7.34 (d,J= 8.8 Hz, 1H), 5.71-5.57 (m, 1H), 4.75-4.62 (m, 1H), 3.30-3.22 (m, 2H), 3.17-3.08 (m, 2H), 3.05-2.95 (m, 1H), 2.63-2.50 (m, 1H), 2.40-2.29 (m, 2H), 2.28-2.19 (m, 1H), 1.88 (s, 3H), 1.50 (t,J= 6.8 Hz, 6H), 1.46 (d,J= 6.4 Hz, 3H), 1.33 (t,J= 7.4 Hz, 3H), 0.79 (t,J= 7.4 Hz, 3H). Process 1, intermediate 1 and intermediates 73 93 556 1H NMR (400 M Hz, CD3OD): δ ppm 9.45 (s, 1H), 8.97 (s, 1H), 8.18 (d,J= 8.8 Hz, 1H), 7.99 (s, 1H), 7.37 (d,J= 8.8 Hz, 1H), 5.73-5.58 (m, 1H), 4.74-4.64 (m, 1H), 3.30-3.21 (m, 2H), 3.17-3.08 (m, 2H), 3.06-2.95 (m, 1H), 2.69-2.55 (m, 1H), 2.41-2.20 (m, 3H), 1.94 (s, 3H), 1.55-1.43 (m, 9H), 1.34 (t,J= 7.4 Hz, 3H), 0.83 (t,J= 7.4 Hz, 3H). Process 1, intermediate 1 and intermediates 72 94 556 1 H-NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1H), 9.29 (s, 1H), 8.54 (s, 1H), 8.14 (d,J= 8.4 Hz, 1H), 8.12 (s, 1H), 7.23 (d,J= 8.8 Hz, 1H), 5.68-5.58 (m, 1H), 3.42-3.33 (m, 2H), 3.06-2.98 (m, 4H), 2.50-2.40 (m, 1H), 2.39-2.28 (m, 2H), 2.28-2.18 (m, 1H), 1.83-1.78 (m, 3H), 1.54 (s, 3H), 1.51 (d,J= 6.0 Hz, 3H), 1.45 (s, 3H), 1.39 (d,J= 7.2 Hz, 3H), 0.78 (t,J= 7.4 Hz, 3H). Process 1, intermediate 3 and intermediates 31 95 556 1H-NMR (400 MHz, CD3OD): δ ppm 9.42 (s, 1H), 9.23 (s, 1H), 8.14 (d,J= 8.4 Hz, 1H), 8.07 (s, 1H), 7.25 (d,J= 8.8 Hz, 1H), 5.71-5.57 (m, 1H), 3.41-3.3 (m, 2H), 3.06-2.95 (m, 4H), 2.57-2.47 (m, 1H), 2.40-2.21 (m, 3H), 1.86 (s, 3H), 1.57-1.49 (m, 6H), 1.45 (s, 3H), 1.39 (d,J= 7.2 Hz, 3H), 0.80 (t, J = 7.4 Hz, 3H). Process 1, intermediate 3 and intermediates 54 96 556 1 H NMR (400 MHz, CD3OD): δ ppm 9.46 (s, 1H), 8.46 (s, 1H), 8.18 (d,J= 8.8 Hz, 1H), 8.06 (s, 1H), 8.18 (d,J= 8.8 Hz, 1H), 5.67-5.60 (m, 1H), 4.65-4.51 (m, 1H), 3.43-3.32 (m, 2H), 3.01 (s, 3H), 2.56-2.45 (m, 1H), 2.42-2.30 (m, 2H), 2.22-2.12 (m, 1H), 1.85 (s, 3H), 1.54-1.42 (m, 9H), 1.31 (s, 3H), 0.80 - 0.73 (m, 3H). Process 1, intermediate 97 and intermediates 31 97 556 1H NMR (400 MHz, CD3OD): δ ppm 9.43 (s, 1H), 8.55 (s, 1H), 8.16 (d,J= 8.8 Hz, 1H), 8.11 (s, 1H), 7.58 (d,J= 8.8 Hz, 1H), 5.67-5.60 (m, 1H), 4.60-4.51 (m, 1H), 3.40-3.32 (m, 2H), 3.01 (s, 3H), 2.45-2.30 (m, 3H), 2.22-2.12 (m, 1H), 1.77 (s, 3H), 1.54-1.40 (m, 9H), 1.30 (s, 3H), 0.76-0.70 (m, 3H). Process 1, intermediate 97 and intermediates 54 98 556 1 H-NMR (400 MHz, CD3OD): δ ppm 9.38 (d,J= 3.2 Hz, 2H), 8.21 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 7.23 (d,J= 8.8 Hz, 1H), 5.65-5.55 (m, 1H), 3.29-3.27 (m, 2H), 3.17-3.06 (m, 2H), 3.05-2.95 (m, 1H), 2.35-2.2.22 (m, 2H), 1.78 (d,J= 8.0 Hz, 6H), 1.48 (d,J= 6.0 Hz, 3H), 1.43 (s, 3H), 1.38 (d,J= 6.8 Hz, 3H), 1.32 (t,J= 7.6 Hz, 3H). Process 1, intermediate 3 and intermediates 71 The second dissolution isomer from chiral SFC Tube Column: Daicel Chiralpak AD (250 mm × 30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​MEOH]; B%: 50%-50%) 99 556 1 H-NMR (400 MHz, CD3OD): δ ppm 9.38 (d,J= 4.4 Hz, 2H), 8.18 (s, 1H), 8.13 (d,J= 8.8 Hz, 1H), 7.20 (d,J= 8.4 Hz, 1H), 5.65-5.55 (m, 1H), 3.26-3.22 (m, 2H), 3.17-3.06 (m, 2H), 3.05-2.95 (m, 1H), 2.35-2.2.22 (m, 2H), 1.78 (d,J= 8.0 Hz, 6H), 1.48 (d,J= 6.0 Hz, 3H), 1.43 (s, 3H), 1.38 (d,J= 6.8 Hz, 3H), 1.32 (t,J= 7.6 Hz, 3H). Process 1, intermediate 3 and intermediates 71 The first dissolution isomer from chiral SFC Tube Column: Daicel Chiralpak AD (250 mm × 30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​MEOH]; B%: 50%-50%) 100 566 1H NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1 H), 8.29 (s, 1 H), 8.15 (d,J= 8.8 Hz, 1 H), 8.05 (s, 1 H), 7.63 (d,J= 8.8 Hz, 1 H), 5.5-5.37 (m, 1 H), 3.90-3.76 (m, 1 H), 3.02-2.95 (m, 2 H), 2.93 (s, 3 H), 2.73-2.64 (m, 2 H), 2.42-2.32 (m, 1 H), 2.20-2.09 (m, 1 H), 1.78 (s, 3 H), 1.58-1.51 (m, 2 H), 1.41 (s, 6 H), 1.28 (d,J= 2.4 Hz, 2 H), 0.79-0.72 (m, 3 H). Process 1, intermediate 15 and intermediate products twenty four 101 566 1 H-NMR (400 MHz, CD3OD): δ ppm 9.33 (s, 1H), 8.91 (s, 1H), 8.20 (s, 1H), 8.12 (d,J= 8.8 Hz, 1H), 7.21 (d,J= 8.4 Hz, 1H), 5.56-5.35 (m, 1H), 3.90-3.77 (m, 2H), 3.20-3.12 (m, 1H), 3.10-3.02 (m, 2H), 3.01-2.92 (m, 2H), 2.74-2.64 (m, 2H), 1.53 (s, 3H), 1.49 (d,J= 7.2 Hz, 3H), 1.44 (s, 4H), 1.37-1.33 (m, 3H), 0.75-0.66 (m, 1H), 0.58-0.49 (m, 1H), 0.46-0.31 (m, 2H). Step 2, intermediate 3 and intermediates 74 The final compound derived from the first dissolution isomer by preparative HPLC Tube Column: Phenomenex Gemini-NX C18 75×30 mm×3 µm; Moving phase: [Water (0.05% ammonia v / v) - ACN]; B%: 26%-56%), which is after step 1 of synthesis method 2. 102 566 1 H-NMR (400 MHz, CD3OD): δ ppm 9.37 (s, 1H), 9.28 (s, 1H), 8.16-8.08 (m, 2H), 7.22 (d,J= 8.8 Hz, 1H), 5.53-534 (m, 1H), 3.93-3.77 (m, 1H), 3.06-2.91 (m, 3H), 2.75-2.64 (m, 2H), 2.61-2.51 (m, 1H), 1.86 (d,J= 8.8 Hz, 6H), 1.53 (s, 3H), 1.44 (s, 3H), 1.40 (d,J= 7.2 Hz, 3H), 1.17-1.04 (m, 4H) Process 1, intermediate 3 and intermediates 32 103 568 1 H NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1H), 8.44 (s, 1H), 8.18-8.12 (m, 2H), 7.56 (d,J= 8.8 Hz, 1H), 5.74-5.65 (m, 1H), 3.41-3.32 (m, 1H), 2.93 (s, 3H), 2.45-2.37 (m, 1H), 2.16-2.08 (m, 1H), 1.78 (s, 6H), 1.59-1.54 (m, 2H), 1.52-1.46 (m, 6H), 1.44-1.37 (m, 6H), 1.31-1.26 (m, 2H). Process 1, intermediate 15 and intermediate products 52 104 568 1 H NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 8.37 (s, 1H), 8.16 (d,J= 8.8 Hz, 1H), 8.09 (s, 1H), 7.59 (d,J= 8.8 Hz, 1H), 5.75-5.65 (m, 1H), 4.66-4.60 (m, 1H), 3.40-3.33 (m, 1H), 2.93 (s, 3H), 2.46-2.31 (m, 2H), 2.18-2.08 (m, 1H), 1.77 (s, 3H), 1.67-1.60 (m, 1H), 1.53-1.45 (m, 7H), 1.38 (d,J= 6.8 Hz, 3H), 1.27-1.18 (m, 2H), 0.76 (t,J= 7.2 Hz, 3H). Process 1, intermediate 12 and intermediates 53 105 568 1 H NMR (400 M Hz, CD3OD): δ ppm 9.41 (s, 1H), 8.40 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 8.13 (s, 1H), 7.58 (d,J= 8.8 Hz, 1H), 5.69-5.54 (m, 1H), 3.41-3.33 (m, 2H), 3.00 (s, 3H), 2.43-2.24 (m, 3H), 2.18-2.00 (m, 1H), 1.72 (s, 3H), 1.60-1.53​​ (m, 2H), 1.51 (d,J= 6.0 Hz, 3H), 1.42 (s, 6H), 1.28 (d,J= 2.8 Hz, 2H), 0.74 (t,J= 7.4 Hz, 3H). Process 1, intermediate 15 and intermediate products 31 106 568 1H-NMR (400 MHz, CD3OD): δ ppm 9.39 (s, 1H), 9.15 (s, 1H), 8.18-8.11 (m, 2H), 7.30 (d,J= 8.4 Hz, 1H), 5.68-5.59 (m, 1H), 4.71-4.64 (m, 1H), 3.40-3.33 (m, 2H), 3.07-2.97 (m, 1H), 2.70-2.60 (m, 1H), 2.44-2.33 (m, 3H), 2.22-2.11 (m, 1H), 1.75 (s, 3H), 1.53-1.48 (m, 6H), 1.46 (d,J= 6.4 Hz, 3H), 1.14-1.03 (m, 4H), 0.74 (t,J= 7.2 Hz, 3H). Process 1, intermediate 1 and intermediates 75 The second dissolution isomer from chiral SFC Tube Column: Daicel Chiralpak AD (250 mm×30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​ETOH]; B%: 50%-50%) 107 568 1 H-NMR (400 MHz, CD3OD): δ ppm 9.39 (s, 1H), 9.17 (s, 1H), 8.18-8.12 (m, 2H), 7.30 (d,J= 8.8 Hz, 1H), 5.67-5.59 (m, 1H), 4.71-4.64 (m, 1H), 3.38-3.32 (m, 2H), 3.08-2.99 (m, 1H), 2.71-2.62 (m, 1H), 2.43-2.32 (m, 3H), 2.21-2.10 (m, 1H), 1.75 (s, 3H), 1.53-1.48 (m, 6H), 1.46 (d,J= 6.8 Hz, 3H), 1.16-1.09 (m, 2H), 1.08-1.02 (m, 2H), 0.74 (t,J= 7.2 Hz, 3H). Process 1, intermediate 1 and intermediates 75 The first dissolution isomer from chiral SFC Tube Column: Daicel Chiralpak AD (250 mm×30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​ETOH]; B%: 50%-50%) 108 568 1 H-NMR (400 MHz, CD3OD): δ ppm 9.46 (s, 1H), 9.36 (s, 1H), 8.30 (s, 1H), 8.14 (d,J= 8.8 Hz, 1H), 7.23 (d,J= 8.8 Hz, 1H), 5.75-5.65 (m, 1H), 3.40-3.34 (m, 1H), 3.21 (s, 2H), 2.94 (s, 3H), 2.46-2.38 (m, 1H), 2.18-2.09 (m, 1H), 1.70 (s, 3H), 1.65-1.59 (m, 1H), 1.55-1.48 (m, 12H), 0.70-0.49 (m, 4H). Process 1, intermediate 5 and intermediate products 76 109 568 1H-NMR (400 MHz, CD3OD): δ ppm 9.37 (s, 1H), 9.28 (s, 1H), 8.29 (s, 1H), 8.14 (d,J= 8.8 Hz, 1H), 7.35 (d,J= 8.8 Hz, 1H), 5.74-5.65 (m, 1H), 4.69-4.60 (m, 1H), 3.40-3.34 (m, 1H), 3.06-2.98 (m, 1H), 2.93 (s, 3H), 2.46-2.38 (m, 1H), 2.17-2.08 (m, 1H), 1.70-1.60 (m, 4H), 1.53-1.44 (m, 12H), 0.66-0.43 (m, 4H). Process 1, intermediate 1 and intermediates 76 110 568 1 H-NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 8.69 (s, 1H), 8.53 (s, 1H), 8.35 (s, 1H), 8.15 (br d,J= 8.6 Hz, 1H), 7.34 (d,J= 8.6 Hz, 1H), 5.83-5.71 (m, 1H), 4.27 (br d,J= 8.8 Hz, 1H), 3.44-3.37 (m, 1H), 3.23-3.12 (m, 1H), 2.96 (s, 3H), 2.45 (td,J= 5.0, 14.4 Hz, 1H), 2.17 (td,J= 7.6, 14.8 Hz, 1H), 1.68 (br d,J= 2.4 Hz, 1H), 1.58-1.49 (m, 12H), 1.45 (s, 3H), 0.97-0.88 (m, 1H), 0.76 (br t,J= 8.4 Hz, 1H), 0.57 (br s, 2H) Process 1, intermediate 3 and intermediates 78 111 568 1H-NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 9.11 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 7.98 (s, 1H), 7.29 (d,J= 8.8 Hz, 1H), 5.39 (q,J= 7.4 Hz, 1H), 3.38-3.32 (m, 2H), 3.08 (q,J= 7.6 Hz, 2H), 3.00 (q,J= 7.2 Hz, 1H), 2.91 (dtd,J= 2.8, 7.2, 9.6 Hz, 2H), 2.70-2.55 (m, 1H), 2.24-2.13 (m, 2H), 2.02 (d,J= 13.0 Hz, 6H), 1.53 (s, 3H), 1.45 (s, 3H), 1.42-1.33 (m, 6H) Process 1, intermediate 3 and intermediates 80 The second dissolution isomer from chiral SFC Tube Column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 µm); Moving phase: [ACN / EtOH (0.1%NH3H2O)];B%:50%-50%) 112 568 1 H-NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 9.30 (s, 1H), 8.18-8.07 (m, 2H), 7.23 (d,J= 8.8 Hz, 1H), 5.55 (t,J= 6.0 Hz, 1H), 3.39 (d,J= 7.6 Hz, 2H), 3.15-2.98 (m, 4H), 2.65-2.56 (m, 4H), 1.85 (d,J= 8.8 Hz, 6H), 1.54 (s, 3H), 1.46 (s, 3H), 1.42-1.35 (m, 6H) Process 1, intermediate 3 and intermediates 80 The first dissolution isomer from chiral SFC Tube Column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 µm); Moving phase: [ACN / EtOH (0.1%NH3H2O)]; B%: 50%-50%) 113 568 1 H-NMR (400 MHz, CD3OD): δ ppm 9.39 (s, 1H), 9.35 (s, 1H), 8.15-8.10 (m, 2H), 7.20 (d,J= 8.4 Hz, 1H), 5.58-5.55 (m, 1H), 3.43 (d,J= 7.46 Hz, 2H), 3.12-2.99 (m, 2H), 2.97 (s, 3H), 2.64-2.57 (m, 4 H), 2.40-2.30 (m, 1H), 2.24-2.14 (m, 1H), 1.73 (s, 3H), 1.54 (s, 3H), 1.45 (s, 3H), 1.38 (d,J= 7.2 Hz, 3H), 0.78-0.68 (m, 3H). Process 1, intermediate 3 and intermediates 49 114 568 1 H-NMR (400 MHz, 6d-DMSO): δ ppm 10.73 (s, 1H), 9.50 (s, 1H), 9.30 (s, 1H), 8.17-8.13 (m, 1H), 8.07 (d,J= 8.8 Hz, 1H), 7.31 (d,J= 8.8 Hz, 1H), 5.33-5.23 (m, 1H), 3.36 (d,J= 7.6 Hz, 2H), 3.01-2.96 (m, 1H), 2.94 (s, 3H), 2.82-2.72(m, 2H), 2.17-2.01 (m, 5 H), 1.63-1.56 (m, 3H), 1.44 (s, 3H), 1.37 (s, 3H), 1.33-1.25 (m, 3H), 0.68-0.61 (m, 3H)。 Process 1, intermediate 3 and intermediates 48 115 568 1H-NMR (400 MHz, CD3OD): δ ppm 9.31 (s, 1H), 8.83 (s, 1H), 8.14-8.06 (m, 2H), 7.22 (d,J= 8.4 Hz, 1H), 5.46-5.38 (m, 1H), 4.48-4.44 (m, 1H), 3.92-3.73 (m, 1H), 3.16-3.10 (m, 1H), 3.09-3.02 (m, 2H), 3.00-2.91 (m, 2H), 2.75-2.63 (m, 2H), 2.03-1.78 (m, 2H), 1.51 (s, 3H), 1.48 (d,J= 7.2 Hz, 3H), 1.44 (s, 3H), 1.42-1.26 (m, 5H), 0.99-0.93 (m, 3H). Step 2, intermediate 3 and intermediates 81 116 568 1 H NMR (400 MHz, CD3OD): δ ppm 9.38 (s, 1H), 9.31 (s, 1H), 8.15-8.10 (m, 2H), 7.23 (d,J=8.8 Hz, 1H), 5.48-5.40 (m, 1H), 3.95-3.80 (m, 1H), 3.24-3.20 (m, 1H), 3.05-2.95 (m, 3H), 2.71-2.60 (m, 2H), 1.85 (d,J=8.8 Hz, 6H), 1.54 (s, 3H), 1.45 (s, 3H), 1.40 (d,J=7.2 Hz, 3H), 1.36 (d,J=6.8 Hz, 6H). Process 1, intermediate 3 and intermediates 83 117 568 1H-NMR (400 MHz, CD3OD): δ ppm 9.35 (s, 2H), 8.15-8.11 (m, 2H), 7.19 (d,J= 8.8 Hz, 1H), 5.47-5.40 (m, 1H), 3.87-3.78 (m, 1H), 3.09-3.02 (m, 3H), 3.00-2.93 (m, 2H), 2.73-2.65 (m, 2H), 2.42-2.30 (m, 1H), 2.22-2.09 (m, 1H), 1.73 (d,J= 6.0 Hz, 3H), 1.54 (s, 3H), 1.45 (s, 3H), 1.40-1.33 (m, 6H), 0.75-0.71 (m, 3H). Process 1, intermediate 3 and intermediates 45 118 569 1 H-NMR (400 MHz, CD3OD): δ ppm 9.43 (s, 1H), 9.21 (s, 1H), 8.52 (s, 1H), 8.16 (d,J= 8.4 Hz, 1H), 8.05 (s, 1H), 7.28 (d,J= 8.4 Hz, 1H), 5.44-5.40 (m, 1H), 3.80-3.75 (m, 1H), 3.08-3.92 (m, 3H), 2.89 (s, 6H), 2.75-2.66 (m, 2H), 1.97 (d,J= 9.8 Hz, 6H), 1.54 (s, 3H), 1.46 (s, 3H), 1.41 (d,J= 7.2 Hz, 3H). Process 1, intermediate 3 and intermediates 64 119 569 1H-NMR (400 MHz, CD3OD): δ ppm 9.42 (s, 1H), 9.29 (s, 1H), 8.55 (s, 1H), 8.14 (d,J= 8.8 Hz, 1H), 8.10 (s, 1H), 7.24 (d,J= 8.8 Hz, 1H), 5.67-5.61 (m, 1H), 4.16-4.07 (m, 1H), 3.10-2.98 (m, 3H), 2.82-2.73 (m, 2H), 1.87 (d,J= 9.2 Hz, 6H), 1.54 (s, 3H), 1.45 (s, 3H), 1.40 (d,J= 7.6 Hz, 3H). Process 1, intermediate 3 and intermediates 63 120 570 1 H-NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 8.98 (s, 1H), 8.51(s, 1H), 8.13 (d,J= 8.8 Hz, 1H), 7.99 (s, 1H), 7.33 (d,J= 4.8 Hz, 1H), 5.56-5.50 (m, 1H), 4.68-4.63 (m, 1H), 4.00 (s, 2H), 3.41 (d,J= 7.6 Hz, 1H), 3.37 (s, 3H), 3.31-2.97 (m, 2H), 2.96 (s, 3H), 2.59 (t,J= 6.4 Hz, 4H), 1.88 (s, 3H), 1.47 (dd,J=10, 7.2 Hz, 6H). Process 1, intermediate 1 and intermediates 51 121 570 1H-NMR (400 MHz, CD3OD): δ ppm 9.39 (s, 1H), 9.09 (s, 1H), 8.51(s, 1H), 8.17 (d,J= 8.8 Hz, 1H), 8.07 (s, 1H), 7.35 (d,J= 8.8 Hz, 1H), 5.40-5.36 (m, 1H), 4.71-4.65 (m, 1H), 4.00-3.90 (m, 2H), 3.39 (s, 1H), 3.38 (s, 3H), 3.37 (s, 1H), 3.06-3.01 (m, 1H), 2.97 (s, 3H), 2.95-2.87 (m, 2H), 2.66-2.61 (m, 1H), 2.22-2.15 (m, 2H), 1.84 (s, 3H), 1.50 (dd,J= 12.4, 7.2 Hz, 6H). Process 1, intermediate 1 and intermediates 50 122 570 1 H-NMR (400 MHz, CD3OD): δ ppm 9.37 (s, 1H), 9.12 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 8.11-8.08 (m, 1H), 7.32 (d,J= 8.8 Hz, 1H), 5.44 (J= 7.2 Hz, 1H), 4.72-4.63 (m, 1H), 4.58 (s, 1H), 4.03-3.88 (m, 2H), 3.87-3.78 (m, 1H), 3.36 (s, 3H), 3.06 (q,J= 7.6 Hz, 2H), 3.03-2.91 (m, 3H), 2.74-2.64 (m, 2H), 1.80 (s, 3H), 1.49 (dd,J= 6.8, 13.2 Hz, 6H), 1.35 (t,J= 7.6 Hz, 3H) Process 1, intermediate 1 and intermediates 84 123 570 1H-NMR (400 MHz, CD3OD): δ ppm 9.37 (s, 1H), 9.33 (s, 1H), 8.15-8.10 (m, 2H), 7.22 (d,J= 8.8 Hz, 1H), 5.48-5.40 (m, 1H), 3.95 (s, 2H), 3.85-3.80 (m, 1H), 3.37 (s, 3H), 3.05-2.95 (m, 6H), 2.70-2.65 (m, 2H), 1.80 (s, 3H), 1.54 (s, 3H), 1.47-1.35(m, 6H). Process 1, intermediate 3 and intermediates 85 124 570 1 H-NMR (400 MHz, CD3OD): δ ppm 9.38 (s, 1H), 9.32 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 8.09 (s, 1H), 7.21 (d,J= 8.8 Hz, 1H), 5.77-5.65 (m, 1H), 3.36 (m, 1H), 3.23 (s, 2H), 2.93 (s, 3H), 2.49-2.36 (m, 2H), 2.24-2.07 (m, 2H), 1.83 (s, 3H), 1.53 (d,J= 2.4 Hz, 6H), 1.50 (m, 6H), 1.27 (m, 1H), 1.10-0.97 (m, 1H), 0.88-0.82 (m, 3H). Process 1, intermediate 5 and intermediate products 67 125 570 1H-NMR (400 MHz, CD3OD): δ ppm 9.43 (s, 1H), 9.06 (s, 1H), 8.54 (s, 1H), 8.17 (d,J= 8.8 Hz, 1H), 8.01 (s, 1H), 7.37 (d,J= 8.4 Hz, 1H), 5.79-5.66 (m, 1H), 4.76-4.64 (m, 1H), 3.42-3.34 (m, 1H), 3.07-2.97 (m, 1H), 2.94 (s, 3H), 2.66-2.52 (m, 1H), 2.42 (m, 1H), 2.23-2.09 (m, 2H), 1.92 (s, 3H), 1.57-1.48 (m, 9H) 1.46 (d,J= 6.4 Hz, 3H), 1.38-1.27 (m, 1H), 1.07-0.93 (m, 1H), 0.91-0.82 (m, 3H). Process 1, intermediate 1 and intermediates 67 126 570 1 H-NMR (400 MHz, CD3OD): δ ppm 9.40 (d,J= 15.2 Hz, 2H), 8.17-8.12 (m, 2H), 7.19 (d,J= 8.8 Hz, 1H), 5.64-5.59 (m, 1H), 3.37-3.33 (m, 1H), 3.09-3.04 (m, 1H), 3.00 (s, 3H), 2.41-2.30 (m, 3H), 2.15-2.07 (m, 1H), 1.73 (s, 3H), 1.55 (s, 3H), 1.51 (d,J= 6.0 Hz, 3H), 1.44 (s, 3H), 1.40 (d,J= 6.8 Hz, 3H), 1.36-1.17 (m, 2H), 1.05-0.96 (m, 1H), 0.84-0.80 (m, 3H). Process 1, intermediate 3 and intermediates 69 127 570 1 H-NMR (400 MHz, CD3OD): δ ppm 9.36 (s, 1H), 9.15 (s, 1H), 8.28-8.00 (m, 2H), 7.29 (d,J= 8.8 Hz, 1H), 5.80-5.61 (m, 1H), 4.73-4.56 (m, 1H), 3.45-3.35 (m, 1H), 3.14-3.06 (m, 2H), 3.06-2.98 (m, 1H), 2.49-2.30 (m, 2H), 2.23-2.03 (m, 2H), 1.73 (s, 3H), 1.51-1.43 (m, 12H), 1.34-1.27 (m, 3H), 0.78-0.68 (m, 3H). Process 1, intermediate 1 and intermediates 86 128 570 1 H-NMR (400 MHz, CD3OD): δ ppm 9.36 (d,J= 3.2 Hz, 2H), 8.20 (s, 1H), 8.12 (d,J= 8.8 Hz, 1H), 7.22 (d,J= 8.8 Hz, 1H), 5.74-5.63 (m, 1H), 3.43-3.34 (m, 1H), 3.14-2.99 (m, 3H), 2.45-2.36 (m, 1H), 2.19-2.06 (m, 1H), 1.80 (d,J= 7.6 Hz, 6H), 1.53 (s, 3H), 1.50-1.46(m, 6H), 1.45(s, 3H), 1.39 (d,J= 7.2 Hz, 3H), 1.33-1.28 (m, 3H). Process 1, intermediate 3 and intermediates 70 129 570 1H-NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1H), 9.28 (s, 1H), 8.14 (d,J= 8.4 Hz, 1H), 8.11 (s, 1H), 7.24 (d,J= 8.8 Hz, 1H), 5.75-5.66 (m, 1H), 3.42-3.35 (m, 1H), 3.05-2.99 (m, 1H), 2.93 (s, 3H), 2.54-2.38 (m, 2H), 2.30-2.20 (m, 1H), 2.18-2.08 (m, 1H), 1.82 (s, 3H), 1.58-1.48 (m, 9H), 1.46 (s, 3H), 1.39 (d,J= 7.2 Hz, 3H), 0.78 (t,J= 7.2 Hz, 3H). Process 1, intermediate 3 and intermediates 53 130 570 1 H NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 8.59 (s, 1H), 8.16 (d,J= 8.8 Hz, 1H), 8.14 (s, 1H), 7.57 (d,J= 8.8 Hz, 1H), 5.75-5.60 (m, 1H), 4.63-4.53 (m, 1H), 3.41-3.33 (m, 1H), 2.93 (s, 3H), 2.47-2.31 (m, 2H), 2.18-2.02 (m, 2H), 1.75 (s, 3H), 1.53-1.42 (m, 12H), 1.31 (s, 3H), 0.76-0.70 (m, 3H). Process 1, intermediate 97 and intermediates 53 131 570 1H NMR (400 MHz, CD3OD): δ =9.29 (s, 1H), 9.22 (s, 1H), 8.06 (d,J= 8.8 Hz, 1H), 8.02 (s, 1H), 7.14 (d,J= 8.8 Hz, 1H), 5.45~5.33 (m, 1H), 3.37 - 3.30 (m, 1H), 3.08 - 3.06 (m, 2H), 2.96 - 2.92 (m, 2H), 2.62~2.55 (m, 1H), 1.75 (d,J= 7.6 Hz, 7H), 1.44 (s, 3H), 1.35 (d,J= 8.4 Hz, 6H), 1.29 (d,J= 7.2 Hz, 3H), 1.27 - 1.26 (m, 3H), 1.22 (d,J= 7.2 Hz, 3H) Process 1, intermediate 3 and intermediates 87 The first of the three peaks of chiral SFC Tube Column: Daicel Chiralpak AS (250 mm × 30 mm, 10 µm); Moving phase: [0.1% [NH3H2O ​​ETOH]; B%: 40%-40%), followed by the second dissolution isomer after the additional chiral SFC. Column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​MEOH]; B%: 50%-50%) 132 570 1H NMR (400 M Hz, CD3OD): δ ppm 9.43 (s, 1H), 9.20 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 8.04 (s, 1H), 7.26 (d,J= 8.4 Hz, 1H), 5.71-5.57 (m, 1H), 3.30-3.23 (m, 2H), 3.17-3.08 (m, 2H), 3.04-2.94 (m, 1H), 2.64-2.51 (m, 1H), 2.42-2.24 (m, 3H), 1.94-1.87 (m, 3H), 1.57-1.49 (m, 6H), 1.48-1.43 (m, 3H), 1.42-1.37 (m, 3H), 1.34 (t,J= 7.4 Hz, 3H), 0.81 (t,J= 7.6 Hz, 3H). Process 1, intermediate 3 and intermediates 73 133 570 1 H NMR (400 M Hz, CD3OD): δ ppm 9.42 (s, 1H), 9.21 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 8.05 (s, 1H), 7.26 (d,J= 8.8 Hz, 1H), 5.70-5.57 (m, 1H), 3.30-3.21 (m, 2H), 3.18-3.08 (m, 2H), 3.04-2.95 (m, 1H), 2.63-2.51 (m, 1H), 2.39-2.23 (m, 3H), 1.93-1.85 (m, 3H), 1.58-1.50 (m, 6H), 1.46 (s, 3H), 1.40 (d,J= 8.8 Hz, 3H), 1.34 (t,J= 7.4 Hz, 3H), 0.81 (t,J= 7.4 Hz, 3H). Process 1, intermediate 3 and intermediates 72 134 572 1H-NMR (400 MHz, CD3OD): δ ppm 9.37 (s, 1H), 9.21 (s, 1H), 8.18 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 7.32 (d,J= 8.8 Hz, 1H), 5.74-5.66 (m, 1H), 4.71-4.63 (m, 1H), 3.98-3.92 (m, 1H), 3.85-3.79 (m, 1H), 3.38-3.35 (m, 1H), 3.34 (s, 3H), 3.08-3.01 (m, 1H), 2.93 (s, 3H), 2.45-2.38 (m, 1H), 2.17-2.08 (m, 1H), 1.73 (s, 3H), 1.53-1.46 (m, 12H). Process 1, intermediate 1 and intermediates 88 135 558 1 H NMR (400 MHz, CD3OD): δ ppm 9.44 (s, 1H), 9.24 (s, 1H), 8.14 (d,J= 8.8 Hz, 1H), 8.07 (s, 1H), 7.26 (d,J= 8.8 Hz, 1H), 4.59 (t,J= 6.4 Hz, 2H), 4.05 (d,J= 9.6Hz, 1H), 3.96 (d,J= 9.6 Hz, 1H), 3.50-3.40 (m, 5H), 3.10-3.00 (m, 4H), 2.50-2.40 (m, 2H), 1.89 (s, 3H), 1.54 (s, 3H), 1.47 (s, 3H), 1.40 (d, J = 7.2 Hz, 3H). Process 1, intermediate 3 and intermediates 99 136 582 1H NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 8.33 (s, 1H), 8.16 (d,J= 8.8 Hz, 1H), 8.10 (s, 1H), 7.62 (d,J= 8.8 Hz, 1H), 5.75-5.65 (m, 1H), 3.40-3.33 (m, 1H), 2.93 (s, 3H), 2.45-2.30 (m, 2H), 2.18-2.08 (m, 2H), 1.76 (s, 3H), 1.56-1.53​​ (m, 2H), 1.52-1.1.47 (m, 6H), 1.42 (s, 6H), 1.31-1.27 (m, 2H), 0.76 (d,J= 7.2 Hz, 3H). Process 1, intermediate 15 and intermediate products 53 137 582 1 H-NMR (400 MHz, CD3OD): δ ppm 9.44 (s, 1H), 9.37 (s, 1H), 8.28 (s, 1H), 8.13 (d,J= 8.8 Hz, 1H), 7.26 (d,J= 8.8 Hz, 1H), 5.74-5.65 (m, 1H), 3.40-3.33 (m, 1H), 3.06-3.00 (m, 1H), 2.93 (s, 3H), 2.47-2.37 (m, 1H), 2.17-2.08 (m, 1H), 1.71-1.63 (m, 4H), 1.54-1.47 (m, 9H), 1.45 (s, 3H), 1.39 (d,J= 7.2 Hz, 3H), 0.66-0.43 (m, 4H). Process 1, intermediate 3 and intermediates 76 138 582 1H-NMR (400 MHz, CD3OD): δ ppm 9.35 (s, 1H), 8.83 (s, 1H), 8.54 (s, 1H), 8.26 (s, 1H), 8.12 (d,J= 8.6 Hz, 1H), 7.24 (d,J= 8.8 Hz, 1H), 5.79-5.65 (m, 1H), 3.97 (br d,J= 8.8 Hz, 1H), 3.48-3.35 (m, 1H), 3.21-3.05 (m, 3H), 2.42 (td,J= 5.2, 14.4 Hz, 1H), 2.22-2.06 (m, 1H), 1.54-1.43 (m, 16H), 1.36-1.27 (m, 3H), 0.83-0.74 (m, 1H), 0.65-0.55 (m, 1H), 0.50-0.38 (m, 2H). Process 1, intermediate 3 and intermediates 89 139 584 1 H-NMR (400 MHz, CD3OD): δ ppm 9.42 (s, 1H), 9.28 (s, 1H), 8.53 (s, 1H), 8.14 (d,J= 8.8 Hz, 1H), 8.06 (s, 1H), 7.25 (d,J= 8.8 Hz, 1H), 5.59-5.51 (m, 1H), 4.02-3.93 (m, 2H), 3.43 (d,J= 7.6 Hz, 2H), 3.38 (s, 3H), 3.10-3.01 (m, 2H), 2.97 (s, 3H), 2.61 (t,J= 6.4 Hz, 3H), 1.84 (s, 3H), 1.54 (s, 2H), 1.46 (s, 3H), 1.40 (d,J= 7.2 Hz, 3H). Process 1, intermediate 3 and intermediates 51 140 584 1H-NMR (400 MHz, CD3OD): δ ppm 9.39 (s, 1H), 9.22 (s, 1H), 8.51 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 8.03 (s, 1H), 7.25 (d,J= 8.4 Hz, 1H), 5.42-5.35 (m, 1H), 4.08 (d,J= 10 Hz, 1H), 3.97 (d,J= 10 Hz, 1H), 3.41 (s, 3H), 3.38 (d,J= 7.2 Hz 1H), 3.02-3.01 (m, 1H), 2.95-2.90 (m, 2H), 2.68-2.58 (m, 1H), 2.25-2.14 (m, 2H), 1.90 (s, 3H), 1.55 (s, 3H), 1.48 (s, 3H), 1.40 (d,J= 7.2 Hz, 3H). Process 1, intermediate 3 and intermediates 50 141 584 1 H-NMR (400 MHz, CD3OD): δ ppm 9.39 (s, 1H), 9.36 (s, 1H), 8.17 (s, 1H), 8.13 (d,J= 8.8 Hz, 1H), 7.21 (d,J= 8.8 Hz, 1H), 5.44 (J= 7.2 Hz, 1H), 4.67-4.52 (m, 1H), 3.95-3.85 (m, 2H), 3.85-3.75 (m, 1H), 3.35 (s, 3H), 3.06 (q,J= 7.2 Hz, 3H), 3.02-2.92 (m, 2H), 2.74-2.64 (m, 2H), 1.74 (s, 3H), 1.54 (s, 3H), 1.48-1.45 (m, 3H), 1.40 (d,J= 7.2 Hz, 3H), 1.35 (t,J= 7.6 Hz, 3H) Process 1, intermediate 3 and intermediates 84 142 584 1 H-NMR (400 MHz, CD3OD): δ ppm 9.39 (s, 1H), 9.34 (s, 1H), 8.14 (d,J= 8.4 Hz, 1H), 8.10 (s, 1H), 7.23 (d,J= 8.8 Hz, 1H), 5.76-5.65 (m, 1H) 3.42-3.33 (m, 1H), 3.09-3.00 (m, 1H), 2.93 (s, 3H), 2.55-2.37 (m, 2H), 2.20-2.06 (m, 2H), 1.82 (s, 3H), 1.55 (s, 3H), 1.52-1.48 (m, 6H), 1.44 (s, 3H), 1.41 (d,J= 6.8 Hz, 3H), 1.34-1.20 (m, 1H), 1.08-0.94 (m, 1H), 0.88-0.81 (m, 3H). Process 1, intermediate 3 and intermediates 67 143 584 1 H-NMR (400 MHz, CD3OD): δ ppm 9.37 (s, 1H), 9.34 (s, 1H), 8.16 (s, 1H), 8.13 (d,J= 8.8 Hz, 1H), 7.21 (d,J= 8.4 Hz, 1H), 5.74-5.63 (m, 1H), 3.45-3.34 (m, 1H), 3.13-3.01 (m, 3H), 2.45-2.32 (m, 2H), 2.24-2.09 (m, 2H), 1.75 (s, 3H), 1.54 (s, 3H), 1.50-1.47 (m, 6H), 1.45 (s, 3H), 1.39 (d,J= 7.2 Hz, 3H), 1.33-1.28 (m, 3H), 0.77-0.71 (m, 3H). Process 1, intermediate 3 and intermediates 86 144 586 1H-NMR (400 MHz, CD3OD): δ ppm 9.38 (s, 1H), 9.36 (s, 1H), 8.19 (s, 1H), 8.13 (d,J= 8.4 Hz, 1H), 7.22 (d,J= 8.8 Hz, 1H), 5.74-5.66 (m, 1H), 3.95-3.85 (m, 2H), 3.37-3.33 (m, 4H), 3.09-3.02 (m, 1H), 2.93 (s, 3H), 2.45-2.37 (m, 1H), 2.18-2.08 (m, 1H), 1.75 (s, 3H), 1.54 (s, 3H), 1.51-1.48 (m, 6H), 1.46 (s, 3H), 1.40 (d,J= 6.8 Hz, 3H). Process 1, intermediate 3 and intermediates 88 145 596 1 H-NMR (400 MHz, CD3OD): δ ppm 9.37 (s, 1H), 9.35 (s, 1H), 8.14-8.11 (m, 2H), 7.22 (d,J= 8.8 Hz, 1H), 5.50-5.40 (m, 1H), 3.94 (s, 2H), 3.88-3.84 (m, 1H), 3.37 (s, 3H), 3.04-2.97 (m, 3H), 2.75-2.63 (m, 2H), 2.57-2.52 (m, 1H), 1.80 (s, 3H), 1.54 (s, 3H), 1.47 (s, 3H), 1.40 (d,J= 7.2 Hz, 3H), 1.14-1.05 (m, 4H). Process 1, intermediate 3 and intermediates 91 146 568 1H NMR (400 MHz, CD3OD): δ ppm 9.42 (s, 1H), 8.31 (s, 1H), 8.15 (d,J=8.4 Hz, 1H), 8.08 (s, 1H), 7.61 (d,J=8.4 Hz, 1H), 5.70-5.60 (m, 1H), 3.40-3.30 (m, 2H), 3.00 (s, 3H), 2.40-2.30 (m, 3H), 2.25-2.10 (m, 1H), 1.76 (s, 3H), 1.60-1.55 (m,5H), 1.50 (s, 6H), 1.35-1.25 (m, 2H), 0.76 (t,J=7.2 Hz, 3H). Process 1, intermediate 15 and intermediate products 54 147 554 1 H NMR (400 MHz, CD3OD): δ ppm 9.44 (s, 1H), 8.58 (s, 1H), 8.24 (s, 1H), 8.15 (d,J=8.4 Hz, 1H), 8.02 (s, 1H), 7.63 (d,J=8.4 Hz, 1H), 5.70-5.60 (m, 1H), 4.70-4.60 (m, 1H), 3.45-3.30 (m, 2H), 3.00 (s, 3H), 2.55-2.45 (m, 1H), 2.43-2.40 (m, 2H), 2.39-2.20 (m, 1H), 1.84 (s, 3H), 1.60-1.50 (m, 5H), 1.36 (d,J=6.8 Hz, 3H), 1.30-1.15 (m, 2H), 0.80 (t,J=6.8 Hz, 3H). Process 1, intermediate 12 and intermediates 54 148 542 1H NMR (400 MHz, CD3OD): δ ppm 9.42 (s, 1H), 9.34 (s, 1H), 8.56 (s, 1H), 8.15 (d,J=8.4 Hz, 1H), 8.05 (s, 1H), 7.18 (d,J=8.4 Hz, 1H), 5.70-5.60 (m, 1H), 4.95-4.90 (m, 1H), 3.40-3.30 (m, 2H), 3.05-2.95 (m, 4H), 2.60-2.55 (m, 1H), 2.40-2.20 (m, 3H), 1.89 (s, 3H), 1.51 (d,J=6.4 Hz, 6H), 1.32 (d,J=6.4 Hz, 3H), 0.85 (t,J=6.4 Hz, 3H). Process 1, intermediate 93 and intermediates 54 149 540 1 H NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1H), 9.33 (s, 1H), 8.56 (s, 1H), 8.14 (d,J=8.8 Hz, 1H), 8.02 (s, 1H), 7.18 (d,J=8.8 Hz, 1H), 5.50-5.40 (m, 1H), 4.95-4.90 (m, 1H), 3.85-3.80 (m, 1H), 3.05-2.95 (m, 6H), 2.73-2.55 (m, 3H), 2.35-2.20 (m, 1H), 1.91 (s, 3H),1.51 (d,J=6.4 Hz, 3H), 1.31 (d,J=6.4 Hz, 3H), 0.80 (t,J=6.4 Hz, 3H). Process 1, intermediate 93 and intermediates twenty four 150 554 1H NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 9.06 (s, 1H), 8.52 (s, 1H), 8.18 (d,J=8.4, 1H), 8.06 (s, 1H), 7.35 (d,J=8.4, 1H), 5.20-5.10 (m, 1H), 4.73-4.65 (m, 1H), 3.50-3.40 (m, 1H), 3.20-3.03 (m, 2H), 2.95 (s, 3H), 2.60-2.50 (m, 1H), 2.49-2.40 (m, 1H), 2.35-2.20 (m, 1H), 1.92 (s, 3H), 1.53-1.15 (m, 10H), 0.83 (s, 3H). Process 1, intermediate 1 and intermediates 96 151 554 1 H NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 9.06 (s, 1H), 8.55 (s, 1H), 8.18 (d,J=8.4, 1H), 8.06 (s, 1H), 7.32 (d,J=8.4, 1H), 5.20-5.10 (m, 1H), 4.73-4.69 (m, 1H), 3.50-3.40 (m, 1H), 3.20-3.03 (m, 2H), 2.94 (s, 3H), 2.60-2.40 (m, 2H), 2.30-2.15 (m, 1H), 1.86 (s, 3H),1.53-1.13 (m, 10H), 0.82-0.75 (m, 3H). Process 1, intermediate 1 and intermediates 95 152 556 1 H NMR (400 MHz, CD3OD): δ ppm 9.39 (s, 2H), 8.16 (d,J= 8.4 Hz, 1H), 8.10 (s, 1H), 7.18 (d,J= 8.4 Hz, 1H), 5.76-5.65 (m, 1H), 4.96-4.90 (m, 1H), 3.43-3.35 (m, 1H), 3.07-2.98 (m, 1H), 2.94 (s, 3H), 2.59-2.47 (m, 1H), 2.47-2.38 (m, 1H), 2.32-2.20 (m, 1H), 2.19-2.09 (m, 1H), 1.85 (s, 3H), 1.56-1.48 (m, 9H), 1.33 (d,J= 7.2 Hz, 3H), 0.79 (t,J= 7.2 Hz, 3H)。 Process 1, intermediate 93 and intermediates 53 153 542 1 H NMR (400 MHz, CD3OD): δ ppm 9.43 (s, 1H), 9.39 (s, 1H), 8.15 (s, 1H), 8.13 (d,J= 8.8 Hz, 1H), 7.16 (d,J= 8.8 Hz, 1H), 5.67-5.58 (m, 1H), 4.95-4.91 (m, 1H), 3.42-3.33 (m, 2H), 3.05-3.01 (m, 1H), 3.00 (s, 3H), 2.49-2.40 (m, 1H), 2.39-2.29 (m, 2H), 2.25-2.17 (m, 1H), 1.78 (s, 3H), 1.54-1.49 (m, 6H), 1.32 (d,J= 7.2 Hz, 3H), 0.75 (t,J= 7.4 Hz, 3H)。 Process 1, intermediate 93 and intermediates 31 154 554 1 H NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1 H), 9.17 (s, 1 H), 8.18 (s, 1 H), 8.13 (d,J= 8.4 Hz, 1 H), 7.30 (d,J= 8.8 Hz, 1 H), 5.68-5.57 (m, 1 H), 4.69-4.61 (m, 1 H), 3.22-3.09 (m, 2 H), 3.06-2.93 (m, 2 H), 2.50-2.38 (m, 2 H), 2.21-2.10 (m, 1 H), 2.07-1.94 (m, 2 H), 1.91-1.83 (m, 1 H), 1.78 (d,J=4.4 Hz, 6 H), 1.51-1.47 (m, 6 H), 1.45 (d,J= 6.4 Hz, 3 H). Process 1, intermediate 1 and intermediates 92 By means of the second dissolution peak of chiral SFC Column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​ETOH]; B%: 70%-70%). This peak contains two isomers, which are further separated by a second SFC to obtain the title isomer as the second peak. Tube Column: Daicel Chiralpak IC (250 mm × 50 mm, 10 µm); Moving phase: [Hexane-IPA (1% TFA)]; B%: 50%-50%) 155 554 1 H NMR (400 MHz, CD3OD): δ ppm 9.38 (s, 1 H), 9.12 (s, 1 H), 8.16-8.10 (m, 2 H), 7.30 (d,J= 8.8 Hz, 1 H), 5.73-5.61 (m, 1 H), 4.70-4.60 (m, 1 H), 3.17-3.08 (m, 1 H), 3.05-2.92 (m, 2 H), 2.50-2.40 (m, 1 H), 2.35-2.24 (m, 1 H), 2.23-1.99 (m, 4 H), 1.94-1.86 (m, 1 H), 1.80 (d,J= 6.8 Hz, 6 H), 1.51-1.47 (m, 6 H), 1.45 (d,J= 6.8 Hz, 3 H). Process 1, intermediate 1 and intermediates 92 By means of the second dissolution peak of chiral SFC Tube Column: Phenomenex-Cellulose-2 (250 mm×30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​ETOH]; B%: 70%-70%), This peak contains two isomers, which are further separated by a second SFC to obtain the title isomer as the first peak. Tube Column: Daicel Chiralpak IC (250 mm × 50 mm, 10 µm); Moving phase: [Hexane-IPA (1% TFA)]; B%: 50%-50%) 156 554 1H NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1 H), 9.13 (s, 1 H), 8.17 (s, 1 H), 8.11 (d,J= 8.8 Hz, 1 H), 7.29 (d,J= 8.8 Hz, 1 H), 5.69-5.53 (m, 1 H), 4.67-4.58 (m, 1 H), 3.26-3.10 (m, 2 H), 3.06-2.95 (m, 2 H), 2.49-2.39 (m, 2 H), 2.22-2.11 (m, 1 H), 2.08-1.94 (m, 2 H), 1.92-1.82 (m, 1 H), 1.79 (d,J= 5.6 Hz, 6 H), 1.47-1.51 (m, 6 H), 1.44 (d,J= 6.8 Hz, 3 H). Process 1, intermediate 1 and intermediates 92 By means of the first dissolution peak of chiral SFC Tube Column: Phenomenex-Cellulose-2 (250 mm×30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​ETOH]; B%: 70%-70%), This peak contains two isomers, which are further separated by a second SFC to obtain the title isomer as the second peak. Tube Column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​MEOH]; B%: 70%-70%) 157 554 1 H NMR (400 MHz, CD3OD): δ ppm 9.37 (s, 1 H), 9.13 (s, 1 H), 8.17 (s, 1 H), 8.12 (d,J= 8.8 Hz, 1 H), 7.29 (d,J= 8.8 Hz, 1 H), 5.73-5.60 (m, 1 H), 4.68-4.59 (m, 1 H), 3.18-3.09 (m, 1 H), 3.06-2.95 (m, 2 H), 2.50-2.40 (m, 1 H), 2.34-2.24 (m, 1 H), 2.22-1.99 (m, 4 H), 1.98-1.83 (m, 1 H),1.77 (d,J= 5.6 Hz, 6 H), 1.51-1.47 (m, 6 H), 1.45 (d,J= 6.4 Hz, 3 H)。 Process 1, intermediate 1 and intermediates 92 By means of the first dissolution peak of chiral SFC Tube Column: Phenomenex-Cellulose-2 (250 mm×30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​ETOH]; B%: 70%-70%), This peak contains two isomers, which are further separated by a second SFC to obtain the title isomer as the first peak. Tube Column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​MEOH]; B%: 70%-70%) 158 568 1 H NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1 H), 9.36 (s, 1 H), 8.20 (s, 1 H), 8.13 (d,J= 8.8 Hz, 1 H), 7.21 (d,J= 8.8 Hz, 1 H),5.69-5.58 (m, 1 H), 3.21-3.11 (m, 2 H), 3.05-2.96 (m, 2 H), 2.50-2.39 (m, 2 H), 2.22-2.12 (m, 1 H), 2.08-1.95 (m, 2 H), 1.88 -1.83 (m, 1 H), 1.79 (d,J= 6.8 Hz, 6 H),1.54 (s, 3 H), 1.50 (d,J= 6.0 Hz, 3 H), 1.45 (s, 3 H), 1.40 (d,J= 7.2 Hz, 3 H). Process 1, intermediate 3 and intermediates 92 By means of the second dissolution peak of chiral SFC Tube Column: Daicel Chiralpak OD (250 mm × 30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​MEOH]; B%: 55%-55%), This peak contains two isomers, which are further separated by a second SFC to obtain the title isomer as the second peak. Tube Column: Daicel Chiralpak IC (250 mm × 50 mm, 10 µm); Moving phase: [Hexane-IPA (1% TFA)]; B%: 40%-40%) 159 568 1 H NMR (400 MHz, CD3OD): δ ppm 9.37 (s, 1 H), 9.32 (s, 1 H), 8.17 (s, 1 H), 8.12 (d,J= 8.4 Hz, 1 H), 7.21 (d,J= 8.4 Hz, 1 H), 5.72-5.62 (m, 1 H), 3.18 -3.09 (m, 1 H), 3.08-2.95 (m, 2 H), 2.51-2.40 (m, 1 H), 2.34-2.24 (m, 1 H), 2.23-1.98 (m, 4 H), 1.96-1.85 (m, 1 H), 1.78 (d,J= 9.6 Hz, 6 H), 1.53 (s, 3 H), 1.49 (d,J= 6.0 Hz, 3 H), 1.45 (s, 3 H), 1.39 (d,J= 6.4 Hz, 3 H). Process 1, intermediate 3 and intermediates 92 By means of the second dissolution peak of chiral SFC Tube Column: Daicel Chiralpak OD (250 mm × 30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​MEOH]; B%: 55%-55%), This peak contains two isomers, which are further separated by a second SFC to obtain the title isomer as the first peak. Tube Column: Daicel Chiralpak IC (250 mm × 50 mm, 10 µm); Moving phase: [Hexane-IPA (1% TFA)]; B%: 40%-40%) 160 568 1 H NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1 H), 9.33 (s, 1 H), 8.18 (s, 1 H), 8.12 (d,J= 8.8 Hz, 1 H), 7.21 (d,J= 8.8 Hz, 1 H), 5.68-5.58 (m, 1 1.79 (d,J= 8.4 Hz, 6 H), 1.53 (s, 3 H), 1.49 (d,J= 6.4 Hz, 3 H), 1.44 (s, 3 H), 1.39 (d,J= 7.2 Hz, 3 H). Process 1, intermediate 3 and intermediates 92 By means of the first dissolution peak of chiral SFC Tube Column: Daicel Chiralpak OD (250 mm × 30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​MEOH]; B%: 55%-55%), This peak contains two isomers, which are further separated by a second SFC to obtain the title isomer as the second peak. Tube Column: Daicel Chiralpak IC (250 mm × 30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​MEOH]; B%: 70%-70%) 161 568 1H NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1 H), 9.35 (s, 1 H), 8.21 (s, 1 H), 8.14 (d,J= 8.8 Hz, 1 H), 7.23 (d,J= 8.8 Hz, 1 H), 5.74-5.63 (m, 1 H), 3.20-3.11 (m, 1 H), 3.08-2.98 (m, 2 H), 2.52-2.41 (m, 1 H), 2.36-2.27 (m, 1 H), 2.23- 2.16 (m, 2 H), 2.15-2.01 (m, 2 H), 1.99-1.88 (m, 1 H), 1.81 (d,J= 8.0 Hz, 5 H), 1.56 (s, 3 H), 1.51 (d,J= 6.4 Hz, 3 H), 1.46 (s, 3 H), 1.41 (d,J= 7.2 Hz, 3 H). Process 1, intermediate 3 and intermediates 92 By means of the first dissolution peak of chiral SFC Tube Column: Daicel Chiralpak OD (250 mm × 30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​MEOH]; B%: 55%-55%), This peak contains two isomers, which are further separated by a second SFC to obtain the title isomer as the first peak. Tube Column: Daicel Chiralpak IC (250 mm × 30 mm, 10 µm); Moving phase: [0.1% NH3H2O ​​MEOH]; B%: 70%-70%) 162 582 1H NMR (400 M Hz, CD3OD): δ ppm 9.39 (s, 1H), 8.58 (s, 1H), 8.16 (d,J= 8.8 Hz, 1H), 8.10 (s, 1H), 7.53 (d,J= 8.8 Hz, 1H), 5.43 (t,J= 7.4 Hz, 1H), 3.93 (d,J= 9.6 Hz, 1H), 3.86-3.78 (m, 1H), 3.74 (d,J= 9.2 Hz, 1H), 3.36 (s, 3H), 3.02-2.94 (m, 2H), 2.93 (s, 3H), 2.74-2.63 (m, 2H), 2.03 (s, 1H), 1.70 (s, 3H), 1.63-1.56 (m, 2H), 1.42 (s, 6H), 1.29 (d,J= 2.8 Hz, 2H). Process 1, intermediate 15 and intermediate products 85 163 568 1 H NMR (400 M Hz, CD3OD): δ ppm 9.38 (s, 1H), 8.59 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 8.09 (s, 1H), 7.50 (d,J= 8.8 Hz, 1H), 5.48-5.36 (m, 1H), 4.69-4.60 (m, 1H), 3.92 (d,J= 9.2 Hz, 1H), 3.87-3.72 (m, 2H), 3.37 (s, 3H), 3.03-2.94 (m, 2H), 2.93 (s, 3H), 2.74-2.62 (m, 2H), 1.72 (s, 3H), 1.68-1.62 (m, 1H), 1.58-1.49 (m, 1H), 1.38 (d,J= 6.4 Hz, 3H), 1.26-1.16 (m, 2H). Process 1, intermediate 12 and intermediates 85 164 598 1H NMR (400 MHz, CD3OD): δ ppm 9.38 (s, 1H), 8.58 (s, 1H), 8.15 (d,J= 8.8 Hz, 2H), 8.14 (s, 1H), 7.53 (d,J= 8.8 Hz, 1H), 5.73-5.64 (m, 1H), 3.98-3.90 (m, 1H), 3.75-3.70 (m, 1H), 3.36 (s, 3H), 3.35-3.33 (m, 1H), 2.93 (s, 3H), 2.45-2.37 (m, 1H), 2.17-2.07 (m, 1H), 1.69 (s, 3H), 1.62-1.56 (m, 2H), 1.52-1.47 (m, 6H), 1.42 (s, 6H), 1.32-1.27 (m, 2H). Process 1, intermediate 15 and intermediate products 88 165 584 1 H NMR (400 MHz, CD3OD): δ ppm 9.37 (s, 1H), 8.63 (s, 1H), 8.15 (d,J= 8.4 Hz, 1H), 8.13 (s, 1H), 7.49 (d,J= 8.4 Hz, 1H), 5.73-5.64 (m, 1H), 4.67-4.61 (m, 1H), 3.95-3.88 (m, 1H), 3.77-3.70 (m, 1H), 3.36 (s, 3H), 3.35-3.33 (m, 1H), 2.93 (s, 3H), 2.45-2.36 (m, 1H), 2.17-2.07 (m, 1H), 1.69 (s, 3H), 1.67-1.63 (m, 1H), 1.58-1.53​ (m, 1H), 1.52-1.47 (m, 6H), 1.38 (d,J= 6.4 Hz, 3H), 1.26-1.17 (m, 2H). Process 1, intermediate 12 and intermediates 88 166 526 1 H NMR (400 MHz, CD3OD): δ ppm 9.45 (s, 1H), 8.94 (s, 1H), 8.65-8.38 (m, 1H), 8.17 (d,J= 8.8 Hz, 1H), 7.99 (s, 1H), 7.38 (d,J= 8.8 Hz, 1H), 5.76-5.60 (m, 1H), 4.68-4.57 (m, 1H), 3.11-2.92 (m, 3H), 2.75-2.59 (m, 4H), 2.39-2.24 (m, 3H), 1.97 (s, 3H), 1.56-1.43 (m, 9H), 0.85-0.80 (m, 3H). Process 1, Intermediate 101 and Intermediate 1 167 526 1 H NMR (400 MHz, CD3OD): δ ppm 9.46 (s, 1H), 8.94 (s, 1H), 8.65-8.38 (m, 1H), 8.17 (d,J= 8.8 Hz, 1H), 7.99 (s, 1H), 7.38 (d,J= 8.8 Hz, 1H), 5.68-5.60 (m, 1H), 4.68-4.57 (m, 1H), 3.11-2.92 (m, 3H), 2.75-2.59 (m, 4H), 2.39-2.24 (m, 3H), 1.97 (s, 3H), 1.56-1.43 (m, 9H), 0.85-0.80 (m, 3H). Process 1, Intermediate 102 and Intermediate 1 168 527 1H NMR (400 MHz, CD3OD): δ ppm 9.48 (s, 1H), 9.16 (s, 1H), 8.16 (d,J= 8.8 Hz, 1H), 8.02 (s, 1H), 7.29 (d,J= 8.8 Hz, 1H), 4.73-4.70 (m, 2H), 3.53-3.45 (m, 2H), 3.10 (s, 3H), 3.01-3.00 (m, 1H), 2.48-2.44 (m, 2H), 2.04-1.99 (m, 6H), 1.54 (s, 3H), 1.48-1.40 (m, 6H). Process 1, Intermediate 103 and Intermediate 3 169 527 1 H NMR (400 MHz, CD3OD): δ ppm 9.46 (s, 1H), 9.10 (s, 1H), 8.14 (d,J= 8.8 Hz, 1H), 8.01 (s, 1H), 7.27 (d,J= 8.8 Hz, 1H), 4.73-4.70 (m, 2H), 3.53-3.45 (m, 2H), 3.10 (s, 3H), 3.01-3.00 (m, 1H), 2.48-2.44 (m, 2H), 2.04-1.99 (m, 6H), 1.52 (s, 3H), 1.48-1.40 (m, 6H). Process 1, Intermediate 104 and Intermediate 3 170 171 172 596 1H NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 9.37 (s, 1H), 8.20-8.10 (m, 2H), 7.24 (d,J= 8.8 Hz, 1H), 6.45-6.37 (m, 1H), 3.48-3.32 (m, 2H), 3.07-2.96 (m, 4H), 2.62-2.46 (m, 2H), 1.90-1.86 (m, 6H), 1.54 (s, 3H), 1.47-1.38 (m, 6H). Process 1, Intermediate 105 and Intermediate 3 173 596 1 H NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 9.34 (s, 1H), 8.20-8.10 (m, 2H), 7.26 (d,J= 8.8 Hz, 1H), 6.45-6.37 (m, 1H), 3.48-3.32 (m, 2H), 3.07-2.96 (m, 4H), 2.62-2.46 (m, 2H), 1.90-1.86 (m, 6H), 1.54 (s, 3H), 1.45-1.38 (m, 6H). Process 1, Intermediate 106 and Intermediate 3 174 582 1 H NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 9.24 (s, 1H), 8.20 (s, 1H), 8.16 (d,J=8.8 Hz, 1H), 7.32 (d,J=8.8 Hz, 1H), 6.45-6.37 (m, 1H), 4.71-4.65 (m, 1H), 3.46-3.33 (m, 2H), 3.08-3.00 (m, 4H), 2.56-2.50 (m, 2H), 1.85-1.80 (m, 6H), 1.53-1.44 (m, 6H). Process 1, Intermediate 105 and Intermediate 1 175 582 1 H NMR (400 MHz, CD3OD): δ ppm 9.47 (s, 1H), 9.04 (s, 1H), 8.18 (d,J=8.8 Hz, 1H), 8.03 (s, 1H), 7.38 (d,J=8.8 Hz, 1H), 6.45-6.37 (m, 1H), 4.71-4.65 (m, 1H), 3.46-3.33 (m, 2H), 3.08-3.00 (m, 4H), 2.58-2.50 (m, 2H), 2.05-2.00 (m, 6H), 1.53-1.44 (m, 6H). Process 1, Intermediate 106 and Intermediate 1 176 540 1 H-NMR (400 MHz, CDCl3): δ ppm 9.36 (s, 1H), 8.86 (s, 1H), 8.19-8.08 (m, 2H), 7.26 (d, J = 8.8 Hz, 1H), 5.54-5.33 (m, 1H), 4.47-4.41 (m, 1H), 3.94-3.73 (m, 1H), 3.22-3.12 (m, 1H), 3.04-2.96 (m, 2H), 2.94 (s, 3H), 2.75-2.64 (m, 2H), 2.09-1.85 (m, 2H), 1.56-1.47 (m, 6H), 1.45 (s, 3H), 1.03-0.97 (m, 3H). Step 2, Intermediate 115 and Intermediate 3 177 556 1H NMR (400 MHz, CD3OD): δ ppm 9.42 (s, 1H), 8.55 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 8.11 (s, 1H), 7.58 (d,J= 8.8 Hz, 1H), 5.65-5.60 (m, 1H), 4.62-4.50 (m, 1H), 3.42-3.35 (m, 1H), 3.00 (s, 3H), 2.44-2.28 (m, 3H), 2.18-2.05 (m, 1H), 1.77 (s, 3H), 1.54-1.40 (m, 9H), 1.30 (s, 3H), 0.79-0.67 (m, 3H). Process 1, Intermediate 54 and Intermediate 97 178 556 1 H NMR (400 MHz, CD3OD): δ ppm 9.46 (s, 1H), 8.46 (s, 1H), 8.18 (d,J= 8.8 Hz, 1H), 8.05 (s, 1H), 7.64 (d,J= 8.8 Hz, 1H), 5.67-5.55 (m, 1H), 4.65-4.51 (m, 1H), 3.43-3.33 (m, 2H), 3.01 (s, 3H), 2.57-2.45 (m, 1H), 2.42 - 2.30 (m, 2H), 2.22-2.13 (m, 1H), 1.85 (s, 3H), 1.54-1.49 (m, 6H), 1.48-1.42 (m, 3H), 1.31 (s, 3H), 0.81-0.73 (m, 3H). Process 1, Intermediate 31 and Intermediate 97 179 558 1H NMR (400 MHz, CD3OD): δ ppm 9.43 (s, 1H), 9.24 (s, 1H), 8.15 (d,J= 8.8 Hz, 1H), 8.07 (s, 1H), 7.26 (d,J= 8.8 Hz, 1H), 4.70-4.67 (m, 2H), 4.07-4.04 (m, 1H), 4.00-3.92 (m, 1H), 3.43-3.36 (m, 5H), 3.05-3.01 (m, 4H), 2.49-2.40 (m, 2H), 1.89 (s, 3H), 1.54 (s, 3H), 1.47 (s, 3H), 1.40 (d,J= 7.2 Hz, 3H). Process 1, intermediate 3 and intermediates 99 180 567 1 H NMR (400 MHz, CD3OD): δ ppm 9.49 (s, 1 H), 8.19 (d,J= 8.8 Hz, 1 H), 8.06 (s, 1 H), 7.94 (s, 1 H), 7.76 (d,J= 8.8 Hz, 1 H), 5.76-5.71 (m, 1 H), 4.68-4.62 (m, 1 H), 4.20-4.17 (m, 1 H), 3.31(s, 3 H), 2.64-2.57 (m, 2 H), 2.32-2.12 (m, 2 H), 1.92 (s, 3 H), 1.72 (d,J= 8.0 Hz, 3 H), 1.55 (d,J= 8.0 Hz, 3 H), 1.49-1.42 (m, 1 H), 1.37 (d,J= 6.4 Hz, 3 H), 1.24-1.20 (m, 4 H), 0.85-0.79 (m, 3 H). Process 1, intermediate 107 and intermediate 12 181 567 1H NMR (400 MHz, CD3OD): δ ppm 9.45 (s, 1 H), 8.48 (s, 1 H), 8.18 (d,J= 8.8 Hz, 1 H), 8.12 (s, 1 H), 7.95 (s, 1 H), 7.70 (d,J= 8.8 Hz, 1 H), 5.78-5.65 (m, 1 H), 4.68-4.58 (m, 1 H), 3.38-3.32(m, 1 H), 2.96 (s, 3 H), 2.64-2.40 (m, 2 H), 2.32-2.12 (m, 2 H), 1.92 (s, 3 H), 1.58-1.50 (m, 7H), 1.49-1.42 (m, 1 H), 1.37 (d,J= 6.4 Hz, 3 H), 1.26-1.17 (m, 2 H), 0.85-0.79 (m, 3 H). Process 1, intermediate 108 and intermediate 12 182 569 1 H NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 8.64 (s, 1H), 8.17-8.14 (m, 2H), 7.57 (d,J=8.8 Hz, 1H), 5.72-5.68 (m, 1H), 4.59-4.54 (m, 1H), 3.43-3.40 (m,1H), 2.96 (s, 3H), 2.47-2.37 (m, 2H), 2.15-2.09 (m, 2H), 1.75 (s, 3H), 1.60-1.40 (m, 12H), 1.31 (s, 3H), 0.75-0.71 (m, 3H). Process 1, intermediate 108 and intermediates 97 183 569 1H NMR (400 MHz, CD3OD): δ ppm 9.42 (s, 1H), 8.65 (s, 1H), 8.17-8.14 (m, 2H), 7.57 (d,J=8.8 Hz, 1H), 5.72-5.68 (m, 1H), 4.61-4.54 (m, 1H), 3.43-3.40 (m,1H), 2.98 (s, 3H), 2.47-2.37 (m, 1H), 2.17-2.05 (m, 3H), 1.74 (s, 3H), 1.60-1.40 (m, 12H), 1.33 (s, 3H), 0.75-0.71 (m, 3H). Process 1, intermediate 107 and intermediates 97 184 570 1 H NMR (400 MHz, CD3OD): δ ppm 9.38 (s, 1H), 9.16 (s, 1H), 8.10-8.05 (m, 2H), 7.23 (d,J=8.4 Hz, 1H), 5.88-5.81 (m, 1H), 4.68-4.65 (m, 1H), 3.08-2.99 (m, 1H), 2.95 (s, 3H), 2.50-2.43 (m, 2H), 2.25-2.21 (m, 2H), 1.81 (s, 3H), 1.52-1.44 (m, 15H), 0.79-0.72 (m, 3H). Process 1, intermediate 110 and intermediate 1 185 570 1H NMR (400 MHz, CD3OD): δ ppm 9.38 (s, 1H), 9.11 (s, 1H), 8.10-8.05 (m, 2H), 7.33 (d,J=8.4 Hz, 1H), 5.88-5.81 (m, 1H), 4.68-4.65 (m, 1H), 3.00-2.99 (m, 3H), 2.93 (s, 3H), 2.50-2.43 (m, 2H), 2.25-2.21 (m, 2H), 1.81 (s, 3H), 1.52-1.44 (m, 15H), 0.79-0.72 (m, 3H). Process 1, intermediate 109 and intermediate 1 186 570 1 H NMR (400 MHz, CD3OD): δ ppm 9.41 (s, 1H), 8.59 (s, 1H), 8.16 (d,J=8.8 Hz, 1H), 8.14 (s, 1H), 7.57 (d,J=8.8 Hz, 1H), 5.80-5.60 (m, 1H), 4.63-4.53 (m, 2H), 3.41-3.33 (m, 1H), 2.93 (s, 3H), 2.47-2.31 (m, 2H), 2.18-2.02 (m, 2H), 1.75 (s, 3H), 1.53-1.42 (m, 12H), 1.31 (s, 3H), 0.75-0.71 (m, 3H). Process 1, intermediate 53 and intermediates 97 187 583 1H NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1H), 8.63 (s, 1H), 8.20-8.15 (m, 2H), 7.56 (d,J=8.8 Hz, 1H), 5.85-5.78 (m, 1H), 4.61-4.54 (m, 1H), 2.96 (s, 3H), 2.50-2.45 (m, 1H), 2.40-2.20 (m, 2H), 2.15-2.05 (m, 1H), 1.74 (s, 3H), 1.55-1.44 (m, 15H), 1.31 (s, 3H), 0.76-0.72 (m, 3H). Process 1, intermediate 114 and intermediates 97 188 583 1 H NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1H), 8.63 (s, 1H), 8.20-8.15 (m, 2H), 7.57 (d,J=8.8 Hz, 1H), 5.85-5.78 (m, 1H), 4.61-4.54 (m, 1H), 2.96 (s, 3H), 2.50-2.45 (m, 1H), 2.40-2.20 (m, 2H), 2.15-2.05 (m, 1H), 1.73 (s, 3H), 1.55-1.44 (m, 15H), 1.31 (s, 3H), 0.76-0.72 (m, 3H). Process 1, intermediate 112 and intermediate 97 189 583 1H NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1H), 8.63 (s, 1H), 8.20-8.15 (m, 2H), 7.57 (d,J=8.8 Hz, 1H), 5.85-5.78 (m, 1H), 4.61-4.54 (m, 1H), 2.96 (s, 3H), 2.50-2.45 (m, 1H), 2.40-2.20 (m, 2H), 2.15-2.05 (m, 1H), 1.73 (s, 3H), 1.55-1.44 (m, 15H), 1.32 (s, 3H), 0.76-0.72 (m, 3H). Process 1, intermediate 111 and intermediate 97 190 583 1 H NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1H), 8.63 (s, 1H), 8.20-8.15 (m, 2H), 7.57 (d,J=8.8 Hz, 1H), 5.85-5.80 (m, 1H), 4.61-4.54 (m, 1H), 2.96 (s, 3H), 2.50-2.45 (m, 1H), 2.40-2.20 (m, 2H), 2.15-2.05 (m, 1H), 1.74 (s, 3H), 1.55-1.44 (m, 15H), 1.31 (s, 3H), 0.76-0.72 (m, 3H). Process 1, intermediate 113 and intermediate 97 191 584 1H NMR (400 MHz, CD3OD): δ ppm 9.42 (s, 1H), 8.58 (s, 1H), 8.20-8.15 (m, 2H), 7.62 (d,J=8.8 Hz, 1H), 5.88-5.81 (m, 1H), 4.61-4.54 (m, 1H), 2.94 (s, 3H), 2.50-2.25 (m, 2H), 2.20-2.09 (m, 2H), 1.79 (s, 3H), 1.52-1.44 (m, 15H), 1.32 (s, 3H), 0.79-0.72 (m, 3H). Process 1, intermediate 110 and intermediates 97 192 584 1 H NMR (400 MHz, CD3OD): δ ppm 9.40 (s, 1H), 8.60 (s, 1H), 8.17-8.15 (m, 2H), 7.58 (d,J=8.8 Hz, 1H), 5.85-5.81 (m, 1H), 4.59-4.54 (m, 1H), 2.94 (s, 3H), 2.50-2.31 (m, 2H), 2.27-2.09 (m, 2H), 1.75 (s, 3H), 1.52-1.44 (m, 15H), 1.31 (s, 3H), 0.76-0.72 (m, 3H). Process 1, intermediate 109 and intermediates 97

[0042] The teachings of this invention include pharmaceutically acceptable salts of the compounds disclosed herein (including compounds 1-192 and examples disclosed in Table 1) and their corresponding charge-neutral forms, such as free bases.

[0043] Another embodiment of the invention is a compound disclosed herein, comprising compounds of formula I, II, III, IV, V, VI, or VII, or compounds in Table 1 or the examples, or a pharmaceutically acceptable salt of any of the foregoing, wherein one or more hydrogen atoms are deuterated. Hydrogen has been enriched by deuterium at any of the deuteration sites to at least 50%, 75%, 85%, 90%, 95%, 98%, or 99%. The deuterium enrichment is a mole percentage and is obtained by dividing the number of compounds with deuterium enrichment at the enrichment sites by the number of compounds with hydrogen or deuterium at the enrichment sites.

[0044] As defined herein, the term "medically acceptable salt" means a pharmaceutical salt suitable for use in contact with human and lower animal tissues without adverse toxicity, irritation, or allergic reactions, and in proportion to a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in this art. For example, SM Berge et al. described pharmaceutically acceptable salts in J. Pharm. Sci. (1977) 66:1-19. Compounds of the present invention having a base can form pharmaceutically acceptable salts with pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid) and salts of organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid). Compounds of the present invention having an acid group can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable medically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts), and alkaline earth metal salts (such as magnesium and calcium salts).

[0045] The term "alkyl," used alone or as part of a larger part, such as "alkoxy," "hydroxyalkyl," and the like, means a saturated aliphatic straight-chain or branched monovalent hydrocarbon group. Unless otherwise specified, alkyl groups generally have 1 to 6 carbon atoms (C1-6 alkyl), (i.e., 1, 2, 3, 4, 5, or 6), or alternatively, 1 to 3 carbon atoms (C1-3 alkyl), (i.e., 1, 2, or 3). "C1-6 alkyl" means a group having 1 to 6 carbon atoms arranged in a straight or branched chain, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tributyl, and the like.

[0046] Unless otherwise specified, the term "alkyl" means divalent alkyl, such as C1-C6 alkyl group ‒(CH2)n‒, where n is 1 to 6; C1-C3 alkyl group ‒(CH2)n‒, where n is 1 to 3.

[0047] "Cycloalkyl" means a saturated aliphatic cyclic hydrocarbon cycloalkanes. Unless otherwise specified, cycloalkyl groups have 3 to 8 cyclic carbon atoms (C 3-8 cycloalkyl) (i.e., 3, 4, 5, 6, 7, or 8), alternatively, 3 to 6 cyclic carbon atoms (C 3-6 cycloalkyl) (i.e., 3, 4, 5, or 6), alternatively, 3 to 5 carbon atoms (C 3-5 cycloalkyl) (i.e., 3, 4, or 5). "C 3-6 cycloalkyl" means a group having 3 to 6 carbon atoms arranged in a monocyclic arrangement. C 3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. C 3-5 cycloalkyl groups include cyclopropyl, cyclobutyl, and cyclopentyl.

[0048] The term "halogen" or "halogen" means fluorine or fluorinyl (F), chlorine or chlorinyl (Cl), bromine or bromo (Br), or iodine or iodoyl (I).

[0049] Unless otherwise specified, the term "heterocyclic" means a monocyclic nonaromatic group containing 3 to 8 ring atoms (i.e., "3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered") selected from carbon atoms and 1 or 2 heteroatoms. Each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO); oxygen; and sulfur, including sulfide and sulfide. For example, a 4-6 membered heterocycle containing nitrogen means a monocyclic nonaromatic group containing 2-5 carbon atoms and 1 or 2 nitrogen atoms; a 4-6 membered heterocycle containing oxygen atoms means a monocyclic nonaromatic group containing 2-5 carbon atoms and 1 or 2 oxygen atoms. Representative heterocycles include aza-butyl, morpholino, thiomorpholino, pyrrolidone, pyrrolidin, piperidin, piperidine, lactour, valproic acid, ethylene oxide, oxacyclobutyl, tetrahydrofuran, tetrahydropiperanyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophene, tetrahydrothiopiperanyl, and similar groups.

[0050] The term "hydroxyl" refers to the OH group.

[0051] The term "substituted" refers, regardless of whether it is preceded by the term "as the case may be," to the substitution of a hydrogen substituent in an existing structure by a non-hydrogen substituent. Thus, for example, a substituted alkyl group is an alkyl group in which at least one non-hydrogen substituent replaces a hydrogen substituent on the alkyl group. For example, a monofluoroalkyl group is an alkyl group substituted with one fluorine substituent, and a difluoroalkyl group is an alkyl group substituted with two fluorine substituents. It should be understood that if a substituent has more than one substitution, the non-hydrogen substituents may be the same or different (unless otherwise stated).

[0052] If a group is described as "optionally substituted", the group can be (1) unsubstituted or (2) substituted. If a group is described as optionally substituted with up to a specific number of non-hydrogen substituents, the group can be (1) unsubstituted; or (2) substituted with up to the specific number of non-hydrogen substituents or up to the maximum number of substitutable positions on the substituent (whichever is less). Thus, for example, if a group is described as a cycloalkyl optionally substituted with up to 3 non-hydrogen substituents, any cycloalkyl having less than 3 substitutable positions will be optionally substituted with up to as many non-hydrogen substituents as the cycloalkyl has substitutable positions.

[0053] The term "sulfone" refers to the group -S(O)2-.

[0054] Compounds having one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have the R or S configuration or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereoisomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are non-superimposable mirror images of each other. Diastereoisomers are stereoisomers that are different from each other and are not mirror images having two or more chiral centers.

[0055] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated by "R" or "S" in the chemical name) or structure (e.g., indicated by a "wedge" bond), the indicated configuration is enriched greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9% relative to the opposite configuration (except as set forth in the two paragraphs below, the name "rac" or "racemate" is attached to the structure or name). "Enrichment of the indicated configuration relative to the opposite configuration" is the mole percentage and is determined by dividing the number of compounds having the indicated stereochemical configuration at the chiral center in the mixture by the total number of all compounds having the same or opposite stereochemical configuration.

[0056] When the stereochemical configuration at a chiral center in a compound is depicted by its chemical name (e.g., where the configuration is indicated by "R" or "S" in the name) or structure (e.g., indicated by a "wedge" bond) and the name "rac" or "racemate" is attached to the structure or expressed in the chemical name, it is intended to be a racemic mixture.

[0057] When two or more stereoisomers are described by their chemical names or structures and the chemical names or structures are connected by "or", it is intended that one or the other of the two or more stereoisomers exists, but not both. The enrichment of one stereoisomer relative to the other is as indicated above.

[0058] When the disclosed compound having a chiral center is described by a structure that does not exhibit a configuration at the chiral center, the structure is intended to encompass compounds having an S configuration at the chiral center, compounds having an R configuration at the chiral center, or compounds having a mixture of R and S configurations at the chiral center. When the disclosed compound having a chiral center is described by a chemical name that does not exhibit the configuration "S" or "R" at the chiral center, the name is intended to encompass compounds having an S configuration at the chiral center, compounds having an R configuration at the chiral center, or compounds having a mixture of R and S configurations at the chiral center.

[0059] A racemic mixture means a mixture of 50% being an enantiomer and 50% being its corresponding enantiomers. The teachings of this invention encompass all enantiomerically pure, enantiomerically enriched, diastereomerically pure, diastereomerically enriched, racemic mixtures, and diastereomeric mixtures of the compounds described herein.

[0060] By well-known methods, such as chiral gas chromatography and chiral high-performance liquid chromatography, compounds can be crystallized into chiral salt complexes or crystallized in chiral solvents, and mixtures of enantiomers and diastereomers can be decomposed into their component enantiomers or stereoisomers. Enantiomers and diastereomers can also be obtained from diastereomeric or enantiomeric pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0061] In the experimental section, "peak 1" or "first dissolution isomer" refers to the predetermined reaction product compound obtained by chromatography separation / purification, which dissolves earlier than the second predetermined reaction product compound from the same aforementioned reaction. The second predetermined product compound is called "peak 2" or "second dissolution isomer".

[0062] When a compound is represented by the name or structure indicating a single enantiomer, unless otherwise indicated, the compound is optically pure (also referred to as "enantiomeric purity") of at least 60%, 70%, 80%, 90%, 99%, or 99.9%. Optical purity is the weight of the mixture of the named or described enantiomers divided by the total weight of the mixture of the two enantiomers.

[0063] When the stereochemistry of a compound is revealed by structural naming or description, and the named or described structure covers more than one stereoisomer (e.g., as a diastereomer pair), it should be understood that, unless otherwise indicated, it includes one of the covered stereoisomers or any mixture of the covered stereoisomers. It is further understood that the stereoisomer purity of the named or described stereoisomer is at least 60 wt%, 70 wt%, 80 wt%, 90 wt%, 99 wt%, or 99.9 wt%. Stereoisomer purity in this condition is determined by dividing the total weight of the mixture of stereoisomers covered by the name or structure by the total weight of the mixture of all stereoisomers.

[0064] Use Examples The compounds of the present invention are MAP4K1 inhibitors. The term "inhibitor" as used herein means that the compound or a pharmaceutically acceptable salt thereof inhibits MAP4K1 activity. "Inhibition" herein means a reduction in the activity of the target enzyme compared to the enzyme activity in the absence of an inhibitor. In some alternatives, the term "inhibition" means a reduction in MAP4K1 activity of at least 5%, at least 10%, at least 20%, at least 50%, at least 60%, at least 79%, at least 80%, at least 90%, or at least 95%. In other alternatives, inhibition means a reduction in MAP4K1 activity of 5% to 25%, 25% to 50%, 50% to 70%, or 75% to 100%. In some embodiments, inhibition means a reduction in MAP4K1 activity of about 95% to 100%, for example, a reduction of 95%, 96%, 97%, 98%, 99%, or 100%. Such reductions can be measured using a variety of techniques recognizable to those skilled in the art, including in vitro kinase assays.

[0065] The compounds of the present invention are selective MAP4K1 inhibitors. As used herein, "selective MAP4K1 inhibitor" means a compound or a pharmaceutically acceptable salt thereof that can selectively inhibit MAP4K1 kinase relative to other targets. More specifically, a selective MAP4K1 inhibitor has the ability to selectively inhibit MAP4K1 relative to another kinase. A selective MAP4K1 inhibitor has the ability to selectively reduce target signaling activity relative to deviations from target signaling activity through direct or indirect interaction with the target. The ability to selectively target MAP4K1 with compounds or pharmaceutically acceptable salts provides advantages over non-selective compounds or salts in terms of improved efficacy against the desired target, reduced off-target activity, and increased chances of clinical success.

[0066] MAP4K1 inhibitors that selectively inhibit MAP4K1 may have at least 2-fold activity relative to another kinase (e.g., at least 10-fold; at least 15-fold; at least 20-fold; at least 30-fold; at least 40-fold selectivity; at least 50-fold; at least 60-fold; at least 70-fold; at least 80-fold; at least 90-fold; at least 100-fold; at least 125-fold; at least 150-fold; at least 175-fold; or at least 200-fold). In some alternatives, the selective MAP4K1 inhibitor exhibits at least 15-fold selectivity relative to another kinase (e.g., LCK and MAP4K family members (MAP4K4 (HGK) and MAP4K3 (GLK))). In some alternatives, the selective MAP4K1 inhibitor is selective relative to EGFR and L858R / T790M EGFR. In some alternatives, the selective MAP4K1 inhibitor of the present invention is selective relative to BTK. In some alternatives, the selective MAP4K1 inhibitor of the present invention is selective relative to JNK.

[0067] This invention provides a method for regulating (e.g., inhibiting) MAP4K1 activity in an individual in need, the method comprising administering to the individual a compound provided herein or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of this invention or a pharmaceutically acceptable salt thereof is suitable for therapeutic administration to an individual in need, such as a cancer patient or a patient with a viral infection, to enhance, stimulate, and / or increase immunity. In some cases, the compound of this invention or a pharmaceutically acceptable salt thereof reduces, inhibits, or otherwise weakens SLP76 phosphorylation.

[0068] In some cases, the compounds of the present invention or their pharmaceutically acceptable salts are suitable for therapeutic administration to enhance at least one of the following T cell activities relative to pre-administration: activation, migration, proliferation, survival, and cytolysis. In some cases, T cell activation is characterized by increased levels of IL-2, IFN-γ, or granzyme B produced by T cells relative to pre-administration of the compound or its pharmaceutically acceptable salt. In some cases, the compounds of the present invention or their pharmaceutically acceptable salts are suitable for therapeutic administration to induce changes in cell cycle or cell viability. In some cases, the compounds of the present invention or their pharmaceutically acceptable salts are suitable for improving the function of T effector cells. In some cases, the compounds of the present invention or their pharmaceutically acceptable salts are suitable for inhibiting the suppressive effects of T regulatory cells or improving T cell responses to immunosuppressive factors including adenosine and PGE2.

[0069] In some cases, the compounds of the present invention or their pharmaceutically acceptable salts are suitable for increasing the frequency of CD8+ tumor-infiltrating lymphocytes (TILs). In some cases, the compounds of the present invention or their pharmaceutically acceptable salts are suitable for increasing the CD3+ / Treg ratio. In some cases, the compounds of the present invention or their pharmaceutically acceptable salts are suitable for enhancing interleukins. In some cases, the compounds of the present invention or their pharmaceutically acceptable salts are suitable for enhancing interleukins without affecting IL-6. In some cases, the compounds of the present invention or their pharmaceutically acceptable salts indirectly inhibit cancer cell growth. In some cases, the compounds of the present invention or their pharmaceutically acceptable salts are suitable for activating an immune response to a tumor or virus (i.e., a vaccine) to initiate or generate antiviral / antitumor immunity. In one instance, the compounds of the present invention or their pharmaceutically acceptable salts are used to enhance or increase the response to vaccines (such as cancer vaccines or personalized cancer vaccines (PCV)) or CAR-T cell therapy.

[0070] Methods of treating MAP4K1-dependent diseases or conditions may include administering to an individual in need a therapeutically effective amount of a compound provided herein or a medically acceptable salt thereof. For example, a MAP4K1-dependent disease or condition is cancer. The term "cancer" encompasses all forms of cancer, including but not limited to all forms of carcinoma, melanoma, blastoma, sarcoma, lymphoma, and leukemia. In some embodiments, cancer includes metastatic forms. Additionally, the present invention includes refractory or relapsed malignancies whose growth can be inhibited using compounds of the present invention or medically acceptable salts thereof. For the uses described herein, any of the compounds of the present invention or medically acceptable salts thereof may be used alone or in combination with other therapeutic agents.

[0071] In some embodiments, the treatment induces a sustained response in the individual after treatment is discontinued. A "sustainable response" refers to a continued effect on reducing tumor growth after treatment is discontinued. For example, the tumor size may remain the same or decrease compared to its size at the start of the treatment phase. In some embodiments, the duration of the sustained response is at least the same as the treatment duration, and is at least 1.5 times, 2.0 times, 2.5 times, or 3.0 times the treatment duration.

[0072] The treatment methods disclosed herein may elicit partial or complete responses. As used herein, "complete response" or "CR" means the disappearance of all target lesions; "partial response" or "PR" means a reduction of at least 30% in the sum of the longest diameters (SLD) of the target lesions, with reference to baseline SLD; and "stable disease" or "SD" means that the target lesions have neither shrunk sufficiently to qualify for PR nor increased sufficiently to qualify for PD, with reference to the minimum SLD at the start of treatment. As used herein, "overall response rate" (ORR) refers to the sum of the complete response (CR) rate and the partial response (PR) rate.

[0073] The treatment methods disclosed herein can increase progression-free survival and overall survival in individuals administered a selective MAP4K1 inhibitor. As used herein, "progression-free survival" (PFS) refers to the length of time during and after treatment during which the treated disease (e.g., cancer) does not worsen. PFS may include the amount of time an individual experiences a complete or partial response, as well as the amount of time an individual experiences stable disease.

[0074] As used herein, “overall survival” (OS) refers to the percentage of individuals in a group who are likely to survive after a certain duration.

[0075] In some embodiments, cancers that can be treated with the compounds of the present invention or their pharmaceutically acceptable salts include colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, bladder cancer, stomach cancer, liver cancer, head and neck cancer, lymphoma, leukemia, urothelial carcinoma, Merkel cell carcinoma, gastroesophageal junction cancer, esophageal squamous cell carcinoma, skin squamous cell carcinoma, and melanoma.

[0076] In some embodiments, cancers that can be treated with the compounds of the present invention or their pharmaceutically acceptable salts include colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, bladder cancer, stomach cancer, liver cancer, head and neck cancer, lymphoma, leukemia, and melanoma.

[0077] In some embodiments, cancers that can be treated with the compounds of the present invention or their pharmaceutically acceptable salts include, but are not limited to, solid tumors, including prostate cancer, colorectal cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, brain cancer, and bladder cancer; and hematologic cancers, including lymphomas, leukemias (chronic and acute forms), such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (NHL) (including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin's lymphoma, and multiple myeloma; and myeloproliferative disorders.

[0078] In some embodiments, diseases and conditions that can be treated with the compounds of the present invention or their medically acceptable salts include, but are not limited to, blood cancers, sarcomas, respiratory cancers, gastrointestinal cancers, genitourinary cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0079] Exemplary hematologic malignancies include, for example, lymphomas and leukemias such as ALL, AML, acute myeloid leukemia (APL), CLL, CML, DLBCL, mantle cell lymphoma, non-Hodgkin lymphoma (NHL) including primary mediastinal B-cell lymphoma (PMBCL), relapsed or refractory NHL, relapsed follicular and primary CNS lymphoma, Hodgkin's lymphoma, and myeloproliferative disorders including primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET), myelodyplastic syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's macroglubulinemia, pilocellular lymphoma, chronic myeloid lymphoma, and Burkitt's lymphoma.

[0080] Exemplary sarcomas include, for example, chondrosarcoma, Ewing's sarcoma, Kaburg's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, soft tissue sarcoma and teratoma.

[0081] Exemplary respiratory tract cancers include, for example, lung cancer, such as non-small cell lung cancer (NSCLC), small cell lung cancer, epidermoid carcinoma, bronchial carcinoma (including squamous cell, undifferentiated small cell, undifferentiated large cell), adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, mesothelioma and pleural pulmonary blastoma.

[0082] Exemplary gastrointestinal cancers include, for example, esophageal cancers, including squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; gastric cancers, including carcinoma, lymphoma, and leiomyosarcoma; pancreatic cancers, including ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, and vasoactive intestinal peptide tumor; small intestinal cancers, including adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, and fibroma; large intestinal cancers, including adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyosarcoma; and gallbladder cancers, including adenocarcinoma; as well as intestinal and diffuse gastric adenocarcinoma, rectal cancer, common adenomatous polyps, and hereditary nonpolyposis colorectal cancer.

[0083] Example genitourinary cancers include, for example, cancers of the kidneys, including adenocarcinoma, Wilms' tumor [nephroblastoma], renal cell carcinoma, urethral epithelial carcinoma, glomerular cell tumor (reninoma), angiomyoma, renal eosinophilic adenoma, Bellinio duct carcinoma, clear cell sarcoma of the kidney, and mesodermal nephroma; cancers of the adrenal glands; cancers of the renal pelvis; cancers of the bladder, including transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell carcinoma; cancers of the urethra, including squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; cancers of the prostate, including adenocarcinoma, sarcoma, and carcinoma; cancers of the testes, including seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, and lipoma; cancers of the penis; and cancers of the pancreas.

[0084] Exemplary liver cancers include, for example, liver cancer, including hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, biliary tract cancer and hemangioma.

[0085] Exemplary bone cancers include, for example, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (including reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma), osteochondroma (including osteochondroma, benign chondroma, chondroblastoma, chondromycinous fibroma), osteoid osteoma, and giant cell tumor.

[0086] Exemplary nervous system cancers include, for example, cancers of the skull, including osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans; cancers of the meninges, including meningioma, meningeal sarcoma, and glioma; cancers of the brain, including astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), neuroectodermal tumor, glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, brainstem and hypothalamic gliomas; and cancers of the spinal cord, including neurofibroma, meningioma, glioma, and sarcoma; as well as neuroblastoma and Lhermitte-Duclos disease.

[0087] Example gynecological cancers include, for example, cancers of the uterus, including endometrial cancer; cancers of the cervix, including cervical cancer, pretumoral cervical dysplasia, squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumors, hyalinous cell carcinoma, and papillary adenocarcinoma; cancers of the ovary, including ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, endometrial tumor, high-grade plasma cell carcinoma), follicular cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma, and ovarian male embryonal tumor; cancers of the vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma); cancers of the vagina, including clear cell carcinoma, squamous cell carcinoma, and botryoid sarcoma (embryosarcoma); cancers of the labia; and cancers of the fallopian tubes.

[0088] Exemplary skin cancers include melanoma, sebaceous carcinoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloid.

[0089] Examples of breast cancer include, for example, ER+ / HER2- breast cancer, triple-negative breast cancer (TNBC), invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

[0090] Exemplary head and neck cancers include, for example, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cancer, and pharyngeal cancer, including oropharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, nasal cancer and sinus cancer, salivary gland cancer, oral cancer, eye cancer, acoustic neuroma, pituitary adenoma, pharyngeal and thyroid cancer (medullary and papillary) and parathyroid cancer.

[0091] Other cancers include, for example, sweat gland cancer, spinal axis tumors, thoracic cancer, sickle cell anemia, and environment-induced cancers, including those induced by asbestos.

[0092] In some embodiments, the compounds of the present invention or their pharmaceutically acceptable salts are used to treat advanced melanoma, advanced NSCLC or advanced head and neck squamous cell carcinoma, including cases where the individual is difficult to treat with or has only partially responded to immune checkpoint inhibitor therapy.

[0093] In some cases, MAP4K1-dependent diseases or conditions are caused by viral infections, such as those caused by hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella-zoster virus, coxsackie virus, and human immunodeficiency virus (HIV).

[0094] Combination Therapy The compounds of the present invention or their pharmaceutically acceptable salts may be administered as a sole medicine or in combination with one or more other anticancer agents for the treatment of cancer, wherein the combination does not cause unacceptable adverse effects. In some embodiments, the other anticancer agents are immuno-oncology agents, anticancer agents as enzyme / protein / receptor inhibitors, radiation, or chemotherapy.

[0095] The compounds of the present invention or their pharmaceutically acceptable salts may be co-formulated with immuno-oncology agents. Immuno-oncology agents include, for example, small molecule drugs, antibodies, antibody-drug conjugates, or other biological agents or small molecules. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one state, the antibody is a monoclonal antibody. In another state, the monoclonal antibody is a humanized antibody or a human antibody. In yet another state, the antibody is a bispecific antibody.

[0096] In one state, the immuno-oncology agent is either (i) a stimulator (including costimulatory) of receptors or (ii) an antagonist that inhibits (including co-inhibitory) signals on T cells, both of which induce an amplification of antigen-specific T cell responses (commonly referred to as immune checkpoint regulators, and in some cases as immune checkpoint inhibitors).

[0097] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to costimulatory or coinhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-binding ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to members of the homologous TNF receptor family. These include CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTFIR, LIGHT, DCR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNPβ, TNFR2, TNF a, LTR, and lymphotoxin α. 1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0098] In one embodiment, a T cell response can be stimulated by a combination of the compound of the present invention or a pharmaceutically acceptable salt thereof with one or more of the following: (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor), such protein being CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galactoglobulin 9, CEACAM-1, BTLA, CD69, galactoglobulin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; and (ii) a agonist of a protein that stimulates T cell activation, such protein being B7-1, B7-2, CD28, 4-1BB. (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.

[0099] In one formulation, the compound of the present invention or a pharmaceutically acceptable salt thereof may be administered in combination with at least one other immune checkpoint inhibitor. In other formulations, the compound of the present invention or a pharmaceutically acceptable salt thereof may be administered for the treatment of NSCLC resistant to immune checkpoint inhibitors, including cases where the individual is difficult to treat with platinum and / or paclitaxel and / or docetaxel therapy or has a partial response to it. Where appropriate, the compound of the present invention or a pharmaceutically acceptable salt thereof may be administered in combination with at least one other anticancer agent, such as paclitaxel, docetaxel, or platinum anticancer therapy. The compound of the present invention or a pharmaceutically acceptable salt thereof may be administered as first-line treatment for NSCLC exhibiting high PD-LI (≥50% tumor proportion score (TPS), wild-type EGFR, or wild-type ALK).

[0100] Other agents that can be combined with the compounds of the present invention or their pharmaceutically acceptable salts for the treatment of cancer include antagonists that inhibit receptors on NK cells or agonists that activate receptors on NK cells. For example, the compounds of the present invention or their pharmaceutically acceptable salts can be combined with antagonists of KIR, such as lirilumab.

[0101] Other agents used in combination therapy with the MAP4K1 inhibitors disclosed herein include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists, such as CSF-1R antagonist antibodies including RG7155 or FPA-008.

[0102] In another embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof may be used with one or more of the following: agonists that bind to positive costimulatory receptors; blockers that attenuate signal transduction by inhibiting receptors; antagonists; and one or more agents that systemically increase the frequency of anti-tumor T cells; agents that overcome different immunosuppressive pathways in the tumor microenvironment (e.g., blocking inhibitory receptor binding (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by depletion of ex vivo anti-CD25 beads), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell dysfunction or exhaustion); and agents that trigger innate immune activation and / or inflammation at the tumor site.

[0103] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab. In another embodiment, the immuno-oncology agent is a PD-1 antagonist, such as an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012 / 145493). Immuno-oncology agents may also include pidilizumab (CT-011), although its specificity for PD-1 binding has been questioned. Another approach to targeting the PD-1 receptor is a recombinant protein called AMP-224, which is formed by fusing the extracellular domain of PD-L2 (B7-DC) with the Fc portion of IgG1.

[0104] In another category, immuno-oncology agents are PD-L1 antagonists, such as PD-L1 antagonist antibodies. Suitable PD-L1 antibodies include, for example, atezolizumab (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0105] In another category, the immuno-oncology agent is a LAG-3 antagonist, such as an anti-LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218) or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0106] In another category, immuno-oncology agents are CD137 (4-1BB) agonists, such as agonist CD137 antibodies. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (W012 / 32433).

[0107] In another category, the immuno-oncology agent is a GITR activator, such as an activating GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116) and MK-4166 (WO1 1 / 028683).

[0108] In another variant, the immuno-oncology agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO2006 / 122150, WO07 / 75598, WO08 / 36653, WO08 / 36642), indoximod, or NLG-919 (WO09 / 73620, WO09 / 1156652, WO11 / 56652, WO12 / 142237).

[0109] In another variant, the immuno-oncology agent is an OX40 agonist, such as an agonist OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469. In another variant, the immuno-oncology agent is an OX40L antagonist, such as an antagonist OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0110] In another embodiment, the immuno-oncology agent is a CD40 agonist, such as an agonist CD40 antibody. In yet another embodiment, the immuno-oncology agent is a CD40 antagonist, such as an antagonist CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0111] In another category, immuno-oncology agents are CD27 agonists, such as agonist CD27 antibodies. Suitable CD27 antibodies include, for example, varlilumab.

[0112] In another variant, the immuno-oncology agent was MGA271 (targeting B7H3) (WO1 1 / 109400).

[0113] The compounds of the present invention or their pharmaceutically acceptable salts can be used in combination with anticancer agents, such anticancer agents being enzyme / protein / receptor inhibitors that exhibit different preferences in modulating the activity of the target to treat such conditions. Targeting more than one signaling pathway (or more than one biomolecule involved in a specified signaling pathway) can reduce the likelihood of drug resistance developing in cell populations and / or reduce the toxicity of treatment.

[0114] The compounds of the present invention or their pharmaceutically acceptable salts may be used in combination with one or more other enzyme / protein / receptor inhibitors used for the treatment of cancer. For example, the compounds of the present invention or their pharmaceutically acceptable salts may be used in combination with one or more inhibitors of the following kinases used for the treatment of cancer: Akt1, Akt2, Akt3, TGF-βPv, PKA, PKG, PKC, CaM kinase, phosphatase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFotR, PDGFpR, CSFIR, KIT, FLK-II, KD R / FLK-1, KRAS, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt 2. Flt4, EphAl, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf.

[0115] In some embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof may be combined with one or more of the following inhibitors used to treat cancer. Non-limiting examples of inhibitors that can be combined with the compounds of the present invention or their pharmaceutically acceptable salts for the treatment of cancer include FGFR inhibitors (FGFR1, FGFR2, FGFR3, or FGFR4, such as fisogatinib, AZD4547, BAY 1187982, ARQ087, BGJ398, BIBF1120, TKI258, lucitinib, dovitinib, TAS-120, JJ-42756493, Debiol347, INCB54828, INCB62079, and INCB63904) and JAK inhibitors (JAK1 and / or JAK2, such as ruxolitinib, baricitinib, or itacitinib). (INCB39110)), IDO inhibitors (e.g., epacadostat and NLG919), LSD1 inhibitors (e.g., GSK2979552, INCB59872 and INCB60003), TDO inhibitors, PI3K-δ inhibitors (e.g., INCB50797 and INCB50465), PI3K-γ inhibitors (such as PI3K-selective inhibitors (e.g., eganelisib)) or dual PI3K-δ / selective inhibitors (e.g., ... Duvelisib, CSF1R inhibitors (e.g., PLX3397 and LY3022855), TAM receptor tyrosine kinase inhibitors (Tyro-3, Axl, and Mer), angiogenesis inhibitors (e.g., bevacizumab), interleukin receptor inhibitors, bromine and superterminal family member inhibitors (e.g., bromine domain inhibitors or BET inhibitors, such as OTX015, CPI-0610, INCB54329, and INCB57643), and adenosine receptor antagonists, or combinations thereof. HDAC inhibitors, such as panobinostat and vorinostat, may be combined with the compounds of this invention or their pharmaceutically acceptable salts. c-Met inhibitors, such as onartumzumab, tivantnib, and capmatinib (INC-280), may be combined with the compounds of this invention or their pharmaceutically acceptable salts. Inhibitors of BTK, such as ibrutinib, can be combined with the compounds of the present invention or their pharmaceutically acceptable salts.Inhibitors of mTOR, such as rapamycin, sirolimus, temsirolimus, and everolimus, may be combined with the compounds of the present invention or their pharmaceutically acceptable salts. Inhibitors of Raf, such as vemurafenib and dabrafenib, may be combined with the compounds of the present invention or their pharmaceutically acceptable salts. Inhibitors of MEK, such as trametinib, selumetinib, and GDC-0973, may be combined with the compounds of the present invention or their pharmaceutically acceptable salts. Inhibitors of KIT include avapritinib, BLU-263, imatinib, sunitinib, regorafenib, ripritinib (DCC2618), PLX9486, PLX3397, crenolanib, CDX-0158, and CDX-0159. Inhibitors of RET include pralsetinib, selperctinib, alectinib, levatinib, cabozantinib, BOS172738 (DS-5010), SL-1001, TPX-0046, sitravatinib (MGCD516), and RXDX-105. Inhibitors of Hsp90 (e.g., tanespimycin), cyclin-dependent kinases (e.g., palbociclib), PARP (e.g., olaparib), Pim kinases (e.g., LGH447, INCB053914, and SGI-1776), and KRAS (e.g., sotorasib) may also be combined with the compounds of the present invention or their pharmaceutically acceptable salts.

[0116] The compounds of the present invention or pharmaceutically acceptable salts thereof may be used in combination with one or more agents for treating cancer. In some embodiments, the agents are alkylating agents, proteasome inhibitors, corticosteroids, or immunomodulators. Examples of alkylating agents include bendamustine, nitrogen mustard, ethylimine derivatives, alkyl sulfonates, nitrosoureas and triazine, uracil nitrogen mustard, nitrogen mustard, cyclophosphamide, ifosfamide, melphalan, chlorambucil chlorbutyric acid, piperobromethane, triethylmelamine, triethylphosphothiophosphatidylcholine, busulfan, carmustine, lomustine, streptozotocin, dacarbazine, and temozolomide. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone.

[0117] The compounds of the present invention or their pharmaceutically acceptable salts may be administered in combination with one or more anticancer drugs, such as chemotherapeutic agents. Exemplary chemotherapeutic agents include any of the following: abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, hexamethylmelamine, anastrozole, arsenic trioxide, aspartate aminotransferase, axitinib, azacytidine, bevacizumab, bexarotene, baricitinib, bicalutamide, bleomycin. Bortezomib, bortezomib, brivanib, buparlisib, intravenous busulfan, oral busulfan, calotestosterone, capecitabine, carmustine, cediranib, cetuximab, chlorisamine, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, actinomycin, dalteparin sodium Sodium, dasatinib, actinomycin, daunorubicin, decitabine, degarelix, denileukin, denileukin diftitox, deoxymyotrophic acid, dexrazoxane, doxorubicin, droloxafine, dromostanolone propionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin, erlotinib, estradiol mustard, etoposide phosphate, etoposide, exemestane, fentanyl citrate.citrate, filgrastim, fluxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab, ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon alpha-2a, irinotecan, lapatinib dimethylbenzenesulfonate ditosylate, lenalidomide, letrozole, leuprolide acetate, levamisole, lomustine, nitrogen mustard, medroxyprogesterone acetate, melphalan, mercaptopurine, methoxypterin, methoxsalen, mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolone phenylpropionate phenpropionate, navelbene, necitumumab, nelarabine, neratinib, nilotinib, nilutamide, nofetumomab, oserelin, paclitaxel, pamidronate, panitumumab, pazopanib, pegfilgrastim, pemetrexeddisodium), pentostatin, pilaralisib, piperobromidine, plicamycin, cisplatin, carboplatin, oxaliplatin, ponatinib, prednisone, procarbazine, quinacrine, rasburicase, regorafenib, reloxafine, rituximab, ruxolitinib, sorafenib, streptozotocin, sunitinib, sunitinib maleate, and other similar products. Tamoxifen, tegafur, temozolomide, teniposide, testrolide, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, retinoids, triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronic acid.

[0118] Other anticancer agents include antibody therapy, such as trastuzumab.

[0119] The compounds of the present invention or pharmaceutically acceptable salts thereof may be administered as a sole medicine or in combination with one or more antiviral agents for the treatment of chronic viral infections, wherein such combination does not cause unacceptable adverse effects. Chronic viral infections include, but are not limited to, diseases caused by: hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella-zoster virus, Coxsackie virus, and human immunodeficiency virus (HIV). Parasitic infections (e.g., malaria) may also be treated by the methods described above, wherein, where appropriate, compounds known to treat parasitic conditions are added instead of antiviral agents.

[0120] Suitable antiviral agents intended for use in combination with the compounds of the present invention or their pharmaceutically acceptable salts may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors and other antiviral drugs.

[0121] Examples of suitable NRTIs include, for example, zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-I0652; emitricitabine [(-)-FTC]; β-L-FD4 (also known as β-L-D4C and named β-L-2',3'-dideoxy-5-fluoro-cytosine nucleoside); DAPD ((-)-β-D-2,6-diamine-purine dioxane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (l-(ethoxy-methyl)-5-(l-methylethyl)-6-(phenylmethyl)-(2,4(lH,3H)-pyrimidinidone); and (+)-tetracyclic coumarin A (NSC-675451) and B. Typical suitable protease inhibitors include saquiNavir (Ro 31-8959); ritonavir (ABT-538); indiNavir (MK-639); and nelfinavivir. (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project No. 11607.

[0122] When administering more than one pharmaceutical agent to an individual, they may be administered simultaneously, separately, sequentially, or in combination (e.g., for more than two agents). For example, when administered with an additional anticancer or antiviral agent, the disclosed compound or its pharmaceutically acceptable salt may be administered simultaneously in the same pharmaceutical formulation or in separate pharmaceutical formulations. Alternatively, when administered with an additional anticancer or antiviral agent, the disclosed compound or its pharmaceutically acceptable salt may be administered at different times, depending on the administration requirements of the additional anticancer or antiviral agent.

[0123] The disclosed pharmaceutical compositions comprise one or more compounds provided herein (such as compounds of formula I, II, III, IV, V, VI, or VII), and typically at least one additional substance, such as excipients, known therapeutic agents other than the therapeutic agents of the present invention, and combinations thereof. In some embodiments, the disclosed compounds or pharmaceutically acceptable salts thereof may be used in combination with other agents known to have beneficial activity targeting the diseases or conditions listed above. For example, the disclosed compounds or pharmaceutically acceptable salts thereof may be administered alone or in combination with one or more anticancer or antiviral agents.

[0124] As used herein, the terms “administer,” “administering,” “administration,” and similar terms refer to methods that enable the delivery of a composition to a desired site of biological action. These methods include, but are not limited to, intra-articular, intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, percutaneous, transrectal, and similar methods. Administration techniques that can be used with the pharmaceuticals and methods described herein can be found, for example, in: Goodman and Gilman, *The Pharmacological Basis of Therapeutics*, current edition; Pergamon; and Remington’s *Pharmaceutical Sciences* (current edition), Mack Publishing Co., Easton, Pa.

[0125] "Individual" is a mammal, preferably a human, but may also be an animal requiring veterinary treatment, such as companion animals (e.g., dogs, cats and similar animals), livestock (e.g., cattle, sheep, pigs, horses and similar animals) and laboratory animals (e.g., rats, mice, guinea pigs and similar animals).

[0126] The precise amount of the compound or its pharmaceutically acceptable salt administered to provide an individual's "effective dose" will depend on the administration method, the type and severity of the disease or condition, and individual characteristics such as general health status, age, sex, weight, and tolerance to the drug. Those skilled in the art will be able to determine the appropriate dosage based on these and other factors. When administered in combination with other therapeutic agents, such as anticancer or antiviral agents, the "effective dose" of any additional therapeutic agent will depend on the type of drug used. Appropriate dosages of approved therapeutic agents are known, and those skilled in the art can adjust these dosages according to the individual's condition, the type of condition being treated, and the amount of the compound of the invention or its pharmaceutically acceptable salt used, following, for example, the dosages reported in the literature and recommended in the Physician's Desk Reference (57th edition, 2003).

[0127] The term "effective dose" means the amount that, when administered to an individual, produces a favorable or desired outcome, including clinical outcomes, such as the inhibition, suppression, or reduction of symptoms of the condition being treated in the individual compared to a control. For example, an effective therapeutic dose may be given in unit dosage form (e.g., 0.1 mg to about 50 g / day, or 1 mg to about 5 g / day; and in another alternative, 10 mg to 1 g / day).

[0128] Taking into account the details of the case (e.g., the individual, the disease, the disease condition involved, the specific treatment, and whether the treatment is preventative), the attending clinician will select a specific administration pattern and dosing regimen. Treatment may involve daily or more-than-daily (e.g., weekly or monthly) administration over a period of days to months or even years.

[0129] The pharmaceutical composition of the present invention is formulated to be compatible with its intended route of administration. In one embodiment, the composition is formulated according to conventional procedures for administration to a human via intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration. In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0130] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that facilitate the formulation and / or administration to and / or absorption by an individual of an active agent and can be included in the compositions of the present invention without causing significant adverse toxicological effects on the individual. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, standard saline solutions, lactated Ringer's solution, standard sucrose, standard glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethyl cellulose, polyvinylpyrrolidone, and pigments and the like. Such formulations may be sterile and, where necessary, mixed with excipients (such as lubricants, preservatives, stabilizers, humectants, emulsifiers, salts that affect osmotic pressure, buffers, colorants, and / or aromatic substances and their analogues), which do not produce harmful reactions with the compounds provided herein or interfere with the activity of the compounds provided herein. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds.

[0131] General synthetic methods and intermediates The synthetic schemes for preparing the compounds in Table 1 are listed in the last row of Table 1 and the complete details of each synthetic scheme are described in Procedures 1 and 2 (below) in the General Synthetic Methods and Intermediates section.

[0132] Process 1 Process 1 illustrates a synthetic scheme for preparing compound iv. An azide-substituted chloroheterocyclic intermediate i can be coupled to a substituted aniline ii under Pd-catalyzed coupling conditions to give iii. The azide intermediate iii can be reduced under catalytic hydrogenation conditions with a catalyst such as Pd / C or PtO2 to give amine compound iv, which are examples of MAP4K1 inhibitors described herein.

[0133] Process 2 Process 2 illustrates a synthetic scheme for preparing compound iv. The sulfinamide-substituted chloroheterocyclic intermediate i can be coupled to the substituted aniline ii under Pd-catalyzed coupling conditions to give iii. The sulfinamide group of intermediate iii can be converted to an amine under acidic conditions such as HCl to give amine compound iv, which are examples of MAP4K1 inhibitors described herein.

[0134] The following examples are intended to illustrate, but are not intended to be limiting in any way.

[0135] Example Abbreviations ACN Acetonitrile (“MeCN”) AcOH Acetic acid ATP Adenosine triphosphate BrettPhos Dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine t-BuOK Potassium terbutoxide C Celsius DBU Diazabicyclo[5.4.0]undecyl-7-ene DCE Dichloroethane DCM Dichloromethane DIAD Diisopropyl azodicarboxylate DIBAL Diisobutylaluminum hydrogenate DIPEA Diisopropylethylamine DMBNH 2,4-dimethoxybenzylamine DMF Dimethylformamide DMSO Dimethyl sulfoxide DTT Dithiothreitol eq Equivalent EA Ethyl acetate EDTA Ethyl diaminetetraacetic acid Et 2O Diethyl ether EtSH Ethyl mercaptan FA Formic acid h Hour HEPES 4-(2-Hydroxyethyl)-1-piperazine ethanesulfonic acid HPLC High Performance Liquid Chromatography IBX 2-Iodooxybenzoic acid IC50 50% Inhibition Concentration IPA Isopropanol KF Potassium fluoride KOAc Potassium acetate LiHMDS Bis(trimethylsilyl)acetamide lithium MeMgBr Methyl magnesium bromide min min MTBE Methyl tributyl ether MeOH Methanol MsCl Methanesulfonyl chloride NBS N-bromobutyldiimide NMO N-methyl sulfoline N-oxide NMP N-methyl-2-pyrrolidone Oxone Potassium peroxide monosulfate PE Petroleum ether PrMgBr Isopropyl magnesium bromide SFC Supercritical Fluorescence Chromatography TEA Trimethylamine THF Tetrahydrofuran TFA Trifluoroacetic acid TfOH Trifluoromethanesulfonic acid TMEDA Tetramethyl ethyldiamine TSN 3-Azide trimethylsilane

[0136] The method for preparing the compounds of the present invention can be carried out in a suitable solvent readily chosen by those skilled in organic synthesis. A suitable solvent is one that does not react with the starting material (reactant), intermediate, or product at the reaction temperature, for example, within the range of the solvent's freezing temperature to its boiling temperature. The specified reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, the solvent suitable for that specific reaction step can be selected by those skilled in the art.

[0137] The preparation of the compounds of the present invention may involve the protection and removal of various chemical groups. Whether protection and deprotection are required, and the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemical role of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons: New Jersey, (2014), which is incorporated herein by reference in its entirety.

[0138] The reaction can be monitored using any suitable method known in this art. For example, product formation can be monitored by spectroscopic means such as nuclear magnetic resonance (NMR) spectroscopy (e.g., 1H or 13C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV-Vis), mass spectrometry (MS), or by chromatographic methods such as high-performance liquid chromatography (HPLC) or thin-layer chromatography (TLC). Analytical instruments and methods for compound characterization:

[0139] LC-MS: Unless otherwise indicated, all liquid chromatography-mass spectrometry (LC-MS) data (purity and identity of the analyzed samples) were obtained using an Agilent Model 6120 mass spectrometer at 22.4°C using an Agilent Model-1260 LC system equipped with an Agilent Poroshel 120 (EC-C18, 2.7 µm particle size, 3.0 × 50 mm) reverse-phase column and ES-API ionization. The mobile phase consisted of a mixture of 0.1% FA in water and 0.1% FA in acetonitrile. A constant gradient of 95% aqueous / 5% organic to 5% aqueous / 95% organic mobile phase was used over a 4-minute process. The flow rate was kept constant at 1 mL / min.

[0140] Preparative LC-MS: Preparative HPLC was performed at 22.4°C on a Shimadzu Discovery VP® preparative system equipped with a Luna 5u C18(2) 100A, AXIA packaged, 250 × 21.2 mm reversed-phase column. The mobile phase consisted of a mixture of 0.1% FA in water and 0.1% FA in ACN. A constant gradient of 95% aqueous / 5% organic to 5% aqueous / 95% organic mobile phases was used over a 25-minute process. The flow rate was kept constant at 20 mL / min. The microwave-controlled reaction was performed in a Biotage Initiator microwave apparatus.

[0141] Silicone chromatography: Silicone chromatography was performed on a Teledyne Isco CombiFlash® Rf unit or a Biotage® Isolera Four unit.

[0142] Proton NMR: Unless otherwise indicated, all 1H NMR spectra were obtained using a Varian 400MHz Unity Inova 400 MHz NMR instrument (acquisition time = 3.5 s, 1 s delay; 16 to 64 scans). Under characterization, all protons are reported in parts per million (ppm) relative to residual DMSO (2.50 ppm) in DMSO-d6 solvent.

[0143] Those familiar with this technique will recognize that modifications to the gradient, column length, and flow rate are possible, and that some conditions may be more suitable for compound characterization than others, depending on the chemical substance being analyzed.

[0144] Synthetic intermediates

[0145] Intermediates 1 and 2: (7S,8R)-2-amino-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one (intermediate 1) and (7R,8S)-2-amino-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one (intermediate 2), each represented by the structures shown below: (precursor I of intermediate 1) and (precursor I of intermediate 2). Each represented by the structures shown below: (precursor II of intermediate 1) and (precursor II of intermediate 2). Each represented by the structures shown below: (intermediate 1) and (intermediate 2).

[0146] Step 1: Methyl 2-chloro-6-methoxynicotinate (E)-2-(but-2-en-2-yl)-6-methoxynicotinate K3PO4 (120 g, 565 mmol, 3.00 equivalent) and Pd(dppf)Cl2-CH2Cl2 (7.70 g, 9.42 mmol, 0.05 equivalent) were added to a solution of methyl 2-chloro-6-methoxynicotinate (38.0 g, 188 mmol, 1.00 equivalent) and (Z)-2-(but-2-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (44.6 g, 245 mmol, 1.30 equivalent) in THF (320 mL) and H2O (80.0 mL). The reaction mixture was stirred at 70°C under N2 for 2 hours. The reaction mixture was diluted with water (300 mL) and extracted with EA (250 mL × 3). The organic layers were combined and dried over sodium sulfate, then filtered and concentrated under vacuum to give the residue. The residue was purified by preparative HPLC (ACN-H₂O gradient with 0.1% TFA additive). The product-containing solvent was adjusted to pH 8-9 using solid sodium carbonate and the mixture was extracted with EA (300 mL × 3). The combined organic layers were washed with brine (500 mL), dried over Na₂SO₄, filtered, and concentrated to give the title compound as a yellow oil (37.0 g, 167 mmol, 88.7% yield).

[0147] Step 2: A solution of methyl (E)-2-(but-2-en-2-yl)-6-methoxynicotinate (37.0 g, 167 mmol, 1.00 equivalent) in TfOH (171 g, 1.15 mol, 101 mL, 6.85 equivalent) was stirred at 80 °C for 0.5 hours. The mixture was then cooled to ambient temperature, poured into a saturated NaHCO3 aqueous solution (1000 mL), and extracted with EA (300 mL × 5). The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by rapid silica column chromatography (gradient dissolution, 1% to 25% EA-PE) to give the title compound as a yellow oil (30.0 g, 144 mmol, 86.6% yield).

[0148] Step 3: A mixture of 2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one (30.0 g, 144 mmol, 1.00 equivalent) and pyridine hydrochloride (41.8 g, 361 mmol, 2.50 equivalent) was stirred at 150 °C for 0.5 h. The reaction mixture was purified directly by silica gel rapid column chromatography (gradient dissolution, 2% to 10% MeOH-DCM) to give the title compound (26.0 g, 134 mmol, 92.9% yield) as a yellow solid.

[0149] Step 4: Racemic-(7S,8S)-2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one and racemic-(7S,8R)-2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one. DBU (60.8 mL, 403 mmol, 3.00 equivalents) was added to a solution of 2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one (26.0 g, 134 mmol, 1.00 equivalents) in toluene (290 mL). The reaction mixture was stirred at 100 °C for 12 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by rapid silica column chromatography (gradient dissolution, 1% to 10% MeOH-DCM) to give the title compound in the form of a mixture of isomers, which was used in the next step without further purification.

[0150] Step 5: Racemic-(7S,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one and racemic-(7S,8R)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one were stirred at 100°C. Racemic-(7S,8S)-2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one and racemic-(7S,8R)-2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one (26.0 g, 134 mmol, 1 equivalent) were heated in POCl3 (150 °C). The mixture was dissolved in 1 mL (1.61 mol, 11.9 equivalents) for 1 hour. The reaction mixture was then cooled to ambient temperature and poured into a saturated aqueous solution of NaHCO3 (2 L) at 0–10 °C. The quenched mixture was extracted with EA (300 mL × 3), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The cis and trans racemic isomers were separated by preparative HPLC (column: Phenomenex Luna C18 250 × 50 mm × 10 µm; mobile phase: [water (0.1% TFA)-ACN]; B%: 35% ACN-55% CAN, 20 min). Racemic-(7S,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one was the first compound to dissolve and was obtained as a white solid. MS (ES+) C 10H 10ClNO 2 Demand value: 211, Experimental value: 212 [M+H]+. 1H NMR: 400 MHz, CDCl 3δ 8.29 (d, J= 8.2 Hz, 1H), 7.39 (d, J= 8.2 Hz, 1H), 4.83 (dq, J= 3.2, 6.6 Hz, 1H), 3.09 (dq, J= 3.2, 7.2 Hz, 1H), 1.49 (d, J= 6.5 Hz, 3H), 1.30 (d, J= 7.2 Hz, 3H). Racemic-(7S,8R)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one was the second compound to dissolve and was obtained as a white solid. MS (ES+) C 10H 10ClNO 2 Required value: 211, Experimental value: 212 [M+H]+.1H NMR: 400 MHz, CDCl 3δ 8.28 (d, J= 8.2 Hz, 1H), 7.38 (d, J= 8.2 Hz, 1H), 4.58 - 4.43 (m, 1H), 3.05 (quin, J= 7.2 Hz, 1H), 1.56 - 1.40 (m, 6H).

[0151] Step 6: (7S,8R)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one and (7R,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one racemic-(7S,8R)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one were separated by SFC (column: DAICEL CHIRALPAK AD (250 mm × 50 mm, 10 µm); mobile phase: MeOH / CO 2) to obtain the first dissociative isomer (peak 1) and the second dissociative isomer (peak 2) in the form of a white solid.

[0152] Step 7: (7S,8R)-2-((2,4-dimethoxybenzyl)amino)-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one DIPEA (7.48 g, 57.8 mmol, 10.1 mL, 2.50 equivalents) and DMBNH 2 (5.03 g, 30.1 mmol, 4.53 mL, 1.30 equivalents) were added to a solution of (7S,8R)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one (from the first dissolution isomer (peak 1)) (4.90 g, 23.1 mmol, 1.00 equivalents) in NMP (50.0 mL). The reaction mixture was stirred at 100°C for 1 hour, then poured into water (500 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (7.93 g, crude) as a yellow oil, which was used directly in the next step. MS (ES+) C 19H 11N 2O 4 Required value: 342, Experimental value: 343 [M+H]+.

[0153] Step 8: (7S,8R)-2-amino-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one was stirred at 70°C in a solution of (7S,8R)-2-((2,4-dimethoxybenzyl)amino)-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one (7.93 g, 23.1 mmol, 1.00 equivalent) in HCl / dimethylalkanes (4.00 M, 50.0 mL, 8.64 equivalent) for 1 hour. The reaction mixture was then concentrated and partitioned between saturated sodium bicarbonate aqueous solutions (100 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated. The residue was wet-milled in MTBE (50 mL) for 10 minutes and filtered to give a yellow solid. The yellow solid was dried under vacuum to give intermediate 1 of the title compound (3.23 g, 16.4 mmol, 71.2% yield, 98.1% purity). MS (ES+) C 10H 12N 2O 2 Required value: 192, Experimental value: 193 [M+H]+. ¹H NMR: 400 MHz, DMSO- d⁶ δ 7.77 (d, J = 8.6 Hz, ¹H), 6.97 (s, 2H), 6.40 (d, J = 8.6 Hz, ¹H), 4.43–4.21 (m, ¹H), 2.88–2.65 (m, ¹H), 1.35 (d, J = 6.4 Hz, 3H), 1.25 (d, J = 7.0 Hz, 3H). The absolute stereochemistry of the title compound was determined by the X-ray crystal structure of the final compound prepared from this intermediate.

[0154] Steps 9 and 10: The title compound (intermediate 2) of (7R,8S)-2-amino-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one was prepared separately from (7R,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one (the second dissolution isomer of step 6 (peak 2)) using the same two-step procedure as described in steps 7 and 8 of intermediate 2. MS (ES+) C 10H 12N 2O 2 Required value: 192, Experimental value: 193 [M+H]+. 1H NMR: 400 MHz, DMSO- d 6δ 7.77 (d, J= 8.6 Hz, 1H), 6.97 (s, 2H), 6.40 (d, J= 8.6 Hz, 1H), 4.43 - 4.21 (m, 1H), 2.88 - 2.65 (m, 1H), 1.35 (d, J= 6.4 Hz, 3H), 1.25 (d, J= 7.0 Hz, 3H).

[0155] Intermediates 3 and 4: (R)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one and (S)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one, each represented by the structures shown below: (precursor of intermediate 3) and (precursor of intermediate 4). Each represented by the structures shown below: (intermediate 3) and (intermediate 4).

[0156] Steps 1-5: The racemic 2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one title compound was prepared from methyl 2-chloro-6-methoxynicotinate and 4,4,5,5-tetramethyl-2-(3-methylbut-2-en-2-yl)-1,3,2-dioxaborhecyclopentane using a procedure similar to that described in steps 1-3, 5 and 7 of intermediate 1 above.

[0157] Step 6: (R)-2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one and (S)-2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one racemic 2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one were separated by SFC (column: DAICEL CHIRALPAK AS-H (250 mm × 30 mm, 5 µm); mobile phase: [0.1% NH4OH MeOH in CO2]) to obtain ( R)-2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one (first isomer (precursor to intermediate 3), 0.55 g, 79% yield) and (S)-2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one (second isomer (precursor to intermediate 4), 0.55 g, 79% yield). The intermediates were separated and were present as a yellow oil.

[0158] Steps 7 and 8: (R)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one and (S)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one title compounds (intermediates 3 and 4) were dissociated from the first and second isomers, respectively, using the same procedure as described in step 8 of intermediate 1, i.e., (R)-2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one and (S)-2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one and (S)-2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one. Preparation of [b]pyridin-5-one. Intermediate 3, (R)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one, was obtained as a yellow solid. MS (ES+) C 11H 14N 2O 2 Required value: 206, Experimental value: 207 [M+H]+. 1H-NMR (400 MHz, CD 3OD): δ ppm 7.89 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 2.85–2.80 (m, 1H), 1.41 (s, 6H), 1.27 (d, J = 7.2 Hz, 3H). Intermediate 4, (S)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one, was obtained as a yellow solid. MS (ES+) C 11H 14N 2O 2 Required value: 206, Experimental value: 207 [M+H]+. 1H-NMR (400 MHz, CD 3OD): δ ppm 7.89 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 2.85–2.80 (m, 1H), 1.41 (s, 6H), 1.27 (d, J = 7.2 Hz, 3H). The absolute stereochemistry of the title compound was determined by the X-ray crystal structure of the final compound prepared from this intermediate.

[0159] Intermediate 5: 2-amino-7,7-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one

[0160] Step 1: A mixture of 2,2-dimethyltetrahydro-4H-piperano[4,3-b]pyridin-2-one in toluene (4.00 L) was heated at 145 °C for 2 hours using a Dean-Stark separator. The aqueous layer (approximately 16 mL) was removed from the Dean-Stark separator, and the reaction mixture was cooled to 15 °C. After cooling, propyl-2-ylamide (539 g, 7.80 mol, 2.00 equivalent) was added, and the reaction mixture was heated to 150 °C. The reaction mixture was heated at 150 °C for 10 hours, followed by cooling to ambient temperature. The cooled reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel rapid column chromatography (10% methanol-dichloromethane) to give the title compound (560 g, 62% yield) as a yellow solid.

[0161] Step 2: A solution of 2-chloro-7,7-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridine in POCl3 (350 mL, 3.77 mol, 9.64 equivalents) was heated to 100°C for 6 hours. The reaction mixture was then cooled to ambient temperature and concentrated under vacuum. The residue was poured onto ice water (1.00 L). The mixture was extracted with EA (750 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (363 g, 82.2% yield) as a brown oil.

[0162] Step 3: Add a mixture of 2-chloro-7,7-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one to a solution of NaIO4 (487 g, 2.28 mol, 3.00 equivalent) in water (1.20 L) and 2-chloro-7,7-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridine (150 g, 759 mmol, 1.00 equivalent) in MeCN (50.0 mL) and CCl4 (2.70 L). Cool the mixture to 0°C and then add RuCl3 (11.0 g, 53.1 mmol, 0.07 equivalent). Stir the reaction mixture at 0°C for 0.5 h, then raise the temperature to 20°C and hold for 11.5 h. Add a saturated aqueous solution of sodium sulfite (1.00 L) and filter the mixture. The filtrate was extracted with EA (500 mL × 3), and the organic layers were combined. The combined organic layers were washed with brine (1.00 L), dried over Na₂SO₄, filtered, and concentrated to give the title compound as a yellow solid (132 g, 624 mmol, 82.1% yield).

[0163] Step 4: 2-((2,4-dimethoxyphenylmethyl)amino)-7,7-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one was added to a solution of 2-chloro-7,7-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one (135 g, 638 mmol, 1.00 equivalent) and DIPEA (222 mL, 1.28 mol, 2.00 equivalent) in NMP (1.08 L) at ambient temperature. The reaction mixture was heated to 140°C for 2 hours and then cooled to ambient temperature. The reaction mixture was then partitioned between water (700 mL) and EA. The layers were separated, and the aqueous layer was further extracted with EA (500 mL × 3). The organic layers were combined and washed with brine (400 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (160 g) as a yellow solid. The crude product was used directly in the next step.

[0164] Step 5: 2-amino-7,7-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one was added to 2-((2,4-dimethoxybenzyl)amino)-7,7-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one (150 g, 438 mmol, 1.00 equivalent) at 20 °C with HCl (4.0 M in dimethyl ether, 1.20 L). The reaction mixture was heated to 60 °C for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was poured into a saturated aqueous solution of NaHCO3 (1.00 L) and extracted with EA (500 mL × 4). The combined organic layers were washed with brine (500 × 2), dried over Na2SO4, filtered, and concentrated. The residue was dissolved in EA (300 mL) and petroleum ether (150 mL) was added dropwise to give a yellow slurry. The solid was filtered and collected to give the title compound as a yellow solid (52.0 g, 60.9% yield). MS (ES+) C 10H 12N 2O 2 Required value: 192, Experimental value: 193 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ 7.76 (d, J = 8.4 Hz, 1H), 6.98 (s, 2H), 6.39 (d, J = 8.8 Hz, 1H), 2.89 (s, 2H), 1.37 (s, 6H).

[0165] Intermediate 6: 2-amino-7,7-dimethylfurano[3,4-b]pyridine-5(7H)-one

[0166] Step 1: Methyl 6-methoxy-2-(prop-1-en-2-yl)nicotinate Pd(dppf)Cl₂ (544 mg, 744 µmol, 0.500 equivalents) and cesium fluoride (4.52 g, 29.8 mmol, 2.00 equivalents) were added to a mixture of methyl 2-chloro-6-methoxynicotinate (3.00 g, 14.9 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborhecyclopentane (3.75 g, 22.3 mmol) in MeCN (50 mL). The mixture was stirred at 70 °C under a nitrogen atmosphere for 2 hours, and then cooled to ambient temperature. The reaction mixture was then poured onto water (200 mL) and extracted with EA (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by silica gel rapid column chromatography (gradient dissolution, 1% to 2% EA-petroleum ether) to give the title compound (3.0 g, crude substance) as a colorless solid.

[0167] Step 2: A solution of methyl 6-methoxy-2-(prop-1-en-2-yl)nicotinate (3.00 g, 14.5 mmol) in TfOH (17.0 g, 113 mmol, 10 mL) was stirred at 25 °C for 12 hours. The reaction mixture was then poured over water (50 mL), and a saturated aqueous solution of sodium bicarbonate was added to adjust the pH to 7. The mixture was extracted with EA (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the residue. The residue was purified by silica gel rapid column chromatography (gradient dissolution, 10% to 33% EA-petroleum ether) to give the title compound (2.3 g, 82% yield) as a yellow solid.

[0168] Steps 3-6: The title compound 2-amino-7,7-dimethylfurano[3,4-b]pyridin-5(7H)-one was prepared from 2-methoxy-7,7-dimethylfurano[3,4-b]pyridin-5(7H)-one using the four-step procedure described in steps 3, 5, 7 and 8 of intermediate 1. MS (ES+) C 9H 10N 2O 2 Required value: 178, Experimental value: 179 [M+H]+.

[0169] Intermediate 7: 2-amino-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one

[0170] Step 1: The title compound 2-amino-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one was prepared from tetrahydro-4H-piperano-4-one using the same five-step procedure described in steps 1-5 of intermediate 5. MS (ES+) C 8H 8N 2O 2 Required value: 164, Experimental value: 165 [M+H]+. 1H NMR, 400 MHz, DMSO- d6, δ = 7.77 (d, J = 8.8 Hz, 1H), 7.01 (s, 2H), 6.41 (d, J = 8.8 Hz, 1H), 4.44 - 4.41 (m, 2H), 2.88 - 2.85 (m, 2H).

[0171] Intermediate 8: 2-amino-8-methyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one

[0172] Step 1: 2-Methoxy-8-methyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one was added dropwise at 0°C to a solution of methyl 6-methoxy-2-(prop-1-en-2-yl)nicotinate (10.0 g, 48.3 mmol, 1.00 equivalent) in THF (100 mL). The mixture was heated to 20°C and stirred at that temperature for 2 hours. Subsequently, the reaction mixture was cooled to 0°C and NaHCO3 (20.3 g, 241 mmol, 5.00 equivalent) was added dropwise to water (35.0 mL) and H2O2 (30% in water, 69.6 mL, 724 mmol, 15.0 equivalent). The reaction mixture was stirred at 20°C for 30 minutes and then at 30–45°C for 12 hours. The reaction mixture was then poured into a saturated aqueous solution of Na₂SO₃ (200 mL) and extracted with EA (50.0 mL × 3). The organic layers were combined and washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (gradient dissolution, 5% to 15% EA-petroleum ether) to give the title compound as a yellow solid (15.0 g, 77.6 mmol, 80.4% yield).

[0173] Steps 2-5: The title compound, 2-methoxy-8-methyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one, was prepared from 2-methoxy-8-methyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one using the four-step procedure described in steps 3, 5, 7, and 8 of intermediate 1. MS (ES+) C 9H 10N 2O 2 Required value: 178, Experimental value: 179 [M+H]+. 1H NMR: 400 MHz, DMSO- d6 δ 7.76 (d, J= 8.6 Hz, 1H), 7.01 (s, 2H), 6.40 (d, J= 8.6 Hz, 1H), 4.44 (dd, J= 11.2 Hz, 4.4 Hz, 1H), 4.12 (dd, J= 11.0 Hz, 6.8 Hz, 1H), 2.93 (td, J= 7.0 Hz, 4.4 Hz, 1H), 1.20 (d, J= 7.0 Hz, 3H).

[0174] Intermediate 9: 2'-amino-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridine]-5'-one

[0175] Step 1: Methyl 2-(3-bromo-6-chloropyridin-2-yl)acetate was added to a solution of 3-bromo-6-chloro-2-methylpyridine (20.0 g, 96.9 mmol) in THF (300 mL) under nitrogen atmosphere at 25 °C. After 2.5 h, dimethyl carbonate (14.0 g, 155 mmol) was added to the mixture and the mixture was stirred at 25 °C for 13.5 h. The reaction mixture was then added to a saturated aqueous solution of NH4Cl (1000 mL) and extracted with EA (60 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by silica gel rapid column chromatography (gradient dissolution, 0% to 10% EA-petroleum ether) to give the title compound (18.0 g, 70% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ ppm 7.81 (d, J= 8.4 Hz, 1H), 7.16 (d, J= 8.0 Hz, 1H), 4.03 9s, 2H), 3.74 (s, 3H).

[0176] Step 2: Methyl 1-(3-bromo-6-chloropyridin-2-yl)cyclopropane-1-carboxylate was added at 25°C to a solution of 1,2-dibromoethane (10.7 g, 56.7 mmol) and methyl 2-(3-bromo-6-chloropyridin-2-yl)acetate (10.0 g, 37.8 mmol) in toluene (50 mL). The reaction mixture was stirred at 25°C for 16 hours, then diluted with water (300 mL) and extracted with EA (200 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel column chromatography (gradient dissolution, 0% to 10% EA-petroleum ether) to give the title compound as a yellow solid (6.10 g, 56% yield). ¹H NMR (400 MHz, CDCl₃): δ ppm 7.81 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 3.66 (s, 3H), 1.81–1.75 (m, 2H), 1.46–1.41 (m, 2H).

[0177] Step 3: (1-(3-bromo-6-chloropyridin-2-yl)cyclopropyl)methanol was added to a solution of methyl 1-(3-bromo-6-chloropyridin-2-yl)cyclopropane-1-carboxylate (5.40 g, 18.6 mmol) in DCM (80 mL) at -78 °C under nitrogen. The reaction mixture was stirred for 0.5 h at -78 °C, then quenched by adding saturated NH4Cl aqueous solution (50 mL), diluted with water (200 mL), and extracted with EA (200 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude title compound (5.00 g, crude substance) as a yellow solid, which was used in the next step without further purification.

[0178] Step 4: Methyl 5'-side-oxy-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridine]-2'-carboxylate was added to a solution of (1-(3-bromo-6-chloropyridin-2-yl)cyclopropyl)methanol in MeOH (25 mL) and DMF (25 mL) under a nitrogen atmosphere. The suspension was degassed under vacuum and purged several times with carbon monoxide. The mixture was stirred at 80 °C for 16 hours under carbon monoxide (50 psi). The reaction mixture was then concentrated to remove methanol, diluted with water (100 mL), and extracted with EA (60 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The title compound (1.8 g, crude substance) was obtained as a yellow solid and used in the next step without further purification. MS (ES+) C 10H 10N 2O 2 Required value: 233, Experimental value: 234 [M+H]+.

[0179] Step 5: 5'-Side-oxy-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridine]-2'-carboxylic acid. Lithium hydroxide (555 mg, 23.2 mmol) was added to a solution of methyl 5'-side-oxy-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridine]-2'-carboxylic acid (1.80 g, 7.72 mmol) in methanol (30 mL) and water (10 mL). The reaction mixture was stirred at 25°C for 0.5 hours, followed by concentration to remove methanol. The mixture was diluted with water (60 mL) and extracted with EA (50 mL × 3). The aqueous layer was acidified by adding aqueous hydrochloric acid (6 M, 5 mL), followed by extraction with EA (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.20 g, 71% yield) as a brown solid, which was used without further purification.

[0180] Step 6: Tributyl 5'-(5'-side-oxy-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridine]-2'-yl)aminocarboxylic acid was added to a solution of 5'-side-oxy-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridine]-2'-carboxylic acid (1.20 g, 5.47 mmol) in terbutanol (20 mL). The reaction mixture was stirred at 100 °C for 1 hour, then cooled to ambient temperature, diluted with water (60 mL), and extracted with EA (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by silica gel rapid column chromatography (gradient dissolution, 0% to 50% EA-petroleum ether) to give the title compound (330 mg, 19% yield) as a yellow solid and 2'-amino-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridine]-5'-one (420 mg, 28% yield) as a yellow oil.

[0181] Step 7: 2'-amino-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridine]-5'-one was added at 25°C to a solution of (5'-side-oxy-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridine]-2'-yl)tributyl carbamate (100 mg, 344 µmol) in dimethyl methacrylate (1.5 mL). The reaction mixture was stirred for 10 minutes and then concentrated. DCM (2 mL) and TFA (1 mL, 13.5 mmol) were added to the residue, and the reaction mixture was stirred at 25°C for 30 minutes. The reaction mixture was then concentrated, and EA (5 mL) was added to the residue. The mixture was neutralized by adding saturated NaHCO3 aqueous solution (20 mL) and extracted with EA (15 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (60.0 mg, 92% yield) as a yellow oil, which was used in the next step without further purification. MS (ES+) C 12H 11NO 4 Required value: 190, Experimental value: 191 [M+H]+.

[0182] Intermediates 10 and 11: (R)-2-amino-8-methyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one and (S)-2-amino-8-methyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one, each of which is represented by one of the structures shown below: [The structures are represented by one of the structures shown below:] [The structures are represented by one of the structures shown below:]

[0183] Step 1: (R)-2-chloro-8-methyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one and (S)-2-chloro-8-methyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one racemic-2-chloro-8-methyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one (from the title compound of Step 3 of Intermediate 8, 700 mg, 3.54 mmol) were separated by SFC (Daicel Chiralpak IG, with a MeOH gradient in CO2 with 0.1% NH4OH), yielding two peaks respectively. The first isomer (330 mg, 47% yield) and the second isomer (330 mg, 47% yield) were obtained as yellow solids.

[0184] Steps 2 and 3: The title compound (intermediate 10), one of (R or S)-2-amino-8-methyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one, was prepared from one of (R or S)-2-chloro-8-methyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one (from the first dissolution isomer of step 1) using the same two-step procedure as described in steps 4 and 5 of intermediate 5. MS (ES+) C 9H 10N 2O 2 Required value: 178, Experimental value: 179 [M+H]+.

[0185] Steps 3 and 4: The title compound (Intermediate 11), the remaining one of (R or S)-2-amino-8-methyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one, was prepared from the remaining one of (R or S)-2-chloro-8-methyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one (from the second dissolution isomer of Step 1) using the same two-step procedure as described in Steps 4 and 5 of Intermediate 2. MS (ES+) C 9H 10N 2O 2 Required value: 178, Experimental value: 179 [M+H]+.

[0186] Intermediates 12 and 13: (R)-2'-amino-7'-methyl-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridine]-5'-one and (S)-2'-amino-7'-methyl-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridine]-5'-one, each of which is represented by one of the structures shown below:

[0187] Step 1: 1-(3-bromo-6-chloropyridin-2-yl)cyclopropane-1-carboxaldehyde was added to a solution of (1-(3-bromo-6-chloropyridin-2-yl)cyclopropane)methanol (2.65 g, 10.1 mmol) in EA (80 mL). The reaction mixture was stirred at 80 °C for 1 hour, followed by the addition of IBX (2.00 g, 3.29 mmol, 46% purity). The reaction mixture was stirred at 80 °C for 0.5 hours, then filtered and concentrated to give the title compound (2.60 g, crude) as a yellow solid, which was used without further purification. MS (ES+) C 9H 7BrClNO Required value: 261, Experimental value: 262 [M+H]+.

[0188] Step 2: 1-(1-(3-bromo-6-chloropyridin-2-yl)cyclopropyl)ethanol-1-ol was added at 0°C to a solution of 1-(3-bromo-6-chloropyridin-2-yl)cyclopropane-1-carboxaldehyde (2.60 g, 9.98 mmol) in THF (80 mL). The reaction mixture was stirred for 10 minutes, then quenched by adding saturated NH4Cl aqueous solution (80 mL), diluted with water (40 mL), and extracted with EA (80 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (2.70 g, crude) as a yellow oil, which was used without further purification. MS (ES+) C10H11N2O2 Required value: 277, Experimental value: 278 [M+H]+.

[0189] Steps 3-5: The title compound (7'-methyl-5'-sideoxy-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridine]-2'-yl)aminocarbamate tributyl ester was prepared from 1-(1-(3-bromo-6-chloropyridin-2-yl)cyclopropyl)ethanol using a procedure similar to that described in steps 4-6 of intermediate 9 above. 1H NMR (400 MHz, CDCl 3): δ ppm 8.29 (d, J= 8.8 Hz, 1H), 7.90 (d, J= 8.8 Hz, 1H), 7.31 (s, 1H), 4.63-4.53 (m, 1H), 1.61 (s, 3H), 1.53 (s, 9H), 1.38-1.35 (m, 1 H), 1.09-1.00 (m, 2H).

[0190] Step 6: (R)-(7'-methyl-5'-sideoxy-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridin]-2'-yl)tributyl carbamate and (S)-(7'-methyl-5'-sideoxy-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridin]-2'-yl)tributyl carbamate (7'-methyl-5'-sideoxy-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridin]-2'-yl)tributyl carbamate (400 mg) were administered via SFC (column: REGIS (s,s) WHELK-O1 (250 mm × 50 mm, 10 µm), with 0.1% NH Separation was performed using the EtOH gradient in CO₂ of 4OH, yielding two separate peaks. The first isomer (100 mg, 24% yield) and the second isomer (140 mg, 34% yield) were obtained as yellow solids.

[0191] Step 7: TFA (2.31 g, 20.3 mmol) was added to a solution of (R or S)-(7'-methyl-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridin]-2'-yl)tributyl carbamate (from the first dissolution isomer of Step 6, 100 mg) in DCM (6 mL). The reaction mixture was stirred at 25 °C for 30 min, then quenched with saturated NaHCO3 aqueous solution (30 mL) and extracted with DCM (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (intermediate 12, 70 mg, crude substance) as a yellow oil, which was used without further purification. MS (ES+) C 11H 12N 2O 2 Required value: 204, Experimental value: 205 [M+H]+.

[0192] Step 8: The title compound (intermediate 13), the remaining one of (R or S)-2'-amino-7'-methyl-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridin]-5'-one, was prepared from one of (R or S)-(7'-methyl-5'-sideoxy-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridin]-2'-yl)aminocarbamate tributyl esters (from the second dissolution isomer of step 6) using the same procedure as described in step 7 of intermediate 12. MS (ES+) C 11H 12N 2O 2 Required value: 204, Experimental value: 205 [M+H]+.

[0193] Intermediate 14: 2-amino-8,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one

[0194] Step 1: Methyl 2-(3-bromo-6-chloropyridin-2-yl)-2-methylpropionate was prepared by adding sodium hydride (2.91 g, 72.8 mmol, 60% purity) to a solution of methyl 2-(3-bromo-6-chloropyridin-2-yl)acetate (5.50 g, 20.8 mmol) in THF (20 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min, followed by the addition of iodomethane (7.38 g, 51.9 mmol). The reaction mixture was heated to 25 °C and stirred for 45 min, then quenched with water (30 mL) and extracted with EA (30 mL × 2). The combined organic layers were concentrated to give the residue. The residue was purified by silica gel rapid column chromatography (gradient dissolution, 0% to 10% EA-petroleum ether) to give the title compound (5.5 g, 90% yield) as a yellow oil. 1H NMR (400 MHz, CD 3OD): δ ppm 7.97 (d, J= 8.4 Hz, 1H), 7.20 (d, J= 8.4 Hz, 1H), 3.95 (s, 2H), 1.50 (s, 6H)

[0195] Steps 2-6: The title compound 2-amino-8,8-dimethyl-7,8-dihydro-5H-piperano[4,3-b]pyridin-5-one was prepared using a procedure similar to that described in steps 3-6 of intermediate 9 and step 7 of intermediate 12. MS (ES+) C 10H 12N 2O 2 Required value: 192, Experimental value: 193 [M+H]+. 1H NMR (400 MHz, 6 d-DMSO): δ ppm 7.77 (d, J= 8.8 Hz, 1H), 7.01 (s, 2H), 6.40 (d, J= 8.8 Hz, 1H), 4.15 (s, 2H), 1.21 (s, 6H).

[0196] Intermediate 15: 2'-amino-7',7'-dimethyl-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridine]-5'-one

[0197] Step 1: 2-(1-(3-bromo-6-chloropyridin-2-yl)cyclopropyl)prop-2-ol was added to a solution of methyl 1-(3-bromo-6-chloropyridin-2-yl)cyclopropane-1-carboxylate (1.3 g, 4.47 mmol) in THF (10 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 10 min, then poured into water (20 mL) and extracted with EA (50 mL × 3). The organic layer was dried over sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by column chromatography (SiO2, PE / EA = 1 / 0 to 50 / 1) to give the title compound (500 mg, 38% yield) as a colorless oil.

[0198] Steps 2-5: The title compound 2'-amino-7',7'-dimethyl-5'H,7'H-spiro[cyclopropane-1,8'-piperano[4,3-b]pyridine]-5'-one was prepared from 2-(1-(3-bromo-6-chloropyridin-2-yl)cyclopropyl)prop-2-ol using a procedure similar to that described in steps 4-6 of intermediate 9 and step 7 of intermediate 12 above. ¹H NMR (400 MHz, CDCl₃): δ ppm 8.05 (d, J = 8.4 Hz, 1H), 6.36 (d, J = 8.8 Hz, 1H), 4.85 (s, 2H), 1.42–1.32 (m, 8H), 1.06–1.03 (m, 2H).

[0199] Intermediate 16: 4-Bromo-1,6-dichloro-2,7-diphenyl ether

[0200] Step 1: 4-Bromo-6-chloro-2,7-diphenyl-1(2H)-one NBS (70.9 g, 398 mmol, 1.20 equivalent) was added to a solution of 6-chloro-2,7-diphenyl-1(2H)-one (60.0 g, 332 mmol, 1.00 equivalent) in DMF (600 mL). The reaction mixture was stirred at 20 °C for 2 hours, then poured into water (1 L) and filtered. The filter cake was dried under vacuum to give 90.8 g of 4-bromo-6-chloro-2,7-diphenyl-1(2H)-one (crude matter) as a brown solid. MS (ES+) C 8H 4BrClN 2O Required value: 260, Experimental value: 261 [M+H]+.

[0201] Step 2: 4-Bromo-1,6-dichloro-2,7-dichloro-1(2H)-one (70.8 g, 272 mmol, 1.00 equivalent) was added fractionally to POCl3 (484 g, 3.16 mol, 293 mL, 11.5 equivalent) at 25 °C. The reaction mixture was then stirred at 110 °C for 3 hours. The reaction mixture was then concentrated under vacuum, and the residue was adjusted to pH 8 with a saturated aqueous solution of Na2CO3 at 25 °C. The mixture was extracted with DCM (500 mL × 3), washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound as a yellow solid (75.0 g, 269 mmol, 98.9% yield). MS (ES+) C 8H 3BrCl 2N 2 Demand value: 278, Experimental value: 279 [M+H]+.

[0202] Intermediate 17: 4-(2-azidopropyl-2-yl)-1,6-dichloro-2,7-diphenyl ether

[0203] Step 1: A suspension of 4-bromo-1,6-dichloro-2,7-dichloro-2,7-dichloro-4 ...

[0204] Step 2: A solution of 4-bromo-6-chloro-1-methoxy-2,7-diphenyl ether (47.0 g, 171 mmol, 1.00 equivalent), tributyl(1-ethoxyvinyl)stanane (74.4 g, 206 mmol, 69.6 mL, 1.20 equivalent), and Pd(PPh 3) 4 (19.8 g, 17.1 mmol, 0.10 equivalent) in toluene (500 mL) was stirred at 80 °C under N 2 for 16 hours. The reaction mixture was then cooled to 20 °C and poured into a saturated KF aqueous solution (500 mL) and stirred for 1 hour. The aqueous mixture was extracted with EA (300 mL × 3), and the organic layers were combined. Vacuum concentration of the combined organic layers yielded the title compound (64.0 g, crude product) as a yellow oil. MS (ES+) C 13H 13ClN 2O 2 Required value: 264, Experimental value: 265 [M+H]+.

[0205] Step 3: 1-(6-chloro-1-methoxy-2,7-diphenyl-4-yl)ethyl-1-one: An aqueous solution of HCl (1.50 M, 20.1 mL, 0.10 equivalents) was added to a solution of 6-chloro-4-(1-ethoxyvinyl)-1-methoxy-2,7-diphenyl ether (80.0 g, 302 mmol, 1.00 equivalents) in THF (480 mL) and H₂O (80 mL). The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was then poured into a saturated aqueous solution of NaHCO₃ (500 mL) and extracted with EA (300 mL × 2). The organic layers were combined and concentrated under vacuum. The residue was purified by rapid silica gel column chromatography (gradient dissolution, 5% to 50% EA-PE) to give the title compound as a white solid (28.0 g, 118 mmol, 39.1% yield). MS (ES+) C 11H 9ClN 2O 2 Required value: 236, Experimental value: 237 [M+H]+.

[0206] Step 4: 2-(6-chloro-1-methoxy-2,7-diphenyl-4-yl)prop-2-ol was added to a solution of 1-(6-chloro-1-methoxy-2,7-diphenyl-4-yl)ethyl-1-one (28.0 g, 118 mmol, 1.00 equivalent) in THF (300 mL) at 0–10 °C. The mixture was stirred at 0–10 °C for 2 hours, and then poured into a saturated aqueous solution of NH4Cl (300 mL) and extracted with EA (200 mL × 2). The organic layers were combined and concentrated under vacuum to give the title compound (33 g, crude product) as a yellow oil. MS (ES+) C12H13ClN2O2 Required value: 252, Experimental value: 253 [M+H]+.

[0207] Step 5: 4-(2-azidopropyl-2-yl)-6-chloro-1-methoxy-2,7-diphenyl ether was added at 25°C to a solution of 2-(6-chloro-1-methoxy-2,7-diphenyl-4-yl)prop-2-ol (28.0 g, 50.3 mmol, 45.4% purity, 1.00 equivalent) and BF3·Et2O (15.5 g, 50.3 mmol, 13.5 mL, 46.0% purity, 1.00 equivalent) in DCM (280 mL). The reaction mixture was stirred at 25°C for 12 hours, and then partitioned between a saturated aqueous solution of NaHCO3 (350 mL) and DCM (200 mL). The layers were separated, and the aqueous layer was further extracted with DCM (200 mL). The organic layer was combined and washed with brine (200 mL), dried over sodium sulfate, filtered, and then concentrated. The residue was purified by silica gel rapid column chromatography (gradient dissolution, 2% to 50% EA-PE) to give the title compound as a grayish-white solid (20.0 g, 65.% yield, 91% purity). MS (ES+) C 12H 12ClN 5O Required value: 277, Experimental value: 278 [M+H]+.

[0208] Step 6: 4-(2-azidopropyl-2-yl)-6-chloro-2,7-diphenyl-1-ol was prepared at 25°C by adding an aqueous HCl solution (2 M, 163 mL, 5.00 equivalents) to a solution of 4-(2-azidopropyl-2-yl)-6-chloro-1-methoxy-2,7-diphenyl ether (20.0 g, 65.5 mmol, 91% purity, 1.00 equivalents) in THF (200 mL). The reaction mixture was stirred at 25°C for 12 hours, then poured into a saturated aqueous NaHCO3 solution (1.00 L) and extracted with EA (500 mL × 2). The organic layers were combined and washed with brine (500 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (19.0 g, 96% yield, 88% purity) as a yellow solid. MS (ES+) C 11H 10ClN 5O Required value: 263, Experimental value: 264 [M+H]+.

[0209] Step 7: 4-(2-azidopropyl-2-yl)-1,6-dichloro-2,7-diphenyl ether POCl 3 (2.54 g, 16.5 mmol, 1.54 mL, 4.37 equivalents) and Et 3N (1.01 g, 9.99 mmol, 1.39 mL, 2.63 equivalents) were added to a mixture of 4-(2-azidopropyl-2-yl)-6-chloro-2,7-diphenyl-1-ol 7 (1.00 g, 3.79 mmol, 1.00 equivalents) and ACN (20.0 mL). The reaction mixture was then heated to 100°C for 20 hours. The reaction mixture was then concentrated, and the residue was diluted with EA. The diluted residue was quenched with water, and the mixture was adjusted to pH 8 with an aqueous sodium carbonate solution. The mixture was then extracted with EA, and the organic layer was washed with brine. The washed organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by rapid silica gel column chromatography (gradient dissolution, 0% to 5% EA-PE) to give the title compound (14.2 g, 84% yield) as a pale yellow solid. MS (ES+) C 11H 9Cl 2N 2 Required value: 281, Experimental value: 282 [M+H]+. 1H-NMR (400 MHz, DMSO- d 6): δ ppm 9.57 (s, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 1.83 (s, 6H).

[0210] Intermediate 18: (S)-4-(2-azido-1-methoxypropyl-2-yl)-1,6-dichloro-2,7-diphenyl ether

[0211] Step 1: 6-Chloro-1-methoxy-4-(prop-1-en-2-yl)-2,7-dioxane was added to a solution of 4-bromo-6-chloro-1-methoxy-2,7-dioxane (the title compound from step 1 of intermediate 17, 12.4 g, 45.3 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborhecyclopentane (7.62 g, 45.3 mmol) in dioxane (500 mL) and water (50 mL) with Pd(dppf)Cl2 (3.32 g, 4.53 mmol) and K2CO3 (12.5 g, 90.6 mmol). The mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere, then the reaction mixture was diluted with water (200 mL) and extracted with EA (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel rapid column chromatography (PE / EA = 100 / 1 to 10 / 1) to give the title compound (7.00 g, 65% yield) as a white solid.

[0212] Step 2: 2-(6-chloro-1-methoxy-2,7-propin-4-yl)propane-1,2-diol OsO4 (1.02 g, 4.01 mmol) was added to a mixture of 6-chloro-1-methoxy-4-(prop-1-en-2-yl)-2,7-propin (9.4 g, 40.0 mmol) and NMO (9.38 g, 80.1 mmol) in acetone (160 mL) and H2O (40 mL). The reaction mixture was stirred at 25 °C for 12 hours, then quenched with a saturated aqueous KF solution (150 mL) and filtered. The solution was extracted with EA (2 × 300 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to give the title compound (9.3 g, 86% yield) as a yellow oil, which was used in the next step without further purification.

[0213] Step 3: 6-Chloro-4-(1,2-dimethoxypropyl-2-yl)-1-methoxy-2,7-diphenyl ether NaH (4.85 g, 121 mmol, 60% purity) was added to a solution of 2-(6-chloro-1-methoxy-2,7-diphenyl-4-yl)propane-1,2-diol (9.3 g, 34.6 mmol) in THF (150 mL). The reaction mixture was stirred at 25 °C for 0.5 h, followed by the addition of MeI (12.3 g, 86.5 mmol). The reaction mixture was stirred at 25 °C for 0.5 h, and then at 40 °C for 2 h. The reaction mixture was then added to a stirred solution of saturated NH4Cl aqueous solution (50 mL) and extracted with EA (300 mL). The organic layer was washed with saturated NH4Cl aqueous solution (100 mL × 3), dried over Na2SO4, filtered and concentrated to give the title compound (10 g, 85% yield) as a yellow oil, which was used in the next step without further purification.

[0214] Step 4: 4-(2-azido-1-methoxypropyl-2-yl)-6-chloro-1-methoxy-2,7-diphenyl ether was added to a mixture of 6-chloro-4-(1,2-dimethoxypropyl-2-yl)-1-methoxy-2,7-diphenyl ether (9.2 g, 31.0 mmol) and TMSN 3 (17.9 g, 155 mmol) in DCE (150 mL) at 25 °C. The reaction mixture was heated to 60 °C for 6 hours under N2. The reaction mixture was then added to a stirred solution of saturated NaHCO3 aqueous solution (300 mL) and extracted with EA (300 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel rapid column chromatography (20% EA-PE) to give the title compound (8 g, 73% yield) as a colorless oil.

[0215] Step 4: The title compounds (R)-4-(2-azido-1-methoxypropyl-2-yl)-6-chloro-1-methoxy-2,7-diphenyl ether and (S)-4-(2-azido-1-methoxypropyl-2-yl)-6-chloro-1-methoxy-2,7-diphenyl ether were prepared by chiral SFC separation of 4-(2-azido-1-methoxypropyl-2-yl)-6-chloro-1-methoxy-2,7-diphenyl ether (column: Daicel ChiralPak IG (250 × 30 mm, 10 µm); mobile phase: [15% (IPA with 0.1% NH4OH)] to obtain two title isomers. The first dissolution isomer is ( R)-4-(2-azido-1-methoxypropyl-2-yl)-6-chloro-1-methoxy-2,7-diphenyl ether, and the second dissolution isomer is (S)-4-(2-azido-1-methoxypropyl-2-yl)-6-chloro-1-methoxy-2,7-diphenyl ether. The absolute stereochemistry of the title compound was determined by the X-ray crystal structure of the final compound prepared from the second dissolution isomer.

[0216] Step 5: An aqueous solution of HCl (6 M, 5.41 mL) was added to a solution of (S)-4-(2-azido-1-methoxypropyl-2-yl)-6-chloro-1-methoxy-2,7-diphenyl-1-ol in THF (3 g, 9.75 mmol). The mixture was stirred at 25 °C for 12 hours, and then the pH was adjusted to approximately 8 by adding solid NaHCO3. The mixture was extracted with EA (2 × 150 mL), and the organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (2.7 g, 83% yield, 88% purity) as a white solid, which was used in the next step without further purification.

[0217] Step 6: (S)-4-(2-azido-1-methoxypropyl-2-yl)-1,6-dichloro-2,7-diphenyl POCl3 (3.34 g, 21.8 mmol) was added to a mixture of (S)-4-(2-azido-1-methoxypropyl-2-yl)-6-chloro-2,7-diphenyl-1-ol (1.28 g, 4.36 mmol) and TEA (1.16 g, 11.5 mmol) in ACN (20 mL). The mixture was heated to 100 °C for 12 hours. The reaction mixture was then added to a saturated aqueous solution of NH4Cl (50 mL) and extracted with EA (100 mL × 3). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel rapid column chromatography (25% EA-PE) to give the title compound (1.2 g, 88% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ ppm 9.61 (s, 1H), 8.57 (s, 1H), 8.48 (s, 1H), 3.98 (d, J = 9.6 Hz, 1H), 3.78 (d, J = 9.6 Hz, 1H), 3.41 (s, 3H), 1.80 (s, 3H).

[0218] Intermediate 19: (R)-4-(2-azidobutyl-2-yl)-1,6-dichloro-2,7-diphenyl ether

[0219] Step 1: A suspension of 6-chloro-4-(1-ethoxyvinyl)-1-methoxy-2,7-diphenyl ether in toluene (2.20 L) was stirred at 100 °C under N2 for 36 hours. The suspension consisted of 220 g (804 mmol, 1.00 equivalent) of 4-bromo-6-chloro-1-methoxy-2,7-diphenyl ether (220 g, 804 mmol, 1.00 equivalent), tributyl(1-ethoxyvinyl)stanane (264 g, 731 mmol, 246 mL, 0.90 equivalent), and Pd(PPh3)4 (46.4 g, 40.2 mmol, 0.05 equivalent). The mixture was cooled to 25 °C and further tributyl(1-ethoxyvinyl)stanane (0.35 equivalent) was added to the above solution under N2. The mixture was stirred at 100 °C for 12 hours. The mixture was cooled to 25 °C and poured into a saturated KF aqueous solution (2.00 L). The mixture was filtered through a diatomaceous earth mat and the filtrate was extracted with EA (1.00 L × 2). The combined organic layers were concentrated and the residue was purified by column chromatography (SiO2, PE / EA = 20 / 1 to 10 / 1) to give the title compound as a white solid (157 g, 668 mmol, 83.1% yield).

[0220] Step 2: HCl (1.50 M, 39.5 mL, 0.10 equivalent) was added to a solution of 6-chloro-4-(1-ethoxyvinyl)-1-methoxy-2,7-ethidine (157 g, 593 mmol, 1.00 equivalent) in THF (942 mL) and H₂O (157 mL), and the suspension was stirred at 25°C for 1 hour. The mixture was poured into a saturated aqueous solution of NaHCO₃ (1.50 L) and extracted with EA (1.50 L × 2). The combined organic layers were concentrated to obtain the residue. The residue was slurried in PE / EA = 10:1 (550 mL) at 20-25 °C for 10 minutes, followed by filtration of the suspension and drying of the filter cake to give the title compound (114 g) as a white solid. MS (ES+) C 11H 9ClN 2O 2 Required value: 236, Experimental value: 237 [M+H]+.

[0221] Step 3: 2-(6-chloro-1-methoxy-2,7-diphenyl-4-yl)but-2-ol was added to a mixture of 1-(6-chloro-1-methoxy-2,7-diphenyl-4-yl)ethyl-1-one (114 g, 481 mmol, 1.00 equivalent) in THF (2.28 L) at 0–10 °C. The reaction mixture was stirred at 0–10 °C for 0.5 h, then poured into a saturated aqueous solution of NH4Cl (1.50 L) and extracted with EA (1.00 L × 2). The combined organic layers were washed with brine (1.00 L), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EA = 5 / 1 to 2 / 1) to give the title compound (100 g) as a yellow oil. MS (ES+) C 13H 15ClN 2O 2 Required value: 266, Experimental value: 267 [M+H]+.

[0222] Step 4: TMSN 3 (123 mL, 937 mmol, 2.50 equivalents) was added to a solution of 2-(6-chloro-1-methoxy-2,7-diphenyl-4-yl)but-2-ol (100 g, 374 mmol, 1.00 equivalent) and BF3•Et2O (49.2 mL, 187 mmol, 47.0% purity, 0.50 equivalent) in DCM (1.00 L) at 25 °C. The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was then slowly added to a saturated aqueous solution of NaHCO3 (1.00 L) and extracted with DCM (200 mL × 2). The organic layer was washed with brine (1.00 L), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EA = 100 / 1~5 / 1) to give a solid. The solid was slurried in PE / EA = 8 / 1 (90.0 mL) at 25 °C for 10 min, then filtered and the filter cake was dried to give the title compound as a white solid (46.0 g, 155 mmol, 41.5% yield). MS (ES+) C₁₃H₁₄ClN₅O Required value: 291, Experimental value: 292 [M+H]⁺.

[0223] Step 5: (R)-4-(2-azidobutyl-2-yl)-6-chloro-1-methoxy-2,7-diphenyl 4-(2-azidobutyl-2-yl)-6-chloro-1-methoxy-2,7-diphenyl ether (46.0 g, 157 mmol, 98.7% purity, 1.00 equivalent) was separated by SFC (column: Daicel ChiralPak IG (250 × 30 mm, 10 µm); mobile phase: [0.1% NH3H2O ​​MEOH]; B%: 20% - 20%). The second dissolution peak was concentrated to give the title compound (21.5 g, 46.7% yield) as a white solid. The absolute stereochemistry of the title compound was determined by the X-ray crystal structure of the final compound prepared from this intermediate 19. MS (ES+) C 13H 14ClN 5O Required value: 291, Experimental value: 292 [M+H]+.

[0224] Step 6: HCl (3.00 M, 122 mL, 5.07 equivalents) was added to a solution of (R)-4-(2-azidobut-2-yl)-6-chloro-2,7-diphenyl-1-ol in THF (215 mL) at 25 °C. The suspension was then stirred at 25 °C for 12 hours, followed by stirring at 30 °C for 12 hours. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 (500 mL) and extracted with EA (150 mL × 2). The mixture was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated. The residue was slurried in PE (100 mL) at 25 °C for 10 minutes, then filtered and the filter cake was dried to give the title compound (18.5 g) as a white solid. MS (ES+) C 12H 12ClN 5O Required value: 277, Experimental value: 278 [M+H]+.

[0225] Step 7: The following three reactions of (R)-4-(2-azidobut-2-yl)-1,6-dichloro-2,7-diphenyl ether were carried out in parallel and combined for purification. POCl₃ (10.3 mL, 110 mmol, 5.00 equivalent) and Et₃N (8.03 mL, 57.6 mmol, 2.60 equivalent) were added to a solution of (R)-4-(2-azidobut-2-yl)-6-chloro-2,7-diphenyl ether-1-ol (6.16 g, 22.1 mmol, 1.00 equivalent) in MeCN (190 mL). The reaction mixture was stirred at 120 °C for 64 hours, followed by concentration to obtain the residue. The residue was diluted with EA (500 mL), then quenched with water (500 mL) at 20–30 °C and stirred at 30 °C for 30 min. The mixture was adjusted to pH 8 at 25°C by adding a saturated aqueous solution of Na₂CO₃, followed by extraction with EA (500 mL × 2). The combined organic layers were washed with brine (500 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EA = 1 / 0 ~ 8 / 1) to give the title compound (18.0 g, 88.4% yield) as a pale yellow solid. MS (ES+) C₁₂H₁₁Cl₂N₅ Required value: 295, Experimental value: 296 [M+H]⁺. 1H NMR (400 MHz, CDCl 3): δ 9.62 (s, 1H), 8.52 (s, 1H), 8.43 (s, 1H), 2.03 - 2.16 (m, 2H), 1.61-1.89 (m, 3H), 0.85 - 0.89 (m, 3H).

[0226] Intermediate 20: 4-(2-azidopropyl-2-yl)-6-chloro-1-((1-(methanesulfonyl)azacyclobutane-3-yl)oxy)-2,7-diphenyl

[0227] Step 1: 3-((4-bromo-6-chloro-2,7-diphenyl-1-yl)oxy)azacyclobutane-1-carboxylic acid tributyl ester was added to a solution of 3-hydroxyazacyclobutane-1-carboxylic acid tributyl ester (2.06 g, 11.9 mmol) in THF (84 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 0.5 h, followed by the addition of 4-bromo-1,6-dichloro-2,7-diphenyl ether (3 g, 10.8 mmol) and stirring at 20 °C for another 0.5 h. The reaction mixture was then quenched by the slow addition of 80 mL of water at 0 °C, followed by extraction with EA (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO₂, PE / EA = 1 / 0 to 10 / 1) to give the title compound as a white solid (4.00 g, 88% yield). MS (ES+) C₁₆H₁₇BrClN₃O₃ Required value: 415, Experimental value: 416 [M+H]⁺.

[0228] Step 2: Tributyl 3-((6-chloro-4-(1-ethoxyvinyl)-2,7-diphenyl-1-yl)oxy)azicyclic butane-1-carboxylic acid was added to a solution of tributyl 3-((4-bromo-6-chloro-2,7-diphenyl-1-yl)oxy)azicyclic butane-1-carboxylic acid (4.00 g, 9.65 mmol) in toluene (100 mL) along with Pd(PPh 3) 4 (1.11 g, 965 µmol) and tributyl(1-ethoxyvinyl)stanane (3.48 g, 9.65 mmol, 3.26 mL). The reaction mixture was stirred at 80 °C under nitrogen for 16 hours, followed by the addition of a saturated aqueous solution of potassium fluoride. The mixture was stirred for 4 hours, and then extracted with EA (100 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by column chromatography (SiO2, PE / EA = 1 / 0 to 10 / 1) to give the title compound as a white solid (3.40 g, 43% yield).

[0229] Step 3: Tributyl 3-((4-acetyl-6-chloro-2,7-diphenyl-1-yl)oxy)azacyclobutane-1-carboxylic acid was added to a solution of 3-((6-chloro-4-(1-ethoxyvinyl)-2,7-diphenyl-1-yl)oxy)azacyclobutane-1-carboxylic acid (3.40 g, 4.19 mmol) in THF (68 mL) and H₂O (8 mL). The mixture was stirred at 20 °C for 0.5 h, then diluted with water (20 mL) and the pH of the mixture was adjusted to 8-9 by adding a saturated sodium bicarbonate aqueous solution. The mixture was extracted with DCM (20 mL × 3), the combined organic layers were washed with water (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 0 to 1 / 1) to give the title compound as a white solid (1.4 g, 83% yield).

[0230] Step 4: Tributyl 3-((6-chloro-4-(2-hydroxypropyl-2-yl)-2,7-diphenyl-1-yl)oxy)azacyclobutane-1-carboxylic acid was added to a solution of tributyl 3-((4-acetyl-6-chloro-2,7-diphenyl-1-yl)oxy)azacyclobutane-1-carboxylic acid (1.4 g, 3.71 mmol, 1 equivalent) in THF (30 mL). The reaction mixture was stirred at 20 °C for 1 hour, then poured into a saturated aqueous solution of ammonium chloride (30 mL), diluted with water (20 mL), and extracted with EA (3 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 0 to 1 / 1) to give the title compound as a white solid (1.2 g, 76% yield).

[0231] Step 5: 2-(1-(azacyclobutane-3-yloxy)-6-chloro-2,7-diphenyl-4-yl)prop-2-ol was added to a solution of 3-((6-chloro-4-(2-hydroxypropyl-2-yl)-2,7-diphenyl-1-yl)oxy)azacyclobutane-1-carboxylic acid tributyl ester (1.10 g, 2.79 mmol) in dimethyl HCl (4 M, 11 mL). The reaction mixture was stirred at 20 °C for 0.5 h, then concentrated to give a residue. A saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with DCM (20 mL × 3). The combined organic layers were washed with water (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 250×50 mm×10 µm; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 12%-42%, 20 min) to give the title compound (300 mg, 32% yield) as a white solid.

[0232] Step 6: 2-(6-chloro-1-((1-(methanesulfonyl)azacyclobutan-3-yl)oxy)-2,7-diphenyl-4-yl)prop-2-ol was added to a solution of 2-(1-(azacyclobutan-3-yloxy)-6-chloro-2,7-diphenyl-4-yl)prop-2-ol (50 mg, 170 µmol) and triethylamine (51.7 mg, 511 µmol, 71.1 µL) in DCM (5 mL) with MsCl (21.5 mg, 187 µmol, 14.5 µL). The reaction mixture was stirred at 25 °C for 2 hours, followed by quenching with water (20 mL). The mixture was extracted with EA (20 mL × 3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by preparative TLC (PE / EA=0:1) to give the title compound (40 mg, 61% yield) as a white solid.

[0233] Step 7: Add TMSN 3 (265 µL, 2.02 mmol) and InBr 3 (172 mg) to a solution of 4-(2-azidopropyl-2-yl)-6-chloro-1-((1-(methanesulfonyl)azacyclobutane-3-yl)oxy)-2,7-narin-4-yl)prop-2-ol (150 mg, 403 µmol) in DCM (5 mL). Stir the mixture at 20 °C for 1 hour, then add water (20 mL) and adjust the pH to 8-9 by adding saturated sodium bicarbonate solution. The mixture was extracted with DCM (20 mL × 3), and the combined organic layers were washed with water (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by column chromatography (SiO₂, PE / EA = 1 / 1 to 0 / 1) to give the title compound as a white solid (120 mg, 75% yield). MS (ES+) C₁₅H₁₇ClN₆O₃S Required value: 396, Experimental value: 397 [M+H]⁺.

[0234] Intermediate 21: 3-((4-(2-azidopropyl-2-yl)-6-chloro-2,7-diphenyl)oxy)thione-butane 1,1-dioxide

[0235] Step 1: NaH (10.6 mg, 266 µmol, 60% purity) was added to a solution of thiocyclobutane-3-ol (17.6 mg, 195 µmol) in THF (1 mL). The mixture was stirred for 10 minutes, followed by the addition of 4-(2-azidopropyl-2-yl)-1,6-dichloro-2,7-diphenyl ether (intermediate 17, 50 mg, 177 µmol) and stirring at 20 °C for 50 minutes. The reaction mixture was quenched by adding saturated ammonium chloride aqueous solution (2 mL) and extracted with EA (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (59 mg, 99% yield) as a white solid.

[0236] Step 2: Oxone (216 mg, 351 µmol) was added to a solution of 3-((4-(2-azidopropyl-2-yl)-6-chloro-2,7-diphenyl-1-yl)oxy)thiocyclobutane 1,1-dioxide in THF (0.9 mL) and water (0.3 mL). The mixture was stirred at 20 °C for 1 hour, then quenched by adding saturated sodium sulfite aqueous solution (10 mL) and extracted with EA (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (60 mg, 93% yield) as a white solid. 1H-NMR (400 MHz, CDCl 3): δ ppm 9.47 (s, 1H), 8.41 (s, 1H), 8.17 (s, 1H), 5.72 (tt, J= 4.0, 7.8 Hz, 1H), 4.81 - 4.70 (m, 2H), 4.45 (dd, J= 3.8, 15.6 Hz, 2H), 1.82 (s, 6H).

[0237] Intermediate 22: 4-(2-azidopropyl-2-yl)-6-chloro-1-(cis-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl

[0238] Step 1: NaH (1.97 g, 49.3 mmol, 60% purity) was added to a solution of cis-3-(methanesulfonyl)cyclobut-1-ol (5.70 g, 37.9 mmol) in THF (260 mL) at 0 °C. The mixture was stirred for 0.5 h, followed by the addition of 4-(2-azidopropyl-2-yl)-1,6-dichloro-2,7-diphenyl ether (10.7 g, 37.9 mmol) and stirring of the reaction mixture at 25 °C for 0.5 h. The reaction mixture was quenched by the addition of water (200 mL) and extracted with EA (200 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (16 g, crude substance) as a white solid, which was used in the next step without further purification. MS (ES+) C 16H 18ClN 5O 3S Required value: 395, Experimental value: 396 [M+H]+.

[0239] Intermediate 23: 4-(2-azidopropyl-2-yl)-6-chloro-1-(3-(methanesulfonyl)propoxy)-2,7-diphenyl

[0240] Step 1: The title compound 4-(2-azidopropyl-2-yl)-6-chloro-1-(3-(methanesulfonyl)propoxy)-2,7-dichloro-1 ...

[0241] Intermediate 24: The title compound 4-((R)-2-azidobutyl-2-yl)-6-chloro-1-((1s,3S)-3-(methanesulfonyl)cyclobutoxy)-2,7-dichloro ...

[0242] Intermediate 25: 3-((4-(2-azidopropyl-2-yl)-6-chloro-2,7-diphenyl-1-yl)oxy)-3-methylthiocyclobutane 1,1-dioxide Steps 1-2: 3-((4-(2-azidopropyl-2-yl)-6-chloro-2,7-diphenyl-1-yl)oxy)-3-methylthiocyclobutane 1,1-dioxide The title compound was prepared from 4-(2-azidopropyl-2-yl)-1,6-dichloro-2,7-diphenyl ether and 3-methylthiocyclobutane-3-ol using a procedure similar to that described in steps 1-2 of intermediate 21. MS (ES+) C 15H 16ClN 5O 3S Desired value: 381, Experimental value: 382 [M+H]+.

[0243] Intermediate 26: 3-(((4-(2-azidopropyl-2-yl)-6-chloro-2,7-diphenyl-1-yl)oxy)methyl)thionylbutane 1,1-dioxide

[0244] Step 1: The title compound 3-(((4-(2-azidopropyl-2-yl)-6-chloro-2,7-diphenyl-1-yl)oxy)methyl)thiocyclic butane 1,1-dioxide was prepared from 4-(2-azidopropyl-2-yl)-1,6-dichloro-2,7-diphenyl ether and 3-(hydroxymethyl)thiocyclic butane 1,1-dioxide using a procedure similar to that described above for intermediate 22. MS (ES+) C 15H 16ClN 5O 3S Required value: 381, Experimental value: 382 [M+H]+.

[0245] Intermediate 27: 4-(2-azidopropyl-2-yl)-6-chloro-1-(trans-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl

[0246] Step 1: The title compound 4-(2-azidopropyl-2-yl)-6-chloro-1-(trans-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl ether was prepared from 4-(2-azidopropyl-2-yl)-1,6-dichloro-2,7-diphenyl ether and trans-3-(methanesulfonyl)cyclobut-1-ol using a procedure similar to that described above for intermediate 22. MS (ES+) C 16H 18ClN 5O 3S Required value: 395, Experimental value: 396 [M+H]+.

[0247] Intermediates 28 and 29: (R)-4-(2-azidopropyl-2-yl)-6-chloro-1-((4-(methanesulfonyl)but-2-yl)oxy)-2,7-diphenyl ether and (S)-4-(2-azidopropyl-2-yl)-6-chloro-1-((4-(methanesulfonyl)but-2-yl)oxy)-2,7-diphenyl ether, each of which is represented by one of the structures shown below:

[0248] Step 1: 4-(Methylthio)but-2-one Oxone® (10.4 g, 16.9 mmol) was added to a solution of 4-(methylthio)but-2-one (2.00 g, 16.9 mmol) in THF (100 mL) and water (20 mL). The reaction mixture was stirred at 25 °C for 2 hours, then quenched with water (30 mL), and the pH was adjusted to 8 by adding saturated sodium carbonate aqueous solution (20 mL). Extraction was performed with EA (30 mL × 3). The combined organic layers were washed with a saturated sodium thiosulfate solution (30 mL) and brine. The organic layers were dried over sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by column chromatography (SiO2, PE / EA = 3:1 to 0:1) to give the title compound (0.80 g, 31% yield) as a white solid.

[0249] Step 2: 4-(methanesulfonyl)but-2-ol was added fractionally to a solution of 4-(methanesulfonyl)but-2-one (400 mg, 2.66 mmol) in methanol (10 mL) using NaBH4 (202 mg, 5.33 mmol). The mixture was stirred at 25 °C for 0.5 h, then poured into water (40 mL) and extracted with EA (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / EA = 0:1) to give the title compound (300 mg, 74% yield) as a yellow gel.

[0250] Step 3: The title compound 4-(2-azidopropyl-2-yl)-6-chloro-1-((4-(methanesulfonyl)but-2-yl)oxy)-2,7-dichlorodiphenyl ether was prepared from 4-(2-azidopropyl-2-yl)-1,6-dichloro-2,7-dichlorodiphenyl ether and 4-(methanesulfonyl)but-2-ol using a procedure similar to that described above for intermediate 22. MS (ES+) C 16H 20ClN 5O 3S Required value: 397, Experimental value: 398 [M+H]+.

[0251] Step 4: (R)-4-(2-azidopropyl-2-yl)-6-chloro-1-((4-(methanesulfonyl)but-2-yl)oxy)-2,7-diphenyl ether and (S)-4-(2-azidopropyl-2-yl)-6-chloro-1-((4-(methanesulfonyl)but-2-yl)oxy)-2,7-diphenyl ether (330 mg, 829 µmol) were subjected to a chiral SFC (column: Daicel Chiralpak AD (250 mm × 30 mm, 10 µm); mobile phase: [0.1% NH3H2O] IPA]; B%: 30%-30%) was separated to obtain one of (R or S)-4-(2-azidopropyl-2-yl)-6-chloro-1-((4-(methanesulfonyl)but-2-yl)oxy)-2,7-phenylene as the first soluble isomer (130 mg, 45% yield, yellow oil, intermediate 28) and the other of (R or S)-4-(2-azidopropyl-2-yl)-6-chloro-1-((4-(methanesulfonyl)but-2-yl)oxy)-2,7-phenylene as the second soluble isomer (130 mg, 39% yield, yellow oil, intermediate 29).

[0252] Intermediate 28: MS (ES+) C 16H 20ClN 5O 3S Demand value: 397, Experimental value: 398 [M+H]+.

[0253] Intermediate 29: MS (ES+) C 16H 20ClN 5O 3S Required value: 397, Experimental value: 398 [M+H]+. Intermediate 30: (R)-4-(methanesulfonyl)but-2-ol

[0254] Step 1: Methyl (R)-3-((tributyldimethylsilyl)oxy)butyrate was added fractionally to a mixture of methyl (R)-3-hydroxybutyrate (50 g, 423 mmol, 48.5 mL), imidazole (43.2 g, 635 mmol), and DMAP (25.9 g, 212 mmol) in DMF (1000 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, and then heated to 25 °C and stirred for another 12 hours. The reaction mixture was then diluted with H₂O (300 mL) and EA (500 mL). The organic layer was washed with saturated NH₄Cl aqueous solution (3 × 300 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (PE / EA=50 / 1) to give the title compound as a colorless oil (91 g, 93% yield).

[0255] Step 2: (R)-3-((tributyldimethylsilyl)oxy)but-1-ol A mixture of methyl (R)-3-((tributyldimethylsilyl)oxy)butyrate (45.5 g, 196 mmol) in THF (500 mL) was cooled to -70°C, and then DIBAL (1 M in toluene, 450 mL) was added dropwise. The resulting mixture was stirred at -70°C for 30 minutes, then heated to 25°C and stirred for another 2 hours. The reaction mixture was added to a stirred solution of NaOH (58.7 g, 1.47 mol) in H₂O (300 mL), and filtered to remove solids. The filtrate was washed with brine (3 × 300 mL) and saturated Na₂SO₃ aqueous solution (200 mL), dried over Na₂SO₄, filtered and concentrated to obtain the title compound (40 g, crude substance) in a colorless oily state, which was used directly in the next step without further purification.

[0256] Step 3: MsCl (61.0 g, 532 mmol) was added to a mixture of (R)-3-((tri-butyldimethylsilyl)oxy)butanol (80 g, 391 mmol) and TEA (70.5 g, 697 mmol) in DCM (500 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour, followed by dilution with H₂O (100 mL). The organic layer was washed with a saturated aqueous solution of NH₄Cl (3 × 300 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated to give the title compound (110 g, crude substance) as a colorless oil.

[0257] Step 4: A mixture of sodium methanethiol (54.6 g, 779 mmol) and (R)-3-((tri-butyldimethylsilyl)oxy)butyl methanesulfonic acid (110 g, 389 mmol) in DMF (500 mL) was stirred at 25 °C for 2 hours. The reaction mixture was then diluted with EA (500 mL), and the organic layer was washed with brine (3 × 300 mL) and concentrated to give the title compound (82.6 g, 90% yield) as a colorless oil, which was used directly in the next step without further purification.

[0258] Step 5: Oxone® (509 g, 827 mmol) was added fractionally to a mixture of (R)-tert-butyldimethyl((4-(methanesulfonyl)but-2-yl)oxy)silane (77.6 g, 331 mmol) and NaHCO3 (222 g, 2.65 mol) in THF (1000 mL) and H2O (200 mL). The mixture was stirred at 25°C for 3 hours. The reaction mixture was filtered, and the organic layer of the filtrate was washed with saturated Na2SO3 aqueous solution (3 × 300 mL), dried over Na2SO4, filtered, and concentrated to give 81 g of crude product containing 60% of the corresponding sulfene. Half of the crude product (42 g) and NaHCO3 (113 g, 1.34 mol) were dissolved in THF (1000 mL) and H2O (500 mL), followed by the sequential addition of Oxone (206 g, 335 mmol). The mixture was stirred at 25 °C for 2 hours and then filtered. The organic layer of the filtrate was washed with a saturated aqueous solution of Na2SO3 (500 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (44.6 g, 99.8% yield) as a colorless oil, which was used directly in the next step without further purification.

[0259] Step 6: (R)-4-(methanesulfonyl)but-2-ol was added to HCl / MeOH (4 M, 178 mL) at 25 °C with (R)-tert-butyldimethyl((4-(methanesulfonyl)but-2-yl)oxy)silane (44.6 g, 167 mmol). The mixture was stirred at 25 °C for 1 hour, then filtered and concentrated to give the residue. The residue was purified by column chromatography (PE / EA = 5 / 1, followed by MeOH) to give the title compound (18.7 g, 73% yield) as a yellow semi-solid. 1H NMR (400 MHz, CD 3Cl): δ ppm 4.08 -3.95 (m, 1H), 3.25-3.10 (m, 2H), 2.94 (s, 3H), 2.30 (br s, 1H), 2.06-1.87 (m, 2H), 1.27 (d, J=6.0 Hz, 3H).

[0260] Intermediate 31: 4-((R)-2-azidobutyl-2-yl)-6-chloro-1-(((R)-4-(methanesulfonyl)but-2-yl)oxy)-2,7-diphenyl

[0261] Step 1: At 25°C, NaH (7.14 g, 179 mmol, 60% purity) was added to a mixture of (R)-4-(methanesulfonyl)but-2-ol (15.37 g, 101 mmol) in THF (300 mL). The mixture was stirred for 1 hour, followed by the addition of THF (150 mL) containing (R)-4-(2-azidobut-2-yl)-1,6-dichloro-2,7-diphenyl ether (23 g, 77.7 mmol). The reaction mixture was stirred at 25°C for 1.5 hours, followed by the addition to a saturated aqueous solution of NH4Cl (500 mL). The mixture was extracted with EA (500 mL), and the organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (31 g, 93% yield) as a yellow oil. 1H NMR (400 MHz, CDCl 3): δ ppm 9.41 (s, 1H), 8.37 (s, 1H), 8.13 (s, 1H), 5.71-5.64 (m, 1H), 3.26-3.16 (m, 2H), 2.95 (s, 3H), 2.40-2.36 (m, 2H), 2.10-2.05 (m, 1H), 1.97-1.80 (m, 4H), 1.52 (d, J= 6.0 Hz, 3H), 0.90-0.85 (m, 3H).

[0262] Intermediate 32: 4-(2-azidopropyl-2-yl)-6-chloro-1-(cis-3-(cyclopropylsulfonyl)cyclobutoxy)-2,7-diphenyl

[0263] Step 1: Trans-3-(benzylmethyloxy)cyclobutyl methanesulfonate was added to a solution of trans-3-(benzylmethyloxy)cyclobut-1-ol (1.9 g, 10.7 mmol) and NEt 3 (3.24 g, 32.0 mmol) in DCM (38 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour, then diluted with water (40 mL) and extracted with DCM (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (2.9 g, crude substance) as a yellow oil, which was used in the next step without further purification.

[0264] Step 2: A solution of trans-3-(benzylmethyloxy)cyclobutyl)ethanethiol ester in DMSO (12 mL) was stirred at 50 °C for 12 hours. The reaction mixture was diluted with water (40 mL) and extracted with PE (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (890 mg, 64% yield) as a white oil, which was used in the next step without further purification. MS (ES+) C 13H 16O 2S Required value: 236, Experimental value: 237 [M+H]+.

[0265] Step 3: K₂CO₃ (1.47 g, 10.7 mmol) was added to a solution of S-trans-3-(benzylmethyloxy)cyclobutane-1-thiol in methanol (20 mL). The reaction mixture was stirred at 70 °C for 1 hour, followed by the addition of NaOH (284 mg, 7.11 mmol) and stirring at 70 °C for another 2 hours. The reaction mixture was diluted with water (40 mL) and extracted with EA (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by column chromatography (SiO₂, PE / EA = 1 / 0 to 10 / 1) to give the title compound (500 mg, 72% yield) as a white oil.

[0266] Step 4: Potassium tributoxide (173 mg, 1.54 mmol) and bromocyclopropane (202 mg, 1.67 mmol, 134 µL) were added to a solution of cis-3-(benzylmethyloxy)cyclobutane-1-thiol (250 mg, 1.29 mmol) in DMSO (6 mL). The reaction mixture was incubated at 80 °C for 2 hours, followed by dilution with water (15 mL) and extraction with EA (15 mL × 4). The combined organic layers were washed with brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by column chromatography (SiO2, PE / EA = 1 / 0 to 10 / 1) to give the title compound (120 mg, 40% yield) as a yellow oil. MS (ES+) C 14H 18OS Required value: 234, Experimental value: 235 [M+H]+.

[0267] Step 5: Oxone® (629 mg, 1.02 mmol) was added to a solution of ((cis-3-(cyclopropylsulfonylurea)cyclobutoxy)methyl)benzene in cis-3-(benzylmethyloxy)cyclobutyl)(cyclopropyl)thione (120 mg, 512 µmol) in THF (9 mL) and water (3 mL). The reaction mixture was stirred at 25°C for 1 hour, followed by quenching with an aqueous solution of saturated sodium sulfite (40 mL). The reaction mixture was diluted with water (20 mL) and extracted with EA (60 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to a white oily title compound (120 mg, 88% yield), which was used in the next step without further purification.

[0268] Step 6: A solution of BCl₃ (1 M, 2 mL) was added to a solution of ((cis-3-(cyclopropylsulfonylurea)cyclobutoxy)methyl)benzene (100 mg, 375 µmol) in DCM (4 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour, then quenched by the addition of methanol (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by column chromatography (SiO₂, PE / EA = 1 / 0 to 0 / 1) to give the title compound (65 mg, 98% yield) as a white oil. MS (ES+) C₇H₁₂O₃S Required value: 176, Experimental value: 177 [M+H]⁺.

[0269] Step 7: The title compound 4-(2-azidopropyl-2-yl)-6-chloro-1-(cis-3-(cyclopropylsulfonyl)cyclobutoxy)-2,7-diphenyl ether was prepared from 4-(2-azidopropyl-2-yl)-1,6-dichloro-2,7-diphenyl ether and cis-3-(cyclopropylsulfonyl)cyclobut-1-ol using a procedure similar to that described above for intermediate 22. MS (ES+) C 18H 20ClN 5O 3S Required value: 421, Experimental value: 422 [M+H]+.

[0270] Intermediate 33: 5-bromo-3-chloroisoquinoline-8-ol

[0271] Step 1: (E)-2-(hydroxyimino)-7-methoxy-2,3-dihydro-1H-indone was added to a solution of 7-methoxy-2,3-dihydro-1H-indone (99.0 g, 599 mmol, 1.00 equivalent) in THF (500 mL) at -10-0 °C. Then, HCl (4 M in MeOH, 15.0 mL, 0.10 equivalent) was added dropwise to the mixture at -10-0 °C. The reaction mixture was stirred at 0 °C for 2 hours, then concentrated to give a residue. The residue was slurried in PE / EA = 20:1 (200 mL) and filtered to give the title compound (107 g, 87% yield) as a yellow solid. MS (ES+) C 10H 9NO 3 Demand value: 191, Experimental value: 192 [M+H]+.

[0272] Step 2: 1,3-Dichloro-8-methoxyisoquinoline was added to a solution of (E)-2-(hydroxyimino)-7-methoxy-2,3-dihydro-1H-indene-1-one (107 g, 522 mmol, 1.00 equivalent) in dimethyl ether (500 mL) at 0-10 °C. POCl3 (126 g, 827 mmol, 76.9 mL, 1.59 equivalent) and HCl (4 M in dimethyl ether, 1.31 mL, 0.01 equivalent) were added. The reaction mixture was stirred at 70 °C for 12 hours, then cooled to 25 °C and quenched with water (2.00 L). The quenched mixture was extracted with DCM (500 mL × 4), and the organic layer was washed with brine (500 mL × 2), dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO₂, PE / EA = 20 / 1 to 10 / 1) to give the title compound as a pale yellow solid (48.8 g, 40.9% yield). MS (ES+) C₁₀H₇Cl₂NO Required value: 227, Experimental value: 228 [M+H]⁺.

[0273] Step 3: 3-Chloro-8-methoxyisoquinoline was added to a solution of 1,3-dichloro-8-methoxyisoquinoline (48.8 g, 213 mmol, 1.00 equivalent) in THF (250 mL) at 25°C. TMEDA (37.3 g, 320 mmol, 48.4 mL, 1.50 equivalent) and Pd(dppf)Cl₂ (1.57 g, 2.14 mmol, 0.01 equivalent) were then slowly added to the reaction mixture, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was then poured into 1 N HCl (1.00 L) and extracted with EA (200 mL × 3). The combined organic layers were filtered through a Celite® filter, and the filtrate was washed with brine (500 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO₂, PE / EA = 20 / 1 to 5 / 1) to give the title compound (26.7 g, 64.3% yield) as a pale yellow solid. MS (ES+) C₁₀H₈ClNO₃ Required value: 193, Experimental value: 194 [M+H]⁺.

[0274] Step 4: 5-Bromo-3-chloro-8-methoxyisoquinoline was reacted at 25°C with NBS (29.3 g, 165 mmol, 1.20 equivalent) added to a solution of 3-chloro-8-methoxyisoquinoline (26.7 g, 137 mmol, 1.00 equivalent) in MeCN (300 mL). The reaction mixture was stirred at 70°C for 1 hour, then cooled to 25°C. The mixture was filtered, and the filter cake was washed with MeCN (100 mL). The filter cake was collected and dried under vacuum. The filtrate was purified by column chromatography (SiO2, PE / EA = 1:0 to 1:1, Rf = 0.45) to give the title compound (26.17 g, 69.6% yield) as a grayish-white solid. MS (ES+) C10H7BrClNO₃ Required value: 273, Experimental value: 274 [M+H]⁺.

[0275] Step 5: 5-Bromo-3-chloroisoquinoline-8-ol was added once to a solution of 5-bromo-3-chloro-8-methoxyisoquinoline (3.00 g, 11.01 mmol) in DCM (50 mL) with BBr 3 (13.8 g, 55.0 mmol). The reaction mixture was stirred at 50 °C for 12 hours, then quenched with MeOH (15 mL) and concentrated to give the residue. The residue was purified by column chromatography (PE / EA = 10:1 to 1:1) to give the title compound (2.5 g, 88% yield) as a yellow solid. 1H NMR (400 MHz, 6 d-DMSO): δ ppm 11.3 (s, 1H), 9.21 (s, 1H), 7.84 (d, J= 8.4 Hz, 1H), 7.72 (s, 1H), 8.85 (d, J= 8.4 Hz, 1H).

[0276] Intermediate 34: 5-(2-azidopropyl-2-yl)-3-chloro-8-((4-(methanesulfonyl)but-2-yl)oxy)isoquinoline

[0277] Step 1: 4-(methanesulfonyl)but-2-yl methanesulfonate was added to a solution of 4-(methanesulfonyl)but-2-ol (50 mg, 328 µmol) in DCM (5 mL) with TEA (99.7 mg, 985 µmol) and MsCl (753 mg, 657 µmol). The reaction mixture was stirred at 25 °C for 2 hours, then poured into water (20 mL) and extracted with DCM (20 mL × 3). The organic layer was washed with water (20 mL × 3) and concentrated to give the title compound (60.0 mg, 79% yield) as a yellow solid, which was used in the next step without further purification.

[0278] Step 2: 5-Bromo-3-chloro-8-((4-(methanesulfonyl)but-2-yl)oxy)isoquinoline was added at 25°C in a single step to a solution of 4-(methanesulfonyl)but-2-yl methanesulfonic acid (400 mg, 1.55 mmol) in DMF (3 mL) with K₂CO₃ (642 mg, 4.64 mmol), followed by the addition of 5-bromo-3-chloroisoquinoline-8-ol (intermediate 33) (756 mg, 3.28 mmol) to the reaction mixture. The reaction mixture was stirred at 45°C for 12 hours, then poured into water (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with water (20 mL × 3) and concentrated to give the residue. The residue was purified by preparative TLC (PE / EA=1:1) to give the title compound as a yellow solid (600 mg, 1.53 mmol, 99% yield).

[0279] Steps 3-6: The title compound 5-(2-azidopropyl-2-yl)-3-chloro-8-((4-(methanesulfonyl)but-2-yl)oxy)isoquinoline was prepared using a four-step procedure similar to that described in steps 2-5 of intermediate 17.

[0280] Intermediate 35: 5-(2-azidopropyl-2-yl)-3-chloro-8-(cis-3-(methanesulfonyl)cyclobutoxy)isoquinoline

[0281] Step 1: Cis-3-(benzylmethyloxy)cyclobutyl methanesulfonate was added to a solution of 3-benzylmethyloxycyclobutanol (2.5 g, 14.0 mmol) and TEA (4.26 g, 42.1 mmol) in DCM (25 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour, then poured into water (20 mL) and extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (3.5 g, 97% yield) as a yellow solid.

[0282] Step 2: 8-(trans-3-(benzyloxy)cyclobutoxy)-5-bromo-3-chloroisoquinoline was reacted at 25°C with K₂CO₃ (2.46 g, 17.8 mmol) added to a solution of 5-bromo-3-chloro-isoquinoline-8-ol (intermediate 33) (2.3 g, 8.90 mmol) and cis-3-(benzyloxy)cyclobutyl methanesulfonate (3.5 g, 13.7 mmol) in DMF (20 mL). The reaction mixture was stirred at 100°C for 6 hours, then diluted with water (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (80 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (SiO₂, PE / EA = 40 / 1 to 6 / 1) to give the title compound as a white solid (2.7 g, 72% yield). ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.40 (s, 1H), 7.97 (s, 1H), 7.83–7.79 (m, 1H), 7.41–7.28 (m, 5H), 6.55 (d, J = 8.4 Hz, 1H), 5.10–5.01 (m, 1H), 4.53–4.47 (m, 2H), 4.46–4.38 (m, 1H), 3.00–2.32 (m, 4H).

[0283] Step 3: trans-3-((5-bromo-3-chloroisoquinoline-8-yl)oxy)cyclobut-1-ol was added to a solution of 8-(trans-3-(benzylmethyloxy)cyclobutoxy)-5-bromo-3-chloroisoquinoline (2.0 g, 4.78 mmol) in DCM (30 mL) at 0 °C with BCl3 (1 M, 14.3 mL). The reaction mixture was stirred at 0 °C for 1 hour, then poured into a saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with EA (2 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.55 g, 99% yield) as a white solid.

[0284] Step 4: Trans-3-((5-bromo-3-chloroisoquinoline-8-yl)oxy)cyclobutyrate of methanesulfonate was added to a solution of trans-3-((5-bromo-3-chloroisoquinoline-8-yl)oxy)cyclobut-1-ol (1.55 g, 4.72 mmol) in DCM (30 mL) at 0 °C, along with TEA (1.43 g, 14.2 mmol) and MsCl (810 mg, 7.08 mmol). The reaction mixture was stirred at 0 °C for 1 hour, then poured into water (50 mL) and extracted with DCM (2 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.9 g, 99% yield) as a white solid.

[0285] Step 5: S-(cis-3-((5-bromo-3-chloroisoquinoline-8-yl)oxy)cyclobutyl)ethanethiol ester was mixed with potassium ethanethiol (1.60 g, 14.0 mmol) in DMSO (30 mL). The mixture was stirred at 100 °C for 2 hours, then poured into water (150 mL) and extracted with EA (3 × 150 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by SiO2 column chromatography (PE / EA = 50:1 to 20:1) to give the title compound (1.8 g, 99% yield) as a yellow solid.

[0286] Step 6: NaOH (931 mg, 23.3 mmol) was added to a solution of S-(cis-3-((5-bromo-3-chloroisoquinoline-8-yl)oxy)cyclobutane-1-thiol in THF (20 mL), MeOH (10 mL), and water (10 mL). The reaction mixture was stirred at 20 °C for 2 hours, and then the pH was adjusted to 5-6 by adding an aqueous HCl solution (1 M). The mixture was then diluted with EA (100 mL) and washed with brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.5 g, 93% yield) as a yellow solid.

[0287] Step 7: 5-Bromo-3-chloro-8-(cis-3-(methylthio)cyclobutoxy)isoquinoline was reacted with NaH (69.6 mg, 1.74 mmol, 60% purity) and methyl iodoforme (494 mg, 3.48 mmol) in THF (8 mL). The reaction mixture was stirred at 20 °C for 1 hour, then quenched with water (20 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by SiO₂ column chromatography (PE / EA = 50:1 to 20:1) to give the title compound (400 mg, 96% yield) as a white solid.

[0288] Step 8: Oxone® (686 mg, 1.12 mmol) was added to a solution of 5-bromo-3-chloro-8-(cis-3-(methanesulfonyl)cyclobutoxy)isoquinoline (200 mg, 558 µmol) in THF (3 mL) and water (1 mL). The reaction mixture was stirred at 20 °C for 1 hour, then quenched by adding saturated sodium sulfite aqueous solution (5 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (210 mg, 96% yield) as a white solid.

[0289] Steps 9-12: The title compound 5-(2-azidopropyl-2-yl)-3-chloro-8-(cis-3-(methanesulfonyl)cyclobutoxy)isoquinoline was prepared using a four-step procedure similar to that described in steps 2-5 of intermediate 17.

[0290] Intermediate 36: 4-(2-azidopropyl-2-yl)-6-chloro-N-(cis-3-(methanesulfonyl)cyclobutyl)-2,7-diphenyl-1-amine

[0291] Step 1: 4-(2-azidopropyl-2-yl)-6-chloro-N-(cis-3-(methanesulfonyl)cyclobutyl)-2,7-diphenyl-1-amine was added to a solution of 4-(2-azidopropyl-2-yl)-1,6-dichloro-2,7-diphenyl-1-amine (100 mg, 354 µmol) in NMP (2 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours, then diluted with water (20 mL) and extracted with EA (30 mL × 4). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by preparative TLC (PE / EA=1:1) to give the title compound (100 mg, 58% yield) as a yellow oil. MS (ES+) C 16H 19ClN 6O 2S Required value: 394, Experimental value: 395 [M+H]+.

[0292] Intermediate 37: 4-(2-azidopropyl-2-yl)-6-chloro-1-((1S,2R,3S and 1R,2S,3R)-2-methyl-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl

[0293] Step 1: t-BuOK (1.14 g, 10.1 mmol) was added to a solution of ((allyloxy)methyl)benzene (1 g, 6.75 mmol) in DMSO (10 mL), and the mixture was stirred at 60 °C for 2 hours. The reaction mixture was diluted with saturated NH4Cl aqueous solution (300 mL) and extracted with EA (500 mL). The organic layer was washed with brine (3 × 300 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (823 mg, 82% yield) as a yellow oil, which was used in the next step without further purification.

[0294] Steps 2 and 3: 2,2,2-Trichloroacetyl chloride (4.91 g, 27.0 mmol) was added dropwise to a mixture of ((prop-1-en-1-yloxy)methyl)benzene (2 g, 13.5 mmol) and copper / zinc (16.0 g, 124 mmol) in Et 2O (40 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h, and then added to a mixture of saturated NH 4Cl aqueous solution (40 mL) and MeOH (50 mL). The resulting mixture was stirred at 50 °C for 10 min, then filtered and concentrated to remove residual MeOH. The mixture was extracted with EA (100 mL) and the organic layer was dried over Na 2SO 4, filtered, and concentrated. The residue was purified by silicone column chromatography (PE / EA = 50 / 1 to 30 / 1) to give a colorless oil of a mixture of (2S,3S and 2R,3R)-3-(benzylmethyloxy)-2-methylcyclobut-1-one and (2S,3R and 2R,3S)-3-(benzylmethyloxy)-2-methylcyclobut-1-one (660 mg, 26% yield). A mixture of diastereomers (460 mg, 2.42 mmol) was dissolved in THF (10 mL) and NaBH₄ (183 mg, 4.84 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours, then diluted with H₂O (20 mL) and extracted with EA (50 mL). The organic layer was dried under vacuum to give a colorless oil of the title compound (450 mg, 97% yield, not a pure diastereomer), which was used in the next step without further purification.

[0295] Step 4: At 0°C, MsCl (402 mg, 3.51 mmol) was added to a mixture of (1 R,2 S,3 S and 1 S,2 S,3 R)-3-(benzylmethyloxy)-2-methylcyclobut-1-ol (450 mg, 2.34 mmol) and TEA (474 ​​mg, 4.68 mmol) in DCM (10 mL). The reaction mixture was stirred at 0°C for 0.5 hours, then diluted with EA (50 mL) and washed with saturated NH4Cl aqueous solution (3 × 50 mL). The organic layer was concentrated to give the title compound (600 mg, crude substance) as a colorless oil, which was used in the next step without further purification.

[0296] Step 5: A mixture of sodium methanethiol (259 mg, 3.70 mmol) and methanesulfonic acid (1 R,2 R,3 S and 1 R,2 S,3 R)-3-(benzylmethyloxy)-2-methylcyclobutyl(methyl)thione in DMF (10 mL) was stirred at 25 °C for 2 hours. The reaction mixture was then diluted with EA (100 mL), washed with brine (3 × 100 mL), and the organic layer was concentrated to give the title compound (420 mg, crude) as a yellow oil, which was used in the next step without further purification.

[0297] Step 6: (1S,2R,3S and 1R,2S,3R)-2-methyl-3-(methylthio)cyclobut-1-ol was added to a solution of ((1S,2R,3S and 1R,2S,3R)-3-(benzylmethyloxy)-2-methylcyclobutyl)(methyl)thione (420 mg, 1.89 mmol) in DCM (5 mL) with BCl3 (2.37 g, 20.2 mmol). The reaction mixture was stirred at 25 °C for 2 hours, followed by the addition of methanol, and the mixture was filtered and concentrated. The residue was purified by silicone column chromatography (PE / EA = 5 / 1 followed by MeOH) to give the title compound (180 mg, 72% yield) as a yellow oil.

[0298] Step 7: Add NaH (136 mg, 3.40 mmol, 60% purity) to a solution of (1 S,2 R,3 S and 1 R,2 S,3 R)-2-methyl-3-(methylthio)cyclobutoxy)-2,7-dichloro-1-((1 S,2 R,3 S and 1 R,2 S,3 R)-2-methyl-3-(methylthio)cyclobut-1-ol (180 mg, 1.36 mmol) in THF (10 mL) and stir the mixture at 25 °C for 0.5 hours. Then add THF (10 mL) containing 4-(2-azidopropyl-2-yl)-1,6-dichloro-2,7-dichloro-1 ... The mixture was stirred at 25°C for 1 hour, then quenched with water (20 mL) and extracted with EA (15 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to give the residue. The residue was purified by silicone column chromatography (PE / EA = 20 / 1 to 5 / 1) and subsequently by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 µm; mobile phase: [water (0.225% FA)-ACN]; B%: 70%–100%, 10 min) to give the title compound (130 mg, 48% yield) as a colorless oil. 1H NMR (400 MHz, CDCl 3): δ ppm 9.44 (s, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 5.34-5.25 (m, 1H), 3.59-3.53 (m, 1H), 3.05-3.00 (m, 1H), 2.55-2.50 (m, 2H), 2.11 (s, 3H), 1.79 (s, 6H), 1.34 (d, J=7.2 Hz, 3H).

[0299] Step 8: Add Oxone (529 mg, 860 µmol) to a mixture of 4-(2-azidopropyl-2-yl)-6-chloro-1-((1 S,2 R,3 S and 1 R,2 S,3 R)-2-methyl-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl ether (130 mg, 344.01 µmol), NaHCO3 (231 mg, 2.75 mmol, 107 µL) in THF (10 mL) and H2O (4 mL). The reaction mixture was stirred at 25°C for 1.5 hours, then diluted with EA (50 mL) and H₂O (30 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated to give the title compound (120 mg, 85% yield) as a colorless oil. MS (ES+) C₁₇H₂₀ClN₅O₃S Requirement value: 409, Experimental value: 410 [M+H]⁺.

[0300] Intermediate 38: 4-(2-azidopropyl-2-yl)-6-chloro-1-((1S,2R,3R and 1R,2S,3S)-2-methyl-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl

[0301] Step 1: DIAD (4.42 g, 21.9 mmol) was added dropwise to a solution of (1 R,2 S,3 S and 1 R,2 S,3 R)-3-(benzylmethyloxy)-2-methylcyclobut-1-ol (1.4 g, 7.28 mmol), 4-nitrobenzoic acid (2.43 g, 14.6 mmol), and PPh 3 (5.73 g, 21.9 mmol) in THF (30 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours, then diluted with saturated NH 4Cl aqueous solution (50 mL) and extracted with EA (150 mL). The organic layer was dried over Na 2SO 4, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / EA=20 / 1) to give the title compound (2 g, 80% yield) as a colorless oil.

[0302] Step 2: LiOH•H₂O (2.46 g, 58.6 mmol) was added to a solution of 4-nitrobenzoic acid (1S,2R,3S and 1R,2S,3R)-3-(benzylmethyloxy)-2-methylcyclobut-1-ol and (1R,2R,3R)-3-(benzylmethyloxy)-2-methylcyclobut-1-ol in THF (15 mL) and H₂O (5 mL) at 25°C. The reaction mixture was stirred at 25°C for 1 hour, and then at 60°C for 1 hour. The reaction mixture was then diluted with an aqueous solution of NaHCO₃ (50 mL) and EA (100 mL). The organic layer was dried over a saturated aqueous solution of NaHCO3 (3 × 50 mL) with Na2SO4, filtered, and concentrated to give the title compound (1.02 g, 90% yield) as a colorless oil.

[0303] Steps 3-7: The title compound 4-(2-azidopropyl-2-yl)-6-chloro-1-((1S,2R,3R and 1R,2S,3S)-2-methyl-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl ether title compound was prepared from (1S,2S,3S)-3-(benzylmethyloxy)-2-methylcyclobut-1-ol and (1R,2R,3R)-3-(benzylmethyloxy)-2-methylcyclobut-1-ol using a procedure similar to that described in steps 4-8 of intermediate 37. During step 6, the penultimate intermediate was purified by preparative HPLC (column: Phenomenex Luna C18 150×40 mm×15 µm; mobile phase: [water (0.225% FA)-ACN]; B%: 78%-88%, 10 min) to remove minor stereoisomers. MS (ES+) C 17H 20ClN 5O 3S Required value: 409, Experimental value: 410 [M+H]+.

[0304] Intermediates 39 and 40: 4-(2-azidopropyl-2-yl)-6-chloro-1-((1S,2R,3R)-2-methyl-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl ether and 4-(2-azidopropyl-2-yl)-6-chloro-1-((1R,2S,3S)-2-methyl-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl ether, each of which is represented by one of the structures shown below:

[0305] Step 1: 4-(2-azidopropyl-2-yl)-6-chloro-1-((1S,2R,3R)-2-methyl-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl ether and racemic-4-(2-azidopropyl-2-yl)-6-chloro-1-((1R,2S,3S)-2-methyl-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl ether (190 mg, 464 µmol) via chiral SFC (column: Daicel ChiralPak IG (250×30 mm, 10 The mobile phase was [0.1% NH3H2O ​​MEOH]; B%: 40%-40%). The first peak (intermediate 39 (50 mg, 26% yield) was separated into a white solid and the second peak (intermediate 40, 57 mg, 30% yield) was separated into a white solid.

[0306] Intermediate 39: MS (ES+) C 17H 20ClN 5O 3S Demand value: 409, Experimental value: 410 [M+H]+.

[0307] Intermediate 40: MS (ES+) C 17H 20ClN 5O 3S Demand value: 409, Experimental value: 410 [M+H]+.

[0308] Intermediates 41 and 42: cis-4-(2-azidopropyl-2-yl)-6-chloro-1-((-3-(methanesulfonyl)cyclopentyl)oxy)-2,7-diphenyl ether and trans-4-(2-azidopropyl-2-yl)-6-chloro-1-((-3-(methanesulfonyl)cyclopentyl)oxy)-2,7-diphenyl ether

[0309] Step 1: 3-(methylthio)cyclopentan-1-one was added once at 0°C to a solution of cyclopentan-2-en-1-one (10.0 g, 122 mmol) in ACN (100 mL) with AcOH (8.05 g, 134 mmol). Then, at 0°C, 50 mL of water containing sodium methanethiol (17.7 g, 253 mmol) was added dropwise to the solution. The reaction mixture was stirred at 60°C for 1.5 hours, then poured into water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silicone column chromatography (PE / EA = 10:1–1:1) to give the title compound (15.0 g, 95% yield) as a yellow oil.

[0310] Step 2: 3-(methylthio)cyclopentan-1-ol was added fractionally to a solution of 3-(methylthio)cyclopentan-1-one (2.00 g, 15.4 mmol) in MeOH (20 mL) with NaBH4 (1.16 g, 30.7 mmol). The reaction mixture was stirred at 25 °C for 2 hours, then poured into water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by silicone column chromatography (PE:EA = 10:1 to 1:1) and concentrated under vacuum to give the title compound (1.50 g, 74% yield) as a yellow oil.

[0311] Steps 3 and 4: The title compounds cis-4-(2-azidopropyl-2-yl)-6-chloro-1-((-3-(methanesulfonyl)cyclopentyl)oxy)-2,7-dichloro-2 ... The cis and trans isomers were separated by preparative TLC (PE / EA=1:1) to obtain intermediate 42 (racemic trans isomer, 100 mg, 16% yield) and intermediate 41 (racemic cis isomer, 100 mg, 16% yield).

[0312] Intermediate 41: MS (ES+) C 17H 20ClN 5O 3S Demand value: 409, Experimental value: 410 [M+H]+.

[0313] Intermediate 42: ¹H NMR (400 MHz, CDCl₃): δ ppm 9.36 (s, 1H), 8.35 (s, 1H), 8.19 (s, 1H), 5.80 - 5.75 (m, 1H), 3.75 - 3.70 (m, 1H), 3.48 (s, 2H), 2.93 (s, 3H), 2.57-2.48 (m, 2H), 2.30-2.25 (m, 3H), 2.23-2.20 (m, 1H), 1.80 (s, 6H). MS (ES+) C₁₇H₂₀ClN₅O₃S Required value: 409, Experimental value: 410 [M+H]⁺.

[0314] Intermediate 43: 3-(((4-(2-azidopropyl-2-yl)-6-chloro-2,7-diphenyl-1-yl)oxy)methyl)tetrahydrothiophene 1,1-dioxide

[0315] Step 1: The title compound 3-(((4-(2-azidopropyl-2-yl)-6-chloro-2,7-diphenyl-1-yl)oxy)methyl)tetrahydrothiophene 1,1-dioxide was prepared from 4-(2-azidopropyl-2-yl)-1,6-dichloro-2,7-diphenyl ether and 3-(hydroxymethyl)tetrahydrothiophene 1,1-dioxide using a procedure similar to that described above for intermediate 22. MS (ES+) C 16H 18ClN 5O 3S Required value: 395, Experimental value: 396 [M+H]+.

[0316] Intermediate 44: 4-(2-azidopropyl-2-yl)-6-chloro-1-(cis-3-(ethylsulfonylmethane)cyclobutoxy)-2,7-diphenyl

[0317] Step 1: Sodium ethanethiol (328 mg, 3.90 mmol) was added to a solution of trans-3-(benzylmethyloxy)cyclobutyl)(ethyl)thionyl methanesulfonate (0.5 g, 1.95 mmol) in DMF (2 mL). The reaction mixture was stirred at 100 °C for 0.5 h, then diluted with water (100 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by silica gel chromatography (PE / EA = 1:0 to 20:1) to give the title compound (160 mg, 37% yield) as a colorless oil.

[0318] Steps 2-4: The title compound 4-(2-azidopropyl-2-yl)-6-chloro-1-(cis-3-(ethylsulfonylurea)cyclobutoxy)-2,7-diphenyl ether was prepared using a procedure similar to that described in steps 5-7 of intermediate 32.

[0319] Intermediate 45: 4-((R)-2-azidobutyl-2-yl)-6-chloro-1-(cis-3-(ethylsulfonylmethane)cyclobutoxy)-2,7-diphenyl

[0320] Step 1: The title compound 4-((R)-2-azidobutyl-2-yl)-6-chloro-1-(cis-3-(ethylsulfonylurea)cyclobutoxy)-2,7-dichlorodiphenyl ether was prepared using a procedure similar to that described in Step 1 of intermediate 22, from (R)-4-(2-azidobutyl-2-yl)-1,6-dichloro-2,7-dichlorodiphenyl ether and cis-3-(ethylsulfonylurea)cyclobut-1-ol (described in the preparation of intermediate 44). MS (ES+) C 18H 22ClN 5O 3S Required value: 423, Experimental value: 424 [M+H]+.

[0321] Intermediate 46: (S)-N-(1-(6-chloro-1-(cis-3-(ethylsulfonylurea)cyclobutoxy)-2,7-diphenyl-4-yl)propyl)-2-methylpropane-2-sulfinamide

[0322] Step 1: The title compound 4-bromo-6-chloro-1-(cis-3-(ethylsulfonylurea)cyclobutoxy)-2,7-dichloro ...

[0323] Step 2: 6-Chloro-1-(cis-3-(ethylsulfonylurea)cyclobutoxy)-4-vinyl-2,7-diphenyl ether (1.35 g, 3.33 mmol, 1 equivalent), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborhexacyclopentane (563.75 mg, 3.66 mmol, 620.87 µL, 1.1 equivalent), Pd(dppf)Cl₂ (243.49 mg, 332.76 µmol, 0.1 equivalent), and K₂CO₃ (919.82 mg, 6.66 mmol, 2 equivalent) were dissolved in H₂O (2 mL) and diphenyl ether (10 mL) The mixture was degassed and purged three times with N2, and then stirred at 80°C for 2 hours. The reaction mixture was then diluted with H2O (100 mL) and extracted with EA (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 1 / 1) to give the title compound (700 mg, 60% yield) as a yellow oil.

[0324] Step 3: 6-Chloro-1-(cis-3-(ethylsulfonylurea)cyclobutoxy)-2,7-vinyl-2,7-carboxaldehyde was bubbled with ozone at -78°C into a solution of 6-chloro-1-(cis-3-(ethylsulfonylurea)cyclobutoxy)-4-vinyl-2,7 ... MS (ES+) C 15H 15ClN 2O 4S Required value: 354, Experimental value: 355 [M+H]+.

[0325] Step 4: Add Ti(Oi-Pr)4 (2.04 g, 7.19 mmol, 2.12 mL, 3 equivalents) to a solution of (S)-N-((E)-(6-chloro-1-(cis-3-(ethylsulfonylurea)cyclobutoxy)-2,7-diphenyl-4-yl)methylene)-2-methylpropane-2-sulfinamide in THF (10 mL). The mixture was stirred at 60°C for 2 hours, then quenched by adding H₂O (50 mL) at 25°C, diluted with EA (50 mL), and filtered. The filtrate was extracted with EA (80 mL × 3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by column chromatography (SiO₂, PE / EA = 0 / 1 to 1 / 1) to give the title compound (1 g, 91% yield) as a yellow solid.

[0326] Step 4: (S)-N-(1-(6-chloro-1-(cis-3-(ethylsulfonylurea)cyclobutoxy)-2,7-diphenyl-4-yl)propyl)-2-methylpropane-2-sulfinamide was added to a solution of (S)-N-((E)-(6-chloro-1-(cis-3-(ethylsulfonylurea)cyclobutoxy)-2,7-diphenyl-4-yl)methylene)-2-methylpropane-2-sulfinamide (300 mg, 655 µmol, 1 equivalent) in THF (10 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 15 minutes, then quenched by adding ammonium chloride aqueous solution (45 mL) and extracted with EA (45 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (400 mg, crude substance) as a yellow oil, which was used in the next step without further purification. MS (ES+) C 21H 30ClN 3O 4S 2 Required value: 487, Experimental value: 488 [M+H]+.

[0327] Intermediate 47: 4-(2-azidopropyl-2-yl)-6-chloro-1-(3-((methanesulfonyl)methyl)cyclobutoxy)-2,7-diphenyl

[0328] Step 1: LiAlH₄ (689 mg, 18.16 mmol) was added to a solution of methyl 3-(phenylmethyloxy)cyclobutane-1-carboxylate (2 g, 9.08 mmol) in THF (60 mL) at 0 °C. The reaction mixture was stirred at 0–25 °C for 1 hour, and then quenched by adding water (6 mL) and NaOH aqueous solution (20 mL, 15% MW) at 0 °C. The reaction mixture was then extracted with EA (40 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (1.8 g, crude) as a colorless oil, which was used directly in the next step. MS (ES+) C₁₂H₁₆O₂ Required value: 192, Experimental value: 193 [M+H]⁺.

[0329] Step 2: The title compound (3-(benzylmethyloxy)cyclobutyl)methanesulfonate was prepared from (3-(benzylmethyloxy)cyclobutyl)methanol using a procedure similar to that described in step 3 of intermediate 30.

[0330] Step 3: MeSNa (1.82 g, 11.1 mmol) was added to a solution of ((3-(phenylmethyloxy)cyclobutyl)methyl)(methyl)thione in DMF (10 mL). The reaction mixture was stirred at 100 °C for 1 hour, then diluted with water (40 mL) and extracted with EA (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the residue. The residue was purified by column chromatography (SiO2, PE / EA = 1 / 0 to 10 / 1) to give the title compound (2 g) as a colorless oil. MS (ES+) C 13H 18OS required value: 222, experimental value: 223 [M+H]+.

[0331] Steps 4-6: The title compound 4-(2-azidopropyl-2-yl)-6-chloro-1-(3-((methanesulfonyl)methyl)cyclobutoxy)-2,7-diphenyl ether was prepared using a procedure similar to that described in steps 5-7 of intermediate 32. MS (ES+) C 17H 20ClN 5O 3S Required value: 409, Experimental value: 410 [M+H]+.

[0332] Intermediates 48 and 49: 4-((R)-2-azidobutyl-2-yl)-6-chloro-1-(cis-3-((methanesulfonyl)methyl)cyclobutoxy)-2,7-diphenyl ether and 4-((R)-2-azidobutyl-2-yl)-6-chloro-1-(trans-3-((methanesulfonyl)methyl)cyclobutoxy)-2,7-diphenyl ether

[0333] Step 1: The title compound 4-((R)-2-azidobutyl-2-yl)-6-chloro-1-(cis-3-((methanesulfonyl)methyl)cyclobutoxy)-2,7-dichloro-2,7-dichloro-2-ol and 4-((R)-2-azidobutyl-2-yl)-6-chloro-1-(trans-3-((methanesulfonyl)methyl)cyclobutoxy)-2,7-dichloro-2-ol were prepared using a procedure similar to that described in Step 1 of intermediate 31, from 3-((methanesulfonyl)methyl)cyclobut-1-ol and (R)-4-(2-azidobutyl-2-yl)-1,6-dichloro-2,7-dichloro-2-ol. The mixture of diastereomers was separated by SFC (column: Daicel ChiralPak IG (250×30 mm, 10 µm); mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 60%-60%) to obtain intermediate 48 (cis isomer, 220 mg, 63% yield) and intermediate 49 (trans isomer, 90 mg, 26% yield) as a colorless oil.

[0334] Intermediate 48: MS (ES+) C 18H 22ClN 5O 3S Demand value: 423, Experimental value: 424 [M+H]+.

[0335] Intermediate 49: MS (ES+) C 18H 22ClN 5O 3S Demand value: 423, Experimental value: 424 [M+H]+.

[0336] Intermediates 50 and 51: 4-((S)-2-azido-1-methoxypropyl-2-yl)-6-chloro-1-(cis-3-((methanesulfonyl)methyl)cyclobutoxy)-2,7-diphenyl ether and 4-((S)-2-azido-1-methoxypropyl-2-yl)-6-chloro-1-(trans-3-((methanesulfonyl)methyl)cyclobutoxy)-2,7-diphenyl ether

[0337] Step 1: The title compound 4-((S)-2-azido-1-methoxypropyl-2-yl)-6-chloro-1-(cis-3-((methanesulfonyl)methyl)cyclobutoxy)-2,7-dichloro-2 ... The mixture of diastereomers was separated by SFC (column: Daicel ChiralPak IG (250×30 mm, 10 µm); mobile phase: [0.1% NH3H2O ​​MeOH]; B%: 70%-70%) to give yellow oily intermediate 50 (cis isomer, 360 mg, 20% yield) and yellow oily intermediate 51 (trans isomer, 120 mg, 6.50% yield).

[0338] Intermediate 50: MS (ES+) C 18H 22ClN 5O 4S Demand value: 439, Experimental value: 440 [M+H]+.

[0339] Intermediate 51: MS (ES+) C 18H 22ClN 5O 4S Demand value: 439, Experimental value: 440 [M+H]+.

[0340] Intermediate 52: 4-(2-azidopropyl-2-yl)-6-chloro-1-(((2R,4R)-4-(methanesulfonyl)pent-2-yl)oxy)-2,7-diphenyl

[0341] Step 1: (2R,4R)-4-((tributyldimethylsilyl)oxy)pentane-2-ol) was added to a solution of (2R,4R)-pentane-2,4-diol (3.80 g, 36.5 mmol) in THF (120 mL) at 0 °C. The reaction mixture was stirred for 30 minutes, followed by the addition of tributyldimethylchlorosilane (6.05 g, 40.1 mmol) and stirring at 25 °C for 1.5 hours. The reaction mixture was then added to water (200 mL) and extracted with EA (150 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silicone column chromatography (PE / EA = 1:0 to 5:1) to give the title compound as a colorless oil (7.80 g, 98% yield).

[0342] Step 2: 4-Nitrobenzoic acid (2S,4R)-4-((tributyldimethylsilyl)oxy)pentan-2-yl ester was added at 0°C to a solution of (2R,4R)-4-((tributyldimethylsilyl)oxy)pentan-2-ol (1.00 g, 4.58 mmol), compound 4-nitrobenzoic acid (1.53 g, 9.16 mmol), and triphenylphosphine (3.60 g, 13.7 mmol) in THF (34 mL). The reaction mixture was stirred at 0°C for 30 minutes, followed by stirring at 25°C for 15.5 hours. The mixture was diluted with water (50 mL) and extracted with EA (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silicone column chromatography (PE / EA = 1:0 to 10:1) to give the title compound (1.50 g, 78% yield) as a yellow oil.

[0343] Step 3: LiOH•H₂O (977 mg, 40.8 mmol) was added to a solution of (2 S,4 R)-4-((tri-butyldimethylsilyl)oxy)pentan-2-ol in THF (12 mL) and water (4 mL). The reaction mixture was stirred at 60 °C for 1 hour, then diluted with water (50 mL) and extracted with EA (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (890 mg, 100% yield) as a yellow oil, which was used in the next step without further purification.

[0344] Step 4: At 0°C, TEA (1.24 g, 12.2 mmol) and MsCl (934 mg, 8.15 mmol) were added to a solution of (2 S,4 R)-4-((tributyldimethylsilyl)oxy)pentane-2-ol) in DCM (15 mL). The reaction mixture was stirred for 1 hour, then diluted with water (100 mL) and extracted with DCM (80 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.20 g, 99% yield) as a yellow oil, which was used in the next step without further purification.

[0345] Step 5: Sodium methanethiol (709 mg, 10.1 mmol) was added to a solution of methanesulfonic acid (2S,4R)-4-((tributyldimethylsilyl)oxy)pentyl-2-yl ester (1.20 g, 4.05 mmol) in DMF (30 mL). The reaction mixture was stirred at 25 °C for 0.5 h, then diluted with water (80 mL) and extracted with EA (60 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (1.00 g, 99% yield) as a yellow oil, which was used in the next step without further purification.

[0346] Step 6: Oxone® (4.95 g, 8.05 mmol) was added to a solution of tributyldimethyl(((2R,4R)-4-(methanesulfonyl)pent-2-yl)oxy)silane (1.00 g, 4.02 mmol) in THF (14 mL) and water (7 mL). The reaction mixture was stirred at 25 °C for 0.5 h, then quenched by adding saturated sodium sulfite aqueous solution (30 mL) and extracted with EA (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (1.10 g, 97% yield) as a yellow oil, which was used without further purification.

[0347] Step 7: (2R,4R)-4-(methanesulfonyl)pentan-2-ol was added to a solution of tributyldimethyl(((2R,4R)-4-(methanesulfonyl)pentan-2-yl)oxy)silane (1.10 g, 3.92 mmol) in THF (8 mL) with an aqueous HCl solution (6 M, 2 mL). The reaction mixture was stirred at 25 °C for 0.5 h, then diluted with water (50 mL) and extracted with EA (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by silicone column chromatography (PE / EA = 1:0 to 0:1) to give the title compound (230 mg, 35% yield) as a yellow oil.

[0348] Step 8: The title compound 4-(2-azidopropyl-2-yl)-6-chloro-1-(((2 R,4 R)-4-(methanesulfonyl)pent-2-yl)oxy)-2,7-dichloro-2,7-diphenyl ether was prepared from (2 R,4 R)-4-(methanesulfonyl)pent-2-ol and 4-(2-azidopropyl-2-yl)-1,6-dichloro-2,7-diphenyl ether using a procedure similar to that described in Step 1 of intermediate 22. MS (ES+) C 17H 22ClN 5O 3S Required value: 411, Experimental value: 412 [M+H]+.

[0349] Intermediate 53: 4-((R)-2-azidobutyl-2-yl)-6-chloro-1-(((2R,4R)-4-(methanesulfonyl)pent-2-yl)oxy)-2,7-diphenyl

[0350] Step 1: The title compound 4-((R)-2-azidobutyl-2-yl)-6-chloro-1-(((2R,4R)-4-(methanesulfonyl)pentan-2-yl)oxy)-2,7-dichloro-2,7-diphenyl ether was prepared from (2R,4R)-4-(methanesulfonyl)pentan-2-ol and (R)-4-(2-azidobutyl-2-yl)-1,6-dichloro-2,7-diphenyl ether using a procedure similar to that described in Step 1 of intermediate 22. MS (ES+) C 18H 24ClN 5O 3S Required value: 425, Experimental value: 426 [M+H]+.

[0351] Intermediate 54: 4-((R)-2-azidobut-2-yl)-6-chloro-1-(((S)-4-(methanesulfonyl)but-2-yl)oxy)-2,7-dichloro-2-idine Step 1: 4-((R)-2-azidobut-2-yl)-6-chloro-1-(((S)-4-(methanesulfonyl)but-2-yl)oxy)-2,7-dichloro-2-idine The title compound was prepared from 4-(methanesulfonyl)but-2-ol and (R)-4-(2-azidobut-2-yl)-1,6-dichloro-2,7-diidine using a procedure similar to that described in Step 1 of Intermediate 22. The resulting mixture of diastereomers was separated by SFC (column: Daicel Chiralpak AD-H (250 mm × 30 mm, 5 µm); mobile phase: [0.1% NH3H2O ​​IPA]; B%: 35%-35%) to obtain the title compound as the first dissolution isomer. Stereochemistry of this mixture and intermediate 31 prepared from enantiomerically pure starting materials was determined by chiral SFC analysis.

[0352] Intermediate 55: (R)-4-(2-azidopropyl-2-yl)-6-chloro-1-((4-(methanesulfonyl)but-2-yl)oxy)-2,7-diphenyl

[0353] Step 1: The title compound (R)-4-(2-azidopropyl-2-yl)-6-chloro-1-((4-(methanesulfonyl)but-2-yl)oxy)-2,7-dichloro-2 ...

[0354] Intermediates 56 and 57: 4-((R)-1-azido-1-cyclopropylethyl)-6-chloro-1-(cis-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl ether and 4-((S)-1-azido-1-cyclopropylethyl)-6-chloro-1-(cis-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl ether, each of which is represented by one of the structures shown below:

[0355] Step 1: 1-(6-chloro-1-hydroxy-2,7-diphenyl-4-yl)ethyl-1-one was added to a solution of 1-(6-chloro-1-methoxy-2,7-diphenyl-4-yl)ethyl-1-one (the title compound from step 3 of intermediate 17, 3.00 g, 12.7 mmol) in THF (30 mL) with an aqueous solution of HCl (6 M, 20 mL). The reaction mixture was stirred at 25 °C for 16 hours, then diluted with water (80 mL) and extracted with EA (60 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (2.80 g, crude), which was used in the next step without any further purification.

[0356] Step 2: 1-(1,6-Dichloro-2,7-diphenyl-4-yl)ethyl-1-one 1-(6-chloro-1-hydroxy-2,7-diphenyl-4-yl)ethyl-1-one (1.00 g, 4.49 mmol) was added to POCl3 (10 mL), and the reaction mixture was stirred at 100 °C for 2 hours. The mixture was then cooled to room temperature and slowly poured into a saturated sodium bicarbonate aqueous solution (500 mL). The mixture was extracted with EA (200 mL × 3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silicone column chromatography (PE / EA = 1:0 to 3:1) to give the title compound (660 mg, 58% yield) as a white solid.

[0357] Step 3: 1-Cyclopropyl-1-(1,6-dichloro-2,7-diphenyl-4-yl)ethanol-1-ol was added to a solution of 1-(1,6-dichloro-2,7-diphenyl-4-yl)ethanol-1-one (600 mg, 2.49 mmol) in MTBE (200 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 40 min, then diluted with water (80 mL) and extracted with EA (60 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by silicone column chromatography (PE / EA = 1:0 to 3:1) to give the title compound (550 mg, 78% yield) as a yellow solid.

[0358] Step 4: 1-(6-chloro-1-(cis-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl-4-yl)-1-cyclopropyl ethanol-1-ol was added to a solution of cis-3-(methanesulfonyl)cyclobut-1-ol (167 mg, 1.11 mmol) in THF (20 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min, followed by the addition of 1-cyclopropyl-1-(1,6-dichloro-2,7-diphenyl-4-yl)ethanol-1-ol (300 mg, 1.06 mmol) and stirring at 25 °C for 45 min. The reaction mixture was then diluted with water (50 mL) and extracted with EA (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (390 mg, crude substance) as a yellow oil, which was used in the next step without further purification.

[0359] Step 5: TMSN 3 (340 mg, 2.95 mmol) and BF 3·Et 2O (279 mg, 1.97 mmol) were added to a solution of 4-(1-azido-1-cyclopropylethyl)-6-chloro-1-(cis-3-(methanesulfonyl)cyclobutoxy)-2,7-acetidyl-4-yl)-1-cyclopropylethyl-1-ol (390 mg, 983 µmol) in 1,2-DCE (10 mL). The reaction mixture was stirred at 25 °C for 1 hour, then diluted with water (80 mL) and extracted with DCE (60 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by silicone column chromatography (PE / EA = 1:0 to 0:1) to give the title compound (240 mg, 58% yield) as a yellow oil.

[0360] Step 6: 4-((R)-1-azido-1-cyclopropylethyl)-6-chloro-1-(cis-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl ether and 4-((S)-1-azido-1-cyclopropylethyl)-6-chloro-1-(cis-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl ether (240 mg, 569 µmol) were administered via SFC (column: Daicel Chiralpak AY-H (250 mm × 30 mm, 10 µm); mobile phase: [0.1% NH3H2O] IPA]; B%: 40%-40%) was separated to obtain a yellow oily 4-((R)-1-azido-1-cyclopropylethyl)-6-chloro-1-(cis-3-(methanesulfonyl)cyclobutoxy)-2,7-phenidine as the first soluble isomer (intermediate 56, 110 mg, 45% yield) and ...). The other of (S)-1-azido-1-cyclopropylethyl)-6-chloro-1-(cis-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl ether is used as the second dissolution isomer (intermediate 57, 110 mg, 45% yield).

[0361] Intermediate 56: MS (ES+) C 18H 20ClN 5O 3S Demand value: 421, Experimental value: 422 [M+H]+.

[0362] Intermediate 57: MS (ES+) C 18H 20ClN 5O 3S Demand value: 421, Experimental value: 422 [M+H]+.

[0363] Intermediate 58: (S)-N-((6-chloro-1-(cis-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl-4-yl)(cyclopropyl)methyl)-2-methylpropane-2-sulfinamide Steps 1-4: (S)-N-((E)-(6-chloro-1-(cis-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl-4-yl)methylene)-2-methylpropane-2-sulfinamide The title compound was prepared from 4-bromo-1,6-dichloro-2,7-diphenyl ether and cis-3-(methanesulfonyl)cyclobut-1-ol using a procedure similar to that described in steps 1-4 of intermediate 46.

[0364] Step 5: Add magnesium cyclopropyltrimonium bromide (0.5 M, 10.0 mL) to a solution of (S)-N-((6-chloro-1-(cis-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl-4-yl)(cyclopropyl)methyl)-2-methylpropane-2-sulfinamide (500 mg, 1.13 mmol) in MTBE (60 mL). The reaction mixture was stirred at 60 °C for 0.5 h, followed by quenching with saturated NH4Cl aqueous solution (20 mL). The mixture was diluted with water (20 mL) and extracted with EA (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by rapid silica gel chromatography (PE / EA 1:0 to 0:1) to give the title compound (100 mg, 16% yield) as a yellow oil. MS (ES+) C 21H 28ClN 3O 4S 2 Required value: 485, Experimental value: 486 [M+H]+.

[0365] Intermediate 59: 5-(2-azidopropyl-2-yl)-3-chloro-8-(cis-3-(ethylsulfonylurea)cyclobutoxy)isoquinoline Steps 1-6: The title compound 5-(2-azidopropyl-2-yl)-3-chloro-8-(cis-3-(ethylsulfonylurea)cyclobutoxy)isoquinoline was prepared using a procedure similar to that described in steps 7-12 of intermediate 35, from cis-3-((5-bromo-3-chloroisoquinoline-8-yl)oxy)cyclobutane-1-thiol (intermediate 35, step 6) and iodoethane. MS (ES+) C 18H 21ClN 4O 3S Required value: 408, Experimental value: 409 [M+H]+.

[0366] Intermediate 60: 4-(2-azidopropyl-2-yl)-6-chloro-N-(cis-3-(ethylsulfonylurea)cyclobutyl)-2,7-diphenyl-1-amine

[0367] Step 1: Trans-3-((tributoxycarbonyl)amino)cyclobutyl methanesulfonate was added once at 0°C to a solution of tributane (trans-3-hydroxycyclobutyl)aminocarbamate (2.00 g, 10.7 mmol) in DCM (20 mL) with TEA (4.46 mL, 32.1 mmol) and MsCl (2.45 g, 21.4 mmol). The reaction mixture was stirred at 0°C for 1 hour, then poured into water (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (2.83 g, crude substance) as a yellow oil, which was used directly in the next step.

[0368] Step 2: A solution of tributyl (cis-3-(ethylthio)cyclobutyl)aminocarbamate in DMF (20 mL) was prepared by adding sodium ethanethiol (1.80 g, 21.3 mmol) to trans-3-((tributylbutoxycarbonyl)amino)cyclobutyl methanesulfonic acid (2.83 g, 10.7 mmol). The reaction mixture was stirred at 100 °C for 1 hour, then poured into water (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.40 g, 57% yield) as a yellow solid.

[0369] Step 3: Oxone® (1.86 g, 3.03 mmol) was added to a solution of (cis-3-(ethylsulfonylurea)cyclobutyl)aminocarbamate (700 mg, 3.03 mmol) in THF (10 mL) and water (5 mL). The reaction mixture was stirred at 25°C for 1 hour, then poured into water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silicone column chromatography (PE / EA = 10:1 to 1:1) to give the title compound (200 mg, 25% yield) as a yellow solid.

[0370] Step 4: HCl (4 M solution in dimethyl methacrylate, 427 µL) was added to a solution of tributyl cis-3-(ethylsulfonylurea)cyclobutyl-1-amine in dimethyl methacrylate (150 mg, 570 µmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour, then concentrated to give the title compound (90 mg, crude substance) as a yellow oil, which was used in the next step without further purification.

[0371] Step 5: DIPEA (214 mg, 1.65 mmol) was added to a solution of 4-(2-azidopropyl-2-yl)-6-chloro-N-(cis-3-(ethylsulfonylurea)cyclobutyl)-2,7-diphenyl-1-amine in NMP (1 mL). The reaction mixture was stirred at 25 °C for 2 hours, then poured into water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silicone column chromatography (PE / EA = 10:1 to 1:1) to give the title compound (150 mg, 67% yield) as a yellow oil. MS (ES+) C 17H 21ClN 6O 2S Required value: 409, Experimental value: 410 [M+H]+.

[0372] Intermediates 61 and 62: (S)-N-((S)-1-(6-chloro-1-(cis-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl-4-yl)butyl)-2-methylpropane-2-sulfinamide and (S)-N-((R)-1-(6-chloro-1-(cis-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl-4-yl)butyl)-2-methylpropane-2-sulfinamide, each represented by one of the structures shown below:

[0373] Step 1: (S)-N-((S)-1-(6-chloro-1-(cis-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl-4-yl)butyl)-2-methylpropane-2-sulfinamide and (S)-N-((R)-1-(6-chloro-1-(cis-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl-4-yl)butyl)-2-methylpropane-2-sulfinamide at 25°C, to (S)-N-((E)-(6-chloro-1-(cis-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl-4-yl)methylene)-2-methylpropane-2-sulfinamide (the title compound from step 4 of intermediate 58, 200 mg, 450 mg) n-PrMgBr (2 M, 1.13 mL) was added to a solution of µmol in toluene (10 mL). The reaction mixture was stirred at 25 °C for 30 min, followed by quenching with saturated ammonium chloride aqueous solution (20 mL). The mixture was diluted with water (20 mL) and extracted with EA (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150×25 mm×10 µm; mobile phase: [water (0.225% FA)-ACN]; B%: 40%-70%) to give a white solid of (S)-N-((S)-1-(6-chloro-1-(cis-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl-4-yl)butyl)-2-methylpropane-2-sulfinamide as the first dissolution isomer (intermediate 61, 25 mg, 5.5% yield) and a white solid of ( The second dissolution isomer is one of (S)-N-((S)-1-(6-chloro-1-(cis-3-(methanesulfonyl)cyclobutoxy)-2,7-diphenyl-4-yl)butyl)-2-methylpropane-2-sulfinamide (intermediate 62, 30 mg, 6.7% yield).

[0374] Intermediate 61: MS (ES+) C 21H 30ClN 3O 4S 2 Demand value: 487, Experimental value: 488 [M+H]+.

[0375] Intermediate 62: MS (ES+) C 21H 30ClN 3O 4S 2 Demand value: 487, Experimental value: 488 [M+H]+.

[0376] Intermediates 63 and 64: trans-3-((4-(2-azidopropyl-2-yl)-6-chloro-2,7-diphenyl-1-yl)oxy)-N,N-dimethylcyclobutane-1-sulfonamide and cis-3-((4-(2-azidopropyl-2-yl)-6-chloro-2,7-diphenyl-1-yl)oxy)-N,N-dimethylcyclobutane-1-sulfonamide

[0377] Step 1: S-(3-(benzylmethyloxy)cyclobutyl)ethanethiol ester Potassium ethanethiol (2.63 g, 23.0 mmol) was added to a solution of compound 3-(benzylmethyloxy)cyclobutyl 4-methylbenzenesulfonic acid (1.00 g, 3.01 mmol) in ACN (1 mL) and DMF (4 mL). The reaction mixture was stirred at 60 °C for 1 hour, then poured into water (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with water (20 mL × 3), dried over sodium sulfate, filtered, and concentrated to give the title compound (400 mg, 56% yield) as a yellow solid.

[0378] Steps 2 and 3: trans-3-(benzylmethyloxy)-N,N-dimethylcyclobutane-1-sulfenamide and cis-3-(benzylmethyloxy)-N,N-dimethylcyclobutane-1-sulfenamide were added to a solution of S-(3-(benzylmethyloxy)cyclobutyl)ethanethiol ester (400 mg, 1.69 mmol) in ACN (20 mL) and concentrated HCl (845 mg, 8.46 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 3 hours, then poured into water (10 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with water (20 mL × 3), dried over sodium sulfate, filtered, and concentrated. The organic phase was concentrated under vacuum to obtain the residue. Next, dimethylamine (2 M, 3.39 mL) was added to the residue, and the reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was then poured into water (10 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with water (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Synergi C18 150 × 25 mm × 10 µm; mobile phase: [water (0.225% FA)-ACN]; B%: 11%–41%) to give trans-3-(benzylmethyloxy)-N,N-dimethylcyclobutane-1-sulfonamide (200 mg, 44% yield) and cis-3-(benzylmethyloxy)-N,N-dimethylcyclobutane-1-sulfonamide (200 mg, 44% yield) as yellow solids.

[0379] trans-3-(benzylmethyloxy)-N,N-dimethylcyclobutane-1-sulfonamide: 1H NMR (400 MHz, CDCl 3): δ ppm 7.37-7.28 (m, 5H), 4.37 (s, 2H), 4.00-3.94 (m, 1H), 3.32-3.25 (m, 1H), 2.88 (s, 6H), 2.58-2.51 (m, 4H).

[0380] cis-3-(benzylmethyloxy)-N,N-dimethylcyclobutane-1-sulfonamide: 1H NMR (400 MHz, CDCl 3): δ ppm 7.30-7.22 (m, 5H), 4.35 (s, 2H), 4.50-4.40 (m, 1H), 3.75-3.65 (m, 1H), 2.40-2.30 (m, 4H), 1.49 (s, 6H).

[0381] Step 4: Pd / C (5 mg, 74.25 µmol) was added to a solution of trans-3-(benzylmethyloxy)-N,N-dimethylcyclobutane-1-sulfonamide (200 mg, 743 µmol) in methanol (10 mL). The reaction mixture was stirred at 25 °C under hydrogen (15 psi) for 12 hours, then filtered and concentrated to give the title compound (120 mg, 90% yield) as a yellow solid.

[0382] Step 5: trans-3-((4-(2-azidopropyl-2-yl)-6-chloro-2,7-diphenyl-1-yl)oxy)-N,N-dimethylcyclobutane-1-sulfonamide (Intermediate 63) The title compound was prepared from trans-3-hydroxy-N,N-dimethylcyclobutane-1-sulfonamide and 4-(2-azidopropyl-2-yl)-1,6-dichloro-2,7-diphenyl ether using a procedure similar to that described in Step 1 of Intermediate 22.

[0383] Step 6: The title compound cis-3-hydroxy-N,N-dimethylcyclobutane-1-sulfonamide was prepared from cis-3-(benzylmethyloxy)-N,N-dimethylcyclobutane-1-sulfonamide using a procedure similar to that described above for the trans isomer in step 4.

[0384] Step 7: cis-3-((4-(2-azidopropyl-2-yl)-6-chloro-2,7-diphenyl-1-yl)oxy)-N,N-dimethylcyclobutane-1-sulfonamide (Intermediate 64) The title compound was prepared from cis-3-hydroxy-N,N-dimethylcyclobutane-1-sulfonamide and 4-(2-azidopropyl-2-yl)-1,6-dichloro-2,7-diphenyl ether using a procedure similar to that described in Step 1 of Intermediate 22.

[0385] Intermediate 65: 4-((R)-2-azidobutyl-2-yl)-6-chloro-1-((1-(methanesulfonyl)pent-3-yl)oxy)-2,7-diphenyl

[0386] Step 1: 1-(methylthio)pentan-3-one was added to a solution of pentan-1-en-3-one (1 g, 11.9 mmol) in ACN (10 mL) and water (10 mL) with AcOH (785 mg, 13.1 mmol) and sodium methanethiol (1.25 g, 17.8 mmol). The reaction mixture was stirred at 60 °C for 1 hour, then diluted with water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by silica gel chromatography (PE / EA = 1:0 to 50:1) to give the title compound (1.10 g, 70% yield) as a yellow oil.

[0387] Step 2: Oxone® (6.14 g, 9.98 mmol) was added to a solution of 1-(methylthio)pentane-3-one (1.1 g, 8.32 mmol) in THF (40 mL) and water (20 mL). The reaction mixture was stirred at 25 °C for 2 hours, then diluted with water (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with a saturated aqueous sodium sulfite solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.30 g, 95% yield) as a white solid, which was used in the next step without further purification.

[0388] Step 3: NaBH4 (449 mg, 11.9 mmol) was slowly added to a solution of 1-(methanesulfonyl)pentan-3-one (2.60 g, 1.30 mmol) in MeOH (50 mL). The reaction mixture was stirred at 25 °C for 10 min, then diluted with water (100 mL) and concentrated to remove MeOH. The mixture was then extracted with EA (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (650 mg, 50% yield) as a yellow solid, which was used in the next step without further purification.

[0389] Step 4: The title compound 4-((R)-2-azidobutyl-2-yl)-6-chloro-1-((1-(methanesulfonyl)pent-3-yl)oxy)-2,7-dichloro-2,7-diphenyl ether was prepared from 1-(methanesulfonyl)pent-3-ol and (R)-4-(2-azidobutyl-2-yl)-1,6-dichloro-2,7-diphenyl ether using a procedure similar to that described in Step 1 of intermediate 22. MS (ES+) C 18H 24ClN 5O 3S Required value: 425, Experimental value: 426 [M+H]+.

[0390] Intermediates 66 and 67: 4-((R)-2-azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methanesulfonyl)pentan-2-yl)oxy)-2,7-diphenyl ether and 4-((S)-2-azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methanesulfonyl)pentan-2-yl)oxy)-2,7-diphenyl ether, each of which is represented by one of the structures shown below:

[0391] Steps 1-3: The title compound 4-(2-azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methanesulfonyl)pentan-2-yl)oxy)-2,7-diphenyl ketone was prepared from 1-(1,6-dichloro-2,7-diphenyl-4-yl)ethyl-1-one (from the title compound of step 2 of intermediate 56) and n-PrMgBr using a similar procedure as described in steps 3-5 of intermediates 56 and 57.

[0392] Step 4: 4-((R)-2-azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methanesulfonyl)pentan-2-yl)oxy)-2,7-diphenyl ether and 4-((S)-2-azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methanesulfonyl)pentan-2-yl)oxy)-2,7-diphenyl ether (300 mg, 682 µmol) were subjected to SFC (column: Daicel Chiralpak IC (250 mm × 30 mm, 10 µm); mobile phase: [0.1% NH4+] [3H 2O IPA]; B%: 60%-60%) was separated to obtain either 4-((R)-2-azidopent-2-yl)-6-chloro-1-(((2R,4R)-4-(methanesulfonyl)pent-2-yl)oxy)-2,7-diphenyl ether as the first isomer (intermediate 66, 135 mg, 44% yield) and 4-((R)-2-azidopent-2-yl)-6-chloro-1-(((2R,4R)-4-(methanesulfonyl)pent-2-yl)oxy)-2,7-diphenyl ether as the first isomer (intermediate 66, 135 mg, 44% yield) and 4-((R)-2-azidopent-2-yl)-6-chloro-1-(((2R,4R)-4-(methanesulfonyl)pent-2-yl)oxy)-2,7-diphenyl ether as the first isomer (intermediate 66, 135 mg, 44% yield) as the first isomer and 4-((R)-2-azidopent-2-yl)-6-chloro-1-(((2R,4R)-4-(methanesulfonyl)pent-2-yl)oxy)-2,7-diphenyl ether as the first isomer. The other of R)-4-(methanesulfonyl)pent-2-yl)oxy)-2,7-diphenyl ether or 4-((S)-2-azidopent-2-yl)-6-chloro-1-(((2R,4R)-4-(methanesulfonyl)pent-2-yl)oxy)-2,7-diphenyl ether is used as the second dissolution isomer (intermediate 67, 120 mg, 40% yield).

[0393] Intermediate 66: MS (ES+) C 19H 26ClN 5O 3S Demand value: 439, Experimental value: 440 [M+H]+.

[0394] Intermediate 67: MS (ES+) C 19H 26ClN 5O 3S Demand value: 439, Experimental value: 440 [M+H]+.

[0395] Intermediates 68 and 69: 4-((R)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methanesulfonyl)butan-2-yl)oxy)-2,7-diphenyl ether and 4-((S)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methanesulfonyl)butan-2-yl)oxy)-2,7-diphenyl ether, each of which is represented by one of the structures shown below:

[0396] Steps 1-2: The title compound 4-(2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methanesulfonyl)butan-2-yl)oxy)-2,7-diphenyl ether is prepared from 2-(1,6-dichloro-2,7-diphenyl-4-yl)pentan-2-ol (the title compound of step 1 of intermediate 66) and (R)-4-(methanesulfonyl)butan-2-ol using a procedure similar to that described in steps 4-5 of intermediates 56 and 57.

[0397] Step 3: 4-((R)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methanesulfonyl)butan-2-yl)oxy)-2,7-diphenyl ether and 4-((S)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methanesulfonyl)butan-2-yl)oxy)-2,7-diphenyl ether (350 mg, 822 µmol) were subjected to SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 µm); mobile phase: [0.1% NH3H2O] IPA]; B%: 70%-70%) was separated to obtain a colorless oily 4-((R)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methanesulfonyl)butan-2-yl)oxy)-2,7-phenidine or 4-((S)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methanesulfonyl)butan-2-yl)oxy)-2,7-phenidine as the first dissolution isomer (intermediate 68, 185 mg, 52% yield) and a colorless oily 4-((R)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methanesulfonyl)butan-2-yl)oxy)-2,7-phenidine or 4-(( The other of S)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methanesulfonyl)but-2-yl)oxy)-2,7-diphenyl ether is used as the second dissolution isomer (intermediate 69, 190 mg, 54% yield).

[0398] Intermediate 68: MS (ES+) C 18H 24ClN 5O 3S Required value: 425, Experimental value: 426 [M+H]+.

[0399] Intermediate 69: MS (ES+) C 18H 24ClN 5O 3S Demand value: 425, Experimental value: 426 [M+H]+.

[0400] Intermediate 70: 4-(2-azidopropyl-2-yl)-6-chloro-1-(((2R,4R)-4-(ethylsulfonylurea)pent-2-yl)oxy)-2,7-diphenyl

[0401] Step 1: Tributyl(((2R,4R)-4-(ethylthio)pent-2-yl)oxy)dimethylsilane was added to a solution of EtSH (1.94 g, 31.2 mmol) in DMSO (40 mL) at 25 °C with NaOH (1.08 g, 27.0 mmol). The suspension was stirred at 25 °C for 0.5 h, and then DMSO (10 mL) containing (2S,4R)-4-((tributyldimethylsilyl)oxy)pent-2-yl ester (4 g, 13.5 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25 °C for 3.5 h, then diluted with water (40 mL) and extracted with EA (60 mL × 4). The combined organic layers were washed with brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound (3.6 g, crude substance) in a white oily form, which was used directly in the next step.

[0402] Steps 2-4: The title compound 4-(2-azidopropyl-2-yl)-6-chloro-1-(((2R,4R)-4-(ethylsulfonylurea)pent-2-yl)oxy)-2,7-dimethylsilane was prepared using a procedure similar to that described in steps 6 and 7 of intermediate 52 and step 1 of intermediate 22. MS (ES+) C 18H 24ClN 5O 3S Required value: 425, Experimental value: 426 [M+H]+.

[0403] Intermediate 71: 4-(2-azidopropyl-2-yl)-6-chloro-1-((4-(ethylsulfonylurea)but-2-yl)oxy)-2,7-diphenyl ether. Steps 1-4: The title compound was prepared from sodium ethanethiol and but-3-en-2-one using a procedure similar to that described in steps 1-3 of intermediate 65 and step 1 of intermediate 22. MS (ES+) C 17H 22ClN 5O 3S Required value: 411, Experimental value: 412 [M+H]+.

[0404] Intermediates 72 and 73: 4-((R)-2-azidobutyl-2-yl)-6-chloro-1-(((R)-4-(ethylsulfonylurea)but-2-yl)oxy)-2,7-diphenyl ether and 4-((R)-2-azidobutyl-2-yl)-6-chloro-1-(((S)-4-(ethylsulfonylurea)but-2-yl)oxy)-2,7-diphenyl ether, each of which is represented by one of the structures shown below:

[0405] Step 1: The title compound 4-((R)-2-azidobut-2-yl)-6-chloro-1-((4-(ethylsulfonylurea)but-2-yl)oxy)-2,7-dichloro-2 ...

[0406] Step 2: 4-((R)-2-azidobutyl-2-yl)-6-chloro-1-(((R)-4-(ethylsulfonylurea)but-2-yl)oxy)-2,7-diphenyl ether and 4-((R)-2-azidobutyl-2-yl)-6-chloro-1-(((S)-4-(ethylsulfonylurea)but-2-yl)oxy)-2,7-diphenyl ether (370 mg, 869 µmol) were subjected to SFC (column: Daicel Chiralpak IG (250 mm × 30 mm, 10 µm); mobile phase: [0.1% NH3H2O] IPA]; B%: 70%-70%) was separated to obtain a colorless oily 4-((R)-2-azidob...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, 1. Among them: The T series is selected from 4-5 member heterocycles, wherein the heterocycle is substituted by 1-2 R6 atoms as appropriate; Z is absent, or is O or NH; ring A is a C4-6 cycloalkyl or a 4-6 member heterocycle containing nitrogen, wherein the cycloalkyl or heterocycle is substituted by 1-2 R6 atoms as appropriate; the L1 series is selected from C1-C3 alkyl groups, wherein the alkyl group is substituted by 1-2 R11 atoms as appropriate; the L2 series is selected from C1-C3 alkyl groups; B is O or NH; Q is N or CH; x is... 0, 1, or 2; n is 0, 1, 2, 3, or 4; R1 and R2 are each independently selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, and 4 to 6-membered heterocycles, wherein the alkyl group is substituted by 1-2 R3s as appropriate; each R3 is independently selected from halogens, hydroxyl groups, and OR4; each R4 is independently selected from C1-3 alkyl, CF3, CH2F, and CHF2; each R5 is independently selected from C1-2 alkyl, CF3, CH2F, and CHF2, or attached to the same carbon atom. The two R5 atoms, together with the carbon atom to which they are attached, form a C3-5 cycloalkyl group; or the two R5 atoms attached to two adjacent carbon atoms, together with the two adjacent carbon atoms to which they are attached, form a C4-6 cycloalkyl group; each R6 is independently selected from CH3, methoxy, CF3, CH2F, and CHF2; R7 is selected from C1-3 alkyl groups, C3-6 cycloalkyl groups, C1-4 alkyl groups, NR9R10, and 3-5 member heterocycles containing nitrogen or oxygen, wherein the alkyl group, cycloalkyl group, or... The heterocyclic ring is substituted with 1-3 R8s as appropriate; each R8 is independently selected from halogens, C1-3 alkyl groups, hydroxyl groups and C1-3 alkyl groups, wherein the alkyl group is substituted with 1-3 R12s as appropriate; R9 is a C1-2 alkyl group; R10 is a C1-2 alkyl group; each R11 is independently selected from halogens, methoxy groups, C1-2 alkyl groups, CH2F, CHF2 and CF3, or two R11s together with the two adjacent carbon atoms to which they are attached form a cyclopropyl group; and each R12 is a halogen.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula IV:

2. This compound is represented by formula VII:

3. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein: L1 is a bond; T is a ; and L2 is a bond or a methylene group.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein: The ring A group is selected from aziridine, cyclobutyl, cyclopentyl and pyridine, wherein the aziridine, cyclobutyl, cyclopentyl and pyridine are substituted with 1-2 R6 groups as appropriate.

5. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: L1 is a C1-C3 alkyl group substituted with 1-2 R11 ions, depending on the case; and T is...

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein L1 is selected from formulas L-1, L-2, L-3, L-4, L-5, L-6 and L-7:

6. Among them: The symbol '-' indicates a key connected to B; and '-' indicates a key connected to T.

7. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein Z is O.

8. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: T is a 4-5 member heterocycle containing ions, wherein the heterocycle is substituted by 1-2 R6 groups as appropriate; and L1 is selected from ions, methylene and ethyl groups.

9. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are each independently selected from hydrogen, C1-6 alkyl and C3-6 cycloalkyl, wherein the alkyl group is substituted with OR4 as appropriate; each R3 is independently selected from halogen, hydroxyl and OR4; and each R4 is a C1-3 alkyl.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are each independently selected from hydrogen, CH3, CH2CH3, CH2CH2CH3, CH2-OCH3, and cyclopropyl.

11. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: R5 is CH3, or two R5s attached to the same carbon atom together with the carbon atom to which they are attached form a cyclopropyl group; and n is 1, 2, 3 or 4; R7 is selected from C1-3 alkyl, CH2F, CHF2, CF3, C3-6 cycloalkyl and NR9R10; R9 is C1-2 alkyl; and R10 is C1-2 alkyl.

12. The compound of claim 11 or its pharmaceutically acceptable salt, wherein R7 is selected from CH3, CF3, CH2CH3, CH(CH3)2, cyclopropyl and N(CH3)2 and each R11 is independently CH3, CF3 or CH2CH3.

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein each R11 is CH3.

14. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 14. or 15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 17. A pharmaceutical composition comprising a compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

18. Use of a compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 17, for the preparation of a pharmaceutical product that inhibits MAP4K1 in an individual or enhances an immune response.

19. Use of a compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 17, for the preparation of a medicine for treating an individual’s MAP4K1 dependence condition or disease.

20. As claimed in claim 19, wherein the MAP4K1-dependent disease or condition is cancer or a viral infection, wherein the cancer is selected from the group consisting of: colorectal cancer, rectal cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, urethral cancer, bladder cancer, esophageal cancer, stomach cancer, liver cancer, head and neck cancer, lymphoma, leukemia, and melanoma.

Citation Information

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