Heterocyclic compounds as MAP4K1 inhibitors

Abstract

One embodiment of the present disclosure is a compound represented by formula (I), or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined herein. TIFF2024527608000517.tif7272 The compounds of formula (I) are MAP4K1 inhibitors and can be used to treat a disease or disorder in a subject that would benefit from the regulation of MAP4K1 activity.

Description

[Technical Field]

[0001] Related Applications 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.

[0002] The present application relates to MAP4K1 inhibitors and methods of using them, such as to regulate the activity of MAP4K1 in a subject. [Background technology]

[0003] MAP4K1, also known as hematopoietic progenitor kinase 1 (HPK1), was first cloned from hematopoietic progenitor cells (Hu, M.C., et al., Genes Dev, 1996.10(18):2251-64). MAP4K1 is particularly important as a target because it is expressed primarily in hematopoietic cells, such as T cells, B cells, macrophages, dendritic cells, neutrophils, and mast cells (Hu, M.C., et al., Genes Dev, 1996.10(18):2251-64 and Kiefer, F., et al., EMBO J, 1996.15(24):7013-25). MAP4K1 kinase activity is mediated by T cell receptor (TCR) (Liou, J., et al., Immunity, 2000.12(4):p.399-408), B cell receptor (BCR) (Liou, J., et al., Immunity, 2000.12(4):p.399-408), transforming growth factor receptor (TGF-R) (Wang, W., et al., J Biol Chem, 1997.272(36):p.22771-5 and Zhou, G., et al., J Biol Chem, 1999.274(19):p.13133-8), or G s It has been shown that MAP4K1 is induced by activation of the coupled PGE2 receptors (EP2 and EP4) (Ikegami, R, et al., J Immunol, 2001.166(7):p.4689-96). Thus, MAP4K1 regulates various functions of various immune cells.

[0004] MAP4K1 is important in regulating the functions of various immune cells and is involved in autoimmune diseases and antitumor immunity (Shui, JW, et al., Nat Immunol, 2007.8(1):p.84-91 and Wang, X., et al., J Biol Chem, 2012.287(14):p.11037-48). These observations suggest that attenuation of MAP4K1 activity may contribute to autoimmunity in patients. Furthermore, MAP4K1 may also regulate antitumor immunity through a T cell-dependent mechanism. In a PGE2-producing Lewis lung carcinoma tumor model, tumor development was slower in MAP4K1 knockout mice compared to wild-type mice (see US2007 / 0087988). Furthermore, adoptive transfer of MAP4K1-deficient T cells was shown to be more effective in controlling 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) obtained from MAP4K1-knockout mice were more efficient at initiating T cell responses and eliminating Lewis lung carcinoma than wild-type BMDCs (Alzabin, S., et al., J Immunol, 2009, 182(10):6187-94). Data from MAP4K1 kinase-deficient mice indicated that MAP4K1 kinase activity is crucial for conferring the inhibitory function of MAP4K1 on a wide range of immune cells, from CD4+, CD8+, DCs, and NK cells to T regulatory cells (Tregs), and that the kinase domain was sufficiently inactivated to elicit potent antitumor immune responses. Liu et al., PLoS ONE14(3):e0212670, https: / / doi.org / 10.1371 / journal.pone.0212670. Furthermore, loss of MAP4K1 kinase function suppresses tumor growth in preclinical tumor models, and therapeutic co-blockade of MAP4K1 kinase and PD-L1 enhances anti-tumor responses. Hernandez S. et al., Cell Reports 2018 25:80-94.Recently presented results show that tumor growth is inhibited in a CT-26 allograft mouse model using a small molecule MAP4K1 inhibitor (Seungmook, L., Cancer research. AACR Journal, 2019, Abstract 4150). These data validate MAP4K1 as a novel drug target for enhancing antitumor immunity.

[0005] Therefore, there is a need for novel compounds that modulate MAP4K1 activity for the treatment of MAP4K1-dependent diseases or disorders, such as cancer, viral infections, and other diseases and disorders. Of particular importance, there is a need for novel compounds that selectively modulate MAP4K1 activity. Summary of the Invention

[0006] Provided herein are compounds or pharmaceutically acceptable salts thereof, as well as compositions that inhibit MAP4K1 and thereby enhance immune responses in a subject. For example, the IC50 values ​​for MAP4K1 inhibition shown in Table 3 are: 50 The values ​​demonstrate that these compounds are potent inhibitors of MAP4K1. Also disclosed are methods of using the compounds and compositions described herein to treat cancer and viral infections.

[0007] A first embodiment of the present disclosure is a compound represented by formula I: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, T is [ka] and, [ka] and the heterocycle is selected from 4- to 5-membered heterocycles containing 1 to 2 R 6 is optionally replaced by; Z is absent, O or NH; Ring A is C 4-6 A cycloalkyl or a 4- to 6-membered heterocycle containing nitrogen, wherein the cycloalkyl or the heterocycle is a 4- to 6-membered heterocycle containing one to two R 6 is optionally replaced by; L 1 is selected from a bond and a C1-C3 alkylene, and the alkylene is selected from 1 to 2 R 11 is optionally replaced by; L 2 is selected from a bond and C1-C3 alkylene; B is O or NH; Q is N or CH; x is 0, 1, or 2; n is 0, 1, 2, 3, or 4; R 1 and R 2 are each independently hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, and 4- to 6-membered heterocycle, wherein the alkyl is selected from 1 to 2 R 3 is optionally replaced by; Each R 3 are independently selected from halogen, hydroxyl, and OR 4 Selected from; Each R 4 independently, C 1-3 alkyl, CF3, CH2F, and CHF2; Each R 5 independently, C 1-2 alkyl, CF3, CH2F, and CHF2, or Two R's attached to the same carbon atom 5 together with the carbon atoms to which they are attached form C 3-5 Two R's bonded to two adjacent carbon atoms to form a cycloalkyl 5 together with the two adjacent carbon atoms to which they are attached, form C 4-6 Forming a cycloalkyl; Each R 6is independently selected from CH3, methoxy, CF3, CH2F, and CHF2; R 7 is C 1-3 Alkyl, C 3-6 Cycloalkyl, OC 1-4 Alkyl, NR 9 R 10 and a 3- to 5-membered heterocycle containing nitrogen or oxygen, wherein the alkyl, the cycloalkyl, or the heterocycle is selected from 1 to 3 R 8 is optionally replaced by; Each R 8 are independently halogen, C 1-3 , hydroxyl and OC 1-3 alkyl, wherein the alkyl is selected from 1 to 3 R 12 is optionally replaced by; R 9 is C 1-2 alkyl; R 10 is C 1-2 alkyl; Each R 11 are independently halogen, methoxy, C 1-2 alkyl, CH2F, CHF2 and CF3, or two R 11 together with the two adjacent carbon atoms to which they are attached to form a cyclopropyl; Each R 12 is a halogen, or a pharmaceutically acceptable salt thereof.

[0008] Another embodiment of the present disclosure is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0009] Another embodiment of the present disclosure is a method for inhibiting MAP4K1 in a subject in need thereof, comprising contacting MAP4K1 with an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0010] Another embodiment of the present disclosure is a method of treating a MAP4K1-dependent disorder or disease (e.g., treatment of cancer) in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound(s).

[0011] Another embodiment of the present disclosure is the use of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound(s), for the preparation of a medicament for treating a MAP4K1-dependent disorder or disease (e.g., treatment of cancer) in a subject in need thereof.

[0012] Another embodiment of the present disclosure is a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound(s), for use in treating a MAP4K1-dependent disorder or disease (e.g., treatment of cancer) in a subject in need thereof. DETAILED DESCRIPTION OF THE INVENTION

[0013] The disclosed compounds, or pharmaceutically acceptable salts thereof, are MAP4K1 inhibitors that can be used to treat MAP4K1-dependent disorders or diseases, including cancer and viral infections.

[0014] Compound Embodiments Exemplary embodiments include the following: First embodiment: Formula I: [ka] or a pharmaceutically acceptable salt thereof. The variables of Formula I are described in the Summary of the Invention above.

[0015] Second embodiment: Formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein the definitions for the other variables of formula II are as defined in the first embodiment.

[0016] Third embodiment: Formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein the definitions for the other variables in formula III are as defined in the first embodiment.

[0017] Fourth embodiment: Formula IV: [ka] or a pharmaceutically acceptable salt thereof, wherein the definitions for the other variables in formula IV are as defined in the first embodiment.

[0018] Fifth embodiment: Formula V: [ka] or a pharmaceutically acceptable salt thereof, wherein the definitions for the other variables of formula V are as defined in the first embodiment.

[0019] Sixth embodiment: Formula VI: [ka] or a pharmaceutically acceptable salt thereof, wherein the definitions for the other variables of formula VI are as defined in the first embodiment.

[0020] Seventh embodiment: Formula VII: [ka] or a pharmaceutically acceptable salt thereof, wherein the definitions for the other variables of formula VII are as defined in the first embodiment.

[0021] Eighth embodiment: A compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof (L 1 is a bond; T is [ka] and;L 2 is a bond or methylene, and the definitions for the other variables in formulae I, II, III, IV, V, VI and VII are 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 azetidinylene, cyclobutylene, cyclopentylene, and pyrrolidinylene, and the azetidinylene, the cyclobutylene, the cyclopentylene, and the pyrrolidinylene are each independently selected from one to two R 6 and the definitions for the other variables of formulas I, II, III, IV, V, VI and VII are as defined in the first and / or eighth embodiment).

[0023] Tenth 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 the group consisting of one to two R 6 wherein the definitions for the other variables of formulae I, II, III, IV, V, VI and VII are as defined in the first and / or eighth embodiment.

[0024] Eleventh embodiment: A compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof (L 1 is 1 to 2 R 11 T is C1-C3 alkylene optionally substituted with [ka] and the definitions for the other variables in formulae I, II, III, IV, V, VI and VII are as defined in the first embodiment).

[0025] Twelfth embodiment: A compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof (L 1 is 1 to 2 R 11 and the definitions for the other variables of formulas I, II, III, IV, V, VI and VII are as defined in the first and / or eleventh embodiment.

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

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

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

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

[0030] 17th embodiment: A compound represented by formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof, wherein T is a 4- to 5-membered heterocycle containing sulfone, and the heterocycle is fused to one or two R 6 Optionally replaced by ;L 1 is selected from a bond, methylene, and ethylene, and the definitions for the other variables of formulas I, II, III, IV, V, VI, and VII are as defined in the first embodiment.

[0031] 18th embodiment: A compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof, wherein T is a 4-membered heterocycle containing sulfone, and the heterocycle is fused to one or two R 6 and the definitions for the other variables of formulae I, II, III, IV, V, VI and VII are as defined in the first and / or seventeenth embodiment).

[0032] 19th embodiment: A compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof (R 1 and R 2 are each independently hydrogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, wherein the alkyl is selected from OR 3each R 3 are independently selected from halogen, hydroxyl, and OR 4 Each R is selected from 4 independently, C 1-3 alkyl, and the definitions for the other variables of Formulas I, II, III, IV, V, VI and VII are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth and / or eighteenth embodiments.

[0033] 20th embodiment: A compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof (R 1 and R 2 are each independently selected from hydrogen, CH, CHCH, CHCHCH, CH-OCH, and cyclopropyl, and the definitions for the other variables of Formulas I, II, III, IV, V, VI, and VII are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, and / or eighteenth embodiments. In an alternative embodiment, with respect to a compound of Formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof: R 1 and R 2 are CH3 or R 1 is hydrogen and R 2 is CH2CH3; or R 1 is CH3 and R 2 is CH2CH3; or R 1 is CH3 and R 2 is CH2-OCH3; or R 1 is hydrogen and R 2 is CH2CH2CH3; or R 1 is CH3 and R 2 is CH2CH2CH3; or R 1 is hydrogen and R 2 is cyclopropyl; or R 1 is CH3 and R 2is cyclopropyl, and the definitions for the other variables of Formulas I, II, III, IV, V, VI, and VII are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, and / or eighteenth embodiments.

[0034] 21st embodiment: A compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof (R 5 is CH3 or two R bonded to the same carbon atom 5 together with the carbon atom to which they are attached form a cyclopropyl; n is 1, 2, 3, or 4, and the definitions for the other variables of Formulas I, II, III, IV, V, VI, and VII are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, and / or twentieth embodiments. In an alternative embodiment, with respect to a compound represented by Formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof: n is 0; or n is 1, and R 5 is CH3; or n is 2 and each R 5 is CH3; or n is 3 and each R 5 is CH3; or n is 3 and two R 5 together with the carbon atom to which they are attached to form a cyclopropyl, and one R 5 is CH3; or n is 4 and two R 5 together with the carbon atoms to which they are attached to form a cyclopropyl, and two R 5 is CH3, and the definitions for the other variables of Formulas I, II, III, IV, V, VI, and VII are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, and / or twentieth embodiment.

[0035] 22nd embodiment: A compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof (each R 6 is CH3, and the definitions for the other variables of Formulas I, II, III, IV, V, VI, and VII are as defined in the first, eighth, ninth, tenth, seventeenth, eighteenth, nineteenth, twentieth, and / or twenty-first embodiments.

[0036] 23rd embodiment: A compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof (R 7 is C 1-3 Alkyl, CH2F, CHF2, CF3, C 3-6 Cycloalkyl and NR 9 R 10 Selected from;R 9 is C 1-2 alkyl; R 10 is C 1-2 alkyl, and the definitions for the other variables of Formulas I, II, III, IV, V, VI and VII are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, nineteenth, twentieth, twenty-first and / or twenty-second embodiment).

[0037] 24th embodiment: A compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof (R 7 is selected from CH3, CF3, CH2CH3, CH(CH3)2, cyclopropyl, and N(CH3)2, and the definitions for the other variables of Formulas I, II, III, IV, V, VI, and VII are as defined in the first, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, nineteenth, twentieth, twenty-first, and / or twenty-second embodiment).

[0038] 25th embodiment: A compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof (each R 11are independently selected from CH3, CF3, and CH2CH3, and the definitions for the other variables of Formulas I, II, III, IV, V, VI, and VII are 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 embodiment.

[0039] 26th embodiment: A compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt thereof (each R 11 is CH3, and the definitions for the other variables of Formulas I, II, III, IV, V, VI, and VII are 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, with respect to compounds of Formula I, II, or V, or pharmaceutically acceptable salts thereof, B is NH and the definitions for the other variables of Formula I, II, and V are 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] The present disclosure also includes the compounds shown in Table 1 and prepared in the Examples, both in their neutral form and as pharmaceutically acceptable salts thereof. The synthetic protocols used to prepare the compounds of Table 1 are listed in the last column of Table 1, and full details of each synthetic protocol are provided in Schemes 1 and 2 and the General Synthetic Methods and Intermediates section. [Table 1-1] [Table 1-2] [Table 1-3]

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-78

Table 1-79

Table 1-80

Table 1-81

Table 1-82

Table 1-83

Table 1-84

Table 1-85

Table 1-86

Table 1-87

Table 1-89

Table 1-90

Table 1-91

Table 1-92

Table 1-93

Table 1-94

Table 1-95

Table 1-96

Table 1-97

Table 1-98

Table 1-99

Table 1-100

Table 1-101

Table 1-103

Table 1-104

Table 1-105

Table 1-106

Table 1-107

Table 1-108

Table 1-109

Table 1-110

Table 1-111

Table 1-112

Table 1-113

Table 1-114

Table 1-115

Table 1-116

Table 1-117

Table 1-118

Table 1-119

Table 1-120

Table 1-121

Table 1-122

Table 1-123

Table 1-124

Table 1-125

Table 1-126

Table 1-127

Table 1-129

Table 1-131

Table 1-133

Table 1-135

Table 1-138

Table 1-139

Table 1-141

Table 1-145

Table 1-147

Table 1-148

Table 1-149

Table 1-150

Table 1-151

Table 1-152

Table 1-153

Table 1-154

Table 1-155

Table 1-156

Table 1-157

Table 1-158

Table 1-159

Table 1-161

Table 1-166

Table 1-171

[0042] The present teachings include pharmaceutically acceptable salts of the compounds disclosed herein (including compounds 1-192 disclosed in Table 1 and in the Examples), as well as the corresponding charge-neutral forms, e.g., the free bases.

[0043] Another embodiment of the present disclosure is a compound of Formula I, II, III, IV, V, VI, or VII, or a compound of Table 1 or the Examples, or a pharmaceutically acceptable salt of any of the foregoing, in which one or more hydrogen atoms are replaced with deuterium. The deuterium enrichment at any one of the sites where hydrogen is replaced with deuterium is at least 50%, 75%, 85%, 90%, 95%, 98%, or 99%. Deuterium enrichment is expressed as a mole percent and is obtained by dividing the number of compounds enriched with deuterium at the enriched site by the number of compounds having hydrogen or deuterium at the enriched site.

[0044] definition As used herein, the term "pharmaceutically acceptable salt" refers to pharmaceutical salts that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic reaction, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Examples include the pharmaceutically acceptable salts described in S. M. Berge et al., J. Pharm. Sci. (1977) 66:1-19. Compounds of the present teachings having a basic group can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include inorganic acid salts (such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid) and organic acid salts (such as acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid). Compounds of the present teachings that have an acidic group can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (such as sodium salts and potassium salts), and alkaline earth metal salts (such as magnesium salts and calcium salts).

[0045] The term "alkyl," used alone or as part of a larger moiety, e.g., "alkoxy," "hydroxyalkyl," etc., refers to a saturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has one to six carbon atoms (Ci_6 alkyl) (i.e., 1, 2, 3, 4, 5, or 6), or one to three carbon atoms (Ci_3 alkyl) (i.e., 1, 2, or 3). "Ci_6 alkyl" refers to a radical having one to six carbon atoms in a straight-chain or branched arrangement, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.

[0046] The term "alkylene," unless otherwise specified, means a divalent alkyl group, for example, C1-C6 alkyl is the group -(CH2)n- (where n is 1 to 6), and C1-C3 alkyl is the group -(CH2)n- (where n is 1 to 3).

[0047] "Cycloalkyl" means a saturated aliphatic cyclic hydrocarbon ring radical. Unless otherwise specified, cycloalkyl refers to a group having 3 to 8 ring carbon atoms (Ccycloalkyl) (i.e., 3, 4, 5, 6, 7, or 8), or 3 to 6 ring carbon atoms (Ccycloalkyl) (i.e., 3, 4, 5, or 6), or 3 to 5 ring carbon atoms (C 3-5 "C3-6 cycloalkyl" means a radical having from 3 to 6 carbon atoms arranged in a monocyclic ring. C3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. C 3-5 Cycloalkyl includes cyclopropyl, cyclobutyl, and cyclopentyl.

[0048] The term "halogen" or "halo" means fluorine or fluoro (F), chlorine or chloro (Cl), bromine or bromo (Br), or iodine or iodo (I).

[0049] The term "heterocycle," unless otherwise specified, refers to a monocyclic non-aromatic ring radical containing 3 to 8 ring atoms (i.e., "3-, 4-, 5-, 6-, 7-, or 8-membered") selected from carbon atoms and 1 or 2 heteroatoms. Each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxides and sulfones. For example, a 4- to 6-membered heterocycle containing nitrogen refers to a monocyclic non-aromatic ring radical containing 2 to 5 carbon atoms and 1 or 2 nitrogen atoms, and a 4- to 6-membered heterocycle containing an oxygen atom refers to a monocyclic non-aromatic ring radical containing 2 to 5 carbon atoms and 1 or 2 oxygen atoms. Representative heterocycles include azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

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

[0051] The term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of a hydrogen substituent in a given structure with a non-hydrogen substituent. Thus, for example, a substituted alkyl is an alkyl in which at least one non-hydrogen substituent is present in place of a hydrogen substituent on the alkyl group. Illustratively, a monofluoroalkyl is an alkyl substituted with a fluoro substituent, and a difluoroalkyl is an alkyl substituted with two fluoro substituents. When there are two or more substitutions on a substituent, it should be recognized that each non-hydrogen substituent can be the same or different (unless otherwise specified).

[0052] When a group is described as "optionally substituted," the group can be either (1) unsubstituted or (2) substituted. When a group is described as optionally substituted with up to a specified number of non-hydrogen substituents, the group can be either (1) unsubstituted or (2) substituted with fewer of the specified number of non-hydrogen substituents or non-hydrogen substituents up to the maximum number of substitutable positions on the substituent. Thus, for example, if a group is described as cycloalkyl optionally substituted with up to three non-hydrogen substituents, any cycloalkyl having fewer than three substitutable positions can be optionally substituted with up to the same number of non-hydrogen substituents as the cycloalkyl has substitutable positions.

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

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

[0055] When the stereochemical configuration at a chiral center of a compound having one or more chiral centers is represented by its chemical name (e.g., when the configuration is designated by an "R" or "S" chemical name) or structure (e.g., when the configuration is designated by a "wedge" bond), the enrichment of the designated configuration over the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9% (except when the designation "rac" or "racemic" accompanies the structure or name, as described in the next two paragraphs). The "enrichment of the designated configuration over the opposite configuration" is expressed as a mole percent and is determined by dividing the number of compounds having the designated stereochemical configuration at the chiral center(s) by the total number of all compounds having the same or opposite stereochemical configuration in the mixture.

[0056] A racemic mixture is intended when the stereochemical configuration at a chiral center of a compound is indicated in the chemical name (e.g., when the configuration is indicated by an "R" or "S" designation) or structure (e.g., when the configuration is indicated by a "wedge" bond) and the designation "rac" or "racemic" accompanies the structure or is specified in the chemical name.

[0057] When two or more stereoisomers are represented by a chemical name or structure and the name or structure is connected by "or," either one or the other of the two or more stereoisomers, but not both, is intended. Enrichment of one stereoisomer over the other is as described above.

[0058] When a disclosed compound having a chiral center is represented by a structure that does not indicate the configuration at that chiral center, the structure is meant to encompass compounds having the S-configuration at that chiral center, compounds having the R-configuration at that chiral center, or compounds having a mixture of R and S-configurations at that chiral center. When a disclosed compound having a chiral center is represented by a chemical name without indicating the configuration at that chiral center with "S" or "R," the chemical name is meant to encompass compounds having the S-configuration at that chiral center, compounds having the R-configuration at that chiral center, or compounds having a mixture of R and S-configurations at that chiral center.

[0059] A racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. The present teachings encompass all enantiomerically pure, enantiomerically enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, as well as diastereomeric mixtures, of the compounds described herein.

[0060] Enantiomeric and diastereomeric mixtures can be separated into their component enantiomers or stereoisomers by well-known methods such as chiral-phase gas chromatography, chiral-phase high-performance liquid chromatography, crystallizing the compounds as chiral salt complexes, or crystallizing the compounds in chiral solvents. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0061] "Peak 1" or "first eluting isomer" in the Examples section refers to an intended reaction product compound obtained from a chromatographic separation / purification that elutes earlier than a second intended reaction product compound from the same preceding reaction. The second intended reaction product compound is referred to as "Peak 2" or "second eluting isomer."

[0062] If a compound is designated by a name or structure that denotes a single enantiomer, unless otherwise specified, the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure (also referred to as "enantiomerically pure"). Optical purity is the weight of the mixture of the named or represented enantiomer divided by the total weight of the mixture of both enantiomers.

[0063] When the stereochemistry of a disclosed compound is named or represented by a structure, and that named or represented structure encompasses more than one stereoisomer (e.g., as in the case of a diastereomeric pair), it is understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included unless otherwise specified. It is further understood that the stereoisomeric purity of the named or represented stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. Stereoisomeric purity in this case is determined by dividing the total weight of the mixture of stereoisomers encompassed by the name or structure by the total weight of the mixture of all stereoisomers.

[0064] Usage example The compounds of the present disclosure are MAP4K1 inhibitors. The use of the term "inhibitor" means that a compound or a pharmaceutically acceptable salt thereof inhibits the activity of MAP4K1. As used herein, "inhibit" refers to reducing the activity of a target enzyme compared to the activity of the enzyme in the absence of the inhibitor. In some alternatives, the term "inhibit" refers to a decrease in MAP4K1 activity by 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 refers to a decrease in MAP4K1 activity by 5% to 25%, 25% to 50%, 50 to 70%, or 75 to 100%. In some embodiments, inhibition refers to a decrease in MAP4K1 activity by about 95% to 100%, e.g., a 95%, 96%, 97%, 98%, 99%, or 100%. Such a decrease can be measured using a variety of techniques that will be appreciated by those skilled in the art, including in vitro kinase assays.

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

[0066] A MAP4K1 inhibitor that selectively inhibits MAP4K1 may have at least 2-fold activity relative to other kinases (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 selectivity). In some alternatives, the selective MAP4K1 inhibitor exhibits at least 15-fold selectivity over other kinases, such as LCK and MAP4K family members (MAP4K4 (HGK) and MAP4K3 (GLK)). In some alternatives, the selective MAP4K1 inhibitor is selective over EGFR and L858R / T790M EGFR. In some alternatives, the selective MAP4K1 inhibitors of the present disclosure are selective over BTK. In some alternatives, the selective MAP4K1 inhibitors of the present disclosure are more selective than JNK.

[0067] The present disclosure provides a method for modulating (e.g., inhibiting) MAP4K1 activity in a subject in need thereof, comprising administering to the subject a compound provided herein or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of the present disclosure or a pharmaceutically acceptable salt thereof is useful for therapeutic administration to enhance, stimulate, and / or increase immunity in a subject in need thereof, for example, a cancer patient or a patient with a viral infection. In some examples, the compound of the present disclosure or a pharmaceutically acceptable salt thereof reduces, inhibits, or otherwise decreases the phosphorylation of SLP76.

[0068] In some instances, the disclosed compounds or pharmaceutically acceptable salts thereof are useful for therapeutic administration to enhance at least one of T cell activation, priming, migration, proliferation, survival, and cytolytic activity compared to before administration. In certain embodiments, T cell activation is characterized by an increase in the level of IL-2, IFN-γ, or granzyme B production by the T cells compared to before administration of the compound or pharmaceutically acceptable salt. In some instances, the disclosed compounds or pharmaceutically acceptable salts thereof are useful for therapeutic administration to induce changes in cell cycle or cell viability. In some instances, the disclosed compounds or pharmaceutically acceptable salts thereof are useful for improving T effector cell function. In some instances, the disclosed compounds or pharmaceutically acceptable salts thereof are useful for inhibiting the suppressive effects of T regulatory cells or improving T cell responses to immunosuppressants, including adenosine and PGE2.

[0069] In some examples, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are useful for increasing the frequency of CD8+ tumor-infiltrating lymphocytes (TILs). In some examples, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are useful for improving the CD3+ / Treg ratio. In some examples, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are useful for enhancing cytokines. In some examples, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are useful for enhancing cytokines without affecting IL-6. In some examples, the compounds of the present disclosure or pharmaceutically acceptable salts thereof indirectly inhibit the proliferation of cancer cells. In some examples, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are useful for priming an immune response (i.e., a vaccine) against tumors or viruses to promote or generate antiviral / antitumor immunity. In one example, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are useful for enhancing or promoting responses to vaccines (such as cancer vaccines or personalized cancer vaccines (PCVs)) or CAR-T cell therapy.

[0070] A method for treating a MAP4K1-dependent disease or disorder can include administering a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment. For example, the MAP4K1-dependent disease or disorder 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. Furthermore, the present disclosure includes refractory or recurrent malignant tumors whose growth can be inhibited using a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. For the uses described herein, any of the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, can be used alone or in combination with other therapeutic agents.

[0071] In some embodiments, the treatment results in a sustained response in the subject after the treatment is stopped. "Sustained response" refers to the sustained effect of reducing tumor growth after the treatment is stopped. For example, the size of the tumor may remain the same or smaller than the size at the beginning of the administration phase. In some embodiments, the sustained response has a duration at least similar to the treatment period, or at least 1.5, 2.0, 2.5, or 3.0 times the treatment period.

[0072] The treatment methods disclosed herein may result in partial or complete response. As used herein, "complete response" or "CR" refers to the disappearance of all target lesions, "partial response" or "PR" refers to at least a 30% reduction in the sum of the longest diameters (SLD) of the target lesions based on the baseline SLD, and "stable disease" or "SD" refers to a target lesion that has not shrunk enough to qualify as PR or increased enough to qualify as PD based on the smallest SLD since 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 result in increased progression-free survival and overall survival of subjects 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 disease being treated (e.g., cancer) does not worsen. Progression-free survival can include the time during which a subject experiences a complete or partial response, as well as the time during which a patient experiences stable disease.

[0074] As used herein, "overall survival" (OS) refers to the proportion of subjects in a group who are likely to be alive after a specified period of time.

[0075] In some embodiments, cancers treatable with a compound of the present disclosure or a pharmaceutically acceptable salt thereof include colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, bladder cancer, stomach cancer, liver cancer, gastric cancer, head and neck cancer, lymphoma, leukemia, urothelial carcinoma, Merkel cell carcinoma, gastroesophageal junction cancer, esophageal squamous cell carcinoma, cutaneous squamous cell carcinoma, and melanoma. In some embodiments, the cancer is gastroesophageal carcinoma (GEC).

[0076] In some embodiments, cancers treatable with a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, include colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, bladder cancer, gastric cancer, liver cancer, head and neck cancer, lymphoma, leukemia, and melanoma.

[0077] In some embodiments, cancers treatable using a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, include, but are not limited to, solid tumors, including prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, brain cancer, and bladder cancer, as well as hematological cancers, including lymphomas, leukemias (chronic and acute), such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (NHL), including relapsed or refractory NHL and relapsed follicular, Hodgkin's lymphoma, and multiple myeloma, and myeloproliferative disorders.

[0078] In some embodiments, diseases and disorders treatable using compounds of the present disclosure, or pharmaceutically acceptable salts thereof, include, but are not limited to, hematological cancers, sarcomas, respiratory cancers, gastrointestinal cancers, genitourinary cancers, liver cancer, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0079] Exemplary hematological cancers include lymphomas and leukemias such as, for example, ALL, AML, acute promyelocytic leukemia (APL), CLL, CML, DLBCL, mantle cell lymphoma, primary mediastinal large B-cell lymphoma (PMBCL), non-Hodgkin's lymphoma (NHL), including relapsed or refractory NHL, relapsed follicular, and primary CNS lymphoma, Hodgkin's lymphoma, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET), myeloproliferative disorders, including myelodysplastic syndromes (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, chronic myelogenous lymphoma, and Burkitt's lymphoma.

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

[0081] Exemplary respiratory tract cancers include lung cancers such as non-small cell lung cancer (NSCLC), small cell lung carcinoma, epidermoid carcinoma, squamous cell, small undifferentiated cell, large undifferentiated cell bronchogenic carcinoma, adenocarcinoma, alveolar (bronchial) carcinoma, bronchial adenoma, chondroitin hamartoma, mesothelioma, and pleuropulmonary blastoma.

[0082] Exemplary gastrointestinal cancers include, for example, esophageal cancer, including squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; gastric cancer, including carcinoma, lymphoma, and leiomyosarcoma; pancreatic cancer, including ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, and vipoma; small intestinal cancer, including adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; colorectal cancer, including adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma; colon cancer; and gallbladder cancer, including adenocarcinoma; and intestinal and diffuse type gastric adenocarcinoma, rectal cancer, familial adenomatous polyposis carcinoma, and hereditary nonpolyposis colorectal cancer (CRC).

[0083] Exemplary genitourinary cancers include, for example, kidney cancer, including adenocarcinoma, Wilms' tumor (nephroblastoma), renal cell carcinoma, urothelial carcinoma, juxtaglomerular cell tumor (reninoma), angiomyolipoma, renal oncocytoma, Bellinio's duct carcinoma, clear cell sarcoma of the kidney, and mesoblastic nephroma; adrenal gland cancer; renal pelvis cancer; bladder cancer, including transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell carcinoma; urethral cancer, including squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma; prostate cancer, including adenocarcinoma, sarcoma, and carcinoma; testicular cancer, including seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, and lipoma; penile cancer; and pancreatic cancer.

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

[0085] Exemplary bone cancers include, for example, osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphomas including reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondroma including osteochondral exostosis, benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid, and giant cell tumor.

[0086] Exemplary nervous system cancers include, for example, skull cancer, including osteoma, hemangioma, granuloma, xanthomas, and osteitis deformans; meningeal cancer, including meningioma, meningeal sarcoma, and gliomatosis; brain cancer, including astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), neuroectodermal tumor, glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, brain stem and subocular glioma; and spinal cancer, including neurofibroma, meningioma, glioma, and sarcoma; and neuroblastoma and Lhermitte-Dacros disease.

[0087] Exemplary gynecological cancers include, for example, uterine cancer, including endometrial cancer; uterine cancer, including cervical cancer, preneoplastic cervical dysplasia, squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumor, vitreous cell carcinoma, and chorioglandular tubular adenocarcinoma; ovarian cancer, including serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, endometrioid tumor, high-grade serous carcinoma (HGSC) or high-grade serous ovarian carcinoma (HGSOC), granulosa theca cell tumor, Sertoli-Leydegg cell tumor, dysgerminoma, malignant teratoma, and allenoblastoma; vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma); vaginal cancer, including clear cell carcinoma, squamous cell carcinoma, and botryoid sarcoma (embryonal rhabdomyosarcoma); carcinoma of the labia; and fallopian tube cancer.

[0088] Exemplary skin cancers include, for example, melanoma, sebaceous carcinoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, lenticular dysplastic nevi, lipoma, hemangioma, dermatofibroma, and keloids.

[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 cavity cancer, pharyngeal cancer including oropharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, nasal cavity and paranasal sinus cancer, salivary gland cancer, oral cancer, eye cancer, acoustic neuroma, pituitary adenoma, hypopharyngeal cancer, and thyroid cancer (medullary and papillary), and parathyroid cancer.

[0091] Other cancers include, for example, sweat gland carcinoma, spinal axis tumors, breast cancer, sickle cell anemia, and environmentally induced cancers, including asbestos-induced cancer.

[0092] In some embodiments, the disclosed compound or pharmaceutically acceptable salt thereof is for the treatment of advanced melanoma, advanced NSCLC, or head and neck squamous cell carcinoma, including advanced head and neck squamous cell carcinoma, including when the subject is resistant to or has had a partial response to immune checkpoint inhibitor therapy.

[0093] In some examples, the MAP4K1-dependent disease or disorder is a viral infection, such as an infection 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, coxsackievirus, and human immunodeficiency virus (HIV).

[0094] Combination therapy The compound of the present disclosure or its pharmaceutically acceptable salt can be administered as a single pharmaceutical agent or in combination with one or more other anti-cancer drugs for treating cancer, and the combination does not cause unacceptable side effects.In some embodiments, the other anti-cancer drugs are cancer immunotherapeutic agents, anti-cancer drugs that are enzyme / protein / receptor inhibitors, radiation, or chemotherapy.

[0095] The compounds of the present disclosure or pharmaceutically acceptable salts thereof can be formulated with cancer immunotherapeutic agents. Cancer immunotherapeutic agents include, for example, small molecule drugs, antibodies, antibody-drug conjugates, or other biological molecules or small molecules. Examples of biological cancer immunotherapeutic agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one embodiment, the antibody is a monoclonal antibody. In another embodiment, the monoclonal antibody is a humanized antibody or a human antibody. In another embodiment, the antibody is a bispecific antibody.

[0096] In one embodiment, the cancer immunotherapeutic agent is either (i) an agonist of stimulatory (including costimulatory) receptors or (ii) an antagonist of inhibitory (including co-inhibitory) signals on T cells, both of which result in amplification of antigen-specific T cell responses (often referred to as immune checkpoint modulators, or in some cases, immune checkpoint inhibitors).

[0097] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or costimulatory 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-bound ligands that bind to costimulatory or co-inhibitory receptors are 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, The TNF family of molecules binds to cognate TNF receptor family members, including XEDAR, TACI, APRIL, BCMA, LTfiR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin alpha / TNP beta, TNFR2, TNFa, LTR, lymphotoxin a1 beta 2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0098] In one aspect, a T cell response may be stimulated by a combination of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more of: (i) an antagonist (e.g., an immune checkpoint inhibitor) of proteins that inhibit T cell activation, such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin-9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; and (ii) an agonist of proteins that stimulate T cell activation, such as 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 embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof can be administered in combination with at least one other immune checkpoint inhibitor. In another embodiment, the compound of the present disclosure or a pharmaceutically acceptable salt thereof can be administered for the treatment of immune checkpoint inhibitor-resistant NSCLC, including cases where the subject is resistant to or has had a partial response to platinum and / or paclitaxel and / or docetaxel therapy. Optionally, the compound of the present disclosure or a pharmaceutically acceptable salt thereof can be administered in combination with at least one other anticancer agent, such as paclitaxel, docetaxel, or platinum anticancer therapy. In some embodiments, the compound of the present disclosure or a pharmaceutically acceptable salt thereof can be administered after platinum therapy as second- or third-line treatment. The compound of the present disclosure or a pharmaceutically acceptable salt thereof can be administered for the first-line treatment of NSCLC that highly expresses PD-L1 (≥ 50% tumor proportion score (TPS)), wild-type EGFR, or wild-type ALK.

[0100] Other drugs that can be combined with the compound of the present disclosure or its pharmaceutically acceptable salt for the treatment of cancer include the antagonist of inhibitory receptor on NK cell or the agonist of activating receptor on NK cell.For example, the compound of the present disclosure or its pharmaceutically acceptable salt can be combined with the antagonist of KIR, such as lirilumab.

[0101] Still other agents for 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 other aspects, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be used with one or more agonist agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome different immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor engagement (e.g., PD-L1 / PD-1 interactions), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell anergy or exhaustion), and agents that cause innate immune activation and / or inflammation at the tumor site.

[0103] In some embodiments, the cancer immunotherapeutic agent is a CTLA-4 antagonist, such as a CTLA-4 antagonist. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab. In other embodiments, the cancer immunotherapeutic agent is a PD-1 antagonist, such as a PD-1 antagonist. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514, WO2012 / 145493). Cancer immunotherapeutic 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 composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, designated AMP-224.

[0104] In other embodiments, the cancer immunotherapeutic agent is a PD-L1 antagonist, such as an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, atezolizumab (RG7446, WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0105] In other embodiments, the cancer immunotherapeutic agent is a LAG-3 antagonist, such as a LAG-3 antagonistic 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 other embodiments, the cancer immunotherapeutic agent is a CD137 (4-1BB) agonist, such as an antagonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (W012 / 32433).

[0107] In other embodiments, the cancer immunotherapeutic agent is a GITR agonist, such as a GITR antagonistic antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116), and MK-4166 (WO11 / 028683).

[0108] In other embodiments, the cancer immunotherapeutic 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 other embodiments, the cancer immunotherapeutic agent is an OX40 agonist, such as an antagonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469. In other embodiments, the cancer immunotherapeutic agent is an OX40L antagonist, such as an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0110] In other embodiments, the cancer immunotherapeutic agent is a CD40 agonist, such as a CD40 antagonistic antibody. In yet other embodiments, the cancer immunotherapeutic agent is a CD40 antagonist, such as a CD40 antagonistic antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0111] In other embodiments, the cancer immunotherapeutic agent is a CD27 agonist, such as a CD27 antagonist antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0112] In other embodiments, the cancer immunotherapeutic agent is MGA271 (against B7H3) (WO11 / 109400).

[0113] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can be used in combination with anti-cancer drugs that are enzyme / protein / receptor inhibitors that exhibit different preferences in the targets they modulate to treat such conditions. Targeting more than one signaling pathway (or more than one biomolecule involved in a given signaling pathway) can reduce the likelihood of drug resistance developing in a cell population and / or reduce the toxicity of the treatment.

[0114] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can be used in combination with one or more other enzyme / protein / receptor inhibitors to treat cancer. For example, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can be used in combination with one or more other enzyme / protein / receptor inhibitors to treat cancer, including the following kinases: Akt1, Akt2, Akt3, TGF-βPv, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFotR, PDGFpR, CSFIR, KIT, FLK-II, KDR / FLK-1, K It may be combined with one or more inhibitors of RAS, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf.

[0115] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be combined with one or more of the following inhibitors for the treatment of cancer: Non-limiting examples of inhibitors that can be combined with a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the treatment of cancer include FGFR inhibitors (FGFR1, FGFR2, FGFR3, or FGFR4, e.g., fisogatinib, AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258, lucitanib, dovitinib, TAS-120, JJ-42 756493, Debiol347, INCB54828, INCB62079, and INCB63904), JAK inhibitors (JAK1 and / or JAK2, e.g., ruxolitinib, baricitinib, or itacitinib (INCB39110)), IDO inhibitors (e.g., epacadostat and NLG919), LSD1 inhibitors (e.g., GSK2979552, INCB59872, and INCB 60003), TDO inhibitors, PI3K-delta inhibitors (e.g., INCB50797 and INCB50465), PI3K-gamma inhibitors such as PI3K-gamma selective inhibitors (e.g., eganelisib) or dual PI3K-delta / gamma selective inhibitors (e.g., duvelisib), CSF1R inhibitors (e.g., PLX3397 and LY3022855), TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), angiogenesis inhibitors (e.g., bevacizumab), interleukin receptor inhibitors, bromo- and extra-terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, e.g., OTX015, CPI-0610, INCB54329, and INCB57643), and adenosine receptor antagonists or combinations thereof. Inhibitors of HDAC, such as panobinostat and vorinostat, can be combined with compounds of the present disclosure, or pharmaceutically acceptable salts thereof. Inhibitors of c-Met, such as onartumuzumab, tivantnib, and capmatinib (INC-280), can be combined with compounds of the present disclosure, or pharmaceutically acceptable salts thereof.BTK inhibitors, such as ibrutinib, can be combined with compounds of the present disclosure or pharmaceutically acceptable salts thereof. mTOR inhibitors, such as rapamycin, sirolimus, temsirolimus, and everolimus, can be combined with compounds of the present disclosure or pharmaceutically acceptable salts thereof. Raf inhibitors, such as vemurafenib and dabrafenib, can be combined with compounds of the present disclosure or pharmaceutically acceptable salts thereof. MEK inhibitors, such as trametinib, selumetinib, and GDC-0973, can be combined with compounds of the present disclosure or pharmaceutically acceptable salts thereof. KIT inhibitors, such as avapritinib, BLU-263, imatinib, sunitinib, regorafenib, liplitinib (DCC2618), PLX9486, PLX3397, crenolanib, CDX-0158, and CDX-0159. Inhibitors of RET, such as pralsetinib, selpercutinib, alectinib, levatinib, cabozantinib, BOS172738 (DS-5010), SL-1001, TPX-0046, sitravatinib (MGCD516), and RXDX-105. Inhibitors of Hsp90 (e.g., tanespimycin), inhibitors of cyclin-dependent kinases (e.g., palbociclib), inhibitors of PARP (e.g., olaparib), inhibitors of Pim kinases (e.g., LGH447, INCB053914, and SGI-1776), and inhibitors of KRAS (e.g., sotorasib) can also be combined with a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0116] The compounds of the present disclosure or pharmaceutically acceptable salts thereof can be used in combination with one or more drugs for the treatment of cancer. In some embodiments, the drug is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulator. Examples of alkylating agents include bendamustine, nitrogen mustard, ethyleneimine derivatives, alkylsulfonates, nitrosoureas and triazenes, uracil mustard, chlormethine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone.

[0117] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can be administered in combination with one or more anti-cancer agents, such as chemotherapeutic agents, including abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bicalutamide, bleomycin, bortezomib, bortezomib, brivanib, bupalisib, intravenous busulfan, oral busulfan, calsterone, capecitabine, carmustine, cediranib, and cetuximab. Mab, chlorambucil, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine, degarelix, denileukin, denileukin diftitox, deoxycoformycin, dexrazoxane, docetaxel, doxorubicin, droloxafine, dromostanolone propionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin, Erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon alpha 2a, irinotecan, lapatinib nitrile, lenalidomide, Letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, navelbene, necitumumab, nelarabine, neratinib, nilotinib, nilutamide, nofetumomab, oserelin, paclitaxel, pamidronate, panitumumab, pazopanib, pegaspargase, pegfilgrastim,The present invention may include any of pemetrexed disodium, pentostatin, piralalisib, pipobroman, plicamycin, cisplatin, carboplatin, oxaliplatin, ponatinib, prednisone, procarbazine, quinacrine, rasburicase, regorafenib, reloxafin, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate. ,

[0118] Other anti-cancer drug(s) include antibody therapeutics, such as trastuzumab.

[0119] The compound of the present disclosure or its pharmaceutically acceptable salt can be administered as a single pharmaceutical agent or in combination with one or more antiviral agents for treating chronic viral infections, and the combination does not cause unacceptable side 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, coxsackievirus, and human immunodeficiency virus (HIV).Parasitic infections (e.g., malaria) can also be treated by the above method, where a compound known to treat parasitic infection conditions is optionally added instead of an antiviral agent.

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

[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, emtricitabine [(-)-FTC], beta-L-FD4 (also known as beta-L-D4C, designated beta-L-2',3'-dicreoxy-5-fluoro-cytidene), DAPD, ((-)-beta-D-2,6-diamino-purine dioxolane), and rhodenosine (FddA). Exemplary suitable NNRTIs include nevirapine (BI-RG-587), delaviradine (BHAP, U-90152), efavirenz (DMP-266), PNU-142721, AG-1549, MKC-442 (1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione), and (+)-calanolide A (NSC-675451) and B. Exemplary suitable prodrugs include methicone, methicone, and methicone. TEAS inhibitors include saquinavir (Ro31-8959), ritonavir (ABT-538), indinavir (MK-639), nerfunavir (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 two or more drugs are administered to a subject, they can be administered simultaneously, separately, sequentially, or in combination (for example, more than two drugs).For example, when administered together with an additional anticancer drug or antiviral drug, the compound of the present disclosure or its pharmaceutically acceptable salt can be administered simultaneously in the same formulation or in separate formulations.Alternatively, when administered together with an additional anticancer drug or antiviral drug, the compound of the present disclosure or its pharmaceutically acceptable salt can be administered at different times according to the administration requirements of the additional anticancer drug or antiviral drug.

[0123] Pharmaceutical compositions are disclosed that include one or more compounds provided herein (e.g., compounds of Formula I, II, III, IV, V, VI, or VII) and at least one additional substance, typically an excipient, a known therapeutic agent other than those disclosed herein, and combinations thereof. In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can be used in combination with other agents known to have beneficial activity targeting the diseases or disorders listed above. For example, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can be administered alone or in combination with one or more anti-cancer or anti-viral agents.

[0124] The terms "administer," "administering," "administration," and the like, as used herein, refer to methods that can be used to enable delivery of a composition to a site where a biological effect is desired. These methods include, but are not limited to, intra-articular (into a joint), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be used with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed., Pergamon, and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0125] A "subject" is a mammal in need of medical treatment, preferably a human, but can also be an animal in need of veterinary treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0126] The exact amount of the compound or its pharmaceutically acceptable salt administered to provide an "effective amount" to a subject will depend on the method of administration, the type and severity of the disease or condition, and the subject's characteristics, such as overall health, age, sex, weight, and tolerance to the drug. One of ordinary skill in the art will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, e.g., anti-cancer or antiviral agents, the "effective amount" of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by one of ordinary skill in the art depending on the subject's condition, the type of condition(s) being treated, and the amount of the compound of the present disclosure or its pharmaceutically acceptable salt used according to dosages reported in the literature and recommended in, for example, the Physician's Desk Reference (57th ed., 2003).

[0127] The term "effective amount" means an amount that, when administered to a subject, produces beneficial or desired results, including clinical results, e.g., inhibits, suppresses, or reduces the symptoms of the condition being treated in the subject compared to a control. For example, a therapeutically effective amount can be provided in a unit dosage form (e.g., 0.1 mg to about 50 g per day, or 1 mg to about 5 grams per day, or 10 mg to 1 gram per day).

[0128] The particular method and regimen of administration will be selected by the attending physician, taking into account the particulars of the case (e.g., the subject, the disease, the disease state involved, the particular treatment, and whether the treatment is prophylactic). Treatment may involve one or more daily or less than daily (such as weekly or monthly) dosing over a period of several days to several months or even years.

[0129] The pharmaceutical composition of the present disclosure is formulated to be suitable for intended administration route.In one embodiment, the composition is formulated according to routine procedures as a pharmaceutical composition suitable for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans.In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0130] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that aid in the formulation and / or administration of, and / or absorption by, an active agent in a subject and can be included in the compositions of the present disclosure without causing adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavorings, saline solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and dyes. Such preparations are sterilized and, if desired, can be mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or flavoring agents that do not adversely react with 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 protocols used to prepare the compounds in Table 1 are listed in the last column of Table 1, and full details of each synthetic protocol are provided in Schemes 1 and 2 (below) in the General Synthetic Methods and Intermediates section. [ka] Scheme 1 shows a synthetic protocol for preparing compounds of formula iv.

[0132] Azide-substituted chloroheterocycle intermediate i can be coupled with substituted aniline ii under Pd-catalyzed coupling conditions to give iii. The azide intermediate iii can be reduced under catalytic hydrogenation conditions using a catalyst such as Pd / C or PtO to give amine compound iv, which is an example of a MAP4K1 inhibitor described herein. [ka] Scheme 2 shows a synthetic protocol for preparing compounds of formula iv.

[0133] Sulfinamide-substituted chloroheterocyclic intermediate i can be coupled with 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 is an example of the MAP4K1 inhibitors described herein.

[0134] The following examples are intended to be illustrative and not limiting in any way. [Example]

[0135] Abbreviation 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 tert-butoxide C Celsius DBU Diazabicyclo[5.4.0]undec-7-ene DCE Dichloroethane DCM dichloromethane DIAD Disopropyl azodicarboxylate DIBAL Diisobutylaluminum hydride DIPEA Diisopropylethylamine DMBNH2 2,4-Dimethoxybenzylamine DMF Dimethylformamide DMSO dimethyl sulfoxide DTT Dithiothreitol eq equivalent EA Ethyl acetate EDTA Ethylenediaminetetraacetic acid Et2O diethyl ether EtSH Ethanethiol FA formic acid h time HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HPLC High Performance Liquid Chromatography IBX 2-iodoxybenzoic acid IC50 50% inhibitory concentration IPA Isopropanol KF Potassium Fluoride KOAc Potassium Acetate LiHMDS Lithium bis(trimethylsilyl)amide MeMgBr Methylmagnesium bromide min MTBE Methyl tert-butyl ether MeOH Methanol MsCl methanesulfonyl chloride NBS N-Bromosuccinimide NMO N-methylmorpholine N-oxide NMP N-methyl-2-pyrrolidone Oxone potassium peroxymonosulfate PE Petroleum Ether PrMgBr Isopropylmagnesium bromide SFC Supercritical Fluid Chromatography TEA Triethylamine THF tetrahydrofuran TFA trifluoroacetic acid TfOH trifluoromethanesulfonic acid TMEDA Tetramethylethylenediamine TMSN3 Trimethylsilyl Azide

[0136] The method for preparing the compounds of the present disclosure can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.Suitable solvents can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, for example, at a temperature ranging from the freezing temperature of the solvent to the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of two or more solvents.Those skilled in the art can select a suitable solvent for a particular reaction step according to the specific reaction step.

[0137] The preparation of the compounds of the present disclosure may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be easily determined by those skilled in the art. The chemical properties of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 5th ed., John Wiley & Sons: New Jersey, (2014), the entire contents of which are incorporated herein by reference.

[0138] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance (NMR) spectroscopy (e.g., 1 H or 13C), can be monitored by spectroscopic means such as infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry (MS), or 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 noted, all liquid chromatography-mass spectrometry (LC-MS) data (samples analyzed for purity and identity) were acquired 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 dimensions) reverse-phase column and an Agilent Model 6120 mass spectrometer utilizing 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 from 95% aqueous / 5% organic mobile phase to 5% aqueous / 95% organic mobile phase over 4 minutes was used. The flow rate was constant at 1 mL / min.

[0140] Preparative LC-MS: Preparative HPLC was performed at 22.4°C using a Shimadzu Discovery VP® preparative system equipped with a Luna 5u C18(2) 100A, AXIA packed, 250 x 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 was used over 25 minutes from 95% aqueous / 5% organic to 5% aqueous / 95% organic. The flow rate was constant at 20 mL / min. Reactions performed in a microwave were performed in a Biotage Initiator microwave unit.

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

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

[0143] Those skilled in the art will understand that variations in 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 species being analyzed.

[0144] Synthesis of intermediates [ka] Intermediates 1 and 2: (7S,8R)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 1) and (7R,8S)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 2) [ka] Each of them is represented by the structure shown below. [ka] Each of them is represented by the structure shown below. [ka] Each of them is represented by the structure shown below. [ka]

[0145] Step 1: (E)-2-(but-2-en-2-yl)-6-methoxynicotinic acid methyl ester KPO (120 g, 565 mmol, 3.00 equiv) and Pd(dppf)Cl-CHCl (7.70 g, 9.42 mmol, 0.05 equiv) were added to a solution of methyl 2-chloro-6-methoxynicotinate (38.0 g, 188 mmol, 1.00 equiv) and (Z)-2-(but-2-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxolane (44.6 g, 245 mmol, 1.30 equiv) in THF (320 mL) and HO (80.0 mL). The reaction mixture was stirred at 70 °C for 2 h under N. The reaction mixture was diluted with water (300 mL) and extracted with EA (250 mL × 3). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (ACN-H2O gradient with 0.1% TFA additive). The product-containing fractions were adjusted to pH 8-9 with 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 (37.0 g, 167 mmol, 88.7% yield) as a yellow oil.

[0146] Step 2: 2-Methoxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one A solution of (E)-methyl 2-(but-2-en-2-yl)-6-methoxynicotinate (37.0 g, 167 mmol, 1.00 equiv) in TfOH (171 g, 1.15 mol, 101 mL, 6.85 equiv) was stirred at 80 °C for 0.5 h. The mixture was then cooled to ambient temperature, poured into saturated aqueous NaHCO (1000 mL), and extracted with EA (300 mL × 5). The organic layer was dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 1% to 25% EA-PE) to give the title compound (30.0 g, 144 mmol, 86.6% yield) as a yellow oil.

[0147] Step 3: 2-Hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one A mixture of 2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (30.0 g, 144 mmol, 1.00 equiv) and pyridine hydrochloride (41.8 g, 361 mmol, 2.50 equiv) was stirred at 150 °C for 0.5 h. The reaction mixture was directly purified by flash column chromatography on silica gel (gradient elution, 2% to 10% MeOH-DCM) to afford the title compound (26.0 g, 134 mmol, 92.9% yield) as a yellow solid.

[0148] Step 4: rac-(7S,8S)-2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and rac-(7S,8R)-2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one DBU (60.8 mL, 403 mmol, 3.00 equiv) was added to a solution of 2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (26.0 g, 134 mmol, 1.00 equiv) in toluene (290 mL). The reaction mixture was stirred at 100 °C for 12 h, then cooled to ambient temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (gradient elution, 1% to 10% MeOH-DCM) to afford the title compound as a mixture of isomers, which was used in the next step without further purification.

[0149] Step 5: rac-(7S,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and rac-(7S,8R)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one A mixture of rac-(7S,8S)-2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and rac-(7S,8R)-2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (26.0 g, 134 mmol, 1 equiv.) in POCl (150 mL, 1.61 mol, 11.9 equiv.) was stirred at 100 °C for 1 h. The reaction mixture was then cooled to ambient temperature and poured into saturated aqueous NaHCO (2 L) at 0 °C–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 x 50 mm x 10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 35% ACN to 55% CAN, 20 min). rac-(7S,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one was the first eluting compound and was obtained as a white solid. MS (ES+) C 10 H 10 ClNO2 theoretical value: 211, measured value: 212 [M+H] + . 1 H NMR: 400 MHz, CDClδ 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). rac-(7S,8R)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one was the second eluting compound and was obtained as a white solid. MS(ES+)C 10 H 10 ClNO2 theoretical value: 211, measured value: 212 [M+H] + . 1H NMR: 400 MHz, CDCl3δ 8.28 (d, J = 8.2 Hz,1H), 7.38 (d, J = 8.2 Hz,1H), 4.58 - 4.43 (m,1H), 3.05 (quintet, J = 7.2 Hz,1H),1.56 -1.40 (m, 6H).

[0150] Step 6: (7S,8R)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and (7R,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one rac-(7S,8R)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm × 50 mm, 10 μm); mobile phase: MeOH in CO) to give the first eluting isomer (peak 1) as a white solid and the second eluting isomer (peak 2) as a white solid.

[0151] Step 7: (7S,8R)-2-((2,4-dimethoxybenzyl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one DIPEA (7.48 g, 57.8 mmol, 10.1 mL, 2.50 equiv) and DMBNH (5.03 g, 30.1 mmol, 4.53 mL, 1.30 equiv) were added to a solution of (7S,8R)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (first eluting isomer (peak 1) obtained in Step 6 above) (4.90 g, 23.1 mmol, 1.00 equiv) in NMP (50.0 mL). The reaction mixture was stirred at 100 °C for 1 h, 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 19 H 11Theoretical value of N2O4: 342, Measured value: 343 [M+H] + .

[0152] Step 8: (7S,8R)-2-Amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one A solution of (7S,8R)-2-((2,4-dimethoxybenzyl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (7.93 g, 23.1 mmol, 1.00 equiv) in HCl / dioxane (4.00 M, 50.0 mL, 8.64 equiv) was stirred at 70° C. for 1 hour. The reaction mixture was then concentrated, partitioned with saturated aqueous sodium bicarbonate (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 triturated in MTBE (50 mL) for 10 minutes and filtered to give a yellow solid. The yellow solid was dried under vacuum to give the title compound, Intermediate 1 (3.23 g, 16.4 mmol, 71.2% yield, 98.1% purity). MS(ES+)C 10 H 12 Theoretical value of N2O2: 192, Measured value: 193 [M+H] + . 1 H NMR: 400 MHz, DMSO-dδ 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.

[0153] Steps 9 and 10: (7R,8S)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one The title compound (Intermediate 2) was prepared separately from (7R,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (the second eluting isomer (peak 2) in Step 6) using a two-step procedure similar to that described in Steps 7 and 8 for Intermediate 2. MS(ES+)C 10 H 12 Theoretical value of N2O2: 192, Measured value: 193 [M+H] + . 1 H NMR: 400 MHz, DMSO-d6δ 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).

[0154] [ka] Intermediates 3 and 4: (R)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and (S)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one [ka] Each of them is represented by the structure shown below. [ka] Each of them is represented by the structure shown below. [ka]

[0155] Steps 1-5: rac2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one The 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-dioxaborolane using procedures similar to those described above in steps 1-3, 5, and 7 for intermediate 1.

[0156] Step 6: (R)-2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and (S)-2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one Rac2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one was separated by SFC (column: DAICEL CHIRALPAK AS-H (250 mm × 30 mm, 5 μm); mobile phase: 0.1% NH4OH in [CO2]). MeOH]), (R)-2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (first eluting 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-pyrano[4,3-b]pyridin-5-one (second eluting isomer (precursor to intermediate 4), 0.55 g, 79% yield). Each intermediate was isolated as a yellow oil.

[0157] Intermediates 7 and 8: (R)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and (S)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one The title compounds (Intermediates 3 and 4) were prepared from the first and second eluting isomers, (R)-2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and (S)-2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one, using a procedure similar to that described in Step 8 of Intermediate 1. Intermediate 3, (R)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one, was obtained as a yellow solid. MS (ES+) C 11 H 14 Theoretical value of N2O2: 206, Measured value: 207 [M+H] + . 1 H-NMR (400 MHz, CD3OD): 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-pyrano[4,3-b]pyridin-5-one, was obtained as a yellow solid. MS(ES+)C 11 H 14 Theoretical value of N2O2: 206, Measured value: 207 [M+H] + . 1 H-NMR (400 MHz, CD3OD): 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.

[0158] [ka] Intermediate 5: 2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one [ka] Step 1: 7,7-Dimethyl-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-2-one A mixture of 2,2-dimethyltetrahydro-4H-pyran-4-one (500 g, 3.90 mol, 1.00 equiv.) and pyrrolidine (391 mL, 4.68 mol, 1.20 equiv.) in toluene (4.00 L) was heated at 145° C. for 2 hours using a Dean-Stark trap. The aqueous layer (approximately 16 mL) was removed from the Dean-Stark trap, and the reaction mixture was cooled to 15° C. After cooling, prop-2-ynamide (539 g, 7.80 mol, 2.00 equiv.) was added, and the reaction mixture was heated to 150° C. The reaction mixture was heated at 150° C. for 10 hours and cooled to ambient temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel (10% methanol-dichloromethane) to give the title compound (560 g, 62% yield) as a yellow solid.

[0159] Step 2: 2-Chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine A solution of 7,7-dimethyl-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-2-one (500 g, 2.23 mol, 1 eq) in POCl (350 mL, 3.77 mol, 9.64 eq) was heated to 100° C. for 6 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was poured into ice-water (1.00 L). The mixture was extracted with EA (750 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give the title compound (363 g, 82.2% yield) as a brown oil.

[0160] Step 3: 2-Chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one A solution of NaIO4 (487 g, 2.28 mol, 3.00 equiv) in water (1.20 L) was added to a mixture of 2-chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine (150 g, 759 mmol, 1.00 equiv) in MeCN (50.0 mL) and CCl4 (2.70 L). The mixture was cooled to 0 °C, and then RuCl3 (11.0 g, 53.1 mmol, 0.07 equiv) was added. The reaction mixture was stirred at 0 °C for 0.5 h and then warmed to 20 °C for 11.5 h. Saturated aqueous sodium sulfite solution (1.00 L) was added, and the mixture was filtered. 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 Na.sub.2SO.sub.4, filtered, and concentrated to give the title compound (132 g, 624 mmol, 82.1% yield) as a yellow solid.

[0161] Step 4: 2-((2,4-dimethoxybenzyl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (2,4-Dimethoxyphenyl)methanamine (160 g, 957 mmol, 1.50 equiv) was added to a solution of 2-chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (135 g, 638 mmol, 1.00 equiv) and DIPEA (222 mL, 1.28 mol, 2.00 equiv) in NMP (1.08 L) at ambient temperature. The reaction mixture was heated at 140° C. for 2 h and then cooled to ambient temperature. The reaction mixture was 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, washed with brine (400 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound as a yellow solid (160 g). This crude product was used directly in the next step.

[0162] Step 5: 2-Amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one HCl (4.0 M in dioxane, 1.20 L, 11.0 equiv) was added to 2-((2,4-dimethoxybenzyl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (150 g, 438 mmol, 1.00 equiv) at 20 °C. The reaction mixture was heated to 60 °C for 2 h, then cooled to ambient temperature and concentrated in vacuo. The residue was poured into saturated aqueous NaHCO (1.00 L) and extracted with EA (500 mL × 4). The combined organic layers were washed with brine (500 × 2), dried over NaSO, 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 (52.0 g, 60.9% yield) as a yellow solid. MS(ES+)C 10 H 12 Theoretical value of N2O2: 192, Measured value: 193 [M+H] + . 1 H 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).

[0163] [ka] Intermediate 6: 2-amino-7,7-dimethylfuro[3,4-b]pyridin-5(7H)-one [ka] Step 1: Methyl 6-methoxy-2-(prop-1-en-2-yl)nicotinate Pd(dppf)Cl (544 mg, 744 μmol, 0.500 equiv.) and cesium fluoride (4.52 g, 29.8 mmol, 2.00 equiv.) 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-dioxaborolane (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 poured into water (200 mL) and extracted with EA (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 1% to 2% EA-petroleum ether) to give the title compound (3.0 g, crude) as a colorless oil.

[0164] Step 2: 2-Methoxy-7,7-dimethylfuro[3,4-b]pyridin-5(7H)-one 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 h. The reaction mixture was then poured into water (50 mL), and saturated aqueous 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 in vacuo to give a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 10% to 33% EA-petroleum ether) to give the title compound (2.3 g, 82% yield) as a yellow solid.

[0165] Steps 3-6: 2-Amino-7,7-dimethylfuro[3,4-b]pyridin-5(7H)-one The title compound was prepared from 2-methoxy-7,7-dimethylfuro[3,4-b]pyridin-5(7H)-one using the four-step procedure described in steps 3, 5, 7, and 8 for intermediate 1. MS (ES+) C9H 10Theoretical value of N2O2: 178, Measured value: 179 [M+H] + .

[0166] [ka] Intermediate 7: 2-Amino-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one [ka] Step 1: 2-Amino-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one The title compound was prepared from tetrahydro-4H-pyran-4-one using the same five-step procedure described in Steps 1-5 for Intermediate 5. MS (ES+) C8H8N2O2 calculated: 164, found: 165 [M+H] + . 1 H 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).

[0167] [ka] Intermediate 8: 2-amino-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one [ka] Step 1: 2-Methoxy-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one BH3-Me2S (10 M, 5.31 mL, 53.1 mmol, 1.10 equiv) was added dropwise to a solution of methyl 6-methoxy-2-(prop-1-en-2-yl)nicotinate (10.0 g, 48.3 mmol, 1.00 equiv) in THF (100 mL) at 0 °C. The mixture was warmed to 20 °C and stirred at this temperature for 2 h. The reaction mixture was then cooled to 0 °C, and NaHCO3 (20.3 g, 241 mmol, 5.00 equiv) and HO2 (30% in water, 69.6 mL, 724 mmol, 15.0 equiv) in water (35.0 mL) were added dropwise. The reaction mixture was stirred at 20 °C for 30 min and at 30 °C–45 °C for 12 h. The reaction mixture was then poured into saturated aqueous NaSO (200 mL) and extracted with EA (50.0 mL × 3). The organic layers were combined, washed with brine (200 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (gradient elution, 5% to 15% EA-petroleum ether) to afford the title compound (15.0 g, 77.6 mmol, 80.4% yield) as a yellow solid.

[0168] Steps 2-5: -Amino-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one The title compound was prepared from 2-methoxy-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one using the four-step procedure described in steps 3, 5, 7, and 8 for intermediate 1. MS (ES+) C9H 10 Theoretical value of N2O2: 178, Measured value: 179 [M+H] + . 1 H 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).

[0169] [ka] Intermediate 9: 2'-amino-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-5'-one [ka] Step 1: Methyl 2-(3-bromo-6-chloropyridin-2-yl)acetate LiHMDS (1 M, 388 mL) was added to a solution of 3-bromo-6-chloro-2-methylpyridine (20.0 g, 96.9 mmol) in THF (300 mL) at 25 °C under nitrogen. After 2.5 h, dimethyl carbonate (14.0 g, 155 mmol) was added to the mixture and stirred at 25 °C for 13.5 h. The reaction mixture was then added to saturated aqueous 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 flash column chromatography on silica gel (gradient elution, 0% to 10% EA-petroleum ether) to give the title compound (18.0 g, 70% yield) as a yellow oil. 1 H 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).

[0170] Step 2: Methyl 1-(3-bromo-6-chloropyridin-2-yl)cyclopropane-1-carboxylate Tetrabutylammonium bromide (2.44 g, 7.56 mmol) and NaOH (50 mL, 50 wt % in water) were added 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) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h, 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 a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 0% to 10% EA-petroleum ether) to give the title compound (6.10 g, 56% yield) as a yellow solid. 1 H 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).

[0171] Step 3: (1-(3-bromo-6-chloropyridin-2-yl)cyclopropyl)methanol Diisobutylaluminum hydride (1 M, 56 mL) 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) under nitrogen at −78° C. The reaction mixture was stirred at −78° C. for 0.5 h and then quenched by adding saturated aqueous NH4Cl (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 the crude title compound (5.00 g, crude) as a yellow solid, which was used in the next step without further purification.

[0172] Step 4: Methyl 5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-2'-carboxylate Triethylamine (2.31 g, 22.9 mmol) and Pd(dppf)Cl2 (557 mg, 762 μmol) were 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 with carbon monoxide several times. The mixture was stirred under carbon monoxide (50 psi) at 80 °C for 16 h. 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 give a residue. The title compound (1.8 g, crude) was obtained as a yellow solid and used in the next step without further purification. MS (ES+) C 10 H 10 Theoretical value of N2O2: 233, Measured value: 234 [M+H] + .

[0173] Step 5: 5'-Oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-2'-carboxylic acid Lithium hydroxide (555 mg, 23.2 mmol) was added to a solution of methyl 5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-2'-carboxylate (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 h and then concentrated 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), and then the mixture was extracted 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.

[0174] Step 6: tert-Butyl (5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-2'-yl)carbamate Triethylamine (831 mg, 8.21 mmol) and diphenylphosphoryl azide (2.26 g, 8.21 mmol) were added to a solution of 5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-2'-carboxylic acid (1.20 g, 5.47 mmol) in tert-butanol (20 mL). The reaction mixture was stirred at 100°C for 1 h, then cooled to ambient temperature, diluted with water (60 mL), and extracted with EA (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 0% to 50% EA-petroleum ether) to afford the title compound (330 mg, 19% yield) as a yellow solid and 2′-amino-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-5′-one (420 mg, 28% yield) as a yellow oil.

[0175] Step 7: 2'-Amino-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-5'-one HCl in dioxane (4.0 M, 0.5 mL) was added to a solution of tert-butyl (5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-2'-yl)carbamate (100 mg, 344 μmol) in dioxane (1.5 mL) at 25°C. The reaction mixture was stirred for 10 min 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 min. The reaction mixture was then concentrated, and EA (5 mL) was added to the residue. The mixture was neutralized by adding saturated aqueous NaHCO3 (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 12 H 11 NO4 theoretical value: 190, measured value: 191 [M+H] + .

[0176] [ka] Intermediates 10 and 11: (R)-2-amino-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and (S)-2-amino-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one [ka] Each of them is represented by one of the structures shown below. [ka] It is represented by one of the structures shown below. [ka] It is represented by one of the structures shown below. [ka] Step 1: (R)-2-chloro-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and (S)-2-chloro-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one rac-2-Chloro-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (the title compound from Step 3 of Intermediate 8, 700 mg, 3.54 mmol) was separated by SFC (Daicel Chiralpak IG, MeOH gradient in CO containing 0.1% NHOH) to give two separate peaks: the first eluting isomer (330 mg, 47% yield) and the second eluting isomer (330 mg, 47% yield) as yellow solids.

[0177] Steps 2 and 3: One of (R or S)-2-amino-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one The title compound (Intermediate 10) was prepared from one of the (R or S)-2-chloro-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-ones (first eluting isomer from Step 1) using a two-step procedure similar to that described in Steps 4 and 5 for Intermediate 5. MS (ES+) CH 10 Theoretical value of N2O2: 178, Measured value: 179 [M+H] + .

[0178] Steps 3 and 4: The remaining one of (R or S)-2-amino-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one The title compound (Intermediate 11) was prepared from the remaining (R or S)-2-chloro-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (the second eluting isomer from Step 1) using a two-step procedure similar to that described in Steps 4 and 5 for Intermediate 2. MS (ES+) CH 10 Theoretical value of N2O2: 178, Measured value: 179 [M+H] + .

[0179] [ka] Intermediates 12 and 13: (R)-2'-amino-7'-methyl-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-5'-one and (S)-2'-amino-7'-methyl-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-5'-one [ka] Each of them is represented by one of the structures shown below. [ka] It is represented by one of the structures shown below. [ka] Step 1: 1-(3-bromo-6-chloropyridin-2-yl)cyclopropane-1-carbaldehyde IBX (6.50 g, 10.7 mmol, 46% purity) was added to a solution of (1-(3-bromo-6-chloropyridin-2-yl)cyclopropyl)methanol (2.65 g, 10.1 mmol) in EA (80 mL). The reaction mixture was stirred at 80° C. for 1 h, then additional IBX (2.00 g, 3.29 mmol, 46% purity) was added. The reaction mixture was stirred at 80° C. for 0.5 h, 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+) calculated for CHBrClNO: 261, found: 262 [M+H] + .

[0180] Step 2: 1-(1-(3-bromo-6-chloropyridin-2-yl)cyclopropyl)ethan-1-ol Methylmagnesium bromide (3 M, 17 mL) was added to a solution of 1-(3-bromo-6-chloropyridin-2-yl)cyclopropane-1-carbaldehyde (2.60 g, 9.98 mmol) in THF (80 mL) at 0° C. The reaction mixture was stirred for 10 min, then quenched by adding saturated aqueous NH4Cl (80 mL), diluted with water (40 mL), and extracted with EA (80 mL x 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+) C 10 H 11 Theoretical value of N2O2: 277, Measured value: 278 [M+H] + .

[0181] Steps 3-5: tert-Butyl (7'-methyl-5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-2'-yl)carbamate The title compound was prepared from 1-(1-(3-bromo-6-chloropyridin-2-yl)cyclopropyl)ethan-1-ol using a procedure similar to that described in steps 4-6 for intermediate 9. 1 H NMR (400 MHz, CDCl3): 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, 1H), 1.09-1.00 (m, 2H).

[0182] Step 6: (R)-(tert-butyl 7'-methyl-5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-2'-yl)carbamate and (S)-(tert-butyl 7'-methyl-5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-2'-yl)carbamate tert-Butyl (7'-methyl-5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-2'-yl)carbamate (400 mg) was separated by SFC (column: REGIS(s,s)WHELK-O1 (250 mm × 50 mm, 10 μm), EtOH gradient in CO containing 0.1% NH4OH) to give two distinct peaks. The first eluting isomer (100 mg, 24% yield) and the second eluting isomer (140 mg, 34% yield) were obtained as yellow solids.

[0183] Step 7: One of (R or S)-2'-amino-7'-methyl-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-5'-one TFA (2.31 g, 20.3 mmol) was added to a solution of one of the (R or S)-(7'-methyl-5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-2'-yl)carbamate tert-butyl salts (the first eluting isomer from Step 6, 100 mg) in DCM (6 mL). The reaction mixture was stirred at 25 °C for 30 min, then quenched with saturated aqueous NaHCO (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) as a yellow oil, which was used without further purification. MS (ES+) C 11 H 12 Theoretical value of N2O2: 204, Measured value: 205 [M+H] + .

[0184] Step 8: The remaining (R or S)-2'-amino-7'-methyl-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-5'-one The title compound (Intermediate 13) was prepared from one of the (R or S)-tert-butyl (7'-methyl-5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano][4,3-b]pyridin]-2'-yl)carbamate (the second eluting isomer from Step 6) using a procedure similar to that described in Step 7 for Intermediate 12. MS (ES+) C 11 H 12 Theoretical value of N2O2: 204, Measured value: 205 [M+H] + .

[0185] [ka] Intermediate 14: 2-Amino-8,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one [ka] Step 1: Methyl 2-(3-bromo-6-chloropyridin-2-yl)-2-methylpropanoate Sodium hydride (2.91 g, 72.8 mmol, 60% purity) was added 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, and then iodomethane (7.38 g, 51.9 mmol) was added. The reaction mixture was warmed 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 a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 0% to 10% EA-petroleum ether) to give the title compound (5.5 g, 90% yield) as a yellow oil. 1 H NMR (400 MHz, CD3OD): 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).

[0186] Steps 2-6: 2-Amino-8,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one The title compound was prepared using procedures similar to those described in Steps 3-6 of Intermediate 9 and Step 7 of Intermediate 12. MS(ES+)C 10 H 12 Theoretical value of N2O2: 192, Measured value: 193 [M+H] + . 1 H NMR (400 MHz, 6d-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).

[0187] [ka] Intermediate 15: 2'-amino-7',7'-dimethyl-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-5'-one [ka] Step 1: 2-(1-(3-bromo-6-chloropyridin-2-yl)cyclopropyl)propan-2-ol 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) was added MeMgBr (3 M, 14.9 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 layers were combined, dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO, PE / EA = 1 / 0 to 50 / 1) to give the title compound (500 mg, 38% yield) as a colorless oil.

[0188] Steps 2-5: 2'-Amino-7',7'-dimethyl-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-5'-one The title compound was prepared from 2-(1-(3-bromo-6-chloropyridin-2-yl)cyclopropyl)propan-2-ol using procedures similar to those described above in steps 4-6 for intermediate 9 and step 7 for intermediate 12. 1 H 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).

[0189] [ka] Intermediate 16: 4-Bromo-1,6-dichloro-2,7-naphthyridine [ka] Step 1: 4-Bromo-6-chloro-2,7-naphthyridin-1(2H)-one NBS (70.9 g, 398 mmol, 1.20 equiv.) was added to a solution of 6-chloro-2,7-naphthyridin-1(2H)-one (60.0 g, 332 mmol, 1.00 equiv.) 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 4-bromo-6-chloro-2,7-naphthyridin-1(2H)-one (90.8 g, crude) as a brown solid. MS (ES+) calculated for CHBrClNO: 260, found: 261 [M+H] + .

[0190] Step 2: 4-Bromo-1,6-dichloro-2,7-naphthyridine 4-Bromo-6-chloro-2,7-naphthyridin-1(2H)-one (70.8 g, 272 mmol, 1.00 equiv) was added portionwise to POCl (484 g, 3.16 mol, 293 mL, 11.5 equiv) at 25 °C. The reaction mixture was stirred at 110 °C for 3 h. The reaction mixture was then concentrated in vacuo, and the residue was adjusted to pH = 8 with saturated aqueous NaCO at 25 °C. The mixture was extracted with DCM (500 mL × 3), washed with brine (500 mL), dried over NaSO, filtered, and concentrated in vacuo to give the title compound (75.0 g, 269 mmol, 98.9% yield) as a yellow solid. MS (ES+) C8H3BrCl2N2 calculated: 278, found: 279 [M+H] + .

[0191] [ka] Intermediate 17: 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine [ka] Step 1: 4-Bromo-6-chloro-1-methoxy-2,7-naphthyridine A suspension of 4-bromo-1,6-dichloro-2,7-naphthyridine (75.0 g, 269 mmol, 1.00 equiv.) and K2CO3 (111 g, 809 mmol, 3.00 equiv.) in MeOH (3 L) was stirred at 25 °C for 16 h. The reaction mixture was then concentrated in vacuo, and the residue was dissolved in HO (300 mL) and extracted with DCM (100 mL × 2). The combined organic layers were concentrated in vacuo to give a residue. The residue was triturated with PE / EA (40 mL, 20:1) and filtered. The filter cake was dried in vacuo to give the title compound (47.0 g, 171 mmol, 63.6% yield) as a yellow solid.

[0192] Step 2: 6-chloro-4-(1-ethoxyvinyl)-1-methoxy-2,7-naphthyridine A solution of 4-bromo-6-chloro-1-methoxy-2,7-naphthyridine (47.0 g, 171 mmol, 1.00 equiv.), tributyl(1-ethoxyvinyl)stannane (74.4 g, 206 mmol, 69.6 mL, 1.20 equiv.), and Pd(PPh3)4 (19.8 g, 17.1 mmol, 0.10 equiv.) in toluene (500 mL) was stirred at 80 °C under N2 for 16 h. The reaction mixture was then cooled to 20 °C, poured into saturated aqueous KF solution (500 mL), and stirred for 1 h. The aqueous mixture was extracted with EA (300 mL × 3), and the organic layers were combined. The combined organic layers were concentrated in vacuo to give the title compound (64.0 g, crude) as a yellow oil. MS (ES+) C 13 H 13 Theoretical value of ClN2O2: 264, Measured value: 265 [M+H] + .

[0193] Step 3: 1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-one Aqueous HCl (1.50 M, 20.1 mL, 0.10 equiv) was added to a solution of 6-chloro-4-(1-ethoxyvinyl)-1-methoxy-2,7-naphthyridine (80.0 g, 302 mmol, 1.00 equiv) in THF (480 mL) and HO (80 mL). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was then poured into saturated aqueous NaHCO (500 mL) and extracted with EA (300 mL × 2). The organic layers were combined and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (gradient elution, 5% to 50% EA-PE) to afford the title compound (28.0 g, 118 mmol, 39.1% yield) as a white solid. MS (ES+) C 11 Theoretical value of H9ClN2O2: 236, Measured value: 237 [M+H] + .

[0194] Step 4: 2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-ol MeMgBr (3.0 M in diethyl ether, 118 mL, 3.00 equiv.) was added to a solution of 1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-one (28.0 g, 118 mmol, 1.00 equiv.) in THF (300 mL) at 0°C-10°C. The mixture was stirred at 0°C-10°C for 2 h, then poured into saturated aqueous NH4Cl (300 mL) and extracted with EA (200 mL x 2). The organic layers were combined and concentrated in vacuo to give the title compound (33 g, crude) as a yellow oil. MS (ES+) C 12 H 13 Theoretical value of ClN2O2: 252, Measured value: 253 [M+H] + .

[0195] Step 5: 4-(2-azidopropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine TMSN3 (14.4 g, 125 mmol, 16.5 mL, 2.50 equiv) was added to a solution of 2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-ol (28.0 g, 50.3 mmol, 45.4% purity, 1.00 equiv) and BF3.Et2O (15.5 g, 50.3 mmol, 13.5 mL, 46.0% purity, 1.00 equiv) in DCM (280 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 12 h, then saturated NaCl was added. The mixture was partitioned between aqueous HCl (350 mL) and DCM (200 mL). The layers were separated and the aqueous layer was further extracted with DCM (200 mL). The organic layers were combined, washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (gradient elution, 2% to 50% EA-PE) to afford the title compound (20.0 g, 65% yield, 91% purity) as an off-white solid. MS (ES+) C 12 H 12 ClNO theoretical value: 277, measured value: 278 [M+H] + .

[0196] Step 6: 4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-ol Aqueous HCl (2 M, 163 mL, 5.00 equiv.) was added to a solution of 4-(2-azidopropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine (20.0 g, 65.5 mmol, 91% purity, 1.00 equiv.) in THF (200 mL) at 25° C. The reaction mixture was stirred at 25° C. for 12 h, then poured into saturated aqueous NaHCO (1.00 L) and extracted with EA (500 mL×2). The organic layers were combined, 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 11 H 10 ClNO theoretical value: 263, measured value: 264 [M+H] + .

[0197] Step 7: 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine POCl (2.54 g, 16.5 mmol, 1.54 mL, 4.37 equiv) and EtN (1.01 g, 9.99 mmol, 1.39 mL, 2.63 equiv) were added to a mixture of 4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-ol 7 (1.00 g, 3.79 mmol, 1.00 equiv) in ACN (20.0 mL). The reaction mixture was then heated at 100 °C for 20 h. 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 aqueous sodium carbonate. 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 flash column chromatography on silica gel (gradient elution, 0% to 5% EA-PE) to give the title compound (14.2 g, 84% yield) as a pale yellow solid. MS(ES+)C 11 Theoretical value of H9Cl2N2: 281, Measured value: 282 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6): δ ppm 9.57 (s,1H), 8.61 (s,1H), 8.45 (s,1H),1.83 (s, 6H).

[0198] [ka] Intermediate 18: (S)-4-(2-azido-1-methoxypropan-2-yl)-1,6-dichloro-2,7-naphthyridine [ka] Step 1: 6-chloro-1-methoxy-4-(prop-1-en-2-yl)-2,7-naphthyridine To a solution of 4-bromo-6-chloro-1-methoxy-2,7-naphthyridine (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-dioxaborolane (7.62 g, 45.3 mmol) in dioxane (500 mL) and water (50 mL) was added Pd(dppf)Cl (3.32 g, 4.53 mmol) and KCO (12.5 g, 90.6 mmol). The mixture was stirred under a nitrogen atmosphere at 80 °C for 2 h, 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 a residue. The residue was purified by flash column chromatography on silica gel (PE / EA=100 / 1 to 10 / 1) to give the title compound (7.00 g, yield 65%) as a white solid.

[0199] Step 2: 2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propane-1,2-diol OsO (1.02 g, 4.01 mmol) was added to a mixture of 6-chloro-1-methoxy-4-(prop-1-en-2-yl)-2,7-naphthyridine (9.4 g, 40.0 mmol) and NMO (9.38 g, 80.1 mmol) in acetone (160 mL) and HO (40 mL). The reaction mixture was stirred at 25 °C for 12 h, then quenched with saturated aqueous KF solution (150 mL) and filtered. The solution was extracted with EA (2 × 300 mL). The organic phase was dried over NaSO, 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.

[0200] Step 3: 6-chloro-4-(1,2-dimethoxypropan-2-yl)-1-methoxy-2,7-naphthyridine NaH (4.85 g, 121 mmol, 60% purity) was added to a solution of 2-(6-chloro-1-methoxy-2,7-naphthyridin-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, and then MeI (12.3 g, 86.5 mmol) was added. 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 aqueous NH4Cl (50 mL) and extracted with EA (300 mL). The organic layer was washed with saturated aqueous NH4Cl (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.

[0201] Step 4: 4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine BF3.Et2O (8.80 g, 62.0 mmol) was added to a mixture of 6-chloro-4-(1,2-dimethoxypropan-2-yl)-1-methoxy-2,7-naphthyridine (9.2 g, 31.0 mmol) and TMSN3 (17.9 g, 155 mmol) in DCE (150 mL) at 25 °C. The reaction mixture was heated to 60 °C under N2 for 6 h. The reaction mixture was then added to a stirred solution of saturated aqueous NaHCO3 (300 mL) and extracted with EA (300 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel (20% EA-PE) to give the title compound (8 g, 73% yield) as a colorless oil.

[0202] Step 4: (R)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine and (S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine The title compound was prepared by chiral SFC separation of 4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine (column: Daicel ChiralPak IG (250 × 30 mm, 10 μm); mobile phase: [15% (0.1% NH4OH) IPA] to give two title isomers. The first eluting isomer was (R)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine, and the second eluting isomer was (S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine. The absolute stereochemistry of the title compound was determined by the X-ray crystal structure of the final compound prepared from the second eluting isomer.

[0203] Step 5: (S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-2,7-naphthyridin-1-ol Aqueous HCl (6 M, 5.41 mL) was added to a solution of (S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine (3 g, 9.75 mmol) in THF (240 mL). The mixture was stirred at 25 °C for 12 h, and then solid NaHCO was added to adjust the pH to approximately 8. The mixture was extracted with EA (2 × 150 mL), and the organic layer was dried over NaSO, 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.

[0204] Step 6: (S)-4-(2-azido-1-methoxypropan-2-yl)-1,6-dichloro-2,7-naphthyridine POCl (3.34 g, 21.8 mmol) was added to a mixture of (S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-2,7-naphthyridin-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 h. The reaction mixture was then added to saturated aqueous NH Cl (50 mL) and extracted with EA (100 mL × 3). The organic layers were combined, dried over Na SO , filtered, and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel (25% EA-PE) to give the title compound (1.2 g, 88% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3): δ ppm 9.61 (s,1H), 8.57 (s,1H), 8.48 (s,1H), 3.98 (d, J = 9.6Hz,1H), 3.78 (d, J = 9.6Hz,1H), 3.41 (s, 3H),1.80 (s, 3H).

[0205] [ka] Intermediate 19: (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine [ka] Step 1: 6-chloro-4-(1-ethoxyvinyl)-1-methoxy-2,7-naphthyridine A mixture of 4-bromo-6-chloro-1-methoxy-2,7-naphthyridine (220 g, 804 mmol, 1.00 equiv.), tributyl(1-ethoxyvinyl)stannane (264 g, 731 mmol, 246 mL, 0.90 equiv.), and Pd(PPh3)4 (46.4 g, 40.2 mmol, 0.05 equiv.) in toluene (2.20 L) was stirred at 100 °C for 36 h under N2. The mixture was cooled to 25 °C, and tributyl(1-ethoxyvinyl)stannane (0.35 equiv.) was added to the above solution under N2. The mixture was stirred at 100 °C for 12 h. The mixture was cooled to 25 °C and poured into saturated aqueous KF solution (2.00 L). The mixture was filtered through a pad of Celite, 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 (SiO 2 , PE / EA=20 / 1 to 10 / 1) to give the title compound (157 g, 668 mmol, 83.1% yield) as a white solid.

[0206] Step 2: 1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-one To a solution of 6-chloro-4-(1-ethoxyvinyl)-1-methoxy-2,7-naphthyridine (157 g, 593 mmol, 1.00 equiv.) in THF (942 mL) and HO (157 mL), HCl (1.50 M, 39.5 mL, 0.10 equiv.) was added, and the suspension was stirred at 25 °C for 1 h. The mixture was poured into saturated aqueous NaHCO (1.50 L) and extracted with EA (1.50 L × 2). The combined organic layers were concentrated to give a residue. The residue was slurried in PE / EA = 10:1 (550 mL) at 20 °C to 25 °C for 10 min, and the suspension was filtered, and the filter cake was dried to give the title compound (114 g) as a white solid. MS (ES+) C 11 Theoretical value of H9ClN2O2: 236, Measured value: 237 [M+H] + .

[0207] Step 3: 2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)butan-2-ol A solution of 1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-one (114 g, 481 mmol, 1.00 equiv) in THF (2.28 L) was added to a mixture of EtMgBr (3.00 M, 481 mL, 3.00 equiv) at 0°C to 10°C. The reaction mixture was stirred at 0°C to 10°C for 0.5 h, then poured into saturated aqueous NH4Cl (1.50 L) and extracted with EA (1.00 L x 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 13 H 15 Theoretical value of ClN2O2: 266, Measured value: 267 [M+H] + .

[0208] Step 4: 4-(2-azidobutan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine To a solution of 2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)butan-2-ol (100 g, 374 mmol, 1.00 equiv.) and BF3.Et2O (49.2 mL, 187 mmol, 47.0% purity, 0.50 equiv.) in DCM (1.00 L) was added TMSN3 (123 mL, 937 mmol, 2.50 equiv.) at 25 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was then slowly added to saturated aqueous 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 to 5 / 1) to give a solid. The solid was slurried in PE / EA=8 / 1 (90.0 mL) at 25° C. for 10 minutes, then filtered, and the filter cake was dried to give the title compound (46.0 g, 155 mmol, 41.5% yield) as a white solid. MS(ES+)C 13 H 14 ClNO theoretical value: 291, measured value: 292 [M+H] + .

[0209] Step 5: (R)-4-(2-azidobutan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine 4-(2-Azidobutan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine (46.0 g, 157 mmol, 98.7% purity, 1.00 equiv.) was separated by SFC (column: Daicel ChiralPak IG (250 × 30 mm, 10 μm); mobile phase: [0.1% NH₃H₂O MEOH]; B%: 20% to 20%). Concentration of the second eluting peak afforded 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 13 H 14 ClNO theoretical value: 291, measured value: 292 [M+H] + .

[0210] Step 6: (R)-4-(2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-ol To a solution of (R)-4-(2-azidobutan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine (21.5 g, 72.7 mmol, 1.00 equiv) in THF (215 mL) was added HCl (3.00 M, 122 mL, 5.07 equiv) at 25 °C, and the suspension was then stirred at 25 °C for 12 h, followed by stirring at 30 °C for 12 h. The reaction mixture was poured into saturated aqueous NaHCO (500 mL), extracted with EA (150 mL × 2), washed with brine (200 mL), dried over NaSO, filtered, and concentrated. The residue was slurried in PE (100 mL) at 25 °C for 10 min, then filtered, and the filter cake was dried to give the title compound (18.5 g) as a white solid. MS (ES+) C 12 H 12 ClNO theoretical value: 277, measured value: 278 [M+H] + .

[0211] Step 7: (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine The following three reactions were run in parallel and combined for purification. To a solution of (R)-4-(2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-ol (6.16 g, 22.1 mmol, 1.00 equiv) in MeCN (190 mL) was added POCl (10.3 mL, 110 mmol, 5.00 equiv) and EtN (8.03 mL, 57.6 mmol, 2.60 equiv). The reaction mixture was stirred at 120 °C for 64 h and then concentrated to give a residue. The residue was diluted with EA (500 mL) and then quenched with water (500 mL) at 20 °C-30 °C and stirred at 30 °C for 30 min. The mixture was adjusted to pH = 8 by the addition of saturated aqueous NaCO solution at 25 °C and then extracted with EA (500 mL × 2). The combined organic layers were washed with brine (500 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EA = 1 / 0 to 8 / 1) to give the title compound (18.0 g, 88.4% yield) as a pale yellow solid. MS (ES+) C 12 H 11 Cl2N5 theoretical value: 295, measured value: 296 [M+H] + . 1 H NMR (400 MHz, CDCl3): 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).

[0212] [ka] Intermediate 20: 4-(2-azidopropan-2-yl)-6-chloro-1-((1-(methylsulfonyl)azetidin-3-yl)oxy)-2,7-naphthyridine [ka] Step 1: tert-Butyl 3-((4-bromo-6-chloro-2,7-naphthyridin-1-yl)oxy)azetidine-1-carboxylate To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (2.06 g, 11.9 mmol) in THF (84 mL) was added NaH (518 mg, 13.0 mmol, 60% purity) at 0 °C. The reaction mixture was stirred at 20 °C for 0.5 h, and then 4-bromo-1,6-dichloro-2,7-naphthyridine (3 g, 10.8 mmol) was added, and the resulting mixture was stirred at 20 °C for 0.5 h. The reaction mixture was then quenched by slowly adding 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 give a residue. The residue was purified by column chromatography (SiO2, PE / EA = 1 / 0 to 10 / 1) to give the title compound (4.00 g, 88% yield) as a white solid. MS (ES+) C 16 H 17 BrClN3O3 theoretical value: 415, measured value: 416 [M+H] + .

[0213] Step 2: tert-Butyl 3-((6-chloro-4-(1-ethoxyvinyl)-2,7-naphthyridin-1-yl)oxy)azetidine-1-carboxylate To a solution of tert-butyl 3-((4-bromo-6-chloro-2,7-naphthyridin-1-yl)oxy)azetidine-1-carboxylate (4.00 g, 9.65 mmol) in toluene (100 mL) were added Pd(PPh3)4 (1.11 g, 965 μmol) and tributyl(1-ethoxyvinyl)stannane (3.48 g, 9.65 mmol, 3.26 mL). The reaction mixture was stirred under nitrogen at 80 °C for 16 h, and then saturated aqueous potassium fluoride solution was added. The mixture was stirred for 4 h and then extracted with EA (100 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / EA = 1 / 0 to 10 / 1) to give the title compound (3.40 g, 43% yield) as a white solid.

[0214] Step 3: tert-Butyl 3-((4-acetyl-6-chloro-2,7-naphthyridin-1-yl)oxy)azetidine-1-carboxylate To a solution of tert-butyl 3-((6-chloro-4-(1-ethoxyvinyl)-2,7-naphthyridin-1-yl)oxy)azetidine-1-carboxylate (3.40 g, 4.19 mmol) in THF (68 mL) and HO (8 mL) was added HCl (2 M, 2.09 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 the addition of saturated aqueous 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 under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, PE / EA = 10 / 0 to 1 / 1) to give the title compound (1.4 g, 83% yield) as a white solid.

[0215] Step 4: tert-Butyl 3-((6-chloro-4-(2-hydroxypropan-2-yl)-2,7-naphthyridin-1-yl)oxy)azetidine-1-carboxylate To a solution of tert-butyl 3-((4-acetyl-6-chloro-2,7-naphthyridin-1-yl)oxy)azetidine-1-carboxylate (1.4 g, 3.71 mmol, 1 equiv.) in THF (30 mL) was added methylmagnesium bromide (3 M, 6.18 mL, 5 equiv.). The reaction mixture was stirred at 20 °C for 1 h, then poured into saturated aqueous ammonium chloride solution (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 a residue. The residue was purified by column chromatography (SiO, PE / EA = 10 / 0 to 1 / 1) to give the title compound (1.2 g, 76% yield) as a white solid.

[0216] Step 5: 2-(1-(azetidin-3-yloxy)-6-chloro-2,7-naphthyridin-4-yl)propan-2-ol tert-Butyl 3-((6-chloro-4-(2-hydroxypropan-2-yl)-2,7-naphthyridin-1-yl)oxy)azetidine-1-carboxylate (1.10 g, 2.79 mmol) was added to a solution of HCl in dioxane (4 M, 11 mL). The reaction mixture was stirred at 20° C. for 0.5 h and then concentrated to give a residue. Saturated aqueous sodium bicarbonate solution 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% ammonia hydroxide v / v)-ACN]; B%: 12% to 42%, 20 min) to give the title compound (300 mg, 32% yield) as a white solid.

[0217] Step 6: 2-(6-chloro-1-((1-(methylsulfonyl)azetidin-3-yl)oxy)-2,7-naphthyridin-4-yl)propan-2-ol To a solution of 2-(1-(azetidin-3-yloxy)-6-chloro-2,7-naphthyridin-4-yl)propan-2-ol (50 mg, 170 μmol) and triethylamine (51.7 mg, 511 μmol, 71.1 μL) in DCM (5 mL) was added MsCl (21.5 mg, 187 μmol, 14.5 μL). The reaction mixture was stirred at 25° C. for 2 h and then quenched by adding 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 give a 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.

[0218] Step 7: 4-(2-azidopropan-2-yl)-6-chloro-1-((1-(methylsulfonyl)azetidin-3-yl)oxy)-2,7-naphthyridine To a solution of 2-(6-chloro-1-((1-(methylsulfonyl)azetidin-3-yl)oxy)-2,7-naphthyridin-4-yl)propan-2-ol (150 mg, 403 μmol) in DCM (5 mL) was added TMSN3 (265 μL, 2.02 mmol) and InBr3 (172 mg). After the mixture was stirred at 20 °C for 1 h, water (20 mL) was added and the pH was adjusted to 8-9 by the addition of 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 a residue. The residue was purified by column chromatography (SiO2, PE / EA = 1 / 1 to 0 / 1) to give the title compound (120 mg, 75% yield) as a white solid. MS (ES+) C 15 H 17 ClN6O3S theoretical value: 396, measured value: 397 [M+H] + .

[0219] [ka] Intermediate 21: 3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)thietane 1,1-dioxide [ka] Step 1: 4-(2-azidopropan-2-yl)-6-chloro-1-(thietan-3-yloxy)-2,7-naphthyridine To a solution of thietan-3-ol (17.6 mg, 195 μmol) in THF (1 mL) was added NaH (10.6 mg, 266 μmol, purity 60%). After stirring the mixture for 10 min, 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine (Intermediate 17, 50 mg, 177 μmol) was added, and the mixture was stirred at 20° C. for 50 min. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride 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.

[0220] Step 2: 3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)thietane 1,1-dioxide To a solution of 4-(2-azidopropan-2-yl)-6-chloro-1-(thietan-3-yloxy)-2,7-naphthyridine (59.0 mg, 176 μmol) in THF (0.9 mL) and water (0.3 mL) was added Oxone (216 mg, 351 μmol). The mixture was stirred at 20° C. for 1 h, then quenched by the addition of saturated aqueous sodium sulfite 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. 1 H-NMR (400 MHz, CDCl3): 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).

[0221] [ka] Intermediate 22: 4-(2-azidopropan-2-yl)-6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine [ka] Step 1: 4-(2-azidopropan-2-yl)-6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine To a solution of cis-3-(methylsulfonyl)cyclobutan-1-ol (5.70 g, 37.9 mmol) in THF (260 mL) was added NaH (1.97 g, 49.3 mmol, 60% purity) at 0° C. The mixture was stirred for 0.5 h, then 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine (10.7 g, 37.9 mmol) was added, and the reaction mixture was stirred 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) as a white solid, which was used in the next step without further purification. MS (ES+) C 16 H 18 Theoretical value of ClN5O3S: 395, Measured value: 396 [M+H] + .

[0222] [ka] Intermediate 23: 4-(2-azidopropan-2-yl)-6-chloro-1-(3-(methylsulfonyl)propoxy)-2,7-naphthyridine [ka] Step 1: 4-(2-azidopropan-2-yl)-6-chloro-1-(3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine and 3-(methylsulfonyl)propan-1-ol using a procedure similar to that described above for Intermediate 22. MS(ES+)C 15 H 18 ClN5O3S theoretical value: 383, measured value: 384 [M+H] + .

[0223] [ka] Intermediate 24: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((1s,3S)-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine [ka] The title compound was prepared from (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine (Intermediate 19) and cis-3-(methylsulfonyl)cyclobutan-1-ol using a procedure similar to that described above for Intermediate 22. MS(ES+)C 17 H 20 ClN5O3S theoretical value: 409, measured value: 410 [M+H] + .

[0224] [ka] Intermediate 25: 3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-3-methylthietane 1,1-dioxide [ka] Steps 1-2: 3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-3-methylthietane 1,1-dioxide The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine and 3-methylthietan-3-ol using a procedure similar to that described in steps 1-2 of Intermediate 21. MS(ES+)C 15 H 16 ClN5O3S theoretical value: 381, measured value: 382 [M+H] + .

[0225] [ka] Intermediate 26: 3-(((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)methyl)thietane 1,1-dioxide [ka] Step 1: 3-(((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)methyl)thietane 1,1-dioxide The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine and 3-(hydroxymethyl)thietane 1,1-dioxide using a procedure similar to that described above for Intermediate 22. MS(ES+)C 15 H 16 ClN5O3S theoretical value: 381, measured value: 382 [M+H] + .

[0226] [ka] Intermediate 27: 4-(2-azidopropan-2-yl)-6-chloro-1-(trans-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine [ka] Step 1: 4-(2-azidopropan-2-yl)-6-chloro-1-(trans-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine and trans-3-(methylsulfonyl)cyclobutan-1-ol using a procedure similar to that described above for Intermediate 22. MS(ES+)C 16 H 18 Theoretical value of ClN5O3S: 395, Measured value: 396 [M+H] + .

[0227] [ka] Intermediates 28 and 29: (R)-4-(2-azidopropan-2-yl)-6-chloro-1-((4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine and (S)-4-(2-azidopropan-2-yl)-6-chloro-1-((4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine [ka] Each of them is represented by one of the structures shown below. [ka] Step 1: 4-(methylsulfonyl)butan-2-one To a solution of 4-(methylthio)butan-2-one (2.00 g, 16.9 mmol) in THF (100 mL) and water (20 mL) was added Oxone® (10.4 g, 16.9 mmol). The reaction mixture was stirred at 25° C. for 2 h, then quenched with water (30 mL), adjusted to pH 8 by the addition of saturated aqueous sodium carbonate solution (20 mL), and extracted with EA (30 mL × 3). The combined organic layers were washed with a saturated solution of sodium thiosulfate (30 mL) and brine. The organic layers were dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO, PE / EA = 3:1 to 0:1) to give the title compound (0.80 g, 31% yield) as a white solid.

[0228] Step 2: 4-(methylsulfonyl)butan-2-ol To a solution of 4-(methylsulfonyl)butan-2-one (400 mg, 2.66 mmol) in methanol (10 mL) was added NaBH (202 mg, 5.33 mmol) in portions. 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 give a residue. The residue was purified by column chromatography (SiO, PE / EA = 0:1) to give the title compound (300 mg, 74% yield) as a yellow viscous material.

[0229] Step 3: 4-(2-azidopropan-2-yl)-6-chloro-1-((4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine and 4-(methylsulfonyl)butan-2-ol using a procedure similar to that described above for Intermediate 22. MS(ES+)C 16 H 20 ClN5O3S theoretical value: 397, measured value: 398 [M+H] + .

[0230] Step 4: (R)-4-(2-azidopropan-2-yl)-6-chloro-1-((4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine and (S)-4-(2-azidopropan-2-yl)-6-chloro-1-((4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine 4-(2-azidopropan-2-yl)-6-chloro-1-((4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine (330 mg, 829 μmol) was purified by chiral SFC (column: Daicel Chiralpak AD (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH3HO] IPA]; B%: 30% to 30%, to give (R or S)-4-(2-azidopropan-2-yl)-6-chloro-1-((4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine (130 mg, 45% yield, yellow oil, Intermediate 28) as the first eluting isomer and (R or S)-4-(2-azidopropan-2-yl)-6-chloro-1-((4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine (130 mg, 39% yield, yellow oil, Intermediate 29) as the second eluting isomer. Intermediate 28:MS(ES+)C 16 H 20 ClN5O3S theoretical value: 397, measured value: 398 [M+H] + . Intermediate 29: MS(ES+)C 16 H 20 ClN5O3S theoretical value: 397, measured value: 398 [M+H] + .

[0231] [ka] Intermediate 30: (R)-4-(methylsulfonyl)butan-2-ol [ka] Step 1: (R)-3-((tert-butyldimethylsilyl)oxy)butanoate methyl ester To a mixture of (R)-methyl 3-hydroxybutanoate (50 g, 423 mmol, 48.5 mL), imidazole (43.2 g, 635 mmol), and DMAP (25.9 g, 212 mmol) in DMF (1000 mL) was added TBSCl (67.0 g, 444 mmol) portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then warmed to 25 °C and stirred for an additional 12 h. The reaction mixture was then diluted with HO (300 mL) and EA (500 mL). The organic layer was washed with saturated aqueous NHCl (3 × 300 mL), dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography (PE / EA = 50 / 1) to give the title compound (91 g, 93% yield) as a colorless oil.

[0232] Step 2: (R)-3-((tert-butyldimethylsilyl)oxy)butan-1-ol A mixture of (R)-methyl 3-((tert-butyldimethylsilyl)oxy)butanoate (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 min, then warmed to 25° C. and stirred for an additional 2 h. The reaction mixture was added to a stirred solution of NaOH (58.7 g, 1.47 mol) in HO (300 mL) and filtered to remove solids. The filtrate was washed with brine (3×300 mL), washed with saturated aqueous NaSO (200 mL), dried over NaSO, filtered, and concentrated to give the title compound (40 g, crude) as a colorless oil, which was used directly in the next step without further purification.

[0233] Step 3: (R)-3-((tert-butyldimethylsilyl)oxy)butyl methanesulfonate To a mixture of (R)-3-((tert-butyldimethylsilyl)oxy)butan-1-ol (80 g, 391 mmol) and TEA (70.5 g, 697 mmol) in DCM (500 mL) was added MsCl (61.0 g, 532 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then diluted with HO (100 mL). The organic layer was washed with saturated aqueous NHCl (3 × 300 mL). The organic layer was dried over NaSO, filtered, and concentrated to give the title compound (110 g, crude) as a colorless oil.

[0234] Step 4: (R)-tert-butyldimethyl((4-(methylthio)butan-2-yl)oxy)silane A mixture of sodium thiomethoxide (54.6 g, 779 mmol), (R)-3-((tert-butyldimethylsilyl)oxy)butyl methanesulfonate (110 g, 389 mmol) in DMF (500 mL) was stirred for 2 h at 25° C. 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.

[0235] Step 5: (R)-tert-butyldimethyl((4-(methylsulfonyl)butan-2-yl)oxy)silane To a mixture of (R)-tert-butyldimethyl((4-(methylthio)butan-2-yl)oxy)silane (77.6 g, 331 mmol) and NaHCO (222 g, 2.65 mol) in THF (1000 mL) and HO (200 mL) was added Oxone® (509 g, 827 mmol) in portions. The mixture was stirred at 25 °C for 3 h. The reaction mixture was filtered, and the organic layer of the filtrate was washed with saturated aqueous NaSO (3 × 300 mL), dried over NaSO, filtered, and concentrated to give 81 g of crude product, which contained 60% of the corresponding sulfoxide. Half of the crude product (42 g) and NaHCO (113 g, 1.34 mol) were redissolved in THF (1000 mL) and HO (500 mL), then Oxone (206 g, 335 mmol) was added portionwise. The mixture was stirred at 25 °C for 2 h and then filtered. The organic layer of the filtrate was washed with saturated aqueous NaSO (500 mL), dried over NaSO, filtered, and concentrated in vacuo 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.

[0236] Step 6: (R)-4-(methylsulfonyl)butan-2-ol (R)-tert-Butyldimethyl((4-(methylsulfonyl)butan-2-yl)oxy)silane (44.6 g, 167 mmol) was added to HCl / MeOH (4 M, 178 mL) at 25° C. The mixture was stirred at 25° C. for 1 hour, then filtered and concentrated to give a residue. The residue was purified by column chromatography (PE / EA=5 / 1, and then MeOH) to give the title compound (18.7 g, 73% yield) as a yellow semi-solid. 1H NMR (400 MHz, CD3Cl): 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).

[0237] [ka] Intermediate 31: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine [ka] Step 1: To a mixture of (R)-4-(methylsulfonyl)butan-2-ol (15.37 g, 101 mmol) in THF (300 mL) was added NaH (7.14 g, 179 mmol, 60% purity) at 25 °C. The mixture was stirred for 1 h, and then (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine (23 g, 77.7 mmol) in THF (150 mL) was added. The reaction mixture was stirred at 25 °C for 1.5 h and then poured into saturated aqueous NH Cl (500 mL). The mixture was extracted with EA (500 mL), and the organic layer was dried over Na SO , filtered, and concentrated to give the title compound (31 g, 93% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3): 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).

[0238] [ka] Intermediate 32: 4-(2-azidopropan-2-yl)-6-chloro-1-(cis-3-(cyclopropylsulfonyl)cyclobutoxy)-2,7-naphthyridine [ka] Step 1: trans-3-(benzyloxy)cyclobutyl methanesulfonate To a solution of trans-3-(benzyloxy)cyclobutan-1-ol (1.9 g, 10.7 mmol) and NEt (3.24 g, 32.0 mmol) in DCM (38 mL) was added MsCl (2.44 g, 21.3 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, 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) as a yellow oil, which was used in the next step without further purification.

[0239] Step 2: S-trans-3-(benzyloxy)cyclobutyl)ethanethioate A solution of trans-3-(benzyloxy)cyclobutyl methanesulfonate (1.5 g, 5.85 mmol) and potassium ethanethiolate (802 mg, 7.02 mmol) 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 13 H 16 Theoretical value of O2S: 236, Measured value: 237 [M+H] + .

[0240] Step 3: cis-3-(benzyloxy)cyclobutane-1-thiol To a solution of S-trans-3-(benzyloxy)cyclobutyl)ethanethioate (840 mg, 3.55 mmol) in methanol (20 mL) was added K2CO3 (1.47 g, 10.7 mmol). The reaction mixture was stirred at 70 °C for 1 h, then NaOH (284 mg, 7.11 mmol) was added, and the mixture was stirred at 70 °C for an additional 2 h. 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 a 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.

[0241] Step 4: cis-3-(benzyloxy)cyclobutyl)(cyclopropyl)sulfane To a solution of cis-3-(benzyloxy)cyclobutane-1-thiol (250 mg, 1.29 mmol) in DMSO (6 mL) were added potassium tert-butoxide (173 mg, 1.54 mmol) and bromocyclopropane (202 mg, 1.67 mmol, 134 μL). The reaction mixture was heated at 80 °C for 2 h, then diluted with water (15 mL) and extracted 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 a 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 14 H 18 Theoretical OS value: 234, Measured value: 235 [M+H] + .

[0242] Step 5: ((cis-3-(cyclopropylsulfonyl)cyclobutoxy)methyl)benzene To a solution of cis-3-(benzyloxy)cyclobutyl)(cyclopropyl)sulfane (120 mg, 512 μmol) in THF (9 mL) and water (3 mL) was added Oxone® (629 mg, 1.02 mmol). The reaction mixture was stirred at 25° C. for 1 h and then quenched by the addition of saturated aqueous sodium sulfite solution (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 give the title compound (120 mg, 88% yield) as a white oil, which was used in the next step without further purification.

[0243] Step 6: cis-3-(cyclopropylsulfonyl)cyclobutan-1-ol To a solution of ((cis-3-(cyclopropylsulfonyl)cyclobutoxy)methyl)benzene (100 mg, 375 μmol) in DCM (4 mL) was added a solution of BCl3 (1 M, 2 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then quenched by the addition of methanol (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a 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+) CH 12 Theoretical value of O3S: 176, Measured value: 177 [M+H] + .

[0244] Step 7: 4-(2-azidopropan-2-yl)-6-chloro-1-(cis-3-(cyclopropylsulfonyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine and cis-3-(cyclopropylsulfonyl)cyclobutan-1-ol using a procedure similar to that described above for intermediate 22. MS(ES+)C 18 H 20 ClN5O3S theoretical value: 421, measured value: 422 [M+H] + .

[0245] [ka] Intermediate 33: 5-Bromo-3-chloroisoquinolin-8-ol [ka] Step 1: (E)-2-(hydroxyimino)-7-methoxy-2,3-dihydro-1H-inden-1-one t-BuONO (67.9 g, 659 mmol, 78.4 mL, 1.10 equiv.) was added to a solution of 7-methoxy-2,3-dihydro-1H-inden-1-one (99.0 g, 599 mmol, 1.00 equiv.) in THF (500 mL) at -10 to 0 °C, followed by dropwise addition of HCl (4 M in MeOH, 15.0 mL, 0.10 equiv.) to the mixture at -10 to 0 °C. The reaction mixture was stirred at 0 °C for 2 h and 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 10 Theoretical value of H9NO3: 191, Measured value: 192 [M+H] + .

[0246] Step 2: 1,3-Dichloro-8-methoxyisoquinoline To a solution of (£)-2-(hydroxyimino)-7-methoxy-2,3-dihydro-1H-inden-1-one (107 g, 522 mmol, 1.00 equiv) in dioxane (500 mL) was added POCl (126 g, 827 mmol, 76.9 mL, 1.59 equiv) and HCl (4 M in dioxane, 1.31 mL, 0.01 equiv) at 0°C to 10°C. The reaction mixture was stirred at 70°C for 12 h, 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 NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / EA = 20 / 1 to 10 / 1) to give the title compound (48.8 g, 40.9% yield) as a pale yellow solid. MS (ES+) C 10 Theoretical value of H7Cl2NO: 227, Measured value: 228 [M+H] + .

[0247] Step 3: 3-Chloro-8-methoxyisoquinoline To a solution of 1,3-dichloro-8-methoxyisoquinoline (48.8 g, 213 mmol, 1.00 equiv) in THF (250 mL) were added TMEDA (37.3 g, 320 mmol, 48.4 mL, 1.50 equiv) and Pd(dppf)Cl (1.57 g, 2.14 mmol, 0.01 equiv) at 25 °C. NaBH (17.2 g, 456 mmol, 2.13 equiv) was then slowly added to the reaction mixture, and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into 1 N HCl (1.00 L) and extracted with EA (200 mL × 3). The combined organic layer was filtered through Celite®, and the filtrate was washed with brine (500 mL), dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / EA = 20 / 1 to 5 / 1) to give the title compound (26.7 g, yield 64.3%) as a pale yellow solid. MS (ES+) C 10 Theoretical value of H8ClNO: 193, Measured value: 194 [M+H] + .

[0248] Step 4: 5-Bromo-3-chloro-8-methoxyisoquinoline To a solution of 3-chloro-8-methoxyisoquinoline (26.7 g, 137 mmol, 1.00 equiv.) in MeCN (300 mL) was added NBS (29.3 g, 165 mmol, 1.20 equiv.) at 25 °C. The reaction mixture was stirred at 70 °C for 1 h and 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 an off-white solid. MS (ES+) C 10 H7BrClNO theoretical value: 273, measured value: 274 [M+H] + .

[0249] Step 5: 5-Bromo-3-chloroisoquinolin-8-ol To a solution of 5-bromo-3-chloro-8-methoxyisoquinoline (3.00 g, 11.01 mmol) in DCM (50 mL) was added BBr3 (13.8 g, 55.0 mmol) in one portion. The reaction mixture was stirred at 50 °C for 12 h, then quenched with MeOH (15 mL) and concentrated to give a 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. 1 H NMR (400 MHz, 6d-DMSO): δ ppm11.3 (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).

[0250] [ka] Intermediate 34: 5-(2-azidopropan-2-yl)-3-chloro-8-((4-(methylsulfonyl)butan-2-yl)oxy)isoquinoline [ka] Step 1: 4-(methylsulfonyl)butan-2-yl methanesulfonate To a solution of 4-(methylsulfonyl)butan-2-ol (50 mg, 328 μmol) in DCM (5 mL) was added 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.

[0251] Step 2: 5-Bromo-3-chloro-8-((4-(methylsulfonyl)butan-2-yl)oxy)isoquinoline To a solution of compound 4-(methylsulfonyl)butan-2-yl methanesulfonate (400 mg, 1.55 mmol) in DMF (3 mL) was added KCO (642 mg, 4.64 mmol) in one portion at 25 °C, and then 5-bromo-3-chloroisoquinolin-8-ol (Intermediate 33) (756 mg, 3.28 mmol) was added 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 a residue. The residue was purified by preparative TLC (PE / EA = 1:1) to give the title compound (600 mg, 1.53 mmol, 99% yield) as a yellow solid.

[0252] Steps 3-6: 5-(2-azidopropan-2-yl)-3-chloro-8-((4-(methylsulfonyl)butan-2-yl)oxy)isoquinoline The title compound was prepared using a four step procedure similar to that described in steps 2-5 of Intermediate 17. [ka]

[0253] Intermediate 35: 5-(2-azidopropan-2-yl)-3-chloro-8-(cis-3-(methylsulfonyl)cyclobutoxy)isoquinoline [ka] Step 1: cis-3-(benzyloxy)cyclobutyl methanesulfonate To a solution of 3-benzyloxycyclobutanol (2.5 g, 14.0 mmol) and TEA (4.26 g, 42.1 mmol) in DCM (25 mL) was added MsCl (2.41 g, 21.0 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 1 h, then poured into water (20 mL) and extracted with DCM (20 mL × 2). The combined organic layer was 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.

[0254] Step 2: 8-(trans-3-(benzyloxy)cyclobutoxy)-5-bromo-3-chloroisoquinoline To a solution of 5-bromo-3-chloro-isoquinolin-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) was added K2CO3 (2.46 g, 17.8 mmol) at 25 °C. The reaction mixture was stirred at 100 °C for 6 h, 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 (2.7 g, 72% yield) as a white solid. 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).

[0255] Step 3: trans-3-((5-bromo-3-chloroisoquinolin-8-yl)oxy)cyclobutan-1-ol To a solution of 8-(trans-3-(benzyloxy)cyclobutoxy)-5-bromo-3-chloroisoquinoline (2.0 g, 4.78 mmol) in DCM (30 mL) was added BCl (1 M, 14.3 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then poured into saturated aqueous 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.

[0256] Step 4: trans-3-((5-bromo-3-chloroisoquinolin-8-yl)oxy)cyclobutyl methanesulfonate To a solution of trans-3-((5-bromo-3-chloroisoquinolin-8-yl)oxy)cyclobutan-1-ol (1.55 g, 4.72 mmol) in DCM (30 mL) were added TEA (1.43 g, 14.2 mmol) and MsCl (810 mg, 7.08 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, 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.

[0257] Step 5: S-(cis-3-((5-bromo-3-chloroisoquinolin-8-yl)oxy)cyclobutyl)ethanethioate To a solution of trans-3-((5-bromo-3-chloroisoquinolin-8-yl)oxy)cyclobutyl methanesulfonate (1.9 g, 4.67 mmol) in DMSO (30 mL) was added potassium ethanethioate (1.60 g, 14.0 mmol). The mixture was stirred at 100 °C for 2 h, 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 column chromatography on SiO (PE / EA = 50:1 to 20:1) to give the title compound (1.8 g, 99% yield) as a yellow solid.

[0258] Step 6: cis-3-((5-bromo-3-chloroisoquinolin-8-yl)oxy)cyclobutane-1-thiol To a solution of S-(cis-3-((5-bromo-3-chloroisoquinolin-8-yl)oxy)cyclobutyl)ethanethioate (1.80 g, 4.65 mmol) in THF (20 mL), MeOH (10 mL), and water (10 mL) was added NaOH (931 mg, 23.3 mmol). The reaction mixture was stirred at 20° C. for 2 h, and then adjusted to pH=5-6 by addition of aqueous HCl (1 M). The reaction 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.

[0259] Step 7: 5-Bromo-3-chloro-8-(cis-3-(methylthio)cyclobutoxy)isoquinoline To a solution of cis-3-((5-bromo-3-chloroisoquinolin-8-yl)oxy)cyclobutane-1-thiol (400 mg, 1.16 mmol) in THF (8 mL) was added NaH (69.6 mg, 1.74 mmol, 60% purity) and methyl iodide (494 mg, 3.48 mmol). The reaction mixture was stirred at 20 °C for 1 h, 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 column chromatography on SiO (PE / EA = 50:1 to 20:1) to afford the title compound (400 mg, 96% yield) as a white solid.

[0260] Step 8: 5-Bromo-3-chloro-8-(cis-3-(methylsulfonyl)cyclobutoxy)isoquinoline To a solution of 5-bromo-3-chloro-8-(cis-3-(methylthio)cyclobutoxy)isoquinoline (200 mg, 558 μmol) in THF (3 mL) and water (1 mL) was added Oxone® (686 mg, 1.12 mmol). The reaction mixture was stirred at 20° C. for 1 h, then quenched by the addition of saturated aqueous sodium sulfite (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.

[0261] Steps 9-12: 5-(2-azidopropan-2-yl)-3-chloro-8-(cis-3-(methylsulfonyl)cyclobutoxy)isoquinoline The title compound was prepared using a four step procedure similar to that described in steps 2-5 of Intermediate 17. [ka]

[0262] Intermediate 36: 4-(2-azidopropan-2-yl)-6-chloro-N-(cis-3-(methylsulfonyl)cyclobutyl)-2,7-naphthyridin-1-amine [ka] Step 1: 4-(2-azidopropan-2-yl)-6-chloro-N-(cis-3-(methylsulfonyl)cyclobutyl)-2,7-naphthyridin-1-amine To a solution of 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine (100 mg, 354 μmol) in NMP (2 mL) was added DIEA (68.7 mg, 532 μmol, 92.6 μL) and cis-3-(methylsulfonyl)cyclobutan-1-amine (79.3 mg, 532 μmol) 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 layer was washed with brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a 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 16 H 19 ClN6O2S theoretical value: 394, measured value: 395 [M+H] + .

[0263] [ka] Intermediate 37: 4-(2-azidopropan-2-yl)-6-chloro-1-((1S,2R,3S and 1R,2S,3R)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine [ka] Step 1: ((prop-1-en-1-yloxy)methyl)benzene To a solution of ((allyloxy)methyl)benzene (1 g, 6.75 mmol) in DMSO (10 mL) was added t-BuOK (1.14 g, 10.1 mmol), and the mixture was then stirred at 60 °C for 2 h. The reaction mixture was diluted with saturated aqueous NH4Cl (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.

[0264] Steps 2 and 3: (1R,2S,3S and 1S,2R,3R)-3-(benzyloxy)-2-methylcyclobutan-1-ol 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 EtO (40 mL) was added dropwise 2,2,2-trichloroacetyl chloride (4.91 g, 27.0 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 0.5 h and then added to a mixture of saturated aqueous NH Cl (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 SO , filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE / EA = 50 / 1 to 30 / 1) to give a mixture of (2S,3S and 2R,3R)-3-(benzyloxy)-2-methylcyclobutan-1-one and (2S,3R and 2R,3S)-3-(benzyloxy)-2-methylcyclobutan-1-one (660 mg, 26% yield) as a colorless oil. The mixture of diastereomers (460 mg, 2.42 mmol) was dissolved in THF (10 mL) and NaBH (183 mg, 4.84 mmol) was added. The reaction mixture was stirred at 25 °C for 2 h, then diluted with HO (20 mL) and extracted with EA (50 mL). The organic layer was dried in vacuo to give the title compound (450 mg, 97% yield, not a pure diastereomer) as a colorless oil, which was used in the next step without further purification.

[0265] Step 4: (1R,2R,3S and 1S,2S,3R)-3-(benzyloxy)-2-methylcyclobutyl methanesulfonate To a mixture of (1R,2S,3S and 1S,2R,3R)-3-(benzyloxy)-2-methylcyclobutan-1-ol (450 mg, 2.34 mmol) and TEA (474 ​​mg, 4.68 mmol) in DCM (10 mL) was added MsCl (402 mg, 3.51 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h, then diluted with EA (50 mL) and washed with saturated aqueous NH4Cl (3 × 50 mL). The organic layer was concentrated to give the title compound (600 mg, crude) as a colorless oil, which was used in the next step without further purification.

[0266] Step 5: ((1S,2R,3S and 1R,2S,3R)-3-(benzyloxy)-2-methylcyclobutyl)(methyl)sulfane A mixture of sodium methanethiolate (259 mg, 3.70 mmol) and (1R,2R,3S and 1S,2S,3R)-3-(benzyloxy)-2-methylcyclobutyl methanesulfonate (500 mg, 1.85 mmol) in DMF (10 mL) was stirred for 2 h at 25° C. 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.

[0267] Step 6: (1S,2R,3S and 1R,2S,3R)-2-methyl-3-(methylthio)cyclobutan-1-ol To a solution of ((1S,2R,3S and 1R,2S,3R)-3-(benzyloxy)-2-methylcyclobutyl)(methyl)sulfane (420 mg, 1.89 mmol) in DCM (5 mL) was added BCl (2.37 g, 20.2 mmol). The reaction mixture was stirred at 25 °C for 2 h, then methanol was added, and the mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel (PE / EA = 5 / 1 followed by MeOH) to give the title compound (180 mg, 72% yield) as a yellow oil.

[0268] Step 7: 4-(2-azidopropan-2-yl)-6-chloro-1-((1S,2R,3S and 1R,2S,3R)-2-methyl-3-(methylthio)cyclobutoxy)-2,7-naphthyridine To a solution of (1S,2R,3S and 1R,2S,3R)-2-methyl-3-(methylthio)cyclobutan-1-ol (180 mg, 1.36 mmol) in THF (10 mL) was added NaH (136 mg, 3.40 mmol, 60% pure), and the mixture was stirred at 25 °C for 0.5 h, followed by the addition of 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine (384 mg, 1.36 mmol) in THF (10 mL). The mixture was stirred at 25 °C for 1 h, then quenched with water (20 mL) and extracted with EA (15 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated to give a residue. The residue was purified by column chromatography on silica gel (PE / EA=20 / 1 to 5 / 1), and then further purified by preparative HPLC (column: Phenomenex Luna C18 150×25 mm×10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 70% to 100%, 10 min) to give the title compound (130 mg, 48% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): 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).

[0269] Step 8: 4-(2-azidopropan-2-yl)-6-chloro-1-((1S,2R,3S and 1R,2S,3R)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine To a mixture of 4-(2-azidopropan-2-yl)-6-chloro-1-((1S,2R,3S and 1R,2S,3R)-2-methyl-3-(methylthio)cyclobutoxy)-2,7-naphthyridine (130 mg, 344.01 umol), NaHCO (231 mg, 2.75 mmol, 107 uL) in THF (10 mL) and HO (4 mL) was added Oxone (529 mg, 860 umol). The reaction mixture was stirred at 25 °C for 1.5 h and then diluted with EA (50 mL) and HO (30 mL). The organic layer was dried over NaSO, filtered, and concentrated to give the title compound (120 mg, 85% yield) as a colorless oil. MS (ES+) C 17 H 20 ClN5O3S theoretical value: 409, measured value: 410 [M+H] + .

[0270] [ka] Intermediate 38: 4-(2-azidopropan-2-yl)-6-chloro-1-((1S,2R,3R and 1R,2S,3S)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine [ka] Step 1: (1S,2R,3S and 1R,2S,3R)-3-(benzyloxy)-2-methylcyclobutyl 4-nitrobenzoate To a solution of (1R,2S,3S and 1S,2R,3R)-3-(benzyloxy)-2-methylcyclobutan-1-ol (1.4 g, 7.28 mmol), 4-nitrobenzoic acid (2.43 g, 14.6 mmol), and PPh (5.73 g, 21.9 mmol) in THF (30 mL) was added dropwise DIAD (4.42 g, 21.9 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h, then diluted with saturated aqueous NH Cl (50 mL) and extracted with EA (150 mL). The organic layer was dried over Na SO , filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO, PE / EA = 20 / 1) to give the title compound (2 g, 80% yield) as a colorless oil.

[0271] Step 2: (1S,2S,3S)-3-(benzyloxy)-2-methylcyclobutan-1-ol and (1R,2R,3R)-3-(benzyloxy)-2-methylcyclobutan-1-ol To a solution of (1S,2R,3S and 1R,2S,3R)-3-(benzyloxy)-2-methylcyclobutyl 4-nitrobenzoate (2.0 g, 5.86 mmol) in THF (15 mL) and HO (5 mL) was added LiOH·HO (2.46 g, 58.6 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 1 h and then at 60 °C for 1 h. The reaction mixture was then diluted with aqueous NaHCO (50 mL) and EA (100 mL). The organic layer was washed with saturated aqueous NaHCO (3 × 50 mL), dried over NaSO, filtered, and concentrated to give the title compound (1.02 g, 90% yield) as a colorless oil.

[0272] Steps 3-7: 4-(2-azidopropan-2-yl)-6-chloro-1-((1S,2R,3R and 1R,2S,3S)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared from (1S,2S,3S)-3-(benzyloxy)-2-methylcyclobutan-1-ol and (1R,2R,3R)-3-(benzyloxy)-2-methylcyclobutan-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 x 40 mm x 15 um; mobile phase: [water (0.225% FA)-ACN]; B%: 78%-88%, 10 min) to remove the minor stereoisomer. MS (ES+) C 17 H 20 ClN5O3S theoretical value: 409, measured value: 410 [M+H] + .

[0273] [ka] Intermediates 39 and 40: 4-(2-azidopropan-2-yl)-6-chloro-1-((1S,2R,3R)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine and 4-(2-azidopropan-2-yl)-6-chloro-1-((1R,2S,3S)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine [ka] Each of them is represented by one of the structures shown below. [ka] Step 1: 4-(2-azidopropan-2-yl)-6-chloro-1-((1S,2R,3R)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine and 4-(2-azidopropan-2-yl)-6-chloro-1-((1R,2S,3S)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine rac-4-(2-azidopropan-2-yl)-6-chloro-1-((1S,2R,3R and 1R,2S,3S)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine (190 mg, 464 µmol) was separated by chiral SFC (column: Daicel ChiralPak IG (250 × 30 mm, 10 µm); mobile phase: [0.1% NH3HO MeOH]; B%: 40%-40%) to give peaks. The first peak (intermediate 39, 50 mg, 26% yield) was isolated as a white solid, and the second peak (intermediate 40, 57 mg, 30% yield) was isolated as a white solid. Intermediate 39: MS(ES+)C 17 H 20 Theoretical value of ClN5O3: 409, Measured value: 410 [M+H] + . Intermediate 40: MS(ES+)C 17 H 20 Theoretical value of ClN5O3: 409, Measured value: 410 [M+H] + .

[0274] [ka] Intermediates 41 and 42: cis-4-(2-azidopropan-2-yl)-6-chloro-1-((-3-(methylsulfonyl)cyclopentyl)oxy)-2,7-naphthyridine and trans-4-(2-azidopropan-2-yl)-6-chloro-1-((-3-(methylsulfonyl)cyclopentyl)oxy)-2,7-naphthyridine [ka] Step 1: 3-(methylthio)cyclopentan-1-one To a solution of cyclopent-2-en-1-one (10.0 g, 122 mmol) in ACN (100 mL) was added AcOH (8.05 g, 134 mmol) in one portion at 0 °C, and then sodium methanethiolate (17.7 g, 253 mmol) in water (50 mL) was added dropwise to the solution at 0 °C. The reaction mixture was stirred at 60 °C for 1.5 h, 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 a residue. The residue was purified by column chromatography on silica gel (PE / EA = 10:1 to 1:1) to give the title compound (15.0 g, 95% yield) as a yellow oil.

[0275] Step 2: 3-(methylthio)cyclopentan-1-ol To a solution of 3-(methylthio)cyclopentan-1-one (2.00 g, 15.4 mmol) in MeOH (20 mL) was added NaBH (1.16 g, 30.7 mmol) portionwise. The reaction mixture was stirred at 25 °C for 2 h, 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 a residue. The residue was purified by column chromatography on silica gel (PE:EA = 10:1 to 1:1) and concentrated in vacuo to give the title compound (1.50 g, 74% yield) as a yellow oil.

[0276] Steps 3 and 4: cis-4-(2-azidopropan-2-yl)-6-chloro-1-((-3-(methylsulfonyl)cyclopentyl)oxy)-2,7-naphthyridine and trans-4-(2-azidopropan-2-yl)-6-chloro-1-((-3-(methylsulfonyl)cyclopentyl)oxy)-2,7-naphthyridine The title compound was prepared from 3-(methylthio)cyclopentan-1-ol and 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine using a procedure similar to that described in Steps 1 and 2 of Intermediate 21. The cis and trans isomers were separated by preparative TLC (PE / EA=1:1) to give Intermediate 42 (racemic trans isomer, 100 mg, 16% yield) and Intermediate 41 (racemic cis isomer, 100 mg, 16% yield). Intermediate 41: MS(ES+)C 17 H 20 ClN5O3S theoretical value: 409, measured value: 410 [M+H] + . Intermediate 42: 1 H 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+)C 17 H 20 ClN5O3S theoretical value: 409, measured value: 410 [M+H] + .

[0277] [ka] Intermediate 43: 3-(((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)methyl)tetrahydrothiophene 1,1-dioxide [ka] Step 1: 3-(((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)methyl)tetrahydrothiophene 1,1-dioxide The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine and 3-(hydroxymethyl)tetrahydrothiophene 1,1-dioxide using a procedure similar to that described above for intermediate 22. MS(ES+)C 16 H 18 Theoretical value of ClN5O3S: 395, Measured value: 396 [M+H] + .

[0278] [ka] Intermediate 44: 4-(2-azidopropan-2-yl)-6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridine [ka] Step 1: (cis-3-(benzyloxy)cyclobutyl)(ethyl)sulfane To a solution of trans-3-(benzyloxy)cyclobutyl methanesulfonate (0.5 g, 1.95 mmol) in DMF (2 mL) was added sodium ethanethiolate (328 mg, 3.90 mmol). 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 layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a 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.

[0279] Steps 2-4: 4-(2-azidopropan-2-yl)-6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared using procedures similar to those described in steps 5-7 of Intermediate 32.

[0280] [ka] Intermediate 45: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridine [ka] Step 1: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared from (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine and cis-3-(ethylsulfonyl)cyclobutan-1-ol (described in the preparation of Intermediate 44) using a procedure similar to that described in Step 1 of Intermediate 22. MS (ES+) C 18 H 22 ClN5O3S theoretical value: 423, measured value: 424 [M+H] + .

[0281] [ka] Intermediate 46: (S)-N-(1-(6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide [ka] Step 1: 4-Bromo-6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared from 4-bromo-1,6-dichloro-2,7-naphthyridine and cis-3-(ethylsulfonyl)cyclobutan-1-ol (described in the preparation of Intermediate 44) using a procedure similar to that described in Step 1 of Intermediate 22.

[0282] Step 2: 6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-4-vinyl-2,7-naphthyridine A mixture of 4-bromo-6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridine (1.35 g, 3.33 mmol, 1 equiv.), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (563.75 mg, 3.66 mmol, 620.87 µL, 1.1 equiv.), Pd(dppf)Cl (243.49 mg, 332.76 µmol, 0.1 equiv.), and KCO (919.82 mg, 6.66 mmol, 2 equiv.) in HO (2 mL) and dioxane (10 mL) was degassed and purged with N three times, and then the mixture was stirred at 80 °C for 2 h. The reaction mixture was then diluted with HO (100 mL) and extracted with EA (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue, which was purified by column chromatography (SiO, PE / EA=10 / 1 to 1 / 1) to give the title compound (700 mg, yield 60%) as a yellow oil.

[0283] Step 3: 6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridine-4-carbaldehyde Ozone was bubbled through a solution of 6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-4-vinyl-2,7-naphthyridine (700 mg, 1.98 mmol) in DCM (30 mL) at −78° C. for 10 min. The reaction mixture was then flushed with nitrogen and quenched with Me2S (1.02 mL, 13.89 mmol, 7 equiv.). The reaction mixture was warmed to 25° C., stirred for 50 min, and then concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1:0 to 1:1) to give the title compound (500 mg, 71% yield) as a yellow solid. MS (ES+) C 15 H 15 ClN2O4S theoretical value: 354, measured value: 355 [M+H] + .

[0284] Step 4: (S)—N-((E)-(6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide To a solution of 6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridine-4-carbaldehyde (0.85 g, 2.40 mmol, 1 equiv) and (S)-2-methylpropane-2-sulfinamide (435.53 mg, 3.59 mmol, 1.5 equiv) in THF (10 mL) was added Ti(Oi-Pr) (2.04 g, 7.19 mmol, 2.12 mL, 3 equiv). The mixture was stirred at 60 °C for 2 h, then quenched by the addition of HO (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 a residue. The residue was purified by column chromatography (SiO2, PE / EA=0 / 1 to 1 / 1) to give the title compound (1 g, yield 91%) as a yellow solid.

[0285] Step 4: (S)—N-(1-(6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide To a solution of compound (S)—N-((E)-(6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (300 mg, 655 umol, 1 equiv.) in THF (10 mL) was added EtMgBr (3 M, 655 uL, 3 equiv.) at 0° C. The reaction mixture was stirred at 25° C. for 15 min, then quenched by the addition of aqueous ammonium chloride (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) as a yellow oil, which was used in the next step without further purification. MS (ES+) C 21 H 30 ClN3O4S2 theoretical value: 487, measured value: 488 [M+H]+ .

[0286] [ka] Intermediate 47: 4-(2-azidopropan-2-yl)-6-chloro-1-(3-((methylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine [ka] Step 1: (3-(benzyloxy)cyclobutyl)methanol To a solution of methyl 3-(benzyloxy)cyclobutane-1-carboxylate (2 g, 9.08 mmol) in THF (60 mL) was added LiAlH (689 mg, 18.16 mmol) at 0 °C. The reaction mixture was stirred at 0-25 °C for 1 h and then quenched by the addition of water (6 mL) and aqueous NaOH (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+) C 12 H 16 Theoretical value of O2: 192, Measured value: 193 [M+H] + .

[0287] Step 2: (3-(benzyloxy)cyclobutyl)methyl methanesulfonate The title compound was prepared from (3-(benzyloxy)cyclobutyl)methanol using a procedure similar to that described in Step 3 of Intermediate 30.

[0288] Step 3: ((3-(benzyloxy)cyclobutyl)methyl)(methyl)sulfane To a solution of (3-(benzyloxy)cyclobutyl)methyl methanesulfonate (1.5 g, 5.55 mmol) in DMF (10 mL) was added MeSNa (1.82 g, 11.1 mmol). The reaction mixture was stirred at 100° C. for 1 h, 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 a 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 13 H 18 Theoretical OS value: 222, Measured value: 223 [M+H] + .

[0289] Steps 4-6: 4-(2-azidopropan-2-yl)-6-chloro-1-(3-((methylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared using a procedure similar to that described in steps 5-7 of Intermediate 32. MS (ES+) C 17 H 20 ClN5O3S theoretical value: 409, measured value: 410 [M+H] + .

[0290] [ka] Intermediates 48 and 49: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(cis-3-((methylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(trans-3-((methylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine [ka] Step 1: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(cis-3-((methylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(trans-3-((methylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared from 3-((methylsulfonyl)methyl)cyclobutan-1-ol and (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine using a procedure similar to that described in Step 1 of Intermediate 31. The mixture of diastereomers was separated by SFC (column: Daicel Chiralpak IG (250 × 30 mm, 10 μm); mobile phase: [0.1% NH₃HO ETOH]; B%: 60%-60%) to give Intermediate 48 (cis isomer, 220 mg, 63% yield) as a colorless oil and Intermediate 49 (trans isomer, 90 mg, 26% yield) as a colorless oil. Intermediate 48:MS(ES+)C 18 H 22 ClN5O3S theoretical value: 423, measured value: 424 [M+H] + . Intermediate 49:MS(ES+)C 18 H 22 ClN5O3S theoretical value: 423, measured value: 424 [M+H] + . [ka]

[0291] Intermediates 50 and 51: 4-((S)-2-azido-1-methoxypropan-2-yl)-6-chloro-1-(cis-3-((methylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine and 4-((S)-2-azido-1-methoxypropan-2-yl)-6-chloro-1-(trans-3-((methylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine [ka] Step 1: 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(cis-3-((methylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine and 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(trans-3-((methylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared from 3-((methylsulfonyl)methyl)cyclobutan-1-ol and (S)-4-(2-azido-1-methoxypropan-2-yl)-1,6-dichloro-2,7-naphthyridine (Intermediate 18) using a procedure similar to that described in Step 1 of Intermediate 31. The mixture of diastereomers was separated by SFC (Column: Daicel Chiralpak IG (250 × 30 mm, 10 μm); Mobile phase: [0.1% NH₃HO MeOH]; B%: 70%-70%) to give Intermediate 50 (cis isomer, 360 mg, 20% yield) as a yellow oil and Intermediate 51 (trans isomer, 120 mg, 6.50% yield) as a yellow oil. Intermediate 50: MS(ES+)C 18 H 22 ClN5O4S theoretical value: 439, measured value: 440 [M+H] + . Intermediate 51: MS(ES+)C 18 H 22 ClN5O4S theoretical value: 439, measured value: 440 [M+H] + .

[0292] [ka] Intermediate 52: 4-(2-azidopropan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine [ka] Step 1: (2R,4R)-4-((tert-butyldimethylsilyl)oxy)pentan-2-ol To a solution of (2R,4R)-pentane-2,4-diol (3.80 g, 36.5 mmol) in THF (120 mL) was added NaH (1.75 g, 43.8 mmol, 60% purity) at 0 °C. The reaction mixture was stirred for 30 min, and then tert-butyldimethylsilyl chloride (6.05 g, 40.1 mmol) was added, and the reaction mixture was stirred at 25 °C for 1.5 h. 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 give a residue. The residue was purified by silica gel column chromatography (PE / EA = 1:0 to 5:1) to give the title compound (7.80 g, 98% yield) as a colorless oil.

[0293] Step 2: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)pentan-2-yl 4-nitrobenzoate To a solution of (2R,4R)-4-((tert-butyldimethylsilyl)oxy)pentan-2-ol (1.00 g, 4.58 mmol), 4-nitrobenzoic acid (1.53 g, 9.16 mmol), and triphenylphosphine (3.60 g, 13.7 mmol) in THF (34 mL) was added DIAD (2.78 g, 13.74 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then at 25 °C for 15.5 h, diluted with water (50 mL), and extracted with EA (40 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by silica gel column chromatography (PE / EA = 1:0 to 10:1) to give the title compound (1.50 g, 78% yield) as a yellow oil.

[0294] Step 3: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)pentan-2-ol To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)pentan-2-yl 4-nitrobenzoate (1.50 g, 4.08 mmol) in THF (12 mL) and water (4 mL) was added LiOH·HO (977 mg, 40.8 mmol). The reaction mixture was stirred at 60 °C for 1 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 title compound (890 mg, 100% yield) as a yellow oil, which was used in the next step without further purification.

[0295] Step 4: (2S,4R)-4-((tert-butyldimethylsilyl)oxy)pentan-2-yl methanesulfonate To a solution of (2S,4R)-4-((tert-butyldimethylsilyl)oxy)pentan-2-ol (890 mg, 4.07 mmol) in DCM (15 mL) was added TEA (1.24 g, 12.2 mmol) and MsCl (934 mg, 8.15 mmol) at 0° C. The reaction mixture was stirred for 1 h, 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.

[0296] Step 5: tert-butyldimethyl(((2R,4R)-4-(methylthio)pentan-2-yl)oxy)silane To a solution of the compound (2S,4R)-4-((tert-butyldimethylsilyl)oxy)pentan-2-yl methanesulfonate (1.20 g, 4.05 mmol) in DMF (30 mL) was added sodium methanethiolate (709 mg, 10.1 mmol). 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.

[0297] Step 6: tert-butyldimethyl(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)silane To a solution of tert-butyldimethyl(((2R,4R)-4-(methylthio)pentan-2-yl)oxy)silane (1.00 g, 4.02 mmol) in THF (14 mL) and water (7 mL) was added Oxone® (4.95 g, 8.05 mmol). The reaction mixture was stirred at 25° C. for 0.5 h, then quenched by the addition of saturated aqueous sodium sulfite solution (30 mL) and extracted with EA (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound (1.10 g, 97% yield) as a yellow oil, which was used without further purification.

[0298] Step 7: (2R,4R)-4-(methylsulfonyl)pentan-2-ol To a solution of tert-butyldimethyl(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)silane (1.10 g, 3.92 mmol) in THF (8 mL) was added aqueous HCl (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 a residue. The residue was purified by silica gel column chromatography (PE / EA = 1:0 to 0:1) to give the title compound (230 mg, 35% yield) as a yellow oil.

[0299] Step 8: 4-(2-azidopropan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from (2R,4R)-4-(methylsulfonyl)pentan-2-ol and 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine using a procedure similar to that described in Step 1 of Intermediate 22. MS(ES+)C 17 H 22ClN5O3S theoretical value: 411, measured value: 412 [M+H] + .

[0300] [ka] Intermediate 53: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine [ka] Step 1: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from (2R,4R)-4-(methylsulfonyl)pentan-2-ol and (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine using a procedure similar to that described in Step 1 of Intermediate 22. MS(ES+)C 18 H 24 ClN5O3S theoretical value: 425, measured value: 426 [M+H] + .

[0301] [ka] Intermediate 54: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine [ka] Step 1: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from 4-(methylsulfonyl)butan-2-ol and (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine 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% NH₃HO IPA]; B%: 35%-35%) to give the title compound as the first eluting isomer. The stereochemistry was determined by chiral SFC analysis of this mixture and Intermediate 31, which was prepared from enantiomerically pure starting material.

[0302] [ka] Intermediate 55: (R)-4-(2-azidopropan-2-yl)-6-chloro-1-((4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine [ka] Step 1: (R)-4-(2-azidopropan-2-yl)-6-chloro-1-((4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine and (R)-4-(methylsulfonyl)butan-2-ol using a procedure similar to that described in Step 1 of Intermediate 22. MS(ES+)C 16 H 20 ClN5O3S theoretical value: 397, measured value: 398 [M+H] + .

[0303] [ka] Intermediates 56 and 57: 4-((R)-1-azido-1-cyclopropylethyl)-6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine and 4-((S)-1-azido-1-cyclopropylethyl)-6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine [ka] Each of them is represented by one of the structures shown below. [ka] Step 1: 1-(6-chloro-1-hydroxy-2,7-naphthyridin-4-yl)ethan-1-one To a solution of 1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-one (the title compound from Step 3 of Intermediate 17, 3.00 g, 12.7 mmol) in THF (30 mL) was added aqueous HCl (6 M, 20 mL). The reaction mixture was stirred at 25° C. for 16 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 (2.80 g, crude), which was used in the next step without further purification.

[0304] Step 2: 1-(1,6-dichloro-2,7-naphthyridin-4-yl)ethan-1-one 1-(6-Chloro-1-hydroxy-2,7-naphthyridin-4-yl)ethan-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 h. Then, it was cooled to room temperature and saturated aqueous sodium bicarbonate (500 mL) was slowly poured into it. 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 silica gel column chromatography (PE / EA = 1:0 to 3:1) to give the title compound (660 mg, 58% yield) as a white solid.

[0305] Step 3: 1-Cyclopropyl-1-(1,6-dichloro-2,7-naphthyridin-4-yl)ethan-1-ol To a solution of 1-(1,6-dichloro-2,7-naphthyridin-4-yl)ethan-1-one (600 mg, 2.49 mmol) in MTBE (200 mL) was added cyclopropylmagnesium bromide (0.5 M, 15 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 a residue. The residue was purified by silica gel column chromatography (PE / EA = 1:0 to 3:1) to give the title compound (550 mg, 78% yield) as a yellow solid.

[0306] Step 4: 1-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)-1-cyclopropylethan-1-ol To a solution of cis-3-(methylsulfonyl)cyclobutan-1-ol (167 mg, 1.11 mmol) in THF (20 mL) was added NaH (85.0 mg, 2.12 mmol, 60% purity) at 0° C. The reaction mixture was stirred at 0° C. for 15 min, then 1-cyclopropyl-1-(1,6-dichloro-2,7-naphthyridin-4-yl)ethan-1-ol (300 mg, 1.06 mmol) was added, and the mixture was stirred 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) as a yellow oil, which was used in the next step without further purification.

[0307] Step 5: 4-(1-azido-1-cyclopropylethyl)-6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine To a solution of 1-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)-1-cyclopropylethan-1-ol (390 mg, 983 μmol) in 1,2-DCE (10 mL) was added TMSN3 (340 mg, 2.95 mmol) and BF3.Et2O (279 mg, 1.97 mmol). The reaction mixture was stirred at 25 °C for 1 h, 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 a residue. The residue was purified by silica gel column chromatography (PE / EA = 1:0 to 0:1) to give the title compound (240 mg, 58% yield) as a yellow oil.

[0308] Step 6: 4-((R)-1-Azido-1-cyclopropylethyl)-6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine and 4-((S)-1-Azido-1-cyclopropylethyl)-6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine 4-(1-Azido-1-cyclopropylethyl)-6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine (240 mg, 569 μmol) was purified by SFC (column: Daicel Chiralpak AY-H (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH3H2O IPA]; B%: 40% to 40%, and either 4-((R)-1-azido-1-cyclopropylethyl)-6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine or 4-((S)-1-azido-1-cyclopropylethyl)-6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine was identified as the first eluting isomer (Intermediate 56, 110 mg, 45% yield). and the other of 4-((R)-1-azido-1-cyclopropylethyl)-6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine or 4-((S)-1-azido-1-cyclopropylethyl)-6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine as the second eluting isomer (Intermediate 57, 110 mg, 45% yield) as a yellow oil. Intermediate 56: MS(ES+)C 18 H 20 ClN5O3S theoretical value: 421, measured value: 422 [M+H] + . Intermediate 57: MS(ES+)C 18 H 20 ClN5O3S theoretical value: 421, measured value: 422 [M+H] + .

[0309] [ka] Intermediate 58: (S)-N-((6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)(cyclopropyl)methyl)-2-methylpropane-2-sulfinamide [ka] Steps 1-4: (S)-N-((E)-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide The title compound was prepared from 4-bromo-1,6-dichloro-2,7-naphthyridine and cis-3-(methylsulfonyl)cyclobutan-1-ol using a procedure similar to that described in steps 1-4 of Intermediate 46.

[0310] Step 5: (S)—N-((6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)(cyclopropyl)methyl)-2-methylpropane-2-sulfinamide To a solution of (S)-N-((E)-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (500 mg, 1.13 mmol) in MTBE (60 mL) was added cyclopropylmagnesium bromide (0.5 M, 10.0 mL). The reaction mixture was stirred at 60 °C for 0.5 h and then quenched by the addition of saturated aqueous NH4Cl (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 give a residue. The residue was purified by flash 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 21 H 28 Theoretical value of ClN3O4S2: 485, Measured value: 486 [M+H] + .

[0311] [ka] Intermediate 59: 5-(2-azidopropan-2-yl)-3-chloro-8-(cis-3-(ethylsulfonyl)cyclobutoxy)isoquinoline [ka] Steps 1-6: 5-(2-azidopropan-2-yl)-3-chloro-8-(cis-3-(ethylsulfonyl)cyclobutoxy)isoquinoline The title compound was prepared from cis-3-((5-bromo-3-chloroisoquinolin-8-yl)oxy)cyclobutane-1-thiol (Intermediate 35, Step 6) and ethyl iodide using a procedure similar to that described in Steps 7-12 of Intermediate 35. MS (ES+) C 18 H 21 ClN4O3S theoretical value: 408, measured value: 409 [M+H] + .

[0312] [ka] Intermediate 60: 4-(2-azidopropan-2-yl)-6-chloro-N-(cis-3-(ethylsulfonyl)cyclobutyl)-2,7-naphthyridin-1-amine [ka] Step 1: trans-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate To a solution of tert-butyl (trans-3-hydroxycyclobutyl)carbamate (2.00 g, 10.7 mmol) in DCM (20 mL) was added TEA (4.46 mL, 32.1 mmol) and MsCl (2.45 g, 21.4 mmol) in one portion at 0° C. The reaction mixture was stirred at 0° C. for 1 h, 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) as a yellow oil, which was used directly in the next step.

[0313] Step 2: tert-Butyl (cis-3-(ethylthio)cyclobutyl)carbamate To a solution of trans-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate (2.83 g, 10.7 mmol) in DMF (20 mL) was added sodium ethanethiolate (1.80 g, 21.3 mmol). The reaction mixture was stirred at 100° C. for 1 h, 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.

[0314] Step 3: tert-Butyl (cis-3-(ethylsulfonyl)cyclobutyl)carbamate To a solution of tert-butyl (cis-3-(ethylthio)cyclobutyl)carbamate (700 mg, 3.03 mmol) in THF (10 mL) and water (5 mL) was added Oxone® (1.86 g, 3.03 mmol). The reaction mixture was stirred at 25° C. for 1 h, 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 column chromatography on silica gel (PE / EA=10:1 to 1:1) to give the title compound (200 mg, 25% yield) as a yellow solid.

[0315] Step 4: cis-3-(ethylsulfonyl)cyclobutan-1-amine To a solution of tert-butyl (cis-3-(ethylsulfonyl)cyclobutyl)carbamate (150 mg, 570 umol) in dioxane (2 mL) was added HCl (4 M solution in dioxane, 427 uL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then concentrated to give the title compound (90 mg, crude) as a yellow oil, which was used in the next step without further purification.

[0316] Step 5: 4-(2-Azidopropan-2-yl)-6-chloro-N-(cis-3-(ethylsulfonyl)cyclobutyl)-2,7-naphthyridin-1-amine To a solution of cis-3-(ethylsulfonyl)cyclobutan-1-amine (90.0 mg, 551 μmol) and 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine (156 mg, 551 μmol) in NMP (1 mL) was added DIPEA (214 mg, 1.65 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 layer was washed with water (20 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE / EA=10:1 to 1:1) to give the title compound (150 mg, 67% yield) as a yellow oil. MS (ES+) C 17 H 21 ClN6O2S theoretical value: 409, measured value: 410 [M+H] + .

[0317] [ka] Intermediates 61 and 62: (S)-N-((S)-1-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide and (S)-N-((R)-1-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide [ka] Each of them is represented by one of the structures shown below. [ka] Step 1: (S)—N-((S)-1-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide and (S)—N-((R)-1-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide To a solution of (S)-N-((E)-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (the title compound obtained from Step 4 of Intermediate 58, 200 mg, 450 umol) in toluene (10 mL) was added n-PrMgBr (2 M, 1.13 mL) at 25° C. The reaction mixture was stirred at 25° C. for 30 min and then quenched by the addition of saturated aqueous ammonium chloride 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 a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 The mixture was purified using a 150×25 mm×10 μm column; mobile phase: [water (0.225% FA)-ACN]; B%: 40% to 70%. The first eluted isomer (Intermediate 6) was either (S)-N-((S)-1-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide or (S)-N-((R)-1-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide. 1, 25 mg, 5.5% yield) as a white solid and the other of (S)—N-((S)-1-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide or (S)—N-((R)-1-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide as the second eluting isomer (Intermediate 62, 30 mg, 6.7% yield) as a white solid. Intermediate 61: MS(ES+)C 21 H 30 ClN3O4S2 theoretical value: 487, measured value: 488 [M+H] + . Intermediate 62: MS(ES+)C 21 H 30ClN3O4S2 theoretical value: 487, measured value: 488 [M+H] + .

[0318] [ka] Intermediates 63 and 64: trans-3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-N,N-dimethylcyclobutane-1-sulfonamide and cis-3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-N,N-dimethylcyclobutane-1-sulfonamide [ka] Step 1: S-(3-(benzyloxy)cyclobutyl)ethanethioate To a solution of compound 3-(benzyloxy)cyclobutyl 4-methylbenzenesulfonate (1.00 g, 3.01 mmol) in ACN (1 mL) and DMF (4 mL) was added potassium ethanethiolate (2.63 g, 23.0 mmol). 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 layer was 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.

[0319] Steps 2 and 3: trans-3-(benzyloxy)-N,N-dimethylcyclobutane-1-sulfonamide and cis-3-(benzyloxy)-N,N-dimethylcyclobutane-1-sulfonamide To a solution of S-(3-(benzyloxy)cyclobutyl)ethanethioate (400 mg, 1.69 mmol) in ACN (20 mL) and concentrated HCl (845 mg, 8.46 mmol) was added NCS (1.02 g, 7.62 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 3 h, 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 in vacuo to give a residue. Dimethylamine (2 M, 3.39 mL) was then added to the residue, and the reaction mixture was stirred at 25° C. for 12 h. 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-(benzyloxy)-N,N-dimethylcyclobutane-1-sulfonamide (200 mg, 44% yield) as a yellow solid and cis-3-(benzyloxy)-N,N-dimethylcyclobutane-1-sulfonamide (200 mg, 44% yield) as a yellow solid. trans-3-(benzyloxy)-N,N-dimethylcyclobutane-1-sulfonamide: 1 H NMR (400 MHz, CDCl3): δ ppm7.37-7.28 (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). cis-3-(benzyloxy)-N,N-dimethylcyclobutane-1-sulfonamide: 1 H NMR (400 MHz, CDCl3): δ ppm7.30-7.22 (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).

[0320] Step 4: trans-3-Hydroxy-N,N-dimethylcyclobutane-1-sulfonamide To a solution of trans-3-(benzyloxy)-N,N-dimethylcyclobutane-1-sulfonamide (200 mg, 743 μmol) in methanol (10 mL) was added Pd / C (5 mg, 74.25 μmol). The reaction mixture was stirred under hydrogen (15 Psi) at 25° C. for 12 hours, then filtered and concentrated to give the title compound (120 mg, 90% yield) as a yellow solid.

[0321] Step 5: trans-3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-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-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine using a procedure similar to that described in Step 1 of Intermediate 22.

[0322] Step 6: cis-3-Hydroxy-N,N-dimethylcyclobutane-1-sulfonamide The title compound was prepared from cis-3-(benzyloxy)-N,N-dimethylcyclobutane-1-sulfonamide using a procedure similar to that described above in Step 4 for the trans isomer.

[0323] Step 7: cis-3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-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-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine using a procedure similar to that described in Step 1 of Intermediate 22. [ka]

[0324] Intermediate 65: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((1-(methylsulfonyl)pentan-3-yl)oxy)-2,7-naphthyridine [ka] Step 1: 1-(methylthio)pentan-3-one To a solution of pent-1-en-3-one (1 g, 11.9 mmol) in ACN (10 mL) and water (10 mL) were added AcOH (785 mg, 13.1 mmol) and sodium methanethiolate (1.25 g, 17.8 mmol). The reaction mixture was stirred at 60 °C for 1 h, 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 a residue. The residue was purified by silica gel column chromatography (PE / EA = 1:0 to 50:1) to give the title compound (1.10 g, 70% yield) as a yellow oil.

[0325] Step 2: 1-(methylsulfonyl)pentan-3-one To a solution of 1-(methylthio)pentan-3-one (1.1 g, 8.32 mmol) in THF (40 mL) and water (20 mL) was added Oxone® (6.14 g, 9.98 mmol). The reaction mixture was stirred at 25° C. for 2 h, then diluted with water (50 mL) and extracted with EA (50 mL×3). The combined organic layers were washed with 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.

[0326] Step 3: 1-(methylsulfonyl)pentan-3-ol To a solution of 1-(methylsulfonyl)pentan-3-one (2.60 g, 1.30 mmol) in MeOH (50 mL) was slowly added NaBH (449 mg, 11.9 mmol). 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.

[0327] Step 4: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((1-(methylsulfonyl)pentan-3-yl)oxy)-2,7-naphthyridine The title compound was prepared from 1-(methylsulfonyl)pentan-3-ol and (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine using a procedure similar to that described in Step 1 of Intermediate 22. MS(ES+)C 18 H 24 ClN5O3S theoretical value: 425, measured value: 426 [M+H] + . [ka]

[0328] Intermediates 66 and 67: 4-((R)-2-azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((S)-2-azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine [ka] Each of them is represented by one of the structures shown below. [ka] Steps 1-3: 4-(2-azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from 1-(1,6-dichloro-2,7-naphthyridin-4-yl)ethan-1-one (the title compound obtained from Step 2 of Intermediate 56) and n-PrMgBr using procedures similar to those described in Steps 3-5 of Intermediates 56 and 57.

[0329] Step 4: 4-((R)-2-azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((S)-2-azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine 4-(2-azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine (300 mg, 682 μmol) was purified by SFC (column: Daicel Chiralpak IC (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH3H2O IPA]; B%: 60% to 60%, and either 4-((R)-2-azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine or 4-((S)-2-azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine was identified as the first eluting isomer (Intermediate 66, 135 mg, 44% yield). and the other of 4-((R)-2-azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine or 4-((S)-2-azidopentan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine as the second eluting isomer (Intermediate 67, 120 mg, 40% yield) as a yellow solid. Intermediate 66: MS(ES+)C 19 H 26 ClN5O3S theoretical value: 439, measured value: 440 [M+H] + . Intermediate 67: MS(ES+)C 19 H 26 ClN5O3S theoretical value: 439, measured value: 440 [M+H] + .

[0330] [ka] Intermediates 68 and 69: 4-((R)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine and 4-((S)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine [ka] Each of them is represented by one of the structures shown below. [ka] Steps 1-2: 4-(2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from 2-(1,6-dichloro-2,7-naphthyridin-4-yl)pentan-2-ol (the title compound from Step 1 of Intermediate 66) and (R)-4-(methylsulfonyl)butan-2-ol using procedures similar to those described in Steps 4-5 of Intermediates 56 and 57.

[0331] Step 3: 4-((R)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine and 4-((S)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine 4-(2-Azidopentan-2-yl)-6-chloro-1-(((R)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine (350 mg, 822 μmol) was purified by SFC (column: DAICEL Chiralpak AD (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH3H2O IPA]; B%: 70% to 70%, to give either 4-((R)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine or 4-((S)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine as the first eluting isomer (Intermediate 68, 185 mg, 52% yield). The other of 4-((R)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine or 4-((S)-2-azidopentan-2-yl)-6-chloro-1-(((R)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine was obtained as a colorless oil as the second eluting isomer (Intermediate 69, 190 mg, 54% yield). Intermediate 68:MS(ES+)C 18 H 24 ClN5O3S theoretical value: 425, measured value: 426 [M+H] + . Intermediate 69:MS(ES+)C 18 H 24 ClN5O3S theoretical value: 425, measured value: 426 [M+H] + .

[0332] [ka] Intermediate 70: 4-(2-azidopropan-2-yl)-6-chloro-1-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine [ka] Step 1: tert-butyl(((2R,4R)-4-(ethylthio)pentan-2-yl)oxy)dimethylsilane To a solution of EtSH (1.94 g, 31.2 mmol) in DMSO (40 mL) was added NaOH (1.08 g, 27.0 mmol) at 25° C. The suspension was stirred at 25° C. for 0.5 h, and then (2S,4R)-4-((tert-butyldimethylsilyl)oxy)pentan-2-yl methanesulfonate (4 g, 13.5 mmol) in DMSO (10 mL) 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 water-brine (40 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (3.6 g, crude) as a white oil, which was used directly in the next step.

[0333] Steps 2-4: 4-(2-azidopropan-2-yl)-6-chloro-1-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from tert-butyl(((2R,4R)-4-(ethylthio)pentan-2-yl)oxy)dimethylsilane using procedures similar to those described in Steps 6 and 7 of Intermediate 52 and Step 1 of Intermediate 22. MS(ES+)C 18 H 24 ClN5O3S theoretical value: 425, measured value: 426 [M+H] + .

[0334] [ka] Intermediate 71: 4-(2-azidopropan-2-yl)-6-chloro-1-((4-(ethylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine [ka] Steps 1-4: 4-(2-azidopropan-2-yl)-6-chloro-1-((4-(ethylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from sodium ethanethiolate and but-3-en-2-one using procedures similar to those described in Steps 1-3 of Intermediate 65 and Step 1 of Intermediate 22. MS(ES+)C 17 H 22 ClN5O3S theoretical value: 411, measured value: 412 [M+H] + . [ka]

[0335] Intermediates 72 and 73: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-(ethylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-(ethylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine [ka] Each of them is represented by one of the structures shown below. [ka] Step 1: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((4-(ethylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine and 4-(ethylsulfonyl)butan-2-ol using a procedure similar to that described in Step 1 of Intermediate 22.

[0336] Step 2: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-(ethylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-(ethylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((4-(ethylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine (370 mg, 869 μmol) was purified by SFC (column: Daicel Chiralpak IG (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH3H2O IPA]; B%: 70% to 70%, to give either 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-(ethylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine or 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-(ethylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine as the first eluting isomer (Intermediate 72, 140 mg, 38% yield). The second eluting isomer (Intermediate 73, 135 mg, 36% yield) was obtained as a colorless oil, and the other of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-(ethylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine or 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-(ethylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine was obtained as a colorless oil. Intermediate 72: MS(ES+)C 18 H 24 ClN5O3S theoretical value: 425, measured value: 426 [M+H] + . Intermediate 73: MS(ES+)C 18 H 24 ClN5O3S theoretical value: 425, measured value: 426 [M+H] + . [ka]

[0337] Intermediate 74: (S)-N-((6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)(cyclopropyl)methyl)-2-methylpropane-2-sulfinamide [ka] Step 1: (S)—N-((6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)(cyclopropyl)methyl)-2-methylpropane-2-sulfinamide To a solution of (S)-N-((E)-(6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (300 mg, 655 μmol) in toluene (30 mL) was added cyclopropylmagnesium bromide (0.5 M, 6.55 mL) at 25° C. The reaction mixture was stirred at 25° C. for 0.5 h and then quenched by the addition of saturated aqueous ammonium chloride solution (20 mL). The mixture was diluted with water (10 mL) and extracted with EA (40 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by flash silica gel chromatography (PE / EA 1:0 to 0:1) to give the title compound (70 mg, 20% yield) as a yellow oil. MS (ES+) C 22 H 30 Theoretical value of ClN3O4S2: 499, Measured value: 500 [M+H] + . [ka]

[0338] Intermediate 75: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((4-(cyclopropylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine [ka] Step 1: S-(3-oxobutyl)ethanethioate To a solution of pyridine (11.3 g, 143 mmol) and AcOH (6.51 g, 108 mmol) in DCM (120 mL) was added but-3-en-2-one (5.00 g, 71.3 mmol) and potassium ethanethiolate (12.3 g, 108 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h, and then the reaction mixture was diluted with DCM (80 mL). The organic layer was washed with aqueous hydrochloric acid (1 M, 200 mL), saturated aqueous sodium bicarbonate (250 mL × 3), and brine (300 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1:0 to 3:1) to give the title compound (5.40 g, 52% yield) as a yellow oil.

[0339] Step 2: 4-Mercaptobutan-2-ol To a solution of S-(3-oxobutyl)ethanethioate (3.00 g, 20.52 mmol) in THF (60 mL) and MeOH (6 mL) was added NaBH (1.16 g, 30.8 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h, then diluted with HO (100 mL) and extracted with EA (80 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by silica gel column chromatography (PE / EA = 1:0 to 3:1) to give the title compound (2.00 g, 92% yield) as a yellow oil.

[0340] Step 3: 4-(cyclopropylthio)butan-2-ol To a solution of 4-mercaptobutan-2-ol (200 mg, 1.88 mmol) and bromocyclopropane (453 mg, 3.74 mmol) in DMSO (2 mL) was added potassium tert-butoxide (254 mg, 2.26 mmol). The reaction mixture was stirred at 80 °C for 1 h, then diluted with water (50 mL) and extracted with EA (30 mL × 3). The combined organic layer was washed with brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by silica gel column chromatography (PE / EA = 1:0 to 3:1) to give the title compound (150 mg, 54% yield) as a colorless oil.

[0341] Step 4: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((4-(cyclopropylthio)butan-2-yl)oxy)-2,7-naphthyridine To a solution of 4-(cyclopropylthio)butan-2-ol (30.0 mg, 205 μmol) in THF (10 mL) was added NaH (10.0 mg, 250 μmol, purity 60%) at 25°C. After 0.5 h, (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine (40.0 mg, 135 μmol) was added, and the reaction mixture was stirred at 25°C for 15.5 h. DMF (0.05 mL) was then added, and the reaction mixture was stirred at 60°C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EA (20 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 column chromatography (PE / EA = 1:0 to 3:1) to give the title compound (40.0 mg, yield 62%) as a yellow oil.

[0342] Step 5: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((4-(cyclopropylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine To a solution of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((4-(cyclopropylthio)butan-2-yl)oxy)-2,7-naphthyridine (70.0 mg, 172 μmol) in THF (10 mL) and HO (5 mL) was added Oxone® (212 mg, 345 μmol). The reaction mixture was stirred at 15° C. for 1 h, then quenched by the addition of saturated aqueous sodium sulfite solution (100 mL) and stirred at 25° C. for 10 min. The quenched reaction mixture was extracted with EA (50 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 column chromatography (PE / EA=1:0 to 1:1) to give the title compound (70.0 mg, 91% yield) as a yellow oil. MS (ES+) C 19 H 24 ClN5O3S theoretical value: 437, measured value: 438 [M+H] + .

[0343] [ka] Intermediates 76 and 77: 4-((R)-1-azido-1-cyclopropylethyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((S)-1-azido-1-cyclopropylethyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and [ka] Each of them is represented by one of the structures shown below. [ka] Steps 1-2: 4-(1-azido-1-cyclopropylethyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from 1-cyclopropyl-1-(1,6-dichloro-2,7-naphthyridin-4-yl)ethan-1-ol (the title compound obtained from Step 3 of Intermediate 56) and (2R,4R)-4-(methylsulfonyl)pentan-2-ol (Step 7, Intermediate 52) using procedures similar to those described in Steps 4 and 5 of Intermediates 56 and 57. MS (ES+) C 19 H 24 ClN5O3S theoretical value: 437, measured value: 438 [M+H] + .

[0344] Step 3: 4-((R)-1-azido-1-cyclopropylethyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((S)-1-azido-1-cyclopropylethyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine 4-(1-Azido-1-cyclopropylethyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine (360 mg, 822 μmol) was purified by SFC (column: Daicel Chiralpak IG (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH3H2O MeOH]; B%: 60% to 60%, and either 4-((R)-1-azido-1-cyclopropylethyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine or 4-((S)-1-azido-1-cyclopropylethyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine was obtained as the first eluting isomer (Intermediate 76, 120 mg, 32% yield). and the other of 4-((R)-1-azido-1-cyclopropylethyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine or 4-((S)-1-azido-1-cyclopropylethyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine as the second eluting isomer (Intermediate 77, 170 mg, 44% yield) as a yellow oil. Intermediate 76:MS(ES+)C 19 H 24 ClN5O3S theoretical value: 437, measured value: 438 [M+H] + . Intermediate 77:MS(ES+)C 19 H 24 ClN5O3S theoretical value: 437, measured value: 438 [M+H] + .

[0345] [ka] Intermediates 78 and 79: 4-((R)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((S)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine [ka] Each of them is represented by one of the structures shown below. [ka] Step 1: 4-Bromo-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from 4-bromo-1,6-dichloro-2,7-naphthyridine and (2R,4R)-4-(methylsulfonyl)pentan-2-ol using a procedure similar to that described in Step 1 of Intermediate 22.

[0346] Step 2: 6-chloro-4-(2-methylprop-1-en-1-yl)-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine A mixture of 4-bromo-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine (890 mg, 2.18 mmol, 1 equiv), 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane (397.44 mg, 2.18 mmol, 1 equiv), Pd(dppf)Cl (159.73 mg, 218.29 µmol, 0.1 equiv), and KCO (603.40 mg, 4.37 mmol, 2 equiv) in HO (2 mL) and dioxane (10 mL) was degassed and purged with N three times, then the mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with HO (80 mL) and extracted with EA (100 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO, PE / EA = 10 / 1 to 3 / 1) to give the title compound (620 mg, yield 74.18%) as a yellow oil.

[0347] Step 3: 6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine-4-carbaldehyde Ozone was bubbled through a solution of 6-chloro-4-(2-methylprop-1-en-1-yl)-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine (520 mg, 1.36 mmol, 1 equiv) in DCM (60 mL) and MeOH (6 mL) at −78° C. for 10 min. The reaction mixture was then flushed with nitrogen, and MeS (590.63 mg, 9.51 mmol, 698.14 uL, 7 equiv) was added to the mixture. The reaction mixture was warmed to 25° C., stirred for 50 min, and then concentrated to afford the title compound (580 mg, crude) as a yellow oil, which was used in the next step without further purification.

[0348] Step 4: (6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridin-4-yl)(cyclopropyl)methanol To a solution of 6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine-4-carbaldehyde (530 mg, 1.49 mmol, 1 equiv.) in THF (10 mL) was added cyclopropylmagnesium bromide (0.5 M, 5.94 mL, 2 equiv.) at 0° C. The reaction mixture was stirred at 25° C. for 30 minutes, then quenched by the addition of aqueous ammonium chloride (20 mL) at 25° C. and extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (580 mg, crude) as a yellow solid, which was used in the next step without further purification. MS (ES+) C 18 H 23 ClN2O4S theoretical value: 398, measured value: 399 [M+H] + .

[0349] Step 5: 4-(azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine To a solution of (6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridin-4-yl)(cyclopropyl)methanol (530 mg, 1.33 mmol, 1 equiv) in DCE (10 mL) was added TMSN3 (765.36 mg, 6.64 mmol, 873.70 μL, 5 equiv) and BF3.Et2O (377.15 mg, 2.66 mmol, 327.96 μL, 2 equiv). The mixture was stirred at 25 °C for 10 min, then diluted with HO (30 mL) and extracted with DCM (30 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / EA = 10 / 1 to 1 / 1) and preparative HPLC (column: Phenomenex Luna C18 150 x 40 mm x 15 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 44% to 74%, 11 min) to give the title compound (120 mg, 21% yield) as a pale yellow solid. MS (ES+) C 18 H 22ClNOS theoretical value: 423, measured value: 424 M+H] + .

[0350] Step 6: 4-((R)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((S)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine 4-(azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine (120 mg, 283 umol, 1 equiv.) was purified by SFC (column: Daicel Chiralpak IG (250 × 30 mm, 10 um); mobile phase: [0.1% NH3H2O MeOH]; B%: 70%-70%, to give either 4-((R)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine or 4-((S)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine as the first eluting isomer (Intermediate 78, 40 mg, 33% yield). and the other of 4-((R)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine or 4-((S)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine as the second eluting isomer (Intermediate 79, 35 mg, 29% yield) as a white solid. Intermediate 78:MS(ES+)C 18 H 22 ClN5O3S theoretical value: 423, measured value: 424 [M+H] + . Intermediate 79:MS(ES+)C 18 H 22ClN5O3S theoretical value: 423, measured value: 424 [M+H] + .

[0351] [ka] Intermediate 80: 4-(2-azidopropan-2-yl)-6-chloro-1-(3-((ethylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine [ka] Step 1: ((3-(benzyloxy)cyclobutyl)methyl)(ethyl)sulfane To a solution of (3-(benzyloxy)cyclobutyl)methyl methanesulfonate (2.4 g, 8.88 mmol, 1 equiv.) in DMF (30 mL) was added NaSEt (1.49 g, 17.76 mmol, 2 equiv.). The reaction mixture was stirred at 100° C. for 1 h and then quenched by adding saturated aqueous sodium hypochlorite solution (30 mL) at 25° C. The mixture was extracted with EA (50 mL×3), and the combined organic layers were washed with brine (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.6 g, crude) as a colorless oil, which was used in the next step without further purification.

[0352] Steps 2-4: 4-(2-azidopropan-2-yl)-6-chloro-1-(3-((ethylsulfonyl)methyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared using a procedure similar to that described in steps 5-7 of Intermediate 32. MS (ES+) C 18 H 22 ClN5O3S theoretical value: 423, measured value: 424 [M+H] + .

[0353] [ka] Intermediates 81 and 82: (S)-N-((S)-1-(6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide and (S)-N-((R)-1-(6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide [ka] Each of them is represented by the structure shown below. [ka] Step 1: (S)—N-((S)-1-(6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide and (S)—N-((R)-1-(6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide To a solution of (S)-N-((E)-(6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (300 mg, 655 umol) in toluene (20 mL) was added PrMgBr (2 M, 1.64 mL) at 25° C. The reaction mixture was stirred at 25° C. for 1 h, and then saturated aqueous ammonium chloride solution (20 mL) was added. The mixture was diluted with water (10 mL) and extracted with EA (40 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 The mixture was purified using a 75×30 mm×3 μm column; mobile phase: [water (0.225% FA)-ACN]; B%: 48% to 58%. The first elution isomer ( Intermediate 81, 50 mg, 15% yield, and the other of (S)—N-((S)-1-(6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide or (S)—N-((R)-1-(6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide as the second eluting isomer (Intermediate 82, 40 mg, 12% yield) were obtained as white solids. Intermediate 81: MS(ES+)C 22 H 32 Theoretical value of ClN3O4S2: 501, Measured value: 502 [M+H] + . Intermediate 82: MS(ES+)C 22 H 32 Theoretical value of ClN3O4S2: 501, Measured value: 502 [M+H] + .

[0354] [ka] Intermediate 83: 4-(2-azidopropan-2-yl)-6-chloro-1-(cis-3-(isopropylsulfonyl)cyclobutoxy)-2,7-naphthyridine [ka] Step 1: (cis-3-(benzyloxy)cyclobutyl)(isopropyl)sulfane To a solution of propane-2-thiol (579 mg, 7.61 mmol) in DMF (30 mL) was added t-BuOK (1.14 g, 10.1 mmol) at −10° C. The reaction mixture was stirred at −10° C. for 0.5 h, and then trans-3-(benzyloxy)cyclobutyl methanesulfonate (1.3 g, 5.07 mmol) in DMF (3 mL) was added. The reaction mixture was stirred at −10 to 0° C. for 3 h, then diluted with saturated aqueous NH4Cl (300 mL) and extracted with EA (200 mL). The organic layer was washed with brine (3 × 50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 40 mm × 15 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 65% to 72%, 10 min) to give the title compound (311 mg, 26% yield) as a colorless oil.

[0355] Steps 2-4: 4-(2-azidopropan-2-yl)-6-chloro-1-(cis-3-(isopropylsulfonyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared using a procedure similar to those described in steps 5-7 of Intermediate 32. [ka]

[0356] Intermediate 84: 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridine [ka] Step 1: 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared from (S)-4-(2-azido-1-methoxypropan-2-yl)-1,6-dichloro-2,7-naphthyridine and cis-3-(ethylsulfonyl)cyclobutan-1-ol using a procedure similar to that described above for Intermediate 22. MS(ES+)C 18 H 22 ClN5O4S theoretical value: 439, measured value: 440 [M+H] + .

[0357] [ka] Intermediate 85: 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine [ka] Step 1: 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared from (S)-4-(2-azido-1-methoxypropan-2-yl)-1,6-dichloro-2,7-naphthyridine and cis-3-(methylsulfonyl)cyclobutan-1-ol using a procedure similar to that described above for Intermediate 22. MS(ES+)C 17 H 20 ClN5O4S theoretical value: 425, measured value: 426 [M+H] + .

[0358] [ka] Intermediate 86: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine [ka] Step 2: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine and (2R,4R)-4-(ethylsulfonyl)pentan-2-ol (Step 7, Intermediate 52) using a procedure similar to that described in Step 1 of Intermediate 22. MS (ES+) C 19 H 26 ClN5O3S theoretical value: 439, measured value: 440 [M+H] + .

[0359] [ka] Intermediate 87: 4-(2-azidopropan-2-yl)-6-chloro-1-((4-(ethylsulfonyl)-3-methylbutan-2-yl)oxy)-2,7-naphthyridine [ka] Steps 1-4: 4-(2-azidopropan-2-yl)-6-chloro-1-((4-(ethylsulfonyl)-3-methylbutan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from sodium ethanethiolate and but-3-en-2-one using procedures similar to those described in Steps 1-3 of Intermediate 65 and Step 1 of Intermediate 22. MS(ES+)C 18 H 24 ClN5O3S theoretical value: 425, measured value: 426 [M+H]+ .

[0360] [ka] Intermediate 88: 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine [ka]

[0361] Intermediate 88: 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine [ka]

[0362] Step 1: 4-((S)-2-azido-1-methoxypropan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from (S)-4-(2-azido-1-methoxypropan-2-yl)-1,6-dichloro-2,7-naphthyridine and (2R,4R)-4-(methylsulfonyl)pentan-2-ol using a procedure similar to that described in Step 1 of Intermediate 22. MS(ES+)C 18 H 24 ClN5O4S theoretical value: 441, measured value: 442 [M+H] + .

[0363] [ka]

[0364] Step 1: 4-((S)-2-azido-1-methoxypropan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from (S)-4-(2-azido-1-methoxypropan-2-yl)-1,6-dichloro-2,7-naphthyridine and (2R,4R)-4-(methylsulfonyl)pentan-2-ol using a procedure similar to that described in Step 1 of Intermediate 22. MS(ES+)C 18 H 24 ClN5O4S theoretical value: 441, measured value: 442 [M+H] + .

[0365] [ka] Intermediates 89 and 90: 4-((R)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((S)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine [ka] Each of them is represented by the structure shown below. [ka] Steps 1-5: 4-(azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared using a procedure similar to those described in steps 1-5 of Intermediates 78 and 79.

[0366] Step 6: 4-((R)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((S)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine 4-(azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine (150 mg) was analyzed by SFC (Daicel Chiralpak AD-H (250 mm × 30 mm, 5 μm); mobile phase: [0.1% NH3H2O IPA]; B%: 30% to 30%, and either 4-((R)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine or 4-((S)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine was identified as the first eluting isomer (Intermediate 89, 70 mg). and the other of 4-((R)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine or 4-((S)-azido(cyclopropyl)methyl)-6-chloro-1-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine as the second eluting isomer (Intermediate 90, 70 mg) as a white solid.

[0367] [ka] Intermediate 91: 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(cis-3-(cyclopropylsulfonyl)cyclobutoxy)-2,7-naphthyridine [ka] Step 1: 4-((S)-2-Azido-1-methoxypropan-2-yl)-6-chloro-1-(cis-3-(cyclopropylsulfonyl)cyclobutoxy)-2,7-naphthyridine The title compound was prepared from (S)-4-(2-azido-1-methoxypropan-2-yl)-1,6-dichloro-2,7-naphthyridine and cis-3-(cyclopropylsulfonyl)cyclobutan-1-ol using a procedure similar to that described in Step 1 of Intermediate 22. MS(ES+)C 19 H 22 ClN5O4S theoretical value: 451, measured value: 452 [M+H] + .

[0368] [ka] Intermediate 92: 2-(2-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)propyl)tetrahydrothiophene 1,1-dioxide [ka] Step 1: 2-(2-hydroxyethyl)tetrahydrothiophene 1,1-dioxide To a solution of 2-(tetrahydrothiophen-2-yl)ethan-1-ol (1 g, 7.56 mmol) in THF (18 mL) and water (6 mL) was added Oxone® (9.30 g, 15.1 mmol). The reaction mixture was stirred at 25° C. for 1 h and then quenched by the addition of saturated aqueous sodium sulfite 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 give the title compound (750 mg, crude) as a colorless solid. MS (ES+) CH 12 Theoretical value of O3S: 164, Measured value: 165 [M+H] + .

[0369] Step 2: 2-(1,1-dioxidetetrahydrothiophen-2-yl)acetaldehyde To a solution of DMSO (1.43 g, 18.3 mmol, 1.43 mL) in DCM (30 mL) was added oxalyl chloride (1.74 g, 13.7 mmol, 1.20 mL) at −78° C. The reaction mixture was stirred at −78° C. for 20 min, followed by the addition of 2-(2-hydroxyethyl)tetrahydrothiophene 1,1-dioxide (750 mg, 4.57 mmol) in DCM (10 mL). The reaction mixture was stirred at −78° C. for another 20 min, followed by the dropwise addition of TEA (2.77 g, 27.4 mmol) in DCM (10 mL) while maintaining the temperature below −60° C. After the addition, the mixture was stirred at −78° C. for 20 min, 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 title compound (1.1 g, crude) as a colorless oil, which was used in the next step without purification.

[0370] Step 3: 2-(2-hydroxypropyl)tetrahydrothiophene 1,1-dioxide To a solution of 2-(1,1-dioxidetetrahydrothiophen-2-yl)acetaldehyde (1 g, 6.16 mmol) in THF (30 mL) was added MeMgBr (3 M, 6.16 mL) at 0 °C, and the mixture was then stirred at 0 °C for 0.5 h. The reaction mixture was diluted with water (40 mL) and extracted with EA (40 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / EA = 1 / 0 to 0 / 1) to give the title compound (270 mg, 25% yield) as a yellow oil. MS (ES+) CH 14 Theoretical value of O3S: 178, Measured value: 179 [M+H] + .

[0371] Step 4: 2-(2-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)propyl)tetrahydrothiophene 1,1-dioxide The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine and 2-(2-hydroxypropyl)tetrahydrothiophene 1,1-dioxide using a procedure similar to that described above for intermediate 22. MS(ES+)C 18 H 22 ClN5O3S theoretical value: 423, measured value: 424 [M+H] + .

[0372] [ka] Intermediates 93 and 94: (7R,8R)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and (7S,8S)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one [ka] Each of them is represented by one of the structures shown below. [ka] Each of them is represented by one of the structures shown below. [ka] It is represented by one of the structures shown below. [ka] Step 1: (7R,8R)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and (7S,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one rac-(7R,8R)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (reported in Step 5 of Intermediates 1 and 2) (6.0 g, 28.3 mmol) was separated by SFC (Daicel Chiralpak AD, MeOH gradient in CO containing 0.1% NH4OH) to give two separate peaks: the first eluting isomer (3 g, 50% yield) and the second eluting isomer (2.8 g, 46% yield) as yellow solids.

[0373] Steps 2 and 3: One of (7R,8R)- or (7S,8S)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (First eluting isomer of Step 1) The title compound (Intermediate 93) was prepared from either (7R,8R)- or (7S,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one using the same two-step procedure described in Steps 7 and 8 of Intermediate 1. 1 H-NMR (400 MHz, 6d-DMSO): δ ppm 7.76 (d, J= 8.8 Hz, 1H), 7.02 (s, 2H), 6.41 (d, J= 8.8 Hz, 1H), 4.70 (d, J = 3.2, 6.4 Hz, 1H), 2.77-2.66 (m, 1H), 1.31 (d, J= 6.8 Hz, 3H), 1.08 (d, J = 7.2 Hz, 3H). MS(ES+)C 10 H 12 Theoretical value of N2O2: 192, Measured value: 193 [M+H] + .

[0374] Steps 4 and 5: The remaining one of (7R,8R)- or (7S,8S)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one The title compound (Intermediate 94) was prepared from the remaining (7R,8R)- or (7S,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (the second eluting isomer from Step 1) using the same two-step procedure described in Steps 7 and 8 of Intermediate 1. MS(ES+)C 10 H 12 Theoretical value of N2O2: 192, Measured value: 193 [M+H] + .

[0375] [ka] Intermediates 95 and 96: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((1S,2R,3R)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((1R,2S,3R)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine [ka] Each of them is represented by one of the following structures: [ka] Step 1: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((1S,2R,3R)-2-methyl-3-(methylthio)cyclobutoxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((1R,2S,3S)-2-methyl-3-(methylthio)cyclobutoxy)-2,7-naphthyridine The title compound was prepared from rac-(1S,2R,3R)-2-methyl-3-(methylthio)cyclobutan-1-ol and (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine using a procedure similar to that described above for Intermediate 22. The title compound was not isolated but carried on to the next step. MS(ES+)C 18 H22 ClN5OS theoretical value: 391, measured value: 392 [M+H] + .

[0376] Step 2: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((1S,2R,3R)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((1R,2S,3R)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine To a mixture of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((1S,2R,3R)-2-methyl-3-(methylthio)cyclobutoxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((1R,2S,3S)-2-methyl-3-(methylthio)cyclobutoxy)-2,7-naphthyridine (730 mg, 1.86 mmol), NaHCO (1.25 g, 14.9 mmol) in THF (20 mL) and HO (4 mL) was added Oxone® (2.86 g, 4.66 mmol). The reaction mixture was stirred at 25 °C for 2 h, then filtered, diluted with water (20 mL), and extracted with EA (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was redissolved in a mixture of THF (20 mL) and HO (4 mL), and NaHCO3 (1.25 g, 14.9 mmol) and Oxone (2.86 g, 4.66 mmol) were added. The mixture was stirred at 25 °C for 1 h, then filtered, diluted with HO (20 mL), and extracted with EA (50 mL). The organic layer was dried to give a mixture of the title compounds (780 mg, 96% yield) as a colorless semisolid.The mixture was separated by chiral SFC (column: Daicel Chiralpak AD-H (250 mm × 30 mm, 5 μm); mobile phase: [0.1% NH₃H₂O IPA]; B%: 30%–30%) to give either 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((1S,2R,3R)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine or 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((1R,2S,3R)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine (first eluting isomer, intermediate 95, 240 mg, 31% yield). and the other of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((1S,2R,3R)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine or 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((1R,2S,3R)-2-methyl-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine (second eluting isomer, Intermediate 96, 260 mg, 33% yield) was obtained as a colorless semi-solid. Intermediate 95:MS(ES+)C 18 H 22 ClN5O3S theoretical value: 423, measured value: 424 [M+H] + . Intermediate 96:MS(ES+)C 18 H 22 ClN5O3S theoretical value: 423, measured value: 424 [M+H] + .

[0377] [ka] Intermediates 97 and 98: (R)-2-amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and (S)-2-amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one [ka] Steps 1-5: (rac)-2-amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one The title compound was prepared from 2-(3-bromo-6-chloropyridin-2-yl)-2-methylpropan-1-ol using a procedure similar to that described in steps 1-5 of Intermediate 12. 11 H 14 Theoretical value of N2O2: 206, Measured value: 207 [M+H] + .

[0378] Step 6: (R)-2-amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and (S)-2-amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (rac)-2-Amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (120 mg) was separated by SFC (Column: REGIS(s,s)WHELK-O1 (250 mm × 50 mm, 10 μm), MeOH gradient in CO containing 0.1% NH4OH) to give two separate peaks. One of the first eluting isomers, (R or S)-2-amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 97, 60 mg, 50% yield), and one of the second eluting isomers, (R or S)-2-amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 98, 60 mg, 50% yield), were obtained as yellow solids. [ka]

[0379] Intermediate 99: (S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-(3-(methylsulfonyl)propoxy)-2,7-naphthyridine [ka] Step 1: (S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-(3-(methylsulfonyl)propoxy)-2,7-naphthyridine The title compound was prepared from (S)-4-(2-azido-1-methoxypropan-2-yl)-1,6-dichloro-2,7-naphthyridine and 3-(methylsulfonyl)propan-1-ol using a procedure similar to that described above for Intermediate 22. MS(ES+)C 16 H 20 ClN5O4S theoretical value: 413, measured value: 414 [M+H] + . [ka]

[0380] Intermediate 100: (R)-4-(2-azidobutan-2-yl)-6-chloro-1-(3-(methylsulfonyl)propoxy)-2,7-naphthyridine [ka] Step 1: (R)-4-(2-azidobutan-2-yl)-6-chloro-1-(3-(methylsulfonyl)propoxy)-2,7-naphthyridine The title compound was prepared from (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine and 3-(methylsulfonyl)propan-1-ol using a procedure similar to that described above for Intermediate 22. MS(ES+)C 16 H 20 ClN5O3S theoretical value: 397, measured value: 398 [M+H] + .

[0381] [ka] Intermediates 101 and 102: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-((R)-methylsulfinyl)butan-2-yl)oxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-((S)-methylsulfinyl)butan-2-yl)oxy)-2,7-naphthyridine [ka] Step 1: (R)-4-(methylthio)butan-2-ol The title compound was prepared from (R)-tert-butyldimethyl((4-(methylthio)butan-2-yl)oxy)silane using a procedure similar to that described above in Step 5 of Intermediate 30.

[0382] Step 2: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-(methylthio)butan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from (R)-4-(methylthio)butan-2-ol and (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine using a procedure similar to that described above for Intermediate 22. MS(ES+)C 17 H 22 ClN5OS theoretical value: 379, measured value: 380 [M+H] + .

[0383] Step 3: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((2R)-4-(methylsulfinyl)butan-2-yl)oxy)-2,7-naphthyridine To a solution of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-(methylthio)butan-2-yl)oxy)-2,7-naphthyridine (280 mg, 643 umol, 87.2% purity) in DCM (8 mL) was added m-CPBA (196 mg, 964 umol, 85% purity) at 25° C. The mixture was stirred at 25° C. for 1 h, then diluted with DCM (15 mL), washed with water (20 mL×2), filtered, and concentrated to give a residue. The residue was purified by preparative TLC (PE / EA=1 / 2) to give the title compound (220 mg, 86% yield) as a white solid. MS(ES+)C 17 H 22 ClN5O2S theoretical value: 395, measured value: 396 [M+H] + .

[0384] Step 4: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-((R)-methylsulfinyl)butan-2-yl)oxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-((S)-methylsulfinyl)butan-2-yl)oxy)-2,7-naphthyridine 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-(((2R)-4-(methylsulfinyl)butan-2-yl)oxy)-2,7-naphthyridine (220 mg) was separated by SFC (column: Daicel Chiralpak AD (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH3HO-MeOH]; B%: 60%-60%) to obtain two separate peaks. The first eluting isomer, one of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-((R)-methylsulfinyl)butan-2-yl)oxy)-2,7-naphthyridine or 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-((S)-methylsulfinyl)butan-2-yl)oxy)-2,7-naphthyridine (Intermediate 101, 95 mg, 42% yield), and the second eluting isomer, One of the isomers, 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-((R)-methylsulfinyl)butan-2-yl)oxy)-2,7-naphthyridine or 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-((S)-methylsulfinyl)butan-2-yl)oxy)-2,7-naphthyridine (Intermediate 102, 101 mg, 45% yield), was obtained as a colorless oil. MS (ES+) C 17 H 22 ClN5O2S theoretical value: 395, measured value: 396 [M+H] + .

[0385] [ka] Intermediates 103 and 104: (S)-(3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)propyl)(imino)(methyl)-λ 6 -sulfanone and (R)-(3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)propyl)(imino)(methyl)-λ 6 -Sulfanone [ka] Step 1: 4-(2-azidopropan-2-yl)-6-chloro-1-(3-(methylthio)propoxy)-2,7-naphthyridine The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine and 3-(methylthio)propan-1-ol using a procedure similar to that described above for Intermediate 22. MS(ES+)C 15 H 18 ClN5OS theoretical value: 351, measured value: 352 [M+H] + .

[0386] Step 2: (3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)propyl)(imino)(methyl)-λ 6 -Sulfanone 4-(2-Azidopropan-2-yl)-6-chloro-1-(3-(methylthio)propoxy)-2,7-naphthyridine (320 mg, 909 μmol) was dissolved in MeOH (10 mL), followed by the addition of NH4HCO3 (108 mg, 1.36 mmol) and PhI(OAc)2 (586 mg, 1.82 mmol). The reaction mixture was stirred at 25 °C for 16 h, then diluted with saturated aqueous NH4Cl (50 mL) and extracted with EA (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (PE:EA = 0:1) to give the title compound (283 mg, 73% yield) as a yellow solid. MS (ES+) C 15 H 19 ClN6O2S theoretical value: 382, ​​measured value: 383 [M+H] + . LCMS data: M+1(382.9); MW(382.1).

[0387] Step 3: (S)-(3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)propyl)(imino)(methyl)-λ 6-sulfanone and (R)-(3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)propyl)(imino)(methyl)-λ 6 -Sulfanone (3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)propyl)(imino)(methyl)-λ 6 -sulfanone (283 mg) was separated by SFC (column: Daicel Chiralpak AY-H (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH₃H₂O EtOH]; B%: 50%-50%) to give two separate peaks. The first eluting isomer, (S)-(3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)propyl)(imino)(methyl)-λ 6 -sulfanone or (R)-(3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)propyl)(imino)(methyl)-λ 6 - one of the sulfanone (Intermediate 103, 129 mg, 41% yield) and the second eluting isomer, (S)-(3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)propyl)(imino)(methyl)-λ 6 -sulfanone or (R)-(3-((4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)propyl)(imino)(methyl)-λ 6 One of the 4-sulfanones (Intermediate 104, 114 mg, 39% yield) was obtained as a yellow solid. MS (ES+) C 15 H 19 ClN6O2S theoretical value: 382, ​​measured value: 383 [M+H] + .

[0388] [ka] Intermediates 105 and 106: (S)-4-(2-azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine and (R)-4-(2-azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine [ka] Step 1: 1,1,1-trifluoro-4-(methylthio)butan-2-ol To a solution of 3-(methylthio)propanal (2 g, 19.2 mmol) and TMSCF (13.7 g, 96.0 mmol) in THF (40 mL) was added CsCO (6.26 g, 19.2 mmol) at 0 °C, and the mixture was stirred at 25 °C for 16 h. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (PE / EA = 5 / 1) to give WH105714-2 (1.4 g) as a colorless oil.

[0389] Step 2: 4-(2-azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro-4-(methylthio)butan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine and 1,1,1-trifluoro-4-(methylthio)butan-2-ol using a procedure similar to that described above for Intermediate 22, except the reaction mixture was stirred for 16 hours. MS(ES+)C 16 H 17 ClF3N5OS theoretical value: 419, measured value: 420 [M+H] + .

[0390] Step 3: 4-(2-azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from 4-(2-azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro-4-(methylthio)butan-2-yl)oxy)-2,7-naphthyridine using a procedure similar to that described in Step 5 of Intermediate 30. MS(ES+)C 16 H 17 ClF3N5O3S theoretical value: 451, measured value: 452 [M+H] + .

[0391] Step 4: (S)-4-(2-azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine and (R)-4-(2-azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine 4-(2-Azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine (100 mg) was separated by SFC (column: Daicel Chiralpak IG (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH₃H₂O ETOH]; B%: 35%-35%) to give two separate peaks. The first eluting isomer, one of (S)-4-(2-azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine or (R)-4-(2-azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine (Intermediate 105, 35 mg, 35% yield) and the second eluting isomer, One of the isomers, (S)-4-(2-azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine and (R)-4-(2-azidopropan-2-yl)-6-chloro-1-((1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine (Intermediate 106, 36 mg, 35% yield), was obtained as a colorless oil. MS (ES+) C 16 H 17 ClF3N5O3S theoretical value: 451, measured value: 452 [M+H] + .

[0392] [ka] Intermediates 107 and 108: (S)-((2R,4R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)pentan-2-yl)(imino)(methyl)-λ6-sulfanone and (R)-((2R,4R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)pentan-2-yl)(imino)(methyl)-λ6-sulfanone [ka] Step 1: (2R,4R)-4-(methylthio)pentan-2-ol A solution of t-butyldimethyl(((2R,4R)-4-(methylthio)pentan-2-yl)oxy)silane (8.8 g, 35.4 mmol) in HCl / MeOH (4 M, 100 mL) was stirred at 25 °C for 1 h. The reaction mixture was then concentrated to give a residue. The residue was purified by flash column chromatography (gradient elution, 5-100% EA / PE) to give the title compound (3.04 g, 64% yield) as a slightly yellow oil.

[0393] Step 2: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylthio)pentan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from (2R,4R)-4-(methylthio)pentan-2-ol and (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine using a procedure similar to that described above for Intermediate 22. MS(ES+)C 18 H 24 ClN5OS theoretical value: 393, measured value: 394 [M+H] + .

[0394] Step 3: ((2R,4R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)pentan-2-yl)(imino)(methyl)-λ6-sulfanone To a mixture of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylthio)pentan-2-yl)oxy)-2,7-naphthyridine (600 mg, 1.52 mmol) and NHHCO (421 mg, 5.33 mmol) in MeOH (20 mL) was added PhI(OAc) (1.96 g, 6.09 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h, then diluted with saturated aqueous NHCl (30 mL) and extracted with EA (50 mL). The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 x 40 mm x 15 μm; mobile phase: [water (FA)-ACN]; B%: 42% to 72%, 10 min) to give the title compound (360 mg, 47% yield, 84.3% purity) as a slightly yellow semi-solid. MS(ES+)C 18 H 25 ClN6O2S theoretical value: 424, measured value: 425 [M+H] + .

[0395] Step 4: (S)-((2R,4R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)pentan-2-yl)(imino)(methyl)-λ6-sulfanone and (R)-((2R,4R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)pentan-2-yl)(imino)(methyl)-λ6-sulfanone ((2R,4R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)pentan-2-yl)(imino)(methyl)-λ-sulfanone (700 mg) was separated by SFC (column: Daicel Chiralcel OJ-H (250 mm × 30 mm, 5 μm); mobile phase: [0.1% NH3HO-IPA]; B%: 20%-20%) to give two separate peaks. The first eluting isomer, one of (S)-((2R,4R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)pentan-2-yl)(imino)(methyl)-λ-sulfanone or (R)-((2R,4R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)pentan-2-yl)(imino)(methyl)-λ-sulfanone (Intermediate 107, 276 mg, 38% yield) and the second eluting isomer, One of the isomers, (S)-((2R,4R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)pentan-2-yl)(imino)(methyl)-λ-sulfanone or (R)-((2R,4R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)pentan-2-yl)(imino)(methyl)-λ-sulfanone (Intermediate 108, 453 mg, 64% yield), was obtained as a white semi-solid. MS(ES+)C 18 H 25 ClN6O2S theoretical value: 424, measured value: 425 [M+H] + . [ka]

[0396] Intermediates 109 and 110: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-methyl-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-methyl-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine [ka] Step 1: 4-Methyl-4-(methylthio)pentan-2-ol To a mixture of 4-methyl-4-(methylthio)pentan-2-one (1 g, 6.84 mmol) in THF (10 mL) and MeOH (1 mL) was added NaBH (517 mg, 13.7 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 16 h, then quenched with HO (30 mL) and extracted with EA (100 mL). The organic layer was dried over NaSO, filtered, and concentrated to give the title compound (970 mg, 96% yield, crude) as a colorless oil.

[0397] Step 2: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((4-methyl-4-(methylthio)pentan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from 4-methyl-4-(methylthio)pentan-2-ol and (R)-4-(2-azidobutan-2-yl)-1,6-dichloro-2,7-naphthyridine using a procedure similar to that described above for Intermediate 22. MS(ES+)C 19 H 26 ClN5OS theoretical value: 407, measured value: 408 [M+H] + .

[0398] Step 3: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((4-methyl-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine The title compound was prepared from 4-((R)-2-azidobutan-2-yl)-6-chloro-1-((4-methyl-4-(methylthio)pentan-2-yl)oxy)-2,7-naphthyridine using a procedure similar to that described in Step 5 of Intermediate 30. MS(ES+)C 19 H 26 ClN5O3S theoretical value: 439, measured value: 440 [M+H] + .

[0399] Step 4: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-methyl-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-methyl-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-((4-methyl-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine (215 mg) was separated by SFC (column: Daicel Chiralpak IG (250 mm × 50 mm, 10 μm); mobile phase: [0.1% NH3HO MeOH]; B%: 40%-40%) to obtain two separate peaks. The first eluting isomer, one of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-methyl-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine or 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-methyl-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine (Intermediate 109, 100 mg, 47% yield) and the second eluting isomer, One of the isomers, 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-methyl-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine or 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-methyl-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine (Intermediate 110, 100 mg, 46% yield), was obtained as a white solid. MS (ES+) C 19 H 26 ClN5O3S theoretical value: 439, measured value: 440 [M+H] + .

[0400] [ka] Intermediates 111, 112, 113, and 114: (S)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone and (R)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl) -λ6-sulfanone and (S)-((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone and (R)-((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone [ka] Each of them is represented by one of the following structures: [ka] It is represented by one of the following structures: [ka] Each of them is represented by one of the following four structures: [ka] It is represented by one of the following structures: [ka] Each of them is represented by one of the following four structures: [ka] Step 1: 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-methyl-4-(methylthio)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-methyl-4-(methylthio)pentan-2-yl)oxy)-2,7-naphthyridine 4-((R)-2-Azidobutan-2-yl)-6-chloro-1-((4-methyl-4-(methylthio)pentan-2-yl)oxy)-2,7-naphthyridine (500 mg) was separated by SFC (column: Daicel Chiralpak IG (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH3HO MeOH]; B%: 15%-15%) to obtain two separate peaks. The first eluting isomer, 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-methyl-4-(methylthio)pentan-2-yl)oxy)-2,7-naphthyridine and one of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-methyl-4-(methylthio)pentan-2-yl)oxy)-2,7-naphthyridine (precursor I of intermediates 111 and 112, 200 mg, 40% yield) and the second eluting isomer, 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-methyl-4-(methylthio)pentan-2-yl)oxy)-2,7-naphthyridine (precursor I of intermediates 111 and 112, 200 mg, 40% yield). One of the isomers, 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-methyl-4-(methylthio)pentan-2-yl)oxy)-2,7-naphthyridine and 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-methyl-4-(methylthio)pentan-2-yl)oxy)-2,7-naphthyridine (precursor I to intermediates 113 and 114, 200 mg, 40% yield) was obtained as a colorless oil. MS (ES+) C 19 H 26 ClN5OS theoretical value: 407, measured value: 408 [M+H] + .

[0401] Step 2: ((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or ((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone The title compound (Precursor II for Intermediates 111 and 112) was prepared from 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-methyl-4-(methylthio)pentan-2-yl)oxy)-2,7-naphthyridine or 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-methyl-4-(methylthio)pentan-2-yl)oxy)-2,7-naphthyridine (Precursor 1 for Intermediates 111 and 112, first eluting isomer obtained above) using a procedure similar to that described in Step 3 of Intermediate 107. MS (ES+) C 19 H 27 ClN6O2S theoretical value: 438, measured value: 439 [M+H] + .

[0402] Step 3: (S)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone and (R)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfa Non and (S)-((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone and (R)-((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone ((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ-sulfanone or ((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ-sulfanone (precursor II to intermediates 111 and 112, 120 mg) was separated by SFC (column: Daicel Chiralpak IG (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH₃HO in IPA]; B%: 55%-55%) to give two separate peaks.The first eluting isomer, (S)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or (R)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or (S)-((S)-4 One of -((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or (R)-((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone (Intermediate 111, 31 mg, 24% yield) and the second elution The isomers (S)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or (R)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or (S)-((S)-4-((4- One of ((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ-sulfanone or (R)-((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ-sulfanone (Intermediate 112, 75 mg, 59% yield) was obtained as a white solid. MS (ES+) C. 19 H 27 ClN6O2S theoretical value: 438, measured value: 439 [M+H] + .

[0403] Step 4: ((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or ((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone The title compound (Precursor II for Intermediates 113 and 114) was prepared from 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-methyl-4-(methylthio)pentan-2-yl)oxy)-2,7-naphthyridine or 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((S)-4-methyl-4-(methylthio)pentan-2-yl)oxy)-2,7-naphthyridine (Precursor 1 for Intermediates 113 and 114, second eluting isomer obtained above) using a procedure similar to that described in Step 3 of Intermediate 107. MS (ES+) C 19 H 27 ClN6O2S theoretical value: 438, measured value: 439 [M+H] + .

[0404] Step 5: (S)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone and (R)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfa Non and (S)-((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone and (R)-((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone ((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ-sulfanone or ((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ-sulfanone (precursor II to intermediates 113 and 114, 120 mg) was separated by SFC (column: Daicel Chiralpak AD-H (250 mm × 30 mm, 5 μm); mobile phase: [0.1% NH₃HO EtOH]; B%: 20%-20%) to give two separate peaks.The first eluting isomer, (S)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or (R)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or (S)-((S)-4 One of ((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or (R)-((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone (Intermediate 113, 31 mg, 25% yield) and the second elution variant isomer, (S)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or (R)-((R)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ6-sulfanone or (S)-((S)-4-((4-( One of (R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ-sulfanone or (R)-((S)-4-((4-((R)-2-azidobutan-2-yl)-6-chloro-2,7-naphthyridin-1-yl)oxy)-2-methylpentan-2-yl)(imino)(methyl)-λ-sulfanone (Intermediate 114, 60 mg, 5947% yield) was obtained as a white solid. MS (ES+) C. 19 H 27 ClN6O2S theoretical value: 438, measured value: 439 [M+H] + .

[0405] [ka] Intermediates 115 and 116: (S)-N-((S)-1-(6-chloro-1-((cis)-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide and (S)-N-((R)-1-(6-chloro-1-((cis)-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide [ka] Each of them is represented by one of the structures shown below. [ka] Step 1: (S)—N-((S)-1-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide and (S)—N-((R)-1-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)butyl)-2-methylpropane-2-sulfinamide To a solution of (S)—N-((E)-(6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (500 mg, 1.13 mmol) in THF (20 mL) was added EtMgBr (3 M, 1.13 mL) at 0° C. The cold bath was removed, and the reaction mixture was stirred at 25° C. for 30 min. The reaction mixture was then quenched by the addition of saturated aqueous NH4Cl solution (40 mL) and extracted with EA (40 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 The mixture was purified using a 150×40 mm×15 μm column; mobile phase: [water (0.1% TFA)-ACN]; B%: 36% to 46%, 10 min) to obtain either (S)—N-((S)-1-(6-chloro-1-((cis)-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide or (S)—N-((R)-1-(6-chloro-1-((cis)-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide as the first eluting isomer (Intermediate 115, 100 mg, 16% yield) as a white solid, and the other of (S)—N-((S)-1-(6-chloro-1-((cis)-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide or (S)—N-((R)-1-(6-chloro-1-((cis)-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide as the second eluting isomer (Intermediate 116, 100 mg, 17% yield, second fraction) was obtained as a white solid. Intermediate 115: MS(ES+)C 20 H 28 Theoretical value of ClN3O4S2: 44, Measured value: 474 [M+H] + . Intermediate 116: MS(ES+)C 20 H 28Theoretical value of ClN3O4S2: 44, Measured value: 474 [M+H] + .

[0406] Representative methods for synthesizing compounds in Table 1 Example 1a: Synthetic Method 1 [ka] (7S,8R)-2-((5-(2-aminopropan-2-yl)-8-((cis)-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (compound 39) [ka]

[0407] Step 1: (7S,8R)-2-((5-((R)-2-azidobutan-2-yl)-8-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one A mixture of 4-(2-azidopropan-2-yl)-6-chloro-1-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridine (Intermediate 44, 60 mg, 146 μmol), (7S,8R)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 1, 31.0 mg, 161 μmol), BrettPhos G4 precatalyst (6.74 mg, 7.32 μmol), BrettPhos (3.93 mg, 7.32 μmol), and KOAc (35.9 mg, 366 μmol) in dioxane (2 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 100° C. for 4 hours. The reaction mixture was then filtered and concentrated to provide a residue. The residue was purified by preparative TLC (PE / EA=0:1) to give the title compound (40.0 mg, yield 49%) as a white solid.

[0408] Step 2: (7S,8R)-2-((5-(2-aminopropan-2-yl)-8-((cis)-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one To a solution of (7S,8R)-2-((5-((R)-2-azidobutan-2-yl)-8-(cis-3-(ethylsulfonyl)cyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (40.0 mg, 70.7 μmol) in EA (30 mL) was added platinum dioxide (12.1 mg, 53.1 μmol). The suspension was degassed under vacuum and purged with hydrogen several times. The reaction mixture was then stirred under hydrogen (15 psi) at 25° C. for 16 h. The reaction mixture was then filtered and concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 x 30 mm x 3 um; mobile phase: [water (10 mM NH4HCO3)ACN]; B%: 22%-52%) to give the title compound (11.7 mg, 31% yield) as a yellow solid. MS(ES+)C 27 H 33 Theoretical value of N5O5S: 539, Measured value: 540 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ ppm 10.70 (s, 1H), 9.42 (s, 1H), 9.32 (s, 1H), 8.14 (s, 1H), 8.08 (d, J = 8.63 Hz, 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).

[0409] Example 1b: Synthetic Method 1 [ka] (R)-2-((5-(2-aminopropan-2-yl)-8-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Compound 42) [ka]

[0410] Step 1: (R)-2-((5-(2-azidopropan-2-yl)-8-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one A mixture of 4-(2-azidopropan-2-yl)-6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridine (Intermediate 22, 400 mg, 1.01 mmol), (R)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 3, 229 mg, 1.11 mmol), BrettPhos G4 precatalyst (93.0 mg, 101 μmol), BrettPhos (108 mg, 202 μmol), and KOAc (298 mg, 3.03 mmol) in dioxane (8 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 100° C. for 1 hour. The reaction mixture was then filtered and concentrated to provide a residue. The residue was purified by flash column chromatography on silica gel (0-60% EA / PE) to give the title compound (370 mg, 61% yield) as a yellow solid.

[0411] Step 2: (R)-2-((5-(2-aminopropan-2-yl)-8-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one To a solution of (R)-2-((5-(2-azidopropan-2-yl)-8-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (370 mg, 654 umol) in EA (12 mL) was added platinum dioxide (44.6 mg, 196 umol). The suspension was degassed under vacuum and purged with hydrogen several times. The reaction mixture was then stirred under hydrogen (15 psi) at 25° C. for 2 h. The reaction mixture was then filtered and concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 x 40 mm x 15 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 10%-40%) to give the title compound (279 mg, 79% yield) as an off-white solid. MS (ES+) C 27 H 33 Theoretical value of N5O5S: 539, Measured value: 540 [M+H] + . 1 H NMR (400 MHz, CD3OD):δ ppm 9.39 (s, 1 H), 9.21 (s, 1 H), 8.54 (s, 1 H), 8.14 (d, J = 8.8 Hz, 1 H), 8.07-8.03 (m, 1 H), 7.25 (d, J = 8.8 Hz, 1 H), 5.51-5.36 (m, 1 H), 3.92-3.75 (m, 1 H), 3.05-2.95 (m, 3 H), 2.93 (s, 3 H), 2.76-2.63 (m, 2 H), 1.94 (d, J = 11.2 Hz, 6 H), 1.53 (s, 3 H), 1.45 (s, 3 H), 1.40 (d, J = 7.2 Hz, 3 H).

[0412] Example 1c: Synthetic Method 1 [ka] (7S,8R)-2-((5-((R)-2-aminobutan-2-yl)-8-(((R)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (compound 52) [ka]

[0413] Step 1: (7S,8R)-2-((5-((R)-2-azidobutan-2-yl)-8-(((R)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one A mixture of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((R)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridine (Intermediate 31, 130 mg, 316 μmol), (7S,8R)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 1, 60.7 mg, 316 μmol), BrettPhos G4 precatalyst (29.1 mg, 31.6 μmol), BrettPhos (16.9 mg, 31.6 μmol), and KOAc (77.4 mg, 789 μmol) in dioxane (3 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 100° C. for 1 hour. The reaction mixture was then filtered and concentrated to provide a residue. The residue was purified by preparative TLC (PE / EA=1:2) to give the title compound (130 mg, yield 73%) as a yellow solid.

[0414] Step 2: (7S,8R)-2-((5-((R)-2-aminobutan-2-yl)-8-(((R)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one To a solution of (7S,8R)-2-((5-((R)-2-azidobutan-2-yl)-8-(((R)-4-(methylsulfonyl)butan-2-yl)oxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (130 mg, 229 μmol) in EA (10 mL) was added platinum dioxide (39.2 mg, 172 μmol). The suspension was degassed under vacuum and purged with hydrogen several times. The reaction mixture was then stirred under hydrogen (15 psi) at 25° C. for 16 h. The reaction mixture was then filtered and concentrated to give a residue. The residue was purified by silica gel chromatography (PE / EA = 1:0 to 0:1, followed by EA / MeOH = 1:0 to 10:1) to give the title compound (59.0 mg, 46% yield) as a yellow solid. MS (ES+) C 27 H 35 Theoretical value of N5O5S: 541, Measured value: 542 [M+H] + . 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).

[0415] Example 1d: Synthesis Method 1 [ka] (7S,8R)-2-((5-((R)-2-aminobutan-2-yl)-8-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Compound 127) [ka]

[0416] Step 1: (7S,8R)-2-((5-((R)-2-azidobutan-2-yl)-8-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one A mixture of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine (Intermediate 86, 85 mg, 193 umol), (7S,8R)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 1, 37.1 mg, 193 umol), BrettPhos G4 precatalyst (17.8 mg, 19.3 umol), BrettPhos (20.7 mg, 38.6 umol) and KOAc (56.9 mg, 579 umol) in dioxane (3 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 100° C. for 1 hour. The reaction mixture was then filtered and concentrated to provide a residue. The residue was purified by flash column chromatography on silica gel (0-60% EA / PE) to give the title compound (120 mg, 54% yield) as a white solid.

[0417] Step 2: (7S,8R)-2-((5-((R)-2-aminobutan-2-yl)-8-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one To a solution of (7S,8R)-2-((5-((R)-2-azidobutan-2-yl)-8-(((2R,4R)-4-(ethylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (120 mg, 201 umol) in EA (16 mL) was added platinum dioxide (13.7 mg, 60.4 umol). The suspension was degassed under vacuum and purged with hydrogen several times. The reaction mixture was then stirred under hydrogen (15 psi) at 25° C. for 2 h. The reaction mixture was then filtered and concentrated to give a residue. The residue was purified by preparative TLC (EA / MeOH=1:1) to give the title compound (31.2 mg, 27% yield) as a white solid. MS (ES+) C 29 H 39 Theoretical value of N5O5S: 569, Measured value: 570 [M+H] + . 1 H NMR (400 MHz, CD3OD): δ ppm 9.36 (s, 1 H), 9.15 (s, 1 H), 8.28-8.00 (m, 2 H), 7.29 (d, J = 8.8 Hz, 1 H), 5.80-5.61 (m, 1 H), 4.73-4.56 (m, 1 H), 3.45-3.35 (m, 1 H), 3.14-3.06 (m, 2 H), 3.06-2.98 (m, 1 H), 2.49-2.30 (m, 2 H), 2.23-2.03 (m, 2 H), 1.73 (s, 3 H), 1.51-1.43 (m, 12 H), 1.34-1.27 (m, 3 H), 0.78-0.68 (m, 3 H).

[0418] Example 1e: Synthetic Method 1 [ka] 2'-((5-((R)-2-aminobutan-2-yl)-8-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridin-3-yl)amino)-7',7'-dimethyl-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-5'-one (Compound 136) [ka]

[0419] Step 1: 2'-((5-((R)-2-azidobutan-2-yl)-8-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridin-3-yl)amino)-7',7'-dimethyl-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-5'-one A mixture of 4-((R)-2-azidobutan-2-yl)-6-chloro-1-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridine (Intermediate 53, 70.0 mg, 164 μmol), 2′-amino-7′,7′-dimethyl-5′H,7′H-spiro[cyclopropane-1,8′-pyrano[4,3-b]pyridin]-5′-one (Intermediate 15, 36.0 mg, 164 μmol), BrettPhos G4 precatalyst (8.00 mg, 8.22 μmol), BrettPhos (9.00 mg, 16.4 μmol) and KOAc (48.0 mg, 493 μmol) in dioxane (2 mL) was degassed and purged with nitrogen three times, then the mixture was stirred at 100° C. for 3 h. The reaction mixture was then filtered and concentrated to give a residue (90.0 mg, 90% yield, yellow oil) which was used in the next step without further purification.

[0420] Step 2: 2'-((5-((R)-2-aminobutan-2-yl)-8-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridin-3-yl)amino)-7',7'-dimethyl-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-5'-one To a solution of 2'-((5-((R)-2-azidobutan-2-yl)-8-(((2R,4R)-4-(methylsulfonyl)pentan-2-yl)oxy)-2,7-naphthyridin-3-yl)amino)-7',7'-dimethyl-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-5'-one (90.0 mg, 148 μmol) in EA (10 mL) was added platinum dioxide (13.0 mg, 55.3 μmol). The suspension was degassed under vacuum and purged with hydrogen several times. The reaction mixture was then stirred under hydrogen (15 psi) at 25°C for 16 h. The reaction mixture was then filtered and concentrated to give a residue. The residue was purified by preparative TLC (EA / MeOH=10:1) to give the title compound (30.2 mg, 33% yield) as a yellow solid. MS(ES+)C 30 H 39 Theoretical value of N5O5S: 581, Measured value: 582 [M+H] + . 1 H 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), 1.559-1.53 ​​(m, 2H), 1.52-1.47 (m, 6H), 1.42 (s, 6H), 1.31-1.27 (m, 2H), 0.76 (d, J= 7.2 Hz, 3H).

[0421] Example 2: Synthesis Method 2 [ka] (R)-2-((5-((S or R)-amino(cyclopropyl)methyl)-8-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-3-yl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Compound 62) [ka]

[0422] Step 1: (S)—N-((R or S)-cyclopropyl(1-(cis-3-(methylsulfonyl)cyclobutoxy)-6-(((R)-7,7,8-trimethyl-5-oxo-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)amino)-2,7-naphthyridin-4-yl)methyl)-2-methylpropane-2-sulfinamide A mixture of (R)-2-amino-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 3, 44.6 mg, 216 μmol), (S)—N-((6-chloro-1-(cis-3-(methylsulfonyl)cyclobutoxy)-2,7-naphthyridin-4-yl)(cyclopropyl)methyl)-2-methylpropane-2-sulfinamide (Intermediate 58, 100 mg, 206 μmol), BrettPhos (22.1 mg, 41.2 μmol), BrettPhos G4 precatalyst (18.9 mg, 20.6 μmol), and KOAc (60.6 mg, 617 μmol) in dioxane (3 mL) was degassed and purged with nitrogen three times, and then the mixture was stirred at 100° C. for 1 hour. The reaction mixt...

Claims

1. A compound of formula I, 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein in the formula, T is 【Chemical 2】 and [Chemical Formula 3] selected from 4- to 5-membered heterocycles containing, said heterocycle being optionally substituted with 1 to 2 R ６ ; Z is absent, O or NH; Ring A is C ４－６ a cycloalkyl or a 4- to 6-membered heterocycle containing nitrogen, and the cycloalkyl or the heterocycle is optionally substituted with 1 to 2 R ６ ; L １ is selected from a bond and C １ -C ３ alkylene, wherein said alkylene is optionally substituted with 1 to 2 R １１ ; L ２ is selected from a bond and C １ -C ３ alkylene; B is O or NH; Q is N or CH; x is 0, 1, or 2; n is 0, 1, 2, 3, or 4; R １ and R ２ each independently represents hydrogen, C １－６ alkyl, C ３－６ cycloalkyl, or a 4- to 6-membered heterocyclic ring, and the alkyl is optionally substituted with one or two R ３ groups; Each R ３ is independently selected from halogen, hydroxyl, and OR ４ ; Each R ４ is independently selected from C １－３ alkyl, CF ３ , CH ２ F, and CHF ２ ; Each R ５ is independently C １－２ alkyl, CF ３ , CH ２ F, and CHF ２ selected from, or Two Rs bonded to the same carbon atom ５ together with the carbon atom to which they are bonded form a C ３－５ cycloalkyl, or two Rs bonded to two adjacent carbon atoms ５ together with the two adjacent carbon atoms to which they are bonded form a C ４－６ cycloalkyl; Each R ６ is independently selected from CH ３ , methoxy, CF ３ , CH ２ F, and CHF ２ ; R ７ is selected from C １－３ alkyl, C ３－６ cycloalkyl, OC １－４ alkyl, NR ９ R １０ , and a 3- to 5-membered heterocycle containing nitrogen or oxygen, and the alkyl, the cycloalkyl, or the heterocycle is optionally substituted with 1 to 3 R ８ ; Each R ８ is, independently, halogen, C １－３ , hydroxyl and OC １－３ alkyl, wherein said alkyl is optionally substituted with 1 to 3 R １２ ; R ９ is C １－２ alkyl; R １０ is C １－２ alkyl; Each R １１ is independently selected from halogen, methoxy, C １－２ alkyl, CH ２ F, CHF ２ and CF ３ or two Rs １１ together with two adjacent carbon atoms to which they are attached form cyclopropyl; Each R １２ is a halogen, the compound or a pharmaceutically acceptable salt thereof.

2. The compound is formula IV: 【Chemical Formula 6】 or formula VII: 【Chemical Formula 9】 The compound or a pharmaceutically acceptable salt thereof according to claim 1, represented by

3. L １ is a bond; T is 【Chemical Formula 10】 ; optionally L ２ is a bond or methylene; ring A is selected from azetidinylene, cyclobutylene, cyclopentylene and pyrrolidinylene, and the azetidinylene, the cyclobutylene, the cyclopentylene and the pyrrolidinylene are optionally substituted with 1 to 2 R6, The compound or a pharmaceutically acceptable salt thereof according to claim 1.

4. T is L １ is C optionally replaced by 1 to 2 R １１ -C １ -C ３ is alkylene; The compound or a pharmaceutically acceptable salt thereof according to claim 1. 【Chemical 11】

5. Selected from L １ is of formulas L-1, L-2, L-3, L-4, L-5, L-6 and L-7: 【Chemical Formula 12】 wherein represents the bond with B; 【Chemical 13】 ―* represents the bond with T, The compound or a pharmaceutically acceptable salt thereof according to claim 4.

6. Z is O, The compound or a pharmaceutically acceptable salt thereof according to claim 1.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1. T is a 4- to 5-membered heterocyclic ring containing a sulfone, and the heterocyclic ring is optionally substituted with 1 to 2 R ６ ; L １ is selected from bonding, methylene, and ethylene,

8. Optionally R １ and R ２ each independently is selected from hydrogen, C １－６ alkyl, and C ３－６ cycloalkyl, and the alkyl is optionally substituted with OR ３ ; Each R ３ is independently selected from halogen, hydroxyl, and OR ４ ; Each R ４ is C １－３ alkyl R1 and R2 are each independently selected from hydrogen, CH3, CH2CH3, CH2CH2CH3, CH2 - OCH3 and cyclopropyl, The compound or a pharmaceutically acceptable salt thereof according to claim 1.

9. n is 1, 2, 3, or 4; R ５ is CH ３ or two Rs bonded to the same carbon atom ５ together with the carbon atom to which they are bonded form cyclopropyl; R7 is selected from C1-3 alkyl, CH2F, CHF2, CF3, C3-6 cycloalkyl and NR9R10; R9 is C1-2 alkyl; R10 is C1-2 alkyl, The compound or a pharmaceutically acceptable salt thereof according to claim 1.

10. Each R11 is independently CH3, CF3 or CH2CH3, preferably each R11 is CH3, R ７ is selected from CH ３ , CF ３ , CH ２ CH ３ , CH(CH ３ ), ２ cyclopropyl and N(CH ３ ), ２ and is selected from; The compound or a pharmaceutically acceptable salt thereof according to claim 9. A compound selected from

11. 【Fig. 14-1】 【Chemical Formula 14-2】 【Chemical Formula 14-3】 【Chemical 14-4】 【Chemical Formula 14-5】 【Chemical 14-6】 【Chemical Formula 14-7】 【Chemical Formula 14-8】 【Chemical Formula 14-9】 【Chemical 14-10】 【Chemical Formula 14-11】 【Chemical Formula 14-12】 【Chemical Formula 14-13】 【Chemical Formula 14-14】 [[Chemical 14-15]] 【Chemical Formula 14-16】 【Chemical Formula 14-17】 【Chemical 14-18】 【Chemical Formula 14-19】 【Chemical 14-20】 【Chemical 14-21】 【Chemical Formula 14-22】 【Chemical 14-23】 【Chemical 14-24】 【Chemical 14-25】 【Chemical 14-26】 【Chemical 14-27】 【Chemical 14-28】 【Chemical Formula 14-29】 【Chemical 14-30】 【Chemical 14-31】 【Chemical Formula 14-32】 【Chemical 14-33】 【Chemical 14-34】 【Chemical 14-35】 【Chemical 14-36】 【Chemical 14-37】 【Chemical 14-38】 【Chemical 14-39】 【Chemical 14-40】 【Chemical 14-41】 【Chemical 14-42】 【Chemical 14-43】 【Chemical Formula 14-44】 【Chemical 14-45】 【Chemical 14-46】 【Chemical 14-47】 【Chemical 14-48】 【Chemical 14-49】 【Chemical 14-50】 【Chemical Formula 14-51】 【Chemical 14-52】 【Chemical Formula 14-53】 【Chemical Formula 14-54】 【Chemical 14-55】 【Chemical 14-56】 【Chemical 14-57】 [[Chemical 14-58]] 【Chemical 14-59】 【Chemical 14-60】 【Chemical 14-61】 【Chemical 14-62】 【Chemical 14-63】 【Chemical 14-64】 【Chemical 14-65】 【Chemical 14-66】 【Chemical Formula 14-67】 【Chemical 14-68】 【Chemical 14-69】 【Chemical 14-70】 【Chemical Formula 14-71】 【Chemical 14-72】 【Chemical 14-73】 【Chemical Formula 14-74】 【Chemical 14-75】 【Chemical 14-76】 【Chemical Formula 14-77】 【Chemical 14-78】 【Chemical Formula 14-79】 【Chemical 14-80】 【Chemical 14-81】 ​ and a pharmaceutically acceptable salt thereof.

12. The compound is 【Chemical Formula 15-1】 【Chemical Formula 15-2】 Selected from, The compound and a pharmaceutically acceptable salt thereof according to claim 1.

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

14. A pharmaceutical composition for inhibiting MAP4K1 or enhancing an immune response, comprising an effective amount of the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition for treating a MAP4K1-dependent disorder or disease, comprising an effective amount of the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, optionally, the MAP4K1-dependent disorder or disease is cancer or a viral infection, and optionally, the cancer comprises at least one cancer selected from the group consisting of colon cancer, rectal cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, urothelial cancer, bladder cancer, esophageal cancer, gastric cancer, liver cancer, head and neck cancer, lymphoma, leukemia, and melanoma.

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