MAP4K1 inhibitors

Abstract

One embodiment of the present disclosure is a compound represented by Formula I or a pharmaceutically acceptable salt thereof. The variables in Formula I are defined herein. The compound of Formula I is a selective MAP4K1 inhibitor, which can be used to treat a disease or disorder in a subject that benefits from controlling MAP4K1 activity.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 961,463, filed on January 15, 2020, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present application relates to MAP4K1 inhibitors and methods of use thereof, such as controlling the activity of MAP4K1 in a subject. Background Art

[0004] MAP4K1 (also known as hematopoietic progenitor kinase 1 (HPK1)) was originally cloned from hematopoietic progenitor cells (Hu, MC et al., Genes Dev, 1996. 10(18): pp. 2251-64). MAP4K1 is particularly interesting as a target because it is primarily expressed in hematopoietic cells such as T cells, B cells, macrophages, dendritic cells, neutrophils, and mast cells (Hu, MC et al., Genes Dev, 1996. 10(18): pp. 2251-64; Kiefer, F et al., EMBO J, 1996. 15(24): pp. 7013-25). MAP4K1 kinase activity has been shown to be induced upon activation of the T cell receptor (TCR) (Liou, J et al., Immunity, 2000. 12(4): pp. 399-408), B cell receptor (BCR) (Liou, J et al., Immunity, 2000. 12(4): pp. 399-408), transforming growth factor receptor (TGF-R) (Wang, W et al., J Biol Chem, 1997. 272(36): pp. 22771-5; Zhou, G et al., J Biol Chem, 1999. 274(19): pp. 13133-8), or G s MAP4K1 is a cytosolic protein that is coupled to PGE2 receptors (EP2 and EP4) (Ikegami, R et al., Journal of Immunology, 2001. 166(7): pp. 4689-96). Therefore, MAP4K1 regulates a variety of functions of various immune cells.

[0005] MAP4K1 is important in regulating the functions of various immune cells, and it is associated with autoimmune diseases and anti-tumor immunity (Shui, JW et al., Nat Immunol, 2007.8(1): 84-91; Wang, X et al., Journal of Biological Chemistry, 2012.287(14): 11037-48). Those observations suggest that reduced MAP4K1 activity may lead to autoimmunity in patients. In addition, MAP4K1 can also control anti-tumor immunity via T cell-dependent mechanisms. In a Lewis lung cancer tumor model that produces PGE2, tumors develop more slowly 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 than wild-type T cells in controlling tumor growth and metastasis (Alzabin, S et al., Cancer Immunol Immunother, 2010. 59(3): p. 419-29). Similarly, bone marrow-derived dendritic cells (BMDCs) from MAP4K1 knockout mice were more effective in generating T cell responses to eradicate Lewis lung cancer than wild-type BMDCs (Alzabin, S et al., Journal of Immunology, 2009. 182(10): p. 6187-94). Data obtained from MAP4K1 kinase-killed mice indicate that MAP4K1 kinase activity is essential for conferring MAP4K1 inhibitory function in a wide range of immune cells, including CD4+, CD8+, DC, NK to T regulatory cells (Treg), and that inactivation of the kinase domain is sufficient to elicit a robust anti-tumor immune response. Liu et al., PLoS ONE 14(3):e0212670 https: / / doi.org / 10.1371 / journal.pone.0212670. In addition, loss of MAP4K1 kinase function inhibits tumor growth in preclinical tumor models, and therapeutic co-blockade of MAP4K1 kinase and PD-L1 enhances antitumor responses. Hernandez S et al., Cell Reports 2018 25: 80-94. Recently presented results showed tumor growth inhibition in the CT-26 syngeneic mouse model using small molecules (Seungmook, L, Cancer research-AACR Journal, 2019, Abstract 4150). These data confirm that MAP4K1 is a novel drug target for enhancing antitumor immunity.Therefore, there is a need for new compounds that modulate MAP4K1 activity for the treatment of MAP4K1-dependent diseases or disorders, such as cancer, viral infections, and other diseases and disorders. Summary of the invention

[0006] Provided herein are compounds and compositions that inhibit MAP4K1 and thereby enhance the immune response of a subject. For example, the ICs for inhibiting MAP4K1 provided in Example 19 50 The compounds provided herein are selective inhibitors of MAP4K1. Methods of using the compounds and compositions described herein for treating cancer and viral infections are also disclosed.

[0007] One embodiment of the present disclosure is a compound represented by Formula I:

[0008]

[0009] or a pharmaceutically acceptable salt thereof,

[0010] in:

[0011] A 1 and A 2 is selected from N and CH;

[0012] A 3 is selected from CH and N;

[0013] X is selected from C 1-3 Alkyl, OR 6 、NHR 7 and halogens;

[0014] B is selected from CR 11 and N, Y is selected from N and CR 12 , and the bond between Y and B is a double bond; or

[0015] B is C(O), Y is NR 14 , and the bond between Y and B is a single bond; or Y and B together form a 5- to 7-membered heterocyclic ring or C 5-6 cycloalkyl, and the bond between Y and B is a double bond, wherein the heterocyclic ring or cycloalkyl is optionally substituted by 1-6 R 8 replace;

[0016] Each R 8 Independently selected from C 1-3 Alkyl and OH, or

[0017] Two R's attached to the same carbon 8 To form an oxo group, or

[0018] Two R attached to the same carbon atom 8Together with the carbon atom to which they are attached, they form C 3-5 Cycloalkyl, or

[0019] Two R attached to two adjacent carbon atoms 8 Together with the two adjacent carbon atoms to which they are attached, they form C 3-6 Cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted with 1-6 halogens;

[0020] R 1 and R 2 are each independently selected from hydrogen, C 1-4 Alkyl, C 3-5 Cycloalkyl and 3- to 5-membered heterocyclic rings, wherein the alkyl and cycloalkyl groups are optionally substituted by OH, C 1-6 Alkoxy or 1-6 halogen substitutions; or

[0021] R 1 and R 2 Together with the atoms to which they are attached, they form a 4- to 6-membered heterocyclic ring or a C 3-6 Cycloalkyl;

[0022] R 3 and R 4 are each independently selected from hydrogen, C 1-6 Alkyl, OR 16 Substituted C 1-6 Alkyl, C 3-6 Cycloalkyl and a 4- to 6-membered heterocyclic ring; or

[0023] R 3 and R 4 Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or a 4- to 6-membered heterocyclic ring; or

[0024] R 1 and R 3 Together with the atoms to which they are attached, they form a 3- to 6-membered heterocyclic ring;

[0025] R 6 Selected from C 1-3 Alkyl, C 3-6 Cycloalkyl and 4- to 6-membered heterocyclic rings, wherein the alkyl, cycloalkyl and heterocyclic rings are optionally substituted by 1-3 R 9 replace;

[0026] R 7 Selected from hydrogen, C 1-3 Alkyl, C 3-5 Cycloalkyl and 4- to 6-membered heterocyclic rings, wherein the alkyl, cycloalkyl and heterocyclic rings are optionally substituted by 1-3 R 9 replace;

[0027] R 9 Selected from C1-3 Alkyl, halogen-substituted C 3-6 Cycloalkyl, halogen, SO2Me, C 1-3 Alkoxy and OH;

[0028] R 11 Selected from hydrogen, COOH, CN, halogen and C 1-3 Alkoxy;

[0029] R 12 Selected from C 1-5 Alkyl, C 4-6 Cycloalkyl, 3- to 6-membered heterocyclic ring, NHR 13 NR 13 R 13 OR 13 wherein the alkyl, cycloalkyl or heterocyclic ring is optionally substituted by OH, NH2, 1-4 halogens or R 15 replace;

[0030] Each R 13 Independently selected from C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with halogen;

[0031] R 14 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and 4- to 6-membered heterocycle, wherein the alkyl, cycloalkyl or heterocycle is optionally substituted with 1-6 halogens;

[0032] R 15 It is OH, C 1-3 Alkyl or C 3-5 cycloalkyl; and

[0033] R 16 Is H or C 1-3 alkyl.

[0034] 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.

[0035] Another embodiment of the present disclosure is a method of treating a MAP4K1-dependent disorder or disease (e.g., treating cancer or viral infection), comprising administering to a subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound.

[0036] 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 the compound, in the preparation of a medicament for treating a MAP4K1-dependent disorder or disease (eg, treating cancer or viral infection).

[0037] Another embodiment of the present disclosure is a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound, for use in treating a MAP4K1-dependent disorder or disease (eg, treating cancer or viral infection). DETAILED DESCRIPTION

[0038] The disclosed compounds are MAP4K1 inhibitors, which can be used to treat MAP4K1-dependent disorders or diseases. Such diseases or disorders include cancer and viral infections.

[0039] Compound Examples

[0040] Exemplary embodiments include:

[0041] First embodiment: a compound represented by Formula I or a pharmaceutically acceptable salt thereof. The variables in Formula I are described above in the Summary of the Invention.

[0042] Second embodiment: a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein:

[0043] X is selected from OR 6 、NHR 7 and halogens;

[0044] R 3 and R 4 are each independently selected from hydrogen, C substituted by OH 1-6 Alkyl, C 1-6 Alkyl, C 3-6 Cycloalkyl and a 4- to 6-membered heterocyclic ring; or

[0045] R 3 and R 4 Together with the atoms to which they are attached, they form C 3-6 Cycloalkyl or a 4- to 6-membered heterocyclic ring; or

[0046] R 1 and R 3 Together with the atoms to which they are attached, form a 3- to 6-membered heterocyclic ring; and

[0047] The remaining variables in Formula I are described above in the first embodiment.

[0048] The third embodiment: a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein:

[0049] R1 and R 2 are each independently selected from hydrogen, C optionally substituted by OH 1-4 Alkyl, cyclobutyl and oxetanyl;

[0050] R 3 and R 4 are each independently selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl; or R 1 and R 3 Together with the atoms to which they are attached, they form a 3- to 6-membered heterocyclic ring;

[0051] Each R 8 Independently C 1-3 Alkyl; or

[0052] Two R's attached to the same carbon 8 to form an oxo group; or

[0053] Two R attached to the same carbon atom 8 Together with the carbon atom to which they are attached, they form C 3-5 Cycloalkyl; or

[0054] Two R attached to two adjacent carbon atoms 8 Together with the two adjacent carbon atoms to which they are attached, they form C 3-6 Cycloalkyl;

[0055] R 6 Selected from C 1-3 Alkyl and C 3-6 Cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted by 1 to 3 R 9 replace;

[0056] R 7 Selected from C 1-3 Alkyl and C 3-6 Cycloalkyl;

[0057] R 11 Selected from COOH and CN;

[0058] R 12 Selected from C 1-5 Alkyl, C 4-6 Cycloalkyl, 3- to 6-membered heterocyclic ring and OR 13 wherein the alkyl, cycloalkyl or heterocyclic ring is optionally substituted by OH, NH2, 1 to 4 halogens or R 15 replace;

[0059] R 13 It is C 1-6 alkyl;

[0060] R 14 It is C 1-6 Alkyl; and

[0061] R 15 It is C 1-3 Alkyl; and

[0062] The remaining variables in Formula I are described above in the first and / or second embodiments.

[0063] Fourth embodiment: a compound represented by formula II:

[0064]

[0065] or a pharmaceutically acceptable salt thereof. The variables in Formula II are described above in the first, second and / or third embodiment.

[0066] Fifth embodiment: a compound represented by formula III:

[0067]

[0068] or a pharmaceutically acceptable salt thereof. The variables in Formula III are

[0069] This is described above in the first, second and / or third embodiments.

[0070] Sixth embodiment: a compound represented by formula IV:

[0071]

[0072] or a pharmaceutically acceptable salt thereof. The variables in Formula IV are described above in the first, second and / or third embodiment.

[0073] Seventh embodiment: a compound represented by formula V or VI:

[0074]

[0075] or a pharmaceutically acceptable salt thereof, wherein E is CH2, NH or O; each R 8 It is C 1-3 alkyl, and n is 0 to 4; two R attached to the same carbon atom 8 Together with the carbon atom to which they are attached, they form C 3-5 Cycloalkyl; or two R attached to two adjacent carbon atoms 8 Together with the two adjacent carbon atoms to which they are attached, they form C 4-6 Alternatively, E is NH. In another alternative, E is O. The remaining variables in Formulas V and VI are described above in the first, second and / or third embodiment.

[0076] Eighth embodiment: Compound represented by formula V(A) or VI(A):

[0077]

[0078] or a pharmaceutically acceptable salt thereof. The variables in Formula V(A) and VI(A) are described above in the first, second, third and / or seventh embodiment.

[0079] Ninth embodiment: a compound represented by formula V(B) or VI(B):

[0080]

[0081] or a pharmaceutically acceptable salt thereof. The variables in Formula V(B) and VI(B) are described above in the first, second, third and / or seventh embodiment.

[0082] Tenth embodiment: a compound represented by formula V(C) or VI(C):

[0083]

[0084] or a pharmaceutically acceptable salt thereof. The variables in Formula V(C) and VI(C) are described above in the first, second, third and / or seventh embodiment.

[0085] Embodiment 11: A compound represented by any one of Formula I, V, VI, V(A), VI(A), V(B), VI(B), V(C) and VI(C), or a pharmaceutically acceptable salt thereof, wherein R 8 is methyl, and n is 0, 1, 2, 3 or 4. Alternatively, R 8 is methyl, and n is 1; R 8 is methyl, and n is 2; R 8 is methyl, and n is 3; R 8 is methyl, and n is 4; R 8 is ethyl, and n is 0, 1, 2 or 3; R 8 is ethyl, and n is 1; R 8 is ethyl, and n is 2; or R 8 is ethyl, and n is 3. The remaining variables in Formulas I, V, VI, V(A), VI(A), V(B), VI(B), V(C), and VI(C) are as described above in the first, second, third, and / or seventh embodiment.

[0086] Embodiment 12: A compound represented by any one of Formula I, V, VI, V(A), VI(A), V(B), VI(B), V(C) and VI(C), or a pharmaceutically acceptable salt thereof, wherein two R attached to the same carbon atom 8 Together with the carbon atoms to which they are attached, they form a cyclopropyl group; or two R attached to two adjacent carbon atoms 8 Together with the two adjacent carbon atoms to which they are attached, they form a cyclopentyl group. Alternatively, two R 8 Together with the carbon atom to which they are attached, they form a cyclobutyl group. In another alternative, the two R 8 Together with the carbon atoms to which they are attached, they form a cyclopentyl group. In another alternative, the two R attached to two adjacent carbon atoms 8 Together with the two adjacent carbon atoms to which they are attached, they form a cyclobutyl group. 8 Together with the two adjacent carbon atoms to which they are attached, they form a cyclopropyl group. The remaining variables in Formulas I, V, VI, V(A), VI(A), V(B), VI(B), V(C), and VI(C) are as described above in the first, second, third, and / or seventh embodiment.

[0087] Thirteenth embodiment: Compound represented by formula VII, VIII or IX:

[0088]

[0089]

[0090] or a pharmaceutically acceptable salt thereof. The variables in Formulae VII, VIII and IX are as described above in the first, second and / or third embodiment.

[0091] Fourteenth embodiment: Compounds represented by formula VII(A), VIII(A) or IX(A):

[0092]

[0093] or a pharmaceutically acceptable salt thereof. The variables in Formulae VII(A), VIII(A) and IX(A) are as described above in the first, second and / or third embodiment.

[0094] Embodiment 15: A compound represented by any one of Formulas I-IV, VII-IX and VII(A)-IX(A) or a pharmaceutically acceptable salt thereof, wherein R 11 is CN. The remaining variables in Formulas I-IV, VII-IX and VII(A)-IX(A) are as described above in the first, second and / or third embodiment.

[0095] Example 16: A compound represented by any one of Formulas I-IV, VII-IX and VII(A)-IX(A) or a pharmaceutically acceptable salt thereof, wherein R 12 is selected from isopropyl, fluoropropyl, trifluoroisopropyl, isobutyl, tert-butyl, isopropoxy, methylpyrrolidine, methylazetidine and hydroxycyclohexyl. The remaining variables in Formulas I-IV, VII-IX and VII(A)-IX(A) are as described above in the first, second, third and / or fifteenth embodiment.

[0096] Seventeenth embodiment: a compound represented by formula X:

[0097]

[0098] or a pharmaceutically acceptable salt thereof. The variables in Formula X are as described above in the first, second and / or third embodiment.

[0099] Embodiment 18: A compound represented by any one of Formulas I-IV and X or a pharmaceutically acceptable salt thereof, wherein R 14 The remaining variables in Formulas I-IV and X are as described above in the first, second and / or third embodiment.

[0100] Nineteenth embodiment: A compound represented by any one of Formulas I-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A) and X, or a pharmaceutically acceptable salt thereof, wherein X is OR 6 , and R 6 Selected from methyl, ethyl, propyl, isopropyl, trifluoroethyl, trifluoroisopropyl, difluoroethyl, difluoropropyl, difluoroisopropyl, oxetanyl, tetrahydrofuranyl, cyclobutyl and cyclopropyl, wherein cyclopropyl is optionally substituted by methyl or one or two fluorine, wherein cyclobutyl is optionally substituted by OH, wherein oxetanyl is optionally substituted by methyl. The remaining variables in formula I-IV and X are as described above in the first, second, third, seventh, eleventh, twelfth, fifteenth, sixteenth and / or eighteenth embodiment.

[0101] Embodiment 20: A compound represented by any one of Formulas I-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A) and X, or a pharmaceutically acceptable salt thereof, wherein X is OR 6 , and R 6 is selected from methyl, ethyl, propyl, isopropyl, trifluoroethyl, trifluoroisopropyl, difluoroethyl, difluoropropyl, difluoroisopropyl, oxetanyl, tetrahydrofuranyl, cyclobutyl and cyclopropyl, wherein the cyclopropyl group is optionally substituted with methyl or one or two fluorine groups. Alternatively, R6 is methyl; in another alternative embodiment, R 6 is ethyl; in another alternative, R 6 is trifluoroethyl; in another alternative, R 6 is difluoroethyl; in another alternative, R 6 is propyl; in another alternative, R 6 is difluoropropyl; in another alternative, R 6 is isopropyl; in another alternative, R 6 is trifluoroisopropyl; in another alternative, R 6 is difluoroisopropyl; in another alternative, R 6 is methylsulfonylethyl; in another alternative, R 6 is cyclopropyl; in another alternative, R 6 is cyclobutyl; in another alternative, R 6 Optionally R 9 Substitution, where R 9 It is C 1-3 Alkyl, halogen-substituted C 3-6 Cycloalkyl, halogen, C 1-3 alkoxy and OH; in another alternative, R 6 Is R 9 Substituted cyclopropyl, wherein R 9 is methyl or one or two fluorines; in another alternative, R 6 is oxetane; in another alternative embodiment, R 6 is tetrahydropyranyl; in another alternative, R 6 is tetrahydrofuranyl; and in another alternative, R 6 The remaining variables in Formulas I-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A), and X are as described above in the first, second, third, seventh, eleventh, twelfth, fifteenth, sixteenth, and / or eighteenth embodiment.

[0102] Embodiment 21: Compound X represented by any one of Formulas I-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A) or a pharmaceutically acceptable salt thereof, wherein X is NHR 7 , and R 7The remaining variables in Formulas I-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A), and X are described above in the first, second, third, seventh, eleventh, twelfth, fifteenth, sixteenth, and / or eighteenth embodiments.

[0103] Embodiment 22: Compound X represented by any one of Formulas I-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A), or a pharmaceutically acceptable salt thereof, wherein X is methyl. The remaining variables in Formulas I-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A) and X are described in the first, second, third, seventh, eleventh, twelfth, fifteenth, sixteenth and / or eighteenth embodiments above.

[0104] Embodiment 23: A compound represented by any one of Formulas I-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A) and X, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Each is independently selected from hydrogen, methyl, methyl substituted with OCH3, ethyl, hydroxymethyl, cyclopropyl and cyclobutyl. The remaining variables in Formulas I-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A) and X are described in the first, second, third, seventh, eleventh, twelfth, fifteenth, sixteenth, eighteenth, nineteenth, twentieth, twenty-first and / or twenty-second embodiments above.

[0105] Example 24: Compound X represented by any one of Formulas I-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A), or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each independently selected from hydrogen, methyl, hydroxymethyl, ethyl, cyclopropyl and cyclobutyl. 3 and R 4 Each independently selected from C 1-6 Alkyl and C 3-6 Cycloalkyl; in another alternative, R 3 and R 4 Each independently selected from C 1-3 alkyl and cyclopropyl; in another alternative, R 3 is methyl and R 4 is methyl; in another alternative, R 3 is H and R4 is methyl; in another alternative, R 3 is ethyl and R 4 is methyl; in another alternative, R 3 is CH2OH and R 4 is methyl; in another alternative, R 3 is methyl and R 4 is cyclopropyl; in another alternative, and in yet another alternative, R 3 is methyl and R 4 The remaining variables in Formulas I-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A), and X are described above in the first, second, third, seventh, eleventh, twelfth, fifteenth, sixteenth, eighteenth, nineteenth, twentieth, and / or twenty-first embodiments.

[0106] The present disclosure also includes compounds described and prepared in the Examples in Table 1. Synthetic schemes used to prepare the compounds in Table 1 are listed in the last column of Table 1, and the full details of each synthetic scheme are described in Schemes 1-17 in the General Synthetic Methods and Intermediates section.

[0107] Table 1

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175] Included in the present teachings are pharmaceutically acceptable salts of the compounds disclosed herein (including compounds disclosed in Table 1 and the Examples) as well as the corresponding neutral forms.

[0176] In another embodiment of the present disclosure, deuterated is a compound disclosed herein, including compounds of Formulas I-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A) and X, or compounds in Table 1 and the Examples, or any pharmaceutically acceptable salt of the foregoing, wherein one or more hydrogen atoms are replaced by deuterium. The deuterium enrichment at any position where hydrogen has been replaced by deuterium is at least 50%, 75%, 85%, 90%, 95%, 98% or 99%. Deuterium enrichment is a molar percentage and is obtained by dividing the number of compounds having deuterium enrichment at the enriched position by the number of compounds having hydrogen or deuterium at the enriched position.

[0177] definition

[0178] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutical salt that is suitable for use in contact with the tissues of humans and lower animals within the scope of sound medical judgment without excessive toxicity, irritation, allergic response and with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe in J. Pharm. Sci. (1977) 66: 1-19. The compounds of the present teachings having a basic group can form pharmaceutically acceptable salts with pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include, for example, salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and sulfuric acid) and organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid and p-toluenesulfonic acid). The compounds of the present teachings having an acidic group can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).

[0179] The term "alkyl" used alone or as part of a larger moiety, such as "alkoxy", "hydroxyalkyl", etc., means a saturated aliphatic straight or branched chain monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 6 carbon atoms (C 1-6 alkyl), optionally 1 to 3 carbon atoms (C 1-3 alkyl). 1-6The term "alkyl" refers to a straight or branched free radical having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.

[0180] "Alkoxy" means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl, wherein alkyl is as defined above. For example, "C1-6 alkoxy" includes methoxy, ethoxy, propoxy, butoxy, pentyloxy, isopentyloxy, isopropoxy, and hexyloxy.

[0181] The term "halogen" or "halo" refers to fluorine or fluorine (F), chlorine or chlorine (Cl), bromine or bromine (Br), or iodine or iodine (I).

[0182] "Cycloalkyl" means a saturated aliphatic cyclic hydrocarbon ring radical. Unless otherwise specified, a cycloalkyl group has 3 to 8 ring carbon atoms (C 3-8 cycloalkyl) (i.e., 3, 4, 5, 6, 7 or 8), alternatively 3 to 6 ring carbon atoms (C 3-6 cycloalkyl) (i.e., 3, 4, 5 or 6), alternatively 3 to 5 carbon atoms (C 3-5 cycloalkyl) (i.e., 3, 4 or 5). "C 3-6 "Cycloalkyl" refers to a radical having 3 to 6 carbon atoms arranged in a single ring. 3-6 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 3-5 Cycloalkyl groups include cyclopropyl, cyclobutyl and cyclopentyl.

[0183] The term "heterocycle" refers to a monocyclic non-aromatic ring radical, unless otherwise specified, containing 3 to 8 ring atoms selected from carbon atoms and 1 or 2 heteroatoms (i.e., "3, 4, 5, 6, 7 or 8 members"). Each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO); oxygen; and sulfur, including sulfoxides and sulfones. Representative heterocycles include morpholinyl, thiomorpholinyl, pyrrolidonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactam, oxiranyl, oxetane, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, etc.

[0184] The term "substituted", whether or not preceded by the term "optionally", refers to the replacement of hydrogen substituents in a given structure with non-hydrogen substituents. Thus, for example, a substituted alkyl is an alkyl group in which at least one non-hydrogen substituent replaces a hydrogen substituent on the alkyl group. For illustration, a monofluoroalkyl group is an alkyl group substituted with a fluorine substituent, and a difluoroalkyl group is an alkyl group substituted with two fluorine substituents. It should be recognized that if more than one substituent is present on a substituent, each non-hydrogen substituent may be the same or different (unless otherwise specified).

[0185] If a group is described as "optionally substituted," the group can be (1) unsubstituted, or (2) substituted.

[0186] If a group is described as being optionally substituted with up to a specified number of non-hydrogen substituents, then the group can be (1) unsubstituted; (2) substituted with up to that specified number of non-hydrogen substituents or with up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a group is described as being cycloalkyl optionally substituted with up to 3 non-hydrogen substituents, then any cycloalkyl group having fewer than 3 substitutable positions can be optionally substituted with up to as many non-hydrogen substituents as the cycloalkyl group has substitutable positions.

[0187] Compounds with one or more chiral centers can exist in multiple stereoisomeric forms, i.e., each chiral center can have the R or S configuration or can be a mixture of the two. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are 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.

[0188] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is described by its chemical name (e.g., where the configuration is indicated by "R" or "S" in the chemical name) or structure (e.g., where the configuration is indicated by a "wedge-shaped" bond), the enrichment of the specified configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9% (unless the structure or name is accompanied by the designation "rac" or "racemate," as explained in the following two paragraphs). The "enrichment of a specified configuration relative to the opposite configuration" is a molar percentage and is determined by dividing the number of compounds having a specified stereochemical configuration at a chiral center by the total number of all compounds in the mixture having the same or opposite stereochemical configuration.

[0189] When the stereochemical configuration at a chiral center in a compound is described by a chemical name (e.g., where the configuration is indicated by "R" or "S" in the name) or structure (e.g., where the configuration is indicated by a "wedge-shaped" bond), and the name "racemic" or "racemate" accompanies the structure or is specified in the chemical name, a racemic mixture is intended.

[0190] When two or more stereoisomers are described by their chemical names or structures and the names or structures are linked by "or", it means one or the other of the two or more stereoisomers, but not both.

[0191] When a disclosed compound having a chiral center is described by a structure without showing the configuration at the chiral center, the structure is meant to encompass compounds having the S configuration at the chiral center, compounds having the R configuration at the chiral center, or compounds having a mixture of R and S configurations at the chiral center. When a disclosed compound having a chiral center is described by its chemical name without using "S" or "R" to indicate the configuration at the chiral center, the name is meant to encompass compounds having the S configuration at the chiral center, compounds having the R configuration at the chiral center, or compounds having a mixture of R and S configurations at the chiral center.

[0192] A racemic mixture refers to 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 and diastereomeric mixtures of the compounds described herein.

[0193] Enantiomeric and diastereomeric mixtures can be separated into their component enantiomers or stereoisomers by well-known methods such as chiral gas chromatography, chiral high performance liquid chromatography, crystallization of the compound as a chiral salt complex or crystallization of the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically pure or enantiomerically pure intermediates, reagents and catalysts by well-known asymmetric synthesis methods.

[0194] "Peak 1" or "first eluting isomer" in the experimental section refers to the expected reaction product compound obtained from the chromatographic separation / purification, which elutes earlier than the second expected reaction product compound from the same previous reaction. The second expected product compound is referred to as "Peak 2" or "second eluting isomer".

[0195] When a compound is represented by a name or structure indicating a single enantiomer, unless otherwise indicated, the optical purity of the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% (also referred to as "enantiomerically pure"). The optical purity is the weight of the named or depicted enantiomer in the mixture divided by the total weight of the two enantiomers in the mixture.

[0196] When the stereochemistry of a disclosed compound is named or depicted by a structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereoisomer pair), it is understood that, unless otherwise indicated, one of the stereoisomers encompassed or any mixture of the stereoisomers encompassed is included. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. In this case, the stereoisomeric purity is determined by dividing the total weight of the stereoisomers encompassed by the name or structure in the mixture by the total weight of all stereoisomers in the mixture.

[0197] use

[0198] The compounds disclosed herein are MAP4K1 inhibitors. The use of the word "inhibitor" refers to a compound or a pharmaceutically acceptable salt thereof that inhibits the activity of MAP4K1. "Inhibition" herein means reducing the activity of the target enzyme compared to the activity of the target enzyme in the absence of the inhibitor. In some alternatives, the term "inhibit" refers to a reduction in MAP4K1 activity of at least 5%, at least 10%, at least 20%, at least 50%, at least 60%, at least 79%, at least 80%, at least 90% or at least 95%. In other alternatives, inhibition refers to a reduction in MAP4K1 activity of 5% to 25%, 25% to 50%, 50% to 70%, 75% to 100%. In some embodiments, inhibition refers to a reduction in MAP4K1 activity of about 95% to 100%, for example, a reduction in activity of 95%, 96%, 97%, 98%, 99% or 100%. This reduction can be measured using a variety of techniques that will be recognized by those skilled in the art, including in vitro kinase assays.

[0199] The compounds disclosed herein are selective MAP4K1 inhibitors. As used herein, a "selective MAP4K1 inhibitor" refers to a compound or a pharmaceutically acceptable salt thereof that has the ability to selectively inhibit MAP4K1 kinase relative to other targets. More specifically, a selective MAP4K1 inhibitor has the ability to selectively inhibit MAP4K1 relative to another kinase. Selective MAP4K1 inhibitors are able to selectively reduce target signaling activity relative to off-target signaling activity via direct or indirect interactions with the target. The ability to selectively target MAP4K1 with a compound or a pharmaceutically acceptable salt thereof provides advantages in terms of improved efficacy, less off-target activity, and increased probability of clinical success compared to non-selective compounds or salts. A MAP4K1 inhibitor that selectively inhibits MAP4K1 can have at least 2-fold activity relative to another kinase (e.g., at least 10-fold; at least 15-fold; at least 20-fold; at least 30-fold; at least 40-fold selectivity; at least 50-fold; at least 60-fold; at least 70-fold; at least 80-fold; at least 90-fold; at least 100-fold; at least 125-fold; at least 150-fold; at least 175-fold; or at least 200-fold. In some alternatives, the selective MAP4K1 inhibitor exhibits at least 15-fold selectivity relative to another kinase, such as LCK and MAP4K family members (MAP4K4 (HGK) and MAP4K3 (GLK)). In some alternatives, the selective MAP4K1 inhibitor is selective for EGFR and L858R / T790M EGFR. In some alternatives, the selective MAP4K1 inhibitors of the present disclosure are selective for BTK. In some alternatives, the selective MAP4K1 inhibitors of the present disclosure are selective for JNK.

[0200] The present disclosure provides a method for regulating (e.g., inhibiting) MAP4K1 activity in a patient in need thereof, the method comprising administering a compound or a pharmaceutically acceptable salt thereof provided herein to the patient. In certain embodiments, the compounds of the present disclosure or a pharmaceutically acceptable salt thereof may be used for therapeutic administration to enhance, stimulate and / or increase the immunity of a patient in need thereof, such as a cancer patient or a patient with a viral infection. In some cases, the compounds of the present disclosure or a pharmaceutically acceptable salt thereof reduces, inhibits or otherwise reduces pSLP76. In some cases, the compounds of the present disclosure or a pharmaceutically acceptable salt thereof may be used for therapeutic administration to enhance at least one of the activation, priming, migration, proliferation, survival and cytolytic activity of T cells relative to before administration. In certain aspects, T cell activation is characterized by an increase in the level of IL-2, IFN-γ or granzyme B produced by T cells relative to before administration of the compound or a pharmaceutically acceptable salt thereof. In some cases, the compounds of the present disclosure or a pharmaceutically acceptable salt thereof may be used for therapeutic administration to induce changes in the cell cycle or cell viability. In some cases, the compounds of the present disclosure or a pharmaceutically acceptable salt thereof may be used to improve the function of T effector cells. In some cases, the compounds of the present disclosure or their pharmaceutically acceptable salts can be used to suppress the inhibitory effect of T regulatory cells or improve the response of T cells to immunosuppressive factors including adenosine and PGE2. In some cases, the compounds of the present disclosure or their pharmaceutically acceptable salts can be used to increase the frequency of CD8+ tumor infiltrating lymphocytes (TILS). In some cases, the compounds of the present disclosure or their pharmaceutically acceptable salts can be used to improve the CD8+ / Treg ratio. In some cases, the compounds of the present disclosure or their pharmaceutically acceptable salts can be used to enhance cytokines. In some cases, the compounds of the present disclosure or their pharmaceutically acceptable salts can be used to enhance cytokines without affecting IL-6. In some cases, the compounds of the present disclosure or their pharmaceutically acceptable salts indirectly inhibit the growth of cancer cells. In some cases, the compounds of the present disclosure or their pharmaceutically acceptable salts can be used to induce an immune response (i.e., vaccine) to a tumor or virus, for enhancing or producing antiviral / anti-tumor immunity. In one case, the compounds of the present disclosure or their pharmaceutically acceptable salts can be used to enhance or promote the response to a vaccine (e.g., a cancer vaccine or a personalized cancer vaccine (PCV)) or CAR-T cell therapy.

[0201] Methods for treating MAP4K1-dependent diseases or disorders may comprise administering to a patient in need thereof a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof. 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 carcinomas, melanomas, blastomas, sarcomas, lymphomas, leukemias. In some embodiments, cancer includes metastatic forms. In addition, the present disclosure includes refractory or recurrent malignancies whose growth can be inhibited using the compounds of the present disclosure or pharmaceutically acceptable salts thereof. For the uses described herein, any compound of the present disclosure or a pharmaceutically acceptable salt thereof may be used alone or in combination with other therapeutic agents.

[0202] In some embodiments, the treatment results in a sustained response in the subject after the treatment has stopped. A "sustained response" refers to a sustained effect on reducing tumor growth after the treatment has stopped. For example, the tumor size can 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 the same as the duration of treatment, at least 1.5 times, 2.0 times, 2.5 times, or 3.0 times the length of the duration of treatment.

[0203] The treatment methods disclosed herein can result in a 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 a reduction of at least 30% in the sum of the longest diameters (SLD) of target lesions with reference to the baseline SLD; and "stable disease" or "SD" refers to target lesions that are neither sufficiently reduced to meet PR nor sufficiently increased to meet PD, with the smallest SLD since the start of treatment as a reference. As used herein, "overall response rate" (or R) refers to the sum of the complete response (CR) rate and the partial response (PR) rate.

[0204] The treatment methods disclosed herein can result in an increase in 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 treated disease (e.g., cancer) does not worsen. Progression-free survival can include the amount of time a patient experiences a complete response or a partial response, as well as the amount of time a patient experiences stable disease.

[0205] As used herein, "overall survival" (OS) refers to the percentage of subjects in a group who are likely to survive after a specific duration.

[0206] In some embodiments, cancers that can be treated with the compounds of the present disclosure, or pharmaceutically acceptable salts 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.

[0207] In some embodiments, cancers that may be treated with the compounds of the present disclosure, or pharmaceutically acceptable salts 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.

[0208] In some embodiments, cancers that may be treated using the compounds of the present disclosure, or pharmaceutically acceptable salts 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, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, brain cancer, and bladder cancer and hematological cancers, including lymphomas, leukemias (chronic and acute forms), such as ALL, AML, CLL, CML, DLBCL, mantle cell lymphoma, non-Hodgkin lymphoma (NHL), including relapsed or refractory NHL and relapsed follicular, Hodgkin lymphoma and multiple myeloma, and myeloproliferative diseases.

[0209] In some embodiments, diseases and indications that may be treated using the compounds of the present disclosure or pharmaceutically acceptable salts thereof include, but are not limited to, hematological cancers, sarcomas, respiratory tract cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, cancers of the nervous system, gynecological cancers, and skin cancers.

[0210] Exemplary hematological cancers include, for example, lymphomas and leukemias, such as ALL, AML, acute promyelocytic leukemia (APL), CLL, CML, DLBCL, mantle cell lymphoma, non-Hodgkin lymphoma (NHL), including primary mediastinal B-cell lymphoma (PMBCL), relapsed or refractory NHL, relapsed follicular and primary CNS lymphomas, Hodgkin lymphoma, myeloproliferative disorders, including primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET), myelodysplastic syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's Macroglubulinemia, hairy cell lymphoma, chronic myeloid lymphoma, and Burkitt's lymphoma.

[0211] Exemplary sarcomas include, e.g., chondrosarcoma, Ewing sarcoma, Kaposi sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, hamartoma, soft tissue sarcoma, and teratoma.

[0212] Exemplary respiratory tract cancers include, e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC), small cell lung cancer, epidermoid carcinoma, bronchial carcinoma, including squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, enchondromatous hamartoma, mesothelioma, and pleuropulmonary blastoma.

[0213] Exemplary gastrointestinal cancers include, for example, cancers of the esophagus, including squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma; cancers of the stomach, including carcinoma, lymphoma, and leiomyosarcoma; cancers of the pancreas, including ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, and vipoma; cancers of the small intestine, including adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, and fibroma; cancers of the large intestine, including adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyoma; cancers of the colon; and cancers of the gallbladder, including adenocarcinoma; as well as intestinal and diffuse gastric adenocarcinomas, rectal cancer, common adenomatous polyposis carcinoma, and hereditary nonpolyposis colorectal cancer.

[0214] Exemplary genitourinary tract cancers include, for example, cancers of the kidney, including adenocarcinoma, Wilms' tumour or [Nephroblastoma], renal cell carcinoma, urothelial carcinoma, juxtaglomerular cell tumor (nephroma), angiomyolipoma, renal oncocytoma, Bellinio duct carcinoma, renal clear cell sarcoma, and mesoblastic nephroma; adrenal 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.

[0215] Exemplary liver cancers include, for example, liver cancers including hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, biliary tract cancer, and hemangioma.

[0216] 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, bone fibromas including osteochondroma exostosis, benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor.

[0217] Exemplary nervous system cancers include, e.g., skull cancers, including osteomas, hemangiomas, granulomas, xanthomas, and osteitis deformans; meningeal cancers, including meningiomas, meningiosarcomas, and gliomatosis; brain cancers, including astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), neuroectodermal tumors, glioblastomas, glioblastomas multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors, brain stem and hypothalamic gliomas; and spinal cord cancers, including neurofibromas, meningiomas, gliomas, and sarcomas; as well as neuroblastoma and Lhermitte-Duclos disease.

[0218] Exemplary gynecological cancers include, for example, uterine cancer, including endometrial cancer; cervical cancer, including cervical cancer, preneoplastic cervical dysplasia, squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumors, glassy cell carcinoma, and choriocarcinoma; ovarian cancer, including ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, endometrioma), granulosa-thecal cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma, and Wilms' tumor; vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma; vagina, including clear cell carcinoma, squamous cell carcinoma, and botryoid sarcoma (embryonal rhabdomyosarcoma); labia; and fallopian tube.

[0219] Exemplary skin cancers include, for example, melanoma, sebaceous gland carcinoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin carcinoma, nevus dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloids.

[0220] Examples of breast cancer include, e.g., ER+ / HER2- breast cancer, triple negative breast cancer (TNBC), invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.

[0221] Exemplary head and neck cancers include, e.g., glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cancer, pharyngeal cancer, including oropharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, nasal and paranasal cancer, salivary gland cancer, oral cancer, eye cancer, acoustic neuroma, pituitary adenoma, hypopharyngeal cancer, and thyroid (medullary and papillary) and parathyroid cancer.

[0222] Other cancers include, for example, sweat gland cancer, spinal tumors, breast cancer, sickle cell anemia, and environmentally induced cancers, including those caused by asbestos.

[0223] In some instances, 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).

[0224] Combination therapy

[0225] The compounds of the present disclosure or their pharmaceutically acceptable salts can be used as a single pharmaceutical agent or in combination with one or more other anticancer agents for the treatment of cancer, wherein the combination does not cause unacceptable side effects. In some embodiments, the other anticancer agent is an immuno-oncology agent, an anticancer agent as an enzyme / protein / receptor inhibitor, radiation or chemotherapy.

[0226] The compounds of the present disclosure or pharmaceutically acceptable salts thereof can be co-formulated with immuno-oncology agents. Immuno-oncology agents include, for example, small molecule drugs, antibodies or other biological or small molecules. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies and cytokines. In one aspect, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized or human. In another aspect, the antibody is a bispecific antibody.

[0227] In one aspect, the immuno-oncology agent is (i) an agonist of a stimulatory (including co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on T cells, both of which result in the amplification of antigen-specific T cell responses (commonly referred to as immune checkpoint modulators).

[0228] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory 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 co-stimulatory or co-inhibitory receptors is the family of TNF molecules that bind to cognate TNF receptor family members, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTfiR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin alpha / TNPβ, TNFR2, TNF alpha, LTR, lymphotoxin alpha 1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0229] In one aspect, T cell responses can be stimulated by a combination of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, with one or more of the following: (i) antagonists of proteins that inhibit T cell activation (e.g., immune checkpoint inhibitors) 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) agonists 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.

[0230] Other agents that can be combined with the compounds of the present disclosure or their pharmaceutically acceptable salts for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, the compounds of the present disclosure can be combined with antagonists of KIR, such as lirilumab.

[0231] Other agents for combination therapy 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.

[0232] In another aspect, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can be combined with one or more agonists that bind to positive co-stimulatory receptors, blockers that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, overcome different immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor engagement (e.g., PD-L1 / PD-1 interaction), deplete or inhibit Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse / prevent T cell anergy or exhaustion), and agents that elicit innate immune activation and / or inflammation at the tumor site.

[0233] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist, such as an antagonist CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab. In another aspect, the immuno-oncology agent is a PD-1 antagonist, such as an antagonist PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab) or MEDI-0680 (AMP-514; WO2012 / 145493). Immuno-oncology agents may also include pidilizumab (CT-011), although its specificity for PD-1 binding is questioned. Another method of targeting the PD-1 receptor is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, referred to as AMP-224.

[0234] In another aspect, the immuno-oncology agent is a PD-L1 antagonist, such as an antagonist PD-L1 antibody. Suitable PD-L1 antibodies include, for example, TECENTRIQ (atezolizumab) (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0235] In another aspect, the immuno-oncology agent is a LAG-3 antagonist, such as an antagonist LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0236] In another aspect, the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12 / 32433).

[0237] In another aspect, the immuno-oncology agent is a GITR agonist, such as an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116), and MK-4166 (WO11 / 028683).

[0238] In another aspect, the immuno-oncology agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO2006 / 122150, WO07 / 75598, WO08 / 36653, WO08 / 36642), indoximod or NLG-919 (WO09 / 73620, WO09 / 1156652, WO111 / 56652, WO12 / 142237).

[0239] In another aspect, the immuno-oncology agent is an OX40 agonist, such as an agonist OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469. In another aspect, the immuno-oncology agent is an OX40L antagonist, such as an antagonist OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0240] In another aspect, the immuno-oncology agent is a CD40 agonist, such as an agonistic CD40 antibody. In another embodiment, the immuno-oncology agent is a CD40 antagonist, such as an antagonist CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dasitumumab.

[0241] In another aspect, the immuno-oncology agent is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varilumab.

[0242] In another aspect, the immuno-oncology agent is MGA271 (to B7H3) (WO 11 / 109400).

[0243] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can be used in combination with anticancer agents that are enzyme / protein / receptor inhibitors to treat such conditions, the anticancer agents exhibiting different preferences in the targets at which they modulate activity. Targeting more than one signaling pathway (or more than one biomolecule involved in a given signaling pathway) can reduce the likelihood of drug resistance arising in a cell population, and / or reduce the toxicity of the treatment.

[0244] The compounds of the present disclosure or their pharmaceutically acceptable salts can be used in combination with one or more other enzyme / protein / receptor inhibitors for the treatment of cancer. For example, the compounds of the present disclosure or their pharmaceutically acceptable salts can be used in combination with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-βPv, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mT or, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFotR, PDGFpR, CSFIR, KIT, FLK-II , KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt2 , Flt4, EphAl, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf.

[0245] In some embodiments, the compounds of the present invention or their pharmaceutically acceptable salts 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 the compounds of the present invention for the treatment of cancer include FGFR inhibitors (FGFR1, FGFR2, FGFR3 or FGFR4, such as filgotinib, AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258, deritinib, dovitinib, TAS-120, J J-42756493, Debiol347, INCB54828, INCB62079 and INCB63904), JAK inhibitors (JAK1 and / or JAK2, such as ruxolitinib, baricitinib or itatinib (INCB39110)), IDO inhibitors (e.g., epacadostat and NLG919), LSD1 inhibitors (e.g., GSK2979552, INCB59872 and INCB60003), TDO inhibitors, PI3K-δ inhibitors (e.g., INCB50797 and INCB50465), PI3K-γ inhibitors , such as PI3K-γ selective inhibitors (eganelisib) or dual PI3K-δ / γ selective inhibitors (duvelisib), CSF1R inhibitors (e.g., PLX3397 and LY3022855), TAM receptor tyrosine kinases (Tyro-3, Axl and Mer), angiogenesis inhibitors (e.g., Avastin (bevacizumab)), interleukin receptor inhibitors, bromo and extra terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, such as OTX015, CPI-0610, INCB54329 and INCB57643) and adenosine receptor antagonists or combinations thereof. HDAC inhibitors such as panobinostat and vorinostat can be combined with the compounds of the present disclosure. Inhibitors of c-Met such as obinutuzumab, tivantnib and capmatinib (INC-280) are combined with the compounds of the present disclosure or pharmaceutically acceptable salts thereof. BTK inhibitors such as ibrutinib can be combined with compounds of the present invention or pharmaceutically acceptable salts thereof. mT or inhibitors such as rapamycin, sirolimus, temsirolimus and everolimus can be combined with compounds of the present invention or pharmaceutically acceptable salts thereof. Raf inhibitors such as vemurafenib and dabrafenib can be combined with compounds of the present invention or pharmaceutically acceptable salts thereof. MEK inhibitors such as trametinib, selumetinib and GDC-0973 can be combined with compounds of the present invention or pharmaceutically acceptable salts thereof.Inhibitors of KIT include avaprinib, imatinib, sunitinib, regorafenib, ripretinib (DCC2618), PLX9486, PLX3397, crelanib, CDX-0158, CDX-0159. Inhibitors of RET include palacitinib, selpatinib, alectinib, lenvatinib, cabozantinib, BOS172738 (DS-5010), SL-1001, TPX-0046, sitritinib (MGCD516) and RXDX-105. Inhibitors of Hsp90 (e.g., tanspiramycin), cyclin-dependent kinases (e.g., palbociclib), PARP (e.g., olaparib) and Pim kinases (LGH447, INCB053914 and SGI-1776) can also be combined with the compounds or pharmaceutically acceptable salts of the present disclosure.

[0246] Compounds of the present disclosure or pharmaceutically acceptable salts thereof can be used in combination with one or more medicaments for the treatment of cancer. In certain embodiments, the medicament is an alkylating agent, a proteasome inhibitor, a corticosteroid or an immunomodulator. Examples of alkylating agents include bendamustine, nitrogen mustard, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas and triazenes, uracil mustard, chlormethine, cyclophosphamide (CYTOXAN), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene melamine, triethylene thiophosphamide, busulfan, carmustine, lomustine, streptozotocin, dacarbazine and temozolomide. In certain embodiments, the proteasome inhibitor is carfilzomib. In certain embodiments, the corticosteroid is dexamethasone (DEX).

[0247] The compounds of the present disclosure or their pharmaceutically acceptable salts can be administered in combination with one or more anticancer drugs such as chemotherapeutic agents. Exemplary chemotherapeutic agents include any of the following: abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, hexamethylmelamine, anastrozole, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib, bupanib, intravenous busulfan, intravenous, oral busulfanoral, calusterone, capecitabine, carmustine, cediranib, cetuximab, chlorambucil, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib, actinomycin D, daunorubicin, decitabine, degarelix, denileukin, denileukin diftitox, deoxycoformycin, dexrazoxane, docetaxel, doxorubicin, diphenoxylate, dromostanolone propionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citratecitrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab, ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, idelalib, ifosfamide, imatinib mesylate, interferon α2a, irinotecan, lapatinib ditosylate ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolone phenylpropionate phenpropionate, navelbene, naxitozumab, nelarabine, neratinib, nilotinib, nilutamide, nofetumomab, oserelin, paclitaxel, pamidronate, panitumumab, pazopanib, pegaspargase, pegfilgrastim, pemetrexeddisodium), pentostatin, pilaralisib, pipobroman, plicamycin, cisplatin, carboplatin, oxaliplatin, ponatinib, prednisone, procarbazine, quinacridone, regorafenib, reloxafem, rituximab, ruxolitinib, sorafenib, streptozotocin, sunitinib, sunitinib maleate, tamoxifen, tegafur, temozolomide, teniposide, topotecan, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronic acid.

[0248] Other anti-cancer agents include antibody therapeutics, such as trastuzumab (Herceptin).

[0249] The compounds of the present disclosure or their pharmaceutically acceptable salts can be used as a single pharmaceutical agent or in combination with one or more antiviral agents for the treatment of chronic viral infections, wherein 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, coxsackie virus, human immunodeficiency virus (HIV). Parasitic infections (e.g., malaria) can also be treated by the above method, wherein a compound known to treat parasitic diseases is optionally added instead of an antiviral agent.

[0250] 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 drugs.

[0251] Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-I0652; emtricitabine [(-)-FTC]; β-L-FD4 (also known as β-L-D4C and designated β-L-2',3'-dicleoxy-5-fluoro-cytidine); DAPD, ((-)-β-D-2,6-diamino-purine dioxolane); and ferulosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delavirdine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyridinedione); and (+)-calanolide A (NSC-675451)) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfinavir (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, pentafusi; and Yissum Project No. 11607.

[0252] When more than one pharmaceutical agent is administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (e.g., for more than two agents). For example, when administered with another anticancer agent or antiviral agent, the disclosed compounds or pharmaceutically acceptable salts thereof may be administered simultaneously in the same pharmaceutical formulation or simultaneously in separate pharmaceutical formulations. Alternatively, when administered with another anticancer agent or antiviral agent, the disclosed compounds or pharmaceutically acceptable salts thereof may be administered at different times, depending on the dosing requirements of the other anticancer agent or antiviral agent.

[0253] Disclosed are pharmaceutical compositions comprising one or more compounds provided herein (e.g., compounds of Formulas I-IV, V(A)-V(C), VI(A)-VI(C), VII-IX, VII(A)-IX(A), and X) or pharmaceutically acceptable salts thereof, and typically at least one additional substance, such as an excipient, a known therapeutic agent other than the therapeutic agent disclosed herein, and combinations thereof. In some embodiments, the disclosed compounds or pharmaceutically acceptable salts thereof may be used in combination with other agents known to have beneficial activity targeting the above-mentioned diseases or disorders. For example, the disclosed compounds or pharmaceutically acceptable salts thereof may be administered alone or in combination with one or more anticancer agents or antiviral agents and pharmaceutically acceptable salts of these compounds.

[0254] As used herein, the term "administer / administering / administration, etc." refers to methods that can be used to enable the delivery of a composition to a desired biological site of action. These methods include, but are not limited to, intraarticular (in a joint), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhaled, transdermal, rectal, etc. Administration techniques that can be used with the agents and methods described herein are found in, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa., Easton, Pa.

[0255] A "subject" is a mammal in need of medical treatment, preferably a human, but may also be an animal in need of veterinary treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0256] The exact amount of the compound or its pharmaceutically acceptable salt administered to provide an "effective amount" to the subject will depend on the mode of administration, the type and severity of the disease or condition, and on the characteristics of the subject, such as general health, age, sex, weight, and tolerance to drugs. Those skilled in the art will be able to determine the appropriate dose based on these and other factors. When administered in combination with other therapeutic agents, such as when administered in combination with anticancer agents or antiviral agents, the "effective amount" of any additional therapeutic agent will depend on the type of drug used. Suitable doses are known for approved therapeutic agents and can be adjusted by those skilled in the art based on the subject's condition, the type of condition being treated, and the amount of the compound of the present disclosure or its pharmaceutically acceptable salt used, for example, as reported in the literature and recommended in the Physician's Desk Reference (57th edition, 2003).

[0257] The term "effective amount" means an amount that produces a beneficial or desired result when administered to an individual, including a clinical result, such as inhibition, suppression or reduction of symptoms of the individual's treated condition as compared to a control. For example, a therapeutically effective amount can be given in unit dosage form (e.g., 0.1 mg to about 50 g / day, alternatively 1 mg to about 5 g / day; and further alternatively, 10 mg to 1 gram / day).

[0258] The specific mode of administration and administration regimen will be selected by the attending clinician considering the details of the case (e.g., the subject, the disease, the disease state involved, the specific treatment, and whether the treatment is prophylactic). Treatment may involve administration once a day or multiple times a day or less than once a day (e.g., once a week or once a month, etc.) over a period of several days to several months or even years.

[0259] The pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended routes of administration. In an embodiment, the composition is formulated according to conventional 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.

[0260] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that aid in the formulation and / or administration of active agents to subjects and / or aid in the absorption of subjects, and the substances can be included in the compositions of the present disclosure without causing significant adverse toxicological effects to subjects. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solutions, lactated Ringer's solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose or starch), fatty acid esters, carboxymethyl cellulose, polyvinyl pyrrolidone and coloring agents, etc. Such preparations can be sterilized and, if desired, can be mixed with adjuvants that do not react harmfully with the compounds provided herein or interfere with their activity, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for affecting osmotic pressure, buffers, coloring substances and / or aromatic substances, etc. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds.

[0261] General synthetic methods and intermediates

[0262] Compounds of the present disclosure, including salts and N-oxides thereof, can be prepared using organic synthesis techniques known to those of ordinary skill in the art and / or by reference to the schemes and synthetic examples shown below. The following scheme is a synthetic scheme intended to provide general guidance related to the preparation of compounds of the present disclosure. It will be appreciated by those skilled in the art that the general knowledge of organic chemistry can be used to modify or optimize the preparations shown in the schemes to prepare various compounds of the present disclosure.

[0263] The reaction for preparing the disclosed compound can be carried out in a suitable solvent that can be easily selected by the technician in the field of organic synthesis. Suitable solvent can be substantially unreactive with starting material (reactant), intermediate or product at the temperature (for example, the temperature range can be from the freezing temperature of the solvent to the boiling temperature of the solvent) at which the reaction is carried out. A given reaction can be carried out in a mixture of a solvent or more than one solvent. According to specific reactions steps, the technician can select a suitable solvent for a specific reaction step.

[0264] The preparation of the disclosed compounds may involve the protection and deprotection of various chemical groups. Those skilled in the art can easily determine the need for protection and deprotection and the selection of appropriate protecting groups. The chemical properties of protecting groups can be found in, for example, Wuts and Greene's "Protective Groups in Organic Synthesis", 5th edition, John Wiley & Sons: New Jersey (2014), which is incorporated herein by reference in its entirety.

[0265] The reaction can be monitored by any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance (NMR) spectroscopy (e.g., 1 H or 13 C), infrared (IR) spectroscopy, spectrophotometry (e.g., UV-Vis) and mass spectrometry (MS); or chromatographic methods, such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

[0266] Solution 1

[0267]

[0268] Scheme 1 shows a synthetic scheme for preparing compounds of formula via and vib.

[0269] In Scheme 1, R is defined as R as described for the embodiments of the present disclosure. 6 .

[0270] 8-Alkoxy-2,7-naphthyridinylmethyl ketone i (see Scheme 3 for preparation of i) can be reduced with sodium borohydride in methanol to give ii. Alcohol ii can be coupled with aniline under Pd-catalyzed coupling conditions to give iii. Benzyl alcohol iii can be treated with TMSN3 and indium bromide in dichloromethane to give the corresponding azide intermediate iv. Azide iv can be reduced under typical hydrogenation conditions such as Pd and H2 to give amine v. Chiral SFC on racemic amine v can produce the desired isomers via and vib (arbitrarily designated), which are examples of MAP4K1 inhibitors described herein.

[0271] Solution 2

[0272]

[0273] Scheme 2 shows a synthetic scheme for preparing compounds of formula iv.

[0274] In Scheme 2, R is defined as R as described for the embodiments of the present disclosure. 6 or R 7 The other variables in Scheme 2 are as described for the embodiments of the present disclosure.

[0275] 8-Alkoxy substituted 2,7-naphthyridinylbenzyl alcohol intermediate i (see Scheme 3 for preparation of i) can be coupled with aniline under Pd-catalyzed coupling conditions to give ii. Compound ii can be treated with TMSN3 and indium bromide in dichloromethane to produce the corresponding azide intermediate iii. Azide iii can be reduced under typical hydrogenation conditions such as Pd and H2 to produce amine iv, which is an example of a MAP4K1 inhibitor described herein.

[0276] Solution 3

[0277]

[0278] Scheme 3 shows a synthetic scheme for preparing compounds of formula viii.

[0279] In Scheme 3, R is defined as R as described for the embodiments of the present disclosure. 6 or R 7 , and X is O or N. The other variables are as described for the embodiments of the present disclosure.

[0280] The trihalogen intermediate i (see intermediate 31 in the common intermediates for the synthesis of intermediate i) can be treated with an alcohol or an amine to produce intermediate ii. Intermediate ii can be Stille coupled with tributyl(1-ethoxyvinyl)stannane to produce iii. Under acidic conditions, iii can be converted to methyl ketone iv. Subsequent addition of alkyl lithium or alkyl magnesium bromide can produce intermediate v. Compound v can be treated with TMSN3 and indium bromide in dichloromethane to give the corresponding azide intermediate vi. Azide vi can be coupled with an aromatic amine under Pd-catalyzed coupling conditions to produce vii. Compound vii can be reduced under typical hydrogenation conditions such as Pd and H2 to produce amine viii, which is an example of a MAP4K1 inhibitor described herein. The final amine viii can be separated into isomers using chromatography.

[0281] Solution 4

[0282]

[0283] Scheme 4 shows a synthetic scheme for preparing compounds of formula ix.

[0284] In Scheme 4, R is defined as R as described for the embodiments of the present disclosure. 6The other variables in Scheme 4 are as described for the embodiments of the present disclosure.

[0285] Benzylamine i can be condensed with methyl 2,2-diethoxyacetimidate to give 2-aminoquinoline intermediate ii. Intermediate ii can be Stille coupled with tributyl(1-ethoxyvinyl)stannane to produce iii. Under acidic conditions, iii can be converted to methyl ketone iv. 2-Aminoquinoline iv can be diazotized to 2-chloroquinoline v using sodium nitrite and cuprous chloride. Subsequent addition of alkylmagnesium bromide can produce intermediate vi. Compound vi can be coupled with aryl amines under Pd-catalyzed coupling conditions to produce vii. Intermediate vii can be treated with TMSN3 and indium bromide in dichloromethane to give the corresponding azide intermediate viii. Azide viii can be reduced under typical hydrogenation conditions such as Pd and H2 to produce amine ix, which is an example of a MAP4K1 inhibitor described herein.

[0286] Solution 5

[0287]

[0288] Scheme 5 shows a synthetic scheme for preparing compounds of formula iii.

[0289] In Scheme 5, R is defined as R as described for the embodiments of the present disclosure. 7 The other variables in Scheme 5 are as described for the embodiments of the present disclosure.

[0290] Intermediate i (see Scheme 3 for preparation of intermediate i) can be converted to pyridone ii under acidic conditions. Compound ii can be coupled with an alkylamine using a coupling agent such as BOP and DBU in DMF to give compound iii, which is an example of a MAP4K1 inhibitor described herein.

[0291] Solution 6

[0292]

[0293] Scheme 6 shows a synthetic scheme for preparing compounds of formula vii.

[0294] In Scheme 6, R is defined as R as described for the embodiments of the present disclosure. 7 The other variables in Scheme 6 are as described for the embodiments of the present disclosure.

[0295] Intermediate i (see Scheme 3 for preparation of i) can be reduced under Staudinger reaction conditions using triphenylphosphine and water to give amine ii. Conversion to pyridone iii can be performed under acidic conditions. Benzylamine can then be protected with Boc-anhydride and TEA to give intermediate iv. Compound iv can be coupled with alkylamine using coupling agent BOP in DMF to give v. Compound v can be coupled with arylamine under Pd-catalyzed coupling conditions to give vi. The Boc group can be deprotected using HCl or other acidic conditions to give amine vii, which is an example of a MAP4K1 inhibitor described herein.

[0296] Solution 7

[0297]

[0298] Scheme 7 shows a synthetic scheme for preparing compounds of formula viii.

[0299] Trihalogen intermediate i (see Intermediate 32 in Common Intermediates for the Synthesis of Intermediate i) can undergo Stille coupling with tributyl(1-ethoxyvinyl)stannane to give ii. Under acidic conditions, ii can be converted to methyl ketone iii. Compound iii can be treated with alcohol using potassium carbonate in methanol to produce intermediate iv. Subsequent addition of alkylmagnesium bromide can produce intermediate v. Compound v can be treated with TMSN3 and indium bromide in dichloromethane to give the corresponding azide intermediate vi. Azide vi can be coupled with aromatic amines under Pd-catalyzed coupling conditions to produce vii. Compound vii can be reduced under typical hydrogenation conditions such as Pd and H2 to produce amine viii, which is an example of a MAP4K1 inhibitor described herein.

[0300] Solution 8

[0301]

[0302] Scheme 8 shows a synthetic scheme for preparing compounds of formula vii.

[0303] The trihalogen intermediate i (see intermediate 31 in common intermediates for the synthesis of intermediate i) can be treated with an alcohol or an amine to produce intermediate ii. Intermediate ii can undergo Pd-catalyzed carbonylation to produce iii. Subsequent addition of alkyl lithium or alkyl magnesium bromide can produce intermediate iv. Compound iv can be treated with TMSN3 and indium bromide in dichloromethane to produce the corresponding azide intermediate v. Azide v can be coupled with an aryl amine under Pd-catalyzed coupling conditions to produce vi. Compound vi can be reduced under typical hydrogenation conditions such as Pd and H2 to produce amine vii, which is an example of a MAP4K1 inhibitor described herein.

[0304] Solution 9

[0305]

[0306] Scheme 9 shows a synthetic scheme for preparing compounds of formula vi.

[0307] Intermediate i (see Scheme 3 for the preparation of i) can be converted to pyridone ii under acidic conditions. Intermediate ii can be treated with POCl3 to give compound iii, which is then reacted with an alcohol such as oxetane-3-ol, cyclobutanol, methyloxetane-3-ol using potassium carbonate to give 8-alkoxy intermediate iv. Compound iv can be coupled with an aryl amine under Pd-catalyzed coupling conditions to give v. Compound v can be reduced under typical hydrogenation conditions such as Pd and H2 to give amine vi, which is an example of a MAP4K1 inhibitor described herein.

[0308] Solution 10

[0309]

[0310] Scheme 10 shows a synthetic scheme for preparing compounds of formula ii.

[0311] Intermediate i (see Scheme 3 for the preparation of intermediate i) can be converted to methylamine ii by one-pot reduction with Pd / C and H2 followed by reductive amination with formaldehyde in MeOH.

[0312] Solution 11

[0313]

[0314] Scheme 11 shows a synthetic scheme for preparing compounds of formula iv.

[0315] Intermediate i (see Scheme 3 for preparation of i) can be coupled with (tert-butyloxycarbonyl)proline using photoredox catalysis to give compound ii. Compound ii can be coupled with an aryl amine under Pd-catalyzed coupling conditions to give iii. Compound iii can be deprotected under typical Boc-deprotection conditions such as HCl to give amine iv, which is an example of a MAP4K1 inhibitor described herein.

[0316] Solution 12

[0317]

[0318] Scheme 12 shows a synthetic scheme for preparing compounds of formula v.

[0319] Intermediate i can be treated with organolithium and ketone or aldehyde to give compound ii. Compound ii can be treated with TMSN3 and indium bromide or boron trifluoride etherate to give azide compound iii. Compound iii can be coupled with aryl chloride under Pd-catalyzed coupling conditions to give iv. Compound iv can be reduced with Zn and acetic acid to give amine v, which is an example of a MAP4K1 inhibitor described herein.

[0320] Solution 13

[0321]

[0322] Scheme 13 shows a synthetic scheme for preparing compounds of formula vi.

[0323] Intermediate i can be coupled with a borate under Pd catalysis to give compound ii. Compound ii can be treated with an oxidant such as m-CPBA to give the epoxide compound iii. Compound iii can be treated with TMSN3 and indium bromide or boron trifluoride etherate to give the azide compound iv. Compound iv can be coupled with an aryl amine under Pd catalyzed coupling conditions to give v. Compound v can be reduced with hydrogen under Pd catalyzed conditions to give amine vi, which is an example of a MAP4K1 inhibitor described herein.

[0324] Solution 14

[0325]

[0326] Scheme 14 shows a synthetic scheme for preparing compounds of formula iv.

[0327] Intermediate i can be reduced with Zn and acetamine compound ii. Compound ii can be treated with ketones such as oxetane-3-one or aldehydes under reductive amination conditions such as sodium cyanoborohydride to give substituted amine compound iii. Compound iii can be coupled with aryl amines under Pd-catalyzed coupling conditions to give iv, which is an example of a MAP4K1 inhibitor described herein.

[0328] Solution 15

[0329]

[0330] Scheme 15 shows a synthetic scheme for preparing compounds of formula v.

[0331] Intermediate i can be reduced with Zn and acetic acid amine compound ii. Compound ii can be treated with a haloacetate compound such as methyl bromoacetate substituted amine compound iii. Compound iii can be reduced with LiBH4 to give amino alcohol compound iv. Compound iv can be coupled with an aryl amine under Pd-catalyzed coupling conditions to give v, which is an example of a MAP4K1 inhibitor described herein.

[0332] Scheme 16

[0333]

[0334] Scheme 16 shows a synthetic scheme for preparing compounds of formula iii.

[0335] Intermediate i can be coupled with an aryl amine under Pd-catalyzed coupling conditions to give ii. Compound ii can be reduced with hydrogen under Pd-catalyzed conditions to give amine iii, which is an example of a MAP4K1 inhibitor described herein.

[0336] Solution 17

[0337]

[0338] Scheme 17 shows a synthetic scheme for preparing compounds of formula vi.

[0339] Intermediate i can be coupled with an aryl amine under Pd-catalyzed coupling conditions to give ii. Compound ii can be deprotected under acidic conditions such as HCl to give amine iii, which is an example of a MAP4K1 inhibitor described herein.

[0340] The following examples are intended to be illustrative, and are not meant to be limiting in any way.

[0341] example

[0342] abbreviation

[0343] BOP (1H-Benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate

[0344] C degrees Celsius

[0345] DAST Diethylaminosulfur trifluoride

[0346] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0347] DCM Dichloroethane

[0348] DCM Dichloromethane

[0349] DEA Diethylamine

[0350] DIPEA Diisopropylamine

[0351] DMF Dimethylformamide

[0352] DMAP 4-dimethylaminopyridine

[0353] DMB 3,3-dimethyl-1-butanol

[0354] DMSO Dimethyl sulfoxide

[0355] EA Ethyl acetate

[0356] EtOH ethanol;

[0357] h hour

[0358] HPLC High Performance Liquid Chromatography

[0359] IC50 Inhibitory concentration 50%

[0360] IPA Isopropyl Alcohol

[0361] min

[0362] MTBE Methyl tert-butyl ether

[0363] MeCN Acetonitrile

[0364] MeOH Methanol

[0365] NMP N-Methyl-2-pyrrolidone

[0366] PE Petroleum Ether

[0367] rt room temperature

[0368] TEA Triethylamine

[0369] THF Tetrahydrofuran

[0370] TFA Trifluoroacetic acid

[0371] LC-MS :Unless otherwise stated, all liquid chromatography-mass spectrometry (LC-MS) data (samples for purity and characteristic analysis) are obtained by Agilent model-1260LC system, using Agilent model 6120 mass spectrometer, utilizing ES-API ionization acquisition equipped with Agilent Poshel 120 (EC-C18, 2.7 μm particle size, 3.0x50 mm size) reversed phase column (at 22.4°C). Mobile phase is composed of a mixture of solvent 0.1% formic acid in water and 0.1% formic acid in MeCN. Utilize a constant gradient from 95% aqueous / 5% organic to 5% aqueous / 95% organic mobile phase in a 4-minute process. Flow rate is constant at 1 mL / min.

[0372] Preparative LC-MS :Preparative HPLC was performed at Shimadzu Discovery The reaction was carried out on a preparative system equipped with a 250 x 21.2 mm reverse phase column (at 22.4°C) filled with Luna 5u C18 (2) 100A, AXIA. The mobile phase consisted of a mixture of 0.1% formic acid in water and 0.1% formic acid in MeCN. A constant gradient from 95% aqueous / 5% organic to 5% aqueous / 95% organic mobile phase was used over a 25 minute period. The flow rate was constant at 20 mL / min. The reaction was carried out in a microwave in a Biotage Initiator microwave unit.

[0373] Silica gel chromatography : At Teledyne Isco Rf unit or Silica gel chromatography was performed on an Isolera Four unit.

[0374] Proton NMR : Unless otherwise stated, all 1 H NMR spectra were all acquired using a Varian 400 MHz Unity Inova 400 MHz NMR instrument (acquisition time = 3.5 sec with 1 sec delay; 16 to 64 scans). In the case of characterization, all protons are reported in parts per million (ppm) relative to residual DMSO (2.50 ppm) in DMSO-d6 solvent.

[0375] One of ordinary skill in the art will recognize that gradients, column lengths, and flow rates can be modified and that some conditions may be more suitable for compound characterization than others, depending on the chemical species being analyzed.

[0376] Synthesis of intermediates

[0377] I. Synthesis of Arylamine Intermediates

[0378]

[0379] Intermediate 1: 2-(2-fluoropropan-2-yl)pyrimidin-4-amine

[0380]

[0381] Step 1: Ethyl 4-aminopyrimidine-2-carboxylate

[0382] At 0 ℃, triethylamine (285g, 2.81mol, 2.00 equivalents) is added dropwise to a solution of 2-amino-2-iminoacetic acid ethyl hydrochloride (215g, 1.41mol, 1.00 equivalents) and 2-chloropropane-2-enenitrile (112mL, 1.41mol, 1.00 equivalents) in EtOH (1.8L). Allow the mixture to be warming up to 25 ℃ and stir for 6 hours at 25 ℃. Concentrated reaction mixture is also distributed between water (10.0L) and EA (5.0L). Separate each layer, and extract water layer with EtOAc (5.0L x 2). Combine organic layers and use Na2SO4 dry. Filter dry solution, and concentrate filtrate, to obtain the title compound (270g, crude product) as dark brown solid.

[0383] Step 2: 2-(4-aminopyrimidin-2-yl)propan-2-ol

[0384] At -20 ° C, methylmagnesium bromide (900mL, 3.0M, 5.0 equivalents) was added to a solution of 4-aminopyrimidine-2-carboxylic acid ethyl ester (90.0g, 538mmol, 1.00 equivalents) in 2-Me THF (1.00L). The reaction mixture was allowed to warm to 0 ° C and stirred at this temperature for 1 hour. The reaction mixture was diluted with saturated aqueous ammonium chloride (10.0L), and the water layer was extracted with EA (3.0L×4). The organic layers were combined and dried with Na2SO4, and the dried solution was filtered. The filtrate was concentrated to obtain the title compound (50g, crude product) as a dark brown solid.

[0385] Step 3: 2-(2-Fluoropropan-2-yl)pyrimidin-4-amine

[0386] DAST (414 mL, 3.13 mol, 10.0 equiv) was added to a solution of 2-(4-aminopyrimidin-2-yl)propan-2-ol (48.0 g, 313 mmol, 1.00 equiv) in DCM (1.30 L) at 0 ° C. The reaction mixture was stirred at 0 ° C for 0.5 hours and then diluted with water (4.50 L). The reaction mixture was adjusted to pH = 7-8 with aqueous sodium hydroxide solution (0.50 L) and sodium carbonate solution (200 mL), and then extracted with EA (2.00 L x 3). The organic layers were combined and dried with Na2SO4, and the dried solution was filtered and concentrated. The residue was purified by rp-HPLC (neutral conditions) to obtain the title compound (13.0 g) as a white solid. 1 H NMR (400MHz DMSO-d6) δ 8.05-8.07 (d, J = 5.6 Hz), 6.93 (s, 1H), 6.32-6.33 (d, J = 5.6 Hz, 1H), 1.63 (s, 3H), 1.58 (s, 3H).

[0387]

[0388] Intermediate 2: 2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0389]

[0390] Step 1: 7,7-Dimethyl-1,5,7,8-tetrahydro-2H-pyrano[4,3-b]pyridin-2-one

[0391] A mixture of 2,2-dimethyltetrahydro-4H-pyran-4-one (500 g, 3.90 mol, 1.00 equivalent) and pyrrolidine (391 mL, 4.68 mol, 1.20 equivalent) in toluene (4.00 L) was heated to 145 ° C for 2 hours with a Dean-Stark water separator. The water layer (about 16 mL) was removed from the Dean-Stark water separator, and the reaction mixture was cooled to 15 ° C. After cooling, propan-2-yne amide (539 g, 7.80 mol, 2.00 equivalent) was added and the reaction mixture was heated to 150 ° C. The reaction mixture was heated at 150 ° C for 10 hours and then cooled to ambient temperature. The cooled reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (10% methanol-dichloromethane) on silica gel to obtain the title compound (560 g, 62% yield) as a yellow solid.

[0392] Step 2: 2-Chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine

[0393] By POCl (350mL, 3.77mol, 9.64 equivalents) in 7,7-dimethyl-1,5,7,8-tetrahydro-2H-pyrans also [4,3-b] pyridine-2-one (500g, 2.23mol, 1 equivalent) solution is heated to 100 DEG C and continues for 6 hours.Then the reaction mixture is cooled to ambient temperature and concentrated under vacuum.Residue is poured on ice water (1.00L).Extract the mixture with EA (750mL x 2).The organic layer Na2SO4 of merging is dried, filtered and concentrated under vacuum, to obtain the title compound (363g, 82.2% yield) as brown oil.

[0394] Step 3: 2-Chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0395] By NaIO in water (1.20L) (487g, 2.28mol, 3.00 equivalents) solution is added in MeCN (50.0mL) and CCl (2.70L) 2-chloro-7,7-dimethyl-7,8-dihydro-5H-pyrans also [4,3-b] pyridine (150g, 759mmol, 1.00 equivalents) mixture. The mixture is cooled to 0 ° C, then RuCl is added (11.0g, 53.1mmol, 0.07 equivalents). The reaction mixture is stirred at 0 ° C for 0.5 hour, then warming up to 20 ° C for 11.5 hours. Saturated sodium sulfite aqueous solution (1.00L) is added, and the mixture is filtered. Filtrate is extracted with EA (500mL x 3), and organic layers are combined. The combined organic layers were washed with brine (1.00 L), dried over Na 2 SO 4 , filtered and concentrated to give the title compound (132 g, 624 mmol, 82.1% yield) as a yellow solid.

[0396] Step 4: 2-((2,4-dimethoxybenzyl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0397] (2,4-Dimethoxyphenyl)methanamine (160 g, 957 mmol, 1.50 equiv) was added to 2-chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one in NMP (1.08 L) at ambient temperature.

[0398] The mixture was stirred for 2 hours at 4 ℃ for 1 h at 4 ℃ for 30 minutes.Then the mixture was stirred for 2 hours ...

[0399] Step 5: 2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0400] At 20 ° C, HCl (4.0M in dioxane, 1.20L, 11.0 equivalents) is added to 2- ((2,4-dimethoxybenzyl) amino) -7,7- dimethyl -7,8- dihydro -5H- pyrans [4,3-b] pyridine -5- one (150g, 438mmol, 1.00 equivalents). The reaction mixture is heated to 60 ° C for 2 hours, then cooled to ambient temperature and concentrated under vacuum. The residue is poured into saturated NaHCO3 aqueous solution (1.00L) and extracted with EA (500mL x 4). The combined organic layer is washed with brine (500x2), dried and concentrated with Na2SO4. The residue is dissolved in EA (300mL) and petroleum ether (150mL) is added dropwise to obtain a yellow slurry. Filter and collect solid, to obtain the title compound (52.0g, 60.9% yield) as a yellow solid. MS(ES+)C 10 H 12 N2O2 requirement: 192, measured: 193 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.76 (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).

[0401]

[0402] Intermediates 3 and 4: (S)-6-amino-2-(sec-butyl)pyridazin-3(2H)-one and (R)-6-amino-2-(sec-butyl)pyridazin-3(2H)-one

[0403]

[0404] Each of these is represented by one of the structures shown below:

[0405]

[0406] Step 1: 2-(sec-butyl)-6-chloropyridazin-3(2H)-one

[0407] Potassium carbonate (15.6g, 113mmol, 3.05 equivalents) is added to a solution of 6-chloropyridazine-3 (2H) -one (5.00g, 38.3mmol, 1.00 equivalent) and 2-bromobutane (5.17g, 37.7mmol, 0.98 equivalent) in DMF (80mL). The mixture is stirred at 80°C for 4 hours and then cooled to ambient temperature. The cooled reaction mixture is distributed between water and dichloromethane, and each layer is separated. The water layer is further extracted with dichloromethane (200mL × 2), and each layer is combined. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate. The dried solution is filtered, and the filtrate is concentrated under reduced pressure to obtain the title compound (5.90g, crude product) as a yellow oil, which is directly used in the next step.

[0408] Step 2: 2-(sec-butyl)-6-((diphenylmethylene)amino)pyridazin-3(2H)-one

[0409] XantPhos (3.53g, 6.11mmol, 0.200 equivalent), Pd(dba)2 (1.76g, 3.05mmol, 0.100 equivalent) and cesium carbonate (24.9g, 76.4mmol, 2.50 equivalent) are added to a solution of 2-(sec-butyl)-6-chloropyridazine-3(2H)-one (5.70g, 30.5mmol, 1.00 equivalent) and diphenylmethaneimine (6.09g, 33.6mmol, 1.10 equivalent) in dioxane (80mL). The mixture is degassed and purged three times with N2, then heated to 100°C for 4 hours. The reaction mixture is cooled to ambient temperature, diluted with water and extracted three times with EA. The organic layer combined is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 0% to 67% EA-petroleum ether) to give the title compound (1.80 g, 18% yield) as a yellow oil.

[0410] Step 3: 6-amino-2-(sec-butyl)pyridazin-3(2H)-one

[0411] At 25 ° C, HCl (aqueous solution, 6M, 2.01mL) was added to a solution of 2-(sec-butyl)-6-((diphenylmethylene)amino)pyridazine-3(2H)-one (0.80g, 2.4mmol) in tetrahydrofuran (100mL). The reaction mixture was stirred at 25 ° C for 0.5 hours. The reaction mixture was diluted with water (100mL) and extracted with DCM (50mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 0% to 100% EA-petroleum ether) to obtain the title compound (190mg, 47% yield) as a white solid. MS (ES+) CH 13 N3O requirement: 167, measured: 168 [M+H] + .

[0412] Step 4: (S)-6-amino-2-(sec-butyl)pyridazin-3(2H)-one and (R)-6-amino-2-(sec-butyl)pyridazin-3(2H)-one

[0413] 6-Amino-2-(sec-butyl)pyridazin-3(2H)-one (190 mg, 1.14 mmol) was separated by SFC (column: DAICELCHIRALPAK IC (250 mm×30 mm, 5 um); mobile phase: [0.5% DEA in MeOH / CO]; gradient: 5%-20%. One of the (R or S)-6-amino-2-(sec-butyl)pyridazin-3(2H)-ones was obtained as a yellow solid (the first eluting isomer, intermediate 3, 60.0 mg, 31%), MS (ES+): CH 13 N3O requirement: 167, measured: 168 [M+H] + One of the (R or S)-6-amino-2-(sec-butyl)pyridazin-3(2H)-ones (second eluting isomer, intermediate 4, 70.0 mg, 37% yield) was obtained as a yellow solid, MS (ES+) C8H 13 N3O requirement: 167, measured: 168 [M+H] + .

[0414]

[0415] Intermediate 5: 2-amino-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0416]

[0417] Steps 1 and 2: 2-Amino-7,8-dihydro-1,6-naphthyridin-5(6H)-one was prepared from 2-chloro-7,8-dihydro-1,6-naphthyridin-5(6H)-one using the same two-step procedure as described in Steps 4 and 5 in the preparation of Intermediate 2. MS (ES+) C8H9N3O required: 163, found: 164 [M+H] + .

[0418]

[0419] Intermediate 6: 2-isopropoxypyrimidin-4-amine

[0420]

[0421] Step 1: 2-Isopropoxypyrimidin-4-amine

[0422] At 0 ° C, sodium hydride (60% dispersion in oil, 617 mg, 15.4 mmol, 2.00 equivalents) was added to a mixture of propan-2-ol (696 mg, 11.6 mmol, 1.50 equivalents) in tetrahydrofuran (10 mL). The mixture was stirred at 25 ° C for 1 hour, 2-chloropyrimidine-4-amine (1.00 g, 7.72 mmol) was added and the mixture was heated to 60 ° C. After stirring for 12 hours, the reaction mixture was cooled to ambient temperature and quenched by adding water (20 mL). The quenched mixture was extracted with EA (20 mL × 3), and the layers were combined. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase preparative HPLC (column: Xtimate C18 150*25mm*5um; mobile phase: [water (0.05% ammonium hydroxide v / v)-MECN]; B%: 0%-30%, 10 minutes) to give the title compound (140 mg, 12% yield) as a white solid. 1 H-NMR (400MHz, DMSO-d6): δppm 7.93 (d, J = 6.0 Hz, 1H), 7.37 (s, 2H), 6.38 (d, J = 6.0 Hz, 1H), 5.08 (td, J = 6.4, 12.3 Hz, 1H), 1.22 (d, J = 6.0 Hz, 6H).

[0423]

[0424] Intermediates 7 and 8: (S)-6-amino-2-(sec-butyl)nicotinonitrile and (R)-6-amino-2-(sec-butyl)nicotinonitrile

[0425]

[0426] Each of these is represented by one of the structures shown below:

[0427]

[0428] It is represented by one of the structures shown below:

[0429]

[0430] Step 1: 6-amino-2-(but-1-en-2-yl)nicotinonitrile

[0431] Potassium carbonate (3.24 g, 23.4 mmol, 2.00 equiv) and Pd(PPh3)4 (1.35 g, 1.17 mmol, 0.10 equiv) were added to a mixture of 6-amino-2-chloronicotinonitrile (1.80 g, 11.7 mmol, 1.00 equiv) and 2-(but-1-ene-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.30 g, 12.6 mmol, 1.08 equiv) in dioxane (20 mL) and water (4 mL). The mixture was stirred at 100 ° C for 12 hours under nitrogen. The mixture was then cooled to ambient temperature and distributed between water (50 mL) and EA (65 mL). The layers were separated and the aqueous layer was further extracted with EA (65 mL×2). Merge each layer, and the combined layer anhydrous sodium sulfate drying, filter and concentrate, to obtain residue.Residue is passed through the flash column chromatography (gradient elution, 10% to 25% EA-petroleum ether) purification on silica gel, to obtain the title compound (1.50g, 63% yield) as white solid.

[0432] Step 2: 6-amino-2-(sec-butyl)nicotinonitrile

[0433] Palladium on carbon (10wt%, 300mg, 0.282mmol) is added to a mixture of 6-amino-2-(but-1-ene-2-yl) nicotinonitrile (1.50g, 8.66mmol, 1.00 equivalent) in methanol (50mL). The mixture is stirred at 25 ° C for 16 hours under a hydrogen atmosphere (15psi), then filtered through diatomaceous earth. The filtrate is concentrated under reduced pressure to obtain a residue. The residue is purified by flash column chromatography (gradient elution, 5% to 10% EA-petroleum ether) on silica gel to obtain the title compound (950mg, 63% yield) as a yellow solid.

[0434] Step 3: tert-Butyl N-[6-(But-2-yl)-5-cyanopyridin-2-yl]-N-[(tert-butoxy)carbonyl]carbamate

[0435] Di-tert-butyl dicarbonate (2.12 g, 9.70 mmol, 2.00 equiv) and DMAP (59.3 mg, 0.485 mmol, 0.100 equiv) were added to a mixture of 6-amino-2-(sec-butyl)nicotinonitrile (850 mg, 4.85 mmol, 1.00 equiv) and triethylamine (982 mg, 9.70 mmol, 2.00 equiv) in dichloromethane (15 mL). The reaction mixture was stirred at 20 ° C for 2 hours, then water (20 mL) was added, and the resulting mixture was extracted with EA (25 mL×3). The organic layers were combined and dried over anhydrous sodium sulfate. The dried solution was filtered and concentrated to obtain a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 1% to 10% EA-petroleum ether) to obtain the title compound (1.15 g, 80% yield) as a colorless oil.

[0436] Step 4: tert-Butyl N-{6-[(2S)-Butan-2-yl]-5-cyanopyridin-2-yl}-N-[(tert-butoxy)carbonyl]carbamate and tert-butyl N-{6-[(2R)-butan-2-yl]-5-cyanopyridin-2-yl}-N-[(tert-butoxy)carbonyl]carbamate

[0437] Tert-butyl N-[6-(But-2-yl)-5-cyanopyridin-2-yl]-N-[(tert-butoxy)carbonyl]carbamate (950 mg, 2.53 mmol) was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, um); mobile phase: [IPA gradient in CO2 containing 0.5% DEA]; to give two peaks respectively. The absolute stereochemistry of the separated enantiomers is arbitrarily assigned. The first eluting isomer (340 mg, 34% yield) and the second eluting isomer (400 mg, 42% yield) were obtained as colorless oils.

[0438] Step 5: (R or S)-6-amino-2-(sec-butyl)nicotinonitrile

[0439] HCl (4.0M in dioxane, 10.0mL) is added to one of N-{6-[(2R or S)-butyl-2-yl]-5-cyanopyridine-2-yl}-N-[(tert-butoxy)carbonyl]carbamic acid tert-butyl ester (second eluting isomer, 400mg, 1.07mmol) in dioxane (2mL). The reaction mixture is stirred at 20°C for 15 hours and then distributed between saturated sodium bicarbonate aqueous solution (30mL) and EA (35mL). The layers are separated and the aqueous layer is further extracted with EA (35mL×2). The organic layers are combined and dried over anhydrous sodium sulfate. The dried solution is filtered and concentrated to obtain a residue. The residue is purified by flash column chromatography on silica gel (gradient elution, 5% to 25% EA-petroleum ether) to obtain the title compound ((intermediate 7, 160mg, 78% yield) as a yellow oil. MS(ES+)C 10 H 13 N3 requirement: 175, measured: 176 [M+H] + . 1 H-NMR (400MHz, CDCl3): δppm 7.56(d,J=8.4Hz,1H),6.32(d,J=8.4Hz,1H),4.87(s,2H),3.17-3.08(m,1H),1. 83-1.71(m,1H),1.62-1.54(m,1H),1.24(d,J=6.4Hz,3H),0.86(t,J=7.2Hz,3H).

[0440] Step 6: The other one of (R or S)-6-amino-2-(sec-butyl)nicotinonitrile

[0441] The title compound (Intermediate 8) was prepared from the remaining one of tert-butyl N-{6-[(2R or S)-butan-2-yl]-5-cyanopyridin-2-yl}-N-[(tert-butoxy)carbonyl]carbamate (first eluting isomer) using the same procedure as described in Step 5. MS (ES+) C 10 H 13 N3 requirement: 175, measured: 176 [M+H] + . 1 H-NMR (400MHz, CDCl3): δppm7.56(d,J=8.4Hz,1H),6.32(d,J=8.4Hz,1H),4.87(s,2H),3.17-3 .08(m,1H),1.83-1.71(m,1H),1.62-1.54(m,1H),1.24(d,J=6.4Hz,3H),0.86(t,J=7.2Hz,3H).

[0442]

[0443] Intermediate 9: 2-amino-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one

[0444]

[0445] Steps 1 and 2: 2-Amino-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one was prepared from 2-chloro-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one using the same two-step procedure as described in Steps 4 and 5 in the preparation of Intermediate 2. MS (ES+) C 11 H 14 N2O requirement: 190, measured: 191 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δppm 7.75 (d, J = 8.8 Hz, 1H), 6.88 (s, 2H), 6.34 (d, J = 8.8 Hz, 1H), 2.66 (s, 2H), 2.33 (s, 2H), 0.99 (s, 6H).

[0446]

[0447] Intermediate 10: 2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one

[0448]

[0449] Step 1: 5-methoxy-3-(2-methylprop-1-en-1-yl)pyrazine-2-carboxylic acid methyl ester

[0450] Potassium phosphate (7.23 g, 34.1 mmol, 2.99 equiv) and XPhos (G3 precatalyst) (480 mg, 568 μmol, 0.05 equiv) were added to a mixture of methyl 3-chloro-5-methoxypyrazine-2-carboxylate (2.30 g, 11.4 mmol, 1.00 equiv) and 4,4,5,5-tetramethyl-2-(2-methylprop-1-ene-1-yl)-1,3,2-dioxaborolane (3.10 g, 17.0 mmol, 1.49 equiv) in tetrahydrofuran (25 mL) and water (3 mL). The reaction mixture was stirred at 50 ° C for 4 hours under nitrogen. The reaction mixture was then cooled to ambient temperature and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 5% to 50% EA-petroleum ether) to give the title compound (2.00 g, 79% yield) as a white solid.

[0451] Step 2: 5-methoxy-3-(2-methylprop-1-en-1-yl)pyrazine-2-carboxylic acid

[0452] LiOH (1.51 g, 63.0 mmol, 5.00 equivalents) was added to a mixture of 5-methoxy-3-(2-methylprop-1-ene-1-yl)pyrazine-2-carboxylic acid methyl ester (2.80 g, 12.6 mmol, 1.00 equivalents) in methanol (50 mL). The reaction mixture was stirred at 20 ° C for 2 hours and diluted with water (100 mL). HCl aqueous solution (2N) was added to the mixture until pH was 7, and then the mixture was extracted with EA (50 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the title compound (2.40 g, crude product) as a white solid.

[0453] Step 3: 2-Methoxy-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one

[0454] Trimethylsilyl trifluoromethanesulfonate (19.1mL, 106mmol, 10.0 equivalents) is added to a mixture of 5-methoxy-3-(2-methylprop-1-ene-1-yl)pyrazine-2-carboxylic acid (2.20g, 10.6mmol) in DCM (10mL). The reaction mixture is stirred at 20°C for 72 hours and then slowly poured into a saturated aqueous sodium bicarbonate solution (80mL). The reaction mixture is extracted with EA (50mL×3). The combined organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to obtain a residue. The residue is purified by flash column chromatography (gradient elution, 10% to 30% EA-petroleum ether) on silica gel to obtain the title compound (1.00g, 45% yield) as a yellow solid.

[0455] Step 4: 2-Hydroxy-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one

[0456] A mixture of 2-methoxy-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazine-5-one (1.00 g, 4.80 mmol, 1.00 equiv) in pyridine hydrochloride (2.78 g, 24.0 mmol, 5.00 equiv) was stirred at 150 ° C for 1 hour. The reaction mixture was then poured onto water (60 mL) and extracted with EA (50 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (column: Xtimate C18 10 μ 250 mm * 80 mm; mobile phase: [water (0.05% ammonium hydroxide v / v) -MECN]; B%: 0%-7%, 6.5 minutes) to obtain the title compound (600 mg, 64% yield) as a white solid.

[0457] Step 5: 2-Chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one

[0458] A mixture of 2-hydroxy-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazine-5-one (100 mg, 515 μmol) in phosphorus oxychloride (3 mL) was stirred at 100 ° C for 1 hour. After cooling to ambient temperature, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (10 mL) and then extracted with EA (30 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (gradient elution, 20% to 50% EA-petroleum ether) to obtain the title compound (110 mg, crude product) as a yellow solid.

[0459] Steps 6 and 7: 2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one

[0460] The title compound was prepared using the same two-step procedure as described in steps 4 and 5 in the preparation of Intermediate 2 from 2-chloro-7,7-dimethyl-7,8-dihydro-5H-pyrano[3,4-b]pyrazin-5-one. 1 H NMR (400MHz, CDCl3): δppm7.93(s,1H),7.21(d,J=8.4Hz,1H),6.48(d,J=2.0Hz,1H),6.46-6 .44(m,1H),6.43(m,1H),4.57(d,J=5.6Hz,2H),3.82-3.78(m,6H),3.05(s,2H),1.50(s,6H).

[0461]

[0462] Intermediate 11: 2-amino-7,7-dimethylfurano[3,4-b]pyridin-5(7H)-one

[0463]

[0464] Step 1: 6-methoxy-2-(prop-1-en-2-yl)nicotinate methyl ester

[0465] Pd(dppf)Cl2 (544 mg, 744 umol, 0.500 equiv) and cesium fluoride (4.52 g, 29.8 mmol, 2.00 equiv) were added to a mixture of 2-chloro-6-methoxynicotinate (3.00 g, 14.9 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-ene-2-yl)-1,3,2-dioxaborolane (3.75 g, 22.3 mmol) in MeCN (50 mL). The mixture was stirred at 70 ° C for 2 hours under a nitrogen atmosphere and then cooled to ambient temperature. The reaction mixture was then poured onto water (200 mL) and extracted with EA (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to obtain 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.

[0466] Step 2: 2-Methoxy-7,7-dimethylfuro[3,4-b]pyridin-5(7H)-one

[0467] The solution of 6-methoxy-2-(prop-1-ene-2-yl) nicotinate (3.00g, 14.5mmol) in TfOH (17.0g, 113mmol, 10mL) was stirred at 25°C for 12 hours.Then the reaction mixture was poured on water (50mL) and saturated sodium bicarbonate aqueous solution was added to adjust the pH to 7. The reaction mixture was extracted with EA (30mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to obtain a residue. The residue was purified by flash column chromatography (gradient elution, 10% to 33% EA-petroleum ether) on silica gel to obtain the title compound (2.3g, 82% yield) as a yellow solid.

[0468] Step 3-6: 2-amino-7,7-dimethylfuro[3,4-b]pyridin-5(7H)-one

[0469] The title compound was prepared from 2-methoxy-7,7-dimethylfuro[3,4-b]pyridin-5(7H)-one using the two-step procedure described in steps 4 and 5 of intermediate 10 followed by the two-step procedure as described in steps 4 and 5 in the preparation of intermediate 2. MS (ES+) C9H 10 N2O2 requirement: 178, measured: 179 [M+H] + .

[0470]

[0471] Intermediates 12 and 13: (6aR,9aR)-2-amino-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-one and (6aS,9aS)-2-amino-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridine-5(6aH)

[0472]

[0473] Each of these is represented by one of the structures shown below:

[0474]

[0475] It is represented by one of the structures shown below:

[0476]

[0477] It is represented by one of the structures shown below:

[0478]

[0479] Step 1: 2-(Cyclopent-1-en-1-yl)-6-methoxynicotinic acid methyl ester

[0480] Cesium fluoride (5.27 g, 34.7 mmol, 1.99 equiv) and Pd(dppf)Cl2 (1.27 g, 1.74 mmol, 0.100 equiv) were added to a mixture of methyl 2-chloro-6-methoxynicotinate (3.50 g, 17.4 mmol, 1.00 equiv) and 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.05 g, 26.0 mmol, 1.49 equiv) in MeCN (100 mL) and water (5 mL). The reaction mixture was stirred at 75 °C for 2 hours, then cooled to ambient temperature and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 5% to 20% EA-petroleum ether) to give the title compound (3.77 g, 93% yield) as a colorless oil.

[0481] Step 2: 2-Methoxy-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-one

[0482] The title compound was prepared using the same procedure described in step 2 of intermediate 11 from methyl 2-(cyclopent-1-en-1-yl)-6-methoxynicotinate.

[0483] Step 3-4: 2-Chloro-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-one

[0484] The title compound was prepared using the same two-step procedure described in Intermediate 10, Steps 4 and 5, from 2-methoxy-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-one.

[0485] Step 5: (6aR,9aR)-2-chloro-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-one and (6aS,9aS)-2-chloro-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-one

[0486] By SFC (Chiralpak AD-3, in the MeOH gradient of CO containing 0.5% DEA), 2-chloro-7,8,9,9a-tetrahydrocyclopenta [5,6] pyranos [4,3-b] pyridine-5 (6aH) -one (1.5g, 6.71mmol) was separated to give two peaks respectively. The first eluting isomer (720mg, 48% yield) and the second eluting isomer (750mg, 50% yield) as white solid were obtained.

[0487] Steps 6 and 7: (6aR, 9aR)- or (6aS, 9aS)-2-amino-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-one

[0488] The title compound (Intermediate 12) was prepared from one of the (6aR,9aR)- or (6aS,9aS)-2-chloro-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-ones (the first eluting isomer from Step 5) using the same two-step procedure as described in Steps 4 and 5 for Intermediate 2. MS (ES+) C 11 H 12 N2O2 requirement: 204, measured: 205[M+H] +

[0489] Steps 8 and 9: The other of (6aR,9aR)- or (6aS,9aS)-22-amino-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-one

[0490] The title compound (Intermediate 13) was prepared from the remaining one of (6aR,9aR)- or (6aS,9aS)-22-chloro-7,8,9,9a-tetrahydrocyclopenta[5,6]pyrano[4,3-b]pyridin-5(6aH)-one (the second eluting isomer from Step 5) using the same two-step procedure as described in Steps 4 and 5 for Intermediate 2. MS (ES+) C 11 H 12 N2O2 requirement: 204, measured: 205[M+H] +

[0491]

[0492] Intermediate 14: 2-amino-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0493]

[0494] Step 1: 2-Amino-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0495] The title compound was prepared from tetrahydro-4H-pyran-4-one using the same five-step procedure described in steps 1-5 for Intermediate 2. MS (ES+) C8H8N2O2 required: 164, found: 165 [M+H] + . 1 H NMR, 400MHz, DMSO-d6, δ = 7.77 (d, J = 8.8Hz, 1H), 7.01 (s, 2H), 6.41 (d, J = 8.8Hz, 1H), 4.44-4.41 (m, 2H), 2.88–2.85 (m, 2H).

[0496]

[0497] Intermediate 15: 2-amino-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0498]

[0499] Step 1: 2-Methoxy-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0500] At 0°C, BH3-Me2S (10M, 5.31mL, 53.1mmol, 1.10 equiv) was added dropwise to a solution of 6-methoxy-2-(prop-1-ene-2-yl)nicotinic acid methyl ester (10.0g, 48.3mmol, 1.00 equiv) in THF (100mL). The mixture was warmed to 20°C and stirred at this temperature for 2 hours. The reaction mixture was then cooled to 0°C and NaHCO3 (20.3g, 241mmol, 5.00 equiv) was added dropwise in water (35.0mL) and H2O2 (30% in water, 69.6mL, 724mmol, 15.0 equiv). The reaction mixture was stirred at 20°C for 30 minutes and at 30°C-45°C for 12 hours. The reaction mixture was then poured into a saturated Na2SO3 aqueous solution (200mL) and extracted with EA (50.0mL x 3). The organic layers were combined and washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (gradient elution, 5% to 15% EA-petroleum ether) to give the title compound (15.0 g, 77.6 mmol, 80.4% yield) as a yellow solid.

[0501] Step 2-5: -Amino-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0502] The title compound was prepared from 2-methoxy-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one using the two-step procedure described in steps 4 and 5 for intermediate 10 followed by the two-step procedure as described in steps 4 and 5 in the preparation of intermediate 2. MS (ES+) C9H 10 N2O2 requirement: 178, measured: 179 [M+H] + . 1 H NMR: 400MHz, DMSO-d6δ7.76(d,J=8.6Hz,1H),7.01(s,2H),6.40(d,J=8.6Hz,1H),4.44(dd,J=11.2H z, 4.4Hz, 1H), 4.12 (dd, J = 11.0Hz, 6.8Hz, 1H), 2.93 (td, J = 7.0Hz, 4.4Hz, 1H), 1.20 (d, J = 7.0Hz, 3H).

[0503]

[0504] Intermediate 16: 2-amino-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0505]

[0506] Step 1: (E)-6-methoxy-2-(prop-1-en-1-yl)nicotinic acid methyl ester

[0507] A mixture of 2-chloro-6-methoxynicotinic acid methyl ester (25.0 g, 148 mmol, 1.20 equiv), (E)-4,4,5,5-tetramethyl-2-(prop-1-ene-1-yl)-1,3,2-dioxaborolane (20.7 g, 123 mmol, 1.00 equiv), XPhos Pd G3 (5.25 g, 6.20 mmol, 0.05 equiv) and K3PO4 (52.6 g, 248 mmol, 2.00 equiv) in THF (250 mL) and H2O (100 mL) was degassed and purged three times with N2. The mixture was then stirred at 60 °C for 2 hours under N2 atmosphere. The reaction mixture was cooled to ambient temperature and distributed between water (300 mL) and EA (1.20 L). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 5% to 10% EA-petroleum ether) to give the title compound as a yellow oil (25.0 g).

[0508] Step 2: 2-Methoxy-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0509] The solution of (E)-6-methoxy-2-(prop-1-ene-1-yl) nicotinate (25.0g, 120mmol, 1.00eq) in TfOH (100mL) was stirred at 80°C for 1 hour. The reaction mixture was then cooled to ambient temperature and poured into saturated NaHCO3 aqueous solution (1.00L), then extracted with EA (1.00L). The organic layer was washed with water (300mL), dried with Na2SO4, filtered and concentrated under reduced pressure to obtain residue. The residue was purified by flash column chromatography (gradient elution, 2% to 10% EA-petroleum ether) on silica gel to obtain the title compound (20.8g) as a white solid.

[0510] Step 3-6: 2-amino-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0511] The title compound was prepared from 2-methoxy-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one using the two-step procedure described in steps 4 and 5 for intermediate 10 followed by the two-step procedure as described in steps 4 and 5 in the preparation of intermediate 2. MS (ES+) C9H 10N2O2 requirement: 178, measured: 179 [M+H] + . 1 H NMR, 400MHz, DMSO-d6δ7.75(d,J=8.8Hz,1H),7.00(s,2H),6.40(d,J=8.8Hz,1H),4.70-4.45(m,2H),2.90-2.70(m,2H),1.37(d,J=5.6Hz,1H).

[0512]

[0513] Intermediates 17 and 18: (7S,8R)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 17) and (7R,8S)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 18)

[0514]

[0515] Each of these is represented by one of the structures shown below:

[0516]

[0517] It is represented by one of the structures shown below:

[0518]

[0519] It is represented by one of the structures shown below:

[0520]

[0521] Step 1: (E)-2-(But-2-en-2-yl)-6-methoxynicotinic acid methyl ester

[0522] K3PO4 (120 g, 565 mmol, 3.00 equiv) and Pd(dppf)Cl2-CH2Cl2 (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-dioxaborolane ((44.6 g, 245 mmol, 1.30 equiv) in THF (320 mL) and H2O (80.0 mL). The reaction mixture was stirred at 70°C under N2 for 2 h. The reaction mixture was diluted with water (300 mL) and washed with EA (250 mL x 40 mL). 3) extraction. The organic layers were combined and dried over sodium sulfate, then filtered and concentrated under vacuum to obtain a residue. The residue was purified by preparative HPLC (MeCN-H2O gradient containing 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 x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated to obtain the title compound (37.0 g, 167 mmol, 88.7% yield) as a yellow oil.

[0523] Steps 2 and 3: 2-Hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0524] The title compound was prepared using the same procedure as described in step 2 of intermediate 16 followed by the same procedure as described in step 4 for intermediate 10 from (E)-methyl 2-(but-2-en-2-yl)-6-methoxynicotinate.

[0525] 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

[0526] DBU (60.8 mL, 403 mmol, 3.00 equiv) was added to a solution of 2-hydroxy-7,8-dimethyl-7,8-dihydro-5H-pyrans [4,3-b] pyridine-5-one (26.0 g, 134 mmol, 1.00 equiv) in toluene (290 mL). The reaction mixture was stirred at 100 ° C for 12 hours, then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (gradient elution, 1% to 10% methanol-dichloromethane) to obtain the title compound as a mixture of isomers, which was used in the next step without further purification.

[0527] 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

[0528] The title compound was prepared from 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 using the same procedure as described in step 5 of intermediate 10. The cis and trans racemic isomers were separated by preparative HPLC (column: Phenomenex luna C18 250*50mm*10um; mobile phase: [water (0.1% TFA)-MeCN]; B%: 35% MeCN-55% over 20min). Rac-(7S,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one was the first compound to elute and was obtained as a white solid. MS (ES+) C 10 H 10 ClNO2 requirement: 211, measured: 212[M+H] + . 1 H NMR: 400 MHz, CDCl3δ8.29 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 4.83 (dq, J = 3.2, 6.6 Hz, 1H), 3.09 (dq, J = 3.2, 7.2 Hz, 1H), 1.49 (d, J = 6.5 Hz, 3H), 1.30 (d, J = 7.2 Hz, 3H). Racemic-(7S,8R)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one was the second compound to elute and was obtained as a white solid. MS (ES+) C10 H 10 ClNO2 requirement: 211, measured: 212[M+H] + . 1 H NMR: 400MHz, 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 (quin, J = 7.2 Hz, 1H), 1.56-1.40 (m, 6H).

[0529] 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

[0530] Racemic-(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 x 50 mm, 10 um); mobile phase: MeOH in CO2) to give the first eluting isomer (peak 1) as a white solid and the second eluting isomer (peak 2) as a white solid.

[0531] Steps 7 and 8: (7S,8R)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0532] The title compound (Intermediate 17) was prepared separately from the first eluting isomer using the same two-step procedure as described in Steps 4 and 5 for Intermediate 2. MS (ES+) C 10 H 12 N2O2 requirement: 192, measured: 193 [M+H] + . 1 H NMR: 400 MHz, DMSO-d6 δ 7.77 (d, J = 8.6 Hz, 1H), 6.97 (s, 2H), 6.40 (d, J = 8.6 Hz, 1H), 4.43-4.21 (m, 1H), 2.88-2.65 (m, 1H), 1.35 (d, J = 6.4 Hz, 3H), 1.25 (d, J = 7.0 Hz, 3H). The absolute stereochemistry of intermediate 17 was determined by X-ray crystal structure.

[0533] Steps 9 and 10: (7R,8S)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0534] The title compound (Intermediate 18) was prepared separately from the second eluting isomer using the same two-step procedure described in Steps 4 and 5 for Intermediate 2. MS (ES+) C 10 H 12 N2O2 requirement: 192, measured: 193 [M+H] + . 1 H NMR: 400MHz, DMSO-d6δ7.77(d,J=8.6Hz,1H),6.97(s,2H),6.40(d,J=8.6Hz,1H),4 .43-4.21(m,1H),2.88-2.65(m,1H),1.35(d,J=6.4Hz,3H),1.25(d,J=7.0Hz,3H).

[0535]

[0536] Intermediate 19: Racemic-(7S,8S)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0537]

[0538] Steps 1 and 2: rac-(7S,8S)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0539] The title compound was prepared from rac-(7S,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (after the synthesis of Intermediates 17 and 18 in Step 5) using the same two-step procedure described in Steps 4 and 5 for Intermediate 2. MS (ES+) C 10 H 12 N2O2 requirement: 192, measured: 193 [M+H] + . 1 H NMR: δ7.75(d,J=8.6Hz,1H),7.01(s,2H),6.40(d,J=8.6Hz,1H),4.69(d,J=6.6 Hz, 3.2Hz, 1H), 2.63-2.77 (m, 1H), 1.30 (d, J = 6.6Hz, 3H), 1.07 (d, J = 7.2Hz, 3H).

[0540]

[0541] Intermediates 20 and 21: (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

[0542]

[0543] Each of these is represented by one of the structures shown below:

[0544]

[0545]

[0546] It is represented by one of the structures shown below:

[0547]

[0548] Step 1-5: 2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0549] The title compound was prepared using a procedure analogous to that described above for Intermediate 17 from methyl 2-chloro-6-methoxynicotinate and 4,4,5,5-tetramethyl-2-(3-methylbut-2-en-2-yl)-1,3,2-dioxaborolane.

[0550] 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

[0551] 2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one was purified by SFC (column: DAICEL CHIRALPAK AS-H (250 mm*30 mm, 5 um); mobile phase: [0.1% NH4OH in CO2 MeOH]) to obtain one of the (R or S)-2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine-5-one as a yellow solid (the 1st eluting isomer, 0.55 g, 79% yield) and the other one of the (R or S)-2-((2,4-dimethoxybenzyl)amino)-7,7,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine-5-one (the 2nd eluting isomer, 0.55 g, 79% yield) as a yellow solid.

[0552] Steps 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

[0553] The title compounds (Intermediates 20 and 21) were prepared from the 1st and 2nd 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, respectively, using the same procedure as described in Step 5 of Intermediate 2. Intermediate 20, (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 N2O2 requirement: 206, measured: 207 [M+H] + . 1 H-NMR (400 MHz, CD3OD): δppm 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 21, (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 H14 N2O2 requirement: 206, measured: 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 stereochemistry of intermediate 20 was determined using an X-ray crystal structure in the context of another compound.

[0554]

[0555] Intermediate 22: 5-amino-3-isopropylpyrazine-2-carbonitrile

[0556]

[0557] Step 1: 5-amino-3-(prop-1-en-2-yl)pyrazine-2-carbonitrile

[0558] A mixture of 5-amino-3-chloropyrazine-2-carbonitrile (50.0 g, 324 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (81.54 g, 485.3 mmol, 1.50 equiv), KCO (89.42 g, 647.0 mmol, 2.00 equiv) and Pd(PPh) (18.69 g, 16.18 mmol, 0.05 equiv) in dioxane (250 mL) and H0 (50 mL) was stirred at 100 °C under N for 20 hours. The reaction mixture was then cooled to ambient temperature and diluted with EA (800 mL) and H0 (300 mL). The biphasic mixture was then filtered through celite and then partitioned. The organic layer was washed with brine (500 mL x 4) and then dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (gradient elution, 10% to 33% EA-petroleum ether) to afford the title compound (41.0 g, 39.0% yield) as a light yellow solid.

[0559] Step 2: 5-Amino-3-isopropylpyrazine-2-carbonitrile

[0560] Pd / C (10 wt%, 10.0 g) was added to a solution of 5-amino-3-(prop-1-ene-2-yl)pyrazine-2-carbonitrile (45.0 g, 281 mmol, 1.00 equiv) in MeOH (800 mL). The suspension was degassed under vacuum and purged with H2 three times. The reaction mixture was stirred at 25 °C for 16 hours under H2 (15 psi). The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The residue was treated with petroleum ether / EA (110 mL, 10: 1) and stirred at 25 °C for 10 minutes, then filtered. The filter cake was dried under vacuum to obtain the title compound (39.5 g, 85.6% yield) as a light yellow solid. MS (ES+) CH 10 N4 requirement: 162, measured: 163 [M+H] + . 1 H NMR: 400MHz CDCl3δ: 7.83 (s, 1H), 5.07 (br s, 2H), 3.43-3.33 (m, 1H), 1.28 (s, 3H), 1.26 (s, 3H).

[0561]

[0562] Intermediate 23: 6-amino-2-(2-fluoropropan-2-yl)nicotinonitrile

[0563]

[0564] Step 1: 2-Bromo-6-(2-fluoropropan-2-yl)pyridine

[0565] DAST (10.3 g, 63.9 mmol, 3.00 equiv) was added to a solution of 2-(6-bromopyridin-2-yl)propan-2-ol (4.60 g, 21.3 mmol, 1.00 equiv) in dichloromethane (80 mL) at -78 ° C under a nitrogen atmosphere. The reaction mixture was stirred for 1 hour, and then water (20 mL) was added. The reaction mixture was further diluted with water (150 mL) and extracted with EA (150 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (4.50 g, 97% yield) as a yellow oil, which was used in the next step without further purification.

[0566] Step 2: N-(6-(2-fluoropropan-2-yl)pyridin-2-yl)-1,1-diphenylmethaneimine

[0567] A mixture of 2-bromo-6-(2-fluoropropan-2-yl)pyridine (3.99 g, 22.0 mmol, 1.20 equiv), diphenylmethane imine (4.00 g, 18.3 mmol, 1.00 equiv), Pd2(dba)3 (1.68 g, 1.83 mmol, 0.10 equiv), XantPhos (2.12 g, 3.67 mmol, 0.20 equiv) and cesium carbonate (17.9 g, 55.0 mmol, 3.00 equiv) in dioxane (40 mL) was degassed and purged with nitrogen three times. The reaction mixture was stirred at 100 ° C for 1 hour under a nitrogen atmosphere, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 0% to 25% EA-petroleum ether) to give the title compound (5.00 g, 86% yield) as a yellow oil.

[0568] Step 3: 6-(2-fluoropropan-2-yl)pyridin-2-amine

[0569] At 25 ° C, HCl (4.0M in dioxane, 10mL) was added to a solution of N-(6-(2-fluoropropane-2-yl)pyridin-2-yl)-1,1-diphenylmethaneimine (5.30g, 16.7mmol) in dioxane (20mL). The reaction mixture was stirred at 25 ° C for 1 hour and then treated by dropwise addition of saturated aqueous sodium bicarbonate solution (20mL). The crude mixture was diluted with water (50mL) and extracted with EA (60mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (gradient elution, 0% to 20% EA-petroleum ether) to give the title compound (1.20g, 47% yield) as a yellow solid.

[0570] Step 4: 5-Bromo-6-(2-fluoropropan-2-yl)pyridin-2-amine

[0571] N- bromosuccinimide (1.25g, 7.00mmol, 0.900 equivalent) is added to a solution of 6- (2- fluoropropane -2- bases) pyridine -2- amine (1.20g, 7.78mmol, 1.00 equivalent) in chloroform (30mL). The reaction mixture is stirred at 25 ° C for 0.5 hours, then diluted with water (30mL) and extracted with EA (30mL × 3). The combined organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue is purified by flash column chromatography (gradient elution, 0% to 25% EA- petroleum ether) on silica gel to obtain the title compound (480mg, 25% yield) as a yellow oil. 1HNMR (400MHz, CDCl3): δppm 7.59 (d, J = 8.4Hz, 1H), 6.32 (d, J = 8.4Hz, 1H), 4.42 (s, 2H), 1.81 (s, 3H), 1.76 (s, 3H).

[0572] Step 5: 6-amino-2-(2-fluoropropan-2-yl)nicotinonitrile

[0573] A mixture of 5-bromo-6-(2-fluoropropane-2-yl)pyridin-2-amine (200 mg, 858 μmol, 1.00 equiv.), zinc cyanide (302 mg, 2.57 mmol, 3.00 equiv.), DPPF (95.0 mg, 172 μmol, 0.200 equiv.) and Pd2(dba)3 (79.0 mg, 85.8 μmol, 0.100 equiv.) in N,N-dimethylacetamide (2 mL) was degassed and purged with nitrogen three times. The reaction mixture was stirred at 140 ° C under nitrogen for 6 hours. The reaction mixture was then diluted with water (20 mL) and extracted with EA (20 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 0% to 25% EA-petroleum ether) to give the title compound (140 mg, 91% yield) as a brown solid. 1 H NMR (400MHz, CDCl3): δppm 7.68 (d, J = 8.4Hz, 1H), 6.42 (d, J = 8.8Hz, 1H), 4.91 (s, 2H), 1.76 (s, 3H), 1.71 (s, 3H).

[0574]

[0575] Intermediate 24: (S)-5-amino-3-(2-methylpyrrolidin-1-yl)pyrazine-2-carbonitrile

[0576]

[0577] Step 1: (S)-5-amino-3-(2-methylpyrrolidin-1-yl)pyrazine-2-carbonitrile

[0578] N, N-diisopropylethylamine (0.237mL, 1.36mmol, 3.00 equivalents) was added to a mixture of 5-amino-3-chloropyrazine-2-carbonitrile (70.0mg, 453umol, 1.00 equivalents) and (S)-2-methylpyrrolidine (hydrochloride, 71.6mg, 589umol, 1.30 equivalents) in 2-methyl-2-butanol (2mL). The reaction mixture was stirred at 100°C for 3 hours, then poured into 20mL of water and extracted with EA (15mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (90.0mg, crude) as a yellow solid, which was used without further purification. MS (ES+) C 10 H 13 N5 requirement: 203, measured: 204 [M+H] + .

[0579]

[0580] Intermediate 25: (S)-5-amino-3-(2-methylazetidin-1-yl)pyrazine-2-carbonitrile

[0581]

[0582] Step 1: (S)-5-amino-3-(2-methylazetidin-1-yl)pyrazine-2-carbonitrile

[0583] The title compound was prepared from 5-amino-3-chloropyrazine-2-carbonitrile and (S)-2-methylazetidine CSA salt using the same procedure as described in step 1 of intermediate 24. MS (ES+) C9H 11 N5 requirement: 189, measured: 190 [M+H] + .

[0584]

[0585] Intermediate 26: 6-amino-2-(1-fluoropropyl)nicotinonitrile

[0586]

[0587] Step 1: 1-(6-Bromopyrazin-2-yl)propan-1-ol

[0588] At -70 ° C, n-BuLi (2.5M, 6.73mL, 16.8mmol, 2.00 equivalents) was added dropwise to a mixture of 2,6-dibromopyrazine (2.00g, 8.41mmol, 1.00 equivalents) in dichloromethane (20mL), and then propionaldehyde (1.60g, 27.5mmol, 3.27 equivalents) in dichloromethane (3mL) was added to the mixture at -70 ° C. The reaction mixture was stirred at -70 ° C under nitrogen for 1 hour, and then a saturated aqueous ammonium chloride solution (60mL) was added. The reaction mixture was extracted with EA (60mL×3), and the organic layers were combined. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 5% to 10% EA-petroleum ether) to obtain the title compound (1.40g, 74% yield) as a yellow oil.

[0589] Step 2-6: 5-amino-3-(1-fluoropropyl)pyrazine-2-carbonitrile

[0590] The title compound was prepared using the same five-step procedure described in Intermediate 23, Steps 1-5, from 1-(6-bromopyrazin-2-yl)propan-1-ol. 1 H-NMR (400MHz, CD3OD): δppm 7.98 (s, 1H), 5.67-5.50 (m, 1H), 5.34 (s, 2H), 2.18-1.90 (m, 2H), 1.07 (t, J = 7.2Hz, 3H).

[0591]

[0592] Intermediate 27: 2'-aminospiro[cyclopropane-1,7'-pyrano[4,3-b]pyridine]-5'(8'H)-one

[0593]

[0594] Step 1-5: 2'-aminospiro[cyclopropane-1,7'-pyrano[4,3-b]pyridine]-5'(8'H)-one

[0595] The title compound was prepared from 4-oxaspiro[2.5]octan-7-one using the same five-step procedure as described in Steps 1-5 for Intermediate 2. 10 H 10 N2O2 requirement: 190, measured: 191 [M+H] + .

[0596]

[0597] Intermediate 28: 5-amino-3-(1,1,1-trifluoropropan-2-yl)pyrazine-2-carbonitrile compound 63

[0598]

[0599] Step 1: 5-amino-3-(3,3,3-trifluoroprop-1-en-2-yl)pyrazine-2-carbonitrile

[0600] Pd(PPh4)3 (657 mg, 776 umol, 0.200 equiv) and potassium carbonate (1.07 g, 7.76 mmol, 2.00 equiv) were added to a solution of 5-amino-3-chloropyrazine-2-carbonitrile (600 mg, 3.88 mmol, 1.00 equiv) and 4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-ene-2-yl)-1,3,2-dioxaborolane (1.03 g, 4.66 mmol, 1.20 equiv) in dioxane (5 mL) and water (0.5 mL). The mixture was stirred at 80 ° C for 16 hours under nitrogen. The reaction mixture was then cooled to ambient temperature, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Synergi Max-RP 250*50 mm*10 um; mobile phase: [water (0.1% TFA)-MeCN]; B%: 22 MeCN%-52 MeCN%) to give the title compound (200 mg, 24% yield) as a white solid.

[0601] Step 2: 5-amino-3-(1,1,1-trifluoropropan-2-yl)pyrazine-2-carbonitrile

[0602] Chloro rhodium triphenylphosphine (432 mg, 467 umol, 0.50 equiv) was added to a solution of 5-amino-3-(3,3,3-trifluoroprop-1-ene-2-yl)pyrazine-2-carbonitrile (200 mg, 934 umol, 1.00 equiv) in ethanol (10 mL). The reaction mixture was stirred at 50 ° C for 16 hours under H2 (15 psi), then filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250*50mm*10um; mobile phase: [water (0.1% TFA)-MeCN]; B%: 32%-62%) to obtain the title compound (20 mg, 9.9% yield) as a white solid. 1 H-NMR (400MHz, CD3OD): δppm 7.90 (s, 1H), 3.99-3.90 (m, 1H), 1.54 (d, J = 6.8, 3H).

[0603]

[0604] Intermediates 29 and 30: (S)-5-amino-3-(sec-butyl)pyrazine-2-carbonitrile and (R)-5-amino-3-(sec-butyl)pyrazine-2-carbonitrile

[0605]

[0606] Each of these is represented by one of the structures shown below:

[0607]

[0608] Steps 1 and 2: 5-amino-3-(sec-butyl)pyrazine-2-carbonitrile

[0609] The title compound was prepared using the same procedures described in Intermediate 22, Steps 1 and 2.

[0610] Step 3: (S)-5-amino-3-(sec-butyl)pyrazine-2-carbonitrile and (R)-5-amino-3-(sec-butyl)pyrazine-2-carbonitrile

[0611] 5-Amino-3-(sec-butyl)pyrazine-2-carbonitrile (320 mg, 1.82 mmol) was separated by SFC (column: DAICELCHIRALPAK AD-H (250 mm*30 mm, 5 um); mobile phase: EtOH with 0.1% NH4OH gradient in CO2) to obtain one of the (R or S)-5-amino-3-(sec-butyl)pyrazine-2-carbonitrile as an off-white solid (the first eluting isomer, 95 mg, 30% yield) and the other one of the (R or S)-5-amino-3-(sec-butyl)pyrazine-2-carbonitrile as a white solid (the second eluting isomer, 128 mg, 39.7% yield). Peak 1: MS (ES+) C9H 12 N4 requirement: 176, measured: 177 [M+H] + . 1 H-NMR (400MHz, CDCl3) δ = 7.83 (s, 1H), 5.07 (br s, 2H), 3.23-3.03 (m, 1H), 1.81-1.62 (m, 2H), 1.25 (d, J = 6.8Hz, 3H), 0.87 (t, J = 7.6Hz, 3H). Peak 2:MS(ES+)C9H 12 N4 requirement: 176, measured 177 [M+H] + . 1H-NMR (400MHz, CDCl3) δ = 7.83 (s, 1H), 5.08 (br s, 2H), 3.20-3.02 (m, 1H), 1.85-1.64 (m, 2H), 1.25 (d, J = 6.8Hz, 3H), 0.87 (t, J = 7.6Hz, 3H).

[0612] II. Synthesis of Aryl Chloride Intermediates

[0613]

[0614] Intermediate 31: 2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-ol

[0615]

[0616] Step 1: 4-Bromo-6-chloro-2,7-naphthyridin-1(2H)-one

[0617] 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 compound 2 (90.8 g, crude) as a brown solid. MS (ES+) C8H4BrClN2O required: 260, found: 261 [M+H] + .

[0618] Step 2: 4-Bromo-1,6-dichloro-2,7-naphthyridine

[0619] 4-Bromo-6-chloro-2,7-naphthyridin-1(2H)-one (70.8 g, 272 mmol, 1.00 equiv) was added portionwise to POCl3 (484 g, 3.16 mol, 293 mL, 11.5 equiv) at 25°C. The reaction mixture was then stirred at 110°C for 3 hours. The reaction mixture was then concentrated under vacuum, and the residue was adjusted to pH = 8 with saturated aqueous Na2CO3 solution at 25°C. The mixture was extracted with DCM (500 mL×3), washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under vacuum to give the title compound (75.0 g, 269 mmol, 98.9% yield) as a yellow solid. MS (ES+) C8H3BrCl2N2 required: 278, found: 279 [M+H] + .

[0620] Step 3: 4-Bromo-6-chloro-1-methoxy-2,7-naphthyridine

[0621] By 4-bromo-1,6-dichloro-2,7-naphthyridine (75.0g, 269mmol, 1.00 equivalent) in MeOH (3L), KCO (111g, 809mmol, 3.00 equivalent) suspension was stirred at 25 ° C for 16 hours. Then the reaction mixture was concentrated under vacuum, and the residue was dissolved in H O (300mL) and extracted with DCM (100mL x 2). The combined organic layer was concentrated under vacuum to obtain residue. The residue was ground and filtered in petroleum ether / EA (40mL 20: 1). The filter cake was dried under vacuum to obtain the title compound (47.0g, 171mmol, 63.6% yield) as a yellow solid.

[0622] Step 4: 6-Chloro-4-(1-ethoxyvinyl)-1-methoxy-2,7-naphthyridine

[0623] 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 for 16 hours under N2. The reaction mixture was then cooled to 20 ° C and poured into a saturated KF aqueous solution (500 mL) and stirred for 1 hour. The aqueous mixture was extracted with EA (300 mL x 3) and the organic layers were combined. The combined organic layers were concentrated under vacuum to obtain the title compound (64.0 g, crude product) as a yellow oil. MS (ES+) C 13 H 13 ClN2O2 requirement: 264, measured: 265 [M+H] + .

[0624] Step 5: 1-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-one

[0625] Aqueous HCl (1.50M, 20.1mL, 0.10 equiv) was added to a solution of 6-chloro-4-(1-ethoxyvinyl)-1-methoxy-2,7-naphthyridine (80.0g, 302mmol, 1.00 equiv) in THF (480mL) and H2O (80mL). The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was then poured into a saturated aqueous NaHCO3 solution (500mL) and extracted with EA (300mL×2). The organic layers were combined and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (gradient elution, 5% to 50% EA-petroleum ether) to obtain the title compound (28.0g, 118mmol, 39.1% yield) as a white solid. MS(ES+)C 11 H9ClN2O2 requirement: 236, measured: 237 [M+H] + .

[0626] Step 6: 2-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-ol

[0627] MeMgBr (3.0 M in 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 0-10 °C. The mixture was stirred at 0-10 °C for 2 hours, then poured into saturated aqueous NH4Cl solution (300 mL) and extracted with EA (200 mL x 2). The organic layers were combined and concentrated under vacuum to give the title compound (33 g, crude) as a yellow oil. MS (ES+) C 12 H 13 ClN2O2 requirement: 252, measured: 253 [M+H] + .

[0628]

[0629] Intermediate 31a: 4-(2-Azidopropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine can be obtained from 2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-ol after treatment with TMSN3, InBr3 and DCM.

[0630]

[0631] Intermediate 32: 4-bromo-7-chloro-1-iodo-2,6-naphthyridine

[0632]

[0633] Step 1: 5-Bromo-N-tert-butyl-2-chloroisonicotinamide

[0634] Under nitrogen atmosphere, 2-methylpropan-2-amine (1.47 g, 20.2 mmol), EDC HCl (4.85 g, 25.3 mmol) and HOBT (3.41 g, 25.3 mmol) were added to a solution of 5-bromo-2-chloropyridine-4-carboxylic acid (4 g, 16.9 mmol) in DMF (30 mL), and the reaction mixture was stirred at room temperature overnight. Water was added to the resulting solution and the suspension was extracted with EA, then the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography-column chromatography to give 3 g (60.9%) of the title compound as a white solid. MS (ES+) C 10 H 12 BrClN2O requires 290, measured 291 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ8.64(s,1H),8.30(s,1H),7.58(s,1H),1.36(s,9H).

[0635] Step 2: (E)-N-tert-butyl-2-chloro-5-(2-ethoxyvinyl)isonicotinamide

[0636] Under nitrogen atmosphere, 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.49 g, 7.53 mmol), Cs2CO3 (4.46 g, 13.7 mmol) and Pd(dppf)Cl2 (501 mg, 685 μmol) were added to a solution of 5-bromo-N-tert-butyl-2-chloropyridine-4-carboxamide (2 g, 6.85 mmol) in dioxane (30 mL) and H2O (6 mL), and the reaction mixture was stirred at 80°C for 2 hours. The resulting solution was diluted with water and extracted with EA, and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography to give 1.2 g (62.1%) of the title compound as a yellow solid. MS (ES+) C 14 H 19 ClN2O2 required 282, measured 283 [M+H] + . 1HNMR(300MHz,DMSO-d6)δ8.55(s,1H),8.20(s,1H),7.35(d,1H,J=13.0Hz),7.28(s,1 H), 5.79 (d, 1H, J = 13.0Hz), 3.90 (q, 2H, J = 7.0Hz), 1.35 (s, 9H), 1.26 (t, 3H, J = 7.0Hz).

[0637] Step 3: 7-Chloro-2,6-naphthyridin-1(2H)-one

[0638] TFA (20 mL) was added to N-tert-butyl-2-chloro-5-[(E)-2-ethoxyvinyl]pyridine-4-carboxamide (1.2 g, 4.24 mmol) and the reaction mixture was stirred at 100 °C overnight. The resulting mixture was concentrated under vacuum to give 600 mg (91.5%) of the title compound as a red solid. The crude product was used directly in the next step without any further purification. MS (ES+) C8H5ClN2O requires 180, found 181 [M+H] + .

[0639] Step 4: 4-Bromo-7-chloro-2,6-naphthyridin-1(2H)-one

[0640] NBS (3.54 g, 19.9 mmol) was added to a solution of 7-chloro-1,2-dihydro-2,6-naphthyridin-1-one (3 g, 16.6 mmol) in DCM (40 mL) and the reaction mixture was stirred at room temperature for 1 hour. The solid was collected by filtration to give 3 g (69.7%) of the title compound as a white solid. MS (ES+) C8H4BrClN2O requires 258, found 259 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ12.09(s,1H),8.93(s,1H),8.04(s,1H),7.70(d,1H,J=6.0Hz).

[0641] Step 5: 4-Bromo-7-chloro-2,6-naphthyridin-1-yl trifluoromethanesulfonate

[0642] Tf2O (4.34 g, 15.4 mmol) was added dropwise to a solution of 4-bromo-7-chloro-1,2-dihydro-2,6-naphthyridin-1-one (1 g, 3.85 mmol) in DCM (15 mL) and TEA (777 mg, 7.70 mmol) at -78 °C over 10 minutes, and the resulting solution was stirred at -78 °C for 0.5 hours. The mixture was warmed to room temperature and stirred at this temperature for another 0.5 hours. The reaction was then quenched by adding 2 mL of water / ice, extracted with DCM, and the organic layers were then combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified using flash column chromatography to give 1 g (66.6%) of the title compound as a white solid. MS (ES+) C9H3BrClF3N2O3S requires 390, found 391 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ9.47 (s, 1H), 8.78 (s, 1H), 8.14 (d, 1H, J = 0.9Hz).

[0643] Step 6: 4-Bromo-7-chloro-1-iodo-2,6-naphthyridine

[0644] NaI (952 mg, 6.35 mmol) was added to a solution of 4-bromo-7-chloro-2,6-naphthyridin-1-yl trifluoromethanesulfonate (500 mg, 1.27 mmol) in MeCN (9 mL), and the resulting mixture was cooled to 0 ° C, and trifluoromethanesulfonic acid (381 mg, 2.54 mmol) in MeCN (1 mL) was then added dropwise over 10 minutes. The mixture was then stirred at room temperature for 1.5 hours. The resulting solution was extracted with EA, and the organic layers were then combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 500 mg of the title compound as a black solid, which was used directly in the next step without further purification. MS (ES+) C9H3BrClF3N2O3S requires 368, found 369 [M+H] + .

[0645]

[0646] Intermediates 33 and 34: (R)-2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)butan-2-amine and (S)-2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)butan-2-amine

[0647]

[0648] Each of these is represented by one of the following structures:

[0649]

[0650] Step 1: 4-Bromo-6-chloro-1-cyclopropyloxy-2,7-naphthyridine

[0651] At 0 ° C, sodium hydride (4.32 g, 108 mmol, 60% purity) was added to a solution of cyclopropanol (5.75 g, 98.9 mmol) in THF (250 mL). The reaction mixture was stirred at 0 ° C for 20 minutes, and then 4-bromo-1,6-dichloro-2,7-naphthyridine (25.0 g, 90.0 mmol) was added to the reaction mixture. The reaction mixture was warmed to 25 ° C for 40 minutes, then poured into water (1 L) and extracted with ethyl acetate (500 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The crude product was purified by grinding in petroleum ether / EA (240 mL / 20 mL) at 25 ° C to obtain the title compound (45.0 g, 84% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3): δppm9.27(s,1H),8.40(s,1H),7.88(s,1H),4.57-4.50(m,1H),0.95-0.92(m,4H).

[0652] Step 2-3: 1-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)ethan-1-one

[0653] The title compound was prepared using the same two-step sequence as described in Intermediate 31, Steps 4 and 5, from 4-bromo-6-chloro-1-cyclopropyloxy-2,7-naphthyridine.

[0654] Step 4: 2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)butan-2-ol

[0655] To a solution of 1-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)ethan-1-one (27.0 g, 103 mmol) in MTBE (540 mL) was added ethylmagnesium bromide (3.0 M, 103 mL) at 0°C and under a nitrogen atmosphere. The reaction mixture was stirred at 0°C for 15 minutes, then quenched by adding water (1000 mL) and extracted with EA (800 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (34 g, crude) as a yellow oil, which was used directly in the next step.

[0656] Step 5: (R)-2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)butan-2-amine or (S)-2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)butan-2-amine

[0657] Under nitrogen atmosphere, trimethylsilyl azide (35.0 g, 304 mmol, 40 mL) and boron trifluoride ether (34.5 g, 243 mmol, 30 mL) were added to a solution of 2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)butan-2-ol (34.0 g, 116 mmol) in dichloromethane (340 mL) under nitrogen atmosphere. The reaction mixture was stirred at 25 ° C for 2 hours, then diluted with water (1000 mL) and extracted with DCM (800 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 3:1) to give rac-2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)butan-2-amine (15.0 g, 45% yield in two steps) as a yellow solid. The racemic compound was separated by SFC (column: Phenomenex-Cellulose-2 (250 mm×30 mm, 10 um); mobile phase: [0.1% MeOH (containing 0.1% NH OH) in CO 2 ] to give (R)-2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)butan-2-amine or (S)-2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)butan-2-amine (Intermediate 33, first eluting isomer, 2.90 g, 19% yield) as a yellow solid and the second eluting isomer (Intermediate 34, 4.80 g, 32% yield) as a white solid. Intermediate 33: 1 H NMR (400MHz, CDCl3): δppm 9.36(s,1H),8.36(s,1H),8.23(s,1H),4.58-4.51(m,1H),2.10-2.04(m,2H),1.84(s,3H),0.96-0.92(m,4H),0.87(t,J=7.2Hz,3H).

[0658]

[0659] Intermediate 35: 4-(2-azidoprop-2-yl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine

[0660] Intermediate 35 was prepared using procedures similar to those described for intermediates 33 and 34, except in step 4, methylmaganesium Grignard was used and chiral separation was not required.

[0661] Intermediates 36a-36o: Intermediates were prepared using procedures similar to those described for Intermediate 35, except using different reagents as described in Step 1 below.

[0662]

[0663]

[0664]

[0665]

[0666] Intermediates 37 and 38: (R)-4-(2-azidobutan-2-yl)-6-chloro-1-(1-methylcyclopropyloxy)-2,7-naphthyridine and (S)-4-(2-azidobutan-2-yl)-6-chloro-1-(1-methylcyclopropyloxy)-2,7-naphthyridine

[0667] Intermediates 37 and 38 were prepared using a similar procedure as described for Intermediates 33 and 34, except that 1-methylcyclopropan-1-ol was used in step 1. The racemic title compounds were separated by SFC (column: Daicel Chiralpak AD-H (250 mm x 30 mm, 5 um); mobile phase: [IPA (containing 0.1% NHOH) in CO2]) to give (R)-4-(2-azidobutan-2-yl)-6-chloro-1-(1-methylcyclopropoxy)-2,7-naphthyridine or (S)-4-(2-azidobutan-2-yl)-6-chloro-1-(1-methylcyclopropoxy)-2,7-naphthyridine as a white oil (Intermediate 37, first eluting isomer, 200 mg, 29% yield) and the second eluting isomer as a white oil (Intermediate 38, 290 mg, 42% yield). Intermediates 37 and 38: MS (ES+) C 16 H 18 ClN5O requires 331, measured 332 [M+H] + .

[0668]

[0669] Intermediates 39 and 40: (R)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-(1-methylcyclopropyloxy)-2,7-naphthyridine and (S)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-(1-methylcyclopropyloxy)-2,7-naphthyridine

[0670] Intermediates 39 and 40 were prepared using similar procedures as described for Intermediates 33 and 34, except cyclopropylmagnesium bromide was used in step 4 and the reaction was stirred at 60 °C for 30 minutes. The racemic title compounds were separated by SFC (column: Daicel Chiralpak AD-H (250 mm x 30 mm, 5 um); mobile phase: [IPA (containing 0.1% NH4OH) in CO2]) to give: (R)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-(1-methylcyclopropyloxy)-2,7-naphthyridine or (S)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-(1-methylcyclopropyloxy)-2,7-naphthyridine as a yellow solid (Intermediate 39, first eluting isomer, 130 mg, 28% yield) and the second eluting isomer as a yellow solid (Intermediate 40, 150 mg, 32% yield).

[0671]

[0672] Intermediates 41 and 42: (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

[0673]

[0674] Each of these is represented by one of the structures shown below:

[0675]

[0676] It is represented by one of the structures shown below:

[0677]

[0678] It is represented by one of the structures shown below:

[0679]

[0680] 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

[0681] Racemic -(7R, 8R) -2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrans is [4,3-b] pyridine-5-one (6.0g, 28.3mmol) is separated by SFC (Daicel Chiralpak AD, MeOH gradient in CO2, containing 0.1% NH4OH) to give two peaks respectively. Obtain the first eluting isomer (3g, 50% yield) and the second eluting isomer (2.8g, 46% yield) as a yellow solid.

[0682] Steps 2 and 3: (7R,8R)- or (7S,8S)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0683] The title compound (Intermediate 41) was prepared from one of the (7R,8R)- or (7S,8S)-2-chloro-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (the first eluting isomer from Step 1) using the same two-step procedure described in Step 4 and Step 5 for Intermediate 2. 1 H-NMR (400MHz, 6d-DMSO): δppm 7.76(d,J=8.8Hz,1H),7.02(s,2H),6.41(d,J=8.8Hz,1H),4.70(d,J=3.2,6 .4Hz, 1H), 2.77-2.66 (m, 1H), 1.31 (d, J = 6.8Hz, 3H), 1.08 (d, J = 7.2Hz, 3H). MS(ES+)C 10 H 12 N2O2 requirement: 192, measured: 193 [M+H] + .

[0684] Steps 4 and 5: The other one of (7R,8R)- or (7S,8S)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0685] The title compound (Intermediate 42) was prepared from the remaining one of (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 as described in Step 4 and Step 5 for Intermediate 2. MS (ES+) C 10 H 12 N2O2 requirement: 192, measured: 193 [M+H] + .

[0686]

[0687] Intermediates 43 and 44: (R)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-methoxy-2,7-naphthyridine or (S)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-methoxy-2,7-naphthyridine

[0688] Intermediates 43 and 44 were prepared using a similar procedure as described for Intermediates 33 and 34, except methanol was used in step 1 and cyclopropylmagnesium bromide was used in step 4 and the reaction was stirred at 60 °C for 30 minutes. The racemic title compound (1.20 g, 3.95 mmol) was separated by SFC (column: Daicel Chiralpak IG (250 mm x 30 mm, 10 um); mobile phase: [MeOH (containing 0.1% NH4OH) in CO2]) to give: (R)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-methoxy-2,7-naphthyridine or (S)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-methoxy-2,7-naphthyridine as a yellow oil (Intermediate 43, first eluting isomer, 490 mg, 40% yield) and the second eluting isomer as a yellow oil (Intermediate 44, 430 mg, 34% yield).

[0689]

[0690] Intermediate 45: 2'-amino-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-5'-one

[0691]

[0692] Step 1: Methyl 2-(3-bromo-6-chloropyridin-2-yl)acetate

[0693] LiHMDS (1M, 388mL) was added to a solution of 3-bromo-6-chloro-2-methylpyridine (20.0g, 96.9mmol) in THF (300mL) at 25°C under nitrogen. After 2.5 hours, dimethyl carbonate (14.0g, 155mmol) was added to the mixture and stirred at 25°C for 13.5 hours. The reaction mixture was then added to a saturated NH4Cl aqueous solution (1000mL) and extracted with EA (60mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 0% to 10% EA-petroleum ether) to obtain the title compound (18.0g, 70% yield) as a yellow oil. 1H NMR (400MHz, CDCl3): δppm 7.81 (d, J = 8.4Hz, 1H), 7.16 (d, J = 8.0Hz, 1H), 4.03 9s, 2H), 3.74 (s, 3H).

[0694] Step 2: Methyl 1-(3-bromo-6-chloropyridin-2-yl)cyclopropane-1-carboxylate

[0695] At 25 ° C, tetrabutylammonium bromide (2.44g, 7.56mmol) and NaOH (50mL, 50% by weight in water) were added to a solution of 1,2-dibromoethane (10.7g, 56.7mmol) and 2-(3-bromo-6-chloropyridin-2-yl) methyl acetate (10.0g, 37.8mmol)) in toluene (50mL). The reaction mixture was stirred at 25 ° C for 16 hours, then diluted with water (300mL) and extracted with EA (200mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 0% to 10% EA-petroleum ether) to obtain the title compound (6.10g, 56% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3): δppm7.81 (d, J = 8.4Hz, 1H), 7.15 (d, J = 8.0Hz, 1H), 3.66 (s, 3H), 1.81-1.75 (m, 2H), 1.46-1.41 (m, 2H).

[0696] Step 3: (1-(3-bromo-6-chloropyridin-2-yl)cyclopropyl)methanol

[0697] At -78 ℃ and nitrogen, diisobutylaluminum hydride (1M, 56mL) is added to the solution of 1-(3-bromo-6-chloropyridine-2-yl) cyclopropane-1-methyl formate (5.40g, 18.6mmol) in DCM (80mL).Reaction mixture is stirred for 0.5 hour at -78 ℃, then by adding saturated NH4Cl aqueous solution (50mL) cancellation, water (200mL) dilution and with EA (200mL × 3) extraction.The organic layer anhydrous sodium sulfate drying of merging, filter and concentrate, to obtain the thick title compound (5.00g, crude product) as yellow solid, it is used for next step without further purification.

[0698] Step 4: 5'-Oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-2'-carboxylic acid methyl ester

[0699] Under a nitrogen atmosphere, 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). The suspension was degassed under vacuum and purged with carbon monoxide several times. The mixture was stirred at 80 ° C for 16 hours under carbon monoxide (50 psi). The reaction mixture was then concentrated to remove methanol, diluted with water (100 mL) and extracted with EA (60 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The title compound (1.8 g, crude) was obtained as a yellow solid, which was used in the next step without further purification. MS(ES+)C 10 H 10 N2O2 requirement: 233, measured: 234 [M+H] + .

[0700] Step 5: 5'-Oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-2'-carboxylic acid

[0701] Lithium hydroxide (555 mg, 23.2 mmol) was added to a solution of 5'-oxo-5'H, 7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-2'-carboxylic acid methyl ester (1.80 g, 7.72 mmol) in methanol (30 mL) and water (10 mL). The reaction mixture was stirred at 25 ° C for 0.5 hours 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 (6M, 5 mL), and 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.

[0702] Step 6: tert-Butyl (5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-2'-yl)carbamate

[0703] 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-butyl alcohol (20 mL). The reaction mixture was stirred at 100 ° C for 1 hour, then cooled to ambient temperature, diluted with water (60 mL), and extracted with EA (50 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 0% to 50% EA-petroleum ether) to give the title compound as a yellow solid (330 mg, 19% yield) and 2'-amino-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-5'-one (420 mg, 28% yield) as a yellow oil.

[0704] Step 7: 2'-amino-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-5'-one

[0705] At 25 ° C, HCl (4.0M, 0.5mL) in dioxane was added to a solution of (5'-oxo-5'H, 7'H-spiro [cyclopropane-1,8'-pyrano [4,3-b] pyridine] -2'-yl) tert-butyl carbamate (100mg, 344μmol) in dioxane (1.5mL). The reaction mixture was stirred for 10 minutes and then concentrated. DCM (2mL) and TFA (1mL, 13.5mmol) were added to the residue, and the reaction mixture was stirred at 25 ° C for 30 minutes. The reaction mixture was then concentrated and EA (5mL) was added to the residue. The mixture was neutralized by adding saturated NaHCO3 aqueous solution (20mL) and extracted with EA (15mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (60.0mg, 92% yield) as a yellow oil, which was used in the next step without further purification. MS(ES+)C 12 H 11 NO4 requirement: 190, measured: 191 [M+H] + .

[0706]

[0707] Intermediates 46 and 47: (S)-2-amino-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one and (R)-2-amino-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one

[0708]

[0709] Each of these is represented by one of the structures shown below:

[0710]

[0711] It is represented by one of the structures shown below:

[0712]

[0713] It is represented by one of the structures shown below:

[0714]

[0715] Step 1-4: 2-Chloro-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one

[0716] The title compound was prepared from methyl 2-chloro-6-methoxynicotinate and 2-(but-1-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane using procedures analogous to those described for intermediate 17 (steps 1-3, 5), except CsF was used as the base in step 1 and step 2 was carried out at 25 °C for 1 hour.

[0717] Step 5: (S)-2-chloro-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one and (R)-2-chloro-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one

[0718] 2-Chloro-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one (1.9 g, 8.98 mmol) was separated by SFC (column: DAICEL CHIRALPAK AS-H (250 mm*30 mm, 5 um); mobile phase: [0.1% NH4OH EtOH in CO2]) to obtain one of the (R or S)-2-chloro-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one (the 1st eluting isomer, 0.70 g, 37% yield) and the other one of the (R or S)-2-chloro-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one (the 2nd eluting isomer, 0.90 g, 47% yield).

[0719] Steps 6 and 7: (R or S)-2-amino-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one

[0720] The title compound (Intermediate 46) was prepared from (R or S)-2-chloro-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one (first eluting isomer from Step 5) using the same two-step procedure described in Intermediate 2, Steps 4 and 5. 1 H-NMR (400MHz, 6d-DMSO): δppm 7.67 (d, J = 8.4Hz, 1H), 7.29 (s, 2H), 6.52-6.46 (m, 1H), 1.93-1.78 (m, 2H), 1.47 (s, 3H), 0.63 (d, J = 7.2Hz, 3H). MS(ES+)C 10 H 12 N2O2 requirement: 192, measured: 193 [M+H] + .

[0721] Steps 8 and 9: The other of (R or S)-2-amino-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one

[0722] The title compound (Intermediate 47) was prepared from the remaining one of (RS)-2-chloro-7-ethyl-7-methylfuro[3,4-b]pyridin-5(7H)-one (the second eluting isomer from Step 5) using the same two-step procedure as described in Steps 4 and 5 of Intermediate 2. 1 H-NMR (400MHz, 6d-DMSO): δppm 7.68 (d, J = 8.8 Hz, 1H), 7.30 (s, 2H), 6.49 (d, J = 8.8 Hz, 1H), 1.95-1.79 (m, 2H), 1.48 (s, 3H), 0.64 (d, J = 7.4Hz, 3H). MS(ES+)C 10 H 12 N2O2 requirement: 192, measured: 193 [M+H] + .

[0723]

[0724] Intermediates 48 and 49: (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

[0725]

[0726] Each of these is represented by one of the structures shown below:

[0727]

[0728] It is represented by one of the structures shown below:

[0729]

[0730] It is represented by one of the structures shown below:

[0731]

[0732] 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

[0733] Racemic-2-chloro-8-methyl-7,8-dihydro-5H-pyrans is [4,3-b] pyridine-5-one (700mg, 3.54mmol) is separated by SFC (Daicel Chiralpak IG, MeOH, MeOH gradient in CO containing 0.1% NHOH) to obtain two peaks respectively. The first eluting isomer (330mg, 47% yield) and the second eluting isomer (330mg, 47% yield) as a yellow solid are obtained.

[0734] Steps 2 and 3: (R or S)-2-amino-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0735] The title compound (Intermediate 48) was prepared from one of the (R or S)-2-chloro-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-ones (the first eluting isomer from Step 1) using the same two-step procedure as described in Steps 4 and 5 of Intermediate 2. MS (ES+) C9H 10 N2O2 requirement: 178, measured: 179 [M+H] + .

[0736] Steps 3 and 4: The other of (R or S)-2-amino-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0737] The title compound (Intermediate 49) was prepared from the remaining one of (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 the same two-step procedure as described in Steps 4 and 5 of Intermediate 2. MS (ES+) C9H 10 N2O2 requirement: 178, measured: 179 [M+H] + .

[0738]

[0739] Intermediates 50 and 51: (R)-2'-amino-7'-methyl-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-5'-one and (S)-2'-amino-7'-methyl-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-5'-one

[0740]

[0741] Each of these is represented by one of the structures shown below:

[0742]

[0743] It is represented by one of the structures shown below:

[0744]

[0745] Step 1: 1-(3-bromo-6-chloropyridin-2-yl)cyclopropane-1-carbaldehyde

[0746] 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+) C9H7BrClNO required: 261, found: 262 [M+H] + .

[0747] Step 2: 1-(1-(3-bromo-6-chloropyridin-2-yl)cyclopropyl)ethan-1-ol

[0748] Methylmagnesium bromide (3M, 17mL) was added to a solution of 1-(3-bromo-6-chloropyridin-2-yl)cyclopropane-1-carbaldehyde (2.60g, 9.98mmol) in THF (80mL) at 0°C. The reaction mixture was stirred for 10 minutes, then quenched by the addition of saturated aqueous NH4Cl solution (80mL), diluted with water (40mL) and extracted with EA (80mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (2.70g, crude) as a yellow oil, which was used without further purification. MS(ES+)C10 H 11 N2O2 requirement: 277, measured: 278 [M+H] + .

[0749] Step 3-5: tert-Butyl (7'-methyl-5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-2'-yl)carbamate

[0750] The title compound was prepared using procedures analogous to those described above in Intermediate 45, Steps 4-6, from 1-(1-(3-bromo-6-chloropyridin-2-yl)cyclopropyl)ethan-1-ol. 1 H NMR (400MHz, CDCl3): δppm 8.29(d,J=8.8Hz,1H),7.90(d,J=8.8Hz,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).

[0751] Step 6: (R)-tert-butyl(7'-methyl-5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-2'-yl)carbamate and (S)-tert-butyl(7'-methyl-5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-2'-yl)carbamate

[0752] Tert-butyl (7'-methyl-5'-oxo-5'H, 7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-2'-yl)carbamate (400 mg) was separated by SFC (column: REGIS(s,s)WHELK-O1 (250 mm×50 mm, 10 um), EtOH gradient in CO2 containing 0.1% NH4OH) to give two separate peaks. The first eluting isomer (100 mg, 24% yield) and the second eluting isomer (140 mg, 34% yield) were obtained as yellow solids.

[0753] Step 7: (R or S)-2'-amino-7'-methyl-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-5'-one

[0754] TFA (2.31 g, 20.3 mmol) was added to a solution of one of (R or S)-(7'-methyl-5'-oxo-5'H, 7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-2'-yl) tert-butyl carbamate (the first eluting isomer from step 6, 100 mg) in DCM (6 mL). The reaction mixture was stirred at 25 ° C for 30 minutes, then quenched with saturated NaHCO3 aqueous solution (30 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (intermediate 50, 70 mg, crude product) as a yellow oil, which was used without further purification. MS (ES +) C 11 H 12 N2O2 requirement: 204, measured: 205[M+H] + .

[0755] Step 8: The remaining one of (R or S)-2'-amino-7'-methyl-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-5'-one

[0756] The title compound (Intermediate 51) was prepared from one of the tert-butyl (R or S)-(7'-methyl-5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridin]-2'-yl)carbamates (the second eluting isomer from Step 6) using the same procedure as described in Step 7 of Intermediate 50. MS (ES+) C 11 H 12 N2O2 requirement: 204, measured: 205[M+H] + .

[0757]

[0758] Intermediates 52 and 53: (R)-4-(2-azidobutan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine and (S)-4-(2-azidobutan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine

[0759] Intermediates 52 and 53 were prepared using a similar procedure as described for Intermediates 33 and 34, except methanol was used in step 1. The racemic title compound (0.84 g, 2.87 mmol) was separated by SFC (column: Daicel Chiralpak IG (250 mm x 30 mm, 10 um); mobile phase: [MeOH (MeOH (containing 0.1% NHOH) in CO2]) to give: (R)-4-(2-azidobutan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine or (S)-4-(2-azidobutan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine as a yellow oil (Intermediate 52, first eluting isomer, 350 mg, 42% yield) and the second eluting isomer as a yellow solid (Intermediate 53, 360 mg, 43% yield).

[0760]

[0761] Intermediate 54: 2-amino-7,7-dimethyl-8,9-dihydrooxacyclohepten[4,3-b]pyridin-5(7H)-one

[0762]

[0763] Step 1: (E)-methyl 3-(6-((tert-butoxycarbonyl)amino)pyridin-2-yl)acrylate

[0764] Pd(OAc)2(1.23g, 5.49mmol), P(o-tolyl)3(2.51g, 8.24mmol) and diisopropylethylamine (71.0g, 549mmol, 95.7mL) were added to a solution of tert-butyl (6-bromopyridin-2-yl)carbamate (15.0g, 54.9mmol) and methyl acrylate (18.9g, 220mmol, 19.8mL) in DMF (150mL). The reaction mixture was stirred at 100°C for 1 hour, then diluted with EA (200mL) and washed with brine (200mL×3). The organic layer was dried over sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 10% to 33% EA-petroleum ether) to obtain the title compound (7.00g, 39% yield) as a yellow solid.

[0765] Step 2: Methyl 3-(6-((tert-butoxycarbonyl)amino)pyridin-2-yl)propanoate

[0766] Pd / C (100 mg, 10% purity) was added to a solution of (E)-methyl 3-(6-((tert-butoxycarbonyl)amino)pyridin-2-yl)acrylate (7.00 g, 25.2 mmol) in MeOH (100 mL). The mixture was stirred under hydrogen at 25 °C for 12 hours, then filtered and concentrated 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 (6.00 g, 18.6 mmol, 74% yield) as a yellow solid.

[0767] Step 3: tert-Butyl (6-(3-hydroxy-3-methylbutyl)pyridin-2-yl)carbamate

[0768] Methylmagnesium bromide (3M, 35.7mL) was added to a solution of methyl 3-(6-((tert-butoxycarbonyl)amino)pyridin-2-yl)propanoate (6.00g, 21.4mmol) in THF (100mL) at 0°C. The reaction mixture was stirred at 25°C for 0.5 hours, then poured into water (200mL) and extracted with EA (50mL×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 15% to 50% EA-PE) to give the title compound (5.00g, 15.9mmol, 74% yield) as a yellow solid.

[0769] Step 4: tert-Butyl (5-bromo-6-(3-hydroxy-3-methylbutyl)pyridin-2-yl)carbamate

[0770] At 0°C, N-bromosuccinimide (3.17 g, 17.8 mmol) in ACN (50 mL) was added to a solution of tert-butyl (6-(3-hydroxy-3-methylbutyl)pyridin-2-yl)carbamate (5.00 g, 17.8 mmol) in ACN (50 mL). The reaction mixture was stirred at 25°C for 1 hour, then poured into water (200 mL) and extracted with EA (50 mL×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated 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 (4.00 g, 62% yield) as a yellow solid. 1H-NMR (400MHz, CDCl3): δppm 7.72(d,J=8.4Hz,1H),7.65(d,J=8.8Hz,1H),7.39(S,1H),2.99-2.93(m,2H),1.87-1.78(m,2H),1.49(s,9H),1.27(s,6H).

[0771] Step 5: 6-((tert-Butyloxycarbonyl)amino)-2-(3-hydroxy-3-methylbutyl)nicotinic acid

[0772] At -78 ° C, n-butyl lithium (2.5M, 11.1 mL) was added to a solution of tert-butyl (5-bromo-6-(3-hydroxy-3-methylbutyl) pyridin-2-yl) carbamate (2.00 g, 5.57 mmol) in THF (50 mL). The reaction mixture was stirred at -78 ° C for 10 minutes, then carbon dioxide was added and the mixture was stirred at -78 ° C for 20 minutes. The reaction mixture was then poured into water (100 mL) and extracted with EA (30 mL×3). The organic layer was discarded and aqueous ammonium chloride solution was added to the aqueous layer to adjust pH <7. The mixture was extracted with EA (30 mL×5), and the combined organic layers were dried over sodium sulfate, filtered and concentrated to give the title compound (200 mg, crude) as a yellow solid.

[0773] Step 6: tert-Butyl (7,7-dimethyl-5-oxo-5,7,8,9-tetrahydrooxacyclohepta[4,3-b]pyridin-2-yl)carbamate

[0774] Dicyclohexylcarbodiimide (229 mg, 1.11 mmol, 225 μL) was added to a solution of 6-((tert-butoxycarbonyl)amino)-2-(3-hydroxy-3-methylbutyl)nicotinic acid (180 mg, crude) and 4-N,N-dimethylaminopyridine (33.9 mg, 277 μmol) in DCM (20 mL). The reaction mixture was stirred at 25 ° C for 12 hours. The residue was purified by preparative TLC (33% EA-petroleum ether) on silica gel to obtain the title compound (30.0 mg, crude) as a yellow solid.

[0775] Step 7: 2-amino-7,7-dimethyl-8,9-dihydrooxacyclohepten[4,3-b]pyridin-5(7H)-one

[0776] The title compound was prepared using a procedure analogous to that described in Step 7 of Intermediate 50 from tert-butyl (7,7-dimethyl-5-oxo-5,7,8,9-tetrahydrooxepan[4,3-b]pyridin-2-yl)carbamate. 1H-NMR (400MHz, CDCl3): δppm7.92 (d, J = 8.8 Hz, 1H), 6.36 (d, J = 8.8 Hz, 1H), 5.17 (s, 2H), 2.96-2.92 (m, 2H), 2.11-2.09 (m, 2H), 1.33 (s, 6H).

[0777]

[0778] Intermediate 55: 2-amino-8,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0779]

[0780] Step 1: Methyl 2-(3-bromo-6-chloropyridin-2-yl)-2-methylpropanoate

[0781] At 0 ° C, sodium hydride (2.91g, 72.8mmol, 60% purity) was added to a solution of 2-(3-bromo-6-chloropyridin-2-yl) methyl acetate (5.50g, 20.8mmol) in THF (20mL). The reaction mixture was stirred at 0 ° C for 15 minutes, and then iodomethane (7.38g, 51.9mmol) was added. The reaction mixture was warmed to 25 ° C and stirred for 45 minutes, then quenched with water (30mL) and extracted with EA (30mL×2). The combined organic layer was concentrated to obtain a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 0% to 10% EA-petroleum ether) to obtain the title compound (5.5g, 90% yield) as a yellow oil. 1 H NMR (400MHz, CD3OD): δppm 7.97 (d, J = 8.4Hz, 1H), 7.20 (d, J = 8.4Hz, 1H), 3.95 (s, 2H), 1.50 (s, 6H)

[0782] Step 2-6: 2-amino-8,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0783] The title compound was prepared using a procedure analogous to that described in Intermediate 45, Steps 3-6 and Intermediate 50, Step 7. MS (ES+) C 10 H 12 N2O2 requirement: 192, measured: 193 [M+H] + . 1H NMR (400MHz, 6d-DMSO): δppm 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).

[0784]

[0785] Intermediates 56 and 57: (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

[0786]

[0787] Step 1-5: (racemic)-2-amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0788] The title compound was prepared from 2-(3-bromo-6-chloropyridin-2-yl)-2-methylpropan-1-ol using a procedure analogous to that described in Steps 1-5 of Intermediate 50. 11 H 14 N2O2 requirement: 206, measured: 207 [M+H] + .

[0789] 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

[0790] (Racemic)-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 um), methanol gradient in CO2 containing 0.1% NH4OH) to give two peaks respectively. One of the first eluting isomers (R or S)-2-amino-7,8,8-trimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine-5-one (Intermediate 56, 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]pyridine-5-one (Intermediate 57, 60 mg, 50% yield).

[0791]

[0792] Intermediates 58 and 59: (7R,8R)-2-amino-8-ethyl-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and (7S,8S)-2-amino-8-ethyl-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0793]

[0794] Each of these is represented by one of the structures shown below:

[0795]

[0796] It is represented by one of the structures shown below:

[0797]

[0798] Step 1: Methyl 2-(3-bromo-6-chloropyridin-2-yl)butanoate

[0799] At 0 ° C, NaH (1.69 g, 42.2 mmol, 60 wt%) was added to a solution of 2-(3-bromo-6-chloropyridin-2-yl) methyl acetate (9.3 g, 35.2 mmol) in THF (100 mL). The reaction mixture was stirred at 0 ° C for 0.5 hours, and iodoethane (6.03 g, 38.9 mmol) was added to the reaction mixture. The reaction mixture was stirred for 30 minutes, then quenched by adding NH4Cl aqueous solution (20 mL) and extracted with EA (20 mL × 3). The combined organic layer was concentrated under reduced pressure to obtain a residue. The aqueous layer was also concentrated to obtain a residue. The residue was dissolved in EA (500 mL), filtered and concentrated to obtain a residue. The residue was purified by flash column chromatography on silica gel (gradient elution, 0% to 20% EA-PE) to obtain the title compound (6.5 g, 63% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3): δppm 7.71(d,J=8.4Hz,1H),7.04-7.01(m,1H),4.12-4.03(m,1H),3.62(s,3H),2.14-2.09(m,1H),2.02-1.96(m,1H),0.89-0.84(m,3H).

[0800] Step 2-7: tert-Butyl (8-ethyl-7-methyl-5-oxo-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)carbamate

[0801] The title compound was prepared using procedures analogous to those described in Intermediate 45, step 3 and Intermediate 50, steps 1-5, from methyl 2-(3-bromo-6-chloropyridin-2-yl)butanoate.

[0802] Step 8: tert-Butyl ((7R,8R)-8-ethyl-7-methyl-5-oxo-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)carbamate and tert-butyl ((7S,8S)-8-ethyl-7-methyl-5-oxo-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)carbamate

[0803] Tert-butyl (8-ethyl-7-methyl-5-oxo-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)carbamate (200 mg) was separated by SFC (column: Daicel Chiralpak AD-H (250 mm×30 mm, 5 um), IPA gradient in CO2 containing 0.1% NH4OH) to obtain two peaks respectively. The first eluting isomer (80 mg, 40% yield) and the second eluting isomer (70 mg, 35% yield) were obtained as colorless oils.

[0804] Step 9: (7R, 8R or 7S, 8S)-2-amino-8-ethyl-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0805] The title compound (Intermediate 58) was prepared from one of the tert-butyl ((7R, 8R or 7S, 8S)-8-ethyl-7-methyl-5-oxo-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)carbamates (the first eluting isomer from Step 8) using the same procedure as described in Step 7 of Intermediate 50. MS (ES+) C 11 H 14 N2O2 requirement: 206, measured: 207 [M+H] + .

[0806] Step 10: The other one of (7R, 8R or 7S, 8S)-2-amino-8-ethyl-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0807] The title compound (Intermediate 59) was prepared from one of the tert-butyl ((7R, 8R or 7S, 8S)-8-ethyl-7-methyl-5-oxo-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)carbamates (the second eluting isomer from Step 8) using the same procedure as described in Step 7 of Intermediate 50. MS (ES+) C 11 H14 N2O2 requirement: 206, measured: 207 [M+H] + .

[0808]

[0809] Intermediates 60 and 61: (7S,8R)-2-amino-7-ethyl-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and (7R,8S)-2-amino-7-ethyl-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0810]

[0811] Each of these is represented by one of the structures shown below:

[0812]

[0813] It is represented by one of the structures shown below:

[0814]

[0815] It is represented by one of the structures shown below:

[0816]

[0817] Step 1-2: (7S, 8R and 7R, 8S)-7-ethyl-2-methoxy-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0818] The title compound was prepared from (Z)-4,4,5,5-tetramethyl-2-(pent-2-en-2-yl)-1,3,2-dioxaborolane and methyl 2-chloro-6-methoxynicotinate using a similar procedure to that described above for Intermediate 17, except that CsF was used as a base in step 1 and step 2 was performed at 60° C. for 2 hours. The product mixture (4 compounds, cis and trans racemates) was purified by preparative HPLC [column: Phenomenex luna C18 250*80mm*10um; mobile phase: [water (0.225% FA)-ACN]; B%: 45%-75%, 25 minutes] to give the title compound (trans, racemate, 2 g, 27% yield) as a white solid. 1H NMR (400MHz, CDCl3): δppm 8.19(d,J=8.4Hz,1H),6.71(d,J=8.4Hz,1H),4.27-4.22(m,1H),4.01(m,3H),3.10-2.9 7(m,1H),1.91-1.85(m,1H),1.84-1.78(m,1H),1.42(d,J=7.2Hz,3H),1.13-1.08(m,3H)

[0819] Step 3-4: (7S, 8R and 7R, 8S)-2-chloro-7-ethyl-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0820] The title compound was prepared using the same procedure as described in Intermediate 10, Steps 4 and 5, from (7S,8R and 7R,8S)-7-ethyl-2-methoxy-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one.

[0821] Step 5: (7S,8R)-2-chloro-7-ethyl-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and (7R,8S)-2-chloro-7-ethyl-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0822] (7S, 8R and 7R, 8S)-2-chloro-7-ethyl-8-methyl-7,8-dihydro-5H-pyrans is [4,3-b] pyridine-5-one (255mg, 1.13mmol) is separated by SFC (Daicel Chiralpak AD, in the CO containing 0.1% NHOH MeOH gradient in) to give two peaks respectively. Obtain the first eluting isomer (100mg, 39% yield) and the second eluting isomer (120mg, 47% yield) as yellow solid. 1 H NMR (400MHz, CDCl3): δppm 8.29(d,J=8.4Hz,1H),7.39(d,J=8.4Hz,1H),4.36-4.31(m,1H),3.19-3 .12(m,1H),1.87-1.75(m,2H),1.46(d,J=7.2Hz,3H),1.11-1.08(m,3H).

[0823] Steps 6 and 7: (7S,8R)- or (7R,8S)-2-amino-7-ethyl-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0824] The title compound (Intermediate 60) was prepared from one of the (7S,8R)- or (7R,8S)-2-chloro-7-ethyl-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (the first eluting isomer from Step 5) using the same two-step procedure as described in Steps 4 and 5 of Intermediate 2. MS (ES+) C 11 H 14 N2O2 requirement: 206, measured: 207 [M+H] + .

[0825] Steps 8 and 9: The other one of (7S,8R)- or (7R,8S)-2-amino-7-ethyl-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[0826] The title compound (Intermediate 60) was prepared from one of the (7S,8R)- or (7R,8S)-2-chloro-7-ethyl-8-methyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (the second eluting isomer from Step 5) using the same two-step procedure as described in Steps 4 and 5 of Intermediate 2. MS (ES+) C 11 H 14 N2O2 requirement: 206, measured: 207 [M+H] + .

[0827]

[0828] Intermediate 62: 2-amino-7,7-dimethyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0829]

[0830] Step 1: 2-Hydroxy-7,7-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester

[0831] A mixture of tert-butyl 2,2-dimethyl-4-oxopiperidine-1-carboxylate (4.00 g, 17.6 mmol) and pyrrolidine (1.25 g, 17.6 mmol) was dissolved in toluene (60 mL), and the solution was heated to 140 ° C for 5 hours in a container covered with a Dean-Stark trap. The mixture was concentrated, and the residue was then dissolved in toluene (60 mL) and prop-2-ynamide (1.82 g, 26.4 mmol) was added. The reaction mixture was heated to 140 ° C for 16 hours and then concentrated to obtain a residue. The residue was purified by preparative HPLC: reverse phase [ACN / (0.1% TFA in water), 0% to 50%] to obtain the title compound (500 mg, 9.5% yield, 93% purity) as a brown oil. 1 H-NMR (400MHz, CD3OD): δppm7.45 (d, J = 9.6Hz, 1H), 6.54-6.47 (m, 1H), 4.20 (s, 2H), 2.85 (s, 2H), 1.52-1.48 (m, 9H).

[0832] Step 2: 2-Chloro-7,7-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridine

[0833] The title compound was prepared using a procedure analogous to that described in Intermediate 2, Step 2 from tert-butyl 2-hydroxy-7,7-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate.

[0834] Step 3: 2-Chloro-7,7-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester

[0835] The mixture of 2-chloro-7,7-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridine (300mg, 1.53mmol), sodium hydroxide (305mg, 7.63mmol) and Boc2O (665mg, 3.05mmol) in water (50mL) and EtOH (5.0mL) was stirred at 20°C for 0.5 hours. The reaction mixture was extracted with EA (30mL×3), and the combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated to obtain residue. The residue was purified by flash column chromatography (gradient elution, 1% to 25% EA-petroleum ether) on silica gel to obtain the title compound (250mg, 798umol) as a yellow oil.

[0836] Step 4-6: 2-amino-7,7-dimethyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0837] The title compound was prepared using analogous procedures to those described in Intermediate 2, Steps 3-5, from tert-butyl 2-chloro-7,7-dimethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate. 1 H NMR (400MHz, CDCl3): δppm 8.06 (d, J = 8.4Hz, 1H), 6.44 (d, J = 8.4Hz, 1H), 5.48 (s, 1H), 4.80 (s, 2H), 2.89 (s, 2H), 1.34 (s, 6H).

[0838]

[0839] Intermediates 63 and 64: (R)-4-(1-azido-1-cyclobutylethyl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine and (S)-4-(1-azido-1-cyclobutylethyl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine

[0840] Intermediates 63 and 64 were prepared using a procedure similar to that described for Intermediates 33 and 34, except that in step 4, cyclobutylmagnesium bromide was used and the reaction was stirred at 60°C for 1 hour. The reaction was carried out by SFC (column: Daicel Chiralpak AY (250 mm x 50 mm, 10 um); mobile phase: [EtOH (containing 0.1% NH4OH)]) to separate the racemic title compound to give (R)-4-(1-azido-1-cyclobutylethyl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine or (S)-4-(1-azido-1-cyclobutylethyl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine (Intermediate 63, first eluting isomer, 27 mg, 18% yield) as a white solid and (R)-4-(1-azido-1-cyclobutylethyl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine or (S)-4-(1-azido-1-cyclobutylethyl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine (Intermediate 64, 67 mg, 45% yield) as the second eluting isomer of a white solid.

[0841]

[0842] Intermediates 65 and 66: (1S, 3S)-3-(4-aminopyrimidin-2-yl)cyclohexane-1-ol or (1R, 3R)-3-(4-aminopyrimidin-2-yl)cyclohexane-1-ol

[0843]

[0844] Step 1: 3-(4-aminopyrimidin-2-yl)cyclohex-2-en-1-one

[0845] Potassium carbonate (600mg, 4.34mmol) and Pd(dppf)Cl2 (160mg, 218umol) were added to a mixture of 2-chloropyrimidine-4-amine (280mg, 2.16mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)cyclohex-2-ene-1-one (500mg, 2.25mmol) in dioxane (10mL) and water (3mL). The reaction mixture was stirred at 90°C for 16 hours, then poured into water (30mL) and extracted with EA (50mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography [SiO2, petroleum ether / ethyl acetate=2 / 1 to 1:2] to obtain the title compound (300mg, 73.4% yield) as a yellow solid.

[0846] Step 2: 3-(4-aminopyrimidin-2-yl)cyclohex-2-en-1-ol

[0847] NaBH4 (120 mg, 3.17 mmol) was added to a mixture of 3-(4-aminopyrimidin-2-yl)cyclohex-2-ene-1-one (300 mg, 1.59 mmol) in MeOH (2 mL). The reaction mixture was stirred at 20 ° C for 1 hour, then quenched with water (10 mL) and concentrated to obtain a residue. The residue was washed with DCM (10 mL) and filtered, and the filtrate was concentrated to obtain the title compound (290 mg, crude product) as a yellow solid.

[0848] Step 3: rac-(1S,3S)-3-(4-aminopyrimidin-2-yl)cyclohexane-1-ol

[0849] Pd / C (20 mg, 0.304 mmol) was added to a solution of 3-(4-aminopyrimidin-2-yl)cyclohex-2-ene-1-ol (290 mg, 1.52 mmol) in MeOH (10 mL), and the reaction mixture was stirred under hydrogen (50 psi) at 20 ° C for 4 hours. The reaction mixture was then filtered and concentrated to give a residue. The residue contained a mixture of cis- and trans-products, which were separated by preparative HPLC (column: Welch Ultimate AQ-C18 150*30mm*5um; mobile phase: [water (0.1% TFA)-ACN]; B%: 2%-22%, 13 minutes). WH103959-6 (350.0 mg, 1.81 mmol, 58% yield) was used to give the title compound as a TFA salt. The TFA salt of the title compound (7.50 g, 24.41 mmol, from several batches) in MeOH (150 mL) was treated with basic resin (Ambersep 900) (100 g) and stirred for 12 h at 25° C. The mixture was filtered and the filtrate was concentrated to give the title compound (5.40 g, crude) as a white solid.

[0850] Step 4: (1S,3S)-3-(4-aminopyrimidin-2-yl)cyclohexan-1-ol and (1R,3R)-3-(4-aminopyrimidin-2-yl)cyclohexan-1-ol

[0851] Racemic-(1S,3S)-3-(4-aminopyrimidin-2-yl)cyclohexan-1-ol (700 mg) was separated by SFC (column: ChiralPak IC (250 mm*30 mm, 10 um); mobile phase: [0.1% NH3H2O ​​IPA]; B%). To obtain (1S,3S)-3-(4-aminopyrimidin-2-yl)cyclohexane-1-ol or (1R,3R)-3-(4-aminopyrimidin-2-yl)cyclohexane-1-ol as a white solid (Intermediate 65, first eluting isomer, 315 mg, 45% yield) and (1S,3S)-3-(4-aminopyrimidin-2-yl)cyclohexane-1-ol or (1R,3R)-3-(4-aminopyrimidin-2-yl)cyclohexane-1-ol as a white solid (Intermediate 66, second eluting isomer, 320 mg, 45% yield). MS (ES+) C 10 H 15 N3O requirement: 193, measured: 194 [M+H] + .

[0852]

[0853] Intermediate 67: (S)-4-(2-azido-1-methoxyprop-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine

[0854]

[0855] Step 1: 6-Chloro-1-methoxy-4-(prop-1-en-2-yl)-2,7-naphthyridine

[0856] The title compound was prepared using the same procedure described in step 1 of Example 13 from 4-bromo-6-chloro-1-methoxy-2,7-naphthyridine and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0857] Step 2: 2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propane-1,2-diol

[0858] OsO4 (1.02 g, 4.01 mmol) was added to a mixture of 6-chloro-1-methoxy-4-(prop-1-ene-2-yl)-2,7-naphthyridine (9.4 g, 40.0 mmol) and NMO (9.38 g, 80.1 mmol) in acetone (160 mL) and H2O (40 mL). The reaction mixture was stirred at 25 ° C for 12 hours, then quenched and filtered with a saturated KF aqueous solution (150 mL). The solution was extracted with EA (2 x 300 mL). The organic phase was dried with Na2SO4, filtered and concentrated to obtain the title compound (9.3 g, 86% yield) as a yellow oil, which was used in the next step without further purification.

[0859] Step 3: 6-Chloro-4-(1,2-dimethoxypropan-2-yl)-1-methoxy-2,7-naphthyridine

[0860] 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 hours, and then MeI (12.3 g, 86.5 mmol) was added. The reaction mixture was stirred at 25 ° C for 0.5 hours, and then at 40 ° C for 2 hours. The reaction mixture was then added to a stirring solution of saturated NH4Cl aqueous solution (50 mL) and extracted with EA (300 mL). The organic layer was washed with saturated NH4Cl aqueous solution (100 mL x 3), dried with Na2SO4, filtered and concentrated to obtain the title compound (10 g, 85% yield) as a yellow oil, which was used in the next step without further purification.

[0861] Step 4: 4-(2-Azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine

[0862] 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), 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 hours. 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.

[0863] 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

[0864] 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*30mm, 10um); mobile phase: [15% (containing 0.1% NH4OH)] to obtain two isomers. The first isomer to be eluted is (R)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine, and the second isomer to be eluted is the title compound (S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine. The isomers were determined by the X-ray crystal structure of the compound derived from the second isomer.

[0865]

[0866] Intermediates 68 and 69: (S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine and (R)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine

[0867]

[0868] Step 1: rac-2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)propane-1,2-diol

[0869] Sulfuric acid (106 mg, 1.08 mmol, 57.8 uL) was added to a solution of 6-chloro-1-cyclopropoxy-4-(2-methyloxiran-2-yl)-2,7-naphthyridine (prepared as described in step 2 of Example 13, 300 mg, 1.08 mmol) in THF (2 mL) and water (0.5 mL). The reaction mixture was stirred at 60 ° C for 1 hour, then poured into water (100 mL) and extracted with EA (30 mL×3). The organic layer was dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE:EA=5:1 to 1:1) to give the title compound (250 mg, 78% yield) as a white solid.

[0870] Step 2: rac-2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)-1-methoxypropan-2-ol

[0871] At 0 ° C, NaH (40.7 mg, 1.02 mmol, 60% purity) was added to a solution of 2- (6-chloro-1-cyclopropyloxy-2,7-naphthyridine-4-yl) propane-1,2-diol (200 mg, 679 μmol) in THF (5 mL). The reaction mixture was stirred at 0 ° C for 0.5 hours, and then methyl iodide (289 mg, 2.04 mmol, 127 uL) was added. The cooling bath was removed and the reaction mixture was stirred at 25 ° C for 0.5 hours, then poured into water (100 mL) and extracted with EA (30 mL × 3). The organic layer was dried over sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, PE: EA = 5: 1 to 1: 1) to obtain the title compound (70.0 mg, 33% yield) as a yellow solid.

[0872] Step 3: Racemic-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine

[0873] TMSN3 (93.3 mg, 106 uL) and InBr3 (287.06 mg, 810 μmol) were added to a solution of 2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)-1-methoxypropan-2-ol (50.0 mg, 162 μmol) in DCE (2 mL). The reaction mixture was stirred at 50 ° C for 2 hours, then poured into water (100 mL) and saturated aqueous sodium bicarbonate solution was added to adjust to pH>7. The mixture was extracted with EA (20 mL×3), and the organic layer was dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by preparative TLC (PE:EA=2:1) ​​to obtain the title compound (40.0 mg, crude product) as a yellow solid.

[0874] Step 4: (S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine and (R)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine

[0875] Racemic-4-(2-azido-1-methoxyprop-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine (0.35 g, 1.05 mmol) was separated by SFC (column: Daicel Chiralpak IG (250 mm*30 mm, 10 um); mobile phase: [0.1% NH3H2O ​​in MeOH]) to give (S)-4-(2-azido-1-methoxyprop-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine or (R)-4-(2-azido-1-methoxyprop-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine as a white solid (intermediate 68, first wash deisomer, 150 mg, 446 umol, 43% yield) and (S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine or (R)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine (Intermediate 69, second eluting isomer, 140 mg, 417 umol, 40% yield) as a white solid. MS (ES+) C 15 H 16 ClN5O2 requirement: 333, measured: 334 [M+H] + .

[0876]

[0877] Intermediate 70: (S)-4-(2-azido-1-methoxyprop-2-yl)-6-chloro-1-methyl-2,7-naphthyridine

[0878]

[0879] Step 1: (S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-2,7-naphthyridin-1-ol

[0880] Aqueous HCl (6M, 5.41 mL) was added to a solution of (S)-4-(2-azido-1-methoxyprop-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine (intermediate 67) (3 g, 9.75 mmol) in THF (240 mL). The mixture was stirred at 25 °C for 12 hours, and then the pH was adjusted to about 8 by adding solid NaHCO. The mixture was extracted with EA (2X 150 mL), and the organic layer was dried over NaSO, filtered and concentrated to give the title compound as a white solid (2.7 g, 83% yield, 88% purity), which was used in the next step without further purification.

[0881] Step 2: (S)-4-(2-azido-1-methoxypropan-2-yl)-1,6-dichloro-2,7-naphthyridine

[0882] POCl3 (3.34 g, 21.8 mmol) was added to a mixture of (S)-4-(2-azido-1-methoxyprop-2-yl)-6-chloro-2,7-naphthyridine-1-ol (1.28 g, 4.36 mmol) and TEA (1.16 g, 11.5 mmol) in MeCN (20 mL). The mixture was heated to 100 ° C for 12 hours. The reaction mixture was then added to a saturated NH4Cl aqueous solution (50 mL) and extracted with EA (100 mL × 3). The organic layers were combined and dried with Na2SO4, filtered and concentrated to obtain a residue. The residue was purified by flash column chromatography (25% EA-PE) on silica gel to obtain the title compound (1.2 g, 88% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3): δppm 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).

[0883] Step 3: (S)-4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-methyl-2,7-naphthyridine

[0884] Ad2nBuP Pd G3( A Pd G3) (81.6 mg, 112 μmol) and potassium phosphate (714 mg, 3.36 mmol) were added to a mixture of (S)-4-(2-azido-1-methoxyprop-2-yl)-1,6-dichloro-2,7-naphthyridine (350 mg, 1.12 mmol) and methylboronic acid (73.8 mg, 1.23 mmol) in THF (5 mL). The reaction mixture was stirred at 60 ° C for 2 hours, 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 flash column chromatography on silica gel (PE / EA=10 / 1 to 1 / 1) to give the title compound (220 mg, 67% yield) as a white solid. MS (ES+) C 13 H 14 ClN5O requirement: 291, measured: 292 [M+H] + .

[0885]

[0886] Intermediates 71 and 72: (S)-N-((S)-1-(6-chloro-1-methyl-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide and (S)-N-((R)-1-(6-chloro-1-methyl-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide

[0887]

[0888] Step 1: 6-Chloro-1-methoxy-4-vinyl-2,7-naphthyridine

[0889] The title compound was prepared using a procedure similar to that described in Step 1 of Example 13 from 4-bromo-6-chloro-1-methoxy-2,7-naphthyridine and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane. MS (ES+) C 11 H9ClN2O requirement: 220, measured: 221 [M+H] + .

[0890] Step 2-4: 6-Chloro-1-methyl-4-vinyl-2,7-naphthyridine

[0891] The title compound was prepared from 6-chloro-1-methoxy-4-vinyl-2,7-naphthyridine using a procedure analogous to that described in Steps 1-3 of Intermediate 70. MS (ES+) C 11 H9ClN2 requirement: 204, measured: 205 [M+H] + .

[0892] Step 5: 6-Chloro-1-methyl-2,7-naphthyridine-4-carbaldehyde

[0893] A solution of 6-chloro-1-methyl-4-vinyl-2,7-naphthyridine (400mg, 1.95mmol) in MeOH (3mL) and DCM (30mL) was cooled to -78°C. Ozone was bubbled into the reaction mixture, and nitrogen was bubbled through the reaction mixture after 10 minutes. Me2S (364mg, 5.86mmol) was added to the reaction mixture, and the mixture was stirred at 25°C for 50 minutes. The reaction mixture was then concentrated to obtain a residue, and the residue was purified by column chromatography (SiO2, PE: EA = 1 / 0 to 0 / 1) to obtain the title compound (330mg, 78% yield) as a yellow solid. MS (ES+) C 10 H7ClN2O requirement: 206, measured: 207 [M+H] + . 1 H NMR (400MHz, CD3OD): δppm 10.29 (s, 1H), 9.50 (s, 1H), 9.12 (s, 1H), 8.99 (s, 1H), 3.15 (s, 3H).

[0894] Step 6: (S)-N-((6-chloro-1-methyl-2,7-naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfenamide

[0895] MgSO4(576mg, 4.79mmol) and Ti(i-PrO)4(2.72g, 9.58mmol, 2.83mL) are added to the solution of 6-chloro-1-methyl-2,7-naphthyridine-4-carboxaldehyde (330mg, 1.60mmol) and (S)-2-methylpropane-2-sulfinamide (580mg, 4.79mmol) in THF (10mL).The reaction mixture is stirred at 60 ℃ for 12 hours, then diluted with water (70ml) and EA (150ml), stirred at 25 ℃ for 10 minutes, then filtered.The filtrate is extracted with EA (70ml x 3), and the organic layer combined is dried with anhydrous sodium sulfate, filtered and concentrated to obtain residue.The residue is purified by flash column chromatography (gradient elution, 0-60% EA / PE) on silica gel to obtain the title compound (300mg, 58% yield) as a yellow solid. MS(ES+)C 14 H 16 ClN3OS requirement: 309, measured: 310 [M+H] + .

[0896] Step 7: (S)-N-((S)-1-(6-chloro-1-methyl-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide and (S)-N-((R)-1-(6-chloro-1-methyl-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide

[0897] EtMgBr (3M, 915uL) was added to a solution of (S)-N-((6-chloro-1-methyl-2,7-naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (170mg, 549umol) in THF (20mL) at 25°C. The reaction mixture was stirred at 25°C for 30 minutes, then quenched by the addition of saturated aqueous NH4Cl solution (40mL) and extracted with EA (40mL x 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 75×30mm×3um; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 18%-48%, 11.5min) to give the title compounds, respectively. The stereochemistry of the ethylamine stereocenter was arbitrarily assigned.

[0898] Peak 1 (Intermediate 71): (S)-N-((S)-1-(6-chloro-1-methyl-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide or (S)-N-((R)-1-(6-chloro-1-methyl-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide (55 mg, 22% yield) as a yellow oil. MS (ES+) C 16 H 22 ClN3OS requirement: 339, measured: 340 [M+H] + . 1 H NMR (400MHz, CD3OD): δppm 9.43(d,J=0.8Hz,1H),8.59(s,1H),8.07(s,1H),4.91-4.73(m,1H),4.17-4.08(m,1H),3.60 -3.50(m,1H),3.05(s,3H),2.13-2.07(m,1H),2.03(s,1H),1.20(s,9H),0.96-0.89(m,3H).

[0899] Peak 2 (Intermediate 72): (S)-N-((S)-1-(6-chloro-1-methyl-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide or (S)-N-((R)-1-(6-chloro-1-methyl-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide (55 mg, 26% yield) as a yellow oil. MS (ES+) C 16 H 22 ClN3OS requirement: 339, measured: 340 [M+H] + . 1 H NMR (400MHz, CD3OD): δppm 9.43(d,J=0.4Hz,1H),8.61(s,1H),8.06(s,1H),4.88-4.81(m,1H),4.18-4.05(m,1H),3.79-3.68(m,2H),3.5 8-3.53(d,J=3.18Hz,1H),3.05(s,3H),2.28-2.18(m,1H),2.14-2.01(m,1H),1.24(s,9H),0.90-0.86(m,3H).

[0900]

[0901] Intermediates 73 and 74: (S)-N-((S)-1-(3-chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide and (S)-N-((R)-1-(3-chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide

[0902]

[0903] Step 1: (E)-2-(Hydroxyimino)-7-methoxy-2,3-dihydro-1H-inden-1-one

[0904] 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 -10-0°C, and then HCl (4 M in MeOH, 15.0 mL, 0.10 equiv) was added dropwise to the mixture at -10-0°C. The reaction mixture was stirred at 0°C for 2 hours 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 10H9NO3 requirement: 191, measured: 192 [M+H] + .

[0905] Step 2: 1,3-Dichloro-8-methoxyisoquinoline

[0906] To a solution of (E)-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 0-10°C. The reaction mixture was stirred at 70°C for 12 hours, then cooled to 25°C and quenched with water (2.00 L). The quenched mixture was extracted with DCM (500 mL x 4), and the organic layer was washed with brine (500 mL x 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 H7Cl2NO required: 227, measured: 228 [M+H] + .

[0907] Step 3: 3-Chloro-8-methoxyisoquinoline

[0908] To a solution of 1,3-dichloro-8-methoxyisoquinoline (48.8 g, 213 mmol, 1.00 eq) in THF (250 mL) at 25°C was added TMEDA (37.3 g, 320 mmol, 48.4 mL, 1.50 eq) and Pd(dppf)Cl2 (1.57 g, 2.14 mmol, 0.01 eq). Then NaBH4 (17.2 g, 456 mmol, 2.13 eq) was slowly added to the reaction mixture and the reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was poured into 1N HCl (1.00 L) and extracted with EA (200 mL x 3). The combined organic layers were purified by Filter and wash the filtrate with brine (500 mL), dry with Na2SO4, filter and concentrate to obtain a residue. The residue is purified by column chromatography (SiO2, PE / EA=20 / 1 to 5 / 1) to obtain the title compound (26.7 g, 64.3% yield) as a light yellow solid. MS (ES+) C 10 H8ClNO required: 193, measured: 194 [M+H] + .

[0909] Step 4: 5-Bromo-3-chloro-8-methoxyisoquinoline

[0910] To a solution of 3-chloro-8-methoxyisoquinoline (26.7 g, 137 mmol, 1.00 equiv) in MeCN (300 mL) at 25°C was added NBS (29.3 g, 165 mmol, 1.20 equiv). The reaction mixture was stirred at 70°C for 1 hour 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 required: 273, measured: 274 [M+H] + .

[0911] Step 5: 3-Chloro-8-methoxy-5-vinylisoquinoline

[0912] To a mixture of 5-bromo-3-chloro-8-methoxyisoquinoline (1.00 g, 3.67 mmol), potassium vinyl trifluoroborate (688 mg, 5.14 mmol) in EtOH (20.0 mL) and water (2.00 mL) was added TEA (743 mg, 7.34 mmol, 1.02 mL) and Pd(dppf)Cl2.CH2Cl2 (300 mg, 367 μmol), and the mixture was stirred at 80 ° C for 1 hour. The reaction mixture was then concentrated to obtain a residue. The residue was diluted with water (30. mL) and extracted with EA (20 ml x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, PE / EA=1 / 0 to 10 / 1) to obtain the title compound (620 mg, 2.82 mmol, 77% yield) as a yellow solid. MS (ES+) C 12 H 10 ClNO required: 219, measured: 220 [M+H] + .

[0913] Step 6-8: (S)-N-((S)-1-(3-chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide and (S)-N-((R)-1-(3-chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide

[0914] The title compound was prepared from 3-chloro-8-methoxy-5-vinylisoquinoline using a similar procedure as described in steps 5-7 of intermediates 71 and 72. The mixture of diastereomers was separated by preparative HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 32%-62%, 11.5 minutes) to give the title compounds respectively. The stereochemistry of the ethylamine stereocenter was arbitrarily assigned.

[0915] Peak 1 (Intermediate 73): (S)-N-((S)-1-(3-chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide or (S)-N-((R)-1-(3-chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide (15.0 mg, 17% yield) as a yellow oil. MS (ES+) C 17 H 23 ClN2O2S requirement: 354, measured: 355[M+H] + .

[0916] Peak 2 (Intermediate 74): (S)-N-((S)-1-(3-chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide or (S)-N-((R)-1-(3-chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide (15.0 mg, 17% yield) as a yellow oil. MS (ES+) C 17 H 23 ClN2O2S requirement: 354, measured: 355[M+H] + .

[0917]

[0918] Intermediates 75 and 76: (S)-N-((S)-1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide and (S)-N-((R)-1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide

[0919]

[0920] Step 1: 6-Chloro-1-methoxy-2,7-naphthyridine-4-carbaldehyde

[0921] OsO4 (4% in water, 0.576 mL, 0.113 mmol) was added to a mixture of 6-chloro-1-methoxy-4-vinyl-2,7-naphthyridine (step 1, intermediate 71) (1 g, 4.54 mmol), 2,6-lutidine (0.528 mL, 4.53 mmol), NaIO4 (0.969 g, 4.53 mmol) in dioxane (34 mL) and water (11 mL). The reaction mixture was stirred at 25 °C for 2 hours and then partitioned between DCM and water. The organic layer was dried over 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 (360 mg) as a yellow solid.

[0922] Step 2-3: (S)-N-((S)-1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide and (S)-N-((R)-1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide

[0923] The title compound was prepared from 6-chloro-1-methoxy-2,7-naphthyridine-4-carbaldehyde using a procedure analogous to that described in steps 6-7 of intermediate 71. The mixture of diastereomers was separated by SFC (column: Chiralpak IC-H 21 x 250 mm; mobile phase: MeOH in CO2) to give the title compounds individually. The stereochemistry of the ethylamine stereocenter was arbitrarily assigned.

[0924] Peak 1 (Intermediate 75): (S)-N-((S)-1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide or (S)-N-((R)-1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide (70 mg) as a yellow oil. MS (ES+) C 16 H 22 ClN3O2S requirement: 355, measured: 356 [M+H] + .

[0925] Peak 2 (Intermediate 76): (S)-N-((S)-1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide or (S)-N-((R)-1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide (73 mg) as a yellow oil. MS (ES+) C 16 H 22ClN3O2S requirement: 355, measured: 356 [M+H] + .

[0926]

[0927] Intermediates 77 and 78: (R)-N-((S)-1-(3,8-dichloroisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfenamide and (R)-N-((R)-1-(3,8-dichloroisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfenamide

[0928]

[0929] Step 1: 5-Bromo-3,8-dichloroisoquinoline

[0930] To a solution of 5-bromo-8-chloro-isoquinolin-3-amine (2 g, 7.77 mmol, 1 eq.) and benzyl(triethyl)ammonium chloride (3.54 g, 15.53 mmol, 2 eq.) in DCM (20 mL) at 0°C was added t-BuONO (3.20 g, 31.07 mmol, 3.69 mL, 4 eq.). The mixture was stirred at 30°C for 12 h, then poured into saturated aqueous NaHCO3 (100 mL) and extracted with EA (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / EA=50 / 1 to 5 / 1) to give the title compound (1.1 g, 3.97 mmol, 51.14% yield) as a yellow solid.

[0931] Step 2-5: (R)-N-((S)-1-(3,8-dichloroisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide and (R)-N-((R)-1-(3,8-dichloroisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide

[0932] The title compound was prepared from 5-bromo-3,8-dichloroisoquinoline using a procedure analogous to that described in step 1 of Example 13, step 1 of intermediate 75, and steps 6-7 of intermediate 71. The mixture of diastereomers was separated by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 2) followed by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 2) to afford the title compound, respectively. The stereochemistry of the ethylamine stereocenter was arbitrarily assigned.

[0933] Peak 1 (Intermediate 77): (R)-N-((S)-1-(3,8-dichloroisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfenamide and (R)-N-((R)-1-(3,8-dichloroisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfenamide as yellow solid (35 mg, 21% yield). MS (ES+) C 16 H 20 Cl2N2OS requirement: 358, measured: 359 [M+H] + .

[0934] Peak 2 (Intermediate 78): (R)-N-((S)-1-(3,8-dichloroisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfenamide and (R)-N-((R)-1-(3,8-dichloroisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfenamide as yellow solid (35 mg, 19% yield). MS (ES+) C 16 H 20 Cl2N2OS requirement: 358, measured: 359 [M+H] + .

[0935]

[0936] Intermediates 79 and 80: (S)-N-((S)-1-(6-chloro-1-(1-methylcyclopropyloxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide and (S)-N-((R)-1-(6-chloro-1-(1-methylcyclopropyloxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide

[0937]

[0938] The title compound was prepared from (S,E)-N-((6-chloro-1-(1-methylcyclopropyloxy)-2,7-naphthyridin-4-yl)methylene)-2-methylpropane-2-sulfinamide (which was prepared from 4-bromo-1,6-dichloro-2,7-naphthyridine (Intermediates 33 and 34) using a similar procedure as described in step 7 of intermediate 71. The mixture of diastereomers was separated by preparative TLC (petroleum ether:ethyl acetate=1:1) to give the title compounds, respectively. The stereochemistry of the ethylamine stereocenter was arbitrarily assigned.

[0939] Peak 1 (Intermediate 79): (S)-N-((S)-1-(6-chloro-1-(1-methylcyclopropyloxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide or (S)-N-((R)-1-(6-chloro-1-(1-methylcyclopropyloxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide (20 mg, 36% yield) as a yellow solid. MS (ES+) C 19 H 26 ClN3O2S requirement: 395, measured: 396 [M+H] + .

[0940] Peak 2 (Intermediate 80): (S)-N-((S)-1-(6-chloro-1-(1-methylcyclopropyloxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide or (S)-N-((R)-1-(6-chloro-1-(1-methylcyclopropyloxy)-2,7-naphthyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide (20 mg, 41% yield) as a white solid. MS (ES+) C 19 H 26 ClN3O2S requirement: 395, measured: 396 [M+H] + .

[0941]

[0942] Intermediates 81 and 82: (S)-4-(1-azido-2-methoxyethyl)-6-chloro-1-methoxy-2,7-naphthyridine and (R)-4-(1-azido-2-methoxyethyl)-6-chloro-1-methoxy-2,7-naphthyridine

[0943]

[0944] Step 1-3: (S)-4-(1-azido-2-methoxyethyl)-6-chloro-1-methoxy-2,7-naphthyridine or (R)-4-(1-azido-2-methoxyethyl)-6-chloro-1-methoxy-2,7-naphthyridine

[0945] The title compound was prepared from 6-chloro-1-methoxy-4-vinyl-2,7-naphthyridine (Step 1, Intermediate 71) using a procedure analogous to that described in Steps 2-4 of Intermediate 67, except that the dimethoxy intermediate was isolated after Step 2 and used in Step 3. The product was purified by Chiral-SFC (column: Daicel Chiralpak AD (250 mm x 400 mm)). 50mm, 10um); mobile phase: [0.1% NH3H2O-MeOH]) was used to separate the racemic mixture (6.5g, 22.1mmol) to give (S)-4-(1-azido-2-methoxyethyl)-6-chloro-1-methoxy-2,7-naphthyridine or (R)-4-(1-azido-2-methoxyethyl)-6-chloro-1-methoxy-2,7-naphthyridine as a white solid (Intermediate 81, first eluting isomer, 3.2g, 45% yield) and (S)-4-(1-azido-2-methoxyethyl)-6-chloro-1-methoxy-2,7-naphthyridine or (R)-4-(1-azido-2-methoxyethyl)-6-chloro-1-methoxy-2,7-naphthyridine as a white solid (Intermediate 82, second eluting isomer, 3g, 46% yield). 1 H NMR (400MHz, CDCl3): δppm9.43(s,1H),8.25(s,1H),7.86(s,1H),5.03-4. 99(m,1H),4.18(s,3H),3.84-3.79(m,1H),3.78-3.74(m,1H),3.45(s,3H).

[0946]

[0947] Intermediate 83: 5-amino-3-(2-fluoropropan-2-yl)pyrazine-2-carbonitrile

[0948]

[0949] Step 1-6: 5-amino-3-(2-fluoropropan-2-yl)pyrazine-2-carbonitrile

[0950] The title compound was prepared from 2,6-dibromopyrazine using the same six-step procedure as described in step 1 of Intermediate 26 (using acetone instead of propionaldehyde) and steps 1-5 of Intermediate 23. MS (ES+) C8H9FN4 required: 180, found: 181 [M+H] + .

[0951]

[0952] Intermediate 84: 6-Chloro-4-iodo-1-methoxy-2,7-naphthyridine

[0953]

[0954] Step 1: 6-Chloro-4-iodo-2,7-naphthyridin-1(2H)-one

[0955] NIS (1.31 g, 5.81 mmol) was added to a solution of 6-chloro-2,7-naphthyridin-1(2H)-one (1.00 g, 5.54 mmol) in AcOH (20 mL). The reaction mixture was stirred at 23 °C for 60 h, then the acetic acid was removed in vacuo. The residue was treated with saturated aqueous NaHCO3 solution, stirred for 1 h, then filtered. The filter cake was washed with water and dried under vacuum to give the title compound (1.52 g, 90%) as an off-white solid. MS (ES+) CH4ClIN2O required: 306, found: 307 [M+H] + .

[0956] Step 2-3: 6-Chloro-4-iodo-1-methoxy-2,7-naphthyridine

[0957] The title compound was prepared from 6-chloro-4-iodo-2,7-naphthyridin-1(2H)-one using the same two-step procedure described in steps 2-3 of intermediate 31. MS (ES+) C9H6ClIN2O required: 320, found: 321 [M+H] + .

[0958]

[0959] Intermediate 85: 2'-amino-7',7'-dimethyl-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-5'-one

[0960]

[0961] Step 1: 2-(1-(3-bromo-6-chloropyridin-2-yl)cyclopropyl)propan-2-ol

[0962] At 25 ° C, MeMgBr (3M, 14.9 mL) was added to a solution of 1-(3-bromo-6-chloropyridin-2-yl)cyclopropane-1-formic acid methyl ester (1.3 g, 4.47 mmol) in THF (10 mL). The reaction mixture was stirred at 25 ° C for 10 minutes, then poured into water (20 mL) and extracted with EA (50 mL × 3). The organic layers were combined and dried over sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, PE / EA=1 / 0 to 50 / 1) to obtain the title compound (500 mg, 38% yield) as a colorless oil.

[0963] Step 2-5: 2'-amino-7',7'-dimethyl-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-5'-one

[0964] The title compound was prepared from 2-(1-(3-bromo-6-chloropyridin-2-yl)cyclopropyl)propan-2-ol using procedures analogous to those described in Intermediate 45, Steps 4-6 and Intermediate 50, Step 7. 1 H NMR (400MHz, CDCl3): δppm 8.05 (d, J = 8.4Hz, 1H), 6.36 (d, J = 8.8Hz, 1H), 4.85 (s, 2H), 1.42-1.32 (m, 8H), 1.06-1.03 (m, 2H).

[0965]

[0966] Example 1: 5-(1-aminoethyl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine (1)

[0967]

[0968] Step 1: 1-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-ol

[0969] Sodium borohydride (120 mg, 3.17 mmol) was added to a solution of 1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-one (500 mg, 2.11 mmol) in methanol (10 mL) and the mixture was stirred at 25 ° C for 10 minutes. The reaction was quenched by adding water (5 mL) and extracted with EA (5 mL × 3). The combined organic layer was concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography to obtain the title compound (400 mg, 79% yield) as an off-white solid.

[0970] Step 2: 1-(6-((2-(2-fluoropropan-2-yl)pyrimidin-4-yl)amino)-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-ol

[0971] 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos) (90.0 mg, 168 umol) and BrettPhos Pd G4 (154.28 mg, 167.60 umol) were added to a mixture of 1-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-ol (400 mg, 1.68 mmol), 2-(2-fluoropropan-2-yl)pyrimidine-4-amine (Intermediate 1, 312 mg, 2.01 mmol) and potassium acetate (822 mg, 8.38 mmol) in dioxane (20 mL). The solution was degassed and purged with N2 3 times, and the mixture was stirred at 100 ° C for 1 hour under N2 atmosphere. The reaction mixture was quenched by adding water (30 mL) and extracted with EA (30 mL×3). The combined organic layers were washed with water (60 mL x 3) and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography and reverse phase preparative HPLC to give the title compound (280 mg, 45% yield) as a white solid. MS (ES+) C 18 H 20 FN5O2 requires 357, measured 358 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δppm 10.70(s,1H),9.31(s,1H),8.94-8.76(m,1H),8.48(d,J=5.6Hz,1H),8.17(s,1H),8.07(d,J=5.6Hz,1H),7.25(d,J=5 .6Hz,1H),5.28-5.18(m,1H),4.11-4.03(m,3H),1.82(d,J=2.4Hz,3H),1.76(d,J=2.4Hz,3H),1.50(d,J=6.4Hz,3H).

[0972] Step 3: 5-(1-azidoethyl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine

[0973] Under an atmosphere of nitrogen, trimethylsilyl azide (116 mg, 1.01 mmol) and indium bromide (238 mg, 672 umol) were added to a solution of 1-(6-((2-(2-fluoropropan-2-yl)pyrimidin-4-yl)amino)-1-methoxy-2,7-naphthyridin-4-yl)ethan-1-ol (120 mg, 336 umol) in dichloromethane (10 mL). The mixture was stirred at 25 ° C for 6 hours. TLC showed that the starting material was consumed and new spots were detected. The reaction mixture was poured into water (20 mL) and extracted with EA (20 mL×3). The combined organic layers were concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC [petroleum ether: EA=1:1] to obtain the title compound (80 mg, 61% yield) as a white solid. MS (ES+) C 18 H 19 FN8O requires 382, ​​measured 383 [M+H] +

[0974] Step 4: 5-(1-aminoethyl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine

[0975] Under N2, Pd / C (10.0 mg, 78.5 umol, 10% purity) was added to a solution of 5-(1-azidoethyl)-N-(2-(2-fluoropropane-2-yl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridine-3-amine (50 mg, 131 umol) in methanol (10 mL). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25 ° C for 4 hours under H2 (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to remove the solvent. The residue was diluted with EA (10 mL) and extracted with water (10 mL×3). The combined organic layer was washed with EA (5 mL×3) and concentrated under reduced pressure to obtain a residue. The residue was merged with the previous batch (20 mg). The combined residues were purified by reverse phase preparative HPLC (column: Phenomenex Gemini 150×25 mm×10 um; mobile phase: [water (10 mM NH4HCO3)-MECN]; B%: 30%-51%, 7 minutes) to give the title compound (45 mg, 60% yield) as a white solid. MS (ES+) C 18 H 21 FN6O requires 356, measured 357 [M+H] + . 1 HNMR (400MHz, DMSO-d6): δppm 9.59-9.46(m,1H),8.86(s,1H),8.04(s,1H).

[0976] Step 5: (R or S)-5-(1-aminoethyl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine

[0977] 5-(1-aminoethyl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine (60 mg, 168 umol) was separated by SFC (column: DAICEL CHIRALPAK AS (250 mm×30 mm, 10 um); mobile phase: [0.1% NH3H2O ​​MeOH]; B%: 30 MeOH(NH4OH)%-30 MeOH(NH4OH)%, 5.0 min; 65 min) to give 2 isomers (first eluting isomer (12.9 mg, 26% yield) and second eluting isomer (13.7 mg, 29% yield)) as brown solids (stereochemistry arbitrarily assigned). Spectral analysis of isomer 1: MS (ES+) C 18 H 21 FN6O requires 356, measured 357 [M+H] + . 1 H NMR (400 MHz, CD3OD): δppm 9.33 (s, 1H), 8.83 (s, 1H), 8.41 (d, J = 6.0 Hz, 1H), 8.20 (s, 1H), 7.20 (d, J = 6.0 Hz, 1H), 4.70 (q, J = 6.8 Hz, 1H), 4.13 (s, 3H), 1.87 (d, J = 2.0 Hz, 3H), 1.81 (d, J = 2.0 Hz, 3H), 1.59 (d, J = 6.8 Hz, 3H). Spectral analysis of isomer 2: MS (ES+) C 18 H 21 FN6O requires 356, measured 357 [M+H] + . 1 H NMR (400MHz, CD3OD): δppm 9.23(s,1H),8.74(s,1H),8.30(br s,1H),8.09(d,J=3.2Hz,1H),7.08(s,1H),4.60(s,1H),4.02(d,J=4.0Hz,3H),1.84-1.61(m,6H),1.49(s,3H),1.19(s,1H).

[0978]

[0979] Example 2: 5-(2-aminopropan-2-yl)-N-(2-(tert-butyl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine (3)

[0980]

[0981] Step 1: 2-(6-((2-(tert-butyl)pyrimidin-4-yl)amino)-1-methoxy-2,7-naphthyridin-4-yl)propan-2-ol

[0982] 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos) (40.0 mg, 75.2 μmol) and BrettPhos Pd G4 (69.0 mg, 75.2 μmol) were added to a mixture of 2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-ol (Intermediate 31, 190 mg, 752 μmol), 2-(tert-butyl)pyrimidin-4-amine (125 mg, 827 μmol) and potassium acetate (221 mg, 2.26 mmol) in dioxane (3 mL). The solution was degassed and purged with N2 3 times, and then the mixture was stirred at 100 ° C. for 1 hour under N2 atmosphere. LCMS showed that the desired mass was detected and the starting material was consumed. The reaction mixture was concentrated, and the residue was purified by reverse phase preparative HPLC (column: Phenomenex Gemini 150×25 mm×10 um; mobile phase: [water (10 mM NH 4 HCO 3 )-MeCN]; B%: 50%-71%, 7 minutes) to give the title compound (106.9 mg, 39% yield) as a white solid. MS (ES+) C 20 H 25 N5O2 required 367, measured 368 [M+H] + . 1 H NMR (400MHz, CD3OD): δppm 9.36(s,1H),8.76(s,1H),8.31(d,J=6.0Hz,1H),8.14(s,1H),7.40(d,J=6.0Hz,1H),4.12(s,3H),1.79(s,6H),1.45(s,9H).

[0983] Step 2: 5-(2-azidopropan-2-yl)-N-(2-(tert-butyl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine

[0984] Under N2, indium bromide (183 mg, 517 umol) and trimethylsilyl azide (33.0 mg, 284 umol, 37 uL) were added to a solution of 2-(6-((2-(tert-butyl)pyrimidin-4-yl)amino)-1-methoxy-2,7-naphthyridin-4-yl)propan-2-ol (95.0 mg, 259 umol) in dichloromethane (8 mL). The mixture was stirred at 25 ° C for 16 hours. LCMS showed that the desired mass was detected and the starting material was consumed. The reaction mixture was diluted with water (15 mL) and extracted with dichloromethane (15 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (100 mg, 99% yield) as a yellow solid, which was used in the next step without further purification. MS (ES+) C 20 H 24 N8O required 392, measured 393 [M+H] + . 1 H NMR (400MHz, CDCl3): δppm 9.43(s,1H),8.67(s,1H),8.48(d,J=5.6Hz,1H),8.14(s,1H),7.21-7.12(m,1H),4.16(s,3H),1.84(s,6H),1.50(s,9H).

[0985] Step 3: 5-(2-aminopropan-2-yl)-N-(2-(tert-butyl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine

[0986] Under N2, Pd / C (40.0 mg, 10% purity) was added to a solution of 5-(2-azidopropane-2-yl)-N-(2-(tert-butyl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridine-3-amine (80.0 mg, 204 umol) in methanol (8 mL). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25 ° C for 16 hours under H2 (15 psi). LCMS showed that the desired mass was detected and the starting material was consumed. The reaction mixture was filtered and concentrated. The residue was purified by reverse phase preparative HPLC (column: Phenomenex Gemini 150×25 mm×10 um; mobile phase: [water (10 mM NH4OAc)-MECN]; B%: 20%-71%, 7 minutes) and then by preparative TLC to give the title compound (31.5 mg, 42% yield) as a white solid. MS (ES+) C 20 H 26 N6O requirement: 366, measured: 367 [M+H] + . 1H NMR (400MHz, CD3OD): δppm 9.39(s,1H),8.58(s,1H),8.34(d,J=5.6Hz,1H),8.19(s,1H),7.47(d,J=6.0Hz,1H),4.12(s,3H),1.76(s,6H),1.45(s,9H).

[0987]

[0988] Example 3a: 5-(2-aminopropan-2-yl)-N-(2-(tert-butyl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine (34)

[0989]

[0990] Step 1: 2-((5-(2-azidopropan-2-yl)-8-methoxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one

[0991] 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos) (30.9 mg, 57.6 μmol) and BrettPhos Pd G4 (26.5 mg, 28.8 μmol) were added to a mixture of 2-amino-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one (Intermediate 9, 80.0 mg, 288 μmol), 4-(2-azidopropan-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine (Intermediate 31a, 56.0 mg, 294 μmol) and potassium acetate (84.8 mg, 864 μmol) in dioxane (2 mL). The solution was degassed and purged with a nitrogen atmosphere three times, and then the mixture was stirred at 100° C. under a nitrogen atmosphere for 1 hour. LCMS showed that the required mass was detected and the starting material was consumed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography to give the title compound (120 mg, 78% yield) as a white solid. MS (ES+) C 23 H 25 N7O2 requires 431, measured 432 [M+H] + .

[0992] Step 2: 2-((5-(2-aminopropan-2-yl)-8-methoxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one

[0993] Pd / C (232 μmol, 10% purity) was added to a solution of 2-((5-(2-azidopropan-2-yl)-8-methoxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydroquinolin-5(6H)-one (100 mg, 232 μmol) in methanol (2 mL) under H. The suspension was degassed under vacuum and purged with H several times. The mixture was stirred at 25 °C under H (15 psi) for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (10 mM NH4HCO3)-MeCN]; B%: 30%-60%, 10 minutes) to give the title compound (4.80 mg, 4.9% yield) as a white solid. MS (ES+) C 23 H 27 N5O2 requirement 405, measured 406 [M+H] + . 1 H NMR (400MHz, CD3OD): δppm 9.47(s,1H),9.33(s,1H),8.19(s,1H),8.11(d,J=8.8Hz,1H),7.09(d,J=8. 8Hz,1H),4.12(s,3H),3.04(s,2H),2.53(s,2H),1.84(s,6H),1.14(s,6H).

[0994]

[0995] Example 3b: R-2-((5-(1-amino-1-cyclopropylethyl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (74)

[0996]

[0997] Each of these is represented by one of the structures shown below:

[0998]

[0999] Step 1: 1-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)-1-cyclopropyl-1-ol

[1000] At 15 ° C under a nitrogen atmosphere, cyclopropylmagnesium bromide (3M, 3.17mL) was added to a solution of 1-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)ethan-1-one (500mg, 1.90mmol) in methyl tert-butyl ether (8mL). The mixture was stirred at 60 ° C for 1 hour. LCMS showed that the required mass was detected and the starting material was consumed. The reaction mixture was quenched by adding saturated aqueous ammonium chloride solution (20mL), followed by adding water (20mL) and extracting with EA (30mL×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 to give the title compound (460mg, 72% yield) as a white solid. MS(ES+)C 16 H 17 ClN2O2 requires 304, measured 305 [M+H] + . 1 H NMR (400MHz, CDCl3): δppm 9.32-9.28(m,1H),8.59(d,J=0.8Hz,1H),8.54-8.50(m,1H),4.56-4.48(m,1H), 2.43-2.21(m,1H),1.58(d,J=0.8Hz,1H),1.57-1.48(m,2H),0.73-0.50(m,6H).

[1001] Step 2: 4-(1-azido-1-cyclopropylethyl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine

[1002] Under nitrogen atmosphere, BF3.Et2O (382 mg, 2.69 mmol) was added to a solution of 1-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)-1-cyclopropyl-1-ol (410 mg, 1.35 mmol) and TMSN3 (155 mg, 1.35 mmol) in dichloromethane (8 mL). The reaction mixture was stirred at 25 ° C for 0.5 hours. LCMS showed that the desired mass was detected and the starting material was consumed. The reaction mixture was diluted with water (30 mL) and extracted with EA (30 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 to give the title compound (225 mg, 48% yield) as a colorless oil. MS (ES+) C 16 H 16 ClN5O required 329, measured 330 [M+H] + .

[1003] Step 3: (R)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine and (S)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine

[1004] 4-(1-azido-1-cyclopropylethyl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine (225 mg) was separated by SFC (column: DAICEL CHIRALPAK AD-H (250 mm×30 mm, 5 μm); mobile phase: [0.1% NH 3 H 2 O EtOH]; B%: 25%-25%, 4 minutes; 180 minutes). The title compound (35 mg, 16% yield; first eluting isomer ((S)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine)) and (50 mg, 22% yield; second eluting isomer ((R)-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine)) were obtained as white solids. The stereochemistry of the isomers was determined based on the X-ray crystal structure of compound 75. MS (ES+) C 16 H 16 ClN5O required 329, measured 330 [M+H] + .

[1005] Step 4: R-2-((5-(1-azido-1-cyclopropylethyl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[1006] 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos) (11.4 mg, 21.2 umol) and BrettPhos Pd G4 (9.77 mg, 10.6 umol) were added to a mixture of 2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 2, 22.4 mg, 117 umol), R-4-(1-azido-1-cyclopropylethyl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine (second eluting isomer from step 3, 35 mg, 106 umol) and potassium acetate (31.3 mg, 318 μmol) in dioxane (4 mL). The mixture was degassed and purged with a nitrogen atmosphere 3 times, then stirred at 60 ° C for 1 hour under a nitrogen atmosphere. LCMS showed that the required mass was detected and the starting material was consumed. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC to obtain the title compound (50 mg, 93% yield) as a yellow solid. MS (ES +) C 26 H 27 N7O3 required 485, measured 486 [M+H] + .

[1007] Step 5: R-2-((5-(1-amino-1-cyclopropylethyl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[1008] Zn (23.6 mg, 360 umol) and acetic acid (43.3 mg, 721 umol) were added to a solution of R-2-((5-(1-azido-1-cyclopropylethyl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (35 mg, 72.1 umol) from step 4 in tetrahydrofuran (6 mL), and the mixture was stirred at 25 ° C for 0.5 hours. LCMS showed that the desired mass was detected and the starting material was consumed. The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase preparative HPLC to give the title compound (13.4 mg, 39% yield) as a yellow solid. MS (ES+) C 26 H 29 N5O3 required 459, measured 460 [M+H] + . 1H NMR (400MHz, CD3OD): δppm 9.27(s,1H),9.19(s,1H),8.52(s,1H),8.15-8.11(m,2H),7.24(d,J=8.8Hz,1H),4.54-4.46(m,1H),3.18(d,J=0.8Hz ,2H),1.84(s,3H),1.65-1.56(m,1H),1.52(d,J=7.6Hz,6H),0.94-0.86(m,4H),0.84-0.67(m,3H),0.65-0.54(m,1H).

[1009]

[1010] Example 4: 5-(2-aminopropan-2-yl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxyisoquinolin-3-amine (5)

[1011]

[1012] Step 1: Methyl 2,2-diethoxyacetimidate

[1013] 2,2-diethoxyMeCN (8.4 g, 65 mmol, 9 mL) was added to a solution of Na (149.5 mg, 6.5 mmol, 154.1 uL) in MeOH (70 mL). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was filtered, washed with petroleum ether: MeOH (2: 1; 3 times), and the filtrate was then concentrated under reduced pressure to obtain the title compound (10 g, crude) as a white oil.

[1014] Step 2: N-(5-bromo-2-methoxybenzyl)-2,2-diethoxyacetimidamide

[1015] Under an atmosphere of N2, methyl 2,2-diethoxyacetimidate (8.9 g, 55.5 mmol) was added to a solution of (5-bromo-2-methoxy-phenyl)methylamine (10 g, 46.3 mmol) in MeOH (100 mL). The mixture was stirred at 25 ° C for 12 hours. LCMS showed that the required MS was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was diluted with H2O (50 mL) and extracted with DCM 200 mL (50 mL×4). The combined organic layer was washed with saturated NaCl aqueous solution (50 mL), dried with Na2SO4, filtered and concentrated under reduced pressure to obtain the title compound (12 g, crude product) as a white solid, which was used in the next step without further purification.

[1016] Step 3: 5-Bromo-8-methoxyquinolin-3-amine

[1017] At 0°C, N-(5-bromo-2-methoxybenzyl)-2,2-diethoxyacetimidamide (11 g, 31.9 mmol) was added to H2SO4 (111.61 g, 1.1 mol, 60.6 mL, 98% purity), and the mixture was stirred at 25°C for 3 hours under an atmosphere of N2. The reaction mixture was quenched by adding NaOH (120 g) in H2O (5 L) at 0°C and extracted with 2-MeTHF (1 L×2). The combined organic layers were washed with saturated aqueous NaCl solution (1 L), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase preparative HPLC to obtain the title compound (3 g, 11.8 mmol, 37% yield) as a yellow solid.

[1018] Step 4: 5-(1-ethoxyvinyl)-8-methoxyisoquinolin-3-amine

[1019] Under N2 atmosphere, Pd(PPh3)4 (1.02 g, 884.8 μmol) and tributyl(1-ethoxyvinyl)stannane (6.79 g, 18.8 mmol, 6.3 mL) were added to a solution of 5-bromo-8-methoxyisoquinolin-3-amine (2.8 g, 11.1 mmol) in toluene (30 mL). The mixture was stirred at 100 ° C for 4 hours under N2 atmosphere. The reaction mixture was quenched by adding CsF aqueous solution (60 mL) at 0 ° C and extracted with EA (40 mL×3). The combined organic layer was washed with saturated sodium chloride aqueous solution (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the title compound (2.7 g, crude product) as a brown oil, which was used in the next step without further purification.

[1020] Step 5: 1-(3-amino-8-methoxyisoquinolin-5-yl)ethan-1-one

[1021] Under N2 atmosphere, a mixture of 5-(1-ethoxyvinyl)-8-methoxyisoquinolin-3-amine (2.7 g, 11.1 mmol) in THF (20 mL) and HCl (1 M, 11 mL) was stirred at 25°C for 30 min. The reaction mixture was filtered to give the title compound (1.1 g, crude) as a yellow solid, which was used in the next step without further purification.

[1022] Step 6: 1-(3-chloro-8-methoxyisoquinolin-5-yl)ethan-1-one

[1023] Under N2 atmosphere, pyridine hydrochloride (1.03g, 8.9mmol), CuCl (25.2mg, 254.3umol, 6.08uL) and NaNO2 (614.2mg, 8.9mmol) were added to a solution of 1-(3-amino-8-methoxyisoquinolin-5-yl)ethan-1-one (550mg, 2.5mmol) in DCM (5mL). Then at -10°C, HCl (37.6mg, 381.5umol, 36.9uL, 37% purity) was added to the reaction mixture, and the mixture was stirred at 0°C for 30 minutes. The mixture was stirred at 25°C for 1 hour under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography to obtain the title compound (530mg, 44% yield) as a white solid.

[1024] Step 7: 2-(3-chloro-8-methoxyquinolin-5-yl)propan-2-ol

[1025] Under N2 atmosphere, MeMgBr (3M in THF, 1.41 mL) was added to a solution of 1-(3-chloro-8-methoxyisoquinolin-5-yl)ethan-1-one (200 mg, 848.7 umol) in THF (2 mL), and the reaction mixture was stirred at 25 ° C for 1 hour under N2 atmosphere. The reaction mixture was quenched by adding H2O (10 mL) at 0 ° C. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography to give the title compound (580 mg, 90.5% yield) as a yellow solid.

[1026] Step 8: 2-(3-((2-(2-fluoropropan-2-yl)pyrimidin-4-yl)amino)-8-methoxyisoquinolin-5-yl)propan-2-ol

[1027] Under N2 atmosphere, [2-(2-aminophenyl)phenyl]-chloropalladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (62.5 mg, 79.5 umol) was added to a solution of 2-(3-chloro-8-methoxyisoquinolin-5-yl)propan-2-ol (200 mg, 794.6 umol), Cs2CO3 (517.7 mg, 1.59 mmol) and 2-(2-fluoropropan-2-yl)pyrimidin-4-amine (Intermediate 1, 135.6 mg, 874 umol) in dioxane (2 mL). The mixture was stirred at 120 °C for 12 hours under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography to give the title compound (250 mg, 84% yield) as a yellow solid. 1H-NMR(400MHz,CD3OD)δppm 9.41(s,1H),9.02(s,1H),8.34(d,1H,J=6.0Hz),7.76(d,1H,J=8.0Hz),7.33 (d, 1H, J = 6.0Hz), 6.84 (d, 1H, J = 8.4Hz), 4.05 (s, 3H), 1.84 (t, 12H, J = 9.2Hz). MS(ES+)C 20 H 23 FN4O2 requires 370, measured 371 [M+H] + .

[1028] Step 9: 5-(2-azidopropan-2-yl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxyisoquinolin-3-amine

[1029] Under N2 atmosphere, indium tribromide (248.8 mg, 701.9 umol) and trimethylsilyl azide (60.6 mg, 526.4 umol, 69.2 uL) were added to a solution of 2-(3-((2-(2-fluoropropan-2-yl)pyrimidin-4-yl)amino)-8-methoxyisoquinolin-5-yl)propan-2-ol (130 mg, 350.9 umol) in dichloromethane (2 mL). The mixture was stirred at 25 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H2O (5 mL) and extracted with EA (5 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride solution (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (138 mg, crude) as a brown oil, which was used in the next step without further purification.

[1030] Step 10: 5-(2-aminopropan-2-yl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxyisoquinolin-3-amine

[1031] Zn (228.2 mg, 3.5 mmol) and AcOH (0.2 mL) were added to a solution of 5-(2-azidopropan-2-yl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxyisoquinolin-3-amine (138 mg, 349 umol) in THF (2 mL) and IPA (0.4 mL). The mixture was stirred at 25° C. for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase preparative HPLC (column: Kromasil 150×25 mm×10 um; mobile phase: [water (0.04% NH3H2O+10 mM NH4HCO3)-MECN]; B%: 15%-45%, 10 minutes) to give the title compound (64 mg, 49% yield) as a white solid. 1 H-NMR(400MHz,CD3OD)δppm 9.42(s,1H),9.03(s,1H),8.35(d,1H,J=6.0Hz),7.76(d,1H,J=8.4Hz),7.28( d, 1H, J = 5.6Hz), 6.85 (d, 1H, J = 8.4Hz), 4.05 (s, 3H), 1.80 (t, 13H, J = 10.8Hz). MS(ES+)C 20 H 24 FN5O requirement: 369, measured: 370 [M+H] + .

[1032]

[1033] Example 5: 4-(2-aminopropan-2-yl)-N6-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-N1-methyl-2,7-naphthyridine-1,6-diamine (6)

[1034]

[1035] Step 1: 4-(2-aminopropan-2-yl)-6-((2-(2-fluoropropan-2-yl)pyrimidin-4-yl)amino)-2,7-naphthyridin-1(2H)-one

[1036] HCl (1.5M, 0.18mL) was added to a solution of 5-(2-aminopropan-2-yl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridin-3-amine (prepared similarly to Example 3a, 20.0mg, 54umol) in tetrahydrofuran (2mL), and the solution was stirred at 25°C for 16 hours. The reaction mixture was basified by adding saturated aqueous sodium bicarbonate solution (5mL) and then water (15mL), and the mixture was extracted with EA (15mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (19.0mg, 99% yield) as a yellow solid, which was used in the next step without further purification. MS(ES+)C 18 H 21 FN6O requires 356, measured 357 [M+H] + . 1 H NMR (400MHz, CD3OD): δppm 9.30(s,1H),8.84(s,1H),8.42(d,J=6.0Hz,1H),7.42(d,J=6.0Hz,1H),7.38(s,1H),1.81(s,3H),1.75(s,3H),1.70(s,6H).

[1037] Step 2: 4-(2-aminopropan-2-yl)-N6-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-N1-methyl-2,7-naphthyridine-1,6-diamine

[1038] DBU (6.0 mg, 42.1 umol, 6.3 uL) and BOP (19 mg, 42.1 umol) were added to a solution of methylamine (2M in THF, 1 mL) in DMF (1 mL), followed by 4-(2-aminopropan-2-yl)-6-((2-(2-fluoropropan-2-yl)pyrimidin-4-yl)amino)-2,7-naphthyridin-1(2H)-one (10.0 mg, 28.1 umol). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted with water (15 mL) and extracted with EA (15 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase preparative HPLC to give the title compound (3.4 mg, 32% yield) as a yellow solid. MS (ES+) C 19 H 24 FN7 requirement 369, measured 370 [M+H] + . 1H NMR (400MHz, CD3OD): δppm9.22(s,1H),8.89(s,1H),8.37(d,J=6.0Hz,1H),8.04( s,1H),7.32(d,J=6.0Hz,1H),3.05(s,3H),1.81(s,3H),1.76(s,3H),1.74(s,6H).

[1039]

[1040] Example 6: 5-((5-(2-aminopropan-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)amino)-3-isopropylpyrazine-2-carbonitrile (8)

[1041]

[1042] Step 1: 2-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-amine

[1043] Triphenylphosphine (2.05g, 7.83mmol) is added to a solution of 4-(2-azidopropane-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine (intermediate 31a, 870mg, 3.13mmol) in tetrahydrofuran (20mL) and water (5mL), and the mixture is stirred at 60°C for 5 hours. The reaction mixture is diluted with water (15mL) and extracted with EA (15mL×3). The combined organic layer is dried over anhydrous sodium sulfate, filtered and concentrated. The residue is purified by flash column chromatography to obtain the title compound (1.7g, crude product) as a white solid.

[1044] 1 H NMR (400MHz, CDCl3): δppm 9.24 (s, 1H), 9.07 (s, 1H), 7.75 (s, 1H), 4.03 (s, 3H), 1.81 (s, 6H).

[1045] Step 2: 4-(2-aminopropan-2-yl)-6-chloro-2,7-naphthyridin-1(2H)-one

[1046] HCl (3M, 11mL) was added to a solution of 2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-amine (1.70g, 6.75mmol) in tetrahydrofuran (15mL), and the mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (15mL) and extracted with EA (15mL×3). The aqueous phase was alkalized by adding saturated sodium bicarbonate aqueous solution (5mL) and extracted with EA (15mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound (430mg, 27% yield) as a yellow solid, which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3): δppm 9.42 (s, 1H), 9.12 (s, 1H), 8.7 (s, 1H), 1.72 (s, 6H).

[1047] Step 3: tert-Butyl (2-(6-chloro-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)propan-2-yl)carbamate

[1048] Triethylamine (128mg, 1.26mmol, 176uL) is added to a solution of 4-(2-aminopropan-2-yl)-6-chloro-2,7-naphthyridine-1(2H)-one (100mg, 421umol) and (Boc)2O (459mg, 2.1mmol, 483uL) in dichloromethane (2mL), and the mixture is stirred at 25°C for 1 hour. The reaction mixture is diluted with water (15mL) and extracted with dichloromethane (15mL×3). The combined organic layer is dried over anhydrous sodium sulfate, filtered and concentrated. The residue is purified by preparative TLC (silica, petroleum ether: EA=5:1) to obtain the title compound (20.0mg, 14% yield) as a yellow solid. 1 HNMR (400MHz, CDCl3): δppm 9.40 (s, 1H), 8.03 (s, 1H), 7.78 (s, 1H), 4.98 (s, 1H), 1.70 (s, 6H), 1.65 (s, 9H).

[1049] Step 4: tert-Butyl (2-(6-chloro-1-(methylamino)-2,7-naphthyridin-4-yl)propan-2-yl)carbamate

[1050] DBU (14 mg, 88.8 umol, 13.4 uL) and BOP (39 mg, 88.8 umol) and then methylamine (2M in THF, 22 mL) were added to a solution of tert-butyl (2-(6-chloro-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)propan-2-yl)carbamate (20.0 mg, 59.2 umol) in DMF (1 mL), and the mixture was stirred at 25 ° C for 1 hour. The reaction mixture was diluted with water (15 mL) and extracted with EA (15 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (20.0 mg, 96% yield) as a white solid, which was used in the next step without further purification. MS (ES+) C 17 H 23 ClN4O2 requires 350, measured 351 [M+H] + .

[1051] Step 5: tert-Butyl (2-(6-((5-cyano-6-isopropylpyrazin-2-yl)amino)-1-(methylamino)-2,7-naphthyridin-4-yl)propan-2-yl)carbamate

[1052] 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos) (6 mg, 11.4 umol) and BrettPhos Pd G4 (10 mg, 11.4 umol) were added to a mixture of tert-butyl (2-(6-chloro-1-(methylamino)-2,7-naphthyridin-4-yl)propan-2-yl)carbamate (40 mg, 114 umol), 5-amino-3-isopropylpyrazine-2-carbonitrile (20 mg, 123 umol) and potassium acetate (34 mg, 342 umol) in dioxane (2 mL). The solution was degassed and purged with N2 3 times, and the mixture was then stirred at 100 ° C for 1 hour under N2 atmosphere. The reaction mixture was diluted with water (15 mL) and extracted with EA (15 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (silica, petroleum ether:EA=1:1) to give the title compound (30 mg, 55% yield) as a yellow solid. MS (ES+) C 25 H 32 N8O2 required 476, measured 477 [M+H] +

[1053] Step 6: 5-((5-(2-aminopropan-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)amino)-3-isopropylpyrazine-2-carbonitrile

[1054] Hydrochloric acid in dioxane (4M, 1 mL) was added to a solution of tert-butyl (2-(6-((5-cyano-6-isopropylpyrazin-2-yl)amino)-1-(methylamino)-2,7-naphthyridin-4-yl)propan-2-yl)carbamate (25 mg, 52.5 umol) in dioxane (1 mL), and the solution was stirred at 25°C for 10 minutes. The reaction mixture was concentrated and the residue was purified by reverse phase preparative HPLC (column: Luna C18 150*25 5u; mobile phase: [water (0.075% TFA)-MeCN]; B%: 5%-35%, 9 minutes) to give the title compound (14.9 mg, 74% yield) as a yellow solid. MS (ES+) C 20 H 24 N8 requirement 376, measured 377 [M+H] + . 1 H NMR (400MHz, CD3OD): δppm 9.49(s,1H),9.08(s,1H),8.28(s,1H),7.56(s,1H),3.55-3.46(m,1H),3.24(s,3H),2.00(s,6H),1.42(d,J=7.2Hz,6H).

[1055]

[1056] Example 7: 2-((5-(2-aminopropan-2-yl)-8-methoxy-2,6-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (46)

[1057]

[1058] Step 1: 4-Bromo-7-chloro-1-(1-ethoxyvinyl)-2,6-naphthyridine

[1059] Pd(PPh3)4(313mg, 271umol) was added to a mixture of 4-bromo-7-chloro-1-iodo-2,6-naphthyridine (intermediate 32, 1.0g, 2.71mmol) and tributyl(1-ethoxyvinyl)stannane (1.0g, 2.77mmol, 935uL) in toluene (20mL). The solution was degassed and purged with nitrogen 3 times, and the mixture was then stirred at 100°C for 16 hours under an atmosphere of nitrogen. The reaction mixture was quenched by adding a saturated potassium fluoride solution (50mL), then diluted with water (20mL) and extracted with EA (50mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (petroleum ether: EA=1:0 to 10:1) to obtain the title compound (640mg, 75% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3): δppm 9.43(s,1H),8.79(s,1H),8.30(d,J=0.8Hz,1H),4.88-4.85(m,1H),4.72-4.69(m,1H),4.15-4.08(m,2H),1.49(t,J=6.8Hz,3H).

[1060] Step 2: 1-(4-bromo-7-chloro-2,6-naphthyridin-1-yl)ethan-1-one

[1061] HCl in dioxane (4M, 6mL) and water (1mL) is added to 4-bromo-7-chloro-1-(1-ethoxyvinyl)-2,6-naphthyridine (640mg, 2.04mmol), and the solution is stirred at 60°C for 2 hours. The reaction mixture is alkalized by adding saturated sodium bicarbonate aqueous solution (10mL), followed by water (20mL). The aqueous layer is extracted with EA (20mL×3). The combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated. The residue is purified by flash column chromatography (petroleum ether: EA=1:0 to 10:1) to obtain the title compound (550mg, 94% yield) as a yellow solid.

[1062] Step 3: 1-(7-Chloro-4-methoxy-2,6-naphthyridin-1-yl)ethan-1-one

[1063] Potassium carbonate (799mg, 5.78mmol) was added to a solution of 1-(4-bromo-7-chloro-2,6-naphthyridin-1-yl)ethan-1-one (550mg, 1.93mmol) in methanol (15mL), and the solution was stirred at 25°C for 16 hours. The reaction mixture was concentrated, diluted with water (30mL) and extracted with EA (30mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (410mg, 90% yield) as a yellow solid, which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3): δppm 9.51 (s, 1H), 9.10 (d, J = 1.2Hz, 1H), 8.28 (s, 1H), 4.23 (s, 3H), 2.80 (s, 3H).

[1064] Step 4: 2-(7-chloro-4-methoxy-2,6-naphthyridin-1-yl)propan-2-ol

[1065] At 0 ° C under an atmosphere of nitrogen, methylmagnesium bromide (3M in THF, 2mL) was added to a solution of 1-(7-chloro-4-methoxy-2,6-naphthyridin-1-yl)ethan-1-one (410mg, 1.73mmol) in tetrahydrofuran (15mL). The solution was stirred at 0 ° C for 10 minutes. The reaction mixture was quenched by adding water (25mL) and extracted with EA (25mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography (petroleum ether: EA=1:0 to 3:1) to obtain the title compound (110mg, 22% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3): δppm 9.53 (d, J = 0.8Hz, 1H), 8.21 (s, 1H), 8.09 (s, 1H), 5.38 (s, 1H), 4.13 (s, 3H), 1.78 (s, 6H).

[1066] Step 5: 1-(2-azidopropan-2-yl)-7-chloro-4-methoxy-2,6-naphthyridine

[1067] Under an atmosphere of nitrogen, indium bromide (224 mg, 633 umol) and trimethylsilyl azide (91.0 mg, 791 umol) were added to a solution of 2-(7-chloro-4-methoxy-2,6-naphthyridin-1-yl)propan-2-ol (80.0 mg, 317 umol) in 1,2-dichloroethane (3 mL). The mixture was stirred at 60 ° C for 16 hours. The reaction mixture was diluted with water (15 mL) and extracted with dichloromethane (15 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (petroleum ether: EA=3:1) to obtain the title compound (30.0 mg, 32% yield) as a yellow solid. MS(ES+)C 12 H 12 ClN5O required 277, measured 278 [M+H] +

[1068] Step 6: 2-((5-(2-azidopropan-2-yl)-8-methoxy-2,6-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[1069] 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos) (12 mg, 21.6 umol) and BrettPhos Pd G4 (10 mg, 10.8 umol) were added to a mixture of 1-(2-azidopropane-2-yl)-7-chloro-4-methoxy-2,6-naphthyridine (30 mg, 108 umol), 2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 2, 22.0 mg, 113 umol) and potassium acetate (32.0 mg, 324 umol) in dioxane (2 mL). The solution was degassed and purged with nitrogen 3 times, and the mixture was then stirred at 100 ° C for 1 hour under a nitrogen atmosphere. The reaction mixture was concentrated and the residue was purified by preparative TLC (petroleum ether:EA=1:1) to give the title compound (20.0 mg, 43% yield) as a yellow solid. MS (ES+) C 22 H 23 N7O3 requires 433, measured 434 [M+H] + .

[1070] Step 7: 2-((5-(2-aminopropan-2-yl)-8-methoxy-2,6-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[1071] Under an atmosphere of nitrogen, Pd / C (20 mg, 10% purity) was added to a solution of 2-((5-(2-azidopropan-2-yl)-8-methoxy-2,6-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrans and [4,3-b]pyridine-5-one (20 mg, 46.1 umol) in EA (6 mL). The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred at 50 ° C for 3 hours under hydrogen (15 psi). The reaction mixture was filtered and concentrated. The residue was purified by preparative TLC (methanol: EA = 1: 10) to give the title compound (5.8 mg, 28% yield) as a yellow solid. MS (ES +) C 22 H 25 N5O3 required 407, measured 408 [M+H] + . 1 H NMR (400MHz, CD3OD): δppm 9.43(s,1H),8.14(d,J=8.8Hz,1H),8.06(s,1H),7.17(d,J=8.4Hz,1H),4.13(s,3H),3.22(s,2H),1.92(s,6H),1.54(s,6H).

[1072]

[1073] Example 8: (7S,8R)-2-((5-(2-aminopropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (66)

[1074]

[1075] Step 1: 6-Chloro-1-cyclopropyloxy-2,7-naphthyridine-4-carboxylic acid methyl ester

[1076] [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1.09 g, 1.335 mmol) was added to a mixture of 4-bromo-6-chloro-1-cyclopropyloxy-2,7-naphthyridine (4 g, 13.35 mmol) and triethylamine (2.233 ml, 16.02 mmol) in MeOH (30 ml) and DMF (15 ml). The reaction vessel was capped under CO (50 psi) and allowed to stir at 50 °C. After 2 hours, the reaction mixture was evaporated to dryness and the residue was purified using flash column chromatography (0-15% EA / hexanes) to give the title compound (2.31 g, 62% yield) as a white solid. MS (ES+) C 13H 11 ClN2O3 required 278, measured 279 [M+H] +

[1077] Step 2: 2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)propan-2-ol

[1078] Methylmagnesium bromide (3.47ml, 10.41mmol) is added to a solution of 6-chloro-1-cyclopropyloxy-2,7-naphthyridine-4-carboxylic acid methyl ester (580mg, 2.08mmol) in THF (20ml). After 1 hour, the reaction mixture was diluted with saturated NH4Cl aqueous solution and extracted with EA. The organic layer was dried, filtered and evaporated. Flash column chromatography (0-40% EA / hexane) was used to purify the residue to obtain the title compound (393mg, 67.7% yield). MS (ES+) C 14 H 15 ClN2O2 required 278, measured 279 [M+H] +

[1079] Step 3: 4-(2-azidopropan-2-yl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine

[1080] At 0 ° C, indium bromide (III) (6.36g, 17.94mmol) and azidotrimethylsilane (4.72ml, 35.9mmol) were added to a solution of 2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)propan-2-ol (2.5g, 8.97mmol) in CH2Cl2 (80ml), and the reaction mixture was allowed to stir overnight. Another 1 equivalent of indium bromide (III) and azidotrimethylsilane were added, and the reaction mixture was heated to 40 ° C for 48 hours. The reaction was filtered through diatomaceous earth and evaporated. Flash column chromatography (0-20% EA / hexane) was used to purify the residue to obtain the title compound (1.9g, 69.7% yield). MS (ES+) C 14 H 14 ClN5O requires 303, measured 304 [M+H] +

[1081] Step 4: (7S,8R)-2-((5-(2-azidopropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[1082] Chloro{[brettphos][2-(2-aminoethylphenyl)palladium(II)]} / [brettphos] (0.57 g, 0.63 mmol) was added to a mixture of (7S,8R)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 17, 1.323 g, 6.88 mmol), 4-(2-azidoprop-2-yl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine (1.9 g, 6.26 mmol) and potassium acetate (3.07 g, 31.3 mmol) in dioxane (60 ml). The reaction vessel was capped under N2 and heated at 100°C. After 30 minutes, the reaction was filtered and evaporated. The residue was then purified using flash column chromatography (0-80% EA / hexanes) to give the title compound (1.74 g, 60% yield). 1 H NMR (400MHz, DMSO-d6) δ10.76(s,1H),9.25(s,1H),9.18(s,1H),8.21(s,1H),8.09(d,J=8.7Hz,1H),7.37(d,J=8.7Hz,1H),4.59(p,J=6.3Hz,1 H), 4.51 (dq, J = 6.3, 4.1, 3.3Hz, 1H), 3.05–2.93 (m, 1H), 1.82 (d, J = 2.0Hz, 5H), 1.44 (d, J = 7.1Hz, 3H), 1.37 (d, J = 6.5Hz, 3H), 0.89–0.78 (m, 4H). MS(ES+)C 24 H 25 N7O3 required 459, measured 460 [M+H] + .

[1083] Step 5: (7S,8R)-2-((5-(2-aminopropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[1084] Under an atmosphere of nitrogen, Pd / C (3 g, 10%) is added to a solution of (7S, 8R)-2-((5-(2-azidopropyl-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrans [4,3-b] pyridine-5-one (10.76 g, 23.42 mmol) in 100 ml of EA. The suspension is degassed under vacuum and purged with hydrogen several times. The reaction mixture is stirred at room temperature overnight under hydrogen. The reaction mixture is then transferred to a pressure flask and heated at 50 psi and 50 ° C, and 1.8 g of Pd / C is added in addition until the starting material is consumed. The reaction mixture is cooled to room temperature, filtered and evaporated. The residue is purified via flash column chromatography (0-10% MeOH / DCM) to obtain the title compound (3.7 g, 36.4% yield). MS(ES+)C 24 H 27 N5O3 required 433, measured 434 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H),9.38(s,1H),9.19(d,J=0.7Hz,1H),8.20(s,1H),8.06(d,J=8.7Hz,1H),7.36(d,J=8.7Hz,1H),5.73 (s,1H),4.63–4.52(m,1H),4.52–4.43(m,1H),3.03–2.92(m,1H),1.64(d,J=2.0Hz,6H),1.39(dd,J=24.8,6.8Hz,6H),0.85–0.78(m,4H).

[1085]

[1086] Example 9: 2-((5-(2-aminopropan-2-yl)-8-cyclobutoxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (72)

[1087]

[1088] Step 1: 4-(2-azidopropan-2-yl)-6-chloro-2,7-naphthyridin-1-ol

[1089] Hydrochloric acid (6M, 240uL) was added to a solution of 4-(2-azidopropane-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine (intermediate 31a, 200mg, 720umol) in tetrahydrofuran (1mL), and the solution was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (20mL) and extracted with EA (20mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash column chromatography to obtain the title compound (130mg, 68% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6): δppm 11.90 (s, 1H), 9.20 (s, 1H), 8.02 (s, 1H), 7.43 (d, J = 3.2Hz, 1H), 1.67 (s, 6H).

[1090] Step 2: 4-(2-azidopropan-2-yl)-1,6-dichloro-2,7-naphthyridine

[1091] Phosphorus oxychloride (2.86 g, 18.7 mmol, 1.7 mL) was added to 4-(2-azidopropyl-2-yl)-6-chloro-2,7-naphthyridine-1-ol (130 mg, 493 umol), and the solution was stirred at 110 ° C for 1 hour. The reaction mixture was concentrated and the residue was dissolved in EA (10 mL). The mixture was diluted with saturated sodium bicarbonate aqueous solution (20 mL) and extracted with EA (10 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound (110 mg, 79% yield) as a yellow solid, which was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6): δppm 9.61 (d, J = 0.8Hz, 1H), 8.63 (s, 1H), 8.47 (s, 1H), 1.84 (s, 6H).

[1092] Step 3: 4-(2-azidopropan-2-yl)-6-chloro-1-cyclobutyloxy-2,7-naphthyridine

[1093] Potassium carbonate (132 mg, 957 μmol) was added to a solution of 4-(2-azidopropane-2-yl)-1,6-dichloro-2,7-naphthyridine (90.0 mg, 319 μmol) and cyclobutanol (69.0 mg, 957 μmol) in MeCN (5 mL), and the reaction mixture was concentrated at 60 ° C for 4 hours; diluted with water (20 mL) and extracted with EA (20 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC to obtain the title compound (50.0 mg, 49% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3): δppm9.45(s,1H),8.32(s,1H),8.17(s,1H),5.48-5.37(m,1H),2. 62-2.52(m,2H),2.36-2.23(m,2H),1.98-1.87(m,1H),1.79(s,6H),1.77-1.71(m,1H).

[1094] Step 4: 4-(2-azidopropan-2-yl)-6-chloro-1-cyclobutyloxy-2,7-naphthyridine

[1095] 2-(Dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos) (10 mg, 18.9 umol) and BrettPhos Pd G4 (9 mg, 9.44 umol) were added to a mixture of 2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine-5-one (intermediate 2, 20 mg, 104 umol), 4-(2-azidopropane-2-yl)-6-chloro-1-cyclobutyloxy-2,7-naphthyridine (30 mg, 94.4 umol) and potassium acetate (28 mg, 283 umol) in dioxane (2 mL). The solution was degassed and purged with nitrogen 3 times, and the mixture was then stirred at 100 ° C for 1 hour under a nitrogen atmosphere. The reaction mixture was concentrated and the residue was purified by preparative TLC to give the title compound (26.3 mg, 60% yield) as a yellow solid. MS (ES+) C 25 H 29 N5O3 required 447, measured 448 [M+H] + . 1HNMR (400MHz, CD3OD): δppm9.37(s,1H),9.32(s,1H),8.15(d,J=8.8Hz,1H),8.10(s,1H),7.21(d,J=8.8Hz,1H),5.48-5.35 (m,1H),3.22(s,2H),2.62-2.51(m,2H),2.34-2.22(m,2H),1.96-1.91(m,1H),1.85(s,6H),1.82-1.74(m,1H),1.53(s,6H).

[1096]

[1097] Example 10: N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxy-5-(2-(methylamino)propan-2-yl)-2,7-naphthyridin-3-amine (17)

[1098]

[1099] Step 1: N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxy-5-(2-(methylamino)propan-2-yl)-2,7-naphthyridin-3-amine

[1100] Under nitrogen, Pd / C (10 mg, 10% purity) and formaldehyde (16.4 mg, 202 umol) were added to a solution of 5-(2-azidopropan-2-yl)-N-(2-(2-fluoropropan-2-yl)pyrimidin-4-yl)-8-methoxy-2,7-naphthyridine-3-amine (100 mg, 252 umol) in methanol (20 mL). The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred at 25 ° C for 16 hours under hydrogen (15 psi). The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase preparative HPLC to give the title compound (16.0 mg, 16% yield) as a white solid. MS (ES+) C 20 H 25 FN6O requires 384, measured 385 [M+H] + . 1 H NMR (400MHz, CD3OD): δppm 9.37(s,1H),9.31(s,1H),8.39(d,J=6.0Hz,1H),8.03(s,1H),7.29(d,J=5 6.0Hz,1H),4.13(s,3H),2.07(s,3H),1.83(s,3H)1.78(s,3H),1.69(s,6H)

[1101]

[1102] Example 11: 2-((8-methoxy-5-(pyrrolidin-2-yl)-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (50)

[1103]

[1104] Step 1: tert-Butyl 2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)pyrrolidine-1-carboxylate

[1105] 6-Chloro-4-iodo-1-methoxy-2,7-naphthyridine (0.4 g, 1.248 mmol), nickel(II) chloride dimethoxyethane adduct (0.016 g, 0.075 mmol), 1-[(tert-butoxy)carbonyl]pyrrolidine-2-carboxylic acid (0.537 g, 2.496 mmol), (4,4'-di-tert-butyl-2,2'-bipyridyl)bis[3,5-difluoro-2-(5-trifluoromethyl-2-pyridyl-kN)phenyl-kC]iridium(III) hexafluorophosphate (0.014 g, 0.012 mmol) and cesium carbonate (1.220 g, 3.74 mmol) were combined in a 40 mL vial. DMF (24.96 ml) was added and the reaction mixture was surrounded by a blue LED light and stirred at ambient temperature for 16 hours. The reaction mixture was diluted with EA and washed with water, saturated brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography (20-100% EA: hexane). The desired fractions were identified, combined, and concentrated under vacuum to give the title compound. MS (ES+) C 18 H 22 ClN3O3 requires 363, measured 364 [M+H] +.

[1106] Step 2: tert-Butyl 2-(6-((7,7-dimethyl-5-oxo-7,8-dihydro-5H-pyrano[4,3-b]pyridin-2-yl)amino)-1-methoxy-2,7-naphthyridin-4-yl)pyrrolidine-1-carboxylate

[1107] 2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (104mg, 0.286mmol), 2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (intermediate 2, 50mg, 0.26mmol), potassium acetate (77mg, 0.780mmol) and BrettPhos Pd G4 mixture and 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (38mg, 0.026mmol) 1:1 mixture were combined in a vial and capped under N2. Dioxane (1.3ml) was added and the mixture was heated to 100°C. After 4 hours, another 38mg of 1:1 catalyst mixture was added and heating was continued for another 12 hours. The mixture was then cooled to ambient temperature and concentrated under vacuum. The residue was purified by flash column chromatography (20-100% EA:hexanes). The desired fractions were identified, combined, and concentrated under vacuum to give the title compound. MS (ES+) C 28 H 33 N5O5 required 519, measured 520 [M+H] +.

[1108] Step 3: 2-((8-methoxy-5-(pyrrolidin-2-yl)-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[1109] 2-(6-((7,7-dimethyl-5-oxo-7,8-dihydro-5H-pyrans [4,3-b] pyridin-2-yl) amino) -1-methoxy -2,7- naphthyridin-4-yl) pyrrolidine -1- carboxylic acid tert-butyl ester (20mg, 0.038mmol) was stirred in 5:1 DCM: TFA for 2 hours. The reaction mixture was diluted with EA and carefully washed with saturated sodium bicarbonate aqueous solution, saturated brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash column chromatography. The desired fractions were identified, combined, and concentrated under vacuum to obtain the title compound. MS (ES+) C 23 H 25 N5O3 required 419, measured 420 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.64(s,1H),9.18(d,J=0.8Hz,1H),8.49(s,1H),8.05(d,J=8.7Hz,1H),7.38–7.31(m,2H),4.22(t,J=6.7Hz,1H),4.06( s,3H),3.21(s,2H),3.15(s,1H),3.09(dt,J=10.4,6.4Hz,1H),2.98(dt ,J=10.1,6.7Hz,1H),2.24–2.09(m,1H),1.84–1.70(m,3H),1.43(s,6H).

[1110]

[1111] Example 12: 2-((5-(2-aminopropan-2-yl)-8-chloroisoquinolin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (104)

[1112]

[1113] Step 1: 2-(3-amino-8-chloroisoquinolin-5-yl)propan-2-ol

[1114] At -70 ° C, n-butyl lithium (2.5 mol / L in n-hexane, 6.21 mL) was added to a solution of 5-bromo-8-chloroisoquinolin-3-amine (Journal of Medicinal Chemistry, 60 (9), 3755-3775; 2017) (800 mg, 3.11 mmol) and TMEDA (1.81 g, 15.5 mmol) in toluene (10 mL). The reaction mixture was stirred at -70 ° C for 0.5 hours, and then acetone (1.80 g, 31.1 mmol) was added to the reaction mixture. The reaction mixture was stirred at -70 ° C for 0.5 hours and then quenched by adding saturated NH4Cl aqueous solution (30 mL) at -70 ° C. After being warming up to environment temperature, reaction mixture is extracted with EA 80mL (40mL x 2), washed with brine 40mL (20mL x 2), dried over sodium sulfate, filtered and concentrated to obtain residue. Residue is purified by flash column chromatography (gradient elution, 10% to 50% ethyl acetate-petroleum ether) on silica gel to obtain the title compound (200mg, 25% yield) as yellow solid. MS (ES+) C 12 H 13 ClN2O requires 236, measured 237 [M+H] + .

[1115] Step 2: 5-(2-azidopropan-2-yl)-8-chloroisoquinolin-3-amine

[1116] TMSN3 (107 mg, 929 umol) was added to a solution of 2-(3-amino-8-chloroisoquinolin-5-yl)propan-2-ol (200 mg, 845 umol) and indium bromide (599 mg, 1.69 mmol) in DCM (8 mL). The reaction mixture was stirred at 25 °C for 16 hours, then diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (210 mg, crude) as a yellow solid. MS (ES+) C 12 H 12 ClN5 requires 261, found 262 [M+H] + .

[1117] Step 3: 2-((5-(2-azidopropan-2-yl)-8-chloroisoquinolin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[1118] Pd2(dba)3(70.0mg, 76.4umol), XantPhos(88.4mg, 153umol) and cesium carbonate (747mg, 2.29mmol) were added to a solution of 5-(2-azidopropane-2-yl)-8-chloroisoquinoline-3-amine (200mg, 764μmol) and 2-chloro-7,7-dimethyl-7,8-dihydro-5H-pyrans [4,3-b] pyridine-5-one (step 1-3, intermediate 2) (162mg, 764μmol) in dioxane (5mL). The reaction mixture was stirred at 80°C for 1 hour, then cooled to ambient temperature, filtered, and concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, PE / EA=10 / 1 to 1 / 1) to give the title compound (210 mg, 60% yield) as a yellow solid. MS (ES+) C 22 H 21 ClN6O2 requires 436, measured 437 [M+H] + .

[1119] Step 4: 2-((5-(2-aminopropan-2-yl)-8-chloroisoquinolin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[1120] Zinc (67.4 mg, 1.03 mmol) and acetic acid (124 mg, 2.06 mmol) were added to a solution of 2-((5-(2-azidopropyl-2-yl)-8-chloroisoquinolin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (90 mg, 206 umol) in THF (5 mL). The reaction mixture was stirred at 15 ° C for 0.5 hours, then filtered and concentrated to obtain a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 38%-68%, 10 minutes) to obtain the title compound (25 mg, 30% yield) as a yellow solid. MS (ES+) C 22 H 23 ClN4O2 requires 410, measured 411 [M+H] + . 1 H-NMR (400MHz, CD3OD): δppm 9.61(s,1H),9.42(s,1H),8.12(d,J=8.8Hz,1H),7.79(d,J=8.0Hz,1H),7.48( d,J=8.0Hz,1H),7.14(d,J=8.8Hz,1H),3.24(s,2H),1.87(s,6H),1.55(s,6H).

[1121]

[1122] Example 13: (7S,8R)-2-((5-((R)-2-amino-1-hydroxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and (7S,8R)-2-((5-((S)-2-amino-1-hydroxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (139 and 140)

[1123]

[1124] Step 1: 6-Chloro-1-cyclopropyloxy-4-(prop-1-en-2-yl)-2,7-naphthyridine

[1125] A mixture of 4-bromo-6-chloro-1-cyclopropyloxy-2,7-naphthyridine (Intermediates 33 and 34, Step 1) (5.00 g, 16.7 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.09 g, 18.4 mmol), Pd(dppf)Cl2 (1.22 g, 1.67 mmol) and potassium carbonate (4.61 g, 33.4 mmol) in dioxane (30 mL) and water (6 mL) was degassed and purged with nitrogen three times. The reaction mixture was stirred at 60 °C for 2 hours and then concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / EA=10 / 1) to give the title compound (2.50 g, 9.59 mmol, 57% yield) as a white solid.

[1126] Step 2: 6-Chloro-1-cyclopropyloxy-4-(2-methyloxiran-2-yl)-2,7-naphthyridine

[1127] m-CPBA (4.48g, 22.1mmol, 85% purity) is added to a solution of 6-chloro-1-cyclopropyloxy-4-(prop-1-ene-2-yl)-2,7-naphthyridine (2.30g, 8.82mmol) in DCM (100mL). The reaction mixture is stirred at 25 ° C for 12 hours, then quenched by adding saturated aqueous sodium sulfite solution (50mL) and extracted with DCM (50mL). The organic layer is dried over sodium sulfate, filtered and concentrated to obtain a residue. The residue is purified by column chromatography (SiO2, PE / EA=5 / 1) to obtain the title compound (750mg, 2.71mmol, 31% yield) as a white solid.

[1128] Step 3: 2-Azido-2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)propan-1-ol

[1129] TMSN3 (625 mg, 5.42 mmol, 713 uL) and InBr3 (1.92 g, 5.42 mmol) were added to a solution of 6-chloro-1-cyclopropyloxy-4-(2-methyloxirane-2-yl)-2,7-naphthyridine (300 mg, 1.08 mmol) in 1,2-dichloroethane (10 mL). The reaction mixture was stirred at 50 ° C for 0.5 hours, then poured into water (100 mL) and extracted with EA (30 mL×3). The organic layer was dried over sodium sulfate, filtered and concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, PE:EA=5:1 to 1:1) to obtain the title compound (60.0 mg) as a yellow solid.

[1130] Step 4: (7S,8R)-2-((5-(2-azido-1-hydroxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[1131] BrettPhos (Pd, G4) (10mg, 10.9μmol), BrettPhos (8.39mg, 15.6μmol) and potassium acetate (46.0mg, 469μmol) are added to 2-azido-2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl) propan-1-ol (50.0mg) and (7S, 8R) -2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrans [4,3-b] pyridine-5-one (intermediate 17) (36.1mg, 188μmol) solution in dioxane (2mL). The reaction mixture was stirred at 60 ° C for 1 hour and then concentrated to obtain residue. The residue was purified by preparative TLC (ethyl acetate) to obtain the title compound (40.0mg, crude product) as a yellow solid.

[1132] Step 5: (7S,8R)-2-((5-(2-amino-1-hydroxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[1133] Pd(OH)2 / C (10.0 mg, 20% purity) was added to a solution of (7S, 8R)-2-((5-(2-azido-1-hydroxypropane-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine-5-one (40.0 mg, crude) in EA (2 mL). The reaction mixture was stirred at 40 ° C under hydrogen (15 psi) for 12 hours, then filtered and concentrated to give a residue. The residue was purified by preparative TLC (EA:MeOH=10:1) to give the title compound (25.0 mg, 50.7 μmol, 60% yield) as a yellow solid.

[1134] Step 6: (7S,8R)-2-((5-((R)-2-amino-1-hydroxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and (7S,8R)-2-((5-((S)-2-amino-1-hydroxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[1135] (7S,8R)-2-((5-(2-amino-1-hydroxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (20.0 mg, 44.5 μmol) was purified by SFC (column: Daicel Chiralpak IC (250mm*30mm, 10um); mobile phase: [0.1% NH4OH in EtOH]) to obtain (7S,8R)-2-((5-((R)-2-amino-1-hydroxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine-5-one or (7S,8R)-2-((5-((S)-2-amino-1-hydroxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine-5-one as a yellow solid. ketone (first eluting isomer, 3.00 mg, 11% yield) and (7S,8R)-2-((5-((R)-2-amino-1-hydroxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one or (7S,8R)-2-((5-((S)-2-amino-1-hydroxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (second eluting isomer, 3.00 mg, 10% yield) as a yellow solid. First eluting isomer: MS (ES+) C 24 H 27 N5O4 required 449, measured 450 [M+H] + . 1H-NMR (400MHz, CD3OD): δppm 9.33 (s, 1H), 8.92 (s, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.01 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 4.68-4.65 (m, 1H), 4.54 (m, 1H), 4.42-4.38 (m, 1H), 4.11-4.08 (m, 1H), 3.03-3.01 (m, 1H), 1.99 (s, 3H), 1.53-1.45 (m, 6H), 0.91 (m, 4H). Second eluting isomer: MS (ES+) C 24 H 27 N5O4 required 449, measured 450 [M+H] + . 1 H-NMR (400MHz, CD3OD): δppm9.33(s,1H),8.94(s,1H),8.18(d,J=8.8Hz,1H),8.01(s,1H),7.34(d,J=8.4Hz,1H),4.69-4.67(m ,1H),4.55-4.50(m,1H),4.39-4.36(m,1H),4.16-4.13(m,1H),3.06-3.03(m,1H),1.99(s,3H),1.51-1.46(m,6H),0.91(m,4H).

[1136]

[1137] Example 14: 2-((5-(2-(cyclobutylamino)propan-2-yl)-8-methoxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (158)

[1138]

[1139] Step 1: 2-(6-Chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-amine

[1140] Zinc (589 mg, 9.00 mmol) and acetic acid (1.08 g, 18.0 mmol, 1.03 mL) were added to a solution of 4-(2-azidopropane-2-yl)-6-chloro-1-methoxy-2,7-naphthyridine (intermediate 31a) (500 mg, 1.80 mmol) in THF (5.00 mL). The reaction mixture was stirred at 60 ° C for 1 hour, then cooled to ambient temperature and treated with saturated aqueous ammonium hydroxide solution to adjust to pH about 7. The reaction mixture was filtered and concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, PE / EA=1:0 to 3:2) to obtain the title compound (272 mg, 1.08 mmol, 60% yield) as a white solid.

[1141] Step 2: N-(2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-yl)cyclobutanamine

[1142] A solution of 2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-amine (50.0 mg, 199 μmol), cyclobutanone (55.7 mg, 795 μmol, 59.4 μL) and acetic acid (11.9 mg, 199 μmol, 11.4 μL) in MeOH (2.00 mL) was stirred at 15 °C for 0.5 h, then sodium cyanoborohydride (37.5 mg, 596 μmol) was added. The reaction mixture was stirred at 15 °C for 0.5 h, then concentrated to give a residue. The residue was purified by preparative TLC (PE:EA=5:1) to give the title compound (60.0 mg, 196 μmol, 99% yield) as a white oil. MS (ES+) C 16 H 20 ClN3O requires 305, measured 306 [M+H] + .1H NMR (400MHz, CDCl3): δppm 9.38(s,1H),9.16(d,J=0.8Hz,1H),8.08(s,1H),4.13(s,3H),2.87-2.79(m,1H),2.0 3-1.96(m,2H),1.68-1.59(m,2H),1.55(s,6H),1.52-1.45(m,2H),0.08-0.06(m,1H).

[1143] Step 3: 2-((5-(2-(cyclobutylamino)propan-2-yl)-8-methoxy-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[1144] A mixture of N-(2-(6-chloro-1-methoxy-2,7-naphthyridin-4-yl)propan-2-yl)cyclobutanamine (40.0 mg, 131 μmol), Intermediate 2 (25.1 mg, 131 μmol), BrettPhos(Pd, G4) (12.0 mg, 13.1 μmol), BrettPhos (7.02 mg, 13.1 μmol) and potassium acetate (64.2 mg, 654 μmol) in dioxane (1.00 mL) was stirred at 100° C. for 1 hour. The reaction mixture was then concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C1875*30mm*3um; mobile phase: [water (0.1% TFA)-ACN]; B%: 25%-35%, 7 minutes) to give the title compound (27.9 mg, 45% yield) as a yellow solid. MS(ES+)C 26 H 31 N5O3 required 461, measured 462 [M+H] + . 1 H NMR (400MHz, 6d-DMSO): δppm 10.80(s,1H),9.38(s,1H),9.14(s,2H),8.83(s,1H),8.17-8.13(m,2H),7.41-7.39(m,1H),4.11(s,3H),3. 09(s,2H),2.52(s,1H),2.12-2.05(m,2H),1.99(s,5H),1.92-1.87(m,2H),1.69-1.58(m,2H),1.45(s,6H).

[1145]

[1146] Example 15: 2-((8-Cyclopropyloxy-5-(2-((2-hydroxyethyl)amino)propan-2-yl)-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (177)

[1147]

[1148] Step 1: 2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)propan-2-amine

[1149] Zinc (323 mg, 4.94 mmol) was added to a solution of 4-(2-azidopropan-2-yl)-6-chloro-1-cyclopropyloxy-2,7-naphthyridine (Example 8, Step 1-3) (300 mg, 988 μmol) and acetic acid (5297 mg, 4.94 mmol) in THF (8 mL). The reaction mixture was stirred at 25 ° C for 10 minutes, then filtered and concentrated. The residue was purified with a flash column (MeOH=3:1) to give the title compound (200 mg, 73% yield) as a yellow solid. MS (ES+) C 14 H 16 ClN3O required 277, measured 278 [M+H] + .

[1150] Step 2: (2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)propan-2-yl)glycine methyl ester

[1151] Potassium carbonate (179mg, 1.30mmol) is added to a mixture of 2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)propan-2-amine (180mg, 648μmol) and 2-bromoacetic acid methyl ester (297mg, 1.94mmol) in N, N-dimethylformamide (4mL). The reaction mixture is stirred at 60°C for 2 hours, then diluted with water (20mL) and extracted with EA (20mL×3). The combined organic layer is dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue. The residue is purified by flash column chromatography on silica gel (PE:EA=1:0 to 3:1) to obtain the title compound (170mg, 75% yield) as a white solid.

[1152] Step 3: 2-((2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)propan-2-yl)amino)ethan-1-ol

[1153] Lithium borohydride (24.9 mg, 1.14 mmol) was added to a solution of (2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)propan-2-yl)glycine methyl ester (80.0 mg, 229 μmol) in THF (4 mL). The reaction mixture was stirred at 25 ° C for 0.5 hours, then quenched by adding water (10 mL) and extracted with EA (10 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 preparative TLC (PE:EA=1:2) to give the title compound (30.0 mg, 41% yield) as a white solid. MS (ES+) C 16 H 20 ClN3O2 requires 321, measured 322 [M+H]+ .

[1154] Step 4: 2-((8-cyclopropyloxy-5-(2-((2-hydroxyethyl)amino)propan-2-yl)-2,7-naphthyridin-3-yl)amino)-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[1155] BrettPhos (5.00 mg, 9.32 μmol), BrettPhos (Pd, G4) (8.58 mg, 9.32 μmol) and potassium acetate (22.9 mg, 233 μmol) were added to a mixture of 2-((2-(6-chloro-1-cyclopropyloxy-2,7-naphthyridin-4-yl)propan-2-yl)amino)ethan-1-ol (30.0 mg, 93.2 μmol) and 2-amino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (intermediate 2) (26.9 mg, 140 μmol). The reaction mixture was stirred at 80 ° C for 2 hours and then concentrated to give a residue. The residue was purified by preparative TLC (EA: MeOH = 10: 1) and then further purified by preparative HPLC (column: Phenomenex Gemini NX-C18 (75*30mm*3um); mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 33%-63%, 10 minutes) to give the title compound (6.70 mg, 15% yield) as a yellow solid. MS (ES+) C 26 H 31 N5O4 required 477, measured 478 [M+H] + . 1 H NMR (400MHz, CD3OD): δppm 9.91(s,1H),9.23(s,1H),8.18-8.07(m,1H),8.02(s,1H),7.27-7.14(m,1H),4.51-4.36(m,1H), 3.55-3.41(m,2H),3.26(s,2H),2.47-2.37(m,2H),1.82-1.66(m,6H),1.54(s,6H),0.89(s,4H).

[1156]

[1157] Example 16: (7S,8R)-2-((5-((R)-2-amino-1-methoxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and (7S,8R)-2-((5-((S)-2-amino-1-methoxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (184)

[1158]

[1159] Step 1-2: (7S,8R)-2-((5-(2-amino-1-methoxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[1160] The title compound was prepared from 4-(2-azido-1-methoxypropan-2-yl)-6-chloro-1-cyclopropoxy-2,7-naphthyridine (a mixture of intermediates 68 and 69 before separation (after step 3)) and (7S,8R)-2-amino-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (Intermediate 17) using a procedure analogous to that described in steps 4 and 5 of Example 13.

[1161] Step 3: (7S,8R)-2-((5-((R)-2-amino-1-methoxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one and (7S,8R)-2-((5-((S)-2-amino-1-methoxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one

[1162] (7S,8R)-2-((5-(2-amino-1-methoxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one (25.0 mg) was purified by SFC (column: Daicel Chiralpak AS (250 mm*30 mm, 10 um); mobile phase: [0.1% NH3H2O MeOH]) to give (7S,8R)-2-((5-((R)-2-amino-1-methoxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one or (7S,8R)-2-((5-((S)-2-amino-1-methoxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one as a yellow solid (first eluting isomer, 8.00 mg, 3 2% yield) and (7S,8R)-2-((5-((R)-2-amino-1-methoxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one or (7S,8R)-2-((5-((S)-2-amino-1-methoxypropan-2-yl)-8-cyclopropyloxy-2,7-naphthyridin-3-yl)amino)-7,8-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridin-5-one as a yellow solid (second eluting isomer, 9.00 mg, 37% yield). MS (ES+) C 25 H 29 N5O4 required 463, measured 464 [M+H] + . 1 H-NMR (400MHz, CD3OD): δppm 9.24(s,1H),9.20(s,1H),8.19(s,1H),8.13(d,J=8.8Hz,1H),7.29(d,J=8.8Hz,1H),4.69-4.63(m,1H),4.45-4.43(m,1H) ,3.97-3.95(m,1H),3.83-3.81(m,1H),3.35(s,3H),3.06-2.99(m,1H),1.74(s,3H),1.52-1.46(m,6H),0.93-0.87(m,4H).

[1163]

[1164] Example 17: (S)-2'-((5-(1-aminopropyl)-8-methoxyisoquinolin-3-yl)amino)-7',7'-dimethyl-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-5'-one or (R)-2'-((5-(1-aminopropyl)-8-methoxyisoquinolin-3-yl)amino)-7',7'-dimethyl-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-5'-one (207)

[1165]

[1166] Step 1: (S)-N-((R)-1-(3-((7',7'-dimethyl-5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-2'-yl)amino)-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide or (S)-N-((S)-1-(3-((7',7'-dimethyl-5'-oxo-5'H,7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-2'-yl)amino)-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide

[1167] (S)-N-((S)-1-(3-chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide or (S)-N-((R)-1-(3-chloro-8-methoxyisoquinolin-5-yl)propyl)-2-methylpropane-2-sulfinamide (Intermediate 73, 20 mg, 56.4 umol), 2'-amino-7',7'-dimethyl-5'-H, A mixture of 7'H-spiro[cyclopropane-1,8'-pyrano[4,3-b]pyridine]-5'-one (intermediate 85) (14.8 mg, 67.6 umol), BrettPhos (6.05 mg, 11.3 umol), BrettPhos (Pd, G4) (5.19 mg, 5.64 umol) and potassium acetate (16.6 mg, 169 umol) was degassed and purged with nitrogen 3 times. The reaction was stirred at 100 ° C for 1 hour, then filtered and concentrated to give a residue. The residue was purified by preparative TLC (PE: EA = 0: 1) to give the product as a light yellow solid (20 mg, 65% yield). MS (ES +) C 29 H 36 N4O4S required 536, measured 537 [M+H] + .

[1168] Step 2: (S)-2'-((5-(1-aminopropyl)-8-methoxyisoquinolin-3-yl)amino)-7',7'-dimethyl-5'H,7'H-spiro[cycl...

Claims

1. A compound of formula V, VI, VII, VIII, IX or X: or a pharmaceutically acceptable salt thereof, in: A 3 is selected from CH and N; E is CH2, NH or O; R 8 It is C 1-3 alkyl, and n is 0 to 4; two R attached to the same carbon atom 8 The groups together with the carbon atom to which they are attached form the C 3-5 Cycloalkyl; or two R attached to two adjacent carbon atoms 8 The groups, together with the two adjacent carbon atoms to which they are attached, form a C 4-6 Cycloalkyl; X is selected from OR 6 、NHR 7 and halogens; R 1 and R 2 are each independently selected from hydrogen, C optionally substituted by OH 1-4 Alkyl, cyclobutyl and oxetanyl; R 3 and R 4 are each independently selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl; R 6 Selected from C 1-3 Alkyl and C 3-6 Cycloalkyl, wherein the alkyl and cycloalkyl are optionally substituted by 1-3 R 9 replace; R 7 Selected from C 1-3 Alkyl and C 3-5 Cycloalkyl; R 9 Selected from C 1-3 Alkyl, halogen-substituted C 3-6 Cycloalkyl, halogen, C 1-3 Alkoxy and OH; R 11 Selected from COOH and CN; R 12 Selected from C 1-5 Alkyl, C 4-6 Cycloalkyl, 3- to 6-membered heterocyclic ring and OR 13 wherein the alkyl, cycloalkyl or heterocyclic ring is optionally substituted by OH, NH2, 1-4 halogens or R 15 replace; R 13 It is C 1-6 alkyl; R 14 It is C 1-6 Alkyl; and R 15 It is C 1-3 alkyl.

2. The compound according to claim 1, wherein the compound is represented by formula V or VI: or a pharmaceutically acceptable salt thereof, Where E is CH2, NH or O; R 8 It is C 1-3 alkyl, and n is 0 to 4; two R attached to the same carbon atom 8 The groups together with the carbon atom to which they are attached form the C 3-5 Cycloalkyl; or two R attached to two adjacent carbon atoms 8 The groups, together with the two adjacent carbon atoms to which they are attached, form a C 4-6 Cycloalkyl.

3. The compound according to claim 2, wherein the compound is represented by formula V(A) or VI(A): or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, wherein the compound is represented by formula V(B) or VI(B): or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 4, wherein the compound is represented by formula V(C) or VI(C): or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 8 is methyl, and n is 0, 1, 2, 3 or 4.

7. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein two R attached to the same carbon atom 8 Together with the carbon atoms to which they are attached, they form a cyclopropyl group; or two R attached to two adjacent carbon atoms 8 Together with the two adjacent carbon atoms to which they are attached they form a cyclopentyl group.

8. The compound according to claim 1, wherein the compound is represented by Formula VII, VIII or IX: or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8, wherein the compound is represented by formula VII(A), VIII(A) or IX(A): or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 11 It is CN.

11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R 12 Selected from isopropyl, fluoropropyl, trifluoroisopropyl, isobutyl, tert-butyl, isopropoxy, methylpyrrolidine, methylazetidine and hydroxycyclohexyl.

12. The compound according to claim 1, wherein the compound is represented by formula X: or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein R 14 It is isobutyl.

14. The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein X is OR 6 , and R 6 is selected from methyl, ethyl, propyl, isopropyl, trifluoroethyl, trifluoroisopropyl, difluoroethyl, difluoropropyl, difluoroisopropyl, cyclobutyl and cyclopropyl, wherein the cyclopropyl is optionally substituted by methyl or one or two fluorines, and wherein the cyclobutyl is optionally substituted by OH.

15. The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein X is OR 6 , and R 6 is selected from methyl, ethyl, propyl, isopropyl, trifluoroethyl, trifluoroisopropyl, difluoroethyl, difluoropropyl, difluoroisopropyl, cyclobutyl and cyclopropyl, wherein the cyclopropyl group is optionally substituted by methyl or one or two fluorine groups.

16. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein X is NHR 7 , and R 7 Selected from methyl, ethyl, cyclopropyl and cyclobutyl.

17. The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Each is independently selected from hydrogen, methyl, ethyl, cyclopropyl and cyclobutyl.

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

19. The compound according to claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

22. The compound according to claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

23. The compound according to claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

24. The compound according to claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

25. The compound according to claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

26. The compound according to claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 1, wherein the compound is: or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

29. Use of a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition according to claim 28 in the preparation of a medicament for treating a MAP4K1-dependent disease, wherein the MAP4K1-dependent disease is colorectal cancer or lung cancer.

30. The use according to claim 29, wherein the MAP4K1-dependent disease is lung cancer.

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