Azaquinazoline pan KRas inhibitors

Abstract

The present invention relates to compounds that inhibit at least one of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and KRas Q61H, pharmaceutical compositions comprising these compounds, and methods of use thereof.

Description

Technical Field

[0001] The present invention relates to compounds that inhibit multiple mutant forms of KRas, ie, pan-KRas inhibitors. In particular, the present invention relates to pan-KRas compounds, pharmaceutical compositions comprising these compounds, and methods of use thereof. Background Art

[0002] Kirsten rat sarcoma type 2 viral oncogene homolog ("KRas") is a small GTPase and a member of the Ras oncogene family. KRas acts as a molecular switch that cycles between an inactive (GDP-bound) and an active (GTP-bound) state to transmit upstream cellular signals received from multiple tyrosine kinases to downstream effectors, thereby regulating a variety of processes, including cell proliferation (e.g., see Alamgeer et al. (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of activated KRas in malignancies was observed more than three decades ago (e.g., see Santos et al., (1984) Science 223:661-664). Aberrant expression of KRas accounts for up to 20% of all cancers and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas. KRas mutations at codons 12, 13, 61, and other positions of the KRas primary amino acid sequence are present in 88% of all pancreatic cancer patients, 50% of all colon / rectal adenocarcinoma patients, and 32% of lung adenocarcinoma patients (e.g., see Prior et al., (2020) Cancer Res 80:2969-74). Recent publications have also suggested that wild-type Kras inhibition may be a therapeutic option for KRas. WT A feasible treatment strategy for cancers with drug-dependent malignancies (see, for example, Bery et al., (2020) Nat. Commun. 11: 3233).

[0004] The well-known role of KRas in malignancies and the discovery of these frequent mutations in KRas in various tumor types have made KRas a very attractive target for cancer therapy in the pharmaceutical industry. Despite three decades of extensive discovery efforts to develop KRas inhibitors for the treatment of cancer, no KRas inhibitor has been shown to be sufficiently safe and / or effective to obtain regulatory approval (e.g., see McCormick (2015) Clin Cancer Res. 21(8):1797-1801).

[0005] Compounds that inhibit KRas activity remain highly desirable and are under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors (see, for example, Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143 doi:10.1002 / anie201201358) and recent advances in covalent targeting of the KRas G12C allosteric pocket (see, for example, Ostrem et al., (2013) Nature 503:548-551 and Fell et al., (2018) ACS Med. Chem. Lett. 9:1230-1234). Clearly, there remains a continued interest and effort in developing KRas inhibitors, particularly inhibitors of activating KRas mutants.

[0006] Therefore, there is a need to develop new pan-KRas inhibitors that are proven to be sufficiently effective for the treatment of KRas-mediated cancers. Summary of the Invention

[0007] In one aspect of the present invention, compounds that inhibit KRas activity are provided. In certain embodiments, these compounds are represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0008] W is:

[0009] A is aryl or heteroaryl, wherein the aryl or heteroaryl group is optionally substituted by 1-4 R 1 replace;

[0010] B is:

[0011] Y 1 is hydrogen, optionally substituted by 1-4 R 8 substituted L-hydroxy, optionally substituted by 1-4 R 8 Substituted L-alkoxy, halogen, optionally substituted by 1-4 R 9 Substituted L-C3-C6 cycloalkyl, optionally substituted by 1-4 R 8 substituted L-heteroaryl, optionally substituted with 1-4 R 8 Substituted L-aryl, LC(O)-NH2, and substituted by 1-2 oxo (=O) or oxo-containing substituents and optionally further substituted by 1-2 R 8 substituted L-heterocycles;

[0012] Y 2 is hydrogen or C1-C4 alkyl;

[0013] or Y 1 and Y 2 Connection formation:

[0014] wherein X is selected from the group consisting of: a bond, -S-, -O-, -N< bonded to a fused ring, -CH2-, -CH2-N-, -CH2-N-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, -O-CH2-, and -S-CH2-;

[0015] or Y 2 and Z are connected to form V, wherein V is: optionally 1-4 R 8 Replaced Z is hydrogen or 2 connect;

[0016] Each R 1 are independently halogen, cyano, hydroxy, C1-C4 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, -CH2C(=O)N(R 5 )2, -C3-C4 alkynyl (NR 5 )2、-N(R 5 )2, deuterated C2-C4 alkynyl, (C1-C3 alkoxy)haloC1-C3 alkyl- or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with halogen or C1-C3 alkyl;

[0017] Each R 2 are independently hydrogen, hydroxy, halogen, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, -L-OC(O)N(R 5 )2, -CO2R 5 、-CO2N(R 5 )2、=CH2、=CHR 11 or =C(R 11 )2;

[0018] Each R 3 are independently hydrogen, hydroxy, halogen, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, -L-OC(O)N(R 5)2, -CO2R 5 、-CO2N(R 5 )2、=CH2、=CHR 11 or =C(R 11 )2;

[0019] Wherein if V does not exist, at least one of R2 and R3 is =CH2, =CHR 11 or =C(R 11 )2;

[0020] Each R 4 are independently hydrogen, halogen or C1-C3 alkyl;

[0021] Each R 5 are independently hydrogen or C1-C3 alkyl, or two R 5 connected to form a cycloalkyl or heterocyclic ring;

[0022] Each R 6 are independently hydrogen, hydroxy, C1-C4 hydroxyalkyl or heteroaryl,

[0023] Or two R 6 Connected to form a C3-C6 cycloalkyl or heterocyclic ring;

[0024] Each R 7 are independently hydrogen, C1-C3 alkyl, hydroxy, halogen, C1-C3 haloalkyl, -L-NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)N(R 10 )2, -NHC(O)H, -CN, aryl, -(CH2) 1-2 S(O)2N(R 10 )2、-NH-S(O)2N(R 10 )2、-OS(O)2N(R 10 )2、S(O)2R 10 , or heteroaryl or heterocycle optionally substituted independently by 1-2 substituents independently selected from C1-C3 alkyl, -CN and C(O)NH2,

[0025] Two R on the same atom 7 are optionally connected to form a spiro ring selected from C3-C6 cycloalkyl and heterocycle, wherein the spiro ring is optionally substituted with 1-4 substituents independently selected from oxo (=O), halogen, hydroxy, C1-C3 alkyl and -O-(C1-C3 alkyl),

[0026] Two R on adjacent atoms 7are optionally connected to form a bond or a fused ring selected from the group consisting of 8 Substituted C3-C6 cycloalkyl, optionally substituted by 1-4 R 8 substituted heteroaryl, optionally substituted by 1-4 R 8 substituted aryl, and optionally substituted by 1-4 R 8 substituted heterocycle, and

[0027] Two R on non-adjacent atoms 7 Optionally linked to form 1-2 carbon bridges;

[0028] Each R 8 are independently C1-C3 alkyl, hydroxy, halogen, -N(R10)2, -N(R10)C(O)R10, oxo(=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)N(R10)2, heteroaryl, or -CN;

[0029] Each R 9 are independently C1-C3 alkyl, hydroxy, halogen, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2, or -CN;

[0030] Each R 10 are independently hydrogen, halogen, C1-C3 alkyl, or two R 10 connected to form a cycloalkyl or heterocyclic ring optionally substituted with 1-2 C1-C3 alkyl groups;

[0031] Each R 11 are independently halogen;

[0032] each L is independently a bond, -C1-C4 alkyl-, -C1-C4 alkyl-NH-, -NH-, -N(C1-C3 alkyl)-, or cyclopropyl-CH2-;

[0033] Each n is 0-3;

[0034] o is 1-6; and

[0035] p is 1-8.

[0036] In another aspect of the present invention, a pharmaceutical composition is provided, comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0037] In yet another aspect of the invention, a method for inhibiting the activity of a cell containing wild-type KRas or one or more KRas mutations (e.g., KRas mutations G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H) comprises contacting the cell with a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0038] Also provided herein is a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting the cells with an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0039] Also provided is a method for treating cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present invention, or a pharmaceutically acceptable salt thereof.

[0040] Also provided herein is a method of treating a KRas wild-type or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-associated disease or disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0041] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein, for use in therapy.

[0042] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as described herein for use in treating cancer.

[0043] Also provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof for use in inhibiting KRas wild type or various types of KRas mutations, such as KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations.

[0044] Also provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof as described herein for use in treating KRas wild-type-associated diseases or disorders or KRas mutants G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-associated diseases or disorders.

[0045] Also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein in the manufacture of a medicament for treating cancer.

[0046] Also provided herein is the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the activity of a wild-type form of KRas or a mutant form of KRas, including the following mutations: G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H.

[0047] Also provided herein is the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a KRas wild-type-associated disease or disorder or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-associated disease or disorder.

[0048] Also provided herein is a method for treating cancer in a patient in need thereof, comprising: (a) determining that the cancer is associated with KRas wild-type or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations (i.e., KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0049] One potential use of the pan-KRas inhibitors described herein, including pan-KRas inhibitors such as (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (Example 5 herein), is for treating cancers that develop resistance after long-term treatment with KRas G12C inhibitors. Thus, embodiments of the present invention include embodiments in which a patient suffering from cancer is treated with a pan-KRas inhibitor described herein (such as Example 5) after treatment with a G12C inhibitor has become ineffective or less effective due to the emergence of a resistance-conferring mutation.

[0050] Treatment of KRas G12C-mutant cancers with covalent KRas G12C inhibitors, such as adagracilib (MRTX849) or sotogracilib (AMG510), may result in the incorporation of additional mutations that confer resistance to adagracilib. These mutations may confer resistance through multiple mechanisms.

[0051] Mutations that change the mutant cysteine ​​at codon 12 to another amino acid would render current covalent KRasG12C inhibitors ineffective because current inhibitors form a covalent bond with the mutant cysteine ​​amino acid side chain. Similarly, in patients who have a wild-type KRas allele in addition to the KRas G12C mutant allele, a mutation from the wild-type codon 12 glycine to another codon would allow bypass signaling through the new mutant protein in these tumors. The spectrum of codon 12 mutations that may be caused by single nucleotide substitutions in the wild-type gene (glycine codon) includes mutations commonly observed in cancer, such as G12S, G12V, G12R, and G12C. In addition to G12S and G12R, the spectrum of codon 12 mutations that may be caused by single nucleotide base substitutions in cysteine ​​codon 12 includes mutations that are not commonly observed in cancer, G12Y, G12F, and G12W.

[0052] Second-site mutations may also occur at another location in the KRas G12C mutant gene that confer resistance to treatment with KRas G12C inhibitors. These mutations may confer resistance through different mechanisms. RAS proteins are small GTPases that normally cycle between an active GTP-bound state and an inactive GDP-bound state. RAS proteins are loaded with GTP by guanine nucleotide exchange factors (GEFs; e.g., SOS1) activated by upstream receptor tyrosine kinases, triggering subsequent interactions with effector proteins that activate RAS-dependent signaling. RAS proteins hydrolyze GTP to GDP through their intrinsic GTPase activity, which is significantly enhanced by GTPase-activating proteins (GAPs). Mutations at codons 12 and 13 in RAS proteins impair GAP-stimulated GTP hydrolysis, leaving RAS primarily in the GTP-bound active state. Covalent KRas G12C inhibitors currently in clinical development only bind to GDP-bound KRas G12C. Mutations that may or may not occur on the same allele as the G12C mutation (such as codon Q61 mutations) reduce the intrinsic GTPase activity of KRas and may present a mechanism of resistance to treatment with KRas G12C inhibitors by converting KRas to a GTP-loaded state in which it is insensitive to covalent inhibition. Co-mutations (such as R68, H95, and Y96) may occur together with KRas G12C mutations and may reduce the binding affinity of KRas G12C inhibitors to the Switch II binding pocket.

[0053] The pan-KRas inhibitors described herein can exhibit activity against common and uncommon codon 12 mutations or mutations occurring in the KRas protein that reduce the binding of the KRas G12C inhibitor to the KRas protein.

[0054] Also provided herein is a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0055] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof obtained by the method for preparing a compound as described herein. DETAILED DESCRIPTION

[0056] The present invention relates to inhibitors of wild-type KRas and / or various mutant forms of KRas (e.g., KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations). In particular, the present invention relates to compounds that inhibit the activity of wild-type KRas and / or KRas mutants (e.g., G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H), pharmaceutical compositions comprising therapeutically effective amounts of the compounds, and methods of use thereof. definition

[0057] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, and publications mentioned herein are incorporated by reference.

[0058] As used herein, "wild-type KRas" refers to the non-mutated form of the mammalian KRas protein. The assignment of amino acid codons and residue positions of human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "wild-type KRas inhibitors" refer to compounds of the present invention represented by formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of wild-type KRas G12A. As used herein, "wild-type KRas-associated diseases or disorders" refer to diseases or disorders associated with wild-type KRas, mediated by wild-type KRas, or having wild-type KRas. A non-limiting example of a wild-type KRas-associated disease or disorder is a wild-type KRas-associated cancer.

[0059] As used herein, "KRas G12A" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of glycine for alanine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, "KRas G12A inhibitors" refer to compounds of the present invention represented by Formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12A. As used herein, "KRas G12A-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G12A mutation. A non-limiting example of a KRas G12A-associated disease or disorder is a KRas G12A-associated cancer.

[0060] As used herein, "KRas G12C" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of cysteine ​​for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, "KRas G12C inhibitors" refer to compounds of the present invention represented by Formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12C. As used herein, "KRas G12C-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G12C mutation. A non-limiting example of a KRas G12C-associated disease or disorder is a KRas G12CD-associated cancer.

[0061] As used herein, "KRas G12D" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of aspartic acid for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Asp. As used herein, "KRas G12D inhibitors" refer to compounds of the present invention represented by Formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12D. As used herein, "KRas G12D-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G12D mutation. A non-limiting example of a KRas G12D-associated disease or disorder is a KRas G12D-associated cancer.

[0062] As used herein, "KRas G12R" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of arginine for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, "KRas G12R inhibitors" refer to compounds of the present invention represented by formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12R. As used herein, "KRas G12R-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G12R mutation. A non-limiting example of a KRas G12R-associated disease or disorder is a KRas G12R-associated cancer.

[0063] As used herein, "KRas G12S" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of serine for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, "KRas G12S inhibitors" refer to compounds of the present invention represented by formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12S. As used herein, "KRas G12S-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G12S mutation. A non-limiting example of a KRas G12S-associated disease or disorder is a KRas G12S-associated cancer.

[0064] As used herein, "KRas G12V" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of valine for glycine at amino acid position 12. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variantp.Gly12Asp. As used herein, "KRas G12V inhibitors" refer to compounds of the present invention represented by formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12V. As used herein, "KRas G12V-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G12V mutation. A non-limiting example of a KRas G12V-associated disease or disorder is a KRas G12V-associated cancer.

[0065] As used herein, "KRas G13D" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of aspartic acid for glycine at amino acid position 13. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G13D inhibitors" refer to compounds of the present invention represented by Formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G13D. As used herein, "KRas G13D-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G13D mutation. A non-limiting example of a KRas G13D-associated disease or disorder is a KRas G13D-associated cancer.

[0066] As used herein, "KRas Q61H" refers to a mutant form of the mammalian KRas protein that contains an amino acid substitution of histidine for glutamine at amino acid position 61. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116: Variant p.Gly12Asp. As used herein, "KRas Q61H inhibitors" refer to compounds of the present invention represented by Formula (I) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas Q61H. As used herein, "KRas Q61H-related diseases or disorders" refers to diseases or disorders associated with, mediated by, or having KRas Q61H mutations. A non-limiting example of a KRas Q61H-related disease or disorder is a KRas Q61H-related cancer.

[0067] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and / or exhibits at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer with wild-type KRas or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations (e.g., as determined using a regulatory agency-approved (e.g., FDA-approved) test or kit). In some embodiments, the subject has a tumor that is positive for wild-type KRas or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations (e.g., as determined using a regulatory agency-approved test or kit). The subject can be a subject having a tumor that is positive for wild-type KRas or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations (e.g., identified as positive using a regulatory agency-approved (e.g., FDA-approved) test or kit). The subject can be a subject whose tumor has wild-type KRas or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations (e.g., wherein the tumor is identified using a regulatory agency-approved (e.g., FDA-approved) kit or test). In some embodiments, the subject is suspected of having a cancer associated with a wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H gene. In some embodiments, the subject has a clinical record indicating that the subject has a tumor with wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutation (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).

[0068] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether a patient has wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation using a sample from a patient (e.g., a patient suspected of having a wild-type KRas-associated or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H-associated cancer, a patient having one or more symptoms of a wild-type KRas-associated or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H-associated cancer, and / or a patient at increased risk for developing a wild-type KRas-associated or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H-associated cancer). The detection can include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., reverse transcription PCR and quantitative real-time reverse transcription PCR). As is well known in the art, the detection is typically performed, for example, using at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

[0069] The term "regulatory agency" is an agency in a country that is responsible for approving pharmaceuticals for medical use in that country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0070] The term "acyl" refers to -C(O)CH3.

[0071] As used herein, the terms "C1-C6 alkyl," "C1-C4 alkyl," and "C1-C3 alkyl" refer to straight-chain and branched aliphatic groups having 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms, respectively. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0072] The terms "C1-C3 haloalkyl" and "C1-C4 haloalkyl" refer to a C1-C3 alkyl chain or a C1-C4 alkyl chain, respectively, as defined herein, in which one or more hydrogens have been replaced by halogen. Examples include trifluoromethyl, difluoromethyl, and fluoromethyl.

[0073] A "C1-C4 alkylene" group is a C1-C4 alkyl group as defined above that is positioned between and serves to connect two other chemical groups. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0074] The terms "C1-C3 alkoxy" and "C1-C4 alkoxy" refer to -OC1-C3 alkyl and -OC1-C4 alkyl, respectively, wherein the alkyl portion is as defined above.

[0075] As used herein, the term "cycloalkyl" includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbon atoms (e.g., 3 to 8 carbon atoms, and as a further example, 3 to 6 carbon atoms), wherein the cycloalkyl group is optionally further substituted by one or more R as defined herein. 8 or R 9 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term "cycloalkyl" also includes bridged cycloalkyl groups, such as bicyclo[1.1.1]pentyl.

[0076] As used herein, the terms "C1-C3 hydroxyalkyl" and "C1-C4 hydroxyalkyl" refer to -C1-C3 alkylene-OH and -C1-C4 alkylene-OH, respectively.

[0077] As used herein, the term "C2-C4 hydroxyalkynyl" refers to -C2-C4 alkynylene-OH.

[0078] "Aryl" is a C6-C 14 An aromatic moiety, optionally substituted by one or more R 8 or R 9 As an example, aryl is C6-C 10 Aryl. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl. "Aryl" also refers to a bicyclic or tricyclic ring system, wherein one or both rings in the aryl ring system may be saturated or partially saturated, respectively, and wherein if the ring system comprises two saturated rings, the saturated rings may be fused or spirocyclic. Examples of aryl ring systems comprising two saturated rings, wherein the rings are spirocyclic, include the following ring systems:

[0079] "Aryl C1-C6 alkyl" or "aralkyl" comprises an aryl group covalently linked to an alkyl group, either of which may independently be optionally substituted or unsubstituted. Examples of aralkyl groups are (C6-C 10) aryl (C1-C6) alkyl -, including but not limited to benzyl, phenethyl and naphthylmethyl. An example of a substituted aryl C1-C6 alkyl is wherein the alkyl group is substituted with a hydroxyalkyl group.

[0080] A "heterocyclyl" or "heterocyclic" group is a ring structure having 3 to 12 atoms (e.g., 4 to 8 atoms), one or more of which is selected from the group consisting of N, O, and S, wherein the ring N atom can be oxidized to NO, and the ring S atom can be oxidized to SO or SO2, with the remaining ring atoms being carbon. A heterocyclyl group can be a monocyclic, bicyclic, spirocyclic, or bridged ring system. A heterocyclic group is optionally substituted at one or more positions on a ring carbon or ring nitrogen by one or more R 8 or R 9 Substitute (where R 6 As defined for Formula I). ​​The heterocyclic group is also independently optionally substituted by alkyl, aralkyl, alkylcarbonyl on the ring nitrogen atom, or by lower alkyl on sulfur. The example of the heterocyclic group includes but is not limited to epoxy, azetidinyl, aziridine (aziridinyl), tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridyl, thiazolidinyl, dithianyl, trithianyl, dioxolane, oxazolidinyl, oxazolidinone base, decahydroquinolinyl, piperidonyl, 4-piperidonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexane base, azabicycloheptane base, azabicyclooctanyl , azabicyclononyl (e.g., octahydroindolizinyl), azaspiroheptyl, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizine], hexahydro-1H-pyrrolizinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, oxazaspirononyl, oxazaspirooctyl, diazaspirononyl, oxazabicycloheptyl, hexahydropyrrolazinyl 4(1H)-oxide, tetrahydro-2H-thiopyranyl 1-oxide, and tetrahydro-2H-thiopyranyl 1,1-dioxide. Specifically excluded from the scope of this term are compounds having adjacent cyclic O and / or S atoms.

[0081] As used herein, the term "heteroaryl" refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9 or 10 ring atoms; having 6, 10 or 14 pi electrons shared in the ring array; and having, in addition to carbon atoms, one to three heteroatoms per ring, or one to three heteroatoms in at least one ring, selected from the group consisting of N, O and S. Examples of heteroaryl groups include acridinyl, azoctyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolyl, chromanyl, benzopyranyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furyl, furazanyl, imidazolinyl, imidazole yl, 1H-indazolyl, indolene (indolenyl), indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, Oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiazinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridinyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl , tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl. “Heteroaryl” also refers to a bicyclic ring system having, in addition to carbon atoms, one to three heteroatoms per ring selected from the group consisting of N, O and S, wherein one of the ring systems may be saturated or partially saturated.

[0082] As used herein, an "effective amount" of a compound is an amount sufficient to negatively regulate or inhibit the activity of one or more of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H. Such an amount can be administered as a single dose or can be administered according to a regimen to ensure effectiveness.

[0083] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to ameliorate or in some way reduce the symptoms or halt or reverse the progression of a condition or to downregulate or inhibit the activity of one or more of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H. Such an amount can be administered as a single dose or can be administered according to a regimen to ensure effectiveness.

[0084] As used herein, treatment means any manner in which the symptoms or pathology of a condition, disorder, or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.

[0085] As used herein, amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any relief, whether permanent or temporary, ongoing or transient, attributable to or associated with the administration of the composition. Compound

[0086] In certain embodiments of the present invention, a compound having formula (I) is provided: or a pharmaceutically acceptable salt thereof, wherein:

[0087] W is:

[0088] A is aryl or heteroaryl, wherein the aryl or heteroaryl group is optionally substituted by 1-4 R 1 replace;

[0089] B is:

[0090] Y 1 is hydrogen, optionally substituted by 1-4 R 8 substituted L-hydroxy, optionally substituted by 1-4 R 8 Substituted L-alkoxy, halogen, optionally substituted by 1-4 R 9Substituted L-C3-C6 cycloalkyl, optionally substituted by 1-4 R 8 substituted L-heteroaryl, optionally substituted with 1-4 R 8 Substituted L-aryl, LC(O)-NH2, and substituted by 1-2 oxo (=O) or oxo-containing substituents and optionally further substituted by 1-2 R 8 substituted L-heterocycles;

[0091] Y 2 is hydrogen or C1-C4 alkyl;

[0092] or Y 1 and Y 2 Connection formation: wherein X is selected from the group consisting of: a bond, -S-, -O-, -N< bonded to a fused ring, -CH2-, -CH2-N-, -CH2-N-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, -O-CH2-, and -S-CH2-;

[0093] or Y 2 and Z to form V, where V is: Optionally 1-4 R 8 replaced;

[0094] Z is hydrogen or 2 connect;

[0095] Each R 1 are independently halogen, cyano, hydroxy, C1-C4 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, -CH2C(=O)N(R 5 )2, -C3-C4 alkynyl (NR 5 )2、-N(R 5 )2, deuterated C2-C4 alkynyl, (C1-C3 alkoxy)haloC1-C3 alkyl- or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with halogen or C1-C3 alkyl;

[0096] Each R 2 are independently hydrogen, hydroxy, halogen, C1-C3 haloalkyl, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, -C1-C3-N(R 5)2, -O-(C1-C3 alkyl), -(C1-C3 alkyl)-O-(C1-C3 alkyl), -(C1-C3 alkyl)-O-(C1-C3 alkyl)-C3-C4 cycloalkyl, HC(=O)-, -L-OC(O)N(C1-C10 alkyl)2, -CO2R 5 、-CO2N(R 5 )2、=CH2、=CHR 11 or =C(R 11 )2, or two R 2 connected to form a heterocyclic ring or cycloalkyl group optionally substituted with a C1-C3 alkyl group;

[0097] Each R 3 are independently hydrogen, hydroxy, halogen, C1-C3 haloalkyl, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, -C1-C3-N(R 5 )2, -O-(C1-C3 alkyl), -(C1-C3 alkyl)-O-(C1-C3 alkyl), -(C1-C3 alkyl)-O-(C1-C3 alkyl)-C3-C4 cycloalkyl, HC(=O)-, -L-OC(O)N(C1-C10 alkyl)2, -CO2R 5 、-CO2N(R 5 )2、=CH2、=CHR 11 or =C(R 11 )2, or two R 2 connected to form a heterocyclic ring or cycloalkyl group optionally substituted with a C1-C3 alkyl group;

[0098] If V does not exist, then R 2 and R 3 At least one of =CH2, =CHR 11 or =C(R 11 )2;

[0099] Each R 4 are independently hydrogen, halogen or C1-C3 alkyl;

[0100] Each R 5 are independently hydrogen or C1-C3 alkyl, or two R 5 connected to form a cycloalkyl or heterocyclic ring;

[0101] Each R 6 are independently hydrogen, hydroxy, C1-C4 hydroxyalkyl or heteroaryl,

[0102] Or two R 6 Connected to form a C3-C6 cycloalkyl or heterocyclic ring;

[0103] Each R 7are independently hydrogen, C1-C3 alkyl, C2 alkenyl, hydroxy, halogen, C1-C3 haloalkyl, -L-NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo (=O), LO-(C1-C3 alkyl), LO-(C1-C3 alkyl)-OR 5 、-(C1-C3 alkyl)-OH、-C(O)OH、-C(O)O(C1-C3 alkyl), LC(O)N(R 10 )2, -NHC(O)H, -CN, aryl, -(CH2) 1-2 S(O)2N(R 10 )2、-NH-S(O)2N(R 10 )2、-OS(O)2N(R 10 )2、S(O)2R 10 、-P(O)(R 5 )2 or L-heteroaryl or L-heterocycle optionally substituted independently by 1-2 substituents independently selected from C1-C3 alkyl, -CN and C(O)NH2,

[0104] Two R on the same atom 7 are optionally connected to form a spiro ring selected from C3-C6 cycloalkyl and heterocycle, wherein the spiro ring is optionally substituted with 1-4 substituents independently selected from oxo (=O), halogen, hydroxy, C1-C3 alkyl, cyano and -O-(C1-C3 alkyl),

[0105] Two R on adjacent atoms 7 are optionally connected to form a bond or a fused ring selected from the group consisting of 8 Substituted C3-C6 cycloalkyl, optionally substituted by 1-4 R 8 substituted heteroaryl, optionally substituted by 1-4 R 8 substituted aryl, and optionally substituted by 1-4 R 8 substituted heterocycle, and

[0106] Two R on non-adjacent atoms 7 Optionally linked to form 1-2 carbon bridges;

[0107] Each R 8 are independently C1-C3 alkyl, hydroxy, halogen, -N(R 10 )2、-N(R 10 )C(O)R 10 , oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)N(R 10)2, -C(O)O(C1-C3 alkyl), -C(O)N(R10)2, heteroaryl, heterocycle or -CN;

[0108] Each R 9 are independently C1-C3 alkyl, hydroxy, halogen, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2, or -CN;

[0109] Each R 10 are independently hydrogen, halogen, C1-C3 alkyl, C3-C4 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen and hydroxy, or two R 10 connected to form a cycloalkyl or heterocyclic ring optionally substituted with 1-2 C1-C3 alkyl groups;

[0110] Each R 11 are independently halogen or methyl;

[0111] each L is independently a bond, -O-, -C1-C4 alkyl-, -C1-C4 alkyl-NH-, -NH-, -N(C1-C3 alkyl)-, or cyclopropyl-CH2-;

[0112] Each n is 0-3;

[0113] o is 1-6;

[0114] p is 1-8; and

[0115] q is 1-2.

[0116] In a preferred embodiment, R 11 It's fluorine.

[0117] Embodiments of the present invention also include compounds having formula (IA): or a pharmaceutically acceptable salt thereof, wherein:

[0118] W is:

[0119] A is aryl or heteroaryl, wherein the aryl or heteroaryl group is optionally substituted by 1-4 R 1 replace;

[0120] B is:

[0121] Y 1is hydrogen, optionally substituted by 1-4 R 8 substituted L-hydroxy, optionally substituted by 1-4 R 8 Substituted L-alkoxy, halogen, optionally substituted by 1-4 R 9 Substituted L-C3-C6 cycloalkyl, optionally substituted by 1-4 R 8 substituted L-heteroaryl, optionally substituted with 1-4 R 8 Substituted L-aryl, LC(O)-NH2, and substituted by 1-2 oxo (=O) or oxo-containing substituents and optionally further substituted by 1-2 R 8 substituted L-heterocycles;

[0122] Y 2 is hydrogen or C1-C4 alkyl;

[0123] or Y 1 and Y 2 Connection formation:

[0124] wherein X is selected from the group consisting of: a bond, -S-, -O-, -N< bonded to a fused ring, -CH2-, -CH2-N-, -CH2-N-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, -O-CH2-, and -S-CH2-;

[0125] Each R 1 are independently halogen, cyano, hydroxy, C1-C4 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, -CH2C(=O)N(R 5 )2, -C3-C4 alkynyl (NR 5 )2、-N(R 5 )2, deuterated C2-C4 alkynyl, (C1-C3 alkoxy)haloC1-C3 alkyl- or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with halogen or C1-C3 alkyl;

[0126] Each R 2 are independently hydrogen, hydroxy, halogen, C1-C3 haloalkyl, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, -C1-C3-N(R 5)2, -O-(C1-C3 alkyl), -(C1-C3 alkyl)-O-(C1-C3 alkyl), -(C1-C3 alkyl)-O-(C1-C3 alkyl)-C3-C4 cycloalkyl, HC(=O)-, -L-OC(O)N(C1-C10 alkyl)2, -CO2R 5 、-CO2N(R 5 )2、=CH2、=CHR 11 or =C(R 11 )2, or two R 2 connected to form a heterocyclic ring or cycloalkyl group optionally substituted with a C1-C3 alkyl group;

[0127] Each R 3 are independently hydrogen, hydroxy, halogen, C1-C3 haloalkyl, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, -C1-C3-N(R 5 )2, -O-(C1-C3 alkyl), -(C1-C3 alkyl)-O-(C1-C3 alkyl), -(C1-C3 alkyl)-O-(C1-C3 alkyl)-C3-C4 cycloalkyl, HC(=O)-, -L-OC(O)N(C1-C10 alkyl)2, -CO2R 5 、-CO2N(R 5 )2、=CH2、=CHR 11 or =C(R 11 )2, or two R 2 connected to form a heterocyclic ring or cycloalkyl group optionally substituted with a C1-C3 alkyl group;

[0128] Each R 4 are independently hydrogen, halogen or C1-C3 alkyl;

[0129] Each R 5 are independently hydrogen or C1-C3 alkyl, or two R 5 connected to form a cycloalkyl or heterocyclic ring;

[0130] Each R 6 are independently hydrogen, hydroxy, C1-C4 hydroxyalkyl or heteroaryl,

[0131] Or two R 6 Connected to form a C3-C6 cycloalkyl or heterocyclic ring;

[0132] Each R 7 are independently hydrogen, C1-C3 alkyl, C2 alkenyl, hydroxy, halogen, C1-C3 haloalkyl, -L-NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo (=O), LO-(C1-C3 alkyl), LO-(C1-C3 alkyl)-OR5 、-(C1-C3 alkyl)-OH、-C(O)OH、-C(O)O(C1-C3 alkyl), LC(O)N(R 10 )2, -NHC(O)H, -CN, aryl, -(CH2) 1-2 S(O)2N(R 10 )2、-NH-S(O)2N(R 10 )2、-OS(O)2N(R 10 )2、S(O)2R 10 、-P(O)(R 5 )2 or L-heteroaryl or L-heterocycle optionally substituted independently by 1-2 substituents independently selected from C1-C3 alkyl, -CN and C(O)NH2,

[0133] Two R on the same atom 7 are optionally connected to form a spiro ring selected from C3-C6 cycloalkyl and heterocycle, wherein the spiro ring is optionally substituted with 1-4 substituents independently selected from oxo (=O), halogen, hydroxy, C1-C3 alkyl, cyano and -O-(C1-C3 alkyl),

[0134] Two R on adjacent atoms 7 are optionally connected to form a bond or a fused ring selected from the group consisting of 8 Substituted C3-C6 cycloalkyl, optionally substituted by 1-4 R 8 substituted heteroaryl, optionally substituted by 1-4 R 8 substituted aryl, and optionally substituted by 1-4 R 8 substituted heterocycle, and

[0135] Two R on non-adjacent atoms 7 Optionally linked to form 1-2 carbon bridges;

[0136] Each R 8 are independently C1-C3 alkyl, hydroxy, halogen, -N(R 10 )2、-N(R 10 )C(O)R 10 , oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)N(R 10 )2, -C(O)O(C1-C3 alkyl), -C(O)N(R10)2, heteroaryl, heterocycle or -CN;

[0137] Each R 9are independently C1-C3 alkyl, hydroxy, halogen, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2, or -CN;

[0138] Each R 10 are independently hydrogen, halogen, C1-C3 alkyl, C3-C4 cycloalkyl optionally substituted with 1-2 substituents independently selected from halogen and hydroxy, or two R 10 connected to form a cycloalkyl or heterocyclic ring optionally substituted with 1-2 C1-C3 alkyl groups;

[0139] Each R 11 are independently halogen or methyl;

[0140] each L is independently a bond, -O-, -C1-C4 alkyl-, -C1-C4 alkyl-NH-, -NH-, -N(C1-C3 alkyl)-, or cyclopropyl-CH2-;

[0141] Each n is 0-3;

[0142] o is 1-6;

[0143] p is 1-8; and

[0144] q is 1-2.

[0145] Embodiments also include compounds or salts wherein each R 1 Independently selected from halogen, hydroxy, C1-C3 alkoxy and C1-C4 alkyl.

[0146] Embodiments also include compounds or salts wherein each R 2 , if present, is selected from hydrogen and halogen, and wherein each R 3 , if present, is selected from hydrogen and halogen.

[0147] Embodiments also include compounds or salts wherein each R 7 are independently selected from hydrogen, C1-C4 alkyl, hydroxy, C1-C3 alkoxy, and wherein two R 7 Optionally linked to form 1-2 carbon bridges.

[0148] Embodiments also include compounds or salts wherein each R 6 are independently hydrogen or hydroxy.

[0149] Embodiments also include compounds or salts wherein B is:

[0150] Embodiments also include compounds or salts wherein Y 1 and Y 2 Connection formation:

[0151] Embodiments also include compounds or salts wherein Y 1 and Y 2 Connection formation:

[0152] Embodiments also include compounds or salts wherein Y 1 and Y 2 Connection formation:

[0153] Embodiments also include compounds or salts wherein A is naphthyl.

[0154] Embodiments also include compounds or salts wherein A is indazolyl.

[0155] Embodiments also include compounds or salts wherein A is phenyl.

[0156] Embodiments also include compounds or salts wherein A is pyridinyl.

[0157] In certain embodiments of the present invention, at least one R 1 It is a C1-C4 alkyl group.

[0158] In certain embodiments of the present invention, at least one R 1 is halogen, preferably fluorine or chlorine.

[0159] In certain embodiments of the present invention, at least one R 1 It is a hydroxyl group.

[0160] In certain embodiments of the present invention, at least one R 2 It is a C1-C4 alkyl group.

[0161] In certain embodiments of the present invention, at least one R 2 is halogen, preferably fluorine or chlorine.

[0162] In certain embodiments of the present invention, at least one R 2 It is a hydroxyl group.

[0163] In certain embodiments of the present invention, at least one R 2 =CH2, =CHR 11 or =C(R 11 )2.

[0164] In certain embodiments of the present invention, at least one R 3 It is a C1-C4 alkyl group.

[0165] In certain embodiments of the present invention, at least one R 3 is halogen, preferably fluorine or chlorine.

[0166] In certain embodiments of the present invention, at least one R 3 It is a hydroxyl group.

[0167] In certain embodiments of the present invention, at least one R 3 =CH2, =CHR 11 or =C(R 11 )2.

[0168] In certain embodiments of the present invention, R 4 is halogen, preferably fluorine.

[0169] In certain embodiments of the present invention, at least one R 5 It is a C1-C4 alkyl group.

[0170] In certain embodiments of the present invention, at least one R 5 It's hydrogen.

[0171] In certain embodiments of the present invention, at least one R 6 It is a C1-C4 alkyl group.

[0172] In certain embodiments of the present invention, two R 6 Connected to form a C3-C6 cycloalkyl or heterocyclic ring.

[0173] In certain embodiments of the present invention, at least one R 6 It's hydrogen.

[0174] In certain embodiments of the present invention, two R 6 All are C1-C4 alkyl.

[0175] In certain embodiments of the present invention, two R 6 All are hydrogen.

[0176] In certain embodiments, Y 1 In some of these embodiments, L is a C1-C4 alkyl group. In some of these embodiments, L is NH or N(C1-C3)alkyl.

[0177] In certain embodiments, Y 1is L-heteroaryl, wherein the heteroaryl is thietane dioxide, isothiazolidine dioxide, imidazopyrazine, pyridine or pyrimidine.

[0178] In certain embodiments, Y 1 is L-C3-C6 cycloalkyl, wherein the cycloalkyl is preferably cyclobutane, cyclopentane, cyclohexane or cycloheptane.

[0179] In certain embodiments, Y 1 is an L-heterocycle, wherein the heterocycle is preferably pyrrolidone.

[0180] In certain embodiments of the present invention, Y 2 It's hydrogen.

[0181] In certain embodiments of the present invention, Y 2 is a C1-C4 alkyl group;

[0182] In certain embodiments of the present invention, at least one R 8 It is a C1-C4 alkyl group, preferably a methyl group.

[0183] In certain embodiments of the present invention, at least one R 8 It is hydroxy or C1-C3 alkyl-hydroxy.

[0184] In certain embodiments of the present invention, one or both R 8 It is an oxo group (=O).

[0185] In certain embodiments of the present invention, at least one R 8 is an aryl group or a heteroaryl group.

[0186] In certain embodiments of the present invention, at least one R 8 It is C(O)OH.

[0187] In certain embodiments of the present invention, at least one R 8 It is -C(O)NH2, -C(O)NH(C1-C3 alkyl) or -C(O)N(C1-C3 alkyl)2.

[0188] In certain embodiments of the present invention, R 8 It is -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2.

[0189] In certain embodiments of the present invention, at least one R 9 It is a C1-C4 alkyl group, preferably a methyl group.

[0190] In certain embodiments of the present invention, at least one R 9 It is hydroxy or C1-C3 alkyl-hydroxy.

[0191] In certain embodiments of the present invention, one or both R 9 It is an oxo group (=O).

[0192] In certain embodiments of the present invention, at least one R 9 is an aryl group or a heteroaryl group.

[0193] In certain embodiments of the present invention, at least one R 9 It is C(O)OH.

[0194] In certain embodiments of the present invention, at least one R 9 It is -C(O)NH2, -C(O)NH(C1-C3 alkyl) or -C(O)N(C1-C3 alkyl)2.

[0195] In certain embodiments of the present invention, at least one R 11 It's F.

[0196] In certain embodiments of the present invention, Y 1 and Y 2 The linkage forms a piperidine, azepane, azocane, thiazepine, diazepane, oxazepane, azetidine, pyrrolidine, piperazine bonded to a fused ring via the nitrogen, or thiomorpholine.

[0197] In certain embodiments of the present invention, two R 7 Connected to form a spiro ring selected from C3-C6 cycloalkyl and heterocycle, wherein the spiro ring is optionally substituted with oxo (=O), halogen, hydroxy, C1-C3 alkyl and -O-(C1-C3 alkyl).

[0198] In certain embodiments of the present invention, two R 7 are optionally connected to form a bond or a fused ring selected from the group consisting of 8 Substituted C3-C6 cycloalkyl; optionally substituted by 1-4 R 8 substituted heteroaryl, optionally substituted by 1-4 R 8 substituted aryl, and optionally substituted by 1-4 R 8 Substituted heterocycle.

[0199] In certain embodiments of the present invention, two R 7 Optionally linked to form 1-2 carbon bridges.

[0200] Non-limiting examples of compounds of the present invention include: and pharmaceutically acceptable salts thereof

[0201] Non-limiting examples of compounds having formula (I) are selected from the group consisting of the compounds described in the following examples and pharmaceutically acceptable salts thereof.

[0202] In one embodiment, the compound of formula (I) includes dihydrochloride, trihydrochloride, trifluoroacetate, bis-trifluoroacetate and tris-trifluoroacetate of the above compounds. The compound of formula (I) or a pharmaceutically acceptable salt thereof can be formulated into a pharmaceutical composition. Pharmaceutical composition

[0203] In another aspect, the present invention provides a pharmaceutical composition comprising a wild-type Kras, KrasG12A, KrasG12C, KrasG12D, KrasG12R, KrasG12S, KrasG12V, KrasG13D and / or KrasQ61H inhibitor according to the present invention, and a pharmaceutically acceptable carrier, excipient or diluent. The compounds of the present invention can be formulated by any method well known in the art and can be prepared for administration by any route, including but not limited to parenteral, intraperitoneal, intradermal, intracardial, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular, intravitreal, intravenous, intraarterial, oral, buccal, sublingual, transdermal, topical, intranasal, intratracheal, rectal, subcutaneous and topical administration. In certain embodiments, the compounds of the present invention are administered intravenously in a hospital setting. In one embodiment, administration can be by oral route. In some embodiments, the pharmaceutical compositions provided can be administered to a subject in need of treatment by: systemic injection (e.g., intravenous injection); or injection or administration to a relevant site, such as direct injection by a syringe or direct administration to the site when the site is exposed during surgery; or local administration.

[0204] Parenteral administration may be by bolus injection or continuous infusion.Pharmaceutical compositions for injection may be presented in unit dosage form, eg, in ampoules or in multi-dose containers, with an added preservative.

[0205] The pharmaceutical composition provided can also be formulated into a depot preparation. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, these formulations can be modified with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or modified into a slightly soluble derivative, such as a slightly soluble salt.

[0206] If desired, the pharmaceutical composition can be presented in a vial, package, or medical device, including but not limited to a dispenser device that can accommodate one or more unit dosage forms containing the active ingredient. In one embodiment, the dispenser device can include a syringe with a single dose of liquid formulation ready for injection. The syringe can be accompanied by instructions for administration.

[0207] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with a biological system (such as a cell, cell culture, tissue, or organism) and does not interfere with the effectiveness of the biological activity of the active ingredient. Therefore, in addition to the inhibitor, the composition according to the present invention can also contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable preparations is described in, for example, Remington's Pharmaceutical Sciences, 18th edition, edited by A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0208] As used herein, the term pharmaceutically acceptable salt refers to a salt that retains the desired biological activity of the above-mentioned compound and exhibits minimal or no undesirable toxicological effects. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and salts formed with organic acids (e.g., acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid). Compounds can also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, which specifically include compounds having the formula -NR+Z 2 -a quaternary ammonium salt, wherein R is hydrogen, alkyl or benzyl, and Z 2 is a counterion including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methanesulfonate, sulfonate, phosphate or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, glycolate, benzoate and diphenylacetate).

[0209] The active compound is contained in a pharmaceutically acceptable carrier or diluent in sufficient amounts so that a therapeutically effective amount can be delivered to the patient without causing serious toxic effects to the treated patient. In one embodiment, the dosage of the active compound for all of the above situations is in the range of about 0.01 to 300 mg / kg per day, for example 0.1 to 100 mg / kg, and as a further example, 0.5 to about 25 mg per kilogram of recipient body weight per day. In a suitable carrier, a typical topical dose range is 0.01-3% wt / wt. The effective dose range of the pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound to be delivered. If the derivative itself exhibits activity, the weight of the derivative can be used as described above or by other methods known to those skilled in the art to estimate the effective dose.

[0210] Pharmaceutical compositions comprising the compounds of the invention can be used in the methods of use described herein. How to use

[0211] In yet another aspect, the present invention provides a method for inhibiting the activity of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V and / or KRas Q61H in a cell, the method comprising contacting the cell in which the activity of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V and / or Q61H is desired to be inhibited with an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0212] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or an in vivo system. For example, "contacting" wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRasG13D, and / or KRas Q61H with a compound provided herein includes administering a compound provided herein to an individual or patient (e.g., a human) having a wild-type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRasG13D, and / or KRas Q61H mutation, as well as, for example, introducing a compound provided herein into a sample containing cells or purified preparations containing wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRasG13D, and / or KRas Q61H mutation. G12V, KRas G13D, or KRas Q61H mutations.

[0213] In one embodiment, a cell in which inhibition of the activity of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H is desired is contacted with an effective amount of a compound having Formula (I) or a pharmaceutically acceptable salt thereof to downregulate the activity of wild-type KRas or one or more of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and KRas Q61H.

[0214] By negatively regulating the activity of wild-type KRas or one or more of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and KRas Q61H, the methods described herein are intended to inhibit unwanted cell proliferation caused by enhanced wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H activity in cells. Cells can be contacted with a single dose or multiple doses according to a particular treatment regimen to achieve the desired negative regulation of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H. The ability of a compound to bind to wild-type KRas or one or more of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and KRas Q61H can be monitored in vitro using well-known methods, including those described in Examples A and B below. In addition, the inhibitory activity of exemplary compounds in cells can be monitored, for example, by measuring the amount of phosphorylated ERK, for inhibition of one or more of the activities of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H, for example, using the method described in Example C below.

[0215] In another aspect, provided is a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof.

[0216] The compositions and methods provided herein can be used to treat a wild-type KRas-associated or KRasG12A, KRasG12C, KRasG12D, KRasG12R, KRasG12S, KRasG12V, KRasG13D and / or KRasQ61H-associated cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the wild-type KRas-associated or KRasG12A, KRasG12C, KRasG12D, KRasG12R, KRasG12S, KRasG12V, KRasG13D or KRasQ61H-associated cancer is lung cancer.

[0217] The compositions and methods provided herein can be used to treat a variety of cancers, including tumors such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More particularly, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, the following tumor types: astrocytic carcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer and thyroid cancer, as well as sarcomas. More specifically, these compounds are useful in the treatment of: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, cartilage hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma) , glucagonoma, gastrinoma, carcinoid tumor, vasodilator peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyomas, hemangiomas, lipomas, neurofibromas, fibromas), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia); bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (glandular Cancer: testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); liver: liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder cancer, ampullary cancer, bile duct cancer; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondrocyte tumors (osteocartilaginous exostoses), benign enchondromas, chondroblastomas, chondromyxoid fibromas, osteoid osteomas, and giant cell tumors; nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastomas multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);Gynecology: Uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical atypical hyperplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulosa cell tumor, Sertoli-Leydig cell tumor In some embodiments, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer. In some embodiments, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer. In some embodiments, the cancer is non-small cell lung cancer.

[0218] The concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions comprising such compounds and salts can also be co-administered with other anti-tumor compounds (e.g., chemotherapy), or used in combination with other treatments (e.g., radiation therapy or surgery) as pre- or post-operative adjuvants.

[0219] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein, for use in therapy.

[0220] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as described herein for use in treating cancer.

[0221] Also provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof for inhibiting wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H.

[0222] Also provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as described herein for use in treating wild-type KRas-associated or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H-associated diseases or disorders.

[0223] Also provided herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein in the manufacture of a medicament for treating cancer.

[0224] Also provided herein is the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the activity of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H.

[0225] Also provided herein is the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a wild-type KRas-associated or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H-associated disease or disorder.

[0226] Also provided herein is a method for treating cancer in a patient in need thereof, comprising: (a) determining that the cancer is associated with wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H mutations (e.g., as determined using a regulatory agency-approved (e.g., FDA-approved) assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound having Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0227] Those skilled in the art will recognize that both in vivo and in vitro assays using appropriate, known and generally accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0228] Those skilled in the art will further recognize that human clinical trials, including first-in-human trials, dose-ranging and efficacy trials, in healthy patients and / or patients suffering from a given disorder can be accomplished according to methods well known in the clinical and medical arts. Reaction schemes and examples

[0229] The compounds of the present invention can be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or other reagents and conventional methods well known to those skilled in the art. For example, the compounds of the present invention can be prepared according to the reaction schemes and examples listed below.

[0230] The compounds of the present invention may have one or more chiral centers and may be synthesized as mixtures of stereoisomers, which are isomers having identical structures that differ in the arrangement of their atoms in space. The compounds may be used as a mixture or may be separated using commercially available reagents and conventional methods well known to those skilled in the art (e.g., using a cyclopentadiene acrylate according to the manufacturer's instructions). (Sigma-Aldrich) or (Diacel Corp. chiral chromatography HPLC column) to separate the individual components / isomers. Alternatively, optically pure chiral reagents and intermediates can be used to prepare individual isomers or enantiomers to synthesize the compounds of the present invention. Unless otherwise indicated, all chiralities (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Unless otherwise indicated, whenever the specification (including the claims) refers to a compound of the present invention, the term "compound" is understood to encompass all chiralities (enantiomers and diastereomers) and racemic forms.

[0231] The compounds of the present invention may be in anhydrous, solvated or hydrated form, and all such forms are encompassed within the scope of the present invention.

[0232] The following intermediates are intended to further illustrate certain embodiments of the present invention and are not intended to limit the scope of the invention. Intermediate 1 8-Fluoro-7-(8-fluoronaphthalen-1-yl)-4-(methylthio)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine

[0233] Step A 8-Fluoro-7-(8-fluoronaphthalen-1-yl)-4-(methylthio)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl oxy)pyrido[4,3-d]pyrimidine : To a solution of 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (500 mg, 1.0 equiv) in DCM (8 mL) was added NaSMe (119 mg, 1.8 equiv). The mixture was stirred at 20 ° C for 2 hours. The mixture was filtered, concentrated and purified by column chromatography (SiO , petroleum ether / ethyl acetate 10: 1 to 0: 1) to give the title compound (260 mg, 58% yield) as a white solid; 1H NMR (400MHz, chloroform-d) δ = 9.22 (s, 1H), 8.01 (br d,J=8.0Hz,1H),7.75(d,J=8.0Hz,1H),7.67-7.61(m,1H),7.60-7.56(m,1H),7.46(dt,J=5.2,8.0Hz,1H),7.16-7.08(m,1H),4.40(br s,2H),3.19(br s,2H),2.79(s,3H),2.75-2.64(m,2H),2.18-2.07(m,2H),1.98-1.86(m,4H),1.77-1.66(m,2H). m / z=479.2. Intermediate 2 5-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0234] To a solution of 2,4-dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (4.55 g, 1.0 equiv) in DCM (50 mL) was added DIPEA (3.92 g, 3.0 equiv) and N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (2.0 g, 0.95 equiv). The mixture was stirred at -40 ° C for 0.5 h. The reaction mixture was quenched with H2O (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, concentrated and purified by reverse phase flash chromatography (C18, 0.1% FA condition) to give the title compound (5.00 g, 78% yield) as a white solid. LCMS (ESI, M+1): m / z=622.2. Intermediate 3 ((3S,7aR)-7a-(Hydroxymethyl)hexahydro-1H-pyrrolazin-3-yl)methyl dimethylcarbamate

[0235] Step A (3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy) 1H-pyrrolizine:To a solution of ((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolazin-7a-yl)methanol (2.00 g, 1.0 equiv) and TEA (1.24 g, 2.5 equiv) in DCM (20 mL) was added TrtCl (2.72 g, 2.0 equiv) at 0 °C. The mixture was stirred at 15 °C for 10 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layer was dried over Na2SO4 and concentrated to give a residue. The residue was purified by column chromatography [SiO2, petroleum ether / ethyl acetate 20:1 to 5:1] to give the title compound (3.40 g, crude) as a colorless oil; LCMS (ESI, M+1): m / z=652.5.

[0236] Step B ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolazin-3-yl)methanol: To a solution of (3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolizine (3.40 g, 1.0 equiv) in DMF (20 mL) was added CsF (7.92 g, 10 equiv). The mixture was stirred at 25 ° C for 6 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was dried over Na2SO4 and concentrated to give a residue. The residue was purified by reverse phase flash chromatography [C18, 0.1% formic acid conditions] to give the title compound (980 mg, 45% yield) as a yellow oil; 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.53-7.19 (m, 15H), 3.52-3.24 (m, 2H), 2.96-2.60 (m, 5H), 2.03 (m, 1H), 1.93-1.83 (m, 1H), 1.82-1.49 (m, 6H); LCMS (ESI, M+1): m / z = 414.2.

[0237] Step C ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolazin-3-yl)methyldimethyl Carbamate:To a solution of ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolazin-3-yl)methanol (930 mg, 1.0 eq) in THF (20 mL) was added NaH (360 mg, 60% purity, 4.0 eq) at 0 ° C. The mixture was stirred at 0 ° C for 10 minutes. Dimethylcarbamoyl chloride (484 mg, 2.0 eq) was added to the mixture at 0 ° C. The mixture was stirred at 15 ° C for 20 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over Na2SO4 and concentrated to give a residue. The residue was purified by reverse phase flash chromatography [C18, 0.1% formic acid conditions] to give the title compound (1.00 g, 83% yield) as a yellow oil; LCMS (ESI, M+1): m / z=485.3.

[0238] Step D ((3S,7aR)-7a-(Hydroxymethyl)hexahydro-1H-pyrrolizin-3-yl)methyldimethylcarbamic acid ester: To a solution of ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolazin-3-yl)methyl dimethylcarbamate (620 mg, 1.0 equiv) in DCM (5 mL) was added TFA (1.46 g, 10 equiv) at 0 ° C. The mixture was stirred at 15 ° C for 3 hours. The mixture was concentrated. MeOH (5 mL) and NaHCO (300 mg) were added to the residue. The mixture was filtered and concentrated to give a residue, which was purified by column chromatography [Al O , petroleum ether / ethyl acetate 2: 1 to 0: 1, ethyl acetate / MeOH 12: 1] to give the title compound (220 mg, 71% yield) as a yellow oil; 1 H NMR (400 MHz, methanol-d4) δ = 4.00 (dq, J = 6.0, 10.8 Hz, 2H), 3.31-3.22 (m, 2H), 3.03-2.96 (m, 2H), 2.95-2.86 (m, 6H), 2.80 (td, J = 5.2, 10.8 Hz, 1H), 2.09-1.46 (m, 8H). Intermediate 4 Dimethyl(1,4-oxazepan-6-yl)phosphine oxide

[0239] Step A: tert-Butyl 6-(dimethylphosphoryl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylateA mixture of tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate (350 mg, 1 eq), methylphosphonomethane (86.5 mg, 1.1 eq), Pd(PPh ) (58.2 mg, 0.05 eq), Et N (204 mg, 2 eq) and methylphosphonomethane (86.5 mg, 1.1 eq) in MeCN (10 mL) was degassed and stirred at 90° C. under an N atmosphere for 10 hours. The reaction mixture was concentrated and purified by preparative HPLC (column: Waters Xbridge 150×25 mm×5 μm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 12%-42%, 9 min). 1 H NMR (400 MHz, chloroform-d) δ = 7.51 (d, J = 15.6 Hz, 1H), 4.35 (br d, J = 7.6 Hz, 2H), 3.99-3.84 (m, 4H), 1.59 (s, 3H), 1.55 (s, 3H), 1.52 (s, 9H)

[0240] Step B tert-Butyl 6-(dimethylphosphoryl)-1,4-oxazepane-4-carboxylate : A mixture of tert-butyl 6-(dimethylphosphoryl)-2,3-dihydro-1,4-oxazepine-4(7H)-formate (100 mg, 1.0 equivalent), Pd / C (50 mg, 60% purity, 1.0 equivalent) in MeOH (1.0 mL) was degassed and purged with H 3 times, and then the mixture was stirred under H atmosphere at 25 ° C for 2 hours. The reaction mixture was filtered with MeOH (20 mL) and concentrated under reduced pressure to give the title compound (100 mg) as a white solid.

[0241] Step C Dimethyl(1,4-oxazepan-6-yl)phosphine oxide To a solution of tert-butyl 6-(dimethylphosphoryl)-1,4-oxazepane-4-carboxylate (100 mg, 1.0 eq) in DCM (2.0 mL) was added TFA (411 mg, 10.0 eq). The mixture was stirred at 25 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (50 mg) as a yellow oil. Intermediate 5 Three isomers of 3-azabicyclo[3.2.1]octane-6,7-diol (stereochemistry is arbitrarily assigned)

[0242] Step A Benzyl 6-hydroxy-3-azabicyclo[3.2.1]octane-3-carboxylateTo a mixture of 3-azabicyclo[3.2.1]octan-6-ol (4.50 g, 1.0 equiv) and NaHCO 3 (11.9 g, 4.0 equiv) in EtOAc (54.0 mL) and water (36.0 mL) was added benzyl chloroformate (8.45 g, 1.4 equiv) and TBAB (1.14 g, 0.1 equiv) at 0° C. The reaction was stirred at 20° C. for 12 hours. The mixture was extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (petroleum ether / ethyl acetate 3: 1 to ethyl acetate / methanol 30: 1) to give the title compound (8.30 g, 90% yield) as a colorless oil.

[0243] Step B Benzyl 6-((methylsulfonyl)oxy)-3-azabicyclo[3.2.1]octane-3-carboxylate: To a mixture of benzyl 6-hydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate (7.50 g, 1.0 equiv) in pyridine (70 mL) was added methanesulfonyl chloride (5.84 g, 1.8 equiv) dropwise at 0°C. The reaction was stirred at 20°C for 0.5 h. The mixture was diluted with water (300 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (10 g, 94% yield) as a light yellow solid.

[0244] Step C Benzyl 3-azabicyclo[3.2.1]oct-6-ene-3-carboxylate: To a mixture of benzyl 6-((methylsulfonyl)oxy)-3-azabicyclo[3.2.1]octane-3-carboxylate (9.00 g, 1.0 equiv) in 2,3,5-trimethylpyridine (25 mL) was added DBU (12.1 g, 3.0 equiv). The reaction was stirred at 170 ° C for 3 hours. The mixture was acidified with 1N HCl (15 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with NaHCO 3 (10 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (3.37 g, 51% yield) as a colorless oil; 1 H NMR (400 MHz, chloroform-d) δ = 7.40-7.28 (m, 5H), 6.02-5.91 (m, 2H), 5.12 (d, J = 2.8 Hz, 2H), 3.85-3.70 (m, 2H), 3.09-2.95 (m, 2H), 2.70-2.63 (m, 1H), 2.61-2.54 (m, 1H), 2.10-2.01 (m, 1H), 1.60-1.57 (m, 1H).

[0245] Step D Benzyl 3-oxa-7-azatricyclo[3.3.1.02,4]nonane-7-carboxylate:To a mixture of 3-azabicyclo [3.2.1] oct-6-ene-3-carboxylic acid benzyl ester (3.47 g, 1.0 equivalent) in DCM (70 mL) was added m-CPBA (6.15 g, 2.0 equivalents). The reaction was stirred at 20 ° C for 5 hours. The mixture was quenched by adding saturated Na2SO3 aqueous solution (70 mL), neutralized with solid NaHCO3, and extracted with DCM (2 × 70 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The mixture was purified by silica gel chromatography (petroleum ether / ethyl acetate 20 / 1 to 3 / 1) to give the title compound (2.50 g, 61% yield) as a light yellow solid; 1 H NMR (400 MHz, chloroform-d) δ = 7.43-7.30 (m, 5H), 5.19-5.08 (m, 2H), 4.02-3.88 (m, 2H), 3.40-3.28 (m, 2H), 3.16-3.04 (m, 2H), 2.45-2.31 (m, 2H), 1.64-1.54 (m, 1H), 1.20-1.13 (m, 1H).

[0246] Step E Benzyl 6,7-dihydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate: To a mixture of benzyl 3-oxa-7-azatricyclo[3.3.1.02,4]nonane-7-carboxylate (2.50 g, 1.0 equiv) in THF (35 mL) was added H2SO4 (2M in water, 72.3 mL, 5.0 equiv). The reaction was stirred at 60°C for 12 hours. The mixture was basified with 40% NaOH in an ice bath and extracted with EtOAc (4 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Phenomenex luna C18 250 x 50 mm x 10 μm; A: water (TFA); B: ACN; B%: 14%-44% over 20 min]. The desired fractions were neutralized with solid K2CO3 and extracted with EtOAc (4 x 50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound as a yellow oil (1.1 g, 37% yield); SFC: Chiralpak AD-3 50×4.6 mm ID, 3 μm; gradient elution: 5% to 40% IPA (0.05% DEA) in CO 2 , t R : 1.411min, 1.468min, 1.599min, 1.707min; LCMS (ESI, M+23): m / z=278.0.

[0247] Step F Isomers of benzyl 6,7-dihydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate:Benzyl 6,7-dihydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate (1.1 g) was separated by SFC [Daicel Chiralpak AD 250 mm × 30 mm, 10 μm; mobile phase: (0.1% NH3·H2O IPA); B%: 30%-30%, C8.4; 244 min]. Four peaks were obtained. For peak 2, sufficient purity was not achieved. SFC: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; gradient elution: 5% to 40% IPA (0.05% DEA) in CO2, 3 mL / min, 220 nm, t R : 1.713 min. (Stereochemistry is arbitrarily assigned)

[0248] Benzyl (1R,5S,6R,7R)-6,7-dihydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate (Peak 1, 260 mg, 23% yield) as a colorless oil.

[0249] Benzyl (1R,5S,6S,7S)-6,7-dihydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate (Peak 3, 260 mg, 23% yield) as a colorless oil.

[0250] Benzyl (1R,5S)-6,7-dihydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate (Peak 4, 230 mg, 20% yield) as a colorless oil.

[0251] Step G Isomers of 3-azabicyclo[3.2.1]octane-6,7-diol, intermediate 5 peak 1: To a mixture of (1R, 5S, 6S, 7S) -6,7-dihydroxy-3-azabicyclo [3.2.1] octane-3-carboxylic acid benzyl ester (80.0 mg, 1.0 equiv) in MeOH (1.5 mL) was added Pd / C (30 mg, 10% purity, 1.0 equiv) under a nitrogen atmosphere. The reaction was degassed and purged with hydrogen several times. The reaction was stirred at 20 ° C under hydrogen (15 psi) for 2 hours. The mixture was filtered and concentrated to give intermediate 5 peak 1 (58.0 mg, 94% yield) as a white solid; LCMS (ESI, M + 1): m / z = 144.2.

[0252] Using the same procedure as described in step G, intermediate 5 peak 3 and intermediate 5 peak 4 were obtained. Intermediate 6 6,7,8,9-Tetrahydro-5H-pyrimido[5,4-c]azepine

[0253] Step A (E)-benzyl 3-((dimethylamino)methylene)-4-oxoazepane-1-carboxylate: A mixture of benzyl 4-oxoazepane-1-carboxylate (10 g, 1.0 equiv) in DMF-DMA (50 mL) was stirred at 100° C. for 12 h. The mixture was concentrated to give the title compound (12.0 g, crude) as a brown oil, which was used directly in the next step without further purification.

[0254] Step B Benzyl 8,9-dihydro-5H-pyrimido[5,4-c]azepine-6(7H)-carboxylate: To a solution of formamidine (2.46 g, 1.1 equiv., AcOH) in EtOH (70 mL) was added EtONa (4.39 g, 3.0 equiv.). The reaction was stirred at 20 ° C for 0.5 h. (E)-benzyl 3-((dimethylamino)methylene)-4-oxoazepane-1-carboxylate (6.50 g, 1.0 equiv.) was added to the mixture. The reaction was stirred at 80 ° C for 2 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC (column: Phenomenex Luna C18 200×40 mm×10 μm; mobile phase: [water(FA)-ACN]; B%: 25%-55%, 10 min) to give the title compound (5.60 mg, 91% yield) as a yellow oil; LCMS (ESI, M+1): m / z=284.0.

[0255] Step C 6,7,8,9-Tetrahydro-5H-pyrimido[5,4-c]azepine: To a solution of benzyl 8,9-dihydro-5H-pyrimido[5,4-c]azepine-6(7H)-carboxylate (300 mg, 1.0 equiv) in MeOH (0.5 mL) was added Pd / C (300 mg, 10% purity) under a nitrogen atmosphere. The suspension was degassed and purged with H2 three times. The reaction was stirred under H2 (15 Psi) at 20°C for 0.5 hours. The mixture was filtered and concentrated to give the title compound (150 mg, 94% yield) as a yellow oil, which was used directly in the next step without further purification. Intermediate 7 6,7,8,9-Tetrahydro-5H-[1,2,3]triazino[5,4-c]azepine

[0256] Step A 2-Amino-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(2H)-carboxylic acid tert-butyl ester:To a solution of tert-butyl 4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(2H)-carboxylate (2.00 g, 1.0 equivalent) in DMF (60 mL) was added t-BuONa (4.05 g, 5.0 equivalents) in portions at 0 ° C. The mixture was stirred at 0 ° C for 0.5 hours. Aminodisulfate (2.86 g, 3.0 equivalents) was added to the mixture in portions at 0 ° C. The reaction was stirred at 0 ° C for 2 hours. The mixture was carefully quenched with water (200 mL) at 0 ° C and extracted with ethyl acetate (3 mL × 80). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC (column: Phenomenex luna C18 250×50 mm×10 μm; mobile phase: [water (FA)-ACN]; B%: 14%-44% over 20 min) to give the title compound (250 mg, 12% yield) as a yellow solid; LCMS (ESI, M-55, M+1): m / z=196.8, 252.9.

[0257] Step B 8,9-Dihydro-5H-[1,2,3]triazine[5,4-c]azepine-6(7H)-carboxylic acid tert-butyl ester: To a solution of tert-butyl 2-amino-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(2H)-carboxylate (200 mg, 1.0 equiv) in DCM (3 mL) and H₂O (3 mL) was added NaIO₄ (254 mg, 1.5 equiv). The reaction was stirred at 20°C for 2 hours. The mixture was quenched with saturated aqueous Na₂S₂O₃ (10 mL) at 0°C and extracted with DCM (2 x 5 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography (C18, 0.1% formic acid conditions) to give the title compound (120 mg, 60% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ = 9.15-8.94 (m, 1H), 4.48 (br s, 2H), 3.67 (br s, 2H), 3.31-3.27 (m, 2H), 1.90-1.65 (m, 2H), 1.34-1.22 (m, 9H).

[0258] Step C 6,7,8,9-Tetrahydro-5H-[1,2,3]triazine[5,4-c]azepine: A solution of tert-butyl 8,9-dihydro-5H-[1,2,3]triazino[5,4-c]azepine-6(7H)-carboxylate (60.0 mg, 1.0 equiv) in HCOOH (1 mL) was stirred at 20° C. for 0.5 h. The mixture was concentrated to give the title compound (50 mg, crude) as a yellow oil, which was used directly in the next step; LCMS (ESI, M+1): m / z=151.2. Intermediate 8 4-Methyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

[0259] Step A 1-((Benzyloxy)methyl)-1H-pyrrole-2,5-dione: To a solution of pyrrole-2,5-dione (5.00 g, 1.0 equiv) in THF (100 mL) was added DIPEA (20.0 g, 3.0 equiv) and ((chloromethoxy)methyl)benzene (16.1 g, 2.0 equiv) at 0 ° C. The reaction was stirred at 0 ° C for 2 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over Na2SO4, concentrated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate 1: 0 to 3: 1) to give the title compound (4.00 g, 36% yield) as a white solid; 1 H NMR (400 MHz, chloroform-d) δ = 7.33-7.28 (m, 3H), 7.27-7.19 (m, 2H), 6.66 (s, 2H), 4.98 (s, 2H), 4.54 (s, 2H).

[0260] Step B 5-Benzyl-2-((benzyloxy)methyl)-4-methyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H, 3aH)-dione: To a solution of 1-((benzyloxy)methyl)-1H-pyrrole-2,5-dione (1.00 g, 1.0 equiv) in THF (100 mL) was added N-benzyl-1-(trimethylsilyl)methanamine (1.78 g, 2.0 equiv) and acetaldehyde (1.01 g, 40% purity, 2.0 equiv). The reaction was stirred at 70 ° C for 7 hours. The reaction mixture was concentrated and purified by column chromatography (SiO , petroleum ether / ethyl acetate 1: 0 to 0: 1) to give the title compound (225 mg, 13% yield) as a colorless oil; 1 H NMR (400 MHz, chloroform-d) δ = 7.26-7.09 (m, 10H), 4.93 (s, 2H), 4.53 (s, 2H), 3.69-3.64 (m, 1H), 3.33 (d, J = 13.2 Hz, 1H), 3.13-3.03 (m, 2H), 3.01-2.94 (m, 1H), 2.81-2.71 (m, 1H), 2.66-2.60 (m, 1H), 1.14 (d, J = 6.4 Hz, 3H).

[0261] Step C 4-Methyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione:To a mixture of 5-benzyl-2-((benzyloxy)methyl)-4-methyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (400 mg, 1.0 equiv) in ethanol (8 mL) was added NH3·MeOH (12 M, 4 mL, 44 equiv) and Pd(OH)2 / C (50.0 mg, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The reaction was stirred at 50 ° C. under H2 (50 Psi) for 24 hours. The reaction mixture was filtered under N2. The filtrate was concentrated and purified by preparative HPLC [Phenomenex luna C18 150×25 mm×10 μm; A: water (FA), B: ACN, B%: 1%-25% over 15 min] to give the title compound (159 mg, 94% yield) as a white solid; 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ = 8.20 (br s, 1H), 3.43-3.11 (m, 3H), 3.06-2.61 (m, 3H), 1.15-0.99 (m, 3H). Intermediate 9 (1R,5S)-3,7-Diazabicyclo[3.3.1]nonane-2,4-dione

[0262] Step A (3S,5R)-1-(tert-Butoxycarbonyl)-5-carbamoylpiperidine-3-carboxylic acid A solution of tert-butyl (1R, 5S)-2,4-dioxo-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate (500 mg, 1.96 mmol, 1.00 equiv) in NH3.HO (32.5 g, 260 mmol, 35.7 mL, 28.0% purity, 132 equiv) was stirred at 80°C under N2 atmosphere for 4 hours. The solvent was removed under reduced pressure to give the crude product (3S, 5R)-1-(tert-butoxycarbonyl)-5-carbamoylpiperidine-3-carboxylic acid (450 mg, crude) as a white solid.

[0263] Step B tert-Butyl (1R,5S)-6,8-dioxo-3,7-diazabicyclo[3.3.1]nonane-3-carboxylateTo a solution of (3S, 5R) -1- (tert-butoxycarbonyl) -5-carbamoylpiperidine -3-carboxylic acid (3.30 g, 12.1 mmol, 1.00 equiv) in THF (10.0 mL) was added CDI (7.86 g, 48.5 mmol, 4.00 equiv). The reaction was stirred at 75 ° C under N2 for 12 hours. The mixture was poured into ice water (20 mL), and then 1N HCI was added until the pH was adjusted to 4. The mixture was extracted with DCM (10.0 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was ground with MTBE (3 V) at 25 ° C for 30 min to give product compound 7 (mmol, 14.6% yield) as a white solid. 1 H NMR: (400MHz, DMSO) δ10.9(s,1H),4.12-4.10(m,2H),3.07-3.04(m,2H),2.62(s,2H),3.30-2.27(m,1H),1.87-1.83(m,1H),1.34(s,9H).

[0264] Step C (1R,5S)-3,7-Diazabicyclo[3.3.1]nonane-2,4-dione To a solution of (1R, 5S)-6,8-dioxo-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (250 mg, 983 μmol, 1.00 equiv) in DCM (2.50 mL) was added TFA (673 mg, 5.90 mmol, 437 μL, 6.00 equiv) at 0 ° C. The reaction was stirred at 20 ° C for 5 hours. The mixture was concentrated under vacuum. The crude product was triturated with EtOAc (10.0 ml) at 25 ° C for 40 min to give (140 mg, 889 μmol, 90.4% yield, 98.0% purity) as a white solid. LCMS (ESI, M+1): m / z=155.1 (M+H) + Intermediate 10 (R)-6-(Methoxymethyl)-6-methyl-1,4-oxazepane

[0265] Step A (R)-6-(Hydroxymethyl)-6-methyl-1,4-oxazepane-4-carboxylic acid benzyl ester:A mixture of [(6R)-6-methyl-1,4-oxazepan-6-yl]methanol (300 mg, 1.0 eq), CbzCl (881 mg, 2.5 eq), K2CO3 (857 mg, 3.0 eq) in EtOAc (4 mL) and H2O (4 mL) was stirred at 28°C for 5 hours. The mixture was extracted with EtOAc 15 mL (5 mL × 3), washed with brine, dried over Na2SO4, filtered and purified by column chromatography (SiO2, petroleum ether / ethyl acetate 20:1 to 3:1) and lyophilized to give the title compound (300 mg, 44% yield) as a yellow solid; 1 HNMR (400 MHz, methanol-d4) δ = 7.44-7.26 (m, 5H), 5.16-5.11 (m, 2H), 3.80-3.68 (m, 2H), 3.65-3.57 (m, 2H), 3.56-3.50 (m, 1H), 3.46-3.42 (m, 1H), 3.42-3.36 (m, 2H), 3.36-3.32 (m, 1H), 3.32-3.28 (m, 2H), 0.89-0.83 (m, 3H) LCMS (ESI, M+1): m / z = 280.2.

[0266] Step B (R)-6-(Methoxymethyl)-6-methyl-1,4-oxazepane-4-carboxylic acid benzyl ester: To a solution of (6R)-6-(hydroxymethyl)-6-methyl-1,4-oxazepane-4-carboxylic acid benzyl ester (300 mg, 1.0 eq) in THF (8 mL) was added NaH (85.9 mg, 60% purity, 2.0 eq) at 0 ° C. The mixture was stirred for 0.5 hours, then CH3I (305 mg, 2.0 eq) was added dropwise and the mixture was stirred at 0 ° C for 2 hours. The mixture was quenched with H2O (3 mL) at 0 ° C, filtered and purified by column chromatography (SiO2, petroleum ether / ethyl acetate 10: 1 to 3: 1) to give the title compound (100 mg, 27% yield) as a white solid; 1 H NMR (400 MHz, methanol-d4) δ = 7.44-7.26 (m, 5H), 5.20-5.08 (m, 2H), 3.77-3.69 (m, 3H), 3.63-3.51 (m, 5H), 3.38-3.32 (m, 2H), 3.21-3.16 (m, 2H), 3.16-3.09 (m, 1H), 0.87 (br d, J = 18.0 Hz, 3H) LCMS (ESI, M+1): m / z = 294.1

[0267] Step C (R)-6-(Methoxymethyl)-6-methyl-1,4-oxazepane: A mixture of (6R)-6-(methoxymethyl)-6-methyl-1,4-oxazepane-4-carboxylic acid benzyl ester (50 mg, 1.0 eq), Pd / C (10 mg, 0.1 eq) in MeOH (5 mL) was degassed and purged with H 3 times, and then the mixture was stirred under H atmosphere (15 psi) at 20° C. for 2 hours. The mixture was filtered and concentrated under reduced pressure to give the title compound (20 mg, 74% yield) as a yellow oil; 1 HNMR (400 MHz, chloroform-d) δ=3.70-3.40 (m, 5H), 3.34 (s, 3H), 3.18 (br s, 2H), 3.06-2.35 (m, 4H), 0.95-0.88 (m, 3H) Intermediate 11 3-(Aminomethyl)-3-methyl-1,2,5-thiadiazolidine 1,1-dioxide

[0268] Step A Tert-butyl (2-amino-2-cyanopropyl)carbamate: To a solution of tert-butyl (2-oxopropyl)carbamate (1.00 g, 1.0 equivalent) in MeOH (10 mL) was added Ti (i-PrO) 4 (1.64 g, 1.0 equivalent) and NH 3 · MeOH (7.00 M, 2.0 equivalents). TMSCN (1.15 g, 2.0 equivalents) was added dropwise to the resulting mixture at 0 ° C. The reaction was stirred at 25 ° C for 16 hours. The mixture was diluted with water (50 mL), filtered, and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were dried over Na 2 SO 4, filtered, concentrated, and purified by flash silica gel chromatography (0-100% ethyl acetate / petroleum ether) to give the title compound (800 mg, 69% yield) as a white solid; 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ = 7.16 (br t, J = 5.6 Hz, 1H), 3.10 (br d, J = 6.0 Hz, 2H), 2.56 (s, 2H), 1.39 (s, 9H), 1.28 (s, 3H).

[0269] Step B Tert-butyl (2,3-diamino-2-methylpropyl)carbamate:To a mixture of tert-butyl (2-amino-2-cyanopropyl)carbamate (200 mg, 1.0 equiv) and MeOH (2 mL) and NH3·MeOH (0.5 mL) was added Raney nickel (257 mg, 3.0 equiv). The reaction was degassed and purged with hydrogen 3 times. The reaction was stirred at 25 ° C under a hydrogen (15 psi) atmosphere for 5 hours. The mixture was filtered and concentrated to give the title compound (80.0 mg, crude product) as a yellow oil.

[0270] Step C Tert-butyl ((3-methyl-1,1-dioxo-1,2,5-thiadiazolidin-3-yl)methyl)carbamate: To a solution of tert-butyl (2,3-diamino-2-methylpropyl)carbamate (80.0 mg, 1.0 eq) in pyridine (3 mL) was added dropwise a solution of sulfonamide (37.8 mg, 1.0 eq) in pyridine (3 mL) at 25° C. The reaction was stirred at 115° C. for 20 hours. The mixture was filtered, concentrated, and purified by preparative TLC (dichloromethane / methanol 10:1) to give the title compound (50 mg, 19% yield) as a yellow oil; 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ = 7.06 (br t, J = 7.2 Hz, 1H), 6.92 (br t, J = 5.6 Hz, 1H), 6.76 (s, 1H), 3.22 (br dd, J = 7.6, 11.6 Hz, 1H), 3.15-3.08 (m, 1H), 3.06-2.97 (m, 1H), 2.96-2.88 (m, 1H), 1.38 (s, 9H), 1.16 (s, 3H).

[0271] Step D 3-(Aminomethyl)-3-methyl-1,2,5-thiadiazolidine 1,1-dioxide: To a solution of tert-butyl ((3-methyl-1,1-dioxo-1,2,5-thiadiazolidin-3-yl)methyl)carbamate (40 mg, 1.0 equiv) in dichloromethane (0.5 mL) was added HCl·dioxane (4 M, 1 mL, 1.0 equiv) dropwise at 0° C. The reaction was stirred at 25° C. for 1 hour. The mixture was concentrated to give the title compound (30.0 mg, crude, HCl) as a brown solid. Intermediate 12 (3aR,8aS)-Hexahydropyrrolo[3,4-d]azepine-1,3(2H,3aH)-dione

[0272] Step A (3aR,8aS)-2-(2,4-dimethoxybenzyl)-1,3-dioxooctahydropyrrolo[3,4-d]azepine tert-Butyl 6-(2H)-formateTo a solution of 1-tert-butoxycarbonylazepane-4,5-dicarboxylic acid (500, 1.0 equiv) in MeCN (5 mL) was added di(1H-imidazol-1-yl)methanone (564 mg, 2.0 equiv) at 20 ° C. After addition, the mixture was stirred at 50 ° C for 1 hour, and (2,4-dimethoxyphenyl)methylamine (291 mg, 1.0 equiv) was added at 20 ° C. The resulting mixture was stirred at 90 ° C for 18 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate 10: 1 to 1: 1) to give the title compound (500 mg, 69% yield) as a colorless oil; LCMS (ESI, M-55): m / z=419.2

[0273] Step B tert-Butyl (3aR,8aS)-1,3-dioxooctahydropyrrolo[3,4-d]azepine-6(2H)-carboxylate To a solution of tert-butyl (3aR, 8aS)-2-[(2,4-dimethoxyphenyl)methyl]-1,3-dioxo-3a,4,5,7,8,8a-hexahydropyrrolo[3,4-d]azepine-6-carboxylate (100 mg, 1.0 equiv) in ACN (5 mL) was added CAN (262 mg, 2.0 equiv) in water (0.5 mL) at 0 ° C. The mixture was then stirred at 20 ° C for 0.5 hours. The mixture was diluted with ethyl acetate (20 mL) and washed with brine (10 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate 1: 1) to give the title compound (25 mg, 39% yield) as a colorless oil; 1 H NMR (400 MHz, chloroform-d) δ = 8.07 (br s, 1H), 3.82-3.66 (m, 1H), 3.61-3.48 (m, 1H), 3.47-3.36 (m, 1H), 3.30 (ddd, J = 6.0, 8.0, 14.2 Hz, 1H), 2.76-2.59 (m, 2H), 2.56-2.35 (m, 2H), 1.76-1.62 (m, 2H), 1.50-1.42 (m, 9H).

[0274] Step C (3aR,8aS)-Hexahydropyrrolo[3,4-d]azepine-1,3(2H,3aH)-dioneTo a solution of tert-butyl (3aR,8aS)-1,3-dioxo-3a,4,5,7,8,8a-hexahydropyrrolo[3,4-d]azepine-6-carboxylate (25 mg, 1.0 eq) in DCM (1.5 mL) was added trifluoroacetic acid (770 mg, 72.5 eq). The mixture was stirred at 20 ° C for 0.5 hours. The mixture was concentrated under reduced pressure to give the title compound as a white solid (25 mg, 95% yield, TFA). The crude product was used in the next step without further purification; LCMS (ESI, M+1): m / z=169.2 Intermediate 13A (1S,3aS,6aR)-3-Oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxamide

[0275] Step A (2S)-1-tert-Butyl 2-ethyl 5-oxo-4-(phenylselenoyl)pyrrolidine-1,2-dicarboxylate: To a solution of (S)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-ethyl ester (2.00 g, 1.0 equivalent) in THF (40 mL) was added LiHMDS (1 M, 8.55 mL, 1.1 equivalents) dropwise at -78 ° C. The mixture was stirred at -78 ° C for 1 hour under an N2 atmosphere. A solution of phenylselenium bromide (2.20 g, 1.2 equivalents) in THF (10 mL) was then added dropwise at -78 ° C. The mixture was stirred at -78 ° C for 2 hours under an N2 atmosphere. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (50 mL) at -78 ° C and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse phase MPLC [C18, 0.1% formic acid conditions] to give the title compound (0.80 g, 25% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.64 (dd, J = 1.2, 8.0 Hz, 2H), 7.35-7.25 (m, 3H), 4.22 (dd, J = 5.0, 8.6 Hz, 1H), 4.15 (d, J = 7.2 Hz, 2H), 3.98 (dd, J = 8.0, 8.6 Hz, 1H), 2.38 (dd, J = 7.2, 8.2 Hz, 2H), 1.45-1.43 (m, 9H), 1.22 (t, J = 7.2 Hz, 4H).

[0276] Step B: (S)-1-tert-Butyl 2-ethyl 5-oxo-1H-pyrrole-1,2(2H,5H)-dicarboxylate:To a solution of (2S)-5-oxo-4-(phenylselenoyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-ethyl ester (2.00 g, 1.0 equivalent) in THF (40 mL) was slowly added dropwise H2O2 (1.15 g, 30% purity, 2.1 equivalents). The resulting mixture was stirred at 35 ° C for 2 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse phase MPLC [C18, 0.1% formic acid conditions] to give the title compound (720 mg, 58% yield) as a brown oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.09 (dd, J = 2.4, 6.0 Hz, 1H), 6.24 (dd, J = 2.0, 6.0 Hz, 1H), 5.16 (t, J = 2.2 Hz, 1H), 4.26 (dq, J = 1.2, 7.2 Hz, 2H), 1.53 (s, 9H), 1.31 (t, J = 7.2 Hz, 3H).

[0277] Step C.( 1S,3aS,6aR)-5-Benzyl-3-oxohexahydropyrrolo[3,4-c]pyrrole-1,2(1H)-dicarboxylic acid 2-tert-Butyl 1-ethyl ester : To a solution of (S)-5-oxo-1H-pyrrole-1,2(2H,5H)-dicarboxylic acid 1-tert-butyl 2-ethyl ester (450 mg, 1.0 equivalent) in DCM (3 mL) was added a solution of TFA (80.4 mg, 0.4 equivalent) in DCM (5 mL). N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methylamine (1.26 g, 3.0 equivalents) in DCM (2 mL) was then added dropwise to the mixture at 0 ° C. The resulting mixture was warmed to 25 ° C and stirred at 25 ° C for 3 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by reverse phase MPLC [C18, 0.1% formic acid conditions] to give the title compound (460 mg, 67% yield). 1H NMR (400 MHz, methanol-d4) δ = 7.34-7.23 (m, 5H), 4.37 (d, J = 2.4 Hz, 1H), 4.29-4.19 (m, 2H), 3.69-3.52 (m, 2H), 3.18-3.08 (m, 2H), 2.94 (br d, J = 10.0 Hz, 1H), 2.80-2.71 (m, 1H), 2.60 (dd, J = 7.8, 9.6 Hz, 1H), 2.48-2.38 (m, 1H), 1.48 (s, 9H), 1.29 (t, J = 7.2 Hz, 3H).

[0278] Step D (1S,3aS,6aR)-5-benzyl-3-oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylic acid ethyl ester: To a solution of 2-tert-butyl 1-ethyl (1S,3aS,6aR)-5-benzyl-3-oxohexahydropyrrolo[3,4-c]pyrrole-1,2(1H)-dicarboxylate (300 mg, 1.0 equiv) in EtOAc (2 mL) was added HCl / dioxane (4 M, 10 mL, 51.8 equiv). The mixture was stirred at 25 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (220 mg, 99% yield) as a white solid; LCMS (ESI, M+1): m / z=289.0.

[0279] Step E (1S,3aS,6aR)-5-Benzyl-3-oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylic acid: To a solution of (1S, 3aS, 6aR) -5-benzyl -3- oxooctahydropyrrolo [3,4-c] pyrrole -1- ethyl carboxylate (220 mg, 1.0 equivalent) in MeOH (9 mL) was added an aqueous NaOH solution (1 M, 3.05 mL, 4.0 equivalents). The mixture was stirred at 40 ° C for 1 hour. The reaction mixture was poured into water (10 mL), and the pH of the mixture was then adjusted to 5 with formic acid. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC [C18, 0.1% formic acid conditions] to give the title compound (110 mg, 55% yield) as a white solid. 1H NMR (400 MHz, methanol-d4) δ = 7.45-7.37 (m, 5H), 4.06 (s, 2H), 3.89 (d, J = 2.2 Hz, 1H), 3.07 (s, 6H); LCMS (ESI, M+1): m / z = 261.0.

[0280] Step F (1S,3aS,6aR)-5-Benzyl-3-oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxamide:To a mixture of (1S,3aS,6aR)-5-benzyl-3-oxooctahyropyrrolo[3,4-c]pyrrole-1-carboxylic acid (90.0 mg, 1.0 equiv., FA salt) and NHCl (47.2 mg, 3.0 equiv.) in DMAc (1 mL) was added PYBROP (164 mg, 1.2 equiv.) and TEA (89.2 mg, 3.0 equiv.), and the mixture was stirred at 40° C. under N atmosphere for 12 hours. MeOH (1 mL) was added to the mixture. The mixture was directly purified by preparative HPLC [C18, 0.1% NH.HO conditions] to give the title compound (21.0 mg, 28% yield). 1H NMR (400MHz, chloroform-d) δ=7.53-7.28(m,5H),6.56(br s,1H),6.29(br s,1H),5.75-5.48(m,1H),3.88(s,1H),3.70(br d,J=13.0Hz,1H),3.64-3.48(m,1H),3.22(br d,J=9.2Hz,1H),3.06-2.86(m,3H),2.61-2.38(m,2H).

[0281] Step G.( 1S,3aS,6aR)-3-oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxamide: To a solution of (1S,3aS,6aR)-5-benzyl-3-oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxamide (21.0 mg, 1.0 equiv) in MeOH (0.5 mL) was added Pd / C (10.0 mg, 10% purity) under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 40 ° C under H2 (15 Psi) atmosphere for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (9.79 mg, crude product), which was used directly in the next step. Intermediate 13B tert-Butyl (1R,3aS,6aR)-1-(cyanomethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0282] Step A (S)-5-(((tert-Butyldimethylsilyl)oxy)methyl)pyrrolidin-2-oneTo a mixture of (5S)-5-(hydroxymethyl)pyrrolidin-2-one (10.0 g, 1.0 eq) and imidazole (8.80 g, 1.5 eq) in dichloromethane (100 mL) was added tert-butyldimethylsilyl chloride (15.7 g, 1.2 eq) portionwise at 0-5°C. After the addition was complete, the resulting mixture was warmed to 25-30°C and stirred for 12 hours. The mixture was diluted with water (150 mL) and separated. The aqueous phase was extracted with dichloromethane (2 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash silica gel chromatography [50%-100% ethyl acetate / petroleum ether] to give the title compound (17.5 g, 83% yield) as a colorless liquid; 1H NMR (400 MHz, CDCl3-d4) δ = 5.98 (br s, 1H), 3.81-3.71 (m, 1H), 3.62 (dd, J = 4.0, 10.0 Hz, 1H), 3.44 (dd, J = 7.6, 10.0 Hz, 1H), 2.40-2.30 (m, 2H), 2.22-2.11 (m, 1H), 1.81-1.69 (m, 1H), 0.88 (s, 9H), 0.06 (s, 6H); LCMS (ESI, M+1): m / z = 230.2.

[0283] Step B (S)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-5-oxopyrrolidine-1-carboxylic acid tert- Butyl ester To a solution of (5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-2-one (2.0 g, 1.0 eq) in dichloromethane (20 mL) was added tert-butyl dicarbonate (2.8 g, 1.5 eq), triethylamine (1.7 g, 2.0 eq) and 4-dimethylaminopyridine (106 mg, 0.1 eq). The resulting mixture was stirred at 25 ° C for 12 hours. The mixture was concentrated under vacuum. The residue was purified by flash silica gel chromatography [ 80g The product was purified by silica flash column with a 100 mL / min gradient of 20% ethyl acetate / petroleum ether as eluent to afford the title compound (2.25 g, 78% yield) as a colorless oil; 1H NMR (400 MHz, CDCl3-d4) δ = 4.22-4.13 (m, 1H), 3.92 (dd, J = 4.0, 10.4 Hz, 1H), 3.69 (dd, J = 2.0, 10.4 Hz, 1H), 2.78-2.64 (m, 1H), 2.38 (ddd, J = 2.0, 9.6, 17.6 Hz, 1H), 2.16-1.96 (m, 2H), 1.54 (s, 9H), 0.88 (s, 9H), 0.04 (d, J = 5.2 Hz, 6H).

[0284] Step C (5S)-5-(((tert-Butyldimethylsilyl)oxy)methyl)-2-oxo-3-(phenylselenoyl) tert-Butyl pyrrolidine-1-carboxylate To a solution of (2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 1.0 equiv) in tetrahydrofuran (25 mL) was added lithium hexamethyldisilazide (1 M, 3.3 mL, 1.1 equiv) dropwise at -60°C under nitrogen. The solution was stirred at -60°C for 0.5 hours, and then a solution of phenyl selenohypochlorite (1.0 g, 1.75 equiv) in tetrahydrofuran (5.0 mL) was added at -60°C. The resulting mixture was stirred at -60°C for another hour, and then warmed to 25°C and stirred at 25°C for 12 hours. The mixture was quenched with saturated ammonium chloride (40 mL) at 0-5°C under nitrogen, and warmed to 25°C and stirred for 0.5 hours. The mixture was extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated and purified by flash silica gel chromatography [10%-15% ethyl acetate / petroleum ether] to give the title compound (740 mg, 50% yield) as a yellow oil.

[0285] Step D (S)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-5-oxo-2,5-dihydro-1H-pyrrolidone Tert-Butylpyrrolidine-1-carboxylate To a solution of (5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-oxo-3-phenylselenoyl-pyrrolidine-1-carboxylic acid tert-butyl ester (740 mg, 1.0 equiv) in dichloromethane (10.0 mL) was added pyridine (362 mg, 3.0 equiv) at -70 ° C., followed by the slow addition of hydrogen peroxide (606 mg, 30% purity, 3.5 equiv). The resulting mixture was allowed to warm to 25 ° C. and stirred at 25 ° C. for 12 hours. The mixture was diluted with water (20 mL) and extracted with dichloromethane (2×10 mL). The combined organic layers were washed with saturated sodium sulfite and brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography [10%-15% ethyl acetate / petroleum] to give the title compound (230 mg, 34% yield) as a colorless oil.

[0286] Step E (1S,3aS,6aR)-5-Benzyl-1-(((tert-butyldimethylsilyl)oxy)methyl)-3-oxo Hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl esterTo a solution of tert-butyl (2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-oxo-2H-pyrrole-1-carboxylate (180 mg, 1.0 equiv) and N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methanamine (391 mg, 3.0 equiv) in dichloromethane (5.0 mL) was added TFA (25 mg, 0.4 equiv) at 0°C. After addition, the resulting mixture was stirred at 25°C for 12 hours. Another portion of N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methanamine (391 mg, 3.0 equiv) was added, followed by TFA (25 mg, 0.4 equiv). The resulting mixture was stirred at 25°C for an additional 12 hours. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC [3-Phenomenex Luna C18 75×30 mm×3 μm; A: water (HCl), B: CH 3 CN, B%: 39%-59% over 6 min] and then lyophilized. The title compound was obtained as a yellow solid (102 mg, 37% yield); LCMS (ESI, M+1): m / z=461.4.

[0287] Step F (1S,3aS,6aR)-5-Benzyl-1-(hydroxymethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2-yl (1H)-tert-Butyl formate: A mixture of tert-butyl (1S,3aS,6aR)-5-benzyl-1-(((tert-butyldimethylsilyl)oxy)methyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (10 g, 1.0 eq) and 4-methylbenzenesulfonic acid; hydrate (4.54 g, 1.1 eq) in THF (120 mL) was stirred at 30° C. for 16 hours. The mixture was concentrated and purified by preparative HPLC (column: Kromasil Eternity XT 250*80mm*10um; mobile phase: [water (ammonium hydroxide v / v)-ACN]; B%: 30%-60%, 16 min) to give the title compound (6.2 g, 80% yield) as a white solid; LCMS (ESI, M+1): m / z=347.1.

[0288] Step G (1R,3aS,6aR)-5-Benzyl-1-(cyanomethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2-yl (1H)-tert-Butyl formate:To a solution of (3aS,6S,6aR)-2-benzyl-6-(hydroxymethyl)-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylic acid tert-butyl ester (1.00 g, 1.0 equiv) in THF (10 mL) was added 2-hydroxy-2-methyl-propionitrile (737 mg, 1.0 equiv) and tributylphosphine (2.04 g, 3.5 equiv). ADDP (2.55 g, 3.5 equiv) was then added to the mixture at 0°C. The mixture was stirred at 50°C for 2 hours. The reaction mixture was poured into saturated aqueous NH4Cl solution (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash silica gel chromatography (0-60% ethyl acetate / petroleum ether) and concentrated in vacuo to give the title compound (600 mg, 58% yield) as a yellow solid; 1 H NMR (400 MHz, chloroform-d) δ = 7.32-7.23 (m, 5H), 7.13-7.13 (m, 1H), 4.07 (ddd, J = 2.1, 4.0, 6.1 Hz, 1H), 3.67 (d, J = 13.2 Hz, 1H), 3.50 (d, J = 13.2 Hz, 1H), 3.25-3.18 (m, 2H), 2.90-2.80 (m, 2H), 2.77 (dd, J = 2.0, 9.2 Hz, 1H), 2.64 (br d, J = 8.8 Hz, 1H), 2.61-2.52 (m, 2H), 1.57 (s, 9H)

[0289] Step H (1R,3aS,6aR)-1-(cyanomethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-methyl Tert-butyl ester: To a solution of tert-butyl (1R, 3aS, 6aR)-5-benzyl-1-(cyanomethyl)-3-oxohexahylopyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (70.0 mg, 1.0 equiv) in MeOH (2 mL) was added Pd / C (50.0 mg, 5% purity, wet). The suspension was degassed and purged with H2 three times. The mixture was stirred at 25 ° C under a hydrogen atmosphere (15 Psi) for 16 hours. The reaction mixture was filtered and concentrated to give the title compound (50.0 mg, 96% yield) as a yellow oil;

[0290] Step I (1S,3aS,6aR)-5-Benzyl-1-(hydroxymethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2-yl (1H)-tert-Butyl formateTo a solution of tert-butyl (1S,3aS,6aR)-5-benzyl-1-(((tert-butyldimethylsilyl)oxy)methyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (10.0 g, 1.0 equiv) in THF (120 mL) was added 4-methylbenzenesulfonic acid hydrate (4.54 g, 1.1 equiv). The mixture was stirred at 45 ° C for 5 hours. The mixture was concentrated and purified by preparative HPLC [column: Kromasil Eternity XT 250×80 mm×10 um; mobile phase: water (ammonium hydroxide v / v)-CAN; B%: 30%-60%, 16 min] to give the title compound (6.20 g, 80% yield) as a white solid; 1H NMR (400 MHz, chloroform-d) δ = 7.27 (br s, 5H), 3.96 (br s,1H),3.84(dd,J=3.6,11.2Hz,1H),3.73-3.61(m,2H),3.56-3.48(m,1H),3.18-3.11(m,1H ), 3.07 (dd, J=2.4, 9.6Hz, 1H), 2.65-2.59 (m, 2H), 1.55 (s, 9H); LCMS (ESI, M+1): m / z=347.2. Intermediate 13C 2-((1R,3aS,6aR)-3-oxooctahydropyrrolo[3,4-c]pyrrol-1-yl)acetamide

[0291] Step A (1R,3aS,6aR)-5-Benzyl-1-(cyanomethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2-yl (1H)-tert-Butyl formate: To a solution of (3aS,6S,6aR)-2-benzyl-6-(hydroxymethyl)-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylic acid tert-butyl ester (1.00 g, 1.0 equiv) in THF (10 mL) was added 2-hydroxy-2-methyl-propionitrile (737 mg, 1.0 equiv) and tributylphosphane (2.04 g, 3.5 equiv). ADDP (2.55 g, 3.5 equiv) was then added to the mixture at 0 ° C. The mixture was stirred at 50 ° C for 2 hours. The reaction mixture was poured into saturated aqueous NH4Cl solution (50 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash silica gel chromatography (0-60% ethyl acetate / petroleum ether) and concentrated in vacuo to give the title compound (600 mg, 58% yield) as a yellow solid; 1H NMR (400 MHz, chloroform-d) δ = 7.32-7.23 (m, 5H), 7.13-7.13 (m, 1H), 4.07 (ddd, J = 2.1, 4.0, 6.1 Hz, 1H), 3.67 (d, J = 13.2 Hz, 1H), 3.50 (d, J = 13.2 Hz, 1H), 3.25-3.18 (m, 2H), 2.90-2.80 (m, 2H), 2.77 (dd, J = 2.0, 9.2 Hz, 1H), 2.64 (br d, J = 8.8 Hz, 1H), 2.61-2.52 (m, 2H), 1.57 (s, 9H)

[0292] Step B (1R,3aS,6aR)-1-(2-amino-2-oxoethyl)-5-benzyl-3-oxohexahydropyrrolo[3,4- c] tert-Butyl pyrrole-2(1H)-carboxylate: To a solution of (3aS,6aR)-2-benzyl-6-(cyanomethyl)-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylic acid tert-butyl ester (500 mg, 79.7% purity, 1.0 eq) in EtOH (9 mL) and H2O (1 mL) was added dimethylphosphinate platinum (2+) dimethylphosphinate (479 mg, 1.0 eq). The mixture was stirred at 60 ° C for 2 hours. The reaction mixture was filtered, concentrated and purified by reverse phase flash chromatography (C18, 0.1% ammonium hydroxide) to give the title compound (420 mg, 90% yield) as a white solid; 1 H NMR (400 MHz, methanol-d4) δ = 7.37-7.28 (m, 5H), 4.23 (dd, J = 2.8, 8.0 Hz, 1H), 3.67-3.53 (m, 2H), 3.29-3.23 (m, 1H), 2.95 (br d, J = 9.6 Hz, 1H), 2.82-2.56 (m, 6H), 1.52 (s, 9H)

[0293] Step C 2-((1R,3aS,6aR)-5-Benzyl-3-oxooctahydropyrrolo[3,4-c]pyrrol-1-yl)acetamide: To a solution of (3aS,6aR)-6-(2-amino-2-oxo-ethyl)-2-benzyl-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylic acid tert-butyl ester (100 mg, 90.2% purity, 1.0 eq) in MeOH (1 mL) was added HCl / dioxane (4 M, 3 mL, 49.7 eq). The mixture was stirred at 20 ° C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the title compound (70.0 mg, 93% yield, HCl) as a white solid.

[0294] Step D 2-((1R,3aS,6aR)-3-oxooctahydropyrrolo[3,4-c]pyrrol-1-yl)acetamide:To a solution of 2-((1R,3aS,6aR)-5-benzyl-3-oxooctahy ropyrrolo[3,4-c]pyrrol-1-yl)acetamide (50.0 mg, 1.0 equiv, HCl) in MeOH (2 mL) was added Pd / C (50.0 mg, 5% purity, wet). The suspension was degassed and purged with H2 three times. The mixture was stirred under an H2 atmosphere (15 Psi) at 25 °C for 2 hours. The reaction mixture was filtered and concentrated to give the title compound (40.0 mg, crude, HCl) as a white solid. Intermediate 13D 1-[(3aS,6S,6aR)-4-oxo-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-6-yl]methanesulfonate

[0295] Step A (3aS,6S,6aR)-2-Benzyl-6-(methylsulfonyloxymethyl)-4-oxo-3,3a,6,6a-tetrakis Tert-Butyl Hydrogen-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate: To a solution of (3aS,6S,6aR)-2-benzyl-6-(hydroxymethyl)-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylic acid tert-butyl ester (1.20 g, 1.0 equiv) and Ms2O (1.81 g, 3.0 equiv) in DCM (10 mL) was added TEA (1.75 g, 5.0 equiv) and DMAP (4.23 mg, 0.01 equiv) at 0°C. The mixture was stirred at 25°C for 2 hours. The mixture was diluted with H2O (20 mL) and extracted with DCM (25 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash silica gel chromatography (10%-30% EtOAc / PE) to give the title compound (1.30 g, 79% yield) as a yellow oil; LCMS (ESI, M+1): m / z = 425.2

[0296] Step B (3aS,6S,6aR)-6-(acetylsulfanylmethyl)-2-benzyl-4-oxo-3,3a,6,6a-tetrahydro- tert-Butyl 1H-pyrrolo[3,4-c]pyrrole-5-carboxylate:To a solution of tert-butyl (3aS,6S,6aR)-2-benzyl-6-(methylsulfonyloxymethyl)-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (1.30 g, 1.0 equiv) and TEA (1.55 g, 5.0 equiv) in DMF (10 mL) was added thioacetic acid (699 mg, 3.0 equiv) at 0 ° C. The mixture was stirred at 25 ° C for 2 hours. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (25 mL×2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash silica gel chromatography (10%-30% EtOAc / PE) to give the title compound (1.10 g, 88% yield) as a yellow oil; LCMS (ESI, M+1): m / z = 405.2

[0297] Step C 1-[(1S,3aS,6aR)-5-Benzyl-3-oxo-1,2,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrolidone] [[piperidin-1-yl]methanesulfonamide]]: To a solution of NCS (495 mg, 5.0 eq) in ACN (18 mL) and HCl (2 M, 0.5 mL, 1.5 eq) was added dropwise a solution of (3aS, 6S, 6aR)-6-(acetylsulfanylmethyl)-2-benzyl-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylic acid tert-butyl ester (300 mg, 1.0 eq) in ACN (12 mL) at 0° C. The mixture was stirred at 25° C. for 1 hour. NH3 was then added . HO (18 mL) was added, and the resulting mixture was stirred at 25° C. for 12 hours. The mixture was concentrated. The crude product was purified by preparative HPLC [Phenomenex Synergi Polar-RP 100×25 mm×4 μm; A: water (TFA), B: ACN, B%: 18%-38% over 7 min] and lyophilized to give the title compound as a white solid (100 mg, 32% yield, TFA); LCMS (ESI, M+1): m / z=310.1

[0298] Step D.1- [(3aS,6S,6aR)-4-oxo-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole- 6-methyl]methanesulfonamide:To a solution of 1-[(1S,3aS,6aR)-5-benzyl-3-oxo-1,2,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-1-yl]methanesulfonamide (100 mg, 1.0 equiv, TFA) in MeOH (2 mL) was added Pd / C (50.0 mg, 10% purity, wet). The mixture was stirred at 25 ° C. under an H atmosphere for 2 hours. The mixture was filtered to remove insoluble material. The filtrate was concentrated to give the title compound (70.0 mg, 89% yield, TFA) as a white solid; LCMS (ESI, M+1): m / z=220.1. Intermediate 14 Azepan-3-yldimethylphosphine oxide

[0299] Step A Tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate: To a solution of tert-butyl 3-oxoazepane-1-carboxylate (5 g, 1.0 eq) in THF (15 mL) was slowly added LiHMDS (1.0 M, 28.1 mL, 1.2 eq) at -78 ° C., and the resulting mixture was stirred for 1 hour at -78 ° C. The reaction mixture was concentrated and purified by column chromatography (SiO , petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to give the title compound (6.6 g, 78% yield) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.14-6.79 (m, 1H), 3.70 (br t, J = 5.6 Hz, 2H), 2.65-2.55 (m, 2H), 1.92-1.75 (m, 4H), 1.50 (s, 9H).

[0300] Step B tert-Butyl 6-(dimethylphosphoryl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate: By 6- (((trifluoromethyl) sulfonyl) oxygen base) -2,3,4,7- tetrahydro -1H- azepine -1- carboxylic acid tert-butyl ester (500mg, 1.0 equivalent), methylphosphonomethane (136mg, 1.2 equivalents), TEA (220mg, 302 μ L, 1.5 equivalents) and Pd (PPh3) 4 (50.2mg, 0.03 equivalents) in ACN (5mL) mixture degassed and N2 purged 3 times, and then the mixture was stirred at 90 DEG C under N2 atmosphere for 3 hours.The reaction mixture was filtered.The filtrate was concentrated and purified by preparative HPLC [C18, 0.1% TFA conditions] to give the title compound (180mg, 43.1% yield, 94.8% purity) as a yellow gum. 1H NMR (400MHz, chloroform-d) δ = 7.37 (d, J = 16.0Hz, 1H), 3.80 (br s, 2H), 2.33 (br d, J = 4.0Hz, 2H), 1.88 (br s, 4H), 1.64 (d, J = 12.8Hz, 6H), 1.51 (s, 9H); LCMS (ESI, M+1): m / z = 274.3.

[0301] Step C tert-Butyl 3-(dimethylphosphoryl)azepane-1-carboxylate: To a solution of tert-butyl 6-(dimethylphosphoryl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (180 mg, 1.0 equiv) in MeOH (2 mL) was added Pd / C (10%, 20 mg) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 25 ° C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (160 mg) as a yellow oil. 1 H NMR (400MHz, chloroform-d) δ = 4.02-3.85 (m, 1H), 3.33-3.24 (m, 1H), 3.21-3.06 (m, 1H) ,2.58-2.28(m,4H),2.19-1.89(m,4H),1.64-1.57(m,6H),1.49-1.44(m,9H).

[0302] Step D Azepan-3-yldimethylphosphine oxide: To a solution of tert-butyl 3-(dimethylphosphoryl)azepane-1-carboxylate (160 mg, 1.0 eq) in DCM (1.0 mL) was added HCl / dioxane (4 M, 1 mL, 6.9 eq). The mixture was stirred at 25 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (120 mg, HCl salt) as a yellow oil. Intermediate 15 3-Amino-4-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide Intermediate 15A 5-Amino-4-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide

[0303] Step A 3-Amino-4-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide:To a mixture of 3-amino-1H-pyrazole-4-carbonitrile (10.0 g, 1.0 equivalent), DIPEA (35.9 g, 3.0 equivalent) in THF (200 mL) was added DMAP (2.26 g, 0.2 equivalent) and dimethylcarbamoyl chloride (14.9 g, 1.5 equivalents). The reaction was stirred at 60 ° C for 12 hours. The mixture was quenched with water (100 ml) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (petroleum ether / ethyl acetate 1: 0 to 0: 1) to give intermediate 15 (5.40 g, 32% yield) as a white solid; 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ = 8.62 (s, 1H), 5.99 (s, 2H), 3.07 (br s, 6H); LCMS (ESI, M-1): m / z = 178.1, and Intermediate 15A (4.44 g, 26% yield) as a light pink solid; 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ = 7.76 (s, 1H), 7.19 (s, 2H), 3.02 (s, 6H). Intermediate 16 (4,5,6,7,8,9-Hexahydropyrazolo[1,5-a][1,4]diazoocin-2-yl)(morpholine)methanone

[0304] Step A: 2-(Morpholine-4-carbonyl)-6,7,8,9-tetrahydropyrazolo[1,5-a][1,4]diazocin-5(4H)-carboxylic Tert-butyl ester To a solution of 5-tert-butoxycarbonyl-6,7,8,9-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazoocine-2-carboxylic acid (50.0 mg, 1.00 equiv) in DMF (1.00 mL) was added morpholine (14.8 mg, 1.00 equiv), HATU (193 mg, 3.00 equiv) and DIPEA (219 mg, 10.0 equiv). The mixture was stirred at 20 ° C for 1 hour. Afterwards, the reaction mixture was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 2). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC [SiO 2 , PE / EA=0 / 1] to give the title compound as a brown oil (25.0 mg, 40% yield, 99% purity); 1H NMR (400MHz, CDCl3) δ = 6.57 (s, 1H), 4.69-4.50 (m, 2H), 4.31 (br s, 2H), 4.05 (br d, J = 18.8Hz, 2H), 3.76 (br s, 4H), 3.70 (br s,2H),3.48-3.24(m,2H),1.89(br s,2H),1.69-1.57(m,2H),1.47(s,9H). LCMS(ESI,M+1):m / z=365.2

[0305] Step B: (4,5,6,7,8,9-Hexahydropyrazolo[1,5-a][1,4]diazoocin-2-yl)(morpholine)methanone A solution of tert-butyl 2-(morpholine-4-carbonyl)-6,7,8,9-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazoocine-5-carboxylate (240 mg, 1.00 equiv) in MeCN (5.00 mL) and HCl / dioxane (4 M, 5.00 mL, 30.37 equiv) was stirred at 20 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent and give the title compound (330 mg, crude) as a colorless oil. LCMS (ESI, M+1): m / z=265.1 Intermediate 16A N,N-Dimethyl-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazooctane-2-carboxamide Intermediate 16B N-ethyl-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazooctane-2-carboxamide

[0306] Intermediates 16A and 16B were synthesized following the 2-step procedure described for Intermediate 16. Intermediate 17 2-Chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine

[0307] To a solution of CF3CH2OH (2.57 g, 1.05 equiv) in THF (50 mL) was added t-BuONa (2 M, 12.8 mL, 1.05 equiv). The mixture was stirred at 20 ° C for 1 hour. To the mixture was added dropwise a solution of 2,4-dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (11.0 g, 1.0 equiv) in THF (100 mL) at -40 ° C. The reaction was stirred at -40 ° C for 0.5 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over Na 2 SO 4 and concentrated to give the title compound (12.0 g, 92% yield) as a yellow solid; LCMS (ESI, M+1, M+3): m / z=514.2, 516.2. Intermediate 18 (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aS)-3-(hydroxymethyl)hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0308] Step A (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido [4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol To a solution of 2,4-dichloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidine (10.0 g, 1.0 eq) and (R)-3-methylpiperidin-3-ol (4.04 g, 1.2 eq, HCl) in dichloromethane (200 mL) was added DIPEA (11.5 g, 4.0 eq) and To the mixture was added 4-[4-(4-[4-(4-oxo-1-yl)-1-piperidin-2-yl)-1-nitro-2-nitropropene] ...

[0309] Step B (R)-1-(2-(((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro- 1H-pyrrolizin-7a-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4, 3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: ((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (4.26 g, 1.1 equiv) and To a solution of molecular sieves (150 mg, 1.0 equiv) in toluene (50 mL) was added t-BuONa (2.73 g, 3.0 equiv). The mixture was stirred at 0 ° C for 10 minutes. To the mixture was then added (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (5.0 g, 1.0 equiv), and the mixture was stirred at 0 ° C for 1 hour. The reaction mixture was filtered and washed with EtOAc (100 mL). The filtrate was quenched with water (30 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reverse phase flash chromatography [C18, 0.1% formic acid condition] to give the title compound (6.60 g, 76% yield) as a yellow liquid; LCMS (ESI, M+1): m / z = 902.6.

[0310] Step C (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S, 7aS)-3-(hydroxymethyl)hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin Pyridine-3-ol To a solution of (R)-1-(2-(((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolazin-7a-yl)methoxy)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (6.60 g, 1.0 eq) in DMF (66 mL) was added CsF (16.7 g, 15 eq). The mixture was stirred at 40 °C for 12 h. The reaction mixture was filtered and washed with EtOAc (30 mL). The filtrate was concentrated and purified by reverse phase flash chromatography [C18, 0.1% formic acid conditions] to give the title compound (4.0 g, 80% yield) as a yellow liquid; LCMS (ESI, M+1): m / z=664.4 Intermediate 19 7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine

[0311] Step A 4-Bromo-5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole:To a solution of 4-bromo-5,6-dimethyl-1H-indazole (4.5 g, 1.0 equiv) and TsOH (104 mg, 0.03 equiv) in DCM (100 mL) was added 3,4-dihydro-2H-pyran (2.56 g, 1.5 equiv) dropwise at 0 ° C. The mixture was stirred at 25 ° C for 6 hours. The mixture was diluted with H2O (30 mL) and saturated NaHCO3 aqueous solution (30 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated and purified by column chromatography [SiO2, petroleum ether / ethyl acetate 15: 1 to 4: 1] to give the title compound (5.7 g, 91% yield) as a yellow oil; 1 H NMR (400 MHz, methanol-d4) δ = 7.88 (s, 1H), 7.46 (s, 1H), 5.74 (dd, J = 2.8, 9.6 Hz, 1H), 4.04-3.95 (m, 1H), 3.84-3.76 (m, 1H), 2.48 (s, 3H), 2.44 (s, 3H), 2.16-2.08 (m, 1H), 2.05-1.95 (m, 1H), 1.90-1.72 (m, 2H), 1.64-1.49 (m, 2H).

[0312] Step B 5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxa Borolan-2-yl)-1H-indazole: To a mixture of 4-bromo-5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (5.7 g, 1.0 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (7.49 g, 1.6 equiv) in DMSO (60 mL) was added AcOK (5.43 g, 3.0 equiv) and Pd(dppf)Cl2 (809 mg, 0.06 equiv) under an N2 atmosphere. The mixture was stirred at 110°C for 0.75 hours. The mixture was filtered through a pad of celite. The filter cake was washed with ethyl acetate (200 mL). The mixture was diluted with H2O (200 mL) and extracted with ethyl acetate (4 x 30 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , concentrated and purified by column chromatography [SiO 2 , petroleum ether / ethyl acetate 20:1 to 15:1] to give the title compound as a light yellow oil (3.3 g, 50% yield); 1H NMR (400MHz, methanol-d4) δ = 8.21 (s, 1H), 7.53 (s, 1H), 5.72 (dd, J = 2.4, 10.0Hz, 1H), 4.04-3.95 (m, 1H), 3.80 (dt, J = 2.8, 11.2Hz ,1H),2.54(s,3H),2.52-2.44(m,1H),2.42(s,3H),2.16-2.06(m,1H),2.00-1.92(m,1H),1.87-1.61(m,3H),1.42(s,12H).

[0313] Step C 7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(hexa 1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine To a mixture of 7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1 g, 1.0 eq), 5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.00 g, 1.2 eq) in methoxycyclopentane (15 mL) was added CsCO (1 M in H0, 3.0 eq) and CataCXium A Pd G (173 mg, 0.1 eq) under N2 atmosphere. The mixture was stirred at 80 ° C for 6 hours. The mixture was diluted with H0 (10 mL) and extracted with ethyl acetate (5×10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , concentrated and purified by reverse phase flash chromatography [water (FA, 0.1%) / acetonitrile = 3 / 1 to 2 / 1] to give the title compound (0.66 g, 44% yield) as a light red solid; LCMS (ESI, M+1): m / z = 615.4. Intermediate 20 4-(8-Fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole

[0314] Step A 5-Benzyl-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester:To a mixture of 1-(dimethylsulfamoyl)pyrazole-4-carboxylic acid ethyl ester (150 g, 1.0 equivalent) in THF (1000 mL) was added HMPA (130 g, 1.2 equivalents) and LDA (2 M, 1.2 equivalents) at -65 ° C under a nitrogen atmosphere. After stirring for 0.5 hours at -65 ° C, bromomethylbenzene (124 g, 1.2 equivalents) was added. The reaction was stirred at -65 ° C for 0.5 hours under a nitrogen atmosphere. The mixture was quenched with water (500 mL) and extracted with ethyl acetate (500 mL × 2). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, concentrated and purified by reverse phase flash chromatography [water (FA, 0.1%) / acetonitrile] to give the title compound (130 g, 45% yield) as a yellow solid.

[0315] Step B 5-Benzyl-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylic acid: A mixture of ethyl 5-benzyl-1-(dimethylsulfamoyl)pyrazole-4-carboxylate (110 g, 1.0 equiv) and NaOH (195 g, 15 equiv) in dioxane (600 mL) and H O (600 mL) was stirred at 25° C. for 1 hour. The mixture was extracted with ethyl acetate (2×1000 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (95 g, crude) as a yellow solid. LCMS (ESI, M+1): m / z=310.0.

[0316] Step C 1H-Benzo[f]indazol-4-ol: A mixture of 5-benzyl-1-(dimethylsulfamoyl)pyrazole-4-carboxylic acid (30.0 g, 1.0 equiv) in CF3SO3H (150 mL) was stirred at 90°C for 2 hours. The mixture was poured into ice water (1000 mL) and extracted with ethyl acetate (2 x 1000 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (43.5 g, crude) as a yellow solid. LCMS (ESI, M+1): m / z = 184.9.

[0317] Step D 1-(Tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-ol: To a mixture of 1H-benzo[f]indazole-4-ol (12.0 g, 1.0 equiv) and TsOH HO (123 mg, 0.01 equiv) in THF (120 mL) was added DHP (10.9 g, 2.0 equiv). The reaction was stirred at 20 ° C for 1 hour. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (2×500 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reverse phase flash chromatography [water (FA, 0.1%) / acetonitrile] to give the title compound (16 g, 74% yield) as a yellow solid.

[0318] Step E 1-(Tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate: To 1-tetrahydropyran-2-ylbenzo[f]indazol-4-ol (9.2 g, 1.0 eq), DIEA (17.3 g, 4.0 eq) and To a mixture of molecular sieves (1.00 g) in DCM (100 mL) was added trifluoromethanesulfonic anhydride (19.3 g, 2.0 equivalents). The reaction was stirred at -40 ° C for 0.5 hours. The mixture was quenched with H2O (200 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated and purified by reverse phase HPLC (0.1% FA conditions) to give the title compound (2.8 g, 20% yield) as a black solid;

[0319] Step F 1-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-aminobenzoyl)-1H-benzo[f]indazole: To a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate (2.80 g, 1.0 equiv), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.95 g, 10 equiv) and TEA (2.12 g, 3.0 equiv) in MeCN (30 mL) was added (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (511 mg, 0.10 equiv). The reaction was stirred at 80 °C for 5 hours. The mixture was concentrated, dissolved in water (20 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reverse phase HPLC (0.1% FA conditions) to give the title compound (800 mg, 30% yield) as a brown solid.

[0320] Step G 4-(8-Fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2- (trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazoleTo a solution of 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[f]indazole (200 mg, 1.0 equiv), 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (232 mg, 1.0 equiv), and CsCO (517 mg, 1.5 M, 3.0 equiv) in methoxycyclopentane (2 mL) was added [2-(2-aminophenyl)phenyl]palladium bis(1-adamantyl)butylphosphine methanesulfonate (38.5 mg, 0.10 equiv). The reaction was stirred at 90° C. for 2 hours. The mixture was filtered and purified by reverse phase HPLC (0.1% FA condition) to give the title compound (320 g, 92% yield) as a brown solid; LCMS (ESI, M+1): m / z = 655.3. Intermediate 21 4-(8-Fluoro-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole

[0321] To a solution of 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[f]indazole (250 mg, 1.0 equiv), 7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (278 mg, 1.0 equiv) and CsCO (646 mg, 1.5 M, 3.0 equiv) in methoxycyclopentane (2 mL) was added [2-(2-aminophenyl)phenyl]palladium bis(1-adamantyl)butylphosphine methanesulfonate (48.1 mg, 0.10 equiv). The reaction was stirred at 90° C. for 2 hours. The mixture was filtered and purified by reverse phase HPLC (0.1% FA condition) to give the title compound (120 mg, 28% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 637.3. Intermediate 22 5-Ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole

[0322] Step A 1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester: To a solution of ethyl 1H-pyrazole-4-carboxylate (20.0 g, 1.0 equiv) and DABCO (17.6 g, 1.1 equiv) in MeCN (200 mL) was added N,N-dimethylsulfamoyl chloride (22.5 g, 1.1 equiv). The mixture was stirred at 25 ° C for 1 hour. The mixture was concentrated and purified by column chromatography [SiO 2, petroleum ether / ethyl acetate 8: 1] to give the title compound (29.0 g, 82% yield) as a white solid; 1 HNMR (400MHz, DMSO-d6) δ = 8.66 (s, 1H), 8.22 (s, 1H), 4.28-4.23 (m, 2H), 2.90 (s, 6H), 1.30-1.26 (m, 3H); LCMS (ESI, M+1): m / z = 248.2.

[0323] Step B Ethyl 2-chloro-5-ethylbenzoate: A mixture of ethyl 5-bromo-2-chlorobenzoate (66.0 g, 1.0 equiv), triethylborane (1 M, 501 mL, 2.0 equiv), K2CO3 (69.2 g, 2.0 equiv) and Pd(PPh3)4 (28.9 g, 0.1 equiv) in DMF (600 mL) and THF (600 mL) was degassed and purged with N2 three times. The mixture was stirred at 70 ° C under an N2 atmosphere for 12 hours. The mixture was filtered and diluted with ethyl acetate (3000 mL). The organic layer was washed with brine (5 × 2000 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO2, petroleum ether / ethyl acetate 10: 1] to give the title compound (98.0 g, 92% yield) as a yellow oil; 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.58 (d, J = 2.0 Hz, 1H), 7.30-7.20 (m, 1H), 7.19-7.16 (m, 1H), 4.36 (dd, J = 7.2, 14.4 Hz, 2H), 2.63-2.57 (m, 2H), 1.38-1.34 (m, 3H), 3.00 (s, 6H), 1.21-1.17 (m, 3H).

[0324] Step C (2-Chloro-5-ethylphenyl)methanol:To a solution of ethyl 2-chloro-5-ethylbenzoate (73.0 g, 1.0 equiv) in THF (500 mL) was added DIBAL-H (1 M, 700 mL, 2.0 equiv) at 0 ° C under N2 atmosphere. The solution was stirred at 0 ° C -25 ° C for 12 hours. The mixture was quenched with ice water (1000 mL) and extracted with ethyl acetate (3 × 500 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO2, petroleum ether / ethyl acetate 10: 1] to give the title compound (49.0 g, 82% yield) as a yellow oil; 1 H NMR (400MHz, chloroform-d) δ = 7.32 (d, J = 1.6Hz, 1H), 7.29-7.22 (m, 1H), 7.07 (dd, J = 2.0, 8.0Hz, 1H), 4.74 (br d,J=3.6Hz,2H),2.64(q,J=7.6Hz,2H),1.26-1.21(m,3H)

[0325] Step D 2-(Bromomethyl)-1-chloro-4-ethylbenzene: To a solution of (2-chloro-5-ethylphenyl)methanol (98.0 g, 1.0 eq) in DCM (600 mL) was slowly added PBr 3 (171 g, 1.1 eq) at 0° C. The mixture was stirred at 0° C. for 2 hours. The mixture was added to a saturated NaHCO 3 solution (2 L) at 0° C. and extracted with ethyl acetate (3×500 mL). The organic layer was dried over Na 2 SO 4 , concentrated, and purified by column chromatography [SiO 2 , petroleum ether / ethyl acetate 1:0] to give the title compound (78.0 g, 58% yield) as a colorless oil.

[0326] Step E 5-(2-chloro-5-ethylbenzyl)-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester: To a mixture of ethyl 1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylate (52.9 g, 1.0 equiv) and HMPA (46.0 g, 1.2 equiv) in THF (550 mL) at -60°C was added LDA (2 M, 128 mL, 1.2 equiv). The mixture was stirred at -60°C for 1 hour. 2-(Bromomethyl)-1-chloro-4-ethylbenzene (60.0 g, 1.2 equiv) was added to the mixture at -60°C. The mixture was stirred at -60°C for 1 hour and then warmed to 15°C and stirred for 12 hours. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (2 x 300 mL). The organic layer was washed with brine (100 ml) and dried over Na2SO4. The organic phase was concentrated and purified by column chromatography [SiO 2 , petroleum ether / ethyl acetate 50:1 to 8:1] to give the title compound as a white solid (35.0 g, 38% yield); 1H NMR (400MHz, chloroform-d) δ = 8.12 (s, 1H), 7.34-7.22 (m, 1H), 6.97 (dd, J = 1.2, 8.0Hz, 1H), 6.43 (s, 1H), 4.77 (s, 2H), 4.25 (q, J = 7 .2Hz, 2H), 3.00 (s, 6H), 2.47 (q, J = 7.6Hz, 2H), 1.24 (t, J = 7.2Hz, 3H), 1.09 (t, J = 7.6Hz, 3H); LCMS (ESI, M+1): m / z = 400.1.

[0327] Step F 5-(2-chloro-5-ethylbenzyl)-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylic acid: A mixture of ethyl 5-(2-chloro-5-ethylbenzyl)-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylate (5.00 g, 1.0 equiv) and NaOH (10.0 g, 20 equiv) in dioxane (30 mL) and H O (30 mL) was stirred at 90 ° C for 2 hours. The mixture was diluted with ethyl acetate (100 mL). The organic layer was dried over Na SO and concentrated to give the title compound (6.00 g, crude) as a yellow solid; LCMS (ESI, M+1): m / z = 372.1.

[0328] Step G 8-Chloro-5-ethyl-1H-benzo[f]indazol-4(9H)-one: A mixture of 5-(2-chloro-5-ethylbenzyl)-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylic acid (6.00 g, 1.0 equiv) in CF3SO3H (102 g, 42 equiv) was stirred at 90 ° C for 1.5 hours. The mixture was quenched with ice water (200 mL) and filtered. The filter cake was partitioned between ethyl acetate (100 mL) and saturated NaHCO3 (100 mL). The organic layer was dried over Na2SO4 and concentrated to give the title compound (3.20 g, 74% yield) as a yellow solid; LCMS (ESI, M+1): m / z=247.0.

[0329] Step H 8-Chloro-5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4(9H)-one: To a solution of 8-chloro-5-ethyl-1H-benzo [f] indazole-4 (9H) -one (12.0 g, 1.0 equiv) and TsOH (838 mg, 0.1 equiv) in THF (120 mL) was added DHP (5.32 g, 1.3 equiv) at 0 ° C. The mixture was stirred at 15 ° C for 0.5 hours. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 × 100 mL). The organic layer was dried and concentrated to give a residue. The residue was purified by column chromatography [SiO2, petroleum ether / ethyl acetate 8: 1 to 2: 1] to give the title compound (8.00 g, 42% yield) as a yellow solid.

[0330] Step I 5-Ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-ol: To a suspension of Pd / C (500 mg, 10% purity) and NaHCO (1.02 g, 1.0 equiv) in MeOH (40 mL) was added 8-chloro-5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4(9H)-one (4.00 g, 1.0 equiv) under N. The suspension was degassed under vacuum and purged with H several times. The mixture was stirred at 15 ° C. under H (15 psi) for 20 hours. The mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography [SiO, petroleum ether / ethyl acetate 30: 1 to 4: 1] to give the title compound (2.40 g, 55% yield) as a yellow oil; LCMS (ESI, M+1): m / z=297.2.

[0331] Step J 5-Ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate: To a solution of 5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-ol (2.40 g, 1.0 equiv) and DIPEA (3.14 g, 3.0 equiv) in DCM (30 mL) was added Tf2O (4.57 g, 2.0 equiv) at -40 ° C. The mixture was stirred at -40 ° C for 15 minutes. The mixture was concentrated and purified by column chromatography [SiO2, petroleum ether / ethyl acetate 100: 1 to 20: 1] to give the title compound (1.00 g, 26% yield) as a yellow solid; LCMS (ESI, M+1): m / z=429.1.

[0332] Step K 5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin Cyclopentan-2-yl)-1H-benzo[f]indazole: To a mixture of 5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate (1.00 g, 1.0 equiv), Pd(dppf)Cl2 (171 mg, 0.1 equiv) and TEA (945 mg, 4.0 equiv) in ACN (20 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.19 g, 4.0 equiv) under N2. The mixture was stirred at 80 ° C for 2 hours. The mixture was quenched with MeOH (3 mL) and concentrated to give a residue. The residue was purified by column chromatography [SiO2, petroleum ether / ethyl acetate 80: 1 to 10: 1] to give the title compound (190 mg, 18% yield) as a yellow oil; LCMS (ESI, M+1): m / z=407.2.

[0333] Step L. 5-ethyl-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole: To 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole was added under N2. To a mixture of 5-ethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[f]indazole (110 mg, 1.0 equiv) and CsCO (1.5 M, 3.0 equiv) in methoxycyclopentane (2 mL) was added CataCXium A Pd G (19.7 mg, 0.1 equiv). The mixture was stirred at 90° C. for 2 hours. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (2×10 mL). The organic layer was dried over NaSO and concentrated to give a residue. The residue was purified by reverse phase flash chromatography [C18, 0.1% formic acid condition] to give the title compound (60.0 mg, 28% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 683.4. Intermediate 23 5-(7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0334] Step A 5-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrafluoroethylene Hydrogen-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamideTo a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (0.3 g, 1.0 equiv) and DIPEA (307 mg, 2.0 equiv) in DCM (6 mL) was added dropwise N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (223 mg, 0.9 equiv) and DIPEA (614 mg, 4.0 equiv) in DMF (2 mL) at -40 ° C. The mixture was stirred at -40 ° C for 0.5 h. The mixture was quenched with H2O (30 mL) at -40 ° C. The mixture was extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was dispersed in petroleum ether / ethyl acetate 2:1 (30 mL). The mixture was stirred for 0.5 h. The mixture was filtered and the solid was dried under reduced pressure to give the title compound (0.48 g, 94% yield) as a yellow solid; LCMS (ESI, M+1, M+3, M+5): m / z = 424.1, 426.1, 428.1.

[0335] Step B 5-(7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine- 4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide To a mixture of 5-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (240 mg, 1.0 eq) and (hexahydro-1H-pyrrolizin-7a-yl)methanol (88 mg, 1.1 eq) in dioxane (1 mL) and DMSO (1 mL) was added DIPEA (183 mg, 2.5 eq) and 4A MS (30 mg). The mixture was stirred at 90° C. under N atmosphere for 14 h. The mixture was filtered and purified by reverse phase flash chromatography [water (FA, 0.1%) / acetonitrile 4:1] to give the title compound (60 mg, 19% yield) as a light yellow solid; LCMS (ESI, M+1, M+3): m / z = 529.3, 531.3. Intermediate 24 5-Chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthol

[0336] Step A (5-Chloro-6-fluoro-4-trimethylstannyl-2-naphthyl)oxy-triisopropyl-silane:A mixture of (8-chloro-7-fluoro-3-triisopropylsilyloxy-1-naphthyl) trifluoromethanesulfonate (800 mg, 1.0 equiv), trimethyl(trimethylstannyl)stannane (8.0 g, 15 equiv), Pd(PPh 3 ) 4 (184 mg, 0.1 equiv) and LiCl (203 mg, 3.0 equiv) in toluene (10 mL) was degassed and purged with N 2 three times. The mixture was stirred at 105 ° C. under an N 2 atmosphere for 12 hours. The reaction was filtered and concentrated, purified by preparative HPLC [C18, 0.1% formic acid conditions] and lyophilized to give the title compound (150 mg, 18% yield) as a colorless liquid; 1 H NMR (400 MHz, chloroform-d) δ = 7.62-7.57 (m, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.30-7.25 (m, 2H), 7.19 (d, J = 2.4 Hz, 1H), 1.37-1.27 (m, 5H), 1.15 (d, J = 7.2 Hz, 18H), 0.50-0.36 (m, 9H).

[0337] Step B 5-Chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methyl (2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol A mixture of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 eq), (5-chloro-6-fluoro-4-trimethylstannyl-2-naphthyl)oxy-triisopropyl-silane (423 mg, 1.2 eq), CuI (39.1 mg, 0.3 eq), Pd(dppf)Cl2 (50.0 mg, 0.1 eq) and BINAP (85.2 mg, 0.2 eq) in toluene (4.0 mL) was degassed and purged with N2 three times, and then the mixture was stirred under N2 atmosphere at 20°C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The crude product was purified by preparative HPLC [C18, 0.1% formic acid conditions] to give the title compound (80 mg, 15.5% yield) as a white solid. 1HNMR (400 MHz, chloroform-d) δ = 9.25 (s, 1H), 7.70 (dd, J = 5.4, 9.1 Hz, 1H), 7.37-7.30 (m, 2H), 7.24 (d, J = 2.0 Hz, 1H), 5.41-5.19 (m, 1H), 5.17-4.95 (m, 2H), 4.45-4.25 (m, 2H), 4.13 (q, J = 7.2 Hz, 1H),3.31-3.18(m,2H),3.04-2.96(m,1H),2.32-2.22(m,1H),2.18-2.11(m,1H),2.02-1.9 3(m,2H),1.83-1.51(m,3H),1.36-1.30(m,3H),1.13(d,J=7.2Hz,17H),0.91-0.78(m,2H). Intermediate 25 7-(6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine

[0338] Step A 6-Chloro-4-fluoro-1H-indazole: To a solution of 4-chloro-2,6-difluoro-benzaldehyde (100 g, 1.0 eq) in dioxane (1.0 L) was added N2H4·H2O (58.1 g, 2.0 eq) dropwise at 25°C for 10 minutes. The mixture was stirred at 25°C for 0.5 hours and at 95°C for 15.5 hours. The reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (95.0 g, crude) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ = 14.08-12.38 (m, 1H), 8.23 ​​(d, J = 0.4Hz, 1H), 7.51 (s, 1H), 7.06 (dd, J = 1.2, 9.6Hz, 1H); LCMS (ESI, M+1): m / z = 171.0.

[0339] Step B 6-Chloro-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole:To a solution of 6-chloro-4-fluoro-1H-indazole (40.0 g, 1.0 equivalent) in THF (200 mL) was added portionwise NaH (14.1 g, 60% purity, 1.5 equivalents) at 0 ° C for 30 minutes. The mixture was stirred at 25 ° C for 0.5 hours. SEM-Cl (46.9 g, 1.2 equivalents) was then added dropwise to the mixture at 0 ° C for 20 minutes. The mixture was stirred at 25 ° C for 1 hour. The mixture was quenched by slowly adding H2O (300 mL) at 0 ° C within 30 minutes. The mixture was extracted with EtOAc (2 × 300 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO2, petroleum ether / ethyl acetate 1: 0 to 10: 1] to obtain the title compound (42.0 g, 60% yield) as a yellow solid; 1 H NMR (400MHz, CDCl3-d) δ = 8.09-8.00 (m, 1H), 7.45-7.37 (m, 1H), 6.88 (dd, J = 1.2, 9.6Hz, 1H), 5 .70(s,2H),3.63-3.46(m,2H),0.96-0.84(m,2H),-0.04(s,9H); LCMS(ESI,M+1):m / z=301.3.

[0340] Step C 6-Chloro-4-fluoro-5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole: To a solution of 2-[(6-chloro-4-fluoro-indazol-1-yl)methoxy]ethyl-trimethyl-silane (20.0 g, 1.0 equivalent) in THF (100 mL) was added LDA (43.2 mL, 1.3 equivalents) dropwise for 5 minutes at -65 ° C. The mixture was stirred at -65 ° C for 55 minutes. Then, a solution of I2 (21.9 g, 1.3 equivalents) in THF (50.0 mL) was slowly added to the mixture at 15 minutes and stirred at -65 ° C for 1 hour. The mixture was quenched with H2O (100 mL) at 0 ° C for 15 minutes. The mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reverse phase flash chromatography [0.1% formic acid conditions] to give the title compound (12.0 g, 42% yield) as a yellow solid; 1 H NMR (400MHz, CDCl3-d) δ = 8.03 (s, 1H), 7.61 (s, 1H), 5.70 (s, 2H), 3.58-3.50 (m, 2H), 0.93-0.86 (m, 2H), -0.04 (s, 9H). LCMS (ESI, M+1): m / z=427.2.

[0341] Step D 6-Chloro-5-cyclopropyl-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole:To a solution of 2-[(6-chloro-4-fluoro-5-iodo-indazol-1-yl)methoxy]ethyl-trimethyl-silane (8.0 g, 1.0 equiv) and cyclopropylboronic acid (3.22 g, 2.0 equiv) in dioxane (80 mL) was added Pd(dppf)Cl2 (1.37 g, 0.1 equiv) and K3PO4 (1.5 M, 37.5 mL, 3.0 equiv). The mixture was degassed and purged with N2 three times and stirred at 100 ° C under N2 for 12 hours. The mixture was diluted with H2O (80 mL) and extracted with EtOAc (2×60 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO2, petroleum ether / ethyl acetate 1:0 to 10:1] to give the title compound (4.10 g, 58% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3-d) δ = 8.00 (d, J = 0.8Hz, 1H), 7.44 (s, 1H), 5.79-5.55 (m, 2H), 3.62-3.48 (m, 2H), 1.90-1.75(m,1H),1.16-1.02(m,2H),0.96-0.80(m,4H),0.01(s,9H); LCMS(ESI,M+1):m / z=341.1.

[0342] Step E 6-Chloro-5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-ol: To a solution of 2-[(6-chloro-5-cyclopropyl-4-fluoro-indazol-2-yl)methoxy]ethyl-trimethyl-silane (4.10 g, 1.0 equiv) and 2-methylsulfonylethanol (2.20 g, 1.5 equiv) in DMF (50 mL) was added portionwise NaH (2.40 g, 60% purity, 5.0 equiv) at 0 ° C for 15 minutes. The mixture was then stirred at 25 ° C for 0.5 hours and at 40 ° C for 11.5 hours. The mixture was quenched at 0 ° C by slowly adding HO (50 mL) within 15 minutes. The mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reverse phase flash chromatography [0.1% formic acid conditions] to give the title compound (2.0 g, 50% yield) as a yellow oil. 1 H NMR(400MHz, CDCl3-d)δ=8.12-7.98(m,1H),7.20(s,1H),6.54(s,1H),5.80-5.58(m,2H),3.66-3.41(m,2H),1.78 -1.60(m,1H),1.27-1.14(m,2H),0.98-0.83(m,2H),0.80-0.69(m,2H),-0.04(s,9H); LCMS(ESI,M+1):m / z=339.3.

[0343] Step F 6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yltrimethoxysilane Fluoromethane sulfonate: To 6-chloro-5-cyclopropyl-1-(2-trimethylsilylethoxymethyl)indazol-4-ol (0.80 g, 1.0 equiv), To a solution of molecular sieves (100 mg), DIPEA (915 mg, 3.0 equivalents) in DCM (8 mL) was added Tf2O (999 mg, 1.5 equivalents). The mixture was degassed and purged with N2 three times and stirred at -40 ° C for 0.5 hours. The mixture was diluted with H2O (3 mL) and extracted with EtOAc (2 × 5 mL). The combined organic layer was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO2, petroleum ether / ethyl acetate 1: 0 to 10: 1] to give the title compound (740 mg, 62% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3-d) δ = 7.98 (s, 1H), 7.70 (s, 1H), 5.70 (s, 2H), 3.55 (t, J = 8.4Hz, 2H), 1.94-1.82 (m, 1H) ,1.31-1.19(m,2H),0.90(t,J=8.4Hz,2H),0.81-0.70(m,2H),-0.05(s,9H); LCMS(ESI,M+1):m / z=471.1.

[0344] Step G 6-chloro-5-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- ((2-(Trimethylsilyl)ethoxy)methyl)-1H-indazole : To a solution of 6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl trifluoromethanesulfonate (300 mg, 1.0 equiv) and Pin2B2 (243 mg, 1.5 equiv) in ACN (6 mL) was added KOAc (125 mg, 2.0 equiv), P(Cy3)-Pd-G3 (46.8 mg, 0.1 equiv) under N2. The mixture was stirred at 90 ° C for 12 hours. The mixture was filtered, concentrated and purified by reverse phase flash chromatography [C18, 0.1% formic acid conditions] to give the title compound (150 mg, 51% yield) as a yellow liquid; 1H NMR (400 MHz, Methanol-d4) δ = 8.13 (d, J = 0.8 Hz, 1H), 7.65 (d, J = 0.4 Hz, 1H), 5.67 (s, 2H), 3.55-3.50 (m, 2H), 2.19-2.10 (m, 1H), 1.47 (s, 12H), 1.10-1.04 (m, 2H), 0.9-0.86 (m, 2H), 0.62-0.56 (m, 2H), -0.05 (s, 9H); LCMS (ESI, M+1): m / z = 449.2.

[0345] Step H 7-(6-chloro-5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-4- 2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin pyridine To a solution of 7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (150 mg, 1.0 eq) and 6-chloro-5-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (192 mg, 1.2 eq) in toluene (3 mL) was added K PO (1.5 M, 713 μL, 3.0 eq) and APhos-Pd-G (22.6 mg, 0.1 eq). The mixture was stirred at 60° C. under N for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO2, petroleum ether / ethyl acetate 10:1 to 1:0] and reverse phase flash chromatography [C18, 0.1% formic acid conditions] to give the title compound (70.0 mg, 28% yield) as a yellow liquid. Intermediate 26 tert-Butyl 2-bromo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate

[0346] Step A Methyl 3-bromo-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazole-5-carboxylate: To a solution of methyl 3-bromo-1H-pyrazole-5-carboxylate (1.0 g, 1.0 eq) in ACN (10.0 mL) was added CsCO (3.2 g, 2.0 eq) and tert-butyl N-(3-bromopropyl)carbamate (1.4 g, 1.2 eq). The reaction was stirred at 15 ° C for 2 hours. The mixture was filtered and purified by flash silica gel chromatography ( 12g Purify on a silica flash column, eluting with a 0-30% ethyl acetate / petroleum ether gradient at 36 mL / min) to give the title compound (1.3 g, 68.3% yield, 95% purity) as a colorless clear liquid. 1 H NMR (400 MHz, chloroform-d) δ = 6.81 (s, 1H), 4.88 (br s, 1H), 4.67-4.57 (m, 2H), 3.96-3.85 (m, 3H), 3.10 (br d, J = 5.6 Hz, 2H), 2.09-1.98 (m, 3H), 1.45 (s, 10H)

[0347] Step B 1-(3-aminopropyl)-3-bromo-1H-pyrazole-5-carboxylic acid methyl ester: To a solution of methyl 3-bromo-1-(3-((tert-butoxycarbonyl)amino)propyl)-1H-pyrazole-5-carboxylate (1.3 g, 1.0 equiv) in dioxane (5.0 mL) was added HCl·dioxane (4 M, 15 mL, 17.1 equiv). The reaction was stirred at 20° C. for 12 hours. The mixture was concentrated under reduced pressure to give the title compound (1.1 g, HCl) as a white solid.

[0348] Step C 2-Bromo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one: A solution of 1-(3-aminopropyl)-3-bromo-1H-pyrazole-5-carboxylic acid methyl ester hydrochloride (1.1 g, 1.0 equivalent) in saturated NaCO (20 mL) solution was stirred at 20°C for 12 hours. The reaction was diluted with HO (30 mL) and extracted with DCM 100 mL (20 mL x 5). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, concentrated, and triturated with DCM / PE at 20°C for 5 minutes to give the title compound (690 mg, 79.3% yield). 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.00-6.93 (m, 1H), 6.84 (s, 1H), 4.49 (t, J = 6.8 Hz, 2H), 3.43-3.38 (m, 3H), 2.32-2.22 (m, 3H); LCMS (ESI, M+1): m / z = 232.0.

[0349] Step D 2-Bromo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine:A mixture of 2-bromo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one (610 mg, 1.0 eq) in THF (5.0 mL) was degassed and purged with N2 three times. BH3·Me2S (10 M, 3.0 eq) was added at 0°C and the reaction was stirred at 20°C for 30 minutes, then at 60°C for 12 hours. The mixture was concentrated under reduced pressure to give the title compound (650 mg, 97% yield, HCl) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 6.55 (s, 1H), 4.48-4.34 (m, 5H), 3.38 (br dd, J = 6.0, 12.0 Hz, 3H), 2.01 (br d, J = 4.0 Hz, 2H).

[0350] Step E tert-Butyl 2-bromo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of 2-bromo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine (650 mg, 1.0 eq., HCl) in DCM (8 mL) was added TEA (520 mg, 716 μL, 2.0 eq.) and Boc2O (842 mg, 1.5 eq.). The mixture was stirred at 25 °C for 2 hours. The reaction was concentrated and the filtrate was purified by flash silica gel chromatography ( 12g The product was purified by silica flash column eluting with a 30 mL / min gradient of 0-30% ethyl acetate / petroleum ether to afford the title compound (250 mg, 28.9% yield, 94.0% purity) as a white solid. H NMR (400 MHz, CHLOROFORM-d) δ = 6.32-6.12 (m, 1H), 4.48-4.35 (m, 4H), 3.78-3.65 (m, 2H), 1.91 (br d, J = 4.4 Hz, 2H), 1.51-1.40 (m, 9H); LCMS (ESI, M+1): m / z = 318.0. Intermediate 27 5-Bromo-N,N,1-trimethyl-1H-pyrazole-3-carboxamide

[0351] Step A 5-Bromo-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester:To a solution of 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (25.0 g, 1.0 equivalent) in acetonitrile (250 mL) was added POBr (184 g, 4.0 equivalents) in portions at 0 ° C under N2. The reaction was stirred at 80 ° C for 12 hours. The mixture was diluted with ethyl acetate (500 mL) and washed with 5% NaHCO solution (3 × 300 mL) and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to give the title compound (13.0 g, 34% yield) as a yellow solid.

[0352] Step B 5-Bromo-1-methyl-1H-pyrazole-3-carboxylic acid: To a solution of 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (13.0 g, 1.0 equiv) in THF (237 mL) was added NaOH (2M in water, 119 mL, 4.0 equiv) in one portion. The reaction was stirred at 25 ° C for 2 hours. The mixture was quenched with concentrated HCl (150 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (5.00 g, crude) as a white solid; LCMS (ESI, M+1, M+3): m / z=204.9, 206.9.

[0353] Step C 5-Bromo-N,N,1-trimethyl-1H-pyrazole-3-carboxamide: To a mixture of 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid (5.00 g, 1.0 equiv) in THF (50 mL) was added dimethylamine (2 M in THF, 24.4 mL, 2.0 equiv) and DIEA (15.8 g, 5.0 equiv) at 0 ° C. HATU (18.5 g, 2.0 equiv) was added. The reaction was stirred at 25 ° C for 0.5 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (SiO 2, petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give the title compound (4.10 g, 72% yield) as a yellow solid; LCMS (ESI, M + 1, M + 3): m / z = 232.0, 234.0. Intermediate 28 tert-Butyl ((5-(dimethylcarbamoyl)-1H-pyrazol-3-yl)methyl)carbamate

[0354] Step A 3-Cyano-1H-pyrazole-5-carboxylic acid methyl ester:To a solution of methyl prop-2-ynoate (5.00 g, 1.0 eq) and 2-aminoacetonitrile (9.91 g, 1.8 eq, HCl) in CHCl (500 mL) and H O (16 mL) was slowly added NaNO (12.3 g, 3.0 eq) at 25°C. The reaction was stirred at 25°C for 3 hours and warmed to 60°C for 12 hours. The reaction mixture was filtered, concentrated, and purified by flash silica gel chromatography. 80g Silica flash column, 30%-50% EtOAc / PE gradient as eluent] to give the title compound as a yellow solid (5.00 g, 54% yield); 1 H NMR (400 MHz, chloroform-d) δ = 11.59 (br s, 1H), 7.23 (s, 1H), 4.01 (s, 3H).

[0355] Step B Methyl 3-(aminomethyl)-1H-pyrazole-5-carboxylate: To a solution of methyl 3-cyano-1H-pyrazole-5-carboxylate (500 mg, 1.0 equivalent) in MeOH (10 mL) was added HCl (0.5 mL) and Pd / C (50.0 mg, 10% purity, wet). The reaction was stirred at 25 ° C under an H atmosphere for 2 hours. The mixture was filtered and concentrated to give the title compound (513 mg, 99% yield) as a yellow oil.

[0356] Step C 3-[(tert-Butoxycarbonylamino)methyl]-1H-pyrazole-5-carboxylic acid methyl ester: To a solution of methyl 3-(aminomethyl)-1H-pyrazole-5-carboxylate (400 mg, 79.7% purity, 1.0 eq) in DCM (10 mL) was added TEA (424 mg, 3.0 eq) and Boc2O (336 mg, 1.1 eq). The reaction was stirred at 25°C for 1 hour. The mixture was filtered, concentrated, and purified by flash silica gel chromatography [ 20g Silica flash column, elution with a 0-65% PE / EtOAc gradient at 20 mL / min] to give the title compound (300 mg, 83% yield) as a white solid; LCMS (ESI, M+1): m / z = 256.2.

[0357] Step D 3-[(tert-Butoxycarbonylamino)methyl]-1H-pyrazole-5-carboxylic acid:To a solution of methyl 3-[(tert-butoxycarbonylamino)methyl]-1H-pyrazole-5-carboxylate (300 mg, 1.0 equiv) in MeOH (10 mL) was added NaOH (1 M, 3.5 mL, 3.0 equiv) in water. The reaction was stirred at 60 ° C for 2 hours. The mixture was poured into water (20 mL) and the pH was adjusted to 5 with HCl (1 M). The mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (280 mg, 99% yield) as a white solid; 1 H NMR (400MHz, DMSO-d6) δ = 13.32-12.96 (m, 1H), 7.35-7.26 (m, 1H), 6.53 (br s, 1H), 4.11 (br d, J = 5.2Hz, 2H), 1.39 (s, 9H).

[0358] Step E Tert-butyl N-[[5-(dimethylcarbamoyl)-1H-pyrazol-3-yl]methyl]carbamate: To a solution of 3-[(tert-butoxycarbonylamino)methyl]-1H-pyrazole-5-carboxylic acid (260 mg, 1.0 eq.) and N-methylmethylamine (439 mg, 5.0 eq., HCl) in DMAc (10 mL) was added TEA (240 mg, 2.2 eq.) dropwise. (Tripyrrolidin-1-yl)phosphonium bromide hexafluorophosphate (653 mg, 1.3 eq.) was then added to the mixture. The reaction was stirred at 40° C. for 12 hours. The mixture was filtered and analyzed by preparative HPLC [Waters Xbridge 150×25 mm×5 μm; A: water (NH 3 . H2O), B:ACN, B%: 10%-40%, over 10 min] to give the title compound (170 mg, 59% yield) as a yellow gum; 1 H NMR (400 MHz, methanol-d4) δ = 6.56-6.43 (m, 1H), 4.28 (br s, 2H), 3.27 (s, 3H), 3.09 (s, 3H), 1.45 (s, 9H). Intermediate 29 3-Cyano-N,N-dimethyl-1H-pyrazole-5-carboxamide

[0359] Step A 3-Cyano-1H-pyrazole-5-carboxylic acid: To a solution of methyl 3-cyano-1H-pyrazole-5-carboxylate (500 mg, 1.0 equiv) in water (15.0 mL) and tetrahydrofuran (15.0 mL) was added lithium hydroxide (158 mg, 2.0 equiv). The reaction was stirred at 50 ° C for 2 hours. The mixture was quenched with water (20.0 mL) and extracted with ethyl acetate (3 × 20.0 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (400 mg, 88% yield) as a yellow oil; 1 H NMR (400MHz, DMSO-d6) δppm 7.27-7.51 (m, 1H).

[0360] Step B 3-Cyano-N,N-dimethyl-1H-pyrazole-5-carboxamide : To a solution of 3-cyano-N,N-dimethyl-1H-pyrazole-5-carboxamide (500 mg, 1.0 equiv) and N-methylmethylamine (2 M, 2.0 equiv, tetrahydrofuran) in N,N-dimethylformamide (25 mL) was added N,N-diisopropylethylamine (1.41 g, 3.0 equiv) and [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethylammonium hexafluorophosphate (2.08 g, 1.50 equiv). The reaction was stirred at 25 ° C for 1 hour. The mixture was concentrated and purified by preparative HPLC [neutral conditions; column: Waters Xbridge C18 150×50 mm×10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 1%-26%, 10 min] to give the title compound (500 mg, 84% yield) as a yellow solid; 1 HNMR (400 MHz, chloroform-d) δ = 2.82 (s, 3H) 2.91 (s, 3H) 7.95 (s, 1H). Intermediate 30 ((3R,7aS)-3-(((tert-Butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolazin-7a-yl)methanol Intermediate 31 ((3S,7aR)-3-(((tert-Butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolazin-7a-yl)methanol

[0361] Step A cis-3-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazine-7a(5H)- Methyl formate and trans-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid Methyl ester: To a solution of 3-(hydroxymethyl)tetrahydro-1H-pyrrolazine-7a(5H)-formic acid methyl ester (10 g, 1 equivalent) and imidazole (10.2 g, 3 equivalents) in DCM (150 mL) was added TBDPSCl (20.7 g, 1.5 equivalents) and DMAP (613 mg, 0.1 equivalents). The reaction was stirred at 25 ° C for 2 hours. The mixture was washed with H2O (2×50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 50: 1-1: 1) and reverse phase flash chromatography (C18, 0.1% formic acid conditions) to obtain two title compounds: Peak 1 (3.4 g, 12% yield) as a yellow oil; LCMS (ESI, M+1): m / z=438.3. Peak 2 (4 g, 13% yield) as yellow oil; LCMS (ESI, M+1): m / z = 438.3.

[0362] Step B ((3R,7aS)-3-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazine-7a (5H)-yl)methanol and ((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazine-7a (5H)-methyl)methanol: To a solution of cis-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid methyl ester (5.0 g, 1.0 equiv) in THF (60 mL) was added LiAlH4 (1.30 g, 3.0 equiv) in portions at -40°C. The reaction was stirred at -40°C for 1 hour. The mixture was quenched with saturated anhydrous sodium sulfate aqueous solution (4 mL), filtered, concentrated and purified by reverse phase flash chromatography (C18, 0.1% formic acid conditions) followed by SFC [column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 um); mobile phase: (0.1% NH3H2O ​​IPA); B%: 50% to 50%, 7.7 min; 470 min] to give the two title compounds:

[0363] Intermediate 30 as a yellow oil (900 mg, 19% yield); 1 H NMR (400MHz, chloroform-d) δ = 7.70 (br t,J=5.6Hz,4H),7.50-7.32(m,6H),3.73-3.52(m,2H),3.33-3.11(m,2H),2.98-2.71(m,3H ),1.98-1.84(m,2H),1.83-1.73(m,2H),1.71-1.64(m,2H),1.63-1.54(m,2H),1.07(s,9H).

[0364] Intermediate 31 as a yellow oil (900 mg, 19% yield); 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.74-7.67 (m, 4H), 7.46-7.37 (m, 6H), 3.74-3.52 (m, 2H), 3.37-3.11 (m, 2H), 3.03-2.71 (m, 3H), 2.01-1.88 (m, 2H), 1.87-1.78 (m, 2H), 1.74-1.65 (m, 2H), 1.63-1.52 (m, 2H), 1.07 (s, 9H). Intermediate 32 ((3R,7aR)-3-(((tert-Butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolazin-7a-yl)methanol Intermediate 33 ((3S,7aS)-3-(((tert-Butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolazin-7a-yl)methanol

[0365] Step A ((3R,7aR)-3-(((tert-Butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazine-7a (5H)-1H-pyrrolizine-7a-yl)methanol and ((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolizine (5H)-methyl)methanol To a solution of trans-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazine-7a(5H)-carboxylic acid methyl ester (3.0 g, 1.0 equiv) in THF (40 mL) was added LiAlH4 (781 mg, 3.0 equiv) in portions at -40°C. The reaction was stirred at -40°C for 1 hour. The mixture was quenched with saturated anhydrous sodium sulfate aqueous solution (3 mL), filtered, concentrated and purified by reverse phase flash chromatography (C18, 0.1% formic acid conditions) and subsequently by SFC [column: DAICELCHIRALPAK IG (250 mm × 30 mm, 10 um); mobile phase: (0.1% NH3H2O ​​MeOH); B%: 30%-30%, 3; 800 min] to give the two title compounds:

[0366] Intermediate 32 (1.0 g, 36% yield) as a yellow oil; 1H NMR (400MHz, chloroform-d) δ = 7.68 (td, J = 1.6, 8.0Hz, 4H), 7.49-7.35 (m, 6H), 3.84-3.65 (m, 2H), 3.33 (br s,2H),3.26-3.15(m,1H),2.93-2.89(m,1H),2.77(br d,J=6.4Hz,1H),2.03-1.95(m,1H),1.84-1.72(m,4H),1.71-1.59(m,3H),1.07(s,9H).

[0367] Intermediate 33 (1.0 g, 36% yield) as a yellow oil; 1 H NMR (400MHz, chloroform-d) δ = 7.67 (brd, J = 7.6Hz, 4H), 7.48-7.37 (m, 6H), 3.95-3.88 (m, 1H), 3.80 (br dd, J = 5.6, 10.8Hz, 1H), 3.34 (br s,2H),3.29-3.19(m,1H),3.00-2.88(m,1H),2.85-2.72(m,1H),2.04-1.95(m,1H),1.84-1.72(m,4H),1.71-1.57(m,3H),1.07(s,9H). Intermediate 34 ((3S,7aR)-7a-(Hydroxymethyl)hexahydro-1H-pyrrolazin-3-yl)methyl dimethylcarbamate

[0368] Step A (3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy) 1H-pyrrolizine To a solution of ((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (6.44 g, 1.0 equiv) and TEA (3.98 g, 2.5 equiv) in DCM (64.4 mL) was added TrtCl (8.77 g, 2.0 equiv) at 0 °C. The reaction was stirred at 15 °C for 12 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over Na2SO4, filtered and concentrated to give the title compound (10.3 g, crude) as a yellow oil; LCMS (ESI, M+1): m / z = 652.8.

[0369] Step B ((3S,7aR)-7a-((Trityloxy)methyl)hexahydro-1H-pyrrolazin-3-yl)methanol: To a solution of (3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolizine (10.3 g, 1.0 equiv) in DMF (20.3 mL) was added CsF (23.9 g, 10 equiv). The reaction was stirred at 25 ° C for 12 hours. The mixture was diluted with water (60 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2×20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse phase flash chromatography (0.1% FA conditions) to give the title compound (4.15 g, 57% yield) as a yellow oil; 1 H NMR (400MHz, CDCl3) δ=7.49-7.38(m,6H),7.29-7.17(m,9H),3.44(dd,J=4.4,10.4Hz,1H),3.27(brdd,J=3.6,10.8Hz,1H ),2.95-2.83(m,3H),2.82-2.73(m,1H),2.62(td,J=6.0,11.2Hz,1H),2.02(s,1H),1.89-1.81(m,1H),1.78-1.48(m,6H).

[0370] Step C ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolazin-3-yl)methyldimethyl Carbamate To a solution of ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolazin-3-yl)methanol (4.15 g, 1.0 equiv) and TEA (3.05 g, 3.0 equiv) in DCM (42 mL) was added (4-nitrophenyl)chloroformate (3.03 g, 1.5 equiv) at 0-5°C under N2. The reaction was stirred at 20°C for 2 hours. To the mixture was added N-methylmethanamine (2.0 M, 7.5 mL, 1.5 equiv) at 0°C under N2. The reaction was stirred at 0°C for 0.5 hours. The mixture was diluted with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse phase flash chromatography (0.1% FA condition) to give the title compound (2.03 g, 41% yield) as a yellow oil; LCMS (ESI, M+1): m / z = 485.7.

[0371] Step D ((3S,7aR)-7a-(Hydroxymethyl)hexahydro-1H-pyrrolizin-3-yl)methyldimethylcarbamic acid esterTo a solution of ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolazin-3-yl)methyldimethylcarbamate (2.03 g, 1.0 equiv) in DCM (20 mL) was added TFA (4.78 g, 10 equiv). The reaction was stirred at 0-25 ° C for 12 hours. The mixture was concentrated, dissolved in MeOH (10 mL), neutralized with solid NaHCO 3 , and purified by column chromatography [Al 2 O 3 , petroleum ether / ethyl acetate = 10 / 1 to 1 / 1, dichloromethane / methanol = 15: 1] to give the title compound (834 mg, 82% yield) as a yellow oil; 1 H NMR (400 MHz, methanol-d4) δ = 4.03-3.93 (m, 2H), 3.41-3.18 (m, 3H), 3.04-2.97 (m, 1H), 2.97-2.84 (m, 6H), 2.80 (td, J = 4.8, 10.4 Hz, 1H), 2.09-1.93 (m, 2H), 1.91-1.82 (m, 1H), 1.82-1.71 (m, 2H), 1.69-1.47 (m, 3H). Intermediate 35 ((3S,7aS)-7a-(Hydroxymethyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate

[0372] Synthesized from ((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolazin-7a-yl)methanol according to Intermediate 34. The title compound was obtained as a yellow oil; 1 HNMR (400 MHz, methanol-d4) δ = 4.00 (dq, J = 6.0, 10.8 Hz, 2H), 3.31-3.22 (m, 2H), 3.03-2.96 (m, 2H), 2.95-2.86 (m, 6H), 2.80 (td, J = 5.2, 10.8 Hz, 1H), 2.09-1.46 (m, 8H). Intermediate 36 5-(Aminomethyl)-1-(trans-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide

[0373] Step A cis-3-(Benzyloxy)cyclobutylmethanesulfonateTo a solution of cis-3-(benzyloxy)cyclobutane-1-ol (1.0 g, 1.0 equivalent), DMAP (68.6 mg, 0.1 equivalent) and TEA (1.7 g, 3.0 equivalents) in DCM (10 mL) was added dropwise methylsulfonyl methanesulfonate (2.0 g, 11.2 mmol, 2.0 equivalents) at 0 ° C under N2. The reaction was stirred at 25 ° C for 2 hours. The mixture was slowly quenched with ice and then extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (25 mL), dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1 to 5 / 1) to obtain the title compound (1.4 g, 97.4% yield) as a yellow liquid. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.39-7.28 (m, 5H), 4.66 (quin, J = 7.2 Hz, 1H), 4.44 (s, 2H), 3.75 (quin, J = 6.8 Hz, 1H), 2.99 (s, 3H), 2.89-2.79 (m, 2H), 2.39-2.30 (m, 2H).

[0374] Step B ((1-(trans-3-(benzyloxy)cyclobutyl)-3-(dimethylcarbamoyl)-1H-pyrazol-5-yl) tert-Butyl (methyl)carbamate: To a mixture of tert-butyl N-[[3-(dimethylcarbamoyl)-1H-pyrazol-5-yl]methyl]carbamate (100 mg, 1.0 equiv) and cis-3-(benzyloxy)cyclobutylmethanesulfonate (143 mg, 1.5 equiv) in DMF (2 mL) was added CsCO (364 mg, 3.0 equiv) in one portion at 25 ° C under N2. The reaction was heated to 90 ° C and stirred for 12 hours. The mixture was poured into ice water (3 mL) and extracted with ethyl acetate (4 mL × 3). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and purified by preparative TLC (SiO2, PE / EA=3:1) to give the title compound (38 mg, 20% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.28-7.21 (m, 5H), 6.49 (s, 1H), 4.93 (br s, 1H), 4.70 (br s, 1H), 4.42-4.39 (m, 3H), 4.26 (br d, J = 5.6 Hz, 2H), 3.27 (s, 3H), 3.02 (s, 3H), 2.71-2.66 (m, 2H), 2.54-2.50 (m, 2H), 1.37 (s, 9H). Other regioisomers were also observed.

[0375] Step C ((3-(dimethylcarbamoyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazol-5-yl)methyl) Tert-Butyl Carbamate:To a solution of tert-butyl ((1-(trans-3-(benzyloxy)cyclobutyl)-3-(dimethylcarbamoyl)-1H-pyrazol-5-yl)methyl)carbamate (175 mg, 1.0 equiv) in MeOH (3 mL) was added Pd / C (100 mg, 10% purity) under N. The suspension was degassed under vacuum and purged with H several times. The reaction was stirred under H (15 psi) at 25 ° C for 1 hour. The mixture was filtered, and the filtrate was concentrated to give the title compound (100 mg, crude) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 6.48 (s, 1H), 5.01-4.89 (m, 1H), 4.60 (br s, 1H), 4.22 (br s, 2H), 4.12-3.92 (m, 3H), 3.35 (s, 2H), 3.32-3.15 (m, 3H), 3.13-2.98 (m, 3H), 2.71 (td, J = 6.0, 12.0 Hz, 2H), 2.47-2.32 (m, 2H), 1.36 (s, 9H).

[0376] Step D 5-(Aminomethyl)-1-(trans-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide: To a solution of tert-butyl ((3-(dimethylcarbamoyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazol-5-yl)methyl)carbamate (100 mg, 1.0 eq) in dioxane (1 mL) was added HCl / dioxane (4 M, 4.0 eq) at 25°C. The reaction was stirred at 25°C for 1 hour. The mixture was concentrated to give the crude product as a yellow solid (70 mg, crude, HCl). LCMS (ESI, M+1): m / z=239.2. Intermediate 37 3-(Aminomethyl)-1-(trans-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide

[0377] Step A cis-3-(Benzyloxy)cyclobutanol: To a solution of 3-(benzyloxy)cyclobutanone (7.00 g, 1.0 equiv) in MeOH (120 mL) was added NaBH4 (1.80 g, 1.2 equiv) in portions at 0°C under a nitrogen atmosphere. The reaction was stirred at 0°C for 1 hour. The mixture was slowly quenched with saturated ammonium chloride solution (300 mL) at 0-5°C, concentrated to remove MeOH, and extracted with EtOAc (70 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (6.88 g, 94% yield) as a colorless liquid. 1H NMR (400 MHz, chloroform-d) δ = 7.39-7.29 (m, 5H), 4.49-4.38 (m, 2H), 3.96-3.87 (m, 1H), 3.64 (t, J = 6.8 Hz, 1H), 2.76-2.68 (m, 2H), 1.98-1.92 (m, 2H).

[0378] Step B 1-(trans-3-(benzyloxy)cyclobutyl)-3-cyano-1H-pyrazole-5-carboxylic acid methyl ester: To a mixture of methyl 5-cyano-1H-pyrazole-3-carboxylate (1.80 g, 1.0 equiv), cis-3-(benzyloxy)cyclobutanol (2.12 g, 1.0 equiv) and PPh3 (6.25 g, 2.0 equiv) in THF (40 mL) was added DIAD (4.82 g, 4.6 mL, 2.0 equiv). The reaction was stirred at 0 ° C for 0.5 hours and at 25 ° C for 12 hours. The mixture was concentrated and purified by flash silica gel chromatography ( 80g Purify by silica flash column, eluting with a 100 mL / min gradient of 30% ethyl acetate in petroleum ether) to give the title compound as a yellow oil (3.00 g, 71% yield); 1 H NMR (400 MHz, chloroform-d) δ = 7.37 (d, J = 4.4 Hz, 4H), 7.34-7.29 (m, 1H), 7.20 (s, 1H), 5.95-5.78 (m, 1H), 4.49 (s, 2H), 4.45 (ddd, J = 2.4, 4.4, 6.8 Hz, 1H), 3.91 (s, 3H), 2.88-2.76 (m, 2H), 2.74-2.62 (m, 2H).

[0379] Step C Methyl 3-(aminomethyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazole-5-carboxylate: To a solution of 1-(trans-3-(benzyloxy)cyclobutyl)-3-cyano-1H-pyrazole-5-carboxylic acid methyl ester (600 mg, 1.0 equivalent) in MeOH (20 mL) and HCl solution (1 mL, 2M in MeOH) was added Pd / C (100 mg, 10% purity, wet). The reaction was degassed and purged with H2 3 times. The reaction was stirred at 25 ° C under H2 atmosphere (15 psi) for 2 hours. The mixture was filtered and concentrated to give the title compound (500 mg, 99% yield, HCl) as a white solid.

[0380] Step D 3-(((tert-Butoxycarbonyl)amino)methyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazole-5-carboxylic acid Methyl esterTo a mixture of methyl 3-(aminomethyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazole-5-carboxylate (500 mg, 1.0 eq., HCl) and TEA (580 mg, 0.8 mL, 3.0 eq.) in dichloromethane (10 mL) was added Boc O (625 mg, 0.6 mL, 1.5 eq.). The reaction was stirred at 30 ° C for 2 hours. The mixture was concentrated and purified by flash silica gel chromatography ( 40g Purify by silica flash column, eluting with a 50%-70% EtOAc / PE gradient at 50 mL / min) to give the title compound as a white solid (200 mg, 31% yield, 95% purity); 1 H NMR (400 MHz, CHLOROFORM-d) δ = 6.76 (s, 1H), 5.82 (br s, 1H), 5.06-4.92 (m, 1H), 4.81-4.69 (m, 1H), 4.34 (br d, J = 4.4 Hz, 2H), 3.86 (s, 3H), 2.93-2.81 (m, 2H), 2.50 (ddd, J = 4.0, 8.4, 13.2 Hz, 2H), 1.48 (s, 9H); LCMS (ESI, M+1): m / z = 326.1.

[0381] Step E: 3-(((tert-Butoxycarbonyl)amino)methyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazole-5-carboxylic acid acid: To a solution of methyl 3-(((tert-butoxycarbonyl)amino)methyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazole-5-carboxylate (200 mg, 1 eq) in MeOH (2 mL) and H2O (1 mL) was added KOH (51.7 mg, 1.5 eq). The mixture was stirred at 40 ° C for 2 hours. The reaction was slowly quenched with ice and then extracted with DCM (5 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (166 mg, crude product) as a white solid; 1 H NMR (400MHz, DMSO-d6) δ=13.43-13.08(m,1H),7.29(br t,J=5.6Hz,1H),6.63(s,1H),5.76-5.66(m,1H),5.15(br d,J=4.4Hz,1H),4.40(br d,J=3.6Hz,1H),4.09(br d,J=5.6Hz,2H),2.70-2.57(m,2H),2.29(ddd,J=4.0,8.5,12.6Hz,2H),1.39(s,9H).

[0382] Step F ((5-(dimethylcarbamoyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazol-3-yl)methyl) tert-Butyl carbamate To a solution of 3-(((tert-butoxycarbonyl)amino)methyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazole-5-carboxylic acid (143 mg, 1.0 equiv) and N-methylmethylamine (93.6 mg, 2.5 equiv, HCl) in DMF (2 mL) was added DIEA (297 mg, 5.0 equiv) and HATU (524 mg, 3.0 equiv). The reaction was stirred at 25 ° C for 12 hours. The residue was poured into ice water (5 mL) and extracted with ethyl acetate (5 mL×3). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na SO , filtered and concentrated under vacuum to give the title compound (155 mg, 94.7% yield) as a yellow liquid.

[0383] Step G 3-(Aminomethyl)-1-(trans-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide: To a solution of tert-butyl ((5-(dimethylcarbamoyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazol-3-yl)methyl)carbamate (155 mg, 1.0 equiv) in dioxane (1 mL) was added HCl / dioxane (4 M, 1 mL). The reaction was stirred at 25 °C for 2 hours. The mixture was concentrated to give the title compound (100 mg, crude, HCl) as a yellow solid. LCMS (ESI, M+1): m / z = 239.0. Example 524 4-(Cyclohex-1-en-1-yl)-8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidine

[0384] A mixture of intermediate 1 (60 mg, 1 equivalent), tributyl (cyclohexen-1-yl) stannane (93.1 mg, 2 equivalents), cuprous 2-hydroxy-3-methyl-benzoate (80.8 mg, 3 equivalents), and Pd (PPh 3 ) 4 (14.5 mg, 0.1 equivalents) in THF (2 mL) was degassed and purged with N 2 three times. The mixture was stirred at 60 ° C. under an N 2 atmosphere for 15 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, concentrated and purified by preparative HPLC (column: Phenomenex Luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 23%-53%, 10 min) to give the title compound (1.27 mg, 2.45 μmol, 1.95% yield) as an off-white solid (0.23% formate salt).1 H NMR (400MHz, methanol-d4) δ = 9.27 (s, 1H), 8.67-8.47 (m, 1H), 8.14 (br d,J=8.0Hz,1H),7.87(d,J=8.0Hz,1H),7.74-7.69(m,1H),7.65-7.62(m,1H),7.54(dt,J=5.0,8.0Hz,1H),7.20(dd,J=7.0,13.2Hz,1H),6.49(br t,J=3.6Hz,1H),4.45(s,2H),3.19(br dd,J=5.8,10.8Hz,2H),2.81(td,J=6.5,10.8Hz,2H),2.70(brs,2H),2.51-2.39(m,2H),2.13(br dd,J=6.5,12.4Hz,2H),2.00-1.81(m,10H). LCMS (ESI, M+1): m / z=513.3. Example 525 5-(8-Fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,6a-dihydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione

[0385] Step A 2-[(2,4-dimethoxyphenyl)methyl]-5-methylene-3a,4,6,6a-tetrahydrocyclopenta[c] Pyrrole-1,3-dione: To a solution of 1-[(2,4-dimethoxyphenyl)methyl]pyrrolidine-2,5-dione (12.0 g, 1.0 equivalent) in THF (200 mL) was added LDA (2M, 144 mL, 6.0 equivalents) at -78 ° C under a nitrogen atmosphere. The mixture was stirred at -78 ° C for 15 min and at 0 ° C for 1 hour. The mixture was cooled to -78 ° C, and a solution of 3-chloro-2-(chloromethyl)prop-1-ene (24.1 g, 4.0 equivalents) in THF (100 mL) was added dropwise. The mixture was warmed to 20 ° C and stirred at 20 ° C for 24 hours. The mixture was quenched with saturated ammonium chloride solution (500 mL) and water (500 mL). The mixture was extracted with EtOAc (300 mL × 2). The organic layer was washed with brine (300 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate 10: 1 to 1: 1) to give the title compound (5.50 g, 21% yield, 55% purity) as a light yellow solid; 1H NMR (400 MHz, chloroform-d) δ = 6.97 (d, J = 8.4 Hz, 1H), 6.44-6.34 (m, 2H), 4.93 (s, 2H), 4.61 (s, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 3.28-3.20 (m, 2H), 2.79-2.69 (m, 2H), 2.69-2.61 (m, 2H)

[0386] Step B 2-[(2,4-dimethoxyphenyl)methyl]-3a,4,6,6a-tetrahydrocyclopenta[c]pyrrole-1,3, 5-Trione: To a solution of 2-[(2,4-dimethoxyphenyl)methyl]-5-methylene-3a,4,6,6a-tetrahydrocyclopenta[c]pyrrole-1,3-dione (2.00 g, 1.0 equiv) in THF (20 mL) and H2O (20 mL) was added NaIO4 (5.68 g, 4.0 equiv) and K2OsO4.2H2O (122 mg, 0.05 equiv). The mixture was stirred at 20 ° C for 3 hours. The mixture was diluted with water (200 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate 20: 1 to 1: 1) to give the title compound (850 mg, 42% yield) as a light yellow oil; 1 H NMR (400 MHz, chloroform-d) δ = 7.14 (d, J = 8.0 Hz, 1H), 6.46-6.41 (m, 2H), 4.66 (s, 2H), 3.79 (s, 3H), 3.77 (s, 3H), 3.56-3.49 (m, 2H), 2.84-2.73 (m, 2H), 2.62-2.51 (m, 2H)

[0387] Step C [2-[(2,4-dimethoxyphenyl)methyl]-1,3-dioxo-6,6a-dihydro-3aH-cyclopentadienyl] [c]pyrrol-5-yl]trifluoromethanesulfonate:To a solution of 2-[(2,4-dimethoxyphenyl)methyl]-3a,4,6,6a-tetrahydrocyclopenta[c]pyrrole-1,3,5-trione (850 mg, 1.0 equiv) in THF (12 mL) was added LDA (2M, 1.7 mL, 1.2 equiv) at -78 ° C under a nitrogen atmosphere. The mixture was stirred at -78 ° C for 0.5 hours. A solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (1.00 g, 1.0 equiv) in THF (6 mL) was added. The reaction mixture was stirred at 20 ° C for 16 hours. The mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (30 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate 20: 1 to 3: 1) to give the title compound as a light yellow oil (410 mg, 34% yield); 1 H NMR (400 MHz, chloroform-d) δ = 7.04 (d, J = 9.2 Hz, 1H), 6.44-6.39 (m, 2H), 5.81 (d, J = 2.0 Hz, 1H), 4.73-4.57 (m, 2H), 3.89 (qd, J = 2.8, 8.1 Hz, 1H), 3.79 (s, 6H), 3.46 (ddd, J = 2.8, 7.8, 10.5 Hz, 1H), 3.16-3.06 (m, 1H), 3.03-2.93 (m, 1H)

[0388] Step D 2-[(2,4-dimethoxyphenyl)methyl]-5-trimethylstannyl-6,6a-dihydro-3aH-cyclopentyl Dieno[c]pyrrole-1,3-dione: To a solution of [2-[(2,4-dimethoxyphenyl)methyl]-1,3-dioxo-6,6a-dihydro-3aH-cyclopenta[c]pyrrol-5-yl]trifluoromethanesulfonate (100 mg, 1.0 equiv) and trimethyl(trimethylstannyl)stannane (90.3 mg, 1.2 equiv) in THF (2 mL) was added LiCl (29.2 mg, 3.0 equiv) and Pd(PPh 3 ) 4 (53.1 mg, 0.2 equiv). The mixture was stirred at 60 ° C under a nitrogen atmosphere for 16 hours. The mixture was filtered and purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate 10: 1 to 2: 1) to give the title compound (50.0 mg, 48% yield) as a light yellow oil; 1H NMR (400MHz, chloroform-d) δ = 6.93 (d, J = 8.0Hz, 1H), 6.43-6.35 (m, 2H), 5.86 (d, J = 2.4Hz, 1H), 4.59 (d, J = 3.6Hz, 2 H),3.95(dt,J=2.4,5.0Hz,1H),3.78(d,J=1.6Hz,6H),3.50-3.41(m,1H),2.97-2.91(m,2H),0.18(s,9H)

[0389] Step E.2 -(3,4-dimethoxybenzyl)-5-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-(tetrahydro-1H-pyrrole (5H-oxazine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,6a-dihydrocyclopenta[c]pyrrole-1,3 (2H,3aH)-dione To a solution of intermediate 1 (40.0 mg, 1.0 eq) and 2-[(2,4-dimethoxyphenyl)methyl]-5-trimethylstannyl-6,6a-dihydro-3aH-cyclopenta[c]pyrrole-1,3-dione (48.9 mg, 1.3 eq) in THF (1 mL) was added thiophene-2-carbonyloxycopper (23.9 mg, 1.5 eq), Pd2(dba)3 (7.65 mg, 0.1 eq) and tri(2-furyl)phosphine (5.82 mg, 0.3 eq). The mixture was stirred at 60 ° C under a nitrogen atmosphere for 12 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate 10: 1 to 0: 1 and ethyl acetate / MeOH 10: 1) to give the title compound as a light yellow solid (50.0 mg, 76% yield); 1HNMR (400 MHz, chloroform-d) δ = 9.23 (d, J = 2.8 Hz, 1H), 8.03 (br d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.69-7.63 (m, 1H), 7.62-7.57 (m, 1H), 7.47 (dt, J = 5.2, 8.0 Hz, 1H), 7.17-7.08 (m, 2H), 6.66 (br s,1H),6.46-6.38(m,2H),4.68(s,2H),4.54-4.31(m,2H),4.29-4.22(m,1H),3.82-3.77(m,3H),3.71(d,J=16.0Hz,4H),3.67- 3.59(m,2H),3.58-3.48(m,1H),3.36-3.02(m,2H),2.86-2.59(m,3H),2.22-2.09(m,2H),2.00-1.86(m,4H),1.82-1.68(m,2H);

[0390] Step F 5-(8-Fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrrolidone Idio[4,3-d]pyrimidin-4-yl)-4,6a-dihydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione To a solution of 2-(3,4-dimethoxybenzyl)-5-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,6a-dihydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione (40.0 mg, 1.0 eq) in ACN (1 mL) was added a solution of CAN (153 mg, 5.0 eq) in H2O (1 mL) at 0°C. The mixture was stirred at 20°C for 12 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (10 mL x 5). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate 10: 1 to 0: 1 and ethyl acetate / MeOH 10: 1) and preparative HPLC [Phenomenex luna C18 150×25 mm×10 um; A: water (FA), B: ACN, B%: 12%-42%, over 10 min] to give the title compound (0.80 mg, 2.2% yield) as a yellow solid (0.40 formate salt); 1H NMR (400MHz, chloroform-d) δ = 9.34 (s, 1H), 8.30-8.23 (m, 1H), 8.03 (br d,J=8.4Hz,1H),7.77(d,J=8.0Hz,1H),7.69-7.64(m,1H),7.63-7.59(m,1H),7.47(dt,J=5.2,8.0Hz,1H),7.18-7.09(m,1H),6.73(br s,1H),4.95-4.85(m,1H),4.84-4.75(m,1H),4.39-4.26(m,1H),3.94-3.8 2(m,2H),3.75-3.67(m,1H),3.67-3.54(m,2H),3.04-2.91(m,2H),2.41(br dd, J=6.0, 13.6Hz, 2H), 2.33-2.26 (m, 2H), 2.12 (br dd, J=6.4, 12.8Hz, 2H), 2.01 (br dd, J=6.4, 13.2Hz, 2H); LCMS (ESI, M+1): m / z=568.2. Example 526 6-(8-Fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)hexahydro-2,6-naphthyridine-1,3(2H,4H)-dione

[0391] Step A Methyl 2-(4-cyanopyridin-3-yl)acetate: To a mixture of 3-methylisonicotinonitrile (2.2 g, 1.0 eq.) and dimethyl carbonate (2.52 g, 1.5 eq.) in THF (20 mL) was added KHMDS (1 M, 37.2 mL, 2.0 eq.) dropwise at -60 ° C. The reaction was stirred at -60 ° C. for 0.5 h. The mixture was quenched with saturated NH4Cl solution (50 ml) and extracted with EtOAc (100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate 20: 1 to 2: 1) to give the title compound (600 mg, 17% yield) as a yellow oil; LCMS (ESI, M+1): m / z = 177.1.

[0392] Step B 2,6-naphthyridine-1,3(2H,4H)-dione:To a mixture of methyl 2-(4-cyanopyridin-3-yl)acetate (300 mg, 1.0 equiv) in toluene (6 mL) was added tris(triphenylphosphine)rhodium(I) chloride (78.8 mg, 0.05 equiv) and (E)-acetaldehyde oxime (503 mg, 5 equiv). The mixture was degassed and purged with nitrogen three times. The reaction was stirred at 110 ° C. under a nitrogen atmosphere for 6 hours. The mixture was concentrated and triturated with methanol (5 ml) at 25 ° C. for 1 hour to give the title compound (170 mg, 45% yield) as a brown solid; LCMS (ESI, M+1): m / z=163.0.

[0393] Step C tert-Butyl 5,7-dioxooctahydro-2,6-naphthyridine-2(1H)-carboxylate: To a mixture of 2,6-naphthyridine-1,3(2H,4H)-dione (170 mg, 1.0 equiv) and (Boc)2O (333 mg, 2.0 equiv) in MeOH (10 mL) was added Pd / C (30 mg, 10% purity). The reaction was degassed and purged with hydrogen three times. The reaction was stirred at 40 ° C under an atmosphere of H2 (50 psi) for 20 hours. The mixture was filtered and concentrated to give the title compound (147 mg, 45% yield) as a brown solid, LCMS (ESI, M-55): m / z=213.0.

[0394] Step D Hexahydro-2,6-naphthyridine-1,3(2H,4H)-dione: To a mixture of tert-butyl 5,7-dioxooctahedral-2,6-naphthyridine-2(1H)-carboxylate (147 mg, 1.0 eq) in dichloromethane (2 mL) was added TFA (770 mg, 12 eq). The reaction was stirred at 25 °C for 0.5 h. The mixture was concentrated to give the title compound (160 mg, crude, TFA salt) as a brown oil.

[0395] Step E 6-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)hexahydro-2,6-naphthyridine-1,3(2H,4H)-dione To a mixture of hexahydro-2,6-naphthyridine-1,3(2H,4H)-dione (160 mg, 5.0 equiv, TFA) and 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (60 mg, 1.0 equiv) in DMF (0.05 mL) were added DIPEA (223 mg, 15 equiv) and Molecular sieves (50 mg). The reaction was stirred at 40 ° C for 16 hours. The mixture was filtered and purified by preparative HPLC [Phenomenex Luna C18 75×30 mm×3 μm; A: water (FA), B: ACN, B%: 5%-35% over 10 min] and lyophilized to give the title compound as a brown solid (7.54 mg, 9.3% yield over two steps) (0.95 formate salt); 1 H NMR (400MHz, methanol-d4)δ=9.18-9.10(m,1H),8.18-8.11(m,1H),7.91-7.85(m,1H) ),7.76-7.69(m,1H),7.67-7.60(m,1H),7.59-7.52(m,1H),7.27-7.16(m,1H) ,4.67(s,2H),4.30-3.89(m,3H),3.74-3.62(m,2H),3.32-3.06(m,4H),2.92- 2.78(m,1H),2.77-2.42(m,3H),2.40-2.31(m,2H),2.30-2.15(m,4H),2.12(br dd, J=6.4, 12.4Hz, 3H); LCMS (ESI, M+1): m / z=599.2. Example 527 (R)-1-(2-(3-aminoazetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0396] Step A (R)-(1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy- tert-Butyl (3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)azetidin-3-yl)carbamate To a mixture of (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (200 mg, 1.0 equiv), tert-butyl N-(azetidin-3-yl)carbamate (130 mg, 2.0 equiv) in dioxane (2 mL) was added DIPEA (244 mg, 5.0 equiv), and the mixture was then stirred at 90 ° C. under an N atmosphere for 12 hours. The reaction mixture was diluted (40 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, and concentrated to give the title compound (200 mg, 80% yield) as a yellow solid; LCMS (ESI, M+1): m / z=665.3.

[0397] Step B (R)-1-(2-(3-aminoazetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)- 8-Fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol To a solution of tert-butyl N-[1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-4-[(3R)-3-hydroxy-3-methyl-1-piperidinyl]pyrido[4,3-d]pyrimidin-2-yl]azetidin-3-yl]carbamate (150 mg, 1.0 eq) in dioxane (1.5 mL) was added HCl / dioxane (4 M, 564 μL, 10.0 eq) at 0 ° C. The mixture was stirred at 0 ° C for 2 hours. The reaction was quenched with saturated sodium bicarbonate (20 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, concentrated and purified by preparative HPLC (C18, A: water [(0.1% FA)-ACN]; B: ACN, B%: 45%-65% over 25 min) to give the title compound (96.3 mg, 82% yield) as a white solid (0.52 g formate salt); 1H NMR (400 MHz, Methanol-d4) δ = 8.98 (d, J = 1.6 Hz, 1H), 8.51 (br s, 1H), 7.67 (dd, J = 6.0, 9.2 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.24 (t, J = 9.2 Hz, 1H), 7.04 (s, 1H), 4.58-4.48 (m, 2H), 4.31 (br d,J=13.2Hz,1H),4.18-4.01(m,4H),3.64-3.50(m,1H),3.47-3.39(m,1H),2.59-2.42(m,1H),2.33-2.19(m,1H ),2.18-2.05(m,1H),1.89-1.68(m,3H),1.26(d,J=13.6Hz,3H),0.82(q,J=7.2Hz,3H); LCMS(ESI,M+1):m / z=521 Example 528 7-(2-(3-aminoazetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

[0398] The title compound was synthesized as a white solid from 7-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione following the 2-step procedure described for Example 527. (0.54 formate salt) 1 H NMR (400MHz, DMSO-d6) δ = 8.87 (d, J = 1.2 Hz, 1H), 8.68 ( d, J = 2.0 Hz, 1H), 7.74 ( dd, J =6.0,9.2Hz,1H),7.39-7.27(m,2H),6.99(dd,J=2.4,6.0Hz,1H),4.35-4.16(m,4H ),3.93-3.69(m,4H),3.55-3.25(m,3H),2.39-2.30(m,1H),2.25-2.12(m,1H),2.1 0-1.96 (m, 2H), 1.94-1.77 (m, 2H), 0.81-0.68 (m, 3H); LCMS (ESI, M+1): m / z=575.3. Example 529 5-(2-(3-aminoazetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0399] The title compound was synthesized as a white solid from 5-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide according to the 2-step procedure described for Example 527. (0.40 formate salt) 1H NMR (400MHz, methanol-d4) δ = 8.95 (s, 1H), 7.66 (dd, J = 6.0, 9.2Hz, 1H), 7.31-7.19 (m, 2H), 7.04 (d, J = 2.4Hz, 1H), 6.65 (s, 1H), 5.2 2-5.01(m,2H),4.57-4.43(m,4H),4.33(td,J=5.6,14.4Hz,2H),4.15-4.06(m,3H),3.32(s,3H),2.56-2.44(m,1H),2.34(br s, 2H), 2.28-2.14 (m, 1H), 0.79 (t, J = 7.2Hz, 3H); LCMS (ESI, M+1): m / z = 614.4. (R)-1-(2-(3-amino-3-methylazetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0400] The title compound was synthesized from (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol and tert-butyl N-(3-methylazetidin-3-yl)carbamate according to the 2-step procedure described for Example 527, except HCl·MeOH was used in step B to yield the desired compound as a white solid. (0.37 formate salt) 1 HNMR (400MHz, methanol-d4) δ = 8.99 (d, J = 2.0Hz, 1H), 7.67 (dd, J = 6.0, 9.2Hz, 1H), 7.29 (d, J = 2. 4Hz,1H),7.27-7.20(m,1H),7.03(s,1H),4.32(brd,J=13.2Hz,1H),4.18(s,4H),4.08(br dd,J=8.4,13.2Hz,1H),3.46(br s,2H),2.50(ddd,J=2.0,7.2,14.4Hz,1H),2.34-2.19(m,1H),2.17-2.03(m,1H),1.90-1.70 (m, 3H), 1.60 (s, 3H), 1.26 (d, J = 13.2Hz, 3H), 0.88-0.78 (m, 3H); LCMS (ESI, M+1): m / z = 535.3. Example 531 7-(2-(3-amino-3-methylazetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

[0401] The title compound was synthesized from 7-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione and tert-butyl N-(3-methylazetidin-3-yl)carbamate according to the 2-step procedure described for Example 527 to produce the desired compound as a white solid. (0.7g formate salt) 1 H NMR (400MHz, DMSO-d6) δ=8.87(s,1H),8.25(s,1H),7.74(dd,J=6.0,8.8Hz,1H),7.39-7.26(m,2H),6.99(dd,J=2.4,6.4Hz,1H),4.39-4.15(m ,3H),3.97-3.89(m,4H),3.51-3.29(m,3H),2.31-1.96(m,4H),1.93-1 .76(m,2H),1.41(s,3H),0.81-0.67(m,3H); LCMS(ESI,M+1):m / z=589.3 Example 532 5-(2-(3-amino-3-methylazetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0402] The title compound was synthesized from 5-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide and tert-butyl N-(3-methylazetidin-3-yl)carbamate according to the 2-step procedure described for Example 527 to produce the desired compound as a white solid. (0.31 formate salt). 1H NMR (400 MHz, methanol-d4) δ = 8.95 (s, 1H), 7.66 (dd, J = 6.0, 9.2 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.24 (t, J = 9.2 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.65 (s, 1H), 5.25-5.03 (m, 2H), 4.56-4.48 (m, 2H), 4.35 (br d,J=15.6Hz,2H),4.12(s,4H),3.33(s,3H),3.32-3.30(m,6H),3.08(s,3H),2.62-2.45(m,1H),2.4 0-2.30 (m, 2H), 2.27-2.16 (m, 1H), 1.56 (s, 3H), 0.80 (t, J = 7.2Hz, 3H); LCMS (ESI, M+1): m / z = 628.4. Example 533 (R)-1-(2-(3-(dimethylamino)azetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0403] The title compound was synthesized from (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol and N,N-dimethylazetidin-3-amine dihydrochloride according to the 2-step procedure described for Example 527 to produce the desired compound as a white solid. (0.2g formate salt) 1H NMR (400 MHz, methanol-d4) δ = 8.97 (d, J = 2.4 Hz, 1H), 8.35 (br s,1H),7.66(dd,J=5.9,9.0Hz,1H),7.29(d,J=2.6Hz,1H),7.24(t,J=9.4Hz,1H),7.08-7.01(m,1H),4.41-4.25(m,3H),4.15-4.02(m,3H),3.6 4-3.48(m,1H),3.47-3.36(m,2H),3.31(s,2H),2.56-2.46(m,1H),2.36 (s,6H),2.24(dqd,J=4.6,7.4,14.5Hz,1H),2.17-2.03(m,1H),1.82(br s, 1H), 1.79-1.69 (m, 2H), 1.26 (d, J=13.4Hz, 3H), 0.89-0.77 (m, 3H); LCMS (ESI, M+1): m / z=: 549.2. Example 534 7-(2-(3-(dimethylamino)azetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

[0404] The title compound was synthesized from 7-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione and N,N-dimethylazetidin-3-amine dihydrochloride according to the 2-step procedure described for Example 527 to produce the desired compound as a white solid. (0.32g formate salt) 1H NMR (400MHz, DMSO-d6) δ = 10.87-10.62 (m, 1H), 10.17-9.53 (m, 1H), 8.87 (s, 1H),8.66(1H),7.75(dd,J=6.0,9.2Hz,1H),7.40-7.26(m,2H),6.99(dd,J=2 .4,6.0Hz,1H),4.37-4.09(m,4H),3.99-3.87(m,2H),3.46-3.38(m,2H),3. 18-3.10(m,1H),2.47-2.17(m,2H),2.13(s,6H),2.09-1.94(m,2H),1.83(br t, J=9.6Hz, 2H), 0.80-0.68 (m, 3H); LCMS (ESI, M+1): m / z=603.4. Example 535 5-(2-(3-(Dimethylamino)azetidin-1-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0405] The title compound was synthesized from 5-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide and N,N-dimethylazetidin-3-amine dihydrochloride according to the 2-step procedure described for Example 527 to produce the desired compound as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ = 8.94 (s, 1H), 7.66 (dd, J = 6.0, 8.8 Hz, 1H), 7.29 (d, J = 2.8 Hz, 1H), 7.24 (t, J = 9.2 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.69 (s, 1H), 5.28-5.02 (m, 2H), 4.52 (br d,J=5.6Hz,2H),4.41-4.27(m,4H),4.16-4.01(m,2H),3.44-3.36(m,1H),3.36-3.32(m,3H),3.08(s,3H),2 .57-2.47(m,1H),2.41-2.28(m,8H),2.27-2.16(m,1H),0.80(t,J=7.2Hz,3H); LCMS(ESI,M+1):m / z=642.4. Example 536 (R)-1-(2-((1-(aminomethyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0406] Step A (R)-1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy (3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropanecarbonitrile : To a solution of t-BuONa (2M, 3.40 mL, 2.0 equiv) in THF was added 1-(hydroxymethyl)cyclopropanecarbonitrile (661 mg, 2.0 equiv). The reaction was stirred at 0 ° C for 0.5 hours under an N2 atmosphere. The mixture was added to a solution of (R)-1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (1.80 g, 1.0 equiv) in THF (10 mL) at 0 ° C. The reaction was stirred at 25 ° C for 2 hours. The reaction mixture was quenched by adding H2O (10 mL) at 0 ° C. The mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reverse phase flash chromatography [C18, 0.1% formic acid condition] to give the title compound (900 mg, 45% yield) as a white solid; LCMS (ESI, M+1): m / z = 590.2.

[0407] Step B (R)-1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)- (4,3-d]pyrimidin-2-yl)pyrido[4,3-d]pyrimidin-1-yl)oxy)methyl)cyclopropanecarbonitrileTo a solution of (R)-1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropanecarbonitrile (400 mg, 1.0 eq) in DCM (4 mL) was added TFA (6.16 g, 4.00 mL) at 0 ° C. The mixture was stirred at 25 ° C for 0.5 h. The reaction mixture was quenched with saturated NaHCO solution (8 mL) at 0 ° C. The mixture was extracted with EtOAc (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by reverse phase flash chromatography [C18, 0.1% formic acid condition] to give the title compound (15.4 mg, 11% yield) as a white solid; LCMS (ESI, M+1): m / z = 546.3.

[0408] Step C (R)-1-(2-((1-(aminomethyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalene- 1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol To a mixture of PtO2 (83.2 mg, 1.0 eq) in MeOH (2.5 mL) was added (R)-1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropanecarbonitrile (200 mg, 1.0 eq) and HCl·MeOH (4 M, 1 mL) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 25 °C for 3 h. The reaction mixture was filtered, concentrated and purified by preparative HPLC [Phenomenexluna C18 150×25 mm×10 μm; A: water (10 mM FA), B: ACN, B%: 13%-43%, over 10 min] to give the title compound (14.3 mg, 6.9% yield) as a light yellow solid (0.9 formate salt); 1 H NMR(400MHz, DMSO-d6)δ=9.23(s,1H),8.38(s,1H),7.77-7.73(m,1H),7.40-7.25(m ,2H),7.10-6.97(m,1H),4.43-4.00(m,4H),3.69-3.43(m,1H),3.41-3.25(m,1H),2 .82(d,J=1.6Hz,1H),2.53-2.51(m,2H),2.44-2.26(m,3H),2.25-1.92(m,2H),1.74 -1.61 (m, 3H), 1.17 (d, J = 9.6Hz, 3H), 0.81-0.53 (m, 7H); LCMS (ESI, M+1): m / z = 550.2. Example 537 (1R,5R,6R)-3-(7-(4-Bromo-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol

[0409] Step A 1-Bromo-5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl) (2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalene-2-ol To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (340 mg, 1.0 eq) in DMF (5.0 mL) was added a solution of NBS (112 mg, 1.1 eq) in DMF (1.5 mL). The mixture was stirred at 20 ° C for 2 hours. The reaction mixture was diluted with Na2SO3 (25 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with NaHCO3 (2×20 mL) and brine (20 mL). The organics were dried over Na2SO4, concentrated and purified by preparative HPLC [Phenomenex Synergi Polar-RP 100×25 mm×4 μm; A: water (TFA), B: ACN; B%: 44%-64% over 7 min] to give the title compound (140 mg, 34% yield) as a yellow solid; 1 H NMR (400MHz, DMSO-d6) δ = 10.85 (br s, 1H), 9.22 (s, 1H), 8.21 (dd, J = 6.0, 9.6Hz, 1H), 7.56 (t, J = 9.6Hz, 1H), 7.23 (s, 1H), 5.47-5.17 (m, 3H), 4.34 -4.14(m,2H),3.18-3.05(m,2H),3.03(s,1H),2.91-2.78(m,1H),2.39-2.31(m,1H),2.17-2.01(m,4H),1.88-1.77(m,3H),0.71(br t, J=7.2Hz, 3H); LCMS (ESI, M+3): m / z=673.0.

[0410] Step B (1R,5R,6R)-3-(7-(4-bromo-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R, (7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo [3.2.1] Octane-6-olTo a solution of 1-bromo-5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (50 mg, 1.0 eq) and (1S,5S,6R)-3-azabicyclo[3.2.1]octan-6-ol (18.3 mg, 1.5 eq, HCl) in DMF (0.15 mL) was added DIPEA (48.1 mg, 5.0 eq) and Molecular sieves (20 mg). The mixture was then stirred at 60 ° C for 12 hours. The mixture was filtered, concentrated and purified by preparative HPLC [Phenomenex luna C18 150×25 mm×10 μm; A: water (FA), B: ACN; B%: 18%-48%, over 10 min] to give the title compound (22 mg, 39% yield, FA) (0.19 formate salt) as a yellow solid; 1 H NMR(400MHz,DMSO-d6)δ=10.83(br s,1H),9.39-9.24(m,1H),8.20(dd,J=6.0,9.6Hz,1H),8.16(s,1H),7.55(dt,J=2.8,9.6Hz,1H),7.23(d,J=16.0Hz,1H),5 .39-5.18(m,1H),4.93-4.66(m,2H),4.64-4.50(m,1H),4.20-4.11(m,2H),4.08-3.95(m,1H),3.80-3.68(m,1H),3.37(br d,J=13.2Hz,1H),3.10(br d,J=8.8Hz,2H),3.03(br s,1H),2.84(br d,J=6.4Hz,1H),2.43-2.31(m,2H),2.20-1.99(m,6H),1.89-1.74(m,4H),1.67(br s, 1H), 1.30-1.21 (m, 1H), 0.73 (br t, J = 7.2Hz, 3H); LCMS (ESI, M+3): m / z = 698.0, 700.0. Example 538 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0411] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (350 mg, 1.00 equiv), 1-oxa-8-azaspiro[3.5]nonane oxalate (305 mg, 1.5 equiv), K3PO4 (1.25 g, 10 equiv) and A mixture of molecular sieves (100 mg) in DMF (2 mL) and ACN (2 mL) was stirred at 60° C. under a N atmosphere for 2 hours. The mixture was filtered and purified by preparative HPLC [column: Waters Xbridge 150×25 mm×5 um; mobile phase: [water (ammonia hydroxide)-ACN]; B%: 41%-71%, 9 min] to give the title compound (140 mg, 36% yield) as a white solid. 1 H NMR (400MHz, methanol-d4) δ = 9.29-9.21 (m, 1H), 7.67 (dd, J = 6.0, 9.2Hz, 1H), 7.30 (d, J = 2.8Hz, 1H), 7.24 (t, J =9.6Hz,1H),7.08(d,J=2.8Hz,1H),5.44-5.16(m,1H),4.68-4.52(m,3H),4.49-4.36(m,1H),4.35-4.29 (m,1H),4.28-4.20(m,1H),3.82(ddd,J=2.4,13.6,19.4Hz,1H),3.54-3.37(m,1H),3.25-3.13(m,3H),3 .00(dt,J=6.0,9.2Hz,1H),2.54-2.44(m,3H),2.37-2.12(m,5H),2.02-1.76(m,6H),0.87-0.69(m,3H). LCMS(ESI,M+1):m / z=620.1 Example 539 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-((R)-1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol Example 540 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol was separated by SFC [conditions: column: REGIS(S,S)WHELK-O1 (250mm×25mm, 10um); mobile phase: [0.1% NH3H2O ​​ETOH]; B%: 40%-40%, 5.5min] to obtain:

[0412] Example 539 (51.3 mg, 36% yield) as a yellow solid. 1 H NMR (400MHz, methanol-d4) δ = 9.26 (d, J = 4.4Hz, 1H), 7.68 (dd, J = 6.0, 8.8Hz, 1H), 7.30 (d, J = 2.8Hz, 1H), 7.25 (t, J = 9 .6Hz,1H),7.08(d,J=2.8Hz,1H),5.40-5.20(m,1H),4.70-4.53(m,3H),4.50-4.37(m,1H),4.37-4.29(m,1H) ,4.29-4.20(m,1H),3.84(dd,J=13.6,17.6Hz,1H),3.57-3.37(m,1H),3.25-3.12(m,3H),3.05-2.96(m,1H), 2.56-2.43(m,3H),2.38-2.12(m,5H),2.03-1.79(m,6H),0.81(q,J=7.6Hz,3H), LCMS(ESI,M+1):m / z=620.3.

[0413] Example 540 (49.5 mg, 34.7% yield) was obtained as a yellow solid. 1H NMR (400MHz, methanol-d4) δ = 9.26 (d, J = 4.0Hz, 1H), 7.67 (dd, J = 6.0, 9.2Hz, 1H), 7.29 (d, J = 2.4Hz, 1H), 7.24 (t, J = 9. 6Hz,1H),7.07(d,J=2.4Hz,1H),5.39-5.22(m,1H),4.69-4.52(m,3H),4.50-4.39(m,1H),4.36-4.31(m,1H),4 .29-4.23(m,1H),3.84(dd,J=13.6,18.0Hz,1H),3.52-3.39(m,1H),3.26-3.18(m,3H),3.05-2.96(m,1H),2.5 4-2.44(m,3H),2.34-2.13(m,5H),2.03-1.82(m,6H),0.81(dt,J=3.6,7.6Hz,3H), LCMS(ESI,M+1):m / z=620.3. Example 541 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-((S)-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0414] To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthol (100 mg, 1 eq) and (S)-3-methylpiperidine (25.1 mg, 1.5 eq) in DMF (0.8 mL) was added DIPEA (109 mg, 5 eq) and The mixture was stirred at 40 ° C for 12 hours. The mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (4 × 5 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated and purified by preparative HPLC [column: Phenomenex Synergi C18 150 × 25 mm × 10 μm; mobile phase: water (FA)-ACN; B%: 20%-50%, 10 minutes] to give the title compound (44.5 mg, 41% yield, 0.2 FA) (1 formate) as a white solid. 1H NMR (400MHz, methanol-d4) δ = 9.02 (s, 1H), 7.68 (dd, J = 6.0, 9.2Hz, 1H), 7.35-7.19 (m, 2H), 7.06 (s, 1H), 5.48-5.24 (m ,1H),4.68-4.49(m,2H),4.44-4.27(m,2H),3.56-3.32(m,4H),3.18-3.04(m,2H),2.49-1.75(m,12H),1.40(br d, J=11.2Hz, 1H), 1.03 (br d, J=6.4Hz, 3H), 0.80 (t, J=7.2Hz, 3H); LCMS (ESI, M+1): m / z=592.3 Example 542 4-(4-((1,2-oxazinan-4-yl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0415] Step A 4-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- tert-Butyl (1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)-1,2-oxazinane-2-carboxylate To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (30.0 mg, 1.0 eq) in dimethylformamide (1.0 mL) was added K 3 PO 4 (107 mg, 10.0 eq) and tert-butyl 4-aminooxazinane-2-carboxylate (20.5 mg, 2.0 eq). The mixture was stirred at 60 ° C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (40.0 mg, crude), LCMS (ESI, M+1): m / z=695.3.

[0416] Step B 4-(4-((1,2-oxazinan-4-yl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrole (oxazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-olTo a solution of tert-butyl 4-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)-1,2-oxazinane-2-carboxylate (30.0 mg, 1.0 equiv) in DCM (1.0 mL) was added TFA (0.2 mL). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated to give a residue, which was purified by preparative HPLC [column: Waters Xbridge 150×25 mm×5 μm; mobile phase: [water (NH 4 HCO 3 )-ACN]; B%: 35%-65%, 10 min] and lyophilized to give the title compound (8.04 mg, 30% yield, 97% purity) as a white solid; 1H NMR (400 MHz, DMSO-d 6 ) δ = 9.96 (s, 1H), 9.43 (s, 1H), 7.77 (dd, J = 6.0, 9.2 Hz, 1H), 7.42-7.31 (m, 2H), 7.2-6.94 (m, 2H), 5.70-5.23 (m, 1H), 4.55-4.41 (m, 2H), 4.11-3.98 (m, 1H), 3.80 (br t,J=10.8Hz,1H),3.26-3.11(m,3H),3.06-2.96(m,1H),2.96-2.84(m,1H),2.81-2.59(m,1H ), 2.41-2.26 (m, 4H), 2.15-1.84 (m, 7H), 0.71 (t, J = 7.2Hz, 3H), LCMS (ESI, M+1): m / z = 595.4. Example 543 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((E)-2-(1-methyl-1H-pyrazol-5-yl)vinyl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0417] Step A (E)-1-Methyl-5-(2-(tributylstannyl)vinyl)-1H-pyrazoleTo a solution of 5-ethynyl-1-methyl-pyrazole (477 mg, 1.0 equivalent) and BuSnH (1.7 g, 1.3 equivalents) in toluene (7 mL) was added AIBN (36.9 mg, 0.05 equivalent). The mixture was stirred at 80 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-35% ethyl acetate / petroleum ether) to obtain the title compound (150 mg, 5.4% yield) as a yellow oil. 1 H NMR (400MHz, chloroform-d) δ = 7.44 (d, J = 1.6Hz, 1H), 6.49-6.45 (m, 1H), 6.37 (d, J = 1.6Hz, 1H), 5.71 (d, J = 2. 8Hz,1H),3.79(s,3H),1.56-1.52(m,6H),1.49-1.43(m,6H),1.34-1.31(m,6H),0.92-0.90(m,9H).

[0418] Step B 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)-4-((E)-2-(1-methyl-1H-pyrazol-5-yl)vinyl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol A mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (35 mg, 1.0 equiv), (E)-1-methyl-5-(2-(tributylstannyl)vinyl)-1H-pyrazole (33.4 mg, 1.3 equiv), copper thiophene-2-carboxylate (18.5 mg, 1.5 equiv), tri(2-furyl)phosphine (1.5 mg, 0.1 equiv) and Pd2(dba)3 (17.8 mg, 0.3 equiv) in THF (1 mL) was stirred at 60°C under N2 atmosphere for 12 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and purified by preparative TLC (SiO2, DCM / MeOH 10: 1), then purified by preparative HPLC [C18, 0.1% formic acid conditions] and lyophilized to give the title compound (4 mg, 10.0% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ = 9.31 (d, J = 6.0 Hz, 1H), 8.26-8.12 (m, 1H), 7.63 (dd, J = 11.2, 15.2 Hz, 1H), 7.57-7.48 (m, 2H), 7.23-7.16 (m, 2H), 7.10-6.86 (m, 1H), 6.78 (dd, J = 1.6, 14.0 Hz, 1H), 5 .48-5.24(m,1H),4.67-4.46(m,2H),4.05(d,J=6.0Hz,3H),3.64-3.48(m,2H),3.44-3.25(m ,2H),3.14-3.07(m,1H),2.50-2.17(m,6H),0.85-0.67(m,4H); LCMS(ESI,M+1):m / z=601.2. Example 544 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbonitrile

[0419] To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthol-2-ol (60.0 mg, 1.0 equiv) and piperidine-4-carbonitrile hydrochloride (55.6 mg, 3.0 equiv, HCl) in DMF (2 mL) was added potassium phosphate (214 mg, 10 equiv) and Molecular sieves (10 mg). The mixture was stirred at 60 ° C for 2 hours. The mixture was filtered and purified by preparative HPLC [column: Waters Xbridge 150×25 mm×5 μm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 43%-73%, 9 minutes] and lyophilized to give the title compound as a yellow solid (16.0 mg, 25% yield); 1H NMR (400MHz, CD3OD) δ = 9.04 (s, 1H), 7.65 (dd, J = 6.0, 8.8Hz, 1H), 7.27 (d, J = 2.4Hz, 1H), 7.23 (t,J=9.6Hz,1H),7.04(d,J=2.4Hz,1H),5.40-5.21(m,1H),4.34-4.24(m,4H),3.96-3.87(m ,2H),3.28-3.17(m,4H),3.04-2.98(m,1H),2.93(s,1H),2.53-2.43(m,1H),2.29-2.04(m,8 H), 2.02-1.95 (m, 2H), 1.92-1.84 (m, 1H), 0.79 (t, J = 6.8Hz, 3H); LCMS (ESI, M+1): m / z = 603.2. Example 545 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(2-(1-methyl-1H-pyrazol-5-yl)ethyl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0420] To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((E)-2-(1-methyl-1H-pyrazol-5-yl)vinyl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (10 mg, 1 eq) in THF (0.5 mL) was added Pd / C (5 mg, 10% purity). The mixture was degassed and purged with H2 3 times, and then the mixture was stirred under H2 atmosphere (15 Psi) at 20 ° C for 12 hours. The reaction mixture was filtered and purified by preparative HPLC [C18, 0.1% NH4HCO3 conditions] and lyophilized to give the title compound (1.4 mg, 12.8% yield) as a white solid. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.14 (d, J = 8.0 Hz, 1H), 6.48-6.34 (m, 2H), 4.66 (s, 2H), 3.78 (d, J = 8.4 Hz, 6H), 3.58-3.46 (m, 2H), 2.86-2.73 (m, 2H), 2.65-2.50 (m, 2H); LCMS (ESI, M+1): m / z = 603.1. Example 546

[0421] (1S,5R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.0]heptan-1-ol. The title compound was synthesized as a yellow solid according to the procedure described for Example 538. (0.3 g formate salt). 1 H NMR (400MHz, CD3OD) δ=9.29(d,J=2.8Hz,1H),7.68(dd,J=6.0,9.2Hz,1H),7.31(d,J=2.4Hz,1H),7.25(t,J=9.6Hz,1 H),7.06(dd,J=2.4,4.8Hz,1H),5.50-5.32(m,1H),4.57-4.46(m,2H),4.45-4.37(m,1H),4.36-4.24(m,1H),4.23-4 .12(m,2H),3.63-3.41(m,3H),3.22-3.14(m,1H),3.05-2.96(m,1H),2.52-2.39(m,2H),2.38-2.30(m,2H),2.29-2. 21(m,2H),2.19-2.07(m,4H),2.06-1.97(m,1H),1.50-1.36(m,1H),0.83-0.77(m,3H); LCMS(ESI,M+1): m / z=606.3. Example 547 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azepane-3-carbonitrile

[0422] The title compound was synthesized according to the procedure described for Example 538, except the reaction mixture was heated at 40 °C for 15 h to give the desired compound as a yellow solid. 1HNMR (400 MHz, methanol-d4) δ = 9.21-9.24 (m, 1H), 8.50 (s, 1H), 7.68 (dd, J = 9.2, 6.0 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 7.02-7.08 (m, 1H), 5.28-5.51 (m, 1H), 4.43-4.58 (m, 3H) ,4.03-4.35(m,3H),3.39-3.65(m,4H),3.13-3.23(m,1H),2.04-2.59(m,11H),1.94-2.01(m, 1H), 1.81-1.92 (m, 1H), 1.48-1.65 (m, 1H), 0.75-0.84ppm (m, 3H); LCMS (ESI, M+1): m / z=617.4. Example 548 ((3S,7aR)-7a-(((7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methyl dimethylcarbamate

[0423] Step A ((3S,7aR)-7a-(((7-Chloro-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido [4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizin-3-yl)methyl dimethylcarbamate To a solution of (R)-1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (165 mg, 1.1 eq) in toluene (5.0 mL) were added ((3S,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolazin-3-yl)methyl dimethylcarbamate (110 mg, 1.0 eq), t-BuONa (131 mg, 3.0 eq) and Molecular sieves (20.0 mg). The mixture was stirred at 0 ° C for 1 hour. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (30 mL). The organic phase was separated and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, dichloromethane / methanol 10: 1) to give the title compound (70.0 mg, 29% yield), LCMS (ESI, M+1): m / z=537.1

[0424] Step B ((3S,7aR)-7a-(((7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4- ((R)-3-Hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolizine- 3-aminomethyl)methyl dimethylcarbamateTo a solution of ((3S,7aR)-7a-(((7-chloro-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methyl dimethylcarbamate) (140 mg, 1.0 equiv) in dioxane (2.00 mL) and H2O (0.50 mL) was added K3PO4 (166 mg, 3.0 equiv), CataCXiumAPdG3 (19.0 mg, 0.1 equiv) and 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100 mg, 1.1 equiv). The mixture was stirred at 90°C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO 2 , DCM / MeOH 10: 1) to give the title compound (80.0 mg, 42% yield) as a yellow solid. LCMS (ESI, M+1): m / z = 725.4

[0425] Step C ((3S,7aR)-7a-(((7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3- methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolazin-3-yl)methyldimethyl Carbamate To a solution of ((3S,7aR)-7a-(((7-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolazin-3-yl)methyl dimethylcarbamate (70.0 mg, 1.0 eq) in EtOAc (3.00 mL) was added HCl / MeOH (4 M, 3.00 mL). The mixture was stirred at 0 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex C18 75×30 mm×3 um; mobile phase: [water (FA)-ACN]; B%: 15%-45%, 7 min) to give the title compound (5.15 mg, 7% yield) as a white solid (1 formate salt); 1H NMR (400MHz, methanol-d4) δ = 9.22 (d, J = 4.4Hz, 1H), 8.53 (s, 1H), 7.61 (dd, J = 4.4, 8.8Hz, 1H), 7.44-7. 35(m,1H),7.33(s,1H),7.24(dd,J=2.4,6.4Hz,1H),4.61-4.53(m,1H),4.40-4.26(m,3H),4.16( td,J=5.2,10.4Hz,1H),4.03(ddd,J=4.0,6.8,10.8Hz,1H),3.65-3.59(m,1H),3.48-3.39(m,1H) ,3.25-3.13(m,2H),3.02-2.94(m,1H),2.93-2.84(m,6H),2.28(td,J=6.4,12.6Hz,1H),2.21(br d,J=2.8Hz,1H),2.12-1.90(m,5H),1.89-1.76(m,5H),1.31-1.27(m,3H), LCMS(ESI,M+1):m / z=681.4 Example 549 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0426] The title compound was synthesized according to the procedure described for Example 541 to yield the desired compound as a yellow solid (0.21 formate salt); 1H NMR (400MHz, methanol-d4) δ = 9.08 (s, 1H), 7.68 (dd, J = 6.0, 8.8Hz, 1H), 7.31 (d, J = 2.4Hz, 1H), 7.25 (t,J=9.2Hz,1H),7.08(d,J=2.4Hz,1H),5.35(d,J=54.0Hz,1H),4.42-4.32(m,2H),4.17(br d,J=12.8Hz,1H),4.13-4.05(m,1H),4.00(br d,J=12.8Hz,1H),3.91-3.81(m,1H),3.36-3.33(m,3H),3.15-3.05(m,1H),2.54-2.26(m,3H),2.24 -2.13(m,2H),2.11-2.00(m,2H),1.99-1.89(m,3H),1.88-1.73(m,8H),1.74-1.73(m,1H),0.80(br t, J=7.2Hz, 3H); LCMS (ESI, M+1): m / z=618.3. Example 550 4-(4-(3-Azabicyclo[4.2.1]nonan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0427] To a solution of 3-azabicyclo[4.2.1]nonane (20.5 mg, 3.0 equiv, HCl) in DMF (0.1 mL) was added K 3 PO 4 (44.8 mg, 5.0 equiv). The mixture was stirred at 25 ° C for 0.5 hours. Then, 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (25.0 mg, 1.0 equiv) and ACN (0.1 mL) were added. The mixture was stirred at 40 ° C for 11.5 hours. The resulting mixture was filtered and purified by preparative HPLC [Waters Xbridge 150×25 mm×5 um; A: water (0.1% NH 4 HCO 3 ), B: ACN, B%: 56%-86%, over 8 min] and lyophilized to give the title compound (6.07 mg, 23% yield) as a white solid; 1H NMR (400MHz, DMSO-d6) δ = 10.19-9.66 (m, 1H), 9.11 (s, 1H), 7.77 (dd, J = 6.0, 9.2Hz, 1H), 7.38-7.3 2(m,2H),7.04(d,J=2.8Hz,1H),5.38-5.21(m,1H),4.32-3.76(m,6H),3.70-3.62(m,1H),3.09(br d,J=6.4Hz,2H),3.01(s,1H),2.83(br d,J=6.0Hz,1H),2.65-2.61(m,1H),2.13(br d,J=4.8Hz,2H),2.03-1.71(m,10H),1.67-1.54(m,2H),1.46-1.38(m,1H),1.24(s,1H),0.77-0.70(m,3H); LCMS(ESI,M+1):m / z=618.3. Example 551 4-(4-(3-Azabicyclo[3.3.1]nonan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0428] The title compound was synthesized according to the procedure described for Example 550 to yield the desired compound as a white solid; 1 H NMR (400MHz, DMSO-d6) δ = 9.95 (br s,1H),9.16(s,1H),7.77(dd,J=6.0,9.2Hz,1H),7.39-7.31(m,2H),7.04(d,J=2.4Hz,1H),5.39- 5.21(m,1H),4.74-4.64(m,2H),4.19-4.08(m,2H),3.78-3.65(m,4H),3.12-3.07(m,2H),2.83(br d,J=6.0Hz,2H),2.07(br d,J=10.8Hz,5H),1.91-1.72(m,8H),1.67(br s, 2H), 1.48-1.41 (m, 1H), 0.73 (t, J = 7.2Hz, 3H); LCMS (ESI, M+1): m / z = 618.5. Example 552 4-(4-(2-Azabicyclo[3.3.1]nonan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0429] The title compound was synthesized according to the procedure described for Example 550 to yield the desired compound as a white solid; 1 H NMR (400MHz, DMSO-d6) δ=10.03-9.86(m,1H),9.16(d,J=5.2Hz,1H),7.76(dd,J=6 .0,9.0Hz,1H),7.38-7.32(m,2H),7.03-6.99(m,1H),5.36-5.20(m,1H),5.04(br d,J=9.9Hz,1H),4.38-4.27(m,1H),4.19-3.93(m,4H),3.13-3.00(m,4H),2.82(br d,J=6.4Hz,1H),2.33(br s,2H),2.12(br d, J=3.5Hz, 4H), 2.02-1.86 (m, 5H), 1.83-1.72 (m, 6H), 0.73 (brt, J=6.8Hz, 3H); LCMS (ESI, M+1): m / z=618.5. Example 553 5-Ethyl-4-(4-(4-ethynyl-4-fluoropiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol

[0430] The title compound was synthesized according to the procedure described for Example 544 to yield the desired compound as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ = 9.08 (s, 1H), 7.67 (dd, J = 5.8, 9.2 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.24 (t, J = 9.6 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 5.47-5.14 (m, 1H), 4.37-4.22 (m, 3H), 4. 22-4.07(m,4H),3.28-3.16(m,3H),3.01(dt,J=5.6,9.2Hz,1H),2.57-2.40(m,1H),2. 33-2.09 (m, 8H), 2.03-1.85 (m, 3H), 0.79 (t, J = 7.2Hz, 3H); LCMS (ESI, M+1): m / z = 620.3. Example 554 4-(4-(5-oxaspiro[3.4]octan-2-ylamino)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0431] The title compound was synthesized according to the procedure described for Example 538 (except no 4A molecular sieves were added) to yield the desired compound as a white solid; 1 H NMR (400MHz, methanol-d4) δ=9.31-9.19(m,1H),7.68(dd,J=6.0,9.2Hz,1H),7.31(d,J=2.8Hz,1H ),7.25(t,J=9.6Hz,1H),7.04(d,J=2.8Hz,1H),5.62-5.31(m,1H),4.62-4.35(m,4H),3.84( t,J=6.4Hz,2H),3.69-3.49(m,3H),2.70-2.61(m,2H),2.52-2.39(m,5H),2.36-2.27(m,1H ), 2.23-2.12 (m, 3H), 2.07-1.98 (m, 5H), 0.78 (t, J = 7.6Hz, 3H); LCMS [ESI, M+1]: m / z = 620.3. Example 555 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0432] Step A (4aR,7aS)-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4-b][1, 4]Oxazine-4(4aH)-carboxylic acid tert-butyl ester A mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (20.0 mg, 1.0 eq), (4aS,7aR)-tert-butyl 3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carboxylate (9.80 mg, 1.1 eq, HCl), K 3 PO 4 (35.8 mg, 5.0 eq) in DMF (0.5 mL) was degassed and stirred at 40° C. under N 2 atmosphere for 2 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 mL×3). The combined organic layers were washed with brine (8 mL), dried over Na 2 SO 4 , filtered and purified by preparative HPLC [C18, 0.1% formic acid conditions] to give the title compound (20 mg, 82.0% yield) as a white solid; 1 H NMR (400 MHz, chloroform-d) δ = 9.22-9.03 (m, 1H), 7.51 (br d,J=4.4Hz,1H),7.21-7.09(m,2H),7.07-6.95(m,1H),5.41-5.16(m,1 H),4.81-4.49(m,1H),4.35-4.02(m,6H),4.01-3.72(m,3H),3.66-3.50 (m,1H),3.40-3.13(m,4H),3.05-2.95(m,1H),2.53-2.36(m,1H),2.34 -2.20(m,2H),2.19-2.07(m,2H),2.01-1.88(m,3H),0.87-0.74(m,3H).

[0433] Step B 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)-4-((4aR,7aS)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)pyrido[4,3-d]pyrimidine-7- 1-Hydroxynaphthalene-2-olTo a solution of tert-butyl (4aR,7aS)-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)hexahydropyrrolo[3,4-b][1,4]oxazine-4(4aH)-carboxylate (20.0 mg, 1.0 equiv) in DCM (0.3 mL) was added HCl·dioxane (0.3 mL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (17 mg, HCl salt) as a yellow solid. 1 H NMR (400 MHz, methanol-d4) δ = 9.54-9.34 (m, 1H), 7.74 (dd, J = 6.0, 9.2 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.32 (t, J = 9.2 Hz, 1H), 7.19 (br d,J=2.8Hz,1H),5.72-5.48(m,1H),5.05-4.91(m,2H),4.74-4.50(m,3H ),4.48-4.24(m,3H),4.20-4.02(m,2H),4.02-3.84(m,4H),3.71-3.62(m ,1H),3.60(s,1H),3.49(dt,J=6.0,10.4Hz,1H),2.83-2.62(m,2H),2.5 8-2.44(m,2H),2.42-2.33(m,2H),2.29-2.15(m,2H),0.91-0.82(m,3H); 19 F NMR (376 MHz, methanol-d4) δ = -120, -136, -174; LCMS (ESI, M+1): m / z = 621.4. Example 556 6-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)morpholin-3-one

[0434] The title compound was synthesized according to the procedure described for Example 538 to yield the desired compound as a white solid; 1H NMR (400 MHz, methanol-d4) δ = 0.79 (t, J = 7.2 Hz, 3H) 1.96-2.07 (m, 1H) 2.09-2.20 (m, 3H) 2.25 (br d,J=8.8Hz,1H)2.30-2.54(m,3H)3.16-3.25(m,1H)3.33-3.41(m,1H)3.43-3.54(m,4H)3.78-3.99(m,2H)4.13-4.29(m,3H)4.40- 4.53(m,2H)5.32-5.52(m,1H)7.04(d,J=2.4Hz,1H)7.25(t,J=9.2Hz,1H)7.31(d,J=2.8Hz,1H)7.68(dd,J=9.2,5.6Hz,1H)8.49(br s, 1H) 9.22 (s, 1H); LCMS (ESI, M+1): m / z=623.2. The title compound was synthesized according to the procedure described for Example 538 to produce the desired compound (0.34 formate salt) as a white solid; 1 H NMR (400 MHz, methanol-d4) δ = 0.79 (t, J = 7.2 Hz, 3H) 1.96-2.07 (m, 1H) 2.09-2.20 (m, 3H) 2.25 (br d,J=8.8Hz,1H)2.30-2.54(m,3H)3.16-3.25(m,1H)3.33-3.41(m,1H)3.43-3.54(m,4H)3.78-3.99(m,2H)4.13-4.29(m,3H)4.40- 4.53(m,2H)5.32-5.52(m,1H)7.04(d,J=2.4Hz,1H)7.25(t,J=9.2Hz,1H)7.31(d,J=2.8Hz,1H)7.68(dd,J=9.2,5.6Hz,1H)8.49(br s,1H)9.22(s,1H). Example 557 5-Ethyl-6-fluoro-4-(8-fluoro-4-((3R,5R)-3-fluoro-5-methoxypiperidin-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0435] The title compound was synthesized according to the procedure described for Example 538 (except no 4A molecular sieves were added) to yield the desired compound as a white solid; 1H NMR (400MHz, methanol-d4) δ = 9.22 (d, J = 5.6 Hz, 1H), 7.68 ( dd, J = 5.6, 9.2 Hz, 1H), 7.31 ( d, J = 2.8 Hz, 1H), 7. 25(t,J=9.6Hz,1H),7.07(dd,J=2.8,10.8Hz,1H),5.55-5.39(m,1H),5.15-4.99(m,1H),4.61-4.43 (m,3H),4.34-4.15(m,2H),3.90-3.65(m,3H),3.65-3.54(m,2H),3.42(s,1H),3.37(s,2H),2.63-2 .39(m,3H),2.37-2.26(m,2H),2.25-1.95(m,6H),0.78(t,J=7.6Hz,3H); LCMS(ESI,M+1):m / z=626.4 Example 558 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazepane 1-oxide

[0436] To a solution of NaIO4 (33.2 mg, 1.1 eq) in water (1 mL) was added a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(1,4-thiazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (90.0 mg, 1.0 eq) in MeOH (0.8 mL) and dioxane (0.6 mL) at 0°C, and the reaction was stirred at 15°C for 12 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The organic layer was washed with brine (10 mL) and dried over Na2SO4. The solvent was concentrated and purified by preparative HPLC [column: Waters Xbridge 150×25 mm×5 μm; A: water (10 mM NH 4 HCO 3 ), B: ACN, B%: 33%-63% over 8 min] to give the title compound (45.1 mg, 49% yield) as a yellow oil. 1H NMR (400MHz, methanol-d4) δ = 9.21 (s, 1H), 7.68 (dd, J = 5.6, 9.2Hz, 1H), 7.40-7.17 (m, 2H), 7.04 (dd, J = 2.4, 17.2Hz, 1H), 5.43-5.21 (m, 1H), 4.51 (br d,J=1.8Hz,1H),4.43-4.04(m,5H),3.40(br s,2H),3.35(br s,1H),3.29-3.09(m,3H),3.08-2.77(m,3H),2.59-2.41(m,1H),2.39-2.09 (m, 5H), 2.08-1.78 (m, 3H), 0.87-0.72 (m, 3H); LCMS (ESI, M+1): m / z=626.3. Example 559 3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carbonitrile

[0437] The title compound was synthesized according to the procedure described for Example 544 to yield the desired compound as a white solid (0.31 formate salt); 1 H NMR (400 MHz, methanol-d4) δ = 9.17-9.03 (m, 1H), 8.51 (br s, 1H), 7.68 (dd, J = 6.0, 8.8 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.25 (t, J = 9.6 Hz, 1H), 7.05 (br s,1H),5.54-5.22(m,1H),4.77-4.68(m,2H),4.47-4.33(m,2H),3.99-3.85(m,1H),3.73-3.59(m,1H),3.56-3.3 6(m,3H),3.25-3.02(m,2H),2.80-2.63(m,2H),2.51-2.30(m,3H),2.24-2.03(m,5H),2.00-1.83(m,2H),1.75(br t, J=8.4Hz, 2H), 0.79 (br t, J=7.2Hz, 3H); LCMS [ESI, M+1]: m / z=629.3. Example 560 (1R,5S,8R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carbonitrile Example 561 (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carbonitrile

[0438] 3-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-8-carbonitrile was purified by SFC (column: DAICEL CHIRALCEL OJ (250 mm×30 mm, 10 um); mobile phase: [0.1% NH 3 H 2 O ETOH]; B%: 50%-50%, 4.0 min) to give Example 560 (5.41 mg, 13% yield) as a yellow solid. 1 H NMR (400MHz, CD3OD) δ = 9.11 (s, 1H), 7.64 (dd, J = 6.0, 9.2Hz, 1H), 7.26 (d, J = 2.4Hz, 1H), 7.22 (t, J = 9.6Hz, 1H), 7.04 (d, J = 2.8Hz, 1H),5.39-5.21(m,1H),4.79-4.62(m,2H),4.36-4.17(m,2H),3.98-3.86(m,2H),3.29-3.13(m,3H),3.05-2.97(m,2H),2.68(br s, 2H), 2.54-2.42 (m, 1H), 2.38-2.20 (m, 2H), 2.19-2.07 (m, 2H), 2.07-1.90 (m, 3H), 1.89-1.82 (m, 2H), 1.80-1.67 (m, 2H), 0.79 (br t, J = 6.0 Hz, 3H). LCMS ([ESI, M+1):]: m / z = 629.3. Example 561 (13.8 mg, 33.8% yield) was obtained as a white solid. 1H NMR (400MHz, CD3OD) δ = 9.04 (s, 1H), 7.67 (dd, J = 6.0, 9.6Hz, 1H), 7.30 (d, J = 2.8Hz, 1H), 7.25 (t, J = 9.6Hz, 1H), 7.05 (d, J = 2.8Hz, 1H),5.41-5.22(m,1H),4.79-4.69(m,2H),4.35-4.22(m,2H),3.70-3.59(m,2H),3.29-3.16(m,4H),3.07-2.99(m,1H),2.75(br s,2H),2.54-2.42(m,1H),2.40-2.20(m,2H),2.19-2.10(m,2H),2.06-1.96 (m,4H),1.95-1.87(m,1H),1.81-1.73(m,2H),0.79(dt,J=2.0,6.8Hz,3H). LCMS([ESI,M+1):]:m / z=629.3. Example 562 4-(4-(7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepin-5(6H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0439] The title compound was synthesized according to the procedure described for Example 541 to yield the desired compound as a white solid (0.09 formate salt); 1 H NMR (400MHz, methanol-d4)δ=9.27-9.15(m,1H),7.94-7.82(m,1H),7.74-7.60(m,1H),7.39-7.20(m,2H),7.11-6.96(m,1H) ,5.66-5.48(m,1H),5.46(s,2H),4.82-4.72(m,2H),4.70-4.45(m,4H),4.06-3.75(m,3H),3.53-3.36(m,1H),2.40(br s, 6H), 2.38-2.25 (m, 2H), 2.23-2.07 (m, 2H), 0.84-0.70 (m, 3H); LCMS (ESI, M+1): m / z=631.3. Example 563 4-(4-(6,7-dihydro-5H-[1,2,4]triazolo[4,3-a][1,4]diazepin-8(9H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0440] Step A 8-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3- d]pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a][1,4]diazepine To a mixture of 2,4-dichloro-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidine (146 mg, 0.80 eq) and 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a][1,4]diazepine (56.0 mg, 1.0 eq) in DMF (1.0 mL) was added DIPEA (157 mg, 3.0 eq) and Molecular sieves (22.81 mg). The mixture was stirred at -40 ° C for 0.2 hours. The mixture was purified by column chromatography [SiO 2, petroleum ether / ethyl acetate 1: 1] to give the title compound as a white solid (200 mg, 89% yield). LCMS (ESI, M+1): m / z = 552.1.

[0441] Step B 8-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-[1, 2,4]triazolo[4,3-a][1,4]diazepine To a mixture of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methanol (115 mg, 2.0 equiv) and 8-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a][1,4]diazepine (200 mg, 1.0 equiv) in dioxane (5.0 mL) was added DIPEA (140 mg, 3.0 equiv) and To the mixture was added 4-[ ...

[0442] Step C 4-(4-(6,7-dihydro-5H-[1,2,4]triazolo[4,3-a][1,4]diazepin-8(9H)-yl)- 8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-7- 1-Hydroxy-5-ethyl-6-fluoronaphthalen-2-ol To a solution of 8-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a][1,4]diazepine (20.0 mg, 1.0 equiv) in dichloromethane (5.0 mL) was added HCl / MeOH (0.5 mL). The mixture was stirred at 0° C. for 1 hour. The mixture was concentrated and purified by preparative HPLC [column: waters Xbridge 150×25 mm×5 μm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 27%-57%, 9 min] and lyophilized to give the title compound (4.0 mg, 21% yield, 99% purity) as a white oil (0.26 formate salt). 1 H NMR (400 MHz, methanol-d4) δ = 9.17 (s, 1H), 8.41 (br s,1H),8.34(s,1H),7.57(dd,J=6.0,9.2Hz,1H),7.20(d,J=2.4Hz,1H),7.15(t,J=9.2Hz,1H),6.94(d,J=2.0Hz,1H),5.41-5.18(m,3H),4.43- 4.33 (m, 2H), 4.30-4.18 (m, 4H), 3.52-3.24 (m, 3H), 3.11-2.99 (m, 1H), 2.38-1.90 (m, 11H), 0.67 (t, J = 7.2Hz, 3H); LCMS (ESI, M+1): m / z = 631.2. Example 564 4-(4-(3-(4H-1,2,4-triazol-4-yl)pyrrolidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0443] The title compound was synthesized according to the procedure described for Example 544 to yield the desired compound as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ = 9.16 (s, 1H), 8.67 (s, 2H), 7.50 (dd, J = 6.0, 8.8 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.08 (t, J = 9.2 Hz, 1H), 6.92 (d, J = 2.8 Hz, 1H), 5.38-5.04 (m, 2H) ,4.59-4.39(m,1H),4.31-4.05(m,5H),3.17-3.03(m,3H),2.90(dt,J=6.0,9.2Hz, 1H),2.64(brdd,J=4.8,6.8Hz,1H),2.55-2.32(m,2H),2.29-2.07(m,2H),2.02(br dd, J=8.0, 9.6Hz, 2H), 1.93-1.70 (m, 3H), 0.68 (br t, J=7.2Hz, 3H); LCMS (ESI, M+1): m / z=631.3. Example 565 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(1-(hydroxymethyl)-5-methyl-3-azabicyclo[3.1.1]heptane-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0444] The title compound was synthesized according to the procedure described for Example 538 to yield the desired compound as a white solid. 1 H NMR (400MHz, methanol-d4) δ = 9.49 (s, 1H), 7.68 (dd, J = 6.0, 8.8Hz, 1H), 7.35-7.20 (m, 2H), 7.06 (d, J = 2.4Hz, 1H), 5.57-5.25 (m, 1H) ,4.65-4.37(m,3H),4.28-3.98(m,4H),3.72-3.38(m,4H),3.25-3.04(m,1H),2.55-2.25(m,4H),2.20-1.96(m,4H),1.75(br d,J=6.8Hz,2H),1.64(br d,J=6.4Hz,2H),1.27(s,3H),0.80(br t, J=7.2Hz, 3H); LCMS (ESI, M+1): m / z=634.5 Example 566 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-3-methylpyrrolidine-2,5-dione

[0445] To a solution of 3-(aminomethyl)-3-methyl-pyrrolidine-2,5-dione (11.0 mg, 1.01 eq., 2HCl) in DMF (1 mL) was added K3PO4 (53.7 mg, 5.0 eq.) and Molecular sieves (30 mg). The mixture was stirred at 40 ° C for 0.5 hours. A solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (30.0 mg, 1.0 equivalent) in ACN (0.4 mL) was added. The mixture was stirred at 40 ° C for 15.5 hours. The reaction mixture was diluted with DMF (1 mL) and filtered. The filtrate was purified by preparative HPLC [Phenomenex Luna C18 150×25 mm×10 um; A: water (FA), B: ACN, B%: 12%-42%, over 11 min], and further purified again by preparative HPLC [Waters Xbridge 150×25 mm×5 um; A: water (NH4HCO3), B: ACN, B%: 33%-63%, over 9 min] and lyophilized to give the title compound (3.95 mg, 12% yield) as an off-white solid; 1 H NMR (400MHz, methanol-d4) δ = 9.23 (s, 1H), 7.70 (dd, J = 5.9, 9.0Hz, 1H), 7.33 (d, J = 2.6Hz, 1H), 7.27 (t, J = 9.4Hz, 1H), 7. 08-7.05(m,1H),5.63-5.39(m,1H),4.67-4.48(m,2H),4.17(dd,J=13.8,15.7Hz,1H),3.91-3.83(m,1H),3.80(br s,3H),3.08(d,J=18.0Hz,1H),2.66(br d, J=18.0Hz, 1H), 2.61-2.42 (m, 3H), 2.41-2.08 (m, 6H), 1.47 (s, 3H), 0.80 (br t, J=7.2Hz, 3H); LCMS (ESI, M+1): m / z=635.4. Example 567 (7S,8aS)-2-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)octahydropyrrolo[1,2-a]pyrazin-7-ol

[0446] The title compound was synthesized according to the procedure described for Example 544 to yield the desired compound as a white solid. 1 H NMR (400MHz, methanol-d4) δ = 9.07 (s, 1H), 7.67 (dd, J = 6.0, 8.8Hz, 1H), 7.30 (d, J = 2.4Hz, 1H),7.25(t,J=9.2Hz,1H),7.04(dd,J=2.4,6.8Hz,1H),5.41-5.17(m,1H),4.77(br d,J=12.4Hz,1H),4.68(br d,J=13.2Hz,1H),4.41-4.34(m,1H),4.33-4.19(m,2H),3.66(brt,J=12.4Hz,1H),3.43-3.34(m,1H),3.28-3.14(m,4H),3.03(br d,J=10.0Hz,2H),2.50-2.36(m,4H),2.33-2.10(m,5H),2.03-1.87(m,3H), 1.56-1.41(m,1H),0.79(dt,J=2.4,7.2Hz,3H); LCMS(ESI,M+1):m / z=635.4 Example 568 (1R,5S,6R,7S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-6,7-diol

[0447] To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (100 mg, 1.0 eq) in DMF (0.5 mL) and DCM (0.5 mL) were added K3PO4 (107 mg, 3.0 eq), (1S,5R,6S,7R)-3-azabicyclo[3.2.1]octane-6,7-diol (purchased from Enamine) (46 mg, 1.5 eq, HCl) and Molecular sieves (20 mg). The mixture was stirred at 40 ° C for 12 hours. The reaction mixture was filtered and purified by preparative HPLC [Phenomenex Synergi C18 150×25 mm×10 μm; A: water (10 mM FA); B: ACN; B%: 11%-41% over 10 min] to give the title compound (25.9 mg, 24% yield) as a white solid (0.2 formate salt). 1 H NMR (400 MHz, methanol-d4) δ = 9.27 (s, 1H), 7.69-7.66 (m, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.25 (t, J = 9.6 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 5.55-5.35 (m, 1H), 4.58-4.42 (m, 2H), 4.21-4.13 (m, 2H), 3.59 (d, J = 6.4 Hz, 6H), 3 .30-3.19(m,2H),2.62-2.49(m,1H),2.48-2.37(m,4H),2.33-2.25(m,1H),2.23-2.12(m,3H),2.10-2 .02 (m, 1H), 1.93 (d, J = 12.4Hz, 1H), 1.73-1.63 (m, 1H), 0.83-0.76 (m, 3H); LCMS (ESI, M+1): m / z = 636.3. Example 569 (1R,5S,6S,7S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-6,7-diol (stereochemistry is arbitrarily assigned)

[0448] The title compound was synthesized from intermediate 5 peak 3 and 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol according to the procedure described for Example 568 to produce the desired compound as a yellow solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ = 9.43-9.14 (m, 1H), 7.70 (dd, J = 6.2, 8.8 Hz, 1H), 7.30 (br t, J = 9.6 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.06-6.93 (m, 1H), 5.41-5.16 (m, 1H), 5.02-4.69 (m, 3H), 4.52-4.42 (m, 1H), 4.22-4.08 (m, 1H), 4.01 (dd, J = 4.0, 10.4 Hz, 1H), 3.82 (br t, J = 5.2 Hz, 1H), 3.76-3.63 (m, 2H), 3.24 (br d,J=13.2Hz,1H),3.09(br d,J=9.2Hz,2H),3.01(br s,1H),2.86-2.79(m,1H),2.25(br s,1H),2.20-1.90(m,7H),1.89-1.74(m,3H),1.69(br dd,J=4.8,11.6Hz,1H),0.70(t,J=7.2Hz,3H); 1 H NMR (400MHz, chloroform-d) δ=9.22-8.84(m,1H),7.58-7.41(m,1H),7.21-7.02(m,2H),6.98-6.57( m,1H),5.38-5.08(m,1H),4.87-4.10(m,5H),4.00-3.65(m,2H),3.55-3.37(m,1H),3.29(br s,2H),3.23-2.92(m,4H),2.52-2.02(m,8H),1.91-1.74(m,3H),1.61-1.51(m,1H),1.17-1.05(m,3H); 19 F NMR (400 MHz, dimethyl sulfoxide-d6) δ = -139.353, -172.075; LCMS (ESI, M+1): m / z = 636.4. Example 570 (1R,5S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-6,7-diol (stereochemistry is arbitrarily assigned)

[0449] The title compound was synthesized from intermediate 5 peak 4 and 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol according to the procedure described for Example 568 to produce the desired compound as a white solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ = 9.97-9.90 (m, 1H), 9.11-9.06 (m, 1H), 7.80-7.73 (m, 1H), 7.39-7.30 (m, 2H), 7.04-7.00 (m, 1H), 5.38-5.19 (m, 1H), 4.91-4.84 (m, 1H), 4.71-4.62 (m, 1H), 4.47-4.38 (m, 1H), 4.28-4.18 (m, 1H), 4.17-4.10 (m, 1 H),4.07-4.02(m,2H),4.01-3.94(m,1H),3.61-3.44(m,2H),3.15-3.05(m,2H),3.02-2.99(m,1H),2.88-2.79(m,1H ),2.26-2.20(m,1H),2.20-2.11(m,2H),2.11-1.96(m,3H),1.95-1.85(m,2H),1.85-1.73(m,4H),0.75-0.69(m,3H); 19 FNMR (400 MHz, dimethyl sulfoxide-d6) δ = -119.629, -139.308, -172.150; LCMS (ESI, M+1): m / z = 636.1. Example 571 (1R,5S,6R,7R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octane-6,7-diol (stereochemistry is arbitrarily assigned)

[0450] The title compound was synthesized from intermediate 5 peak 1 and 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol according to the procedure described for Example 568 to produce the desired compound as a white solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ = 9.93-9.86 (m, 1H), 9.33-9.24 (m, 1H), 7.79-7.73 (m, 1H), 7.38-7.30 (m, 2H), 7.05-6.99 (m, 1H), 5.37-5.18 (m, 1H), 5.02-4.69 (m, 3H), 4.52-4.42 (m, 1H), 4.15-4.09 (m, 1H), 4.07-4.00 (m, 1H), 3.86-3.79 (m, 1 H),3.75-3.65(m,2H),3.28-3.22(m,1H),3.15-3.06(m,2H),3.03-2.99(m,1H),2.86-2.79(m,1H),2.34-2.31(m,1H ),2.28-2.22(m,1H),2.15-2.04(m,4H),2.02-1.91(m,2H),1.89-1.74(m,3H),1.72-1.65(m,1H),0.75-0.68(m,3H); 19 FNMR (400 MHz, dimethyl sulfoxide-d6) δ = -119.622, -139.405, -172.127; LCMS (ESI, M+1): m / z = 636.7. Example 572 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(1-(hydroxymethyl)-2-oxa-6-azabicyclo[3.2.1]octan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0451] The title compound was synthesized according to the procedure described in Example 538 to give the desired compound (0.34 formate salt) as a yellow solid. 1H NMR (400MHz, CD3OD) δ=9.56-9.11(m,1H),7.68(dd,J=6.0,8.8Hz,1H),7.31(d,J=2.8Hz,1H),7.25(t,J=9.6Hz, 1H),7.05(s,1H),5.57-5.27(m,2H),4.50-4.30(m,3H),4.28-4.13(m,1H),4.05-3.95(m,1H),3.92-3.80(m,1H ),3.78-3.69(m,2H),3.46-3.38(m,2H),3.20-3.09(m,1H),2.58-2.39(m,2H),2.38-2.25(m,2H),2.24-2.18(m ,2H),2.15-2.03(m,4H),2.02-1.90(m,2H),1.89-1.77(m,1H),0.84-0.77(m,3H); LCMS(ESI,M+1): m / z=636.3. Example 573 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1,6-dioxa-9-azaspiro[3.6]decan-9-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0452] The title compound was synthesized according to the procedure described in Example 544 to give the desired compound (0.22 formate salt) as a white solid. 1 H NMR (400MHz, CD3OD) δ = 9.56 (s, 1H), 7.68 (dd, J = 6.0, 8.8Hz, 1H), 7.34-7.21 (m, 2H), 7.0 6(dd,J=2.4,8.8Hz,1H),5.46-5.24(m,1H),4.70-4.51(m,4H),4.44-3.95(m,8H),3.92- 3.81(m,1H),3.14-3.07(m,1H),2.76-2.66(m,1H),2.63-2.37(m,3H),2.35-2.13(m,4H ), 2.11-2.03 (m, 2H), 1.99-1.88 (m, 1H), 0.86-0.75 (m, 3H); LCMS (ESI, M+1): m / z=636.4. Example 574 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-3-carboxamide

[0453] Step A tert-Butyl 3-carbamoyl-3-hydroxypiperidine-1-carboxylate: To a solution of tert-butyl 3-cyano-3-hydroxy-piperidine-1-carboxylate (4.00 g, 1 equivalent) in DCM (50 mL) was added H2SO4 (9.54 g, 5.5 equivalents) at 0 ° C. The reaction mixture was stirred at 0 ° C for 2 hours. The pH of the mixture was adjusted to about 7 with an aqueous NaOH solution (7.00 g, 9.9 equivalents, 40% in water). (Boc)2O (19.3 g, 5.0 equivalents) was added. The reaction mixture was stirred at 20 ° C for 16 hours. The reaction mixture was diluted with DCM (50 mL) and water (50 mL) and extracted with DCM (50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified by reverse phase flash chromatography [water (0.1% FA) / acetonitrile] to obtain the title compound (3.9 g, 43% yield) as a yellow oil; 1 H NMR (400MHz, chloroform-d) δ = 6.86 (br s, 1H), 4.04-3.84 (m, 2H), 3.27 (br d, J = 14.0Hz, 1H), 3.10 (br d, J = 6.4Hz, 1H), 2.83 (br t,J=12.6Hz,1H),2.12-1.96(m,1H),1.81-1.62(m,2H),1.61-1.52(m,1H),1.47(s,9H),1.35(s,9H); LCMS(ESI,M+1):m / z=245.3.

[0454] Step B 3-Hydroxypiperidine-3-carboxamide: To a solution of tert-butyl 3-carbamoyl-3-hydroxy-piperidine-1-carboxylate (1.00 g, 1.0 equiv) in MeCN (5 mL) was added HCl in dioxane (4 M, 10 mL). The reaction mixture was stirred at 20 ° C for 1 hour. The mixture was concentrated under vacuum to give the title compound (590 mg, crude, HCl) as a yellow solid.

[0455] Step C 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- (pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-3-carboxamideTo a solution of 3-hydroxypiperidine-3-carboxamide (157 mg, 2 eq., HCl), 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (257 mg, 1.0 eq.) and DIEA (280 mg, 5.0 eq.) in DMF (1 mL) was added Molecular sieves (10 mg). The reaction mixture was stirred at 40 ° C for 16 hours. The mixture was filtered and the filtrate was purified by preparative HPLC [column: Unisil3-100C18 Ultra 150×50mm×3um; A: water (FA), B: ACN, B%: 8%-38%, within 7 min], followed by preparative HPLC [column: Welch Ultimate XB-SiOH 250×50×10um; A: hexane, B: EtOH, B%: 10%-50%, within 15 min] and lyophilized to give the title compound (8.91 mg, 3.2% yield) as a white solid (0.50 formate salt); 1 HNMR (400 MHz, methanol-d4) δ = 9.23 (t, J = 2.8 Hz, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.31 (d, J = 2.8 Hz, 1H), 7.25 (t, J = 9.4 Hz, 1H), 7.06 (t, J = 2.8 Hz, 1H), 5.49-5.24 (m, 1H), 4.71 (br d,J=13.2Hz,1H),4.61-4.29(m,3H),3.94-3.84(m,1H),3.52-3.33(m,4H),3.17-3.04(m,1H),2.52-2.27(m, 4H), 2.26-2.13(m,3H), 2.11-2.02(m,2H), 2.01-1.83(m,3H), 0.85-0.73(m,3H); LCMS (ESI, M+1): m / z=637.3. Example 575 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-5-(hydroxymethyl)pyrrolidine

[0456] Step A ((5-Oxo-3-phenyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-6-yl)methyl)carbamic acid tert-Butyl ester : A mixture of tert-butyl N-(benzenesulfonylmethyl)carbamate (293.71 mg, 1.1 equivalents) in THF (15 mL) was degassed and purged with N2 three times, and then LiHMDS (1 M, 2.07 mL, 2.1 equivalents) was added to the mixture, and then stirred for 30 min at -78 ° C under N2 atmosphere. 3-phenyltetrahydro-3H, 5H-pyrrolo[1,2-c]oxazol-5-one (200 mg, 1.0 equivalents) in THF (3 mL) was added to the mixture and the resulting mixture was stirred for 30 min at -78 ° C under N2 atmosphere. The reaction mixture was quenched at -78 ° C by adding NH4Cl aqueous solution (5 mL), and then diluted with water 30 mL and extracted with ethyl acetate 60 mL (20 mL × 3). The combined organic layers were dried over Na 2 SO 4 , filtered and purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate 1:1) to give the title compound (100 mg, 30.6% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ = 1.38 (s, 9H) 1.59-1.76 (m, 1H) 2.44 (br s,2H)2.95-3.06(m,2H)3.43-3.50(m,1H)4.07-4.16(m,1H)4.17-4.24(m,1H)6.04-6.10(m,1H)6.77-6.91(m,1H)7.30-7.44(m,5H).

[0457] Step B 3-(Aminomethyl)-5-(hydroxymethyl)pyrrolidin-2-one To a solution of tert-butyl ((5-oxo-3-phenyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-6-yl)methyl)carbamate (100 mg, 1.0 eq) in dioxane (3.0 mL) was added HCl / dioxane (4 M, 1.13 mL, 15.0 eq). The mixture was stirred at 25 ° C for 2 hours. The reaction mixture was filtered to give a white solid, which was used in the next step without further purification.

[0458] Step C 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-5-(hydroxymethyl)pyrrole Alkan-2-oneTo a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthol (80 mg, 1.0 eq), 3-(aminomethyl)-5-(hydroxymethyl)pyrrolidin-2-one (40 mg, 1.6 eq) and CH3CN (1.0 mL) in DMF (1 mL) were added K3PO4 (286 mg, 1.35 mmol, 10 eq) and Molecular sieves (100 mg, 25 equivalents). The mixture was stirred at 60 ° C for 2 hours. The reaction mixture was filtered and purified by preparative HPLC [Waters Xbridge 150×25 mm×5 um; mobile phase: [water (ammonium hydroxide v / v)-ACN]; B%: 44%-74%, 9 min] to give the title compound (6.1 mg, 6.71% yield) as a white solid; 1 H NMR (400MHz, methanol-d4) δ = 0.81 (br t, J = 7.6Hz, 3H) 1.77-1.90 (m, 1H) 1.92-2.07 (m, 3H) 2.11-2.29 (m, 4H) 2.37 (br d,J=4.4Hz,1H)2.40-2.54(m,2H)2.99-3.13(m,2H)3.15-3.29(m,3H)3.47-3.58(m,2H)3.67(dd,J=11.2,4.4Hz,1H)3.77(br d,J=4.4Hz,1H)3.86-3.98(m,1H)3.99-4.08(m,1H)4.29-4.39(m,2H)5.26(br s, 1H) 7.06 (s, 1H) 7.23-7.35 (m, 2H) 7.69 (dd, J = 9.2, 6.0Hz, 1H) 9.16 (s, 1H); LCMS (ESI, M+1): m / z = 637.3. Example 576 (3S,5R)-3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-5-(hydroxymethyl)pyrrolidin-2-one

[0459] Step A.( ((3S,6S,7aR)-5-oxo-3-phenyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-6-yl)methane (amino) carbamate:A mixture of tert-butyl N-(p-tolylsulfonylmethyl)carbamate (232 mg, 1.1 equivalents) in THF (3.0 mL) was degassed and purged with nitrogen 3 times, and then LDA (2 M, 2.0 equivalents) was added. The mixture was then stirred at -78 ° C under a nitrogen atmosphere for 30 minutes. And then (3S, 7aR) -3-phenyltetrahydropyrrolo [1,2-c] oxazol-5 (3H) -one (150 mg, 1.0 equivalents) in THF (3.0 mL) was added to the mixture and stirred at -78 ° C under a nitrogen atmosphere for 30 minutes. The mixture was quenched with NH4Cl aqueous solution (5.0 mL) at -78 ° C and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, concentrated and purified by column chromatography [SiO 2 , petroleum ether / ethyl acetate 1:1] to give the title compound as a yellow oil (30.0 mg, 12% yield); LCMS (ESI, M-55): m / z = 277.0

[0460] Step B.( 3S,5R)-3-(Aminomethyl)-5-(hydroxymethyl)pyrrolidin-2-one To a solution of (((3S,6S,7aR)-5-oxo-3-phenyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-6-yl)methyl)carbamate (30.0 mg, 1.0 equiv) in ACN (1.0 mL) was added HCl / dioxane (4.0 M, 1.0 mL). The mixture was stirred at 25 ° C for 6 hours. The reaction mixture was concentrated and purified by preparative TLC [SiO , DCM / MeOH 10 / 1] to give the title compound (10.0 mg, 76% yield) as a yellow solid.

[0461] Step C.( 3S,5R)-3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2- (5H)-(4-((4-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-5-(hydroxymethyl)- 1-Methyl-2-pyrrolidin-2-one To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthol (10.0 mg, 1.0 equiv) in dimethylformamide (1.0 mL) were added K3PO4 (20.0 mg, 1.0 equiv), (3S,5R)-3-(aminomethyl)-5-(hydroxymethyl)pyrrolidin-2-one (5.00 mg, 2.5 equiv) and Molecular sieves (10.0 mg). The mixture was stirred at 60 ° C for 2 hours. The mixture was filtered, concentrated and purified by preparative HPLC [column: Waters Xbridge 150×25 mm×5 um; mobile phase: water (ammonium hydroxide v / v)-ACN; B%: 22%-52%, 9 min] and lyophilized to give the title compound as a yellow solid (2.70 mg, 24% yield); 1 H NMR(400MHz,DMSO-d6)δ=9.92(br s,1H),9.30(s,1H),7.83-7.73(m,2H),7.38-7.31(m,2H),7.00(d,J=1.2Hz,1H),5.48-5 .09(m,1H),4.94-4.71(m,1H),4.21-4.03(m,2H),3.97-3.86(m,1H),3.62-3.50(m,2H), 3.15-2.99(m,3H),2.91-2.77(m,2H),2.73-2.62(m,1H),2.36-2.30(m,2H),2.15-1.99( m,4H),1.88-1.75(m,3H),1.66-1.56(m,1H),1.23(s,1H),1.05(t,J=7.2Hz,1H),0.71(br t, J=7.2Hz, 3H), LCMS (ESI, M+1): m / z=637.2 Example 577 1-((R)-2-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)propyl)-3-methylazetidin-3-ol

[0462] The title compound was synthesized according to the procedure described in Example 544 (except that 4A molecular sieves were not added) to give the desired compound (1 formate salt) as a white solid; 1H NMR (400 MHz, methanol-d4) δ = 9.24 (s, 1H), 8.40 (br s, 1H), 7.69 (dd, J = 6.0, 8.8 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.29-7.22 (m, 1H), 7.09-7.02 (m, 1H), 5.65-5.25 (m, 1H), 4.83-4.70 (m, 1H), 4.65-4.53 (m, 2H), 4.19-3.51 (m, 8H), 3 .24-3.12(m,1H),2.71-2.31(m,4H),2.39-2.20(m,1H),2.29-2.04(m,4H),1.49(d,J=5 .6Hz, 3H), 1.42 (dd, J=4.4, 6.6Hz, 3H), 0.90-0.66 (m, 3H); LCMS (ESI, M+1): m / z=637.4. Example 578 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-((S)-2-(2-hydroxyethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0463] The title compound was synthesized according to the procedure described in Example 538 to give the desired compound as a brown solid; 1 HNMR (400MHz, methanol-d4) δ = 9.14 (d, J = 4.4Hz, 1H), 7.67 (dd, J = 5.6, 9.2Hz, 1H), 7.30 (d, J = 2. 8Hz,1H),7.25(t,J=9.2Hz,1H),7.06(dd,J=2.8,9.6Hz,1H),5.45-5.14(m,1H),4.56(br t,J=14.8Hz,1H),4.37-4.20(m,4H),4.17-4.03(m,2H),3.75(br t,J=5.2Hz,2H),3.70-3.56(m,2H),3.28-3.12(m,3H),3.08-2.96(m,1H),2.55-2.42(m,1 H), 2.35-2.08 (m, 6H), 2.04-1.77 (m, 5H), 0.85-0.71 (m, 3H); LCMS (ESI, M+1): m / z=638.3. Example 579 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(5,7,8,9-tetrahydro-6H-pyrido[3,2-c]azepin-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0464] The title compound was synthesized according to the procedure described in Example 541 to give the desired compound as a white solid (0.8g formate salt); 1 H NMR (400MHz, methanol-d4) δ = 9.17 (s, 1H), 8.37 (dd, J = 1.2, 4.0Hz, 1H), 7.96 (d, J = 7.6 Hz,1H),7.68(dd,J=6.0,9.2Hz,1H),7.36-7.29(m,2H),7.25(t,J=9.2Hz,1H),7 .04(d,J=2.8Hz,1H),5.57-5.37(m,1H),5.25-5.21(m,2H),4.51-4.33(m,4H),3 .81-3.56(m,3H),3.30-3.19(m,3H),2.60-2.06(m,10H),0.77(t,J=7.6Hz,3H). LCMS (ESI, M+1): m / z=641.4. Example 580 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)4-(3-(S-methylsulfonylimino)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0465] The title compound was synthesized according to the procedure described in Example 538 to give the desired compound as an off-white solid; 1HNMR (400MHz, methanol-d4) δ = 9.26 (s, 1H), 7.62 (br dd, J = 6.0, 8.8Hz, 1H), 7.24 (d, J = 2.4Hz, 1H), 7.19 (t, J = 9.6Hz, 1H), 7.04 (br d,J=2.4Hz,1H),5.41-5.20(m,1H),4.45(br s,2H),4.34(br dd,J=4.0,10.4Hz,2H),4.30-4.24(m,1H),4.22-4.04(m,2H),3.27-3.15(m,3H),3.12(s,3H),3.04-2.97(m,1H),2.61(br d,J=4.0Hz,2H),2.45(br d,J=4.8Hz,1H),2.39-2.19(m,2H),2.17-2.07(m,2H),2.02-1.85(m,3H),0.78(br t, J=7.2Hz, 3H); LCMS (ESI, M+1): m / z=641.3. Example 581 4-(4-(4,4-difluoro-5-methylazepan-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0466] The title compound was synthesized following the procedure described in Example 544 to give the desired compound as a white solid. 1 HNMR (400MHz, methanol-d4) δ = 9.16 (s, 1H), 7.67 (dd, J = 5.6, 8.8Hz, 1H), 7.30 (d, J = 2.4Hz, 1H), 7.25 (s, 1H), 7.05 (br s,1H),5.50-5.15(m,1H),4.44-3.89(m,7H),3.17-2.98(m,1H),2.64-2.41(m,3H),2 .37-1.67(m,12H),1.12-1.00(m,3H),0.84-0.75(m,3H); LCMS(ESI,M+1): m / z=642.3. Example 582 4-(4-(8,9-dihydro-5H-pyrimido[5,4-c]azepin-6(7H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0467] The title compound was synthesized following the procedure described in Example 541 using Intermediate 6 to give the desired compound (0.3% formate salt) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ = 9.19 (s, 1H), 8.95 (s, 1H), 8.89 (s, 1H), 7.68 (dd, J = 5.6, 9.2 Hz, 1H), 7.33-7.21 (m, 2H), 7.04 (d, J = 2.8 Hz, 1H), 5.48-5.30 (m, 1H), 5.27-5.13 (m, 2H), 4.54-4 .38(m,2H),4.35-4.19(m,2H),3.56-3.38(m,3H),3.27-3.10(m,3H),2.54-2.27(m,5H), 2.26-2.07 (m, 4H), 2.05-1.91 (m, 1H), 0.78 (t, J = 7.2Hz, 3H); LCMS (ESI, M+1): m / z = 642.3. Example 583 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-thiazane 1,1-dioxide

[0468] The title compound was synthesized following the procedure described in Example 541 to give the desired compound (0.3% formate salt) as a white solid. 1H NMR (400 MHz, methanol-d4) δ = 9.20 (s, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.31 (d, J = 2.8 Hz, 1H), 7.26 (t, J = 9.2 Hz, 1H), 7.05 (d, J = 2.8 Hz, 1H), 5.51-5.26 (m, 1H), 4.54-4.20 (m, 6H), 3.73 (br t,J=5.2Hz,2H),3.61-3.34(m,5H),3.24-3.12(m,1H),2.56-2.45(m,3H),2.44-2.29(m ,2H),2.27-2.05(m,4H),2.05-1.95(m,1H),0.86-0.71(m,3H); (ESI,M+1):m / z=642.3. Example 584 4-(4-(8,9-dihydro-5H-[1,2,3]triazino[5,4-c]azepin-6(7H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0469] The title compound was synthesized following the procedure described in Example 541 using Intermediate 7 to give the desired compound as a yellow solid. 1 H NMR (400MHz, methanol-d4) δ = 9.32 (s, 1H), 9.19 (s, 1H), 7.68 (dd, J = 6.0, 9.2Hz, 1H), 7.30 (s, 1H), 7.25 (t, J = 9.6Hz, 1H), 7.07 -7.01(m,1H),5.42-5.22(m,1H),5.22-5.10(m,1H),4.60-4.13(m,3H),4.10-3.95(m,1H),3.49-3.33(m,2H),3.13(br s,4H),3.09-2.95(m,1H),2.55-2.41(m,2H),2.39(br s,1H),2.22-2.10(m,3H),2.08-1.95(m,3H),1.94-1.80(m,1H),0.84-0.73(m,3H); LCMS(ESI,M+1): m / z=643.1. Example 585 4-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-1-carbonitrile

[0470] Step A 4-((2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4, 3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-1-carbonitrile To a solution of 2,4-dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidine (15 mg, 1.0 eq) and excess 4-aminobicyclo[2.2.2]octane-1-carbonitrile in DMF (3.0 mL) was added DIPEA (38.7 mg, 3.0 eq) and Molecular sieves (45 mg, 9.0 equivalents). The mixture was stirred at -40 ° C for 0.2 hours. The mixture was diluted with ethyl acetate (30 mL) and filtered. The filtrate was washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (70 mg, crude product). The crude product was used in the next step without further purification; LCMS (ESI, M+1): m / z=564.2

[0471] Step B 4-((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)- 2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane- 1-carbonitrile To a solution of 4-((2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-1-carbonitrile (55 mg, 1.0 equiv) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methanol (46.6 mg, 3.0 equiv) in THF (3 mL) was added DIPEA (63 mg, 5.0 equiv) and To the mixture was added 4-[ ...

[0472] Step C 4-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- (1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-1-carbonitrileTo a solution of 4-((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-1-carbonitrile (20 mg, 1.0 equiv) in MeOH (1.5 mL) was added HCl / MeOH (4 M, 1.5 mL, 206 equiv). The mixture was stirred at 0° C. for 0.5 h. The mixture was concentrated and purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 16%-46%, 10 min) and lyophilized to give the title compound (3.8 mg, 20% yield) as a white solid; 1 H NMR (400 MHz, methanol-d4) δ = 9.27 (s, 1H), 7.67 (dd, J = 5.6, 9.2 Hz, 1H), 7.30 (d, J = 2.8 Hz, 1H), 7.24 (t, J = 9.2 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 5.54-5.26 (m, 1H), 4.52-4.26 (m, 2H), 3. 58-3.38(m,3H),3.16(dt,J=6.4,9.6Hz,1H),2.48-2.42(m,1H),2.41-2.31(m,8H),2. 25-2.07(m,11H),2.05-1.91(m,1H),0.77(t,J=7.2Hz,3H); LCMS(ESI,M+1):m / z=643.4 Example 586 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoroazepan-4-ol

[0473] The title compound was synthesized according to the procedure described in Example 538 to give the desired compound as a yellow solid. 1HNMR (400MHz, methanol-d4) δ = 0.74-0.86 (m, 3H) 1.44 (t, J = 7.2Hz, 2H) 1.89 (br s,1H)2.00(brs,2H)2.11-2.28(m,4H)2.31-2.41(m,2H)2.42-2.54(m,1H)2.70-2.90(m ,1H)2.96-3.05(m,1H)3.16-3.26(m,2H)3.43(q,J=7.2Hz,1H)3.87-3.96(m,1H)4.06(br s,1H)4.20-4.34(m,4H)5.18-5.41(m,1H)7.06(dd,J=7.6,2.4Hz,1H)7.18-7.34(m , 2H) 7.66 (dd, J=8.8, 5.6Hz, 1H) 9.17 (d, J=4.0Hz, 1H); LCMS (ESI, M+1): m / z=644.2. Example 587 4-(4-(3-((1H-pyrazol-1-yl)methyl)pyrrolidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol

[0474] The title compound was synthesized according to the procedure described in Example 541 to give the desired compound (0.44 formate salt) as a white solid. 1 H NMR(400MHz, DMSO-d6)δ0.73(br t,J=6.8Hz,3H)1.76-1.88(m,4H)1.99-2.16(m,6H)2.31-2.36(m,1H)2.80-2.91(m,3H)3.10(br d,J=8.4Hz,2H)4.06(br d,J=10.4Hz,2H)4.16(br dd,J=10.4,2.44Hz,2H)4.25-4.36(m,3H)5.19-5.38(m,1H)6.27(brd,J=2.0Hz,1H)7.01(br d, J=2.8Hz, 1H) 7.30-7.40 (m, 2H) 7.48 (br s, 1H) 7.73-7.86 (m, 2H) 8.18 (s, 1H) 9.26 (s, 1H); LCMS (ESI, M+1): m / z=644.6. Example 588 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxamide

[0475] Step A 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrimidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) oxazole-3-carboxylic acid To a solution of 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid (25.0 mg, 1.1 eq) in dimethylformamide (1.0 mL) were added K3PO4 (94.5 mg, 3.0 eq), 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (87.9 mg, 1.0 eq) and Molecular sieves (10.0 mg). The mixture was stirred at 60 ° C for 2 hours. The reaction mixture was partitioned between ethyl acetate (40 mL) and water (30 mL). The organic phase was separated and dried over Na2SO4. It was then filtered and concentrated under reduced pressure to give a yellow solid; LCMS (ESI, M+1): m / z=646.1.

[0476] Step B 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrimidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl) Azole-3-carboxamide To a solution of 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid (30 mg, 1 eq) in DMF (1 mL) was added DIPEA (12.01 mg, 2 eq) NHCl (24.8 mg, 10 eq) and HATU (53.0 mg, 3 eq). The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated and purified by preparative HPLC [column: Waters Xbridge 150×25 mm×5 um; mobile phase: [water (ammonium hydroxide v / v)-ACN]; B%: 28%-58%, 8.5 min] to give the title compound (5.6 mg, 18% yield) as a gray solid (0.6 formate salt); 1H NMR (400MHz, DMSO-d6)δ=9.73-9.28(m,1H),8.24(s,1H),7.82-7.57(m,3H),7.41-7.30(m,2H),7.03( d,J=1.6Hz,1H),5.49-5.20(m,3H),5.15-4.90(m,2H),4.25-4.10(m,2H),3.13-3.06(m,2H),2.84(br d,J=6.0Hz,2H),2.40-2.33(m,1H),2.20-2.02(m,4H),1.88-1.75(m,3H),0.74(br t, J=7.2Hz, 3H), LCMS (ESI, M+1): m / z=645.3 Example 589 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-oxa-8-azaspiro[5.5]undec-3-en-8-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0477] The title compound was synthesized according to the procedure described in Example 538 to give the desired compound as a yellow solid; 1H NMR (400 MHz, Methanol-d4) δ = 9.24-9.14 (m, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.25 (t, J = 9.6 Hz, 1H), 7.06 (dd, J = 2.8, 8.0 Hz, 1H), 5.83-5.67 (m, 2H), 5.42-5.24 (m, 1H), 4.79-4.47 (m, 4H), 4.37-4.23 (m, 2H), 4.06 (br d,J=18.0Hz,1H),3.94-3.82(m,1H),3.70-3.58(m,1H),3.23-3.18(m,1H),3.09-2.97(m,1H),2.54-2.31(m,2H),2.29 -2.18(m,2H),2.17-2.05(m,5H),2.04-1.98(m,2H),1.95-1.87(m,1H),1.80-1.64(m,2H),1.39-1.23(m,1H),0.80(br t,J=7.2Hz,3H). LCMS(ESI,M+1):m / z=646.4, Example 590 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

[0478] The title compound was synthesized using Intermediate 8 according to the procedure described in Example 541 to yield the desired compound as a white solid; (0.10 formate salt). SFC: Chiralcel OD-3 50×4.6 mm ID, 3 μm, isocratic elution: 40% methanol + ACN (0.05% DEA) in CO2, 3 mL / min, t R =0.553min, 1.073min; 1 H NMR (400 MHz, methanol-d4) δ = 9.18 (d, J =2.4Hz,1H),7.76-7.59(m,1H),7.31(d,J=2.4Hz,1H),7.25(t,J=9.2Hz ,1H),7.08-7.04(m,1H),5.55-5.22(m,1H),4.75-4.43(m,3H),4.38-4. 24(m,2H),3.90-3.50(m,2H),3.43-3.34(m,2H),3.07-2.98(m,1H),2.5 4-2.11(m,7H),1.96-1.86(m,1H),1.66-1.50(m,4H),0.84-0.76(m,3H); 19 F NMR (400 MHz, methanol-d4) δ = -121.084, -138.457, -73.675; LCMS (ESI, M+1): m / z = 647.3. Example 591 (1R,5S)-7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,7-diazabicyclo[3.3.1]nonane-2,4-dione

[0479] The title compound was synthesized using Intermediate 9 according to the procedure described in Example 541 to give the desired compound as an off-white solid (0.1 formate salt); 1H NMR (400 MHz, methanol-d4) δ = 9.04 (s, 1H), 7.70-7.66 (m, 1H), 7.34-7.19 (m, 2H), 7.07-7.06 (m, 1H), 5.45-5.31 (m, 1H), 5.01-4.97 (m, 1H), 4.42-4.25 (m, 2H), 4.01-3.78 (m, 2 H),3.55-3.33(m,3H),3.16-3.07(m,1H),2.95-2.93(m,2H),2.58-2.36(m,3H),2. 35-2.15 (m, 4H), 2.10-2.01 (m, 4H), 0.79-0.75 (m, 3H); LCMS (ESI, M+1): m / z=647.4. Example 592 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)octahydropyrido[3,4-d]pyrimidin-2(1H)-one

[0480] The title compound was synthesized according to the procedure described in Example 538 to give the desired compound as a yellow solid. 1 HNMR (400 MHz, methanol-d4) δ = 9.05 (s, 1H), 7.65 (dd, J = 6.0, 8.8 Hz, 1H), 7.30-7.19 (m, 2H), 7.04 (d, J = 2.8 Hz, 1H), 5.45-5.13 (m, 1H), 4.56-4.37 (m, 2H), 4.36-4.21 (m, 2H), 3.93-3.70 (m, 3H) ,3.44(dd,J=4.2,12.4Hz,1H),3.28-3.13(m,4H),3.05-2.96(m,1H),2.57-2.43(m,1H),2.4 1-2.26(m,2H),2.23-2.09(m,3H),2.08-1.94(m,3H),1.93-1.78(m,2H),0.85-0.72(m,3H). LCMS (ESI, M+1): m / z=648.2. Example 593 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-(1-hydroxycyclobutyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0481] The title compound was synthesized following the procedure described in Example 544 to give the desired compound as a white solid. 1 HNMR (400 MHz, methanol-d4) δ = 9.05 (s, 1H), 7.66 (dd, J = 6.0, 8.8 Hz, 1H), 7.29 (d, J = 2.8 Hz, 1H), 7.23 (t, J = 9.2 Hz, 1H), 7.06 (dd, J = 2.8, 4.4 Hz, 1H), 5.45-5.16 (m, 1H), 4.82-4.65 (m, 2H), 4 .38-4.18(m,2H),3.27-2.92(m,6H),2.62-2.41(m,2H),2.37-2.14(m,6H),2.10-2.01(m, 4H), 1.89-1.58 (m, 7H), 1.41-1.24 (m, 1H), 0.87-0.70 (m, 3H); LCMS (ESI, M+1): m / z=648.2. Example 594 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-oxa-8-azaspiro[5.5]undec-8-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0482] The title compound was synthesized according to the procedure described in Example 538 to give the desired compound (0.29 formate salt) as a yellow solid; 1H NMR (400MHz, methanol-d4) δ = 9.38-9.12 (m, 1H), 8.57 (s, 1H), 7.69 (dd, J = 6.0, 8.8Hz, 1H), 7.31 (d, J = 2.0Hz, 1H), 7.26 (t, J = 9.2Hz, 1H), 7.09 (br dd,J=2.4,5.2Hz,1H),5.49-5.13(m,1H),4.74-4.49(m,2H),4.39-4.19(m,2H),3.69-3.55(m,2H),3.50-3.41(m,1H),3.22(br d,J=20.0Hz,2H),3.09-2.95(m,1H),2.57-2.21(m,5H),2.17-1.88(m,6H),1.77-1.42(m,9H),0.82(br t, J=7.2Hz, 3H); LCMS (ESI, M+1): m / z=648.3. Example 595 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(3-(tetrahydrofuran-3-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0483] The title compound was synthesized according to the procedure described in Example 538 to give the desired compound as a yellow solid; 1HNMR (400 MHz, methanol-d4) δ = 9.02 (dd, J = 1.6, 6.0 Hz, 1H), 7.67 (dd, J = 6.0, 8.8 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.24 (t, J = 9.2 Hz, 1H), 7.14-6.98 (m, 1H), 5.39-5.22 (m, 1H), 4.71-4.47 (m, 2H), 4.36-4.20 (m, 2H), 4.02-3 .95(m,1H),3.92-3.83(m,2H),3.77-3.71(m,1H),3.55-3.49(m,1H),3.43-3.36(m,1H),3.24-3.18(m,2H ),3.08-2.95(m,2H),2.69-2.53(m,1H),2.50-2.34(m,2H),2.26-2.18(m,2H),2.14-2.10(m,2H),1.96(br dd,J=8.8,16.8Hz,3H),1.79-1.68(m,3H),1.60-1.47(m,2H),1.34-1.14(m,1H),0.89-0.73(m,3H). LCMS (ESI, M+1): m / z=648.2. Example 596 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(3-((tetrahydrofuran-3-yl)methyl)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0484] The title compound was synthesized according to the procedure described in Example 538 to give the desired compound as a white solid (0.1% formate salt); 1 H NMR (400MHz, DMSO-d6) δ = 9.29 (d, J = 5.6Hz, 1H), 7.77 (dd, J = 6.0, 8.8Hz, 1H), 7.49-7.29 (m, 2H ),7.08(m,1H),5.10(m,1H),4.28-3.99(m,5H),3.92-3.57(m,5H),3.16-2.95(m,4H),2.83(br d, J=6.2Hz, 3H), 2.45 -1.94 (m, 11H), 1.89-1.37 (m, 8H), 0.73 (q, J=7.6Hz, 3H); LCMS (ESI, M+1): m / z=648.4. Example 597 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(3-((tetrahydrofuran-2-yl)methyl)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0485] The title compound was synthesized according to the procedure described in Example 538 to give the desired compound as an off-white solid (0.2% formate salt); 1 HNMR (400 MHz, methanol-d4) δ ppm = 0.80 (q, J = 7.6 Hz, 3H) 1.48-1.60 (m, 1H) 1.68-1.85 (m, 3H) 1.94 (br d, J = 6.4 Hz, 3H) 1.99-2.06 (m, 2H) 2.07-2.20 (m, 3H) 2.20-2.41 (m, 3H) 2.41 -2.60(m,2H)3.00-3.11(m,1H)3.20-3.31(m,3H)3.33-3.46(m,1H)3.68-3.74(m,1 H)3.68-3.92(m,3H)3.92-4.02(m,1H)4.03-4.25(m,2H)4.26-4.33(m,1H)4.34-4.4 3(m,1H)5.23-5.44(m,1H)7.05(dd,J=6.8,2.32Hz,1H)7.25(t,J=9.4Hz,1H)7.30( d,J=2.4Hz,1H)7.68(dd,J=9.2,5.6Hz,1H)8.49-8.59(m,1H)9.26(d,J=4.4Hz,1H). LCMS(ESI,M+1):m / z=648.4 Example 598 2-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-7-oxa-2,9-diazaspiro[4.5]decan-8-one

[0486] The title compound was synthesized according to the procedure described in Example 544 to give the desired compound as a white solid; 1HNMR (400MHz, CD3OD) δ = 9.26 (s, 1H), 7.67 (dd, J = 6.0, 8.8Hz, 1H), 7.29 (d, J = 2.4H z,1H),7.24(t,J=9.6Hz,1H),7.04(d,J=2.8Hz,1H),5.41-5.19(m,1H),4.35-4.22 (m,6H),4.12-3.98(m,2H),3.45-3.39(m,2H),3.27-3.12(m,3H),3.05-2.97(m,1H ),2.56-2.29(m,2H),2.28-2.08(m,6H),2.01-1.86(m,3H),0.79(t,J=6.8Hz,3H). LCMS (ESI, M+1): m / z=649.1. Example 599 10-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3,10-diazabicyclo[4.3.1]decan-4-one

[0487] The title compound was synthesized following the 3-step procedure described in Example 585, except that in Step B the mixture was stirred at 100 °C for 1 h to give the desired compound (0.12 formate salt) as a yellow solid. 1 H NMR (400MHz, CD3OD) δ=9.02(s,1H),7.68(dd,J=5.6,8.8Hz,1H),7.39-7.17(m,2H),7.04(dd,J=2.4,6.0Hz,1H),5.42-5.27(m, 1H),5.14-4.91(m,4H),4.45-4.27(m,2H),4.11-3.93(m,4H),3.86-3.74(m,2H),3.20-3.01(m,3H),2.61-1.88(m,9H),0.79(br t, J=6.8Hz, 3H); LCMS (ESI, M+1): m / z=649.3. Instance 600 8-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-oxa-8-azaspiro[4.5]decan-4-ol

[0488] The title compound was synthesized according to the procedure described in Example 538 to give the desired compound as a white solid (0.41 formate salt); 1H NMR (400 MHz, Methanol-d4) δ = 0.73-0.86 (m, 3H) 1.75 (br d,J=12.8Hz,1H)1.87-2.06(m,5H)2.09-2.26(m,4H)2.32-2.42(m,2H)2.4 5-2.54(m,1H)3.14-3.25(m,1H)3.42-3.66(m,3H)3.78-3.95(m,3H)3.99- 4.10(m,2H)4.37-4.56(m,4H)5.19-5.63(m,1H)7.06(d,J=2.4Hz,1H)7.25 (t,J=9.2Hz,1H)7.31(d,J=2.4Hz,1H)7.68(dd,J=8.8,6.0Hz,1H)8.50(br s, 1H) 9.08 (s, 1H); LCMS (ESI, M+1): m / z=650.3. Example 601 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2-(2-methoxyethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0489] The title compound was synthesized according to the procedure described in Example 544 to give the desired compound as a white solid; 1 HNMR (400MHz, DMSO-d6) δ = 9.15 (d, J = 7.6Hz, 1H), 7.75-7.58 (m, 1H), 7.36-.17 (m, 2H), 6.99 (dd, J = 2.0, 9.6Hz, 1H), 5.37-5.17 (m, 1H), 4.46 (br t,J=12.4Hz,1H),4.23-3.95(m,6H),3.65-3.41(m,6H),3.15-2.96(m,4H),2.87-2.78(m,1H),2.33(br s, 1H), 2.19-1.99 (m, 6H), 1.93-1.64 (m, 6H), 0.73 (td, J = 7.2, 12.4Hz, 3H), LCMS (ESI, M+1): m / z = 652.4. Example 602 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((R)-6-(methoxymethyl)-6-methyl-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol

[0490] The title compound was synthesized according to the procedure described in Example 538 to give the desired compound (1.0 g formate salt) as a yellow solid; 1H NMR (400 MHz, Methanol-d4) δ = 9.28-9.15 (m, 1H), 8.50 (br s, 1H), 7.68 (dd, J = 6.0, 8.8 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 7.05 (dd, J = 2.4, 6.0 Hz, 1H), 5.51-5.33 (m, 1H), 4.67-4.54 (m, 1H), 4.51-4.36 (m, 3H), 4.34-4.20 (m, 2H), 4.19-4.08 (m, 3H), 3.71 (br dd,J=3.2,12.8Hz,1H),3.66-3.53(m,2H),3.52-3.42(m,2H),3.19(brd,J=9.6Hz,4H),2.54-2.32(m,3H),2.27-2.1 1(m,4H),2.06-1.97(m,1H),1.44-1.24(m,1H),0.98(d,J=14.8Hz,3H),0.86-0.76(m,3H)LCMS[ESI,M+1]:m / z=652.4 Example 603 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1-thia-7-azaspiro[3.5]nonane 1-oxide

[0491] The title compound was synthesized according to the procedure described in Example 538 to give the desired compound as a yellow solid. 1HNMR (400MHz, CD3OD) δ = 9.07 (s, 1H), 7.68 (dd, J = 6.0, 8.8Hz, 1H), 7.30 (d, J = 2.8Hz, 1H), 7. 25(t,J=9.6Hz,1H),7.05(s,1H),5.42-5.20(m,1H),4.37-4.20(m,4H),4.14-3.94(m,2H),3 .65(ddd,J=2.8,8.0,11.6Hz,1H),3.29-3.09(m,4H),3.06-2.98(m,9.2Hz,1H),2.74-2.65( m,1H),2.57-2.44(m,2H),2.39-2.26(m,2H),2.25-2.12(m,6H),2.04-1.88(m,3H),0.80(br t,J=7.6Hz,3H). LCMS (ESI, M+1): m / z=652.3. Example 604 7-(7-(8-chloro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide

[0492] Step A 7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine To a solution of 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (500 mg, 1.0 eq) and (8-chloro-3-(methoxymethoxy)naphthalen-1-yl)trimethylstannane (528 mg, 1.2 eq) in toluene (5 mL) was added Ad2nBup-Pd-G3 (83.2 mg, 0.10 eq) under N2. The reaction mixture was stirred at 90 ° C for 12 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (4×10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography [SiO2, petroleum ether / ethyl acetate 5:1 to 1:1] and reverse phase flash chromatography [C18, 0.1% formic acid conditions] to give the title compound (50.0 mg, 7.0% yield) as a yellow oil; LCMS (ESI, M+1): m / z = 625.3.

[0493] Step B 7-(7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- 1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,7-diazaspiro[4.5]decane 2, 2-dioxide To a solution of 7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (70.0 mg, 1.0 equiv) and 2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide (25.6 mg, 1.2 equiv) in dimethylformamide (0.3 mL) were added DIEA (43.4 mg, 3.0 equiv) and Molecular sieves (30 mg). The reaction mixture was stirred at 40° C. for 12 hours. The reaction mixture was filtered and purified by reverse phase flash chromatography [C18, 0.1% formic acid conditions] to give the title compound (30.0 mg, 37% yield) as a white solid.

[0494] Step C 7-(7-(8-chloro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizine- 7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide thing To a solution of 7-(7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide (30.0 mg, 1.0 equiv) in acetonitrile (0.5 mL) was added HCl·dioxane (4 M, 1.0 mL). The reaction mixture was stirred at 0 ° C for 0.5 hours. The reaction mixture was quenched with saturated aqueous NaHCO solution (5 mL) at 0 ° C and extracted with ethyl acetate (4×5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified by preparative HPLC [Waters Xbridge C18 150×50 mm×10 μm; A: water (NH 4 HCO 3 ), B: ACN; B%: 34%-64% in 10 min] to give the title compound (5.92 mg, 21% yield) as a yellow gum; 1H NMR (400MHz, DMSO-d6) δ=10.42-10.09(m,1H),9.09(d,J=4.8Hz,1H),7.85-7.82(m,1H),7.44-7.33(m,4H),7.14-7 .12(m,1H),5.43-5.11(m,1H),4.21-3.98(m,4H),3.83-3.71(m,1H),3.67-3.52(m,1H),3.25-3.16(m,2H),3.14(br s,2H),3.02-2.98(m,1H),2.86-2.77(m,1H),2.30-2.10(m,3H),2.07-2.03 (m, 1H), 2.02-1.91 (m, 3H), 1.87-1.74 (m, 5H); LCMS (ESI, M+1): m / z=671.1. Example 605 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-5,5-difluoro-4-methylazepan-4-ol

[0495] The title compound was synthesized according to the procedure described in Example 538 to give the desired compound as a yellow solid. 1 HNMR (400MHz, methanol-d4)δ=0.72-0.86(m,3H)1.34(br s,3H)1.93-2.07(m,4H)2.11-2.40(m,7H)2.43-2.54(m,1H)3.03(br d,J=5.6Hz,1H)3.18-3.28(m,3H)3.89(br d,J=1.2Hz,1H)4.11-4.41(m,6H)5.38(br s,1H)7.07(br d,J=9.6Hz,1H)7.21-7.33(m,2H)7.68(br dd, J = 8.4, 6.0 Hz, 1H) 9.17 (d, J = 4.0 Hz, 1H). LCMS (ESI, M+1): m / z=658.3. Example 606 2-((1R,3aS,6aR)-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxooctahydropyrrolo[3,4-c]pyrrol-1-yl)acetonitrile

[0496] The title compound was synthesized according to the procedure described in Example 566 using Intermediate 13B (tert-butyl (1R,3aS,6aR)-1-(cyanomethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate) to give the desired compound (0.5% formate salt) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ = 9.34 (d, J = 4.8 Hz, 1H), 8.51-8.45 (m, 1H), 7.71 (dd, J = 6.0, 9.2 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.28 (t, J = 9.2 Hz, 1H), 7.07 (t, J = 3.2 Hz, 1H), 5.56-5.41 (m, 1H), 4.63-4.58 (m,2H),4.55-4.48(m,2H),4.38-4.28(m,1H),4.08-3.95(m,2H),3.77-3.56(m,4H),3.30-3.26 (m,2H),2.92(d,J=5.6Hz,2H),2.59-2.43(m,3H),2.36-2.29(m,1H),2.25-2.16(m,3H),2.04(br s, 1H), 0.81 (q, J = 7.2Hz, 3H); LCMS (ESI, M+1): m / z = 658.2. Example 607 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-((1R,5R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.1.0]hexan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthol

[0497] The title compound was synthesized following the procedure described in Example 544 to give the desired compound as a yellow solid. 1HNMR (400MHz, methanol-d4) δ = 9.27 (d, J = 2.4Hz, 1H), 7.67 (dd, J = 6.0, 8.8Hz, 1H), 7.29 (d, J = 2.4Hz, 1H), 7.24 (t, J = 9.2Hz, 1H), 7. 04(s,1H),5.44-5.16(m,1H),4.77-4.46(m,3H),4.39-4.18(m,3H),3.27-3.11(m,3H),3.01(dt,J=5.6,9.2Hz,1H),2.64(br s,1H),2.55-2.42(m,1H),2.39-2.35(m,3H),2.31-2.09(m,4H),2.05-1.80(m,5H),1.32-1.28(m,1H),0.79(q,J=7.2Hz,3H). LCMS (ESI, M+1): m / z=658.3. Example 608 6-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyridazin-3(2H)-one

[0498] The title compound was synthesized according to the procedure described in Example 538 to give the desired compound as a white solid; 1 HNMR (400 MHz, methanol-d4) δ = 9.32 (s, 1H), 7.70 (dd, J = 6.0, 9.2 Hz, 1H), 7.63 (d, J = 9.6 Hz, 1H), 7.33 (d, J = 2.8 Hz, 1H), 7.27 (t, J = 9.2 Hz, 1H), 7.09-7.00 (m, 2H), 5.57-5.31 (m, 1H), 4.55-4.33 (m, 4H), 3.79 -3.56(m,2H),3.55-3.42(m,3H),3.26-3.11(m,2H),2.59-2.46(m,2H),2.43-2.31(m,2 H),2.29-2.22(m,1H),2.21-2.09(m,3H),2.03-1.87(m,1H),1.41-1.31(m,1H),0.82(br t,J=7.6Hz,3H). LCMS (ESI, M+1): m / z=658.3. Example 609 3-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-3-methyl-1,2,5-thiadiazolidine 1,1-dioxide

[0499] The title compound was synthesized following the procedure described in Example 541 using intermediate 11 to give the desired compound as a white solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ = 9.94 (br s, 1H), 9.36 (s, 1H), 8.92 (br d, J = 5.2 Hz, 1H)...

Claims

1. A compound having formula (I): or a pharmaceutically acceptable salt thereof, wherein: W is: A is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1-4 R 1 replace; B is: Y 1 is hydrogen, optionally substituted with 1-4 R 8 substituted L-hydroxyl, optionally substituted with 1-4 R 8 Substituted L-alkoxy, halogen, optionally substituted by 1-4 R 9 Substituted L-C3-C6 cycloalkyl, optionally substituted by 1-4 R 8 substituted L-heteroaryl, optionally substituted with 1-4 R 8 Substituted L-aryl, LC(O)-NH2, and substituted by 1-2 oxo (=O) or oxo-containing substituents and optionally further substituted by 1-2 R 8 Substituted L-heterocycle; Y 2 is hydrogen or C1-C4 alkyl; or Y 1 and Y 2 Connection formation: wherein X is selected from the group consisting of: a bond, -S-, -O-, -N< bonded to a fused ring, -CH2-, -CH2-N-, -CH2-N-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, -O-CH2-, and -S-CH2-; or Y 2 and Z to form V, where V is: Optionally 1-4 R 8 Replaced Z is hydrogen or Y 2 connect; Each R 1 are independently halogen, cyano, hydroxy, C1-C4 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, -CH2C(=O)N(R 5 )2, -C3-C4 alkynyl (NR 5 )2、-N(R 5 )2, deuterated C2-C4 alkynyl, (C1-C3 alkoxy)halogenated C1-C3 alkyl- or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted by halogen or C1-C3 alkyl; Each R 2 are independently hydrogen, hydroxy, halogen, C1-C3 haloalkyl, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, -C1-C3-N(R 5 )2, -O-(C1-C3 alkyl), -(C1-C3 alkyl)-O-(C1-C3 alkyl), -(C1-C3 alkyl)-O-(C1-C3 alkyl)-C3-C4 cycloalkyl, HC(=O)-, -L-OC(O)N(C1-C10 alkyl)2, -CO2R 5 、-CO2N(R 5 )2, =CH2, =CHR 11 or =C(R 11 )2, or two R 2 connected to form a heterocyclic ring or cycloalkyl group optionally substituted with a C1-C3 alkyl group; Each R 3 are independently hydrogen, hydroxy, halogen, C1-C3 haloalkyl, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, -C1-C3-N(R 5 )2, -O-(C1-C3 alkyl), -(C1-C3 alkyl)-O-(C1-C3 alkyl), -(C1-C3 alkyl)-O-(C1-C3 alkyl)-C3-C4 cycloalkyl, HC(=O)-, -L-OC(O)N(C1-C10 alkyl)2, -CO2R 5 、-CO2N(R 5 )2, =CH2, =CHR 11 or =C(R 11 )2, or two R 2 connected to form a heterocyclic ring or cycloalkyl group optionally substituted with a C1-C3 alkyl group; If V does not exist, then R 2 and R 3 At least one of =CH2, =CHR 11 or =C(R 11 )2; Each R 4 are independently hydrogen, halogen or C1-C3 alkyl; Each R 5 are independently hydrogen or C1-C3 alkyl, or two R 5 connected to form a cycloalkyl or heterocyclic ring; Each R 6 are independently hydrogen, hydroxy, C1-C4 hydroxyalkyl or heteroaryl, Or two R 6 Connected to form a C3-C6 cycloalkyl or heterocyclic ring; Each R 7 are independently hydrogen, C1-C3 alkyl, C2 alkenyl, hydroxy, halogen, C1-C3 haloalkyl, -L-NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo (=O), LO-(C1-C3 alkyl), LO-(C1-C3 alkyl)-OR 5 、-(C1-C3 alkyl)-OH、-C(O)OH、-C(O)O(C1-C3 alkyl), LC(O)N(R 10 )2, -NHC(O)H, -CN, aryl, -(CH2) 1-2 S(O)2N(R 10 )2、-NH-S(O)2N(R 10 )2、-OS(O)2N(R 10 )2、S(O)2R 10 、-P(O)(R 5 )2 or L-heteroaryl or L-heterocycle optionally substituted by 1-2 substituents independently selected from C1-C3 alkyl, -CN and C(O)NH2, Two R on the same atom 7 optionally connected to form a spiro ring selected from C3-C6 cycloalkyl and heterocycle, wherein the spiro ring is optionally substituted by 1-4 substituents independently selected from oxo (=O), halogen, hydroxyl, C1-C3 alkyl, cyano and -O-(C1-C3 alkyl), Two R on adjacent atoms 7 are optionally connected to form a bond or a fused ring selected from optionally 1-4 R 8 Substituted C3-C6 cycloalkyl, optionally substituted by 1-4 R 8 substituted heteroaryl, optionally substituted with 1-4 R 8 substituted aryl, and optionally 1-4 R 8 substituted heterocycle, and Two R on non-adjacent atoms 7 Optionally linked to form 1-2 carbon bridges; Each R 8 are independently C1-C3 alkyl, hydroxy, halogen, -N(R 10 )2、-N(R 10 )C(O)R 10 , oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)N(R 10 )2, -C(O)O(C1-C3 alkyl), -C(O)N(R10)2, heteroaryl, heterocycle or -CN; Each R 9 are independently C1-C3 alkyl, hydroxy, halogen, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2 or -CN; Each R 10 are independently hydrogen, halogen, C1-C3 alkyl, C3-C4 cycloalkyl optionally substituted by 1-2 substituents independently selected from halogen and hydroxy, or two R 10 connected to form a cycloalkyl or heterocyclic ring optionally substituted with 1-2 C1-C3 alkyl groups; Each R 11 are independently halogen or methyl; Each L is independently a bond, -O-, -C1-C4 alkyl-, -C1-C4 alkyl-NH-, -NH-, -N(C1-C3 alkyl)-, or cyclopropyl-CH2-; Each n is 0-3; o is 1-6; p is 1-8; and q is 1-2.

2. A compound having formula (IA): or a pharmaceutically acceptable salt thereof, wherein: W is: A is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1-4 R 1 replace; B is: Y 1 is hydrogen, optionally substituted with 1-4 R 8 substituted L-hydroxyl, optionally substituted with 1-4 R 8 Substituted L-alkoxy, halogen, optionally substituted by 1-4 R 9 Substituted L-C3-C6 cycloalkyl, optionally substituted by 1-4 R 8 substituted L-heteroaryl, optionally substituted with 1-4 R 8 Substituted L-aryl, LC(O)-NH2, and substituted by 1-2 oxo (=O) or oxo-containing substituents and optionally further substituted by 1-2 R 8 Substituted L-heterocycle; Y 2 is hydrogen or C1-C4 alkyl; or Y 1 and Y 2 Connection formation: wherein X is selected from the group consisting of: a bond, -S-, -O-, -N< bonded to a fused ring, -CH2-, -CH2-N-, -CH2-N-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, -O-CH2-, and -S-CH2-; Each R 1 are independently halogen, cyano, hydroxy, C1-C4 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, -CH2C(=O)N(R 5 )2, -C3-C4 alkynyl (NR 5 )2、-N(R 5 )2, deuterated C2-C4 alkynyl, (C1-C3 alkoxy)halogenated C1-C3 alkyl- or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted by halogen or C1-C3 alkyl; Each R 2 are independently hydrogen, hydroxy, halogen, C1-C3 haloalkyl, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, -C1-C3-N(R 5 )2, -O-(C1-C3 alkyl), -(C1-C3 alkyl)-O-(C1-C3 alkyl), -(C1-C3 alkyl)-O-(C1-C3 alkyl)-C3-C4 cycloalkyl, HC(=O)-, -L-OC(O)N(C1-C10 alkyl)2, -CO2R 5 、-CO2N(R 5 )2, =CH2, =CHR 11 or =C(R 11 )2, or two R 2 connected to form a heterocyclic ring or cycloalkyl group optionally substituted with a C1-C3 alkyl group; Each R 3 are independently hydrogen, hydroxy, halogen, C1-C3 haloalkyl, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, -C1-C3-N(R 5 )2, -O-(C1-C3 alkyl), -(C1-C3 alkyl)-O-(C1-C3 alkyl), -(C1-C3 alkyl)-O-(C1-C3 alkyl)-C3-C4 cycloalkyl, HC(=O)-, -L-OC(O)N(C1-C10 alkyl)2, -CO2R 5 、-CO2N(R 5 )2, =CH2, =CHR 11 or =C(R 11 )2, or two R 2 connected to form a heterocyclic ring or cycloalkyl group optionally substituted with a C1-C3 alkyl group; Each R 4 are independently hydrogen, halogen or C1-C3 alkyl; Each R 5 are independently hydrogen or C1-C3 alkyl, or two R 5 connected to form a cycloalkyl or heterocyclic ring; Each R 6 are independently hydrogen, hydroxy, C1-C4 hydroxyalkyl or heteroaryl, Or two R 6 Connected to form a C3-C6 cycloalkyl or heterocyclic ring; Each R 7 are independently hydrogen, C1-C3 alkyl, C2 alkenyl, hydroxy, halogen, C1-C3 haloalkyl, -L-NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo (=O), LO-(C1-C3 alkyl), LO-(C1-C3 alkyl)-OR 5 、-(C1-C3 alkyl)-OH、-C(O)OH、-C(O)O(C1-C3 alkyl), LC(O)N(R 10 )2, -NHC(O)H, -CN, aryl, -(CH2) 1-2 S(O)2N(R 10 )2、-NH-S(O)2N(R 10 )2、-OS(O)2N(R 10 )2、S(O)2R 10 、-P(O)(R 5 )2 or L-heteroaryl or L-heterocycle optionally substituted by 1-2 substituents independently selected from C1-C3 alkyl, -CN and C(O)NH2, Two R on the same atom 7 optionally connected to form a spiro ring selected from C3-C6 cycloalkyl and heterocycle, wherein the spiro ring is optionally substituted by 1-4 substituents independently selected from oxo (=O), halogen, hydroxyl, C1-C3 alkyl, cyano and -O-(C1-C3 alkyl), Two R on adjacent atoms 7 are optionally connected to form a bond or a fused ring selected from optionally 1-4 R 8 Substituted C3-C6 cycloalkyl, optionally substituted by 1-4 R 8 substituted heteroaryl, optionally substituted with 1-4 R 8 substituted aryl, and optionally 1-4 R 8 substituted heterocycle, and Two R on non-adjacent atoms 7 Optionally linked to form 1-2 carbon bridges; Each R 8 are independently C1-C3 alkyl, hydroxy, halogen, -N(R 10 )2、-N(R 10 )C(O)R 10 , oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)N(R 10 )2, -C(O)O(C1-C3 alkyl), -C(O)N(R10)2, heteroaryl, heterocycle or -CN; Each R 9 are independently C1-C3 alkyl, hydroxy, halogen, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2 or -CN; Each R 10 are independently hydrogen, halogen, C1-C3 alkyl, C3-C4 cycloalkyl optionally substituted by 1-2 substituents independently selected from halogen and hydroxy, or two R 10 connected to form a cycloalkyl or heterocyclic ring optionally substituted with 1-2 C1-C3 alkyl groups; Each R 11 are independently halogen or methyl; Each L is independently a bond, -O-, -C1-C4 alkyl-, -C1-C4 alkyl-NH-, -NH-, -N(C1-C3 alkyl)-, or cyclopropyl-CH2-; Each n is 0-3; o is 1-6; p is 1-8; and q is 1-2.

3. The compound or salt according to claim 2, wherein Each R 1 Independently selected from halogen, hydroxy, C1-C3 alkoxy and C1-C4 alkyl.

4. The compound or salt according to claim 2, wherein Each R 2 --if present--selected from =CH2, =CHR 11 or =C(R 11 )2, and wherein each R3, if present, is selected from =CH2, =CHR 11 or =C(R 11 )2.

5. The compound or salt according to claim 2, wherein Each R 7 are independently selected from hydrogen, C1-C4 alkyl, hydroxyl, C1-C3 alkoxy, and wherein two R on non-adjacent atoms 7 Optionally linked to form 1-2 carbon bridges.

6. The compound or salt according to claim 2, wherein Each R 6 are independently hydrogen or hydroxy.

7. The compound or salt according to any one of claims 1 to 6, wherein Y 1 and Y 2 Connection formation:

8. The compound or salt according to any one of claims 1 to 6, wherein Y 1 and Y 2 Connection formation:

9. The compound or salt according to any one of claims 1 to 6, wherein Y 1 and Y 2 Connection formation:

10. The compound or salt according to any one of claims 1 to 9, wherein A is naphthyl.

11. The compound or salt according to any one of claims 1 to 10, wherein At least one R 1 It is a C1-C4 alkyl group.

12. The compound or salt according to any one of claims 1 to 10, wherein At least one R 1 It's a halogen.

13. The compound or salt according to claim 12, wherein The halogen is fluorine.

14. The compound or salt according to any one of claims 1 to 10, wherein At least one R 1 It's a hydroxyl group.

15. The compound or salt according to any one of claims 1 to 14, wherein At least one R 2 =CH2, =CHR 11 or =C(R 11 )2.

16. The compound or salt according to claim 15, wherein R 11 It's fluorine.

17. The compound or salt according to any one of claims 1 to 14, wherein At least one R 2 It's a halogen.

18. The compound or salt according to claim 16, wherein The halogen is fluorine.

19. The compound or salt according to any one of claims 1 to 14, wherein At least one R 2 It's a hydroxyl group.

20. The compound or salt of any one of claims 1 to 14, wherein At least one R 3 =CH2, =CHR 11 or =C(R 11 )2.

21. The compound or salt of claim 20, wherein R 11 It's fluorine.

22. The compound or salt of any one of claims 1 to 21, wherein At least one R 3 It is a C1-C4 alkyl group.

23. The compound or salt of any one of claims 1 to 21, wherein At least one R 3 It's a halogen.

24. The compound or salt of claim 23, wherein The halogen is fluorine.

25. The compound or salt of any one of claims 1 to 21, wherein At least one R 3 It's a hydroxyl group.

26. The compound or salt of any one of claims 1 to 25, wherein R 4 It's a halogen.

27. The compound or salt of claim 26, wherein The halogen is fluorine.

28. The compound or salt of any one of claims 1 to 27, wherein At least one R 5 It is a C1-C4 alkyl group.

29. The compound or salt of any one of claims 1 to 27, wherein At least one R 5 It's hydrogen.

30. The compound or salt of any one of claims 1 to 29, wherein One or two R 6 It is a C1-C4 alkyl group.

31. The compound or salt of any one of claims 1 to 29, wherein One or two R 6 It's hydrogen.

32. The compound or salt of any one of claims 1 to 29, wherein Two R's 6 Connected to form a C3-C6 cycloalkyl or heterocyclic ring.

33. The compound or salt of any one of claims 1 to 6, wherein Y 1 is L-C3-C6 cycloalkyl, L-heteroaryl, L-aryl or L-heterocycle, wherein L is a bond, C1-C4 alkyl, NH or N(C1-C3)alkyl.

34. The compound or salt of claim 33, wherein Y 1 is L-heteroaryl, wherein the heteroaryl is thietane dioxide, isothiazolidine dioxide, imidazopyrazine, pyridine or pyrimidine.

35. The compound or salt of claim 33, wherein Y 1 It is L-C3-C6 cycloalkyl.

36. The compound or salt of claim 35, wherein The cycloalkyl group is cyclobutane, cyclopentane, cyclohexane or cycloheptane.

37. The compound or salt of claim 33, wherein Y 1 It is an L-heterocyclic ring.

38. The compound or salt of claim 37, wherein The heterocycle is pyrrolidone.

39. The compound or salt of claim 1, wherein Y 2 It's hydrogen.

40. The compound or salt of any one of claims 1 to 6, wherein Y 2 It is a C1-C4 alkyl group.

41. The compound or salt of any one of claims 1 to 6, wherein At least one R 8 It is a C1-C4 alkyl group.

42. The compound or salt of any one of claims 1 to 6, wherein At least one R 8 It is hydroxy or C1-C3 alkyl-hydroxy.

43. The compound or salt of any one of claims 1 to 6, wherein One or two R 8 It is an oxo group (=O).

44. The compound or salt of any one of claims 1 to 6, wherein At least one R 8 is an aryl group or a heteroaryl group.

45. The compound or salt of any one of claims 1 to 6, wherein At least one R 8 It is C(O)OH.

46. ​​The compound or salt of any one of claims 1 to 6, wherein At least one R 8 It is -C(O)NH2, -C(O)NH(C1-C3 alkyl) or -C(O)N(C1-C3 alkyl)2.

47. The compound or salt of any one of claims 1 to 6, wherein At least one R 8 It is -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2.

48. The compound or salt of any one of claims 1 to 6, wherein At least one R 9 It is a C1-C4 alkyl group.

49. The compound or salt of any one of claims 1 to 6, wherein At least one R 9 It is hydroxy or C1-C3 alkyl-hydroxy.

50. The compound or salt of any one of claims 1 to 6, wherein One or two R 9 It is an oxo group (=O).

51. The compound or salt of any one of claims 1 to 6, wherein At least one R 9 is an aryl group or a heteroaryl group.

52. The compound or salt of any one of claims 1 to 6, wherein At least one R 9 It is C(O)OH.

53. The compound or salt of any one of claims 1 to 6, wherein At least one R 9 It is -C(O)NH2, -C(O)NH(C1-C3 alkyl) or -C(O)N(C1-C3 alkyl)2.

54. The compound or salt of any one of claims 1 to 6, wherein Y 1 and Y 2 The linkage forms a piperidine, azepane, azocane, thiazepine, diazepane, oxazepane, azetidine, pyrrolidine, piperazine bonded to a fused ring via the nitrogen, or thiomorpholine.

55. The compound or salt of any one of claims 1 to 6, wherein Two R on the same atom 7 Connected to form a spiro ring selected from C3-C6 cycloalkyl and heterocycle, wherein the spiro ring is optionally substituted by one or more substituents selected from oxo (=O), halogen, hydroxyl, C1-C3 alkyl and -O-(C1-C3 alkyl).

56. The compound or salt of any one of claims 1 to 6, wherein Two R on adjacent atoms 7 connected to form a bond or a fused ring, the fused ring being selected from optionally 1-4 R 8 Substituted C3-C6 cycloalkyl, optionally substituted by 1-4 R 8 substituted heteroaryl, optionally substituted with 1-4 R 8 substituted aryl, and optionally 1-4 R 8 Substituted heterocycle.

57. The compound or salt of any one of claims 1 to 6, wherein Two R on non-adjacent atoms 7 Connect to form 1-2 carbon bridges.

58. A compound selected from: and pharmaceutically acceptable salts thereof.

59. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

60. A method for inhibiting the activity of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H in a cell, the method comprising contacting the cell in which it is desired to inhibit KRas activity with an effective amount of a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 60.

61. A method for treating cancer, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 60 to a patient suffering from cancer.

62. The method of claim 62, wherein: The therapeutically effective amount of the compound is between about 0.01 and 100 mg / kg per day.

63. The method of claim 63, wherein: The therapeutically effective amount of the compound is between about 0.1 and 50 mg / kg per day.

64. The method of claim 62, wherein: The cancer is selected from the group consisting of: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, cartilaginous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasodilatory peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract : Kidney (adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gallbladder cancer, ampullary cancer, bile duct cancer; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningosarcomas, gliosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealoma), glioblastoma multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas); Gynecology: uterus (endometrial carcinoma (serous =The following are some of the following: malignant tumors: ovarian (epidermal, ovarian, genital, genital, genital cystadenocarcinoma, cystic cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell tumor, Severe-Lysson cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); hematological: blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

65. The method of claim 65, wherein: The cancer is a KRas G12A-associated cancer.

66. The method of claim 65, wherein: The cancer is a KRas G12C-associated cancer.

67. The method of claim 65, wherein: The cancer is a KRas G12D-associated cancer.

68. The method of claim 65, wherein: The cancer is a KRas G12R-associated cancer.

69. The method of claim 65, wherein: The cancer is a KRas G12S-associated cancer.

70. The method of claim 65, wherein: The cancer is a KRas G12V-associated cancer.

71. The method of claim 65, wherein: The cancer is a KRas G13D-associated cancer.

72. The method of claim 65, wherein: The cancer is a KRas Q61H-related cancer.

73. The method of claim 65, wherein: The cancer is a KRas G12A-associated cancer.

74. The method of claim 65, wherein: The cancer is associated with at least one of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H.

75. The method of any one of claims 65-75, wherein: The cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

76. A method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H mutations; and (b) administering to the patient a therapeutically effective amount of a compound of any one of claims 1-59, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 60.

77. The method of any one of claims 65 to 77, wherein: The administration is performed via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal administration, intramuscular injection, intravitreal injection, intravenous injection, intraarterial injection, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous and local administration.

78. The method of claim 78, wherein: The route of administration is oral.

79. The method of claim 78, wherein: The administration is intravenous injection.

80. The method of claim 78, wherein: The route of administration is intramuscular injection.

81. The method of claim 78, wherein: This route of administration utilizes a delivery device.

82. The method of claim 78, wherein: Administration takes place in a hospital setting.

Images