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 containing the compounds, and methods of use thereof.

Description

[Technical Field]

[0001] The present invention relates to compounds that inhibit multiple mutated forms of KRas, i.e., pan-KRas inhibitors. In particular, the present invention relates to pan-KRas compounds, pharmaceutical compositions containing the compounds, and methods of use thereof. [Background technology]

[0002] Kirsten rat sarcoma 2 viral oncogene homolog ("KRas") is a small GTPase and a member of the Ras family of oncogenes. KRas functions as a molecular switch that cycles between an inactive (GDP-bound) and an active (GTP-bound) state, transmitting upstream cellular signals received from multiple tyrosine kinases to downstream effectors to control diverse processes, including cell proliferation (see, e.g., Non-Patent Document 1).

[0003] The role of activated KRas in malignant tumors was observed more than 30 years ago (see, for example, Non-Patent Document 2). 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 in the KRas primary amino acid sequence are present in 88% of all pancreatic adenocarcinoma patients, 50% of all colorectal adenocarcinoma patients, and 32% of lung adenocarcinoma patients (see, for example, Non-Patent Document 3). Recent publications have also suggested that wild-type Kras inhibition may be a viable therapeutic strategy for treating KRasWT-dependent cancers (see, for example, Non-Patent Document 4).

[0004] The well-known role of KRas in malignant tumors and the discovery of these frequent mutations in KRas in various tumor types have made KRas a very attractive target for the pharmaceutical industry for cancer therapy. Despite 30 years of extensive discovery efforts to develop inhibitors of KRas to treat cancer, KRas inhibitors have yet to demonstrate sufficient safety and / or efficacy to gain regulatory approval (see, e.g., Non-Patent Document 5).

[0005] Compounds that inhibit Kras activity remain highly desirable and under investigation, including compounds that disrupt effectors such as guanine nucleotide exchange factors (see, e.g., Non-Patent Document 6), as well as recent advances in covalent targeting of the allosteric pocket of Kras G12C (see, e.g., Non-Patent Document 7 and Non-Patent Document 8). Clearly, there remains ongoing interest and effort to develop inhibitors of KRas, particularly inhibitors of activating KRas mutants. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Alamgeer et al.,(2013)Current Opin Pharmcol.13:394-401 [Non-patent document 2] Santos et al.,(1984)Science 223:661-664 [Non-patent document 3] Prior et all.,(2020)Cancer Res 80:2969-74 [Non-patent document 4] Bery et al.,(2020)Nat.Commun.11:3233 [Non-patent document 5] McCormick(2015)Clin Cancer Res.21(8):1797-1801 [Non-patent document 6] Sun et al.,(2012)Agnew Chem Int Ed Engl.51(25):6140-6143 doi:10.1002 / anie201201358 [Non-Patent Document 7] Ostrem et al.,(2013)Nature 503:548-551 [Non-patent document 8] Fell et al.,(2018)ACS Med.Chem.Lett.9:1230-1234 Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, there is a need to develop new pan-KRas inhibitors that exhibit sufficient efficacy to treat KRas-mediated cancers. [Means for solving the problem]

[0008] In one aspect of the present invention, compounds are provided that inhibit KRas activity. In certain embodiments, the compounds have the formula (I): [ka] (In the formula, W is [ka] and A is aryl or heteroaryl, and the aryl or heteroaryl is selected from 1 to 4 R 1 is optionally replaced by; B is [ka] and; Y 1 is hydrogen, 1 to 4 R 8 L-hydroxy optionally substituted with one to four R 8 L-alkoxy optionally substituted with halogen, 1 to 4 R 9L-C3-C6 cycloalkyl optionally substituted with 1 to 4 R 8 L-heteroaryl optionally substituted with 1 to 4 R 8 L-aryl optionally substituted with LC(O)-NH and 1-2 oxo (=O) or oxo-containing substituents, and 1-2 R 8 an L-heterocycle optionally further substituted with Y 2 is hydrogen or C1-C4 alkyl; or Y 1 and Y 2 is combined with [ka] Forming X is selected from a bond, -S-, -O-, -N<, -CH2-, -CH2-N-, -CH2-N-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, -O-CH2-, and -S-CH2- attached to a fused ring; or Y 2 and Z combine to form V, and V is a group selected from 1 to 4 R 8 optionally replaced with [ka] and; Z is hydrogen or Y 2 Combined with; 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, deutero 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; 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; 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; When V is absent, at least one of R2 and R3 is ═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 are joined to form a cycloalkyl or heterocycle; Each R 6 are independently hydrogen, hydroxy, C1-C4 hydroxyalkyl, or heteroaryl; The Two R's 6 are linked to form a C3-C6 cycloalkyl or heterocycle; Each R 7are 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 with 1 to 2 substituents independently selected from C1-C3 alkyl, —CN and C(O)NH2; Two R on the same atom 7 are optionally joined to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, said spirocyclic ring being optionally substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, hydroxy, C1-C3 alkyl, and -O-(C1-C3 alkyl); Two R on adjacent atoms 7 is optionally joined to form a bond or 1 to 4 R 8 C3-C6 cycloalkyl optionally substituted with 1-4 R 8 heteroaryl optionally substituted with 1 to 4 R 8 aryl optionally substituted with and 1 to 4 R 8 forming a fused ring selected from heterocycles optionally substituted with Two R on non-adjacent atoms 7 are optionally linked to form one to two carbon bridges; Each R 8are 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), heteroaryl, 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, or two R 10 are joined to form a cycloalkyl or heterocycle optionally substituted with 1 to 2 C1-C3 alkyl; Each R 11 are independently halogen; each L is independently a bond, —C1-C4 alkyl-, —C1-C4 alkyl-NH—, —NH—, —N(C1-C3 alkyl)-, or cyclopropyl-CH2-; each n is 0 to 3; o is 1 to 6; and p is 1 to 8. or a pharmaceutically acceptable salt thereof.

[0009] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0010]

[0013] Yet another aspect of the invention is a method for inhibiting the activity of wild-type KRas in a cell or a cell containing one or more KRas mutations, e.g., KRas mutations G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H, comprising contacting the cell with a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one embodiment, the contacting is performed in vitro. In one embodiment, the contacting is performed in vivo.

[0011] Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, which method comprises contacting a cell with an effective amount of a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0012] Also provided is a method of 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 invention, or a pharmaceutically acceptable salt thereof.

[0013] Also provided herein is a method of treating a KRas wild-type, KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H associated disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0014] Also provided herein is a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in therapy.

[0015] There is also provided herein a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of cancer.

[0016] Also provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof for use in inhibiting wild-type KRas or multiple types of KRas mutations, such as KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations.

[0017] Also provided herein is a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for use in the treatment of a disease or disorder associated with wild-type KRas or a disease or disorder associated with the KRas mutations G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H.

[0018] There is also provided herein the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of cancer.

[0019] Also provided herein is the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of the activity of a wild-type form of KRas or a mutant form of KRas, including the mutations: G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H.

[0020] Also provided herein is the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of 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.

[0021] Also provided herein are methods of 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.

[0022] One potential utility 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-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (Example 5 herein), is in the treatment of cancers that develop resistance after prolonged treatment with a KRas G12C inhibitor. Accordingly, embodiments of the present invention include those in which patients afflicted with cancer are 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 resistance-conferring mutations.

[0023] Treatment of KRas G12C mutant cancers with covalent KRas G12C inhibitors, such as adagrasib (MRTX849) or sotorasib (AMG510), can lead to the incorporation of additional mutations that confer resistance to adagrasib. These mutations may confer resistance through a number of mechanisms.

[0024] Mutations that change the mutant cysteine at codon 12 to another amino acid render current covalent KRas G12C inhibitors ineffective because the current inhibitor covalently binds to the mutant cysteine amino acid side chain. Similarly, in patients with one wild-type KRas allele in addition to the KRas G12C mutant allele, mutation of the wild-type codon 12 glycine to another codon allows bypass signaling in these tumors via a novel mutant protein. The repertoire of codon 12 mutations that can arise from single nucleotide substitutions in the wild-type gene (glycine codon) includes mutations commonly observed in cancer, such as G12S, G12V, G12R, and G12C. The repertoire of codon 12 mutations that can arise from single nucleotide base substitutions at cysteine codon 12 includes G12S and G12R, as well as mutations less frequently observed in cancer, G12Y, G12F, and G12W.

[0025] Second-site mutations can also occur at other positions in the KRas G12C mutant gene, conferring resistance to KRas G12C inhibitor treatment. 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 activated by upstream receptor tyrosine kinases and load GTP via guanine nucleotide exchange factors (GEFs, e.g., SOS1), which trigger subsequent interactions with effector proteins that activate RAS-dependent signaling. RAS proteins hydrolyze GTP to GDP through their intrinsic GTPase activity, which is dramatically 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 bind only to GDP-bound KRas G12C. Mutations such as the Q61 codon mutation, which may or may not occur on the same allele as the G12C mutation, may represent a mechanism of resistance to KRas G12C inhibitor treatment by reducing the intrinsic GTPase activity of KRas and shifting KRas to a GTP-loaded state that is not susceptible to covalent inhibition. Co-mutations such as R68, H95, and Y96 may coexist with the KRas G12C mutation and reduce the binding affinity of KRas G12C inhibitors to the switch II binding pocket.

[0026] The pan-KRas inhibitors described herein may exhibit activity against common and rare codon 12 mutations or KRas G12C mutations that occur in the KRas protein that reduce binding of the inhibitor to the KRas protein.

[0027] Also provided herein are processes for preparing compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0028] Also provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof obtained by the process for preparing the compounds defined herein. DETAILED DESCRIPTION OF THE INVENTION

[0029] The present invention relates to inhibitors of wild-type KRas and / or multiple mutant forms of KRas, such as the 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 mutant KRas such as G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H, pharmaceutical compositions containing therapeutically effective amounts of the compounds, and methods of use thereof.

[0030] definition Unless otherwise defined, 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.

[0031] As used herein, "wild-type KRas" refers to a non-mutated form of a mammalian KRas protein. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "wild-type KRas inhibitor" refers to a compound of the present invention represented by Formula (I) as described herein. These compounds can negatively regulate or inhibit all or a portion of the enzymatic activity of wild-type KRas G12A. As used herein, "wild-type KRas-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having wild-type KRas. A non-limiting example of a wild-type KRas-associated disease or disorder is wild-type KRas-associated cancer.

[0032] As used herein, "KRas G12A" refers to a mutant form of a mammalian KRas protein containing an amino acid substitution of glycine with alanine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G12A inhibitor" refers to a compound of the present invention represented by Formula (I) described herein. These compounds can negatively regulate or inhibit all or a portion 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 KRas G12A-associated cancer.

[0033] As used herein, "KRas G12C" refers to a mutant mammalian KRas protein containing a glycine to cysteine amino acid substitution at amino acid position 12. The amino acid codon and residue position assignments for human KRas are 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) described herein. These compounds can negatively regulate or inhibit all or a portion 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 KRas G12CD-associated cancer.

[0034] As used herein, "KRas G12D" refers to a mutant form of a mammalian KRas protein containing an amino acid substitution of aspartic acid for glycine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G12D inhibitors" refer to compounds of the present invention represented by Formula (I) described herein. These compounds can negatively regulate or inhibit all or a portion 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 KRas G12D-associated cancer.

[0035] As used herein, "KRas G12R" refers to a mutant form of a mammalian KRas protein containing an arginine-for-glycine amino acid substitution at amino acid position 12. The amino acid codon and residue position assignments for human KRas are 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) described herein. These compounds can negatively regulate or inhibit all or a portion 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 KRas G12R-associated cancer.

[0036] As used herein, "KRas G12S" refers to a mutant form of a mammalian KRas protein containing a glycine to serine amino acid substitution at amino acid position 12. The amino acid codon and residue position assignments for human KRas are 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) described herein. These compounds can negatively regulate or inhibit all or a portion 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 KRas G12S-associated cancer.

[0037] As used herein, "KRas G12V" refers to a mutant form of a mammalian KRas protein containing an amino acid substitution of valine for glycine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are 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) described herein. These compounds can negatively regulate or inhibit all or a portion 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 G12A mutation. A non-limiting example of a KRas G12V-associated disease or disorder is KRas G12V-associated cancer.

[0038] As used herein, "KRas G13D" refers to a mutant form of a mammalian KRas protein containing an amino acid substitution of aspartic acid for glycine at amino acid position 13. The amino acid codon and residue position assignments for human KRas are 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) described herein. These compounds can negatively regulate or inhibit all or a portion 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 KRas G13D-associated cancer.

[0039] As used herein, "KRas Q61H" refers to a mutant form of a mammalian KRas protein containing an amino acid substitution of histidine for glutamine at amino acid position 61. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas Q61H inhibitors" refer to compounds of the present invention represented by Formula (I) described herein. These compounds can negatively regulate or inhibit all or a portion of the enzymatic activity of KRas Q61H. As used herein, "KRas Q61H-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas Q61H mutation. A non-limiting example of a KRas Q61H-associated disease or disorder is KRas Q61H-associated cancer.

[0040] 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, cows, sheep, horses, primates, and humans. In some embodiments, the patient is human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a 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 a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation (e.g., as determined using an assay or kit approved by a regulatory agency, e.g., the FDA). 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 an assay or kit approved by a regulatory agency). The subject can be a subject whose tumor is positive for wild-type KRas or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations (e.g., as determined to be positive using an assay or kit approved by a regulatory agency, e.g., the FDA). 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., the tumor is identified as such using a kit or assay approved by a regulatory agency, e.g., the FDA). In some embodiments, the subject is suspected of having a cancer associated with wild-type KRas or the KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H genes.In some embodiments, the subject has clinical records 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 records indicate that the subject should be treated with any of the compositions provided herein).

[0041] In some embodiments of any of the methods or uses described herein, a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a wild-type KRas-related or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-related cancer, a patient with one or more symptoms of a wild-type KRas-related or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-related cancer and / or a patient at increased risk of developing a wild-type KRas-related or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-related cancer) is used to determine whether the patient has wild-type KRas or KRas G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-related cancer. Assays used to determine whether a patient has the G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations 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., RT-PCR and quantitative real-time RT-PCR). As is well known in the art, assays are typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

[0042] The term "regulatory authority" refers to a national agency that approves drugs for medical use in that country. For example, a non-limiting example of a regulatory authority is the U.S. Food and Drug Administration (FDA).

[0043] The term "acyl" refers to -C(O)CH3.

[0044] As used herein, the terms "C1-C6 alkyl," "C1-C4 alkyl," and "C1-C3 alkyl" refer to straight-chain and branched-chain 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.

[0045] The terms "C1-C3 haloalkyl" and "C1-C4 haloalkyl" refer to a C1-C3 alkyl chain or a C1-C4 alkyl chain, respectively, in which one or more hydrogens have been replaced with halogen. Examples include trifluoromethyl, difluoromethyl, and fluoromethyl.

[0046] A "C1-C4 alkylene" group, as defined herein above, is a C1-C4 alkyl group 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.

[0047] The terms "C1-C3 alkoxy" and "C1-C4 alkoxy" refer to -OC1-C3 alkyl and -OC1-C4 alkyl, respectively, wherein the alkyl moiety is as defined herein above.

[0048] The term "cycloalkyl" as used herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, for example, 3 to 8 carbons, and as a further example, 3 to 6 carbons, and cycloalkyl groups may additionally optionally contain one or more R 8 or R 9The cycloalkyl group is substituted with a group. 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 cycloalkyls such as bicyclo[1.1.1]pentanyl.

[0049] As used herein, the terms "C1-C3 hydroxyalkyl" and "C1-C4 hydroxyalkyl" refer to -C1-C3 alkylene-OH and -C1-C4 alkylene-OH, respectively.

[0050] As used herein, the term "C2-C4 hydroxyalkynyl" refers to -C2-C4 alkynylene-OH.

[0051] An "aryl" group is a C6-C14 aromatic moiety containing one to three aromatic rings, and optionally one or more R 8 or R 9 In one embodiment, the aryl group is substituted with a C-C 10 It is an aryl group. 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, where one or two rings of the aryl ring system may be saturated or partially saturated, respectively, and when the ring system contains two saturated rings, the saturated rings may be fused or spirocyclic. Examples of aryl ring systems containing two saturated rings, where the rings are spirocyclic, include the following ring systems: [ka]

[0052] An "araC1-C6 alkyl" or "arylalkyl" group comprises an aryl group covalently bonded to an alkyl group, either of which independently may be optionally substituted or unsubstituted. Examples of aralkyl groups include (C6-C 10)aryl(C1-C6)alkyl-, including, but not limited to, benzyl, phenethyl, and naphthylmethyl. An example of a substituted araC1-C6 alkyl is when the alkyl group is substituted with hydroxyalkyl.

[0053] A "heterocyclyl" or "heterocyclic" group is a ring structure having 3 to 12 atoms, e.g., 4 to 8 atoms, where one or more atoms are selected from the group consisting of N, O, and S, where the ring N atom can be oxidized to NO, the ring S atom can be oxidized to SO or SO, and the remainder of the ring atoms are carbon. A heterocyclyl can be a monocyclic, bicyclic, spirocyclic, or bridged ring system. A heterocyclic group optionally contains one or more R on a ring carbon or ring nitrogen at one or more positions. 8 or R 9 is substituted with an R 6is as defined for formula I. Heterocyclic groups are independently optionally substituted on the ring nitrogen atom with alkyl, aralkyl, alkylcarbonyl or on sulfur with lower alkyl. Examples of heterocyclic groups include, but are not limited to, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 oxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyl, azabicycloheptanyl, azabicyclooctanyl, azabicyclononanyl (e.g., octyl ... hexahydroindolizinyl), azaspiroheptanyl, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizidine], hexahydro-1H-pyrrolidinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyl, oxaazaspirooctanyl, diazaspirononanyl, oxazabioctoheptanyl, hexahydropyrrolidinyl 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 ring O and / or S atoms.

[0054] As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms, having 6, 10, or 14 pi electrons shared in a cyclic array, and having, in addition to carbon atoms, 1 to 3 heteroatoms per ring or 1 to 3 heteroatoms in at least one ring selected from the group consisting of N, O, and S.Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, 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, o Xazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidyl nyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 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, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl."Heteroaryl" also refers to bicyclic ring systems having, in addition to carbon atoms, one to three heteroatoms per ring selected from the group consisting of N, O, and S, where one ring system can be saturated or partially saturated.

[0055] As used herein, an "effective amount" of a compound is an amount sufficient to negatively regulate or inhibit one or more activities 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 according to a regimen, whereby it is effective.

[0056] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to ameliorate or in some manner reduce symptoms, or to halt or reverse the progression of a condition, or 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 according to a regimen, whereby it is effective.

[0057] 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 includes any pharmaceutical use of the compositions herein.

[0058] As used herein, amelioration of symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any relief, permanent or temporary, lasting or transient, that can result from or be associated with administration of the composition.

[0059] compound In certain embodiments of the present invention, formula (I) [ka] (In the formula, W is [ka] and A is aryl or heteroaryl, and the aryl or heteroaryl is selected from 1 to 4 R 1 is optionally replaced by; B is [ka] and; Y 1 is hydrogen, 1 to 4 R 8 L-hydroxy optionally substituted with one to four R 8 L-alkoxy optionally substituted with halogen, 1 to 4 R 9 L-C3-C6 cycloalkyl optionally substituted with 1 to 4 R 8 L-heteroaryl optionally substituted with 1 to 4 R 8 L-aryl optionally substituted with LC(O)-NH and 1-2 oxo (=O) or oxo-containing substituents, and 1-2 R 8 an L-heterocycle optionally further substituted with Y 2 is hydrogen or C1-C4 alkyl; or Y 1 and Y 2 is combined with [ka] Forming X is selected from a bond, -S-, -O-, -N<, -CH2-, -CH2-N-, -CH2-N-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, -O-CH2-, and -S-CH2- attached to a fused ring; or Y 2 and Z combine to form V, and V is a group selected from 1 to 4 R 8 optionally replaced with [ka] and; Z is hydrogen or Y 2 Combined with; 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, deutero 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; 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 join to form a heterocycle or cycloalkyl optionally substituted with C1-C3 alkyl; 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 join to form a heterocycle or cycloalkyl optionally substituted with C1-C3 alkyl; If V is not present, R 2 and R 3 At least one of the following is =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 are joined to form a cycloalkyl or heterocycle; Each R 6 are independently hydrogen, hydroxy, C1-C4 hydroxyalkyl, or heteroaryl; The Two R's 6 are linked to form a C3-C6 cycloalkyl or heterocycle; 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 independently with 1 to 2 substituents independently selected from C1-C3 alkyl, —CN and C(O)NH2; Two R on the same atom 7 are optionally joined to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, said spirocyclic ring being optionally substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, hydroxy, C1-C3 alkyl, cyano, and -O-(C1-C3 alkyl); Two R on adjacent atoms 7 is optionally joined to form a bond or 1 to 4 R 8 C3-C6 cycloalkyl optionally substituted with 1-4 R 8 heteroaryl optionally substituted with 1 to 4 R 8 aryl optionally substituted with and 1 to 4 R 8 forming a fused ring selected from heterocycles optionally substituted with Two R on non-adjacent atoms 7 are optionally linked to form one to two 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 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; Each R 10 are independently hydrogen, halogen, C1-C3 alkyl, C3-C4 cycloalkyl optionally substituted with 1 to 2 substituents independently selected from halogen and hydroxy, or two R 10 join to form a cycloalkyl or heterocycle optionally substituted with 1 to 2 C1-C3 alkyl; 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 to 3; o is 1 to 6; p is 1 to 8; q is 1 to 2) or a pharmaceutically acceptable salt thereof.

[0060] In a preferred embodiment, R 11 is fluorine.

[0061] An embodiment of the present invention is a compound of formula (IA) [ka] (In the formula, W is [ka] and A is aryl or heteroaryl, and the aryl or heteroaryl is selected from 1 to 4 R 1 is optionally replaced by; B is [ka] and; Y 1 is hydrogen, 1 to 4 R 8 L-hydroxy optionally substituted with one to four R 8 L-alkoxy optionally substituted with halogen, 1 to 4 R 9 L-C3-C6 cycloalkyl optionally substituted with 1 to 4 R 8 L-heteroaryl optionally substituted with 1 to 4 R 8 L-aryl optionally substituted with LC(O)-NH and 1-2 oxo (=O) or oxo-containing substituents, and 1-2 R 8 an L-heterocycle optionally further substituted with Y 2 is hydrogen or C1-C4 alkyl; or Y 1 and Y 2 is combined with [ka] Forming X is selected from a bond, -S-, -O-, -N<, -CH2-, -CH2-N-, -CH2-N-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, -O-CH2-, and -S-CH2- bonded to a fused ring; 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, deutero 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; 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 join to form a heterocycle or cycloalkyl optionally substituted with C1-C3 alkyl; 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 join to form a heterocycle or cycloalkyl optionally substituted with C1-C3 alkyl; Each R 4 are independently hydrogen, halogen, or C1-C3 alkyl; Each R 5are independently hydrogen or C1-C3 alkyl, or two R 5 are joined to form a cycloalkyl or heterocycle; Each R 6 are independently hydrogen, hydroxy, C1-C4 hydroxyalkyl, or heteroaryl; The Two R's 6 are linked to form a C3-C6 cycloalkyl or heterocycle; 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 independently with 1 to 2 substituents independently selected from C1-C3 alkyl, —CN and C(O)NH2; Two R on the same atom 7 are optionally joined to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, said spirocyclic ring being optionally substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, hydroxy, C1-C3 alkyl, cyano, and -O-(C1-C3 alkyl); Two R on adjacent atoms 7 is optionally joined to form a bond or 1 to 4 R 8 C3-C6 cycloalkyl optionally substituted with 1-4 R 8heteroaryl optionally substituted with 1 to 4 R 8 aryl optionally substituted with and 1 to 4 R 8 forming a fused ring selected from heterocycles optionally substituted with Two R on non-adjacent atoms 7 are optionally linked to form one to two 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 with 1 to 2 substituents independently selected from halogen and hydroxy, or two R 10 join to form a cycloalkyl or heterocycle optionally substituted with 1 to 2 C1-C3 alkyl; 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 to 3; o is 1 to 6; p is 1 to 8; q is 1 to 2) or a pharmaceutically acceptable salt thereof.

[0062] The embodiment is 1 is independently selected from halogen, hydroxy, C1-C3 alkoxy and C1-C4 alkyl.

[0063] The embodiment is 2 is selected from hydrogen and halogen, and each R 3 Also included are such compounds or salts wherein, when present, is selected from hydrogen and halogen.

[0064] The embodiment is 7 are independently selected from hydrogen, C1-C4 alkyl, hydroxy, and C1-C3 alkoxy, and two R on non-adjacent atoms 7 is optionally attached to form one or two carbon bridges.

[0065] The embodiment is 6 are independently hydrogen or hydroxy.

[0066] In an embodiment, B is [ka] Also included are such compounds or salts wherein:

[0067] The embodiment is Y 1 and Y 2 are combined, [ka] Also included are such compounds or salts which form:

[0068] The embodiment is Y 1 and Y 2 are combined, [ka] Also included are such compounds or salts which form:

[0069] The embodiment is Y 1 and Y 2 are combined, [ka] Also included are such compounds or salts which form:

[0070] Embodiments also include such compounds or salts wherein A is naphthyl.

[0071] Embodiments also include such compounds or salts wherein A is indazolyl.

[0072] Embodiments also include such compounds or salts wherein A is phenyl.

[0073] Embodiments also include such compounds or salts wherein A is pyridyl.

[0074] In certain embodiments of the present invention, at least one R 1 is C1-C4 alkyl.

[0075] In certain embodiments of the present invention, at least one R 1 is a halogen, preferably fluorine or chlorine.

[0076] In certain embodiments of the present invention, at least one R 1 is hydroxy.

[0077] In certain embodiments of the present invention, at least one R 2 is C1-C4 alkyl.

[0078] In certain embodiments of the present invention, at least one R 2 is a halogen, preferably fluorine or chlorine.

[0079] In certain embodiments of the present invention, at least one R 2 is hydroxy.

[0080] In certain embodiments of the present invention, at least one R 2 =CH2, =CHR 11 or =C(R 11 )2.

[0081] In certain embodiments of the present invention, at least one R 3 is C1-C4 alkyl.

[0082] In certain embodiments of the present invention, at least one R 3 is a halogen, preferably fluorine or chlorine.

[0083] In certain embodiments of the present invention, at least one R 3 is hydroxy.

[0084] In certain embodiments of the present invention, at least one R 3 =CH2, =CHR 11 or =C(R 11 )2.

[0085] In certain embodiments of the present invention, R 4 is a halogen, preferably fluorine.

[0086] In certain embodiments of the present invention, at least one R 5 is C1-C4 alkyl.

[0087] In certain embodiments of the present invention, at least one R 5 is hydrogen.

[0088] In certain embodiments of the present invention, at least one R 6 is C1-C4 alkyl.

[0089] In certain embodiments of the present invention, two R 6are bonded to form a C3-C6 cycloalkyl or heterocycle.

[0090] In certain embodiments of the present invention, at least one R 6 is hydrogen.

[0091] In certain embodiments of the present invention, both R 6 is C1-C4 alkyl.

[0092] In certain embodiments of the present invention, both R 6 is hydrogen.

[0093] In certain embodiments, Y 1 is L-C3-C6 cycloalkyl, L-heteroaryl, L-aryl, or L-heterocycle. In some of these embodiments, L is a bond. In some of these embodiments, L is C1-C4 alkyl. In some of these embodiments, L is NH or N(C1-C3) alkyl.

[0094] In certain embodiments, Y 1 is L-heteroaryl, where heteroaryl is thietane dioxide, iso-thiazolidine dioxide, imidazopyrazine, pyridine or pyrimidine.

[0095] In certain embodiments, Y 1 is L-C3-C6 cycloalkyl, and cycloalkyl is preferably cyclobutane, cyclopentane, cyclohexane or cycloheptane.

[0096] In certain embodiments, Y 1 is an L-heterocycle, the heterocycle being preferably pyrrolidinone.

[0097] In certain embodiments of the present invention, Y 2 is hydrogen.

[0098] In certain embodiments of the present invention, Y 2 is C1-C4 alkyl.

[0099] In certain embodiments of the present invention, at least one R 8 is C1-C4 alkyl, preferably methyl.

[0100] In certain embodiments of the present invention, at least one R 8 is hydroxy or C1-C3 alkyl-hydroxy.

[0101] In certain embodiments of the invention, one or two R 8 is oxo (=O).

[0102] In certain embodiments of the present invention, at least one R 8 is aryl or heteroaryl.

[0103] In certain embodiments of the present invention, at least one R 8 is C(O)OH.

[0104] In certain embodiments of the present invention, at least one R 8 is —C(O)NH2, —C(O)NH(C1-C3 alkyl) or —C(O)N(C1-C3 alkyl)2.

[0105] In certain embodiments of the present invention, R 8 is -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2.

[0106] In certain embodiments of the present invention, at least one R 9 is C1-C4 alkyl, preferably methyl.

[0107] In certain embodiments of the present invention, at least one R 9 is hydroxy or C1-C3 alkyl-hydroxy.

[0108] In certain embodiments of the invention, one or two R 9 is oxo (=O).

[0109] In certain embodiments of the present invention, at least one R 9 is aryl or heteroaryl.

[0110] In certain embodiments of the present invention, at least one R 9 is C(O)OH.

[0111] In certain embodiments of the present invention, at least one R 9 is —C(O)NH2, —C(O)NH(C1-C3 alkyl) or —C(O)N(C1-C3 alkyl)2.

[0112] In certain embodiments of the present invention, at least one R 11 is F.

[0113] In certain embodiments of the present invention, Y 1 and Y 2 are linked to form piperidine, azepane, azocane, thiazepine, diazepane, oxazepane, azetidine, pyrrolidine, piperazine, which are linked to the fused ring through the nitrogen or thiomorpholine.

[0114] In certain embodiments of the present invention, two R 7 are joined to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, said spirocyclic ring being optionally substituted with oxo (=O), halogen, hydroxy, C1-C3 alkyl, and -O-(C1-C3 alkyl).

[0115] In certain embodiments of the present invention, two R on adjacent atoms 7 is a bond or 1 to 4 R 8 C3-C6 cycloalkyl optionally substituted with 1-4 R 8 heteroaryl optionally substituted with 1 to 4 R 8 aryl optionally substituted with and 1 to 4 R 8and optionally linked to form a fused ring selected from optionally substituted heterocycles.

[0116] In certain embodiments of the present invention, two R 7 are optionally linked to form one to two carbon bridges.

[0117] Non-limiting examples of compounds of the present invention include: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0118] Non-limiting examples of compounds of formula (I) are selected from the group consisting of the compounds set forth in the Examples below and pharmaceutically acceptable salts thereof.

[0119] In one embodiment, compounds of formula (I) include the bis-hydrochloride, tris-hydrochloride, trifluoroacetic acid, bis-trifluoroacetic acid, and tris-trifluoroacetic acid salts of the above compounds. The compounds of formula (I) or pharmaceutically acceptable salts thereof may be formulated into pharmaceutical compositions.

[0120] Pharmaceutical Composition In another aspect, the present invention provides pharmaceutical compositions comprising a wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H 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 known in the art and prepared for administration by any route, including, but not limited to, parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal, intramuscular, intravitreal, intravenous, intraarterial, oral, buccal, sublingual, transdermal, topical, intranasal, intratracheal, rectal, subcutaneous, and local administration. In certain embodiments, the compounds of the present invention are administered intravenously in a hospital setting. In one embodiment, administration can be by the oral route. In some embodiments, provided pharmaceutical compositions may be administered to a subject in need of treatment by systemic injection, such as by intravenous injection, or by injection or application to the relevant site, such as by direct injection via a syringe or by direct application to the site if the site has been surgically exposed, or by local administration.

[0121] 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.

[0122] The provided pharmaceutical compositions can also be formulated as depot preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the formulation 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 as a sparingly soluble derivative, e.g., as a sparingly soluble salt.

[0123] The pharmaceutical compositions may, if desired, be presented in a vial, pack, or medical device, including, but not limited to, a dispenser device, which may contain one or more unit dosage forms containing the active ingredient. In one embodiment, the dispenser device may include a syringe with a single dose of the liquid formulation ready for injection. The syringe may be accompanied by instructions for administration.

[0124] 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. Thus, in addition to the inhibitor, the composition according to the present invention may contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other substances well known in the art. The preparation of pharmaceutically acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0125] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the compounds identified above and exhibits minimal or no undesired 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 such as 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. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, specifically salts of the formula -NR+Z 2 -, wherein R is hydrogen, alkyl, or benzyl; Z 2is a counterion including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzilate, and diphenylacetate).

[0126] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing significant toxic effects to the patient being treated. In one embodiment, the dose of the active compound for all of the above conditions ranges from about 0.01 to 300 mg / kg per day, e.g., 0.1 to 100 mg / kg, and as a further example, from 0.5 to about 25 mg per kilogram of recipient body weight per day. Typical topical dosages will be in the range of 0.01 to 3% weight / weight in a suitable carrier. The effective dosage range of pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative is active in itself, the effective dosage can be estimated as described above using the weight of the derivative or by other means known to those skilled in the art.

[0127] Pharmaceutical compositions containing the compounds of the present invention can be used in the methods of use described herein.

[0128] How to use In yet another aspect, the present invention provides a method for inhibiting wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, and / or KRas Q61H activity in a cell, the method comprising contacting a cell in which inhibition of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, and / or Q61H activity is desired 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 performed in vitro. In one embodiment, the contacting is performed in vivo.

[0129] As used herein, the term "contacting" refers to bringing the indicated moieties together, either in an in vitro system or in an in vivo system. "Contacting" wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H with a compound provided herein includes administering a compound provided herein to an individual or patient, such as a human, who has wild-type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H mutation, and administering the compound to an individual or patient, such as a human, who has wild-type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H mutation, and A compound provided herein is introduced to a sample containing cells or a purified preparation containing the Q61H mutation.

[0130] In one embodiment, a cell in which inhibition of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H activity is desired is contacted with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to negatively regulate 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.

[0131] By negatively modulating 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 designed to inhibit undesirable cell proliferation resulting from 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 affect 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. Additionally, the inhibitory activity of exemplary compounds in cells can be monitored by measuring inhibition of one or more of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H activity, e.g., the amount of phosphorylated ERK, using, e.g., the methods described in Example C below.

[0132] In another aspect, there is provided a method of treating cancer in a patient in need thereof, comprising administering to said 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 pharmaceutically acceptable salt.

[0133] Compositions and methods are provided herein that can be used to treat wild-type KRas-related or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H-related cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula (I), 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-related or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H-related cancer is lung cancer.

[0134] The compositions and methods provided herein can be used for the treatment of a variety of cancers, including, for example, lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytoma, breast cancer, cervical cancer, colon 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 sarcoma. More specifically, these compounds may be used to treat: cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma), tumor, leiomyoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIP-producing 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 system: 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, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder carcinoma, ampulla carcinoma, bile duct carcinoma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant gigantoma Cysts, chordomas, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibromas, meningiomas, gliomas, sarcomas);Gynecology: Uterus (endometrial cancer), Cervix (cervical carcinoma, preneoplastic cervical dysplasia), Ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), Vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma)), Fallopian tube (carcinoma); Blood: Blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia) Cancers include: lymphoma, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles, dysplastic nevi, lipomas, hemangiomas, dermatofibromas, keloids, psoriasis; and adrenal glands: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer, small cell lung cancer, colon cancer, rectal cancer, or pancreatic cancer. In certain embodiments, the cancer is non-small cell lung cancer.

[0135] The concentration and route of administration to the patient will vary depending on the cancer being treated. The compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions containing such compounds and salts may be co-administered with other anti-neoplastic compounds, for example, chemotherapy, or may also be used as an adjunct, either pre- or post-operatively, in combination with other treatments, such as radiation or surgical intervention.

[0136] Also provided herein is a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in therapy.

[0137] There is also provided herein a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of cancer.

[0138] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for use in inhibiting wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H.

[0139] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for use in the treatment of a disease or disorder associated with wild-type KRas or associated with KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H.

[0140] There is also provided herein the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of cancer.

[0141] Also provided herein is the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H activity.

[0142] Also provided herein is the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with wild-type KRas or associated with KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H.

[0143] Also provided herein are methods of treating cancer in a patient in need thereof, comprising: (a) determining that the cancer is associated with wild-type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H mutation (e.g., determined using an assay or kit approved by a regulatory authority, e.g., the FDA); 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.

[0144] Those skilled in the art will recognize that both in vivo and in vitro tests using suitable, known, and generally accepted cellular and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0145] Those skilled in the art will further recognize that human clinical trials, including first-in-human dose ranging and efficacy studies in healthy patients and / or patients suffering from a given disorder, can be completed according to methods well known in the clinical and medical arts. [Example]

[0146] Reaction Schemes and Examples The compounds of the present invention can be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein or using other reagents and conventional methods known to those skilled in the art. For example, the compounds of the present invention can be prepared according to the following reaction schemes and examples outlined below.

[0147] The compounds of the present invention may have one or more chiral centers and may be synthesized as stereoisomeric mixtures, isomers of identical constitution that differ in the arrangement of their atoms in space. The compounds may be used as mixtures, or the individual components / isomers may be separated using conventional methods for isolating stereoisomers and enantiomers using commercially available reagents and well known to those skilled in the art, such as CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatographic HPLC columns according to the manufacturer's instructions. Alternatively, the compounds of the present invention may be synthesized using optically pure chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Unless otherwise specified, whenever the specification, including the claims, refers to a compound of the present invention, the term "compound" should be understood to encompass all chiral (enantiomers and diastereomers) and racemic forms.

[0148] The compounds of the present invention may be in anhydrous, solvated or hydrated form, and all such forms are embraced within the scope of the present invention.

[0149] The following intermediates are intended to illustrate further specific embodiments of the present invention and are not intended to limit the scope of the invention.

[0150] Intermediate 1 [ka] 8-Fluoro-7-(8-fluoronaphthalen-1-yl)-4-(methylthio)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine [ka] Step A. 8-Fluoro-7-(8-fluoronaphthalen-1-yl)-4-(methylthio)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine: To a solution of 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-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 h. The mixture was filtered, concentrated, and purified by column chromatography (SiO, petroleum ether / ethyl acetate 10:1 to 0:1) to afford the title compound (260 mg, 58% yield) as a white solid. 1 H 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 m / z=479.2.

[0151] Intermediate 2 [ka] 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 [ka] 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 HO (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) to give the title compound (5.00 g, 78% yield) as a white solid. LCMS (ESI, M+1): m / z = 622.2.

[0152] Intermediate 3 [ka] ((3S,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolidin-3-yl)methyl dimethylcarbamate [ka] Step A. (3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolidine: To a solution of ((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolidin-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 h. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (2×100 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.

[0153] Step B. ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methanol: To a solution of (3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolidine (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 h. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 × 50 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] 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.

[0154] Step C. ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methanol (930 mg, 1.0 equiv) in THF (20 mL) was added NaH (360 mg, 60% purity, 4.0 equiv) at 0 °C. The mixture was stirred at 0 °C for 10 minutes. To the mixture was added dimethylcarbamic chloride (484 mg, 2.0 equiv) 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] to give the title compound (1.00 g, 83% yield) as a yellow oil. LCMS (ESI, M+1): m / z=485.3.

[0155] Step D. ((3S,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolidin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolidin-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 h. The mixture was concentrated. To the residue was added MeOH (5 mL) and NaHCO (300 mg). The mixture was filtered and concentrated to give a residue which was purified by column chromatography [AlO, 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 (400MHz, methanol-d4) δ=4.00(dq,J=6.0,10.8Hz,2H),3.31-3.22(m,2H),3.03- 2.96(m,2H),2.95-2.86(m,6H),2.80(td,J=5.2,10.8Hz,1H),2.09-1.46(m,8H).

[0156] Intermediate 4 [ka] Dimethyl(1,4-oxazepan-6-yl)phosphine oxide [ka] Step A: tert-Butyl 6-(dimethylphosphoryl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate: A mixture of tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate (350 mg, 1 equiv.), methylphosphonoylmethane (86.5 mg, 1.1 equiv.), Pd(PPh3)4 (58.2 mg, 0.05 equiv.), Et3N (204 mg, 2 equiv.), and methylphosphonoylmethane (86.5 mg, 1.1 equiv.) in MeCN (10 mL) was degassed and stirred at 90 °C under N2 atmosphere for 10 h. The reaction mixture was concentrated and purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 12% to 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)

[0157] 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)-carboxylate (100 mg, 1.0 equiv.), Pd / C (50 mg, 60% purity, 1.0 equiv.) in MeOH (1.0 mL) was degassed and purged with H three times, then the mixture was stirred under an H atmosphere at 25° C. for 2 h. The reaction mixture was diluted with MeOH (20 mL) and concentrated under reduced pressure to give the title compound (100 mg) as a white solid.

[0158] Step C Dimethyl(1,4-oxazepan-6-yl)phosphine oxide: To a solution of tert-butyl 6-(dimethylphosphoryl)-1,4-oxazepan-4-carboxylate (100 mg, 1.0 equiv.) in DCM (2.0 mL) was added TFA (411 mg, 10.0 equiv.). 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.

[0159] Intermediate 5 [ka] Three isomers of 3-azabicyclo[3.2.1]octane-6,7-diol (stereochemistry arbitrarily assigned) [ka] Step A. Benzyl 6-hydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate: To a mixture of 3-azabicyclo[3.2.1]octan-6-ol (4.50 g, 1.0 equiv.) and NaHCO (11.9 g, 4.0 equiv.) in EtOAc (54.0 mL) and water (36.0 mL) was added benzyl carbonochloridate (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 h. 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 afford the title compound (8.30 g, 90% yield) as a colorless oil.

[0160] 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 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the title compound (10 g, 94% yield) as a pale yellow solid.

[0161] 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 h. The mixture was acidified with 1 N HCl (15 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with NaHCO (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).

[0162] Step D. Benzyl 3-oxa-7-azatricyclo[3.3.1.02,4]nonane-7-carboxylate: To a mixture of benzyl 3-azabicyclo[3.2.1]oct-6-ene-3-carboxylate (3.47 g, 1.0 equiv.) in DCM (70 mL) was added m-CPBA (6.15 g, 2.0 equiv.). The reaction was stirred at 20 °C for 5 h. The mixture was quenched by the addition of saturated aqueous NaSO (70 mL), neutralized with solid NaHCO, 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 afford the title compound (2.50 g, 61% yield) as a pale 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).

[0163] 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 (2 M in water, 72.3 mL, 5.0 equiv.). The reaction was stirred at 60 °C for 12 h. The mixture was basified with 40% NaOH in an ice bath and extracted with EtOAc (4 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Phenomenex Luna C18 250 × 50 mm × 10 μm; A: water (TFA); B: ACN; B%: 14% to 44% in 20 min]. The desired fraction was 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 (1.1 g, 37% yield) as a yellow oil. SFC: Chiralpak AD-3 50 x 4.6 mm ID, 3 μm; gradient elution: IPA (0.05% DEA) in CO2 5% to 40%, t R :1.411 min, 1.468 min, 1.599 min, 1.707 min; LCMS(ESI,M+23): m / z=278.0.

[0164] 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. Sufficient purity was not achieved for peak 2. SFC: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm; gradient elution: 5%–40% IPA (0.05% DEA) in CO₂, 3 mL / min, 220 nm, t R : 1.713 min. (stereochemistry arbitrarily assigned)

[0165] (1R,5S,6R,7R)-benzyl 6,7-dihydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate (peak 1, 260 mg, 23% yield) as a colorless oil.

[0166] (1R,5S,6S,7S)-benzyl 6,7-dihydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate (peak 3, 260 mg, 23% yield) as a colorless oil.

[0167] (1R,5S)-benzyl 6,7-dihydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate (peak 4, 230 mg, 20% yield) as a colorless oil.

[0168] Step G. Isomer of 3-azabicyclo[3.2.1]octane-6,7-diol, Intermediate 5 Peak 1: To a mixture of (1R,5S,6S,7S)-benzyl 6,7-dihydroxy-3-azabicyclo[3.2.1]octane-3-carboxylate (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 under hydrogen (15 psi) at 20 °C for 2 h. 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.

[0169] Intermediate 5 Peak 3 and Intermediate 5 Peak 4 were obtained using the same procedure as described in Step G.

[0170] Intermediate 6 [ka] 6,7,8,9-Tetrahydro-5H-pyrimido[5,4-c]azepine [ka] 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.

[0171] Step B. Benzyl 8,9-dihydro-5H-pyrimido[5,4-c]azepine-6(7H)-carboxylate: To a solution of formimidamide (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. To the mixture was added (E)-benzyl 3-((dimethylamino)methylene)-4-oxoazepane-1-carboxylate (6.50 g, 1.0 equiv.). The reaction was stirred at 80 °C for 2 h. The mixture was diluted with HO (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.

[0172] 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 H three times. The reaction was stirred under H (15 psi) at 20 °C for 0.5 h. The mixture was filtered and concentrated to afford the title compound (150 mg, 94% yield) as a yellow oil, which was used directly in the next step without further purification.

[0173] Intermediate 7 [ka] 6,7,8,9-Tetrahydro-5H-[1,2,3]triazino[5,4-c]azepine [ka] Step A. tert-Butyl 2-amino-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(2H)-carboxylate: To a solution of tert-butyl 4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(2H)-carboxylate (2.00 g, 1.0 equiv.) in DMF (60 mL) was added t-BuONa (4.05 g, 5.0 equiv.) portionwise at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Aminohydrogen sulfide (2.86 g, 3.0 equiv.) was added portionwise to the mixture at 0 °C. The reaction was stirred at 0 °C for 2 h. The mixture was carefully quenched with water (200 mL) at 0 °C and extracted with ethyl acetate (3 × 80 mL). 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% to 44% in 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.

[0174] Step B. tert-Butyl 8,9-dihydro-5H-[1,2,3]triazino[5,4-c]azepine-6(7H)-carboxylate: 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 HO (3 mL) was added NaIO (254 mg, 1.5 equiv.). The reaction was stirred at 20 °C for 2 h. The mixture was quenched with saturated aqueous NaSO (10 mL) at 0 °C and extracted with DCM (2 × 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) to afford 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(brs,2H),3.67(brs,2H),3.31-3.27(m,2H),1.90-1.65(m,2H),1.34-1.22(m,9H).

[0175] Step C. 6,7,8,9-Tetrahydro-5H-[1,2,3]triazino[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.

[0176] Intermediate 8 [ka] 4-Methyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione [ka] 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 h. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over NaSO, concentrated, and purified by column chromatography (SiO, petroleum ether / ethyl acetate 1:0 to 3:1) to afford 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).

[0177] 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 h. The reaction mixture was concentrated and purified by column chromatography (SiO, petroleum ether / ethyl acetate 1:0 to 0:1) to afford 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).

[0178] 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 NH.sub.3·MeOH (12 M, 4 mL, 44 equiv.) and Pd(OH)2 / C (50.0 mg, 10% purity) under a N2 atmosphere. The suspension was degassed and purged with H2 three times. The reaction was stirred under H2 (50 psi) at 50 °C for 24 h. 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% to 25% in 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).

[0179] Intermediate 9 [ka] (1R,5S)-3,7-diazabicyclo[3.3.1]nonane-2,4-dione [ka] 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 under N2 atmosphere at 80 °C for 4 h. The solvent was removed under reduced pressure to give crude (3S,5R)-1-(tert-butoxycarbonyl)-5-carbamoylpiperidine-3-carboxylic acid (450 mg, crude) as a white solid.

[0180] Step B. tert-Butyl (1R,5S)-6,8-dioxo-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate: To 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 N for 12 h. The mixture was poured into ice water (20 mL), and then 1N HCl 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 NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (3V) at 25° C. for 30 min to give the 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).

[0181] Step C. (1R,5S)-3,7-diazabicyclo[3.3.1]nonane-2,4-dione: To a solution of tert-butyl (1R,5S)-6,8-dioxo-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (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 h. The mixture was concentrated in vacuo. The crude product was triturated with ethyl acetate (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). +

[0182] Intermediate 10 [ka] (R)-6-(methoxymethyl)-6-methyl-1,4-oxazepane [ka] Step A. (R)-Benzyl 6-(hydroxymethyl)-6-methyl-1,4-oxazepane-4-carboxylate: A mixture of [(6R)-6-methyl-1,4-oxazepan-6-yl]methanol (300 mg, 1.0 equiv.), CbzCl (881 mg, 2.5 equiv.), and KCO (857 mg, 3.0 equiv.) in EtOAc (4 mL) and HO (4 mL) was stirred at 28 °C for 5 h. The mixture was extracted with 15 mL of ethyl acetate (5 mL × 3), washed with brine, dried over NaSO, filtered, purified by column chromatography (SiO, petroleum ether / ethyl acetate 20:1 to 3:1), and lyophilized to afford the title compound (300 mg, 44% yield) as a yellow solid. 1 H NMR (400MHz, 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.

[0183] Step B. (R)-Benzyl 6-(methoxymethyl)-6-methyl-1,4-oxazepane-4-carboxylate: To a solution of benzyl (6R)-6-(hydroxymethyl)-6-methyl-1,4-oxazepane-4-carboxylate (300 mg, 1.0 equiv.) in THF (8 mL) was added NaH (85.9 mg, 60% purity, 2.0 equiv.) at 0 °C. The mixture was stirred for 0.5 h, then CHCl (305 mg, 2.0 equiv.) was added dropwise, and the mixture was stirred at 0 °C for 2 h. The mixture was quenched with HO (3 mL) at 0 °C, filtered, and purified by column chromatography (SiO, petroleum ether / ethyl acetate 10:1 to 3:1) to afford the title compound (100 mg, 27% yield) as a white solid. 1H NMR (400MHz, 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=18.0Hz,3H)LCMS(ESI,M+1):m / z=294.1

[0184] Step C. (R)-6-(Methoxymethyl)-6-methyl-1,4-oxazepane: A mixture of benzyl (6R)-6-(methoxymethyl)-6-methyl-1,4-oxazepane-4-carboxylate (50 mg, 1.0 equiv.), Pd / C (10 mg, 0.1 equiv.) in MeOH (5 mL) was degassed and purged with H three times, then the mixture was stirred under an atmosphere of H (15 psi) at 20° C. for 2 h. The mixture was filtered and concentrated under reduced pressure to afford the title compound (20 mg, 74% yield) as a yellow oil. 1 H NMR (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)

[0185] Intermediate 11 [ka] 3-(aminomethyl)-3-methyl-1,2,5-thiadiazolidine 1,1-dioxide [ka] Step A. tert-Butyl (2-amino-2-cyanopropyl)carbamate: To a solution of tert-butyl (2-oxopropyl)carbamate (1.00 g, 1.0 equiv.) in methanol (10 mL) was added Ti(i-PrO) (1.64 g, 1.0 equiv.) and NH MeOH (7.00 M, 2.0 equiv.). To the resulting mixture was added TMSCN (1.15 g, 2.0 equiv.) dropwise at 0 °C. The reaction was stirred at 25 °C for 16 h. The mixture was diluted with water (50 mL), filtered, and extracted with ethyl acetate (3 × 100 mL). The combined organic phase was dried over Na SO , filtered, concentrated, and purified by flash silica gel chromatography (0–100% ethyl acetate / petroleum ether) to afford 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).

[0186] 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.) in MeOH (2 mL) and NH.sub.3·MeOH (0.5 mL) was added Raney-Ni (257 mg, 3.0 equiv.). The reaction was degassed and purged with hydrogen three times. The reaction was stirred under an atmosphere of hydrogen (15 psi) at 25° C. for 5 h. The mixture was filtered and concentrated to afford the title compound (80.0 mg, crude) as a yellow oil.

[0187] Step C. tert-Butyl ((3-methyl-1,1-dioxide-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 equiv.) in pyridine (3 mL) was added a solution of sulfamide (37.8 mg, 1.0 equiv.) in pyridine (3 mL) dropwise at 25 °C. The reaction was stirred at 115 °C for 20 h. The mixture was filtered, concentrated, and purified by preparative TLC (dichloromethane / methanol 10:1) to afford 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).

[0188] Step D. 3-(Aminomethyl)-3-methyl-1,2,5-thiadiazolidine 1,1-dioxide: To a solution of tert-butyl ((3-methyl-1,1-dioxide-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 h. The mixture was concentrated to give the title compound (30.0 mg, crude, HCl) as a brown solid.

[0189] Intermediate 12 [ka] (3aR,8aS)-Hexahydropyrrolo[3,4-d]azepine-1,3(2H,3aH)-dione [ka] Step A. (3aR,8aS)-tert-Butyl 2-(2,4-dimethoxybenzyl)-1,3-dioxooctahydropyrrolo[3,4-d]azepine-6(2H)-carboxylate: To 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 the addition, the mixture was stirred at 50° C. for 1 hour, and (2,4-dimethoxyphenyl)methanamine (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.

[0190] Step B. (3aR,8aS)-tert-butyl 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 h. 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 (SiO 2 , petroleum ether / ethyl acetate 1:1) to give the title compound (25 mg, 39% yield) as a colorless oil. 1H 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).

[0191] Step C. (3aR,8aS)-Hexahydropyrrolo[3,4-d]azepine-1,3(2H,3aH)-dione: To 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 equiv.) in DCM (1.5 mL) was added trifluoroacetic acid (770 mg, 72.5 equiv.). The mixture was stirred at 20 °C for 0.5 h. The mixture was concentrated under reduced pressure to give the title compound (25 mg, 95% yield, TFA) as a white solid. The crude product was used in the next step without further purification; LCMS (ESI, M+1): m / z = 169.2

[0192] Intermediate 13A [ka] (1S,3aS,6aR)-3-Oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxamide [ka] Step A. (2S)-1-tert-butyl 2-ethyl 5-oxo-4-(phenylselanyl)pyrrolidine-1,2-dicarboxylate: To a solution of (S)-1-tert-butyl 2-ethyl 5-oxopyrrolidine-1,2-dicarboxylate (2.00 g, 1.0 equiv.) in THF (40 mL) was added LiHMDS (1 M, 8.55 mL, 1.1 equiv.) dropwise at −78 °C. The mixture was stirred at −78 °C for 1 h under a N atmosphere. Then, a solution of phenylhypobromoselenoite (2.20 g, 1.2 equiv.) in THF (10 mL) was added dropwise to the mixture at −78 °C. The mixture was stirred at −78 °C for 2 h under a N atmosphere. The reaction mixture was quenched at −78 °C with saturated aqueous ammonium chloride (50 mL) 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 in vacuo. The residue was purified by reverse-phase MPLC [C18, 0.1% formic acid] to give the title compound (0.80 g, 25% yield) as a yellow oil. H 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).

[0193] Step B: (S)-1-tert-butyl 2-ethyl 5-oxo-1H-pyrrole-1,2(2H,5H)-dicarboxylate: To a solution of (2S)-1-tert-butyl 2-ethyl 5-oxo-4-(phenylselanyl)pyrrolidine-1,2-dicarboxylate (2.00 g, 1.0 equiv.) in THF (40 mL) was slowly added dropwise HO (1.15 g, 30% purity, 2.1 equiv.). The resulting mixture was stirred at 35 °C for 2 h. The reaction mixture was quenched with saturated aqueous 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 in vacuo. The residue was purified by reverse-phase MPLC [C18, 0.1% formic acid] to afford 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).

[0194] Step C. (1S,3aS,6aR)-2-tert-butyl 1-ethyl 5-benzyl-3-oxohexahydropyrrolo[3,4-c]pyrrole-1,2(1H)-dicarboxylate: To a solution of (S)-1-tert-butyl 2-ethyl 5-oxo-1H-pyrrole-1,2(2H,5H)-dicarboxylate (450 mg, 1.0 equiv.) in DCM (3 mL) was added a solution of TFA (80.4 mg, 0.4 equiv.) in DCM (5 mL). Then, N-(methoxymethyl)-1-phenyl-N-(trimethylsilylmethyl)methanamine (1.26 g, 3.0 equiv.) in DCM (2 mL) was added dropwise to the mixture at 0 °C. The resulting mixture was warmed to 25 °C and stirred at 25 °C for 3 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse-phase MPLC [C18, 0.1% formic acid] to give the title compound (460 mg, 67% yield). 1H NMR (400MHz, methanol-d4) δ=7.34-7.23(m,5H),4.37(d,J=2.4Hz,1H),4.29-4.19(m,2H),3.69-3.52(m,2H),3.18-3.08(m,2H),2.94(br d,J=10.0Hz,1H),2.80-2.71(m,1H),2.60(dd,J=7.8,9.6Hz,1H),2.48-2.38(m,1H),1.48(s,9H),1.29(t,J=7.2Hz,3H).

[0195] Step D. (1S,3aS,6aR)-Ethyl 5-benzyl-3-oxohexahydropyrrolo[3,4-c]pyrrole-1-carboxylate: To a solution of (1S,3aS,6aR)-2-tert-butyl 1-ethyl 5-benzyl-3-oxohexahydropyrrolo[3,4-c]pyrrole-1,2(1H)-dicarboxylate (300 mg, 1.0 equiv.) in ethyl acetate (2 mL) was added HCl / dioxane (4 M, 10 mL, 51.8 equiv.). The mixture was stirred at 25 °C for 1 h. 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.

[0196] Step E. (1S,3aS,6aR)-5-Benzyl-3-oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylic acid: To a solution of (1S,3aS,6aR)-ethyl 5-benzyl-3-oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (220 mg, 1.0 equiv.) in MeOH (9 mL) was added aqueous NaOH (1 M, 3.05 mL, 4.0 equiv.). The mixture was stirred at 40 °C for 1 h. The reaction mixture was poured into water (10 mL), and the pH of the mixture was 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) to afford 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.

[0197] 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-oxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylic acid (90.0 mg, 1.0 equiv., FA salt) and NH₄Cl (47.2 mg, 3.0 equiv.) in DMAc (1 mL), PYBROP (164 mg, 1.2 equiv.) and TEA (89.2 mg, 3.0 equiv.) were added. The mixture was then stirred at 40 °C under a N₂ atmosphere for 12 h. MeOH (1 mL) was added. The mixture was directly purified by preparative HPLC (C18, 0.1% NH₃.HO) 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).

[0198] 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 a N atmosphere. The suspension was degassed under vacuum and purged with H several times. The mixture was stirred at 40 °C under a H atmosphere (15 Psi) for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (9.79 mg, crude), which was used directly in the next step.

[0199] Intermediate 13B [ka] (1R,3aS,6aR)-tert-butyl 1-(cyanomethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate [ka] Step A. (S)-5-(((tert-Butyldimethylsilyl)oxy)methyl)pyrrolidin-2-one: To a mixture of (5S)-5-(hydroxymethyl)pyrrolidin-2-one (10.0 g, 1.0 equiv.) and imidazole (8.80 g, 1.5 equiv.) in dichloromethane (100 mL) was added tert-butyldimethylsilyl chloride (15.7 g, 1.2 equiv.) in portions at 0–5° C. After the addition was complete, the resulting mixture was warmed to 25–30° C. and stirred for 12 h. The mixture was diluted with water (150 mL) and separated. The aqueous phase was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. 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.

[0200] Step B. tert-Butyl (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-oxopyrrolidine-1-carboxylate: To a solution of (5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-2-one (2.0 g, 1.0 equiv.) in dichloromethane (20 mL) was added tert-butyl dicarbonate (2.8 g, 1.5 equiv.), triethylamine (1.7 g, 2.0 equiv.), and 4-dimethylaminopyridine (106 mg, 0.1 equiv.). The resulting mixture was stirred at 25° C. for 12 hours. The mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO®, 80 g SepaFlash® silica flash column, elution with a 20% ethyl acetate / petroleum ether gradient at 100 mL / min) to give 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).

[0201] Step C. tert-Butyl (5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-oxo-3-(phenylselanyl)pyrrolidine-1-carboxylate: To a solution of tert-butyl (2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-oxopyrrolidine-1-carboxylate (1.0 g, 1.0 equiv.) in tetrahydrofuran (25 mL) under nitrogen at −60° C. was added lithium hexamethyldisilazide (1 M, 3.3 mL, 1.1 equiv.) dropwise. The solution was stirred at −60° C. for 0.5 h, then a solution of phenylselenohypochlorite (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 an additional 1 h, then warmed to 25° C. and stirred at 25° C. for 12 h. The mixture was quenched with saturated ammonium chloride (40 mL) at 0-5°C under nitrogen and allowed to warm to 25°C with stirring for 0.5 h. 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 afford the title compound (740 mg, 50% yield) as a yellow oil.

[0202] Step D. tert-Butyl (S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate: To a solution of tert-butyl (5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-oxo-3-phenylselanylpyrrolidine-1-carboxylate (740 mg, 1.0 equiv.) in dichloromethane (10.0 mL) at −70° C. was added pyridine (362 mg, 3.0 equiv.), followed by the slow addition of hydrogen peroxide (606 mg, 30% purity, 3.5 equiv.). The resulting mixture was warmed 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 in vacuo. 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.

[0203] Step E. tert-Butyl (1S,3aS,6aR)-5-benzyl-1-(((tert-butyldimethylsilyl)oxy)methyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: To 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 the addition, the resulting mixture was stirred at 25 °C for 12 h. Additional 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 h. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC [3_Phenomenex Luna C18 75 × 30 mm × 3 μm; A: water (HCl), B: CH3CN, B%: 39% to 59% in 6 min] and then lyophilized. The title compound (102 mg, 37% yield) was obtained as a yellow solid. LCMS (ESI, M+1): m / z = 461.4.

[0204] Step F. (1S,3aS,6aR)-tert-butyl 5-benzyl-1-(hydroxymethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: A mixture of (1S,3aS,6aR)-tert-butyl 5-benzyl-1-(((tert-butyldimethylsilyl)oxy)methyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (10 g, 1.0 equiv.) and 4-methylbenzenesulfonic acid; hydrate (4.54 g, 1.1 equiv.) in THF (120 mL) was stirred at 30 °C for 16 h. The mixture was concentrated and purified by preparative HPLC (column: Kromasil Eternity XT 250 × 80 mm × 10 μm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 30% to 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.

[0205] Step G. tert-Butyl (1R,3aS,6aR)-5-benzyl-1-(cyanomethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: To a solution of tert-butyl (3aS,6S,6aR)-2-benzyl-6-(hydroxymethyl)-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (1.00 g, 1.0 equiv.) in THF (10 mL) was added 2-hydroxy-2-methylpropanenitrile (737 mg, 1.0 equiv.) and tributylphosphine (2.04 g, 3.5 equiv.). Then, ADDP (2.55 g, 3.5 equiv.) was added to the mixture at 0 °C and stirred at 50 °C for 2 h. The reaction mixture was poured into saturated aqueous NH4Cl (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. 1H NMR(400MHz,chloroform-d)δ=7.32-7.23(m,5H),7.13-7.13(m,1H),4.07(ddd,J=2.1,4.0,6.1Hz,1H),3.67(d,J=1 3.2Hz,1H),3.50(d,J=13.2Hz,1H),3.25-3.18(m,2H),2.90-2.80(m,2H),2.77(dd,J=2.0,9.2Hz,1H),2.64(br d,J=8.8Hz,1H),2.61-2.52(m,2H),1.57(s,9H)

[0206] Step H. (1R,3aS,6aR)-tert-butyl 1-(cyanomethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: To a solution of (1R,3aS,6aR)-tert-butyl 5-benzyl-1-(cyanomethyl)-3-oxohexahydropyrrolo[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 H three times. The mixture was stirred under a hydrogen atmosphere (15 psi) at 25 °C for 16 h. The reaction mixture was filtered and concentrated to give the title compound (50.0 mg, 96% yield) as a yellow oil.

[0207] Step I. (1S,3aS,6aR)-tert-butyl 5-benzyl-1-(hydroxymethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: To a solution of (1S,3aS,6aR)-tert-butyl 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 h. The mixture was concentrated and purified by preparative HPLC [column: Kromasil Eternity XT 250 × 80 mm × 10 μm; mobile phase: water (ammonia hydroxide v / v)-CAN; B%: 30% to 60%, 16 min] to give the title compound (6.20 g, 80% yield) as a white solid. 1H NMR (400MHz, 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.

[0208] Intermediate 13C [ka] 2-((1R,3aS,6aR)-3-oxooctahydropyrrolo[3,4-c]pyrrol-1-yl)acetamide [ka] Step A. tert-Butyl (1R,3aS,6aR)-5-benzyl-1-(cyanomethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: To a solution of tert-butyl (3aS,6S,6aR)-2-benzyl-6-(hydroxymethyl)-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (1.00 g, 1.0 equiv.) in THF (10 mL) was added 2-hydroxy-2-methylpropanenitrile (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 and stirred at 50 °C for 2 h. The reaction mixture was poured into saturated aqueous NH4Cl (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(400MHz,chloroform-d)δ=7.32-7.23(m,5H),7.13-7.13(m,1H),4.07(ddd,J=2.1,4.0,6.1Hz,1H),3.67(d,J=1 3.2Hz,1H),3.50(d,J=13.2Hz,1H),3.25-3.18(m,2H),2.90-2.80(m,2H),2.77(dd,J=2.0,9.2Hz,1H),2.64(br d,J=8.8Hz,1H),2.61-2.52(m,2H),1.57(s,9H)

[0209] Step B. tert-Butyl (1R,3aS,6aR)-1-(2-amino-2-oxoethyl)-5-benzyl-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate: To a solution of tert-butyl (3aS,6aR)-2-benzyl-6-(cyanomethyl)-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (500 mg, 79.7% purity, 1.0 equiv.) in EtOH (9 mL) and HO (1 mL) was added dimethylphosphinite platinum(2+) dimethylphosphinate (479 mg, 1.0 equiv.). The mixture was stirred at 60 °C for 2 h. The reaction mixture was filtered, concentrated, and purified by reverse-phase flash chromatography (C18, 0.1% ammonium hydroxide) to afford the title compound (420 mg, 90% yield) as a white solid. 1 H NMR (400MHz, methanol-d4)δ=7.37-7.28(m,5H),4.23(dd,J=2.8,8.0Hz,1H),3.67-3.53(m,2H),3.29-3.23(m,1H),2.95(br d,J=9.6Hz,1H),2.82-2.56(m,6H),1.52(s,9H)

[0210] Step C. 2-((1R,3aS,6aR)-5-benzyl-3-oxooctahydropyrrolo[3,4-c]pyrrol-1-yl)acetamide: To a solution of tert-butyl (3aS,6aR)-6-(2-amino-2-oxoethyl)-2-benzyl-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (100 mg, 90.2% purity, 1.0 equiv.) in methanol (1 mL) was added HCl / dioxane (4 M, 3 mL, 49.7 equiv.). The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to afford the title compound (70.0 mg, 93% yield, HCl) as a white solid.

[0211] 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-oxooctahydropyrrolo[3,4-c]pyrrol-1-yl)acetamide (50.0 mg, 1.0 equiv.) (HCl) dissolved in MeOH (2 mL) was added Pd / C (50.0 mg, 5% purity, wet). The suspension was degassed and purged with H three times. The mixture was stirred under an H atmosphere (15 psi) at 25 °C for 2 h. The reaction mixture was filtered and concentrated to give the title compound (40.0 mg, crude, HCl) as a white solid.

[0212] Intermediate 13D [ka] 1-[(3aS,6S,6aR)-4-oxo-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-6-yl]methanesulfonamide [ka] Step A. tert-Butyl (3aS,6S,6aR)-2-benzyl-6-(methylsulfonyloxymethyl)-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate: To a solution of tert-butyl (3aS,6S,6aR)-2-benzyl-6-(hydroxymethyl)-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (1.20 g, 1.0 equiv.) and MsO (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 h. The mixture was diluted with HO (20 mL) and extracted with DCM (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 (1.30 g, 79% yield) as a yellow oil. LCMS (ESI, M+1): m / z = 425.2

[0213] Step B. tert-Butyl (3aS,6S,6aR)-6-(acetylsulfanylmethyl)-2-benzyl-4-oxo-3,3a,6,6a-tetrahydro-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 ethanethiol (699 mg, 3.0 equiv.) at 0 °C, and the mixture was stirred at 25 °C for 2 h. The mixture was diluted with HO (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

[0214] Step C. 1-[(1S,3aS,6aR)-5-benzyl-3-oxo-1,2,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-1-yl]methanesulfonamide: To a solution of NCS (495 mg, 5.0 equiv.) was dissolved in ACN (18 mL) and HCl (2 M, 0.5 mL, 1.5 equiv.). To the solution was added a solution of tert-butyl (3aS,6S,6aR)-6-(acetylsulfanylmethyl)-2-benzyl-4-oxo-3,3a,6,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylate (300 mg, 1.0 equiv.) dropwise. 1S,3aS,6aR) was dissolved in ACN (12 mL) at 0 °C, and the mixture was stirred at 25 °C for 1 h. NH3 。HO (18 mL) was added, and the resulting mixture was stirred at 25 °C for 12 h. 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% to 38% in 7 min] and lyophilized to give the title compound (100 mg, 32% yield, TFA) as a white solid. LCMS (ESI, M+1): m / z = 310.1

[0215] Step D. 1-[(3aS,6S,6aR)-4-oxo-2,3,3a,5,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-6-yl]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.) in TFA (MeOH) (2 mL), Pd / C (50.0 mg, 10% purity, wet) was added. The mixture was stirred under an H atmosphere at 25 °C 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.

[0216] Intermediate 14 [ka] Azepan-3-yldimethylphosphine oxide [ka] 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 equiv.) in THF (15 mL) at −78 °C, LiHMDS (1.0 M, 28.1 mL, 1.2 equiv.) was slowly added, and the resulting mixture was stirred at −78 °C for 1 h. The reaction mixture was concentrated and purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to afford 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).

[0217] Step B. tert-Butyl 6-(dimethylphosphoryl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate: A mixture of tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (500 mg, 1.0 equiv.), methylphosphonoylmethane (136 mg, 1.2 equiv.), TEA (220 mg, 302 μL, 1.5 equiv.), and Pd(PPh) (50.2 mg, 0.03 equiv.) in ACN (5 mL) was degassed and purged with N three times, then the mixture was stirred under N at 90 °C for 3 h. The reaction mixture was filtered. The filtrate was concentrated and purified by preparative HPLC [C18, 0.1% TFA conditions] to give the title compound (180 mg, yield 43.1%, purity 94.8%) as a yellow gum. 1 H 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.

[0218] 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 a N atmosphere. The suspension was degassed and purged with H three times. The mixture was stirred under H (15 psi) at 25 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (160 mg) as a yellow oil. 1 H NMR (400 MHz, 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).

[0219] Step D. Azepan-3-yldimethylphosphine oxide: To a solution of tert-butyl 3-(dimethylphosphoryl)azepane-1-carboxylate (160 mg, 1.0 equiv.) in DCM (1.0 mL) was added HCl / dioxane (4 M, 1 mL, 6.9 equiv.). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound (120 mg, HCl salt) as a yellow oil.

[0220] Intermediate 15 [ka] 3-Amino-4-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide Intermediate 15A [ka] 5-Amino-4-cyano-N,N-dimethyl-1H-pyrazole-1-carboxamide [ka] 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 equiv.), DIPEA (35.9 g, 3.0 equiv.) in THF (200 mL) was added DMAP (2.26 g, 0.2 equiv.), and dimethylcarbamic chloride (14.9 g, 1.5 equiv.). The reaction was stirred at 60 °C for 12 h. The mixture was quenched with water (100 mL) and extracted with ethyl acetate (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. Intermediate 15A (4.44 g, 26% yield) was also obtained as a pale pink solid. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ = 7.76 (s, 1H), 7.19 (s, 2H), 3.02 (s, 6H).

[0221] Intermediate 16 [ka] (4,5,6,7,8,9-Hexahydropyrazolo[1,5-a][1,4]diazocin-2-yl)(morpholino)methanone [ka] Step A: tert-Butyl 2-(morpholine-4-carbonyl)-6,7,8,9-tetrahydropyrazolo[1,5-a][1,4]diazocine-5(4H)-carboxylate: To a solution of 5-tert-butoxycarbonyl-6,7,8,9-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazocine-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 h. After the reaction, the 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, which was purified by preparative TLC [SiO2, PE / EA=0 / 1] to give the title compound (25.0 mg, 40% yield, 99% purity) as a brown oil. 1 H 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.

[0222] Step B: (4,5,6,7,8,9-Hexahydropyrazolo[1,5-a][1,4]diazocin-2-yl)(morpholino)methanone: A solution of tert-butyl 2-(morpholine-4-carbonyl)-6,7,8,9-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazocine-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 h. The reaction mixture was concentrated under reduced pressure to remove the solvent and afford the title compound (330 mg, crude) as a colorless oil. LCMS (ESI, M+1): m / z = 265.1.

[0223] Intermediate 16A [ka] N,N-Dimethyl-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazocine-2-carboxamide Intermediate 16B [ka] N-Ethyl-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazocine-2-carboxamide Intermediates 16A and 16B were synthesized following the two-step procedure described for Intermediate 16.

[0224] Intermediate 17 [ka] 2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine [ka] To a solution of CF3, OH (2.57 g, 1.05 equiv.) in CH2THF (50 mL) was added t-BuONa (2 M, 12.8 mL, 1.05 equiv.). The mixture was stirred at 20 °C for 1 h. To the mixture was added 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) dropwise at -40 °C. The reaction was stirred at -40 °C for 0.5 h. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over Na2SO4 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.

[0225] Intermediate 18 [ka] (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aS)-3-(hydroxymethyl)hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol [ka] 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-fluoropyrido[4,3-d]pyrimidine (10.0 g, 1.0 equiv.) and (R)-3-methylpiperidin-3-ol (4.04 g, 1.2 equiv., HCl) in dichloromethane (200 mL) was added DIPEA (11.5 g, 4.0 equiv.) and 4 Å molecular sieves (1.0 g, 1.0 equiv.). The mixture was stirred at −40° C. for 15 hours. The reaction mixture was filtered, washed with EtOAc (100 mL), and extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (10.0 g, 84% yield) as a yellow liquid. LCMS (ESI, M+1): m / z = 529.2.

[0226] Step B. (R)-1-(2-(((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolidin-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: To a solution of ((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (4.26 g, 1.1 equiv.) and 4 Å molecular sieves (150 mg, 1.0 equiv.) in toluene (50 mL) was added t-BuONa (2.73 g, 3.0 equiv.) at 0° C. 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 ethyl acetate (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] to give the title compound (6.60 g, 76% yield) as a yellow liquid. LCMS (ESI, M+1): m / z=902.6.

[0227] Step C. (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((3S,7aS)-3-(hydroxymethyl)hexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol: (R)-1-(2-(((3S,7aS)-3-(((ter To a solution of (t-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolidin-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 equiv.) in DMF (66 mL) was added CsF (16.7 g, 15 equiv.). The mixture was stirred at 40° C. for 12 hours. 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) to give the title compound (4.0 g, 80% yield) as a yellow liquid. LCMS (ESI, M+1): m / z = 664.4.

[0228] Intermediate 19 [ka] 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 [ka] 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 h. The mixture was diluted with HO (30 mL) and saturated aqueous NaHCO (30 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried over anhydrous NaSO, concentrated, and purified by column chromatography [SiO, petroleum ether / ethyl acetate 15:1 to 4:1] to afford 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).

[0229] Step B. 5,6-Dimethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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'-bi(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)Cl (809 mg, 0.06 equiv.) under a N atmosphere. The mixture was stirred at 110 °C for 0.75 h. The mixture was filtered through a Celite pad. 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 Na2SO4, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate 20:1 to 15:1] to give the title compound (3.3 g, 50% yield) as a pale yellow oil. 1 H 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=2.8,11.2H) z,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).

[0230] Step C. 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: 7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolidine-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine in methoxycyclopentane (15 mL) To a mixture of 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 equiv.), CsCO (1 M in HO, 3.0 equiv.) and CataCXium A Pd G (173 mg, 0.1 equiv.) were added under a N atmosphere. The mixture was stirred at 80 °C for 6 h. The mixture was diluted with HO (10 mL) and extracted with ethyl acetate (5 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, 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 pale red solid. LCMS (ESI, M+1): m / z = 615.4.

[0231] Intermediate 20 [ka] 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)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole [ka] Step A. Ethyl 5-benzyl-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylate: To a mixture of ethyl 1-(dimethylsulfamoyl)pyrazole-4-carboxylate (150 g, 1.0 equiv.) in THF (1000 mL) was added HMPA (130 g, 1.2 equiv.) and LDA (2 M, 1.2 equiv.) at −65° C. under a nitrogen atmosphere. After stirring at −65° C. for 0.5 h, bromomethylbenzene (124 g, 1.2 equiv.) was added. The reaction was stirred at −65° C. under a nitrogen atmosphere for 0.5 h. 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 afford the title compound (130 g, 45% yield) as a yellow solid.

[0232] 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 HO (600 mL) was stirred at 25 °C for 1 h. 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.

[0233] 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 CFSOH (150 mL) was stirred at 90 °C for 2 h. The mixture was poured into ice water (1000 mL) and extracted with ethyl acetate (2 × 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.

[0234] Step D. 1-(Tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-ol: To a mixture of 1H-benzo[f]indazol-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 h. 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 afford the title compound (16 g, 74% yield) as a yellow solid.

[0235] Step E. 1-(Tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazol-4-yl trifluoromethanesulfonate: To a mixture of 1-tetrahydropyran-2-ylbenzo[f]indazol-4-ol (9.2 g, 1.0 equiv.), DIEA (17.3 g, 4.0 equiv.), and 4 Å molecular sieves (1.00 g) in DCM (100 mL) was added trifluoromethanesulfonic anhydride (19.3 g, 2.0 equiv.) at −40° C. The reaction was stirred at −40° C. for 0.5 h. The mixture was quenched with HO (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 condition) to give the title compound (2.8 g, 20% yield) as a black solid.

[0236] Step F. 1-(Tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-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 h. The mixture was concentrated, dissolved in water (20 mL), and extracted with ethyl acetate (3 × 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) to give the title compound (800 mg, 30% yield) as a brown solid.

[0237] Step G. 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)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole: 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5, To a solution of 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-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (232 mg, 1.0 equiv.) and Cs was added CO. 3(To a solution of [2-(2-aminophenyl)phenyl]palladium bis(1-adamantyl)butylphosphane methanesulfonate (517 mg, 1.5 M, 3.0 equiv.) in methoxycyclopentane (2 mL) was added [2-(2-aminophenyl)phenyl]palladium bis(1-adamantyl)butylphosphane 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) to give the title compound (320 g, 92% yield) as a brown solid. LCMS (ESI, M+1): m / z = 655.3.

[0238] Intermediate 21 [ka] 4-(8-Fluoro-2-((hexahydro-1H-pyrrolidin-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 [ka] 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-pyrrolidin-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)butylphosphane methanesulfonate (48.1 mg, 0.10 equiv.). The reaction was stirred at 90 °C for 2 h. 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.

[0239] Intermediate 22 [ka] 5-ethyl-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)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole [ka] Step A. Ethyl 1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylate: 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 h. The mixture was concentrated and purified by column chromatography [SiO, petroleum ether / ethyl acetate 8:1] to afford the title compound (29.0 g, 82% yield) as a white solid. 1 H NMR(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.

[0240] 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.), KCO (69.2 g, 2.0 equiv.), and Pd(PPh) (28.9 g, 0.1 equiv.) in DMF (600 mL) and THF (600 mL) was degassed and purged with N three times. The mixture was stirred at 70 °C under a N atmosphere for 12 h. 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 [SiO, petroleum ether / ethyl acetate 10:1] to afford 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).

[0241] 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.) under a N atmosphere at 0 °C. The solution was stirred at 0–25 °C for 12 h. The mixture was quenched with 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 [SiO, petroleum ether / ethyl acetate 10:1] to afford 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)

[0242] Step D. 2-(Bromomethyl)-1-chloro-4-ethylbenzene: To a solution of (2-chloro-5-ethylphenyl)methanol (98.0 g, 1.0 equiv.) in DCM (600 mL) was slowly added PBr (171 g, 1.1 equiv.) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was added to saturated NaHCO solution (2 L) at 0 °C and extracted with ethyl acetate (3 × 500 mL). The organic layer was dried over NaSO, concentrated, and purified by column chromatography [SiO, petroleum ether / ethyl acetate 1:0] to give the title compound (78.0 g, 58% yield) as a colorless oil.

[0243] Step E. Ethyl 5-(2-chloro-5-ethylbenzyl)-1-(N,N-dimethylsulfamoyl)-1H-pyrazole-4-carboxylate: 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) was added LDA (2 M, 128 mL, 1.2 equiv.) at −60° C. The mixture was stirred at −60° C. for 1 hour. To the mixture was added 2-(bromomethyl)-1-chloro-4-ethylbenzene (60.0 g, 1.2 equiv.) at −60° C. The mixture was stirred at −60° C. for 1 hour and warmed to 15° C. for 12 hours. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (2×300 mL). The organic layer was washed with brine (100 ml) and dried over NaSO. The organic phase was concentrated and purified by column chromatography [SiO, petroleum ether / ethyl acetate 50:1 to 8:1] to give the title compound (35.0 g, 38% yield) as a white solid. 1 H 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.

[0244] 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 HO (30 mL) was stirred at 90 °C for 2 h. The mixture was diluted with ethyl acetate (100 mL). The organic layer was dried over NaSO and concentrated to give the title compound (6.00 g) as a yellow solid. LCMS (ESI, M+1): m / z = 372.1.

[0245] 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 CFSOH (102 g, 42 equiv.) was stirred at 90 °C for 1.5 h. The mixture was quenched with ice water (200 mL) and filtered. The filter cake was partitioned between ethyl acetate (100 mL) and saturated NaHCO (100 mL). The organic layer was dried over NaSO and concentrated to give the title compound (3.20 g, 74% yield) as a yellow solid. LCMS (ESI, M+1): m / z = 247.0.

[0246] 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]indazol-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 h. 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.

[0247] 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 methanol (40 mL) under N 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.). The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (15 psi) at 15 °C for 20 h. 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.

[0248] 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 Tf2. HCl (4.57 g, 2.0 equiv.) was added at -40 °C. The mixture was stirred at -40 °C for 15 min. The mixture was concentrated and purified by column chromatography [SiO2, petroleum ether / ethyl acetate 100:1 to 20:1] to afford the title compound (1.00 g, 26% yield) as a yellow solid. LCMS (ESI, M+1): m / z = 429.1.

[0249] Step K. 5-Ethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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. uiv), Pd(dppf)Cl (171 mg, 0.1 equiv. uiv), and TEA (945 mg, 4.0 equiv. uiv) in ACN (20 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.19 g, 4.0 equiv. uiv) under N. The mixture was stirred at 80 °C for 2 h. 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.

[0250] Step L. 5-Ethyl-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)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole: 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro)pyrido[4,3-d]pyrimidin-7-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[f]indazole in methoxycyclopentane (2 mL) To a mixture of (1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (142 mg, 1.2 equiv.), 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.) was added CataCXium A Pd G (19.7 mg, 0.1 equiv.) under N. 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] to give the title compound (60.0 mg, 28% yield) as a yellow solid. LCMS (ESI, M+1): m / z=683.4.

[0251] Intermediate 23 [ka] 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 [ka] Step A. 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: To 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 a solution of 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) dropwise at −40° C. The mixture was stirred at -40°C for 0.5 hours. The mixture was quenched with H2O (30 mL) at -40°C, and the mixture was extracted with DCM (3 x 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 hours. 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.

[0252] Step B. 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: 5-(2,7-dichloro- To a mixture of 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 equiv.) and (hexahydro-1H-pyrrolidin-7a-yl)methanol (88 mg, 1.1 equiv.) was added DIPEA (183 mg, 2.5 equiv.) and 4A MS (30 mg). The mixture was stirred at 90 °C under a 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 pale yellow solid. LCMS (ESI, M+1, M+3): m / z = 529.3, 531.3.

[0253] Intermediate 24 [ka] 5-chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [ka] Step A. (5-Chloro-6-fluoro-4-trimethylstannyl-2-naphthyl)oxy-triisopropyl-silane: A mixture of (8-chloro-7-fluoro-3-triisopropylsiloxy-1-naphthyl)trifluoromethanesulfonate (800 mg, 1.0 equiv.), trimethyl(trimethylstannyl)stannane (8.0 g, 15 equiv.), Pd(PPh3)4 (184 mg, 0.1 equiv.), and LiCl (203 mg, 3.0 equiv.) in toluene (10 mL) was degassed and purged with N2 three times. The mixture was stirred at 105 °C under a N2 atmosphere for 12 h. The reaction was filtered, concentrated, purified by preparative HPLC [C18, 0.1% formic acid], 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).

[0254] Step B. 5-Chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: 7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2 A mixture of (5-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equiv.), (5-chloro-6-fluoro-4-trimethylstannyl-2-naphthyl)oxy-triisopropylsilane (423 mg, 1.2 equiv.), CuI (39.1 mg, 0.3 equiv.), Pd(dppf)Cl (50.0 mg, 0.1 equiv.), and BINAP (85.2 mg, 0.2 equiv.) was degassed and purged with N three times. The mixture was then stirred under N atmosphere at 20 °C for 12 h. 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] to give the title compound (80 mg, 15.5% yield) as a white solid. 1 H NMR (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 = 7.2H) z,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. 93(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).

[0255] Intermediate 25 [ka] 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 [ka] Step A. 6-Chloro-4-fluoro-1H-indazole: To a solution of 4-chloro-2,6-difluorobenzaldehyde (100 g, 1.0 equiv.) in dioxane (1.0 L) was added N. H·HO (58.1 g, 2.0 equiv.) was added dropwise over 10 min at 25 °C. The mixture was stirred at 25 °C for 0.5 h and at 95 °C for 15.5 h. The reaction mixture was diluted with HO (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.

[0256] 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 equiv) in THF (200 mL) was added NaH (14.1 g, 60% purity, 1.5 equiv) in portions at 0 °C for 30 min. The mixture was stirred at 25 °C for 0.5 h. To the mixture was then added SEM-Cl (46.9 g, 1.2 equiv) dropwise at 0 °C for 20 min. The mixture was stirred at 25 °C for 1 h. The mixture was quenched by the slow addition of HO (300 mL) over 30 min at 0 °C. 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 give 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.

[0257] 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 equiv.) in THF (100 mL) was added LDA (43.2 mL, 1.3 equiv.) dropwise over 5 min at −65 °C. The mixture was stirred at −65 °C for 55 h. Next, a solution of I (21.9 g, 1.3 equiv.) in THF (50.0 mL) was slowly added over 15 min to the mixture and stirred at −65 °C for 1 h. The mixture was quenched with HO (100 mL) at 0 °C for 15 min. 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 condition] to give the title compound (12.0 g, 42% yield) as a yellow solid. 1H 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.

[0258] 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-trimethylsilane (8.0 g, 1.0 equiv.) and cyclopropylboronic acid (3.22 g, 2.0 equiv.) in dioxane (80 mL) was added Pd(dppf)Cl (1.37 g, 0.1 equiv.) and KPO (1.5 M, 37.5 mL, 3.0 equiv.). The mixture was degassed, purged with N three times, and stirred under N at 100 °C for 12 h. The mixture was diluted with HO (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.

[0259] 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 NaH (2.40 g, 60% purity, 5.0 equiv.) in portions over 15 min at 0 °C. The mixture was then stirred at 25 °C for 0.5 h and at 40 °C for 11.5 h. The mixture was quenched by the slow addition of HO (50 mL) over 15 min at 0 °C. 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 condition] 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.

[0260] Step F. 6-Chloro-5-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yl trifluoromethanesulfonate: To a solution of 6-chloro-5-cyclopropyl-1-(2-trimethylsilylethoxymethyl)indazol-4-ol (0.80 g, 1.0 equiv.), 4 Å molecular sieves (100 mg), and DIPEA (915 mg, 3.0 equiv.) in DCM (8 mL) was added TfO (999 mg, 1.5 equiv.). The mixture was degassed and purged with N three times and stirred at -40 °C for 0.5 h. The mixture was diluted with HO (3 mL) and extracted with EtOAc (2 × 5 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 (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.

[0261] 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) under N2, KOAc (125 mg, 2.0 equiv.) and P(Cy3)-Pd-G3 (46.8 mg, 0.1 equiv.) were added. The mixture was stirred at 90 °C for 12 h. The mixture was filtered, concentrated, and purified by reverse-phase flash chromatography (C18, 0.1% formic acid) to afford the title compound (150 mg, 51% yield) as a yellow liquid. 1H NMR (400MHz, methanol-d4) δ=8.13(d,J=0.8Hz,1H),7.65(d,J=0.4Hz,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.

[0262] Step H. 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: 7-chloro-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine To a solution of 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 equiv.) in toluene (3 mL) was added KPO (1.5 M, 713 μL, 3.0 equiv.) and APhos-Pd-G (22.6 mg, 0.1 equiv.). The mixture was stirred at 60 °C under N for 12 h. The reaction mixture was diluted with HO (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 [SiO, petroleum ether / ethyl acetate 10:1 to 1:0] and reverse-phase flash chromatography [C, 0.1% formic acid] to give the title compound (70.0 mg, 28% yield) as a yellow liquid.

[0263] Intermediate 26 [ka] tert-Butyl 2-bromo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate [ka] 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 equiv.) in ACN (10.0 mL) was added CsCO (3.2 g, 2.0 equiv.) and tert-butyl N-(3-bromopropyl)carbamate (1.4 g, 1.2 equiv.). The reaction was stirred at 15 °C for 2 h. The mixture was filtered and purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, elution with a 0-30% ethyl acetate / petroleum ether gradient at 36 mL / min) to afford the title compound (1.3 g, 68.3% yield, 95% purity) as a clear, colorless 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)

[0264] Step B. Methyl 1-(3-aminopropyl)-3-bromo-1H-pyrazole-5-carboxylate: 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 h. The mixture was concentrated under reduced pressure to give the title compound (1.1 g, HCl) as a white solid.

[0265] Step C. 2-Bromo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one: A solution of methyl 1-(3-aminopropyl)-3-bromo-1H-pyrazole-5-carboxylate hydrochloride (1.1 g, 1.0 equiv.) in saturated NaCO (20 mL) was stirred at 20 °C for 12 h. The reaction was diluted with HO (30 mL) and extracted with 100 mL of DCM (20 mL × 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 min 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.

[0266] 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 equiv.) in THF (5.0 mL) was degassed and purged with N2 three times. BH3·Me2S (10 M, 3.0 equiv.) was added at 0 °C, and the reaction was stirred at 20 °C for 30 min and then at 60 °C for 12 h. The mixture was concentrated under reduced pressure to afford the title compound (650 mg, 97% yield, HCl) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=6.55(s,1H),4.48-4.34(m,5H),3.38(br dd,J=6.0,12.0Hz,3H),2.01(br d,J=4.0Hz,2H).

[0267] 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 equiv., HCl) in DCM (8 mL) was added TEA (520 mg, 716 μL, 2.0 equiv.) and BocO (842 mg, 1.5 equiv.). The mixture was stirred at 25 °C for 2 h. The reaction was concentrated and purified by flash silica gel chromatography (ISCO®, 12 g SepaFlash® silica flash column, elution with a 0-30% ethyl acetate / petroleum ether gradient at 30 mL / min) to afford the title compound (250 mg, 28.9% yield, 94.0% purity) as a white solid. 1H 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.

[0268] Intermediate 27 [ka] 5-Bromo-N,N,1-trimethyl-1H-pyrazole-3-carboxamide [ka] Step A. Methyl 5-bromo-1-methyl-1H-pyrazole-3-carboxylate: To a solution of methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate (25.0 g, 1.0 equiv.) in acetonitrile (250 mL) under N was added POBr (184 g, 4.0 equiv.) portionwise at 0 °C. The reaction was stirred at 80 °C for 12 h. 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 (SiO, petroleum ether / ethyl acetate = 1 / 0 to 4 / 1) to afford the title compound (13.0 g, 34% yield) as a yellow solid.

[0269] Step B. 5-Bromo-1-methyl-1H-pyrazole-3-carboxylic acid: To a solution of methyl 5-bromo-1-methyl-1H-pyrazole-3-carboxylate (13.0 g, 1.0 equiv.) in THF (237 mL) was added NaOH (2 M aqueous solution, 119 mL, 4.0 equiv.) in one portion. The reaction was stirred at 25 °C for 2 hours. The mixture was quenched with concentrated hydrochloric acid (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.

[0270] 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 h. 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, petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to afford the title compound (4.10 g, 72% yield) as a yellow solid. LCMS (ESI, M+1, M+3): m / z=232.0,234.0.

[0271] Intermediate 28 [ka] tert-Butyl ((5-(dimethylcarbamoyl)-1H-pyrazol-3-yl)methyl)carbamate [ka] Step A. Methyl 3-cyano-1H-pyrazole-5-carboxylate: To a solution of methyl prop-2-ynoate (5.00 g, 1.0 equiv.) and 2-aminoacetonitrile (9.91 g, 1.8 equiv., HCl) in CHCl (500 mL) and HO (16 mL) was slowly added NaNO (12.3 g, 3.0 equiv.) at 25 °C. The reaction was stirred at 25 °C for 3 h and then warmed to 60 °C for 12 h. The reaction mixture was filtered, concentrated, and purified by flash silica gel chromatography (ISCO®; 80 g Sepaflash® silica flash column, elution with a 30–50% EtOAc / PE gradient) to afford the title compound (5.00 g, 54% yield) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ = 11.59 (br s, 1H), 7.23 (s, 1H), 4.01 (s, 3H).

[0272] Step B. Methyl 3-(aminomethyl)-1H-pyrazole-5-carboxylate: To a solution of methyl 3-cyano-1H-pyrazole-5-carboxylate (500 mg, 1.0 equiv.) in methanol (10 mL) was added HCl (0.5 mL) and Pd / C (50.0 mg, 10% purity, wet). The reaction was stirred under an atmosphere of H at 25 °C for 2 h. The mixture was filtered and concentrated to afford the title compound (513 mg, 99% yield) as a yellow oil.

[0273] Step C. Methyl 3-[(tert-butoxycarbonylamino)methyl]-1H-pyrazole-5-carboxylate: To a solution of methyl 3-(aminomethyl)-1H-pyrazole-5-carboxylate (400 mg, 79.7% purity, 1.0 equiv.) in DCM (10 mL) was added TEA (424 mg, 3.0 equiv.) and BocO (336 mg, 1.1 equiv.). The reaction was stirred at 25 °C for 1 h. The mixture was filtered, concentrated, and purified by flash silica gel chromatography (ISCO®, 20 g Sepaflash® silica flash column, elution with a 0-65% PE / ethyl acetate gradient at 20 mL / min) to afford the title compound (300 mg, 83% yield) as a white solid. LCMS (ESI, M+1): m / z = 256.2.

[0274] 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 methanol (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 afford the title compound (280 mg, 99% yield) as a white solid. 1H 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).

[0275] 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 equiv.) and N-methylmethanamine (439 mg, 5.0 equiv., HCl) in DMAc (10 mL) was added TEA (240 mg, 2.2 equiv.) dropwise. Then, bromo(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (653 mg, 1.3 equiv.) was added to the mixture. The reaction was stirred at 40 °C for 12 h. The mixture was filtered and purified by preparative HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (NH3·H2O), B: ACN, B%: 10% to 40% in 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).

[0276] Intermediate 29 [ka] 3-cyano-N,N-dimethyl-1H-pyrazole-5-carboxamide [ka] 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 afford the title compound (400 mg, 88% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ ppm 7.27-7.51(m,1H).

[0277] 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-methylmethanamine (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)methylidene]dimethylazanium; hexafluorophosphate (2.08 g, 1.50 equiv.). The reaction was stirred at 25 °C for 1 h. The mixture was concentrated and purified by preparative HPLC [neutral condition; column: Waters Xbridge C18 150 × 50 mm × 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 1%-26%, 10 min] to give the title compound (500 mg, 84% yield) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ = 2.82 (s, 3H) 2.91 (s, 3H) 7.95 (s, 1H).

[0278] Intermediate 30 [ka] ((3R,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolidin-7a-yl)methanol Intermediate 31 [ka] ((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolidin-7a-yl)methanol [ka] Step A. Methyl cis-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate and methyl trans-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate: To a solution of methyl 3-(hydroxymethyl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (10 g, 1 equiv.) and imidazole (10.2 g, 3 equiv.) in DCM (150 mL) was added TBDPSCl (20.7 g, 1.5 equiv.) and DMAP (613 mg, 0.1 equiv.). The reaction was stirred at 25 °C for 2 h. The mixture was washed with HO (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 to 1:1) and reverse-phase flash chromatography (C18, 0.1% formic acid) to give the 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 a yellow oil; LCMS (ESI, M+1): m / z = 438.3.

[0279] Step B. ((3R,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol and ((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol: To a solution of methyl cis-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (5.0 g, 1.0 equiv.) in THF (60 mL) was added LiAlH (1.30 g, 3.0 equiv.) in portions at −40° C., and the reaction was stirred at −40° C. for 1 h. 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 condition) followed by SFC [Column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 μm); Mobile phase: (0.1% NH3HO IPA); B%: 50% to 50%, 7.7 min; 470 min] to give the two title compounds:

[0280] 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).

[0281] Intermediate 31 as a yellow oil (900 mg, 19% yield); 1 H NMR(400MHz,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).

[0282] Intermediate 32 [ka] ((3R,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolidin-7a-yl)methanol Intermediate 33 [ka] ((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolidin-7a-yl)methanol [ka] Step A. ((3R,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol and ((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol: To a solution of methyl trans-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidine-7a(5H)-carboxylate (3.0 g, 1.0 equiv.) in THF (40 mL) was added LiAlH (781 mg, 3.0 equiv.) in portions at −40° C. The reaction was stirred at −40° C. for 1 h. 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 condition) followed by SFC [Column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm); Mobile phase: (0.1% NH3H2O MeOH); B%: 30% to 30%, 3; 800 min] to give the two title compounds: Intermediate 32 as a yellow oil (1.0 g, 36% yield); 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). Intermediate 33 as a yellow oil (1.0 g, 36% yield); 1 H NMR(400MHz,chloroform-d)δ=7.67(br d,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).

[0283] Intermediate 34 [ka] ((3S,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolidin-3-yl)methyl dimethylcarbamate [ka] Step A. (3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolidine: To a solution of ((3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidin-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 (3×50 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.

[0284] Step B. ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methanol: To a solution of (3S,7aR)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolidine (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 h. 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) to afford 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(br dd,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).

[0285] Step C. ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolidin-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)carbonochloridate (3.03 g, 1.5 equiv) at 0-5 °C under N. The reaction was stirred at 20 °C for 2 h. N-methylmethanamine (2.0 M, 7.5 mL, 1.5 equiv) was added to the mixture at 0 °C under N. The reaction was stirred at 0 °C for 0.5 h. The mixture was diluted with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse-phase flash chromatography (0.1% FA) to give the title compound (2.03 g, 41% yield) as a yellow oil. LCMS (ESI, M+1): m / z=485.7.

[0286] Step D. ((3S,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolidin-3-yl)methyl dimethylcarbamate: To a solution of ((3S,7aR)-7a-((trityloxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methyl dimethylcarbamate (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 h. The mixture was concentrated, dissolved in methanol (10 mL), neutralized with solid NaHCO3, and purified by column chromatography (Al2O3, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1, dichloromethane / methanol = 15:1) to afford the title compound (834 mg, 82% yield) as a yellow oil. 1H NMR (400MHz, 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=4.8,10.4Hz,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).

[0287] Intermediate 35 [ka] ((3S,7aS)-7a-(hydroxymethyl)hexahydro-1H-pyrrolidin-3-yl)methyl dimethylcarbamate Synthesized from ((3S,7aS)-3-(((tert-butyldiphenylsilyl)oxy)methyl)hexahydro-1H-pyrrolidin-7a-yl)methanol according to Intermediate 34. The title compound was obtained as a yellow oil. 1 H NMR (400MHz, methanol-d4) δ=4.00(dq,J=6.0,10.8Hz,2H),3.31-3.22(m,2H),3.03- 2.96(m,2H),2.95-2.86(m,6H),2.80(td,J=5.2,10.8Hz,1H),2.09-1.46(m,8H).

[0288] Intermediate 36 [ka] 5-(Aminomethyl)-1-(trans-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-3-carboxamide [ka] Step A. cis-3-(benzyloxy)cyclobutyl methanesulfonate: To a solution of cis-3-(benzyloxy)cyclobutan-1-ol (1.0 g, 1.0 equiv.), DMAP (68.6 mg, 0.1 equiv.), and TEA (1.7 g, 3.0 equiv.) in DCM (10 mL) was added methylsulfonyl methanesulfonate (2.0 g, 11.2 mmol, 2.0 equiv.) dropwise at 0 °C under N . The reaction was stirred at 25 °C for 2 h. The mixture was slowly quenched with ice and extracted with DCM (20 mL × 3). The combined organic phase was washed with brine (25 mL), dried over anhydrous Na SO , concentrated, and purified by column chromatography (SiO , petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to afford the title compound (1.4 g, 97.4% yield) as a yellow liquid. 1 H NMR(400MHz,chloroform-d)δ=7.39-7.28(m,5H),4.66(quin,J=7.2Hz,1H),4.44(s,2 H),3.75(quin,J=6.8Hz,1H),2.99(s,3H),2.89-2.79(m,2H),2.39-2.30(m,2H).

[0289] Step B. tert-Butyl ((1-(trans-3-(benzyloxy)cyclobutyl)-3-(dimethylcarbamoyl)-1H-pyrazol-5-yl)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)cyclobutyl methanesulfonate (143 mg, 1.5 equiv.) in DMF (2 mL) was added CsCO (364 mg, 3.0 equiv.) in one portion under N at 25 °C. The reaction was heated to 90 °C and stirred for 12 h. The mixture was poured into ice water (3 mL) and extracted with ethyl acetate (4 mL × 3). The combined organic phase was washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered, and purified by preparative TLC (SiO.sub.2, PE / EA=3:1) to give the title compound (38 mg, 20% yield) as a yellow oil. 1H 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.

[0290] Step C. tert-Butyl ((3-(dimethylcarbamoyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazol-5-yl)methyl)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 h. The mixture was filtered, and the filtrate was concentrated to give the title compound (100 mg, crude) as a white solid. 1 H NMR(400MHz,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=6.0,12.0Hz,2H),2.47-2.32(m,2H),1.36(s,9H).

[0291] 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 equiv.) in dioxane (1 mL) at 25 °C was added HCl / dioxane (4 M, 4.0 equiv.). The reaction was stirred at 25 °C for 1 h. The mixture was concentrated to give the crude product (70 mg, crude, HCl) as a yellow solid. LCMS (ESI, M+1): m / z = 239.2.

[0292] Intermediate 37 [ka] 3-(aminomethyl)-1-(trans-3-hydroxycyclobutyl)-N,N-dimethyl-1H-pyrazole-5-carboxamide: [ka] 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.) portionwise at 0 °C under a nitrogen atmosphere. The reaction was stirred at 0 °C for 1 h. The mixture was slowly quenched with saturated ammonium chloride solution (300 mL) at 0-5 °C, concentrated to remove MeOH, and extracted with ethyl acetate (70 mL × 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. 1 H 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).

[0293] Step B. Methyl 1-(trans-3-(benzyloxy)cyclobutyl)-3-cyano-1H-pyrazole-5-carboxylate: 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 h and at 25 °C for 12 h. The mixture was concentrated and purified by flash silica gel chromatography (ISCO®; 80 g Sepaflash® silica flash column, elution with a 30% ethyl acetate / petroleum ether gradient at 100 mL / min) to afford the title compound (3.00 g, 71% yield) as a yellow oil. 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).

[0294] Step C. Methyl 3-(aminomethyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazole-5-carboxylate: Methyl 1-(trans-3-(benzyloxy)cyclobutyl)-3-cyano-1H-pyrazole-5-carboxylate (600 mg, 1.0 equiv.) was dissolved in MeOH (20 mL) and HCl solution (1 mL, 2 M in MeOH), and Pd / C (100 mg, 10% purity, wet) was added. The reaction was degassed and purged with H three times. The reaction was stirred under an H atmosphere (15 psi) at 25 °C for 2 h. The mixture was filtered and concentrated to give the title compound (500 mg, 99% yield, HCl) as a white solid.

[0295] Step D. Methyl 3-(((tert-butoxycarbonyl)amino)methyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazole-5-carboxylate: To a mixture of methyl 3-(aminomethyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazole-5-carboxylate (500 mg, 1.0 equiv., HCl) and TEA (580 mg, 0.8 mL, 3.0 equiv.) in dichloromethane (10 mL), BocO (625 mg, 0.6 mL, 1.5 equiv.) was added. The reaction was stirred at 30 °C for 2 h. The mixture was concentrated and purified by flash silica gel chromatography (ISCO®, 40 g Sepaflash® silica flash column, elution with 50–70% ethyl acetate / PE gradient at 50 mL / min) to afford the title compound (200 mg, 31% yield, 95% purity) as a white solid. 1 H NMR(400MHz,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=4.4Hz,2H),3.86(s,3H),2.93-2.81(m,2H),2.50(ddd,J=4.0,8.4,13.2Hz,2H),1.48(s,9H);LCMS(ESI,M+1):m / z=326.1.

[0296] Step E: 3-(((tert-butoxycarbonyl)amino)methyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazole-5-carboxylic acid: To a solution of methyl 3-(((tert-butoxycarbonyl)amino)methyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazole-5-carboxylate (200 mg, 1 equiv.) in methanol (2 mL) and HO (1 mL) was added KOH (51.7 mg, 1.5 equiv.). The mixture was stirred at 40 °C for 2 h. The reaction was slowly quenched with ice and extracted with DCM (5 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated to give the title compound (166 mg, crude) as a white solid. 1H 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).

[0297] Step F. tert-Butyl ((5-(dimethylcarbamoyl)-1-(trans-3-hydroxycyclobutyl)-1H-pyrazol-3-yl)methyl)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-methylmethanamine (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 h. The residue was poured into ice water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phase was washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (155 mg, 94.7% yield) as a yellow liquid.

[0298] 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 h. 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.

[0299] Example 524 [ka] 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 [ka] A mixture of Intermediate 1 (60 mg, 1 equiv.), tributyl(cyclohexen-1-yl)stannane (93.1 mg, 2 equiv.), copper 2-hydroxy-3-methylbenzoate (80.8 mg, 3 equiv.), and Pd(PPh3)4 (14.5 mg, 0.1 equiv.) in THF (2 mL) was degassed and purged with N2 three times. The mixture was stirred at 60 °C under a N2 atmosphere for 15 h. 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 afford 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(br s,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.

[0300] Example 525 [ka] 5-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,6a-dihydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione [ka] 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 equiv.) in THF (200 mL) was added LDA (2 M, 144 mL, 6.0 equiv.) under a nitrogen atmosphere at −78°C. The mixture was stirred at −78°C for 15 minutes and then 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 equiv.) 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, petroleum ether / ethyl acetate 10:1 to 1:1) to give the title compound (5.50 g, 21% yield, 55% purity) as a pale yellow solid. 1 H NMR (400MHz, chloroform-d) δ=6.97(d,J=8.4Hz,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)

[0301] 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 HO (20 mL) was added NaIO (5.68 g, 4.0 equiv.) and KOsO.2HO (122 mg, 0.05 equiv.). The mixture was stirred at 20 °C for 3 h. The reaction 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, concentrated, and purified by column chromatography (SiO, petroleum ether / ethyl acetate 20:1 to 1:1) to give the title compound (850 mg, 42% yield) as a pale 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).

[0302] Step C. [2-[(2,4-Dimethoxyphenyl)methyl]-1,3-dioxo-6,6a-dihydro-3aH-cyclopenta[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 (2 M, 1.7 mL, 1.2 equiv.) under a nitrogen atmosphere at −78° C. The mixture was stirred at −78° C. for 0.5 h. 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 h. The mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (30 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (SiO, petroleum ether / ethyl acetate 20:1 to 3:1) to give the title compound (410 mg, 34% yield) as a pale yellow oil. 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).

[0303] Step D. 2-[(2,4-Dimethoxyphenyl)methyl]-5-trimethylstannyl-6,6a-dihydro-3aH-cyclopenta[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(PPh3)4 (53.1 mg, 0.2 equiv.). The mixture was stirred at 60 °C under a nitrogen atmosphere for 16 h. The mixture was filtered and purified by column chromatography (SiO2, petroleum ether / ethyl acetate 10:1 to 2:1) to give the title compound (50.0 mg, 48% yield) as a pale yellow oil. 1 H 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) ,2H),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)

[0304] Step E. 2-(3,4-Dimethoxybenzyl)-5-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,6a-dihydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione: Synthesis of Intermediate 1 (40.0 mg, 1.0 equiv.) and 2-[(2,4-di To a solution of [[(methoxyphenyl)methyl]-5-trimethylstannyl-6,6a-dihydro-3aH-cyclopenta[c]pyrrole-1,3-dione (48.9 mg, 1.3 equiv.)) in THF (1 mL) was added thiophene-2-carbonyloxycopper (23.9 mg, 1.5 equiv.), Pd(dba) (7.65 mg, 0.1 equiv.), and tris(2-furyl)phosphine (5.82 mg, 0.3 equiv.). The mixture was stirred at 60 °C under a nitrogen atmosphere for 12 h. The reaction 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, petroleum ether / ethyl acetate 10:1 to 0:1 and ethyl acetate / MeOH 10:1) to give the title compound (50.0 mg, 76% yield) as a pale yellow solid. 1 H NMR (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);

[0305] Step F. 5-(8-Fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,6a-dihydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione: 2-(3,4-dimethoxybenzyl)-5-(8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((tetrahydro-1H-pyrrolidin-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 (tetrahydro-1H-pyrrolidin-7a(5H)-yl)-2-((tetrahydro-1H-pyrrolidin-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 equiv.) in ACN (1 mL) was added a solution of CAN (153 mg, 5.0 equiv.) in HO (1 mL) at 0° C. The mixture was stirred at 20° C. for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (10 mL × 5). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (SiO, 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 μm; A: water (FA), B: ACN, B%: 12% to 42% in 10 min] to afford the title compound (0.80 mg, 2.2% yield) as a yellow solid (0.40 formate salt). 1H NMR (400 MHz, chloroform-d) δ = 9.34 (s, 1H), 8.30-8.23 (m, 1H), 8.03 (br d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.69-7.64 (m, 1H), 7.63-7.59 (m, 1H), 7.47 (dt, J = 5.2, 8.0 Hz, 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.

[0306] Example 526 [ka] 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 [ka] Step A. Methyl 2-(4-cyanopyridin-3-yl)acetate: To a mixture of 3-methylisonicotinonitrile (2.2 g, 1.0 equiv.) and dimethyl carbonate (2.52 g, 1.5 equiv.) in THF (20 mL) was added KHMDS (1 M, 37.2 mL, 2.0 equiv.) 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 ethyl acetate (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 afford the title compound (600 mg, 17% yield) as a yellow oil. LCMS (ESI, M+1): m / z = 177.1.

[0307] 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 h. The mixture was concentrated and triturated with methanol (5 mL) at 25 °C for 1 h to afford the title compound (170 mg, 45% yield) as a brown solid. LCMS (ESI, M+1): m / z = 163.0.

[0308] 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)O (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 under an atmosphere of H (50 psi) at 40 °C for 20 h. 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.

[0309] Step D. Hexahydro-2,6-naphthyridine-1,3(2H,4H)-dione: To a mixture of tert-butyl 5,7-dioxooctahydro-2,6-naphthyridine-2(1H)-carboxylate (147 mg, 1.0 equiv.) in dichloromethane (2 mL) was added TFA (770 mg, 12 equiv.). 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.

[0310] 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: Hexahydro-2,6-naphthyridine-1,3(2H,4H)-dione (1) in DMF (0.05 mL) To a mixture of 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (60 mg, 1.0 equiv.) and 8-fluoro-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (60 mg, 1.0 equiv.) was added DIPEA (223 mg, 15 equiv.) and 4 Å molecular sieves (50 mg). The reaction was stirred at 40 °C for 16 h. The mixture was filtered and purified by preparative HPLC [Phenomenex Luna C18 75 × 30 mm × 3 μm; A: water (FA), B: ACN, B%: 5% to 35% in 10 min] and lyophilized to afford the title compound (7.54 mg, 9.3% yield over two steps) as a brown solid (0.95% formate salt). 1H 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.

[0311] Example 527 [ka] (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 [ka] Step A. (R)-tert-butyl (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)azetidin-3-yl)carbamate: (R)-1-(2-chloro-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)azetidin-3-yl)carbamate in dioxane (2 mL) To a mixture of N-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (200 mg, 1.0 equiv.) and tert-butyl N-(azetidin-3-yl)carbamate (130 mg, 2.0 equiv.), DIPEA (244 mg, 5.0 equiv.) was added, and the mixture was stirred at 90° C. under a 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.

[0312] 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-piperidyl]pyrido[4,3-d]pyrimidin-2-yl]azetidin-3-yl]carbamate (150 mg, 1.0 equiv.) in dioxane (1.5 mL) was added HCl / dioxane (4 M, 564 μL, 10.0 equiv.) 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% to 65% in 25 min) to afford the title compound (96.3 mg, 82% yield) as a white solid (0.52% formate salt). 1H NMR (400MHz, 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

[0313] Example 528 [ka] 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 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 two-step procedure described for Example 527. (0.54 formate salt) 1 H NMR(400MHz,DMSO-d6)δ=8.87(d,J=1.2Hz,1H),8.68(d,J=2.0Hz,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.

[0314] Example 529 [ka] 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 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 (0.40 formate salt) following the two-step procedure described for Example 527. 1 H 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. 22-5.01(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.

[0315] Example 530 [ka] (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 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 (0.37 formate salt) according to the two-step procedure described for Example 527, except that HCl·MeOH was used in Step B to yield the desired compound as a white solid. 1H NMR (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(br d,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.

[0316] Example 531 [ka] 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 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 following the two-step procedure described for Example 527 to yield the desired compound as a white solid (0.7 formate salt). 1H 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

[0317] Example 532 [ka] 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 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 two-step procedure described for Example 527 to yield 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.

[0318] Example 533 [ka] (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 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 following the two-step procedure described for Example 527 to yield the desired compound as a white solid (0.28 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.

[0319] Example 534 [ka] 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 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 following the two-step procedure described for Example 527 to yield the desired compound as a white solid (0.32 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.

[0320] Example 535 [ka] 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 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 two-step procedure described for Example 527 to yield 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.

[0321] Example 536 [ka] (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 [ka] 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 (2 M, 3.40 mL, 2.0 equiv.) in THF was added 1-(hydroxymethyl)cyclopropanecarbonitrile (661 mg, 2.0 equiv.). The reaction was stirred under a N atmosphere at 0° C. for 0.5 h. 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 the addition of HO (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] to give the title compound (900 mg, 45% yield) as a white solid. LCMS (ESI, M+1): m / z=590.2.

[0322] Step B. (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: To 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 equiv) 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] to give the title compound (15.4 mg, 11% yield) as a white solid. LCMS (ESI, M+1): m / z = 546.3.

[0323] Step C. (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: To a mixture of PtO (83.2 mg, 1.0 equiv.) in MeOH (2.5 mL) under a N atmosphere 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 equiv.) and HCl·MeOH (4 M, 1 mL). The suspension was degassed and purged with H three times. The mixture was stirred under H (15 psi) at 25° C. for 3 h. The reaction mixture was filtered, concentrated, and purified by preparative HPLC [Phenomenex Luna C 18 150 × 25 × 10 μm; A: water (10 mM FA), B: ACN, B%: 13% to 43% in 10 min] to afford the title compound (14.3 mg, 6.9% yield) as a pale 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.

[0324] Example 537 [ka] (1R,5R,6R)-3-(7-(4-bromo-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[3.2.1]octan-6-ol [ka] Step A. 1-Bromo-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: To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (340 mg, 1.0 equiv.) in DMF (5.0 mL) was added a solution of NBS (112 mg, 1.1 equiv.) in DMF (1.5 mL). The mixture was stirred at 20 °C for 2 h. 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% to 64% in 7 min] to afford the title compound (140 mg, 34% yield) as a yellow solid. 1H 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,2 H),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.

[0325] 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-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: 1-Bromo-5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluoro To a solution of (4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (50 mg, 1.0 equiv.) and (1S,5S,6R)-3-azabicyclo[3.2.1]octan-6-ol (18.3 mg, 1.5 equiv., HCl) in DMF (0.15 mL) was added DIPEA (48.1 mg, 5.0 equiv.) and 4 Å molecular sieves (20 mg). The mixture was then stirred at 60° C. for 12 h. 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% to 48% in 10 min] to give the title compound (22 mg, 39% yield, FA) as a yellow solid (0.19% formate salt). 1H 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.

[0326] Example 538 [ka] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(1-thia-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [ka] 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 (350 mg, 1.00 equiv.), 1-oxa-8-azaspiro[3.5]nonane oxalate (305 mg, 1.5 equiv.), KPO (1.25 g, 10 equiv.), and 4 Å molecular sieves (100 mg) in DMF (2 mL) and ACN (2 mL) was stirred at 60 °C for 2 h under a N atmosphere. The mixture was filtered and purified by preparative HPLC [column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (ammonia hydroxide)-ACN]; B%: 41% to 71% in 9 min] to give the title compound (140 mg, 36% yield) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ = 9.29-9.21 (m, 1H), 7.67 (dd, J = 6.0, 9.2 Hz, 1H), 7.30 (d, J = 2.8 Hz, 1H), 7.24 (t, J = 9.6 Hz, 1H), 7.08 (d, J = 2.8 Hz, 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=6.0,9.2H z,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.

[0327] Example 539 [ka] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-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 [ka] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-((S)-1-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [ka] 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 was separated by SFC [Conditions: Column: REGIS(S,S)WHELK-O1 (250 mm x 25 mm, 10 μm); Mobile phase: [0.1% NH₃H₂O / ETOH]; B%: 40%-40%, 5.5 min] to give the following:

[0328] Example 539 (51.3 mg, 36% yield) as a yellow solid. 11H NMR (400 MHz, methanol-d4) δ = 9.26 (d, J = 4.4 Hz, 1H), 7.68 (dd, J = 6.0, 8.8 Hz, 1H), 7.30 (d, J = 2.8 Hz, 1H), 7.25 (t, J = 9.6 Hz, 1H), 7.08 (d, J = 2.8 Hz, 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, 17.6 Hz, 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 = 7.6 Hz, 3H), LCMS (ESI, M+1): m / z = 620.3.

[0329] Example 540 as a yellow solid (49.5 mg, yield 34.7%). 1 1H NMR (400 MHz, methanol-d4) δ = 9.26 (d, J = 4.0 Hz, 1H), 7.67 (dd, J = 6.0, 9.2 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.24 (t, J = 9.6 Hz, 1H), 7.07 (d, J = 2.4 Hz, 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, 18.0 Hz, 1H), 3.52 - 3.39 (m, 1H), 3.26 - 3.18 (m, 3H), 3.05 - 2.96 (m, 1H), 2.54 - 2.44 (m, 3H), 2.34 - 2.13 (m, 5H), 2.03 - 1.82 (m, 6H), 0.81 (dt, J = 3.6, 7.6 Hz, 3H), LCMS (ESI, M+1): m / z = 620.3.

[0330] Example 541 [Chemical Structure Diagram] 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 [ka] 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)naphthalen-2-ol (100 mg, 1 equiv.) and (S)-3-methylpiperidine (25.1 mg, 1.5 equiv.) in DMF (0.8 mL) was added DIPEA (109 mg, 5 equiv.) and 4 Å molecular sieves (20 mg). The mixture was stirred at 40 °C for 12 h. The mixture was diluted with HO (10 mL) and extracted with ethyl acetate (4 × 5 mL). The combined organic layers were dried over anhydrous NaSO, concentrated, and purified by preparative HPLC [column: Phenomenex Synergi C18 150 × 25 × 10 μm; mobile phase: water (FA)-ACN; B%: 20%–50%, 10 min] to give the title compound (44.5 mg, 41% yield, 0.2 FA) as a white solid (monoformate salt). 1 H 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

[0331] Example 542 [ka] 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 [ka] Step A tert-Butyl 4-((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)-1,2-oxazinane-2-carboxylate: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluoro To a solution of (2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (30.0 mg, 1.0 equiv.) in dimethylformamide (1.0 mL) was added KPO (107 mg, 10.0 equiv.) and tert-butyl 4-aminooxazinane-2-carboxylate (20.5 mg, 2.0 equiv.). 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.

[0332] Step B. 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: To a solution of tert-butyl tert-butyl 4-((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)-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 (NHHCO)-ACN]; B%: 35% to 65%, 10 min] and lyophilized to give the title compound (8.04 mg, 30% yield, 97% purity) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=9.96(s,1H),9.43(s,1H),7.77(dd,J=6.0,9.2Hz,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.

[0333] Example 543 [ka] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((E)-2-(1-methyl-1H-pyrazol-5-yl)vinyl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [ka] Step A. (E)-1-Methyl-5-(2-(tributylstannyl)vinyl)-1H-pyrazole: To a solution of 5-ethynyl-1-methylpyrazole (477 mg, 1.0 equiv.) and Bu3SnH (1.7 g, 1.3 equiv.) in toluene (7 mL) was added AIBN (36.9 mg, 0.05 equiv.). The mixture was stirred at 80 °C for 2 h. 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 give the title compound (150 mg, 5.4% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 7.44 (d, J = 7.8 Hz, 1H), 6.49 (td, J = 7.8, 1.6 Hz, 1H), 5.71-2.65 (m, 2H), 2.43-3.79 (m, 1H), 1.56-1.52 (m, 6H), 1.49-1.43 (m, 1H), 1.34-1.31 (m, 6H), 0.92-0.90 (m, 9H).

[0334] Step B. 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((E)-2-(1-methyl-1H-pyrazol-5-yl)vinyl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4 in THF (1 mL) A mixture of 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.), thiophene-2-carbonyloxycopper (18.5 mg, 1.5 equiv.), tris(2-furyl)phosphane (1.5 mg, 0.1 equiv.), and Pd(dba) (17.8 mg, 0.3 equiv.) was stirred at 60 °C for 12 h under a N atmosphere. The mixture was diluted with water (5 mL) and extracted with EtOAc (3 mL × 5). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and purified by preparative TLC (SiO, DCM / MeOH 10:1) followed by preparative HPLC [C18, 0.1% formic acid condition] and lyophilized to give the title compound (4 mg, 10.0% yield) as a yellow solid. 1 H NMR (400MHz, chloroform-d) δ=9.31(d,J=6.0Hz,1H),8.26-8.12(m,1H),7.63(dd,J=11.2,15.2H z,1H),7.57-7.48(m,2H),7.23-7.16(m,2H),7.10-6.86(m,1H),6.78(dd,J=1.6,14.0Hz,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.

[0335] Example 544 [ka] 1-(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)piperidine-4-carbonitrile [ka] 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)naphthalen-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 4 Å molecular sieves (10 mg). The mixture was stirred at 60° C. for 2 h. 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% to 73%, 9 min] to give the title compound (16.0 mg, 25% yield) as a yellow solid. 1 H 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.

[0336] Example 545 [ka] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-(1-methyl-1H-pyrazol-5-yl)ethyl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol [ka] To a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 equivalent) in THF (0.5 mL) was added Pd / C (5 mg, 10% purity). The mixture was degassed and purged with H three times, and then the mixture was stirred under H atmosphere (15 Psi) at 20 °C for 12 hours. The reaction mixture was filtered, purified by preparative HPLC [C18, 0.1% NH4HCO3], and lyophilized to give the title compound (1.4 mg, 12.8% yield) as a white solid. 1 H NMR (400MHz, chloroform-d) δ=7.14(d,J=8.0Hz,1H),6.48-6.34(m,2H),4.66(s,2H),3.78(d,J=8. 4Hz,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.

[0337] Example 546 [ka] (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 (0.38 formate salt) according to the procedure described for Example 538. 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.

[0338] Example 547 [ka] 1-(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)azepane-3-carbonitrile The title compound was synthesized according to the procedure described for Example 538, except the reaction mixture was heated at 40° C. for 15 hours to afford 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.

[0339] Example 548 [ka] ((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 [ka] 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-pyrrolidin-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 equiv.) in toluene (5.0 mL) was added ((3S,7aR)-7a-(hydroxymethyl)hexahydro-1H-pyrrolidin-3-yl)methyl dimethylcarbamate (110 mg, 1.0 equiv.), t-BuONa (131 mg, 3.0 equiv.), and 4 Å 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 (SiO, dichloromethane / methyl alcohol 10:1) to give the title compound (70.0 mg, 29% yield). LCMS (ESI, M+1): m / z=537.1

[0340] 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-pyrrolidin-3-yl)methyl dimethylcarbamate: ((3S,7aR)-7a-(((7-chloro To a solution of (R)-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 HO (0.50 mL) was added KPO (166 mg, 3.0 equiv.), CataCXium A Pd G3 (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 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, 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.

[0341] 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-pyrrolidin-3-yl)methyl dimethylcarbamate: ((3S,7aR)-7a-(((7-(7,8-difluoro-3 To a solution of 1-(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-pyrrolidin-3-yl)methyl dimethylcarbamate (70.0 mg, 1.0 equiv.) in 3.00 mL of EtOAc 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 x 30 mm x 3 um; mobile phase: [water (FA)-ACN]; B%: 15% to 45%, 7 min) to give the title compound (5.15 mg, 7% yield) as a white solid (monoformate salt). 1 H NMR (400 MHz, methanol-d4) δ = 9.22 (d, J = 4.4 Hz, 1H), 8.53 (s, 1H), 7.61 (dd, J = 4.4, 8.8 Hz, 1H), 7.44-7.35 (m, 1H), 7.33 (s, 1H), 7.24 (dd, J = 2.4, 6.4 Hz, 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

[0342] Example 549 [ka] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(6-azaspiro[3.5]nonan-6-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 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). 1 H 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.

[0343] Example 550 [ka] 4-(4-(3-azabicyclo[4.2.1]nonan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [ka] To a solution of 3-azabicyclo[4.2.1]nonane (20.5 mg, 3.0 equiv.) in DMF (0.1 mL) was added KPO (44.8 mg, 5.0 equiv.). The mixture was stirred at 25 °C for 0.5 h. Then, 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 (25.0 mg, 1.0 equiv.) and ACN (0.1 mL) were added. The mixture was stirred at 40 °C for 11.5 h. The resulting mixture was filtered and purified by preparative HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (0.1% NH4HCO3), B: ACN, B%: 56% to 86% in 8 min] and lyophilized to give the title compound (6.07 mg, 23% yield) as a white solid. 1 H 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.

[0344] Example 551 [ka] 4-(4-(3-azabicyclo[3.3.1]nonan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol 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.

[0345] Example 552 [ka] 4-(4-(2-azabicyclo[3.3.1]nonan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol The title compound was synthesized according to the procedure described for Example 550 to yield the desired compound as a white solid. 1H 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(br t,J=6.8Hz,3H);LCMS(ESI,M+1):m / z=618.5.

[0346] Example 553 [ka] 5-ethyl-4-(4-(4-ethynyl-4-fluoropiperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoronaphthalen-2-ol The title compound was synthesized according to the procedure described for Example 544 to yield the desired compound as a yellow solid. 1 H 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.

[0347] Example 554 [ka] 4-(4-(5-oxaspiro[3.4]octan-2-ylamino)-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 The title compound was synthesized according to the procedure described for Example 538 (except that 4A molecular sieves were not added) to yield the desired compound as a white solid. 1 H NMR (400 MHz, methanol-d4) δ = 9.31-9.19 (m, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.31 (d, J = 2.8 Hz, 1H), 7.25 (t, J = 9.6 Hz, 1H), 7.04 (d, J = 2.8 Hz, 1H), 5.62-5.31 (m, 1H), 4.62-4.35 (m, 4H), 3.8 4(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,1 H),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.

[0348] Example 555 [ka] 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 [ka] Step A. tert-Butyl (4aR,7aS)-6-(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)hexahydropyrrolo[3,4-b][1,4]oxazine-4(4aH)-carboxylate: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluoro) A mixture of hexahydro-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 equiv.), tert-butyl (4aS,7aR)-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-4-carboxylate (9.80 mg, 1.1 equiv., HCl), and KPO (35.8 mg, 5.0 equiv.) was degassed and stirred under a N atmosphere at 40 °C 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.sub.2SO.sub.4, filtered, and purified by preparative HPLC [C18, 0.1% formic acid condition] 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).

[0349] Step B. 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-((4aR,7aS)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol: tert-Butyl(4aR,7aS)-6-(7-(8-ethyl-7- To a solution of (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)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.

[0350] Example 556 [ka] 6-(((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)amino)methyl)morpholin-3-one 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 (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 yield the desired compound as a white solid (0.34 formate salt). 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).

[0351] Example 557 [ka] 5-Ethyl-6-fluoro-4-(8-fluoro-4-((3R,5R)-3-fluoro-5-methoxypiperidin-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The title compound was synthesized according to the procedure described for Example 538 (except that 4A molecular sieves were not added) to yield the desired compound as a white solid. 1 H NMR (400 MHz, 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 = 9.6 Hz, 1H), 7.07 (dd, J = 2.8, 10.8 Hz, 1H), 5.55-5.39 (m, 1H), 5.15-4.99 (m, 1H), 4.61-4.4 3(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

[0352] Example 558 [ka] 4-(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)-1,4-thiazepane 1-oxide [ka] To a solution of NaIO (33.2 mg, 1.1 equiv.) in water (1 mL) was added a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(1,4-thiazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (90.0 mg, 1.0 equiv.) in MeOH (0.8 mL) and dioxane (0.6 mL) at 0 °C, and the reaction was stirred at 15 °C for 12 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The organic layer was washed with brine (10 mL) and dried over NaSO. The solvent was concentrated and purified by preparative HPLC [Column: Waters Xbridge 150 × 25 mm × 5 μm; A: water (10 mM NH4HCO3), B: ACN, B%: 33% to 63% in 8 min] to give the title compound (45.1 mg, 49% yield) as a yellow oil. 1 H 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.

[0353] Example 559 [ka] 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[3.2.1]octane-8-carboxamide 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.

[0354] Example 560 [ka] (1R,5S,8R)-3-(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)-3-azabicyclo[3.2.1]octane-8-carbonitrile Example 561 [ka] (1R,5S,8S)-3-(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)-3-azabicyclo[3.2.1]octane-8-carbonitrile [ka] 3-(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)-3-azabicyclo[3.2.1]octane-8-carbonitrile was purified by SFC (Column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm); Mobile phase: [0.1% NH3HO ETOH]; B%: 50% to 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 also 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.

[0355] Example 562 [ka] 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-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol 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). 1H 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.

[0356] Example 563 [ka] 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-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol [ka] 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: 2,4-dichloro-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 in DMF (1.0 mL) To a mixture of [-(methoxymethoxy)-1-naphthyl]-8-fluoropyrido[4,3-d]pyrimidine (146 mg, 0.80 equiv.) and 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a][1,4]diazepine (56.0 mg, 1.0 equiv.) was added DIPEA (157 mg, 3.0 equiv.) and 4 Å molecular sieves (22.81 mg). The mixture was stirred at −40° C. for 0.2 h. The mixture was purified by column chromatography [SiO2, petroleum ether / ethyl acetate 1:1] to afford the title compound (200 mg, 89% yield) as a white solid. LCMS (ESI, M+1): m / z = 552.1.

[0357] Step B. 8-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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: ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-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 in dioxane (5.0 mL) To a mixture of 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 (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.) was added DIPEA (140 mg, 3.0 equiv.) and 4 Å molecular sieves (200 mg, 11 equiv.). The mixture was stirred at 100° C. for 12 hours. The mixture was concentrated and purified by preparative HPLC [Column: Waters Xbridge 150 × 25 mm × 5 μm; Phase: [water (ammonia hydroxide v / v)-ACN]; B%: 36% to 66%, 9 min] to give the title compound (50 mg, 20% yield) as a white solid. LCMS (ESI, M+1): m / z = 675.2.

[0358] 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-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: 8-(7-(8-ethyl-7-fluoro-3-(methoxymethyl) To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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.

[0359] Example 564 [ka] 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-fluoronaphthalen-2-ol The title compound was synthesized according to the procedure described for Example 544 to yield the desired compound as a yellow solid. 1 H NMR (400MHz, methanol-d4) δ=9.16(s,1H),8.67(s,2H),7.50(dd,J=6.0,8.8Hz,1H),7.12(d,J=2.4Hz,1H),7.08(t,J=9.2Hz,1H),6.92 (d,J=2.8Hz,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(br dd,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.

[0360] Example 565 [ka] 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]heptan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The title compound was synthesized according to the procedure described for Example 538 to yield the desired compound as a white solid. 1H 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,1 H),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

[0361] Example 566 [ka] 3-(((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)amino)methyl)-3-methylpyrrolidine-2,5-dione [ka] To a solution of 3-(aminomethyl)-3-methylpyrrolidine-2,5-dione (11.0 mg, 1.01 equiv., 2HCl) in DMF (1 mL) was added KPO (53.7 mg, 5.0 equiv.) and 4 Å molecular sieves (30 mg). The mixture was stirred at 40° C. for 0.5 h. 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)naphthalen-2-ol (30.0 mg, 1.0 equiv.) in ACN (0.4 mL) was added. The mixture was stirred at 40° C. for 15.5 h. 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 μm; A: water (FA), B: ACN, B%: 12% to 42% in 11 min] and further purified by preparative HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3), B: ACN, B%: 33% to 63% in 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.

[0362] Example 567 [ka] (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 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(br t,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

[0363] Example 568 [ka] (1R,5S,6R,7S)-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[3.2.1]octane-6,7-diol [ka] 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)naphthalen-2-ol (100 mg, 1.0 equiv.) in DMF (0.5 mL) and DCM (0.5 mL) was added KPO (107 mg, 3.0 equiv.), (1S,5R,6S,7R)-3-azabicyclo[3.2.1]octane-6,7-diol (purchased from Enamine Ltd.) (46 mg, 1.5 equiv., HCl), and 4 Å molecular sieves (20 mg). The mixture was stirred at 40 °C for 12 h. 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% to 41% in 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.

[0364] Example 569 [ka] (1R,5S,6S,7S)-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[3.2.1]octane-6,7-diol (stereochemistry arbitrarily assigned) 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 yield 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); 1H NMR (400MHz, chloroform-d) δ=9.22-8.84(m,1H),7.58-7.41(m,1H),7.21-7.02(m,2H),6.98-6.5 7(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.

[0365] Example 570 [ka] (1R,5S)-3-(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)-3-azabicyclo[3.2.1]octane-6,7-diol (stereochemistry arbitrarily assigned) 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 yield the desired compound as a white solid. 1H 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,1H),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,1 H),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 F NMR (400 MHz, dimethyl sulfoxide-d6) δ = -119.629, -139.308, -172.150; LCMS (ESI, M+1): m / z = 636.1.

[0366] Example 571 [ka] (1R,5S,6R,7R)-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[3.2.1]octane-6,7-diol (stereochemistry arbitrarily assigned) 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 yield the desired compound as a white solid. 1H 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,1H),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,1 H),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 F NMR (400 MHz, dimethyl sulfoxide-d6) δ = -119.622, -139.405, -172.127; LCMS (ESI, M+1): m / z = 636.7.

[0367] Example 572 [ka] 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 The title compound was synthesized according to the procedure described for Example 538 to yield the desired compound as a yellow solid (0.34 formate salt). 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.

[0368] Example 573 [ka] 5-chloro-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 The title compound was synthesized according to the procedure described for Example 544 to yield the desired compound as a white solid (0.22 formate salt). 1H 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.

[0369] Example 574 [ka] 1-(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-hydroxypiperidine-3-carboxamide [ka] 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 equiv.) in DCM (50 mL) was added H2SO4 (9.54 g, 5.5 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The pH of the mixture was adjusted to 7 with NaOH (7.00 g, 9.9 equiv., 40% in water). (Boc)2O (19.3 g, 5.0 equiv.) was added. The reaction mixture was stirred at 20 °C for 16 h. 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 afford the title compound (3.9 g, 43% yield) as a yellow oil. 1 HNMR(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.

[0370] Step B. 3-Hydroxypiperidine-3-carboxamide: To a solution of tert-butyl 3-carbamoyl-3-hydroxypiperidine-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 h. The mixture was concentrated in vacuo to give the title compound (590 mg, crude, HCl) as a yellow solid.

[0371] Step C. 1-(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-hydroxypiperidine-3-carboxamide: 3-Hydroxypiperidine-3-carboxamide (157 mg, 2 equiv., HCl), 5-ethyl- To a solution of 6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (257 mg, 1.0 equiv.) and DIEA (280 mg, 5.0 equiv.) in DMF (1 mL) was added 4 Å molecular sieves (10 mg). The reaction mixture was stirred at 40° C. for 16 h. The mixture was filtered, and the filtrate was purified by preparative HPLC [Column: Unisil 3-100 C18 Ultra 150 × 50 mm × 3 μm; A: water (FA), B: ACN, B%: 8% to 38% in 7 min] followed by preparative HPLC [Column: Welch Ultimate XB-SiOH 250 × 50 × 10 μm; A: hexane, B: ethanol, B%: 10% to 50% in 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.

[0372] Example 575 [ka] 3-(((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)amino)methyl)-5-(hydroxymethyl)pyrrolidin-2-one [ka] Step A. tert-Butyl ((5-oxo-3-phenyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-6-yl)methyl)carbamate: A mixture of tert-butyl N-(benzenesulfonylmethyl)carbamate (293.71 mg, 1.1 equiv.) in THF (15 mL) was degassed and purged with N three times, then LiHMDS (1 M, 2.07 mL, 2.1 equiv.) was added to the mixture and stirred at −78 °C under N for 30 min. 3-Phenyltetrahydro-3H,5H-pyrrolo[1,2-c]oxazol-5-one (200 mg, 1.0 equiv.) in THF (3 mL) was added to the mixture and stirred at −78 °C under N for 30 min. The reaction mixture was quenched by the addition of aqueous NH4Cl (5 mL) at -78 °C, then diluted with 30 mL of water and extracted with 60 mL of ethyl acetate (20 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and purified by column chromatography (SiO2, 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).

[0373] 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 equiv.) in dioxane (3.0 mL) was added HCl / dioxane (4 M, 1.13 mL, 15.0 equiv.). 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.

[0374] Step C. 3-(((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)amino)methyl)-5-(hydroxymethyl)pyrrolidin-2-one: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)amino)methyl)-5-(hydroxymethyl)pyrrolidin-2-one To a solution of (4-(2,2,2-trifluoroethoxy)pyridin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol (80 mg, 1.0 equiv.), 3-(aminomethyl)-5-(hydroxymethyl)pyrrolidin-2-one (40 mg, 1.6 equiv.), and CHCN (1.0 mL) in DMF (1 mL) was added KPO (286 mg, 1.35 mmol, 10 equiv.) and 4 Å molecular sieves (100 mg, 25 equiv.). The mixture was stirred at 60 °C for 2 h. The reaction mixture was filtered and purified by preparative HPLC [Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 44% to 74%, 9 min] to give the title compound (6.1 mg, 6.71% yield) as a white solid. 1H 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.

[0375] Example 576 [ka] (3S,5R)-3-(((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)amino)methyl)-5-(hydroxymethyl)pyrrolidin-2-one [ka] Step A. (((3S,6S,7aR)-5-oxo-3-phenyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-6-yl)methyl)carbamate: A mixture of tert-butyl N-(p-tolylsulfonylmethyl)carbamate (232 mg, 1.1 equiv.) in THF (3.0 mL) was degassed and purged with nitrogen three times, and then LDA (2 M, 2.0 equiv.) was added. The mixture was then stirred under a nitrogen atmosphere at −78° C. for 30 minutes. Then, (3S,7aR)-3-phenyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (150 mg, 1.0 equiv.) in THF (3.0 mL) was added to the mixture, and the mixture was stirred under a nitrogen atmosphere at −78° C. for 30 minutes. The mixture was quenched with aqueous NH4Cl (5.0 mL) at -78 °C and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate 1:1] to give the title compound (30.0 mg, 12% yield) as a yellow oil. LCMS (ESI, M-55): m / z = 277.0

[0376] 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 h. The reaction mixture was concentrated and purified by preparative TLC [SiO, DCM / MeOH 10 / 1] to afford the title compound (10.0 mg, 76% yield) as a yellow solid.

[0377] Step C. (3S,5R)-3-(((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)amino)methyl)-5-(hydroxymethyl)pyrrolidin-2-one: 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro) To a solution of (10.0 mg, 1.0 equiv.)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol in dimethylformamide (1.0 mL) was added KPO (20.0 mg, 1.0 equiv.), (3S,5R)-3-(aminomethyl)-5-(hydroxymethyl)pyrrolidin-2-one (5.00 mg, 2.5 equiv.), and 4 Å 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 μm; mobile phase: water (ammonia hydroxide v / v)-ACN; B%: 22%–52%, 9 min] and lyophilized to give the title compound (2.70 mg, 24% yield) as a yellow solid. 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

[0378] Example 577 [ka] 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 The title compound was synthesized according to the procedure described for Example 544 (except that 4A molecular sieves were not added) to yield the desired compound as a white solid (monoformate salt). 1 H 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.

[0379] Example 578 [ka] 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 The title compound was synthesized according to the procedure described for Example 538 to yield the desired compound as a brown solid. 1H NMR (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.

[0380] Example 579 [ka] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 The title compound was synthesized according to the procedure described for Example 541 to yield the desired compound as a white solid (0.88 formate salt). 1 H NMR (400 MHz, methanol-d4) δ = 9.17 (s, 1H), 8.37 (dd, J = 1.2, 4.0 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.36-7.29 (m, 2H), 7.25 (t, J = 9.2 Hz, 1H), 7.04 (d, J = 2.8 Hz,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.

[0381] Example 580 [ka] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)4-(3-(S-methylsulfonimidoyl)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The title compound was synthesized according to the procedure described for Example 538 to yield the desired compound as an off-white solid. 1 H NMR (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.

[0382] Example 581 [ka] 4-(4-(4,4-difluoro-5-methylazepan-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-fluoronaphthalen-2-ol 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=9.16(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.

[0383] Example 582 [ka] 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 The title compound was synthesized using Intermediate 6 according to the procedure described for Example 541 to yield the desired compound as a white solid (0.3 formate salt). 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.

[0384] Example 583 [ka] 4-(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)-1,4-thiazepane 1,1-dioxide The title compound was synthesized according to the procedure described for Example 541 to yield the desired compound as a white solid (0.3 formate salt). 1 H 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.

[0385] Example 584 [ka] 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 The title compound was synthesized using Intermediate 7 according to the procedure described for Example 541 to yield the desired compound as a yellow solid. 1H 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.

[0386] Example 585 [ka] 4-((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)bicyclo[2.2.2]octane-1-carbonitrile [ka] 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 equiv.) and excess 4-aminobicyclo[2.2.2]octane-1-carbonitrile in DMF (3.0 mL) was added DIPEA (38.7 mg, 3.0 equiv.) and 4 Å molecular sieves (45 mg, 9.0 equiv.). The mixture was stirred at −40° C. for 0.2 h. The mixture was diluted with ethyl acetate (30 mL) and filtered. The filtrate was washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (70 mg, crude). The crude product was used in the next step without further purification; LCMS (ESI, M+1): m / z = 564.2

[0387] Step B. 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: 4-((2-chloro-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 To a solution of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (46.6 mg, 3.0 equiv.) in THF (3 mL) was added DIPEA (63 mg, 5.0 equiv.) and 4 Å molecular sieves (10 mg, 2.1 equiv.). The mixture was stirred at 60° C. for 12 hours and then at 70° C. for 5 hours. The mixture was diluted with ethyl acetate (30 mL) and filtered. The filtrate was washed with brine (20 mL × 3). The organic phase was filtered, concentrated, and purified by preparative HPLC (column: Phenomenex C18 75 x 30 mm x 3 um; mobile phase: [water (FA)-ACN]; B%: 20% to 50%, 7 min) to give the title compound (25 mg, 35% yield) as a white solid. LCMS (ESI, M+1): m / z = 687.2

[0388] Step C. 4-((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)bicyclo[2.2.2]octane-1-carbonitrile: 4-((7-(8-ethyl-7-fluoro-3-(methoxy To a solution of (2R,7aS)-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 μm; mobile phase: [water (FA)-ACN]; B%: 16% to 46%, 10 min), followed by lyophilization to afford 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

[0389] Example 586 [ka] 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)-5,5-difluoroazepan-4-ol The title compound was synthesized according to the procedure described for Example 538 to yield the desired compound as a yellow solid. 1 H NMR(400MHz, methanol-d4)δ=0.74-0.86(m,3H)1.44(t,J=7.2Hz,2H)1.89(br s,1H)2.00(br s,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.

[0390] Example 587 [ka] 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-fluoronaphthalen-2-ol The title compound was synthesized according to the procedure described for Example 541 to yield the desired compound as a white solid (0.44 formate salt). 1H NMR(400MHz,DMSO-d6)δ 0.73(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(br d,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.

[0391] Example 588 [ka] 5-(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)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxamide [ka] Step A 5-(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)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid: 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid (25.0 mg, 1.1 equiv.) To a solution of 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 (87.9 mg, 1.0 equiv.) in dimethylformamide (1.0 mL) was added KPO (94.5 mg, 3.0 equiv.). The mixture was stirred at 60 °C for 2 h. The reaction mixture was partitioned between ethyl acetate (40 mL) and water (30 mL). The organic phase was separated and dried over NaSO. It was then filtered and concentrated under reduced pressure to give a yellow solid. LCMS (ESI, M+1): m / z = 646.1.

[0392] Step B 5-(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)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-3-carboxamide: 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8- To a solution of fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 equiv.) in DMF (1 mL) was added DIPEA (12.01 mg, 2 equiv.), NH4Cl (24.8 mg, 10 equiv.), and HATU (53.0 mg, 3 equiv.). 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 (ammonia 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). 1 H 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

[0393] Example 589 [ka] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 The title compound was synthesized according to the procedure described for Example 538 to yield 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,

[0394] Example 590 [ka] 5-(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)-4-methyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione The title compound was synthesized using Intermediate 8 according to the procedure described for Example 541 to yield the desired compound as a white solid (0.10 formate salt). SFC: Chiralcel OD-3 50 x 4.6 mm ID, 3 μm; Isocratic elution: 40% methanol + ACN (0.05% DEA) in CO2, 3 mL / min, t R =0.553 min, 1.073 min; 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.

[0395] Example 591 [ka] (1R,5S)-7-(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)-3,7-diazabicyclo[3.3.1]nonane-2,4-dione The title compound was synthesized using Intermediate 9 according to the procedure described for Example 541 to yield 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 ,2H),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.

[0396] Example 592 [ka] 7-(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)octahydropyrido[3,4-d]pyrimidin-2(1H)-one The title compound was synthesized according to the procedure described for Example 538 to yield the desired compound as a yellow solid. 1 H NMR (400MHz, methanol-d4)δ=9.05(s,1H),7.65(dd,J=6.0,8.8Hz,1H),7.30-7.19(m,2H),7.04(d,J=2 .8Hz,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),2.41-2.26(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.

[0397] Example 593 [ka] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-(1-hydroxycyclobutyl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol 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 (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.

[0398] Example 594 [ka] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-8-azaspiro[5.5]undecan-8-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The title compound was synthesized according to the procedure described for Example 538 to yield the desired compound as a yellow solid (0.29 formate salt). 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.

[0399] Example 595 [ka] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-(tetrahydrofuran-3-yl)piperidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The title compound was synthesized according to the procedure described for Example 538 to yield the desired compound as a yellow solid. 1H NMR (400MHz, methanol-d4)δ=9.02(dd,J=1.6,6.0Hz,1H),7.67(dd,J=6.0,8.8Hz,1H),7.30(d,J=2.4Hz,1H) ,7.24(t,J=9.2Hz,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.

[0400] Example 596 [ka] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-((tetrahydrofuran-3-yl)methyl)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The title compound was synthesized according to the procedure described for Example 538 to yield the desired compound as a white solid (0.1 formate salt). 1H 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.

[0401] Example 597 [ka] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(3-((tetrahydrofuran-2-yl)methyl)pyrrolidin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The title compound was synthesized according to the procedure described for Example 538 to yield the desired compound as an off-white solid (0.2% formate salt). 1H NMR (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=6.4Hz,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)3.2 0-3.31(m,3H)3.33-3.46(m,1H)3.68-3.74(m,1H)3.68-3.92(m,3H)3.92-4.02(m,1H)4.03-4.25(m,2H)4.26 -4.33(m,1H)4.34-4.43(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.

[0402] Example 598 [ka] 2-(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)-7-oxa-2,9-diazaspiro[4.5]decan-8-one The title compound was synthesized according to the procedure described for Example 544 to yield the desired compound as a white solid. 1H NMR(400MHz,CD3OD)δ=9.26(s,1H),7.67(dd,J=6.0,8.8Hz,1H),7.29(d,J=2.4Hz,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.

[0403] Example 599 [ka] 10-(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)-8-oxa-3,10-diazabicyclo[4.3.1]decan-4-one The title compound was synthesized according to the three-step procedure described for Example 585, except that in Step B the mixture was stirred at 100° C. for 1 h to yield the desired compound as a yellow solid (0.12 formate salt). 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.

[0404] Example 600 [ka] 8-(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)-1-oxa-8-azaspiro[4.5]decan-4-ol The title compound was synthesized according to the procedure described for Example 538 to yield 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.

[0405] Example 601 [ka] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2-(2-methoxyethyl)-1,4-oxazepan-4-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol The title compound was synthesized according to the procedure described for Example 544 to yield the desired compound as a white solid. 1H NMR(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.

[0406] Example 602 [ka] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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 The title compound was synthesized according to the procedure described for Example 538 to yield the desired compound as a yellow solid (1.05 formate salt). 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(br d,J=9.6Hz,4H),2.54-2.32(m,3H),2.27-2.11(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

[0407] Example 603 [ka] 7-(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)-1-thia-7-azaspiro[3.5]nonane 1-oxide The title compound was synthesized according to the procedure described for Example 538 to yield the desired compound as a yellow solid. 1H NMR(400MHz,CD3OD)δ=9.07(s,1H),7.68(dd,J=6.0,8.8Hz,1H),7.30(d,J=2.8Hz,1H),7.2 5(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.

[0408] Example 604 [ka] 7-(7-(8-chloro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide [ka] Step A. 7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine To a solution of (lysin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (500 mg, 1.0 equiv.) and (8-chloro-3-(methoxymethoxy)naphthalen-1-yl)trimethylstannane (528 mg, 1.2 equiv. niv) in toluene (5 mL) was added Ad2nBup-Pd-G3 (83.2 mg, 0.10 equiv.) under N2. The reaction mixture was stirred at 90 °C for 12 h. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (4 × 10 mL). The combined organic layer was 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] to give the title compound (50.0 mg, 7.0% yield) as a yellow oil. LCMS (ESI, M+1): m / z = 625.3.

[0409] Step B. 7-(7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide: 7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7 To a solution of aS)-2-fluorohexahydro-1H-pyrrolidin-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) was added DIEA (43.4 mg, 3.0 equiv.) and 4 Å molecular sieves (30 mg). The reaction mixture was stirred at 40 °C for 12 h. The reaction mixture was filtered and purified by reverse-phase flash chromatography (C18, 0.1% formic acid) to give the title compound (30.0 mg, 37% yield) as a white solid.

[0410] Step C. 7-(7-(8-chloro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-thia-1,7-diazaspiro[4.5]decane 2,2-dioxide: 7-(7-(8-chloro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-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 (2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-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 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (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 (NH4HCO3), B: ACN; B%: 34% to 64% in 10 min] to give the title compound (5.92 mg, 21% yield) as a yellow gum. 1 H 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.

[0411] Example 605 [ka] 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)-5,5-difluoro-4-methylazepan-4-ol The title compound was synthesized according to the procedure described for Example 538 to yield the desired compound as a yellow solid. 1 H NMR(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=8.4,6.0Hz,1H)9.17(d,J=4.0Hz,1H).LCMS(ESI,M+1):m / z=658.3.

[0412] Example 606 [ka] 2-((1R,3aS,6aR)-5-(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-oxooctahydropyrrolo[3,4-c]pyrrol-1-yl)acetonitrile The title compound was synthesized using Intermediate 13B ((1R,3aS,6aR)-tert-butyl 1-(cyanomethyl)-3-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate) according to the procedure described for Example 566 to yield the desired compound as a white solid (0.5 formate salt). 1H 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), 4.63-4.5 8(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.

[0413] Example 607 [ka] 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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)naphthalen-2-ol The title compound was synthesized according to the procedure described for Example 544 to yield the desired compound as a yellow solid. 1H NMR (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.

[0414] Example 608 [ka] 6-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS...

Claims

1. Equation (I): 【Chemistry 1】 (In the formula, W is 【Chemistry 2】 And, A is an aryl or heteroaryl, and the aryl or heteroaryl has 1 to 4 R １ It is replaced by optional selection; B is, 【Transformation 3】 And; Y １ is L-hydroxy optionally substituted with hydrogen, 1 to 4 R ８ is L-alkoxy optionally substituted with 1 to 4 R ８ is halogen, L-C3-C6 cycloalkyl optionally substituted with 1 to 4 R ９ is L-heteroaryl optionally substituted with 1 to 4 R ８ is L-aryl optionally substituted with 1 to 4 R ８ is L-C(O)-NH optionally substituted with 1 to 4 R ２ and is a L-heterocyclic ring substituted with 1 to 2 oxo(=O) or oxo-containing substituents and optionally further substituted with 1 to 2 R ８ ; Y ２ is hydrogen or a C1-C4 alkyl group; or Y １ and Y ２ They combine, 【Chemistry 4】 Forming, X is bonded to the fused ring and consists of -S-, -O-, -N<, -CH ２ -ien-CH ２ -N-, -CH ２ -N-CH ２ -ien-CH ２ -CH ２ -CH ２ -ien-CH ２ -CH ２ -, -O-CH ２ - and -S-CH ２ - to be selected from; or Y ２ And Z combine to form V, and V consists of 1 to 4 R ８ Replaced by optional selection 【Transformation 5】 And; Z is either hydrogen or Y ２ Combined with; Each R １ These are independently halogens, 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, and -CH ２ C(=O)N(R) ５ ) ２ , -C3-C4 alkynyl (NR ５ ) ２ , -N(R ５ ) ２ , deutero C2-C4 alkynyl, (C1-C3 alkoxy)halo C1-C3 alkyl- or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with a halogen or C1-C3 alkyl; Each R ２ These are independently hydrogen, hydroxyl, halogen, C1-C3 haloalkyl, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, and -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 , -CO ２ R ５ , -CO ２ N(R) ５ ) ２ ❖ = CH ２ ¶=CHR １１ Or = C(R １１ ) ２ Either or two R ２ They bond to form a heterocycle or cycloalkyl group optionally substituted with C1-C3 alkyl groups; Each R ３ These are independently hydrogen, hydroxyl, halogen, C1-C3 haloalkyl, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, and -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 , -CO ２ R ５ , -CO ２ N(R) ５ ) ２ ❖ = CH ２ ¶=CHR １１ Or = C(R １１ ) ２ Either or two R ２ They bond to form a heterocycle or cycloalkyl group optionally substituted with C1-C3 alkyl groups; If V does not exist, R ２ and R ３ At least one of them is = CH ２ ¶=CHR １１ or = C(R １１ ) ２ And; Each R ４ These are independently hydrogen, halogen, or C1-C3 alkyl; Each R ５ These are independently hydrogen or a C1-C3 alkyl group, or two R groups. ５ They bond to form a cycloalkyl or heterocycle; Each R ６ These are independently hydrogen, hydroxyl, C1-C4 hydroxyalkyl or heteroaryl, or Two R's ６ They bond to form C3-C6 cycloalkyl or heterocycles; Each R ７ is, independently, hydrogen, C1-C3 alkyl, C2 alkenyl, hydroxy, halogen, C1-C3 haloalkyl, -L-NH ２ , -NH(C1-C3 alkyl), -N(C1-C3 alkyl) ２ , oxo (=O), L-O-(C1-C3 alkyl), L-O-(C1-C3 alkyl)-OR ５ , -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), L-C(O)N(R １０ ), ２ , -NHC(O)H, -CN, aryl, -(CH ２ ), １～２ S(O) ２ N(R １０ ), ２ , -NH-S(O) ２ N(R １０ ), ２ , -O-S(O) ２ N(R １０ ), ２ , S(O) ２ R １０ , -P(O)(R ５ ), ２ or C1-C3 alkyl, -CN and C(O)NH ２ is optionally independently substituted with one or two substituents independently selected from L-heteroaryl or L-heterocycle, Two R atoms on the same atom ７ These elements are optionally bonded to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocyclic rings, and the spirocyclic ring is optionally substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, hydroxy, C1-C3 alkyl, cyano, and -O-(C1-C3 alkyl). Two Rs on adjacent atoms ７ are optionally joined to form a fused ring selected from a C3-C6 cycloalkyl optionally substituted with 1-4 Rs, a heteroaryl optionally substituted with 1-4 Rs, an aryl optionally substituted with 1-4 Rs, and a heterocycle optionally substituted with 1-4 Rs, and ８ are optionally substituted with 1-4 Rs ８ are optionally substituted with 1-4 Rs ８ are optionally substituted with 1-4 Rs ８ are optionally substituted with 1-4 Rs Two Rs on non-adjacent atoms ７ They optionally bond to form one or two carbon bridges; Each R ８ These are independently C1-C3 alkyl, hydroxy, halogen, and -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, heterocyclic or -CN; Each R ９ These 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)NH ２ -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl) ２ or -CN; Each R １０ is independently hydrogen, halogen, C1-C3 alkyl, C3-C4 cycloalkyl, or two R atoms, optionally substituted with one or two substituents independently selected from halogens and hydroxyls. １０ These combine to form a cycloalkyl or heterocycle optionally substituted with one or two C1-C3 alkyl groups; Each R １１ These are independently halogens or methyl compounds; Each L independently has a bond, -O-, -C1-C4 alkyl-, -C1-C4 alkyl-NH-, -NH-, -N(C1-C3 alkyl)-, or cyclopropyl-CH ２ - and; Each n is between 0 and 3; o is 1 to 6; p is 1 to 8; and (q is between 1 and 2) A compound of or a pharmaceutically acceptable salt thereof.

2. Formula (IA): 【Transformation 6】 (In the formula, W is 【Transformation 7】 And, A is an aryl or heteroaryl, and the aryl or heteroaryl has 1 to 4 R １ It is replaced by optional selection; B is, 【Transformation 8】 And; Y １ It is hydrogen, 1 to 4 R ８ L-hydroxyl molecules are optionally substituted, and 1 to 4 R molecules are also substituted. ８ L-alkoxy, halogen, and 1 to 4 R atoms are optionally substituted. ９ L-C3 to C6 cycloalkyl groups, 1 to 4 R groups, optionally substituted. ８ L-heteroaryls substituted by arbitrary selection, 1 to 4 R ８ L-aryl, L-C(O)-NH replaced by optional substitution. ２ and substituted with one or two oxo (=O) or oxo-containing substituents, and one or two R ８ The L-heterogene is further substituted by arbitrary choice; Y ２ is hydrogen or a C1-C4 alkyl group; or Y １ and Y ２ They combine, 【Chemistry 9】 Forming, X is bonded to the fused ring and consists of -S-, -O-, -N<, -CH ２ -ien-CH ２ -N-, -CH ２ -N-CH ２ -ien-CH ２ -CH ２ -CH ２ -ien-CH ２ -CH ２ -, -O-CH ２ - and -S-CH ２ - Selected from; Each R １ These are independently halogens, 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, and -CH ２ C(=O)N(R) ５ ) ２ , -C3-C4 alkynyl (NR ５ ) ２ , -N(R ５ ) ２ , deutero C2-C4 alkynyl, (C1-C3 alkoxy)halo C1-C3 alkyl- or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with a halogen or C1-C3 alkyl; Each R ２ These are independently hydrogen, hydroxyl, halogen, C1-C3 haloalkyl, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, and -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 , -CO ２ R ５ , -CO ２ N(R) ５ ) ２ ❖ = CH ２ ¶=CHR １１ Or = C(R １１ ) ２ Either or two R ２ They bond to form a heterocycle or cycloalkyl group optionally substituted with C1-C3 alkyl groups; Each R ３ These are independently hydrogen, hydroxyl, halogen, C1-C3 haloalkyl, cyano, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, and -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 , -CO ２ R ５ , -CO ２ N(R) ５ ) ２ ❖ = CH ２ ¶=CHR １１ Or = C(R １１ ) ２ Either or two R ２ They bond to form a heterocycle or cycloalkyl group optionally substituted with C1-C3 alkyl groups; Each R ４ These are independently hydrogen, halogen, or C1-C3 alkyl; Each R ５ These are independently hydrogen or a C1-C3 alkyl group, or two R groups. ５ They bond to form a cycloalkyl or heterocycle; Each R ６ These are independently hydrogen, hydroxyl, C1-C4 hydroxyalkyl or heteroaryl, or Two R's ６ They bond to form C3-C6 cycloalkyl or heterocycles; Each R ７ These are independently hydrogen, C1-C3 alkyl, C2 alkenyl, hydroxy, halogen, C1-C3 haloalkyl, and -L-NH ２ -NH(C1-C3 alkyl), -N(C1-C3 alkyl) ２ , oxo (=O), L-O-(C1-C3 alkyl), L-O-(C1-C3 alkyl)-OR ５ -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), L-C(O)N(R １０ ) ２ ,-NHC(O)H,-CN,aryl,-(CH ２ ) １～２ S(O) ２ N(R) １０ ) ２ ,-NH-S(O) ２ N(R) １０ ) ２ , -O-S(O) ２ N(R) １０ ) ２ , S(O) ２ R １０ , -P(O)(R ５ ) ２ or C1-C3 alkyl, -CN and C(O)NH ２ An L-heteroaryl or L-heterocyclic ring independently substituted by optional choice with one or two substituents independently selected from the above, Two R atoms on the same atom ７ These elements are optionally bonded to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocyclic rings, and the spirocyclic ring is optionally substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, hydroxy, C1-C3 alkyl, cyano, and -O-(C1-C3 alkyl). Two Rs on adjacent atoms ７ These are combined by choice, resulting in a combination of 1 to 4 R ８ C3-C6 cycloalkyl groups, 1-4 R groups, optionally substituted. ８ A heteroaryl substituted by arbitrary selection, with 1 to 4 R ８ The aryl and 1 to 4 R are optionally replaced by choice. ８ A fused ring is formed by selecting from the hetero rings that have been substituted by arbitrary choice, and Two Rs on non-adjacent atoms ７ They optionally bond to form one or two carbon bridges; Each R ８ These are independently C1-C3 alkyl, hydroxy, halogen, and -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, heterocyclic or -CN; Each R ９ These 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)NH ２ -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl) ２ or -CN; Each R １０ is independently hydrogen, halogen, C1-C3 alkyl, C3-C4 cycloalkyl, or two R atoms, optionally substituted with one or two substituents independently selected from halogens and hydroxyls. １０ These combine to form a cycloalkyl or heterocycle optionally substituted with one or two C1-C3 alkyl groups; Each R １１ These are independently halogens or methyl compounds; Each L independently has a bond, -O-, -C1-C4 alkyl-, -C1-C4 alkyl-NH-, -NH-, -N(C1-C3 alkyl)-, or cyclopropyl-CH ２ - and; Each n is between 0 and 3; o is 1 to 6; p is 1 to 8; and (q is between 1 and 2) A compound of or a pharmaceutically acceptable salt thereof.

3. Each R １ The compound according to claim 2 or a pharmaceutically acceptable salt thereof, which is independently selected from halogens, hydroxyls, C1-C3 alkoxys, and C1-C4 alkyls.

4. Each R ２ If it exists, then = CH ２ ¶=CHR １１ or = C(R １１ ) ２ Selected from, each R3 is =CH if present. ２ ¶=CHR １１ or = C(R １１ ) ２ A compound according to claim 2 or a pharmaceutically acceptable salt thereof, selected from the above.

5. Each R ７ R is independently selected from hydrogen, C1-C4 alkyl, hydroxyl, and C1-C3 alkoxy atoms, and consists of two non-adjacent atoms. ７ The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compounds optionally bond to form one or two carbon bridges.

6. Each R ６ The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein is independently hydrogen or hydroxyl.

7. Y １ and Y ２ They combine, 【Chemistry 10】 A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof that forms a compound.

8. Y １ and Y ２ They combine, 【Chemistry 11】 A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof that forms a compound.

9. Y １ and Y ２ They combine, 【Chemistry 12】 A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof that forms a compound.

10. A is naphthyl, the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

11. at least one R １ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound is a C1 to C4 alkyl group.

12. at least one R １ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is a halogen.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein the halogen is fluorine.

14. at least one R １ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is hydroxyl.

15. at least one R ２ is, =CH ２ ¶=CHR １１ or = C(R １１ ) ２ The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

16. R １１ The compound or salt according to claim 15, wherein is fluorine.

17. at least one R ２ The compound or salt according to any one of claims 1 to 6, wherein is a halogen.

18. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein the halogen is fluorine.

19. at least one R ２ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is hydroxyl.

20. at least one R ３ is, =CH ２ ¶=CHR １１ or = C(R １１ ) ２ The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

21. R １１ The compound according to claim 20 or a pharmaceutically acceptable salt thereof, wherein is fluorine.

22. at least one R ３ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound is a C1 to C4 alkyl group.

23. at least one R ３ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is a halogen.

24. The compound according to claim 23 or a pharmaceutically acceptable salt thereof, wherein the halogen is fluorine.

25. at least one R ３ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is hydroxyl.

26. R ４ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is a halogen.

27. The compound according to claim 26 or a pharmaceutically acceptable salt thereof, wherein the halogen is fluorine.

28. at least one R ５ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound is a C1 to C4 alkyl group.

29. at least one R ５ The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

30. One or both R ６ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound is a C1 to C4 alkyl group.

31. One or both R ６ The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

32. Two R's ６ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compounds bond to form a C3-C6 cycloalkyl or heterocycle.

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

34. Y １ The compound according to claim 33 or a pharmaceutically acceptable salt thereof, wherein is an L-heteroaryl, and the heteroaryl is thiethane dioxide, isothiazolidine dioxide, imidazopyrazine, pyridine, or pyrimidine.

35. Y １ The compound according to claim 33 or a pharmaceutically acceptable salt thereof, wherein is an L-C3 to C6 cycloalkyl compound.

36. The compound according to claim 35 or a pharmaceutically acceptable salt thereof, wherein the cycloalkyl is cyclobutane, cyclopentane, cyclohexane, or cycloheptane.

37. Y １ The compound according to claim 33 or a pharmaceutically acceptable salt thereof, wherein is an L-heterocyclic compound.

38. The compound according to claim 37 or a pharmaceutically acceptable salt thereof, wherein the heterocycle is pyrrolidinone.

39. Y ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

40. Y ２ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound is a C1 to C4 alkyl group.

41. at least one R ８ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound is a C1 to C4 alkyl group.

42. at least one R ８ The compound according to any one of claims 1 to 6, wherein is a hydroxyl or C1-C3 alkylhydroxyl compound, or a pharmaceutically acceptable salt thereof.

43. One or two R ８ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound is oxo (=O).

44. at least one R ８ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is an aryl or heteroaryl compound.

45. at least one R ８ The compound according to any one of claims 1 to 6, wherein is C(O)OH, or a pharmaceutically acceptable salt thereof.

46. at least one R ８ is -C(O)NH ２ -C(O)NH(C1-C3 alkyl) or -C(O)N(C1-C3 alkyl) ２ The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

47. at least one R ８ is, -NH ２ -NH(C1-C3 alkyl), -N(C1-C3 alkyl) ２ The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

48. at least one R ９ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound is a C1 to C4 alkyl group.

49. at least one R ９ The compound according to any one of claims 1 to 6, wherein is a hydroxyl or C1-C3 alkylhydroxyl compound, or a pharmaceutically acceptable salt thereof.

50. One or two R ９ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the compound is oxo (=O).

51. at least one R ９ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is an aryl or heteroaryl compound.

52. at least one R ９ The compound according to any one of claims 1 to 6, wherein is C(O)OH, or a pharmaceutically acceptable salt thereof.

53. at least one R ９ is -C(O)NH ２ -C(O)NH(C1-C3 alkyl) or -C(O)N(C1-C3 alkyl) ２ The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

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

55. Two R atoms on the same atom ７ The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein the compounds are bonded to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocyclic rings, and the spirocyclic ring is optionally substituted with one or more substituents selected from oxo(=O), halogen, hydroxy, C1-C3 alkyl and -O-(C1-C3 alkyl).

56. Two Rs on adjacent atoms ７ It is bonded, bonded or 1 to 4 R ８ C3-C6 cycloalkyl groups, 1-4 R groups, optionally substituted. ８ A heteroaryl substituted by arbitrary selection, with 1 to 4 R ８ The aryl and 1 to 4 R are optionally replaced by choice. ８ A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein a fused ring is formed by selecting from a heterocycle that has been optionally substituted.

57. Two Rs on non-adjacent atoms ７ The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein the compounds bond to form one or two carbon bridges. 【Request Item 58】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Chemistry 58】 【Chemistry 59】 【Transformation 60】 【Chemistry 61】 【Transformation 62】 【Transformation 63】 【Chemistry 64】 【Transformation 65】 【Chemical Formula 66】 【Transformation 67】 【Transformation 68】 Compounds 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 6 and 58 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

60. The pharmaceutical composition according to claim 60 for inhibiting the intracellular activity of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H.

61. A pharmaceutical composition for treating cancer, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6 and 58 or a pharmaceutically acceptable salt thereof.

62. The pharmaceutical composition according to claim 61, wherein the therapeutically effective amount of the compound is approximately 0.01 to 100 mg / kg per day.

63. The pharmaceutical composition according to claim 62, wherein the therapeutically effective amount of the compound is approximately 0.1 to 50 mg / kg per day.

64. The aforementioned cancers include: heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, cartilaginous hamartoma, mesothelioma; Gastrointestinal tract: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIP-producing tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, will Musculoskeletal tumors (nephroblastoma, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminoma, teratoma, fetal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder cancer, ampullary carcinoma, cholangiocarcinoma; bone: osteogenic sarcoma, fibrosarcoma, malignant fibrous sarcoma Histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondrosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteoosteitis), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiforme, Oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma); Gynecology: Uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified cancer), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma); The pharmaceutical composition according to claim 61, selected from the group consisting of: blood: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorder, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, mole, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

65. The pharmaceutical composition according to claim 64, wherein the cancer is KRas G12A-related cancer, KRas G12C-related cancer, KRas G12D-related cancer, KRas G12R-related cancer, KRas G12S-related cancer, KRas G12V-related cancer, KRas G13D-related cancer, or KRas Q61H-related cancer.

66. The pharmaceutical composition according to claim 64, wherein the cancer is related to at least one of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H.

67. The pharmaceutical composition according to claim 61, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

68. The pharmaceutical composition according to claim 59 for treating cancer determined to be associated with wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H mutations.

69. The pharmaceutical composition according to claim 61, administered via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasacral, intrathecal, intramuscular, intravitreous, intravenous, intraarterial, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous, and local administration.

70. The pharmaceutical composition according to claim 69, wherein the administration is performed orally, intravenously, or intramuscularly, the administration is performed using a delivery device, or the administration is performed in a hospital.

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