KRAS G12S and G12C inhibitors

Abstract

The present invention relates to compounds that inhibit KRas G12S and / or KRas G12C. In particular, the present invention relates to compounds that inhibit the activity of KRas G12S and / or KRas G12C, pharmaceutical compositions comprising said compounds, and methods of use thereof.

Description

[0001] Invention Field

[0002] This invention relates to compounds that inhibit the activity of KRas G12S and / or KRas G12C. In particular, this invention relates to compounds that inhibit the activity of KRas G12S and / or KRas G12C, pharmaceutical compositions comprising said compounds, and methods of using said compounds. Background of the Invention

[0004] Kirsten Rat Sarcoma 2 viral oncogene homolog (“KRas”) is a small GTPase belonging to the Ras oncogene family. KRas acts as a molecular switch, cycling between an inactive state (GDP-binding) and an active state (GTP-binding), transducing upstream cellular signals from various tyrosine kinases to downstream effectors, thereby regulating a variety of processes, including cell proliferation (e.g., see Alamgeer et al., (2013) Current Opin Pharmcol. 13: 394-401).

[0005] The role of activated KRas in malignant tumors has been observed for over thirty years (e.g., see Santos et al., (1984) Science 223: 661-664). Aberrant expression of KRas accounts for up to 20% of all cancers, and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas and downstream signaling have been reported in 25-30% of lung adenocarcinomas (e.g., see Samatar and Poulikakos, (2014) Nat Rev Drug Disc 13 (12): 928-942, doi:10.1038 / nrd428). In lung adenocarcinoma, single nucleotide substitutions leading to missense mutations at codons 12 and 13 of the KRas primary amino acid sequence account for approximately 40% of these KRas-driven mutations. KRAS G12S mutations are found in 2% of colorectal cancer patients, 0.6% of ovarian cancer patients, 0.5% of non-small cell lung cancer patients, 0.2% of bladder and gastric cancer patients, and 0.1% of pancreatic ductal adenocarcinoma, breast cancer, and endometrial cancer patients (The AACR Project GENIE Consortium. AACR Project GENIE: Powering Precision Medicine Through An International Consortium, Cancer Discovery 2017. Cohort v.13.1-public).

[0006] The well-known role of KRas in malignant diseases and the discovery of these frequent mutations in KRas across various tumor types have made KRas a highly attractive target for cancer therapy in the pharmaceutical industry. Despite extensive research over the past three decades to develop KRas inhibitors for cancer treatment, only a very small number of KRas inhibitors have demonstrated sufficient safety and / or efficacy to obtain regulatory approval.

[0007] There remains a great need for and ongoing research into compounds that inhibit KRas activity, including those that disrupt effectors (such as guanine nucleotide exchange factors) (e.g., see Sun et al., (2012) Agnew Chem Int EdEngl. 51(25):6140-6143 doi: 10.1002 / anie201201358) and recent advances in covalent targeting of the KRas G12C allosteric pocket (e.g., see Ostrem et al., (2013) Nature 503: 548-551 and Fell et al., (2018) ACS Med. Chem. Lett. 9: 1230-1234). Clearly, there is still ongoing interest and effort in developing KRas inhibitors, particularly those that activate KRas mutants, including KRas G12S and KRas G12C.

[0008] Therefore, there is a need to develop new KRas G12S and / or KRas G12C inhibitors that have sufficient potency in treating KRas G12S-mediated and / or KRas G12C-mediated cancers. Invention Overview

[0010] In one aspect of the invention, compounds are provided that inhibit the activity of KRas G12S and / or KRas G12C.

[0011] In some embodiments, the compound is represented by formula (Ia) or (Ib):

[0012]

[0013] Or its pharmaceutically acceptable salt, wherein:

[0014] A is selected from: , , , , , , , , , , and ;

[0015] B is selected from:

[0016] , , ;

[0017] X is a bond, N, methylene, ethylene, or propylene;

[0018] D is either CO or SO2;

[0019] E is N or CR 10 ;

[0020] Y represents a bond, O, or NR. 5 ;

[0021] Z is a bond, a C1-C4 alkyl group, a heterocyclic group, a heteroaryl group, or an aryl group, wherein Z is optionally substituted by 1-3 substituents selected from halogens, C1-C4 alkyl groups, C1-C4 haloalkyl groups, oxoalkyl groups, and OR groups. 12 、N(R 12 2. COR 12 and cyano;

[0022] Each R 2 Independently, it is hydrogen, hydroxyl, halogen, C1-C3 alkyl, spirocyclopropyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, CHF2, HC(=O)-, -OC(O)N(R) 5 )2、-CO2R 5 -CO2N(R) 5 )2、=CH2、=CHR 11 or = C(R) 11 )2, where R 2 Optionally by one or more R 4 replace;

[0023] R 3 It is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally surrounded by one or more R groups. 8 replace;

[0024] R 4 It is a bond, halogen, or C1-C3 alkyl;

[0025] Each R 5 It is independently hydrogen or C1-C3 alkyl;

[0026] Each R 6 It is independently hydrogen, hydroxyl, C1-C4 alkyl, C1-C4 hydroxyalkyl or heteroaryl, or two R 6Linkage forms C3-C6 cycloalkyl or heterocyclic rings;

[0027] Each R 8 It is independently a halogen, cyano, hydroxyl, cycloalkyl, C1-C3 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 or -S-C1-C3 haloalkyl;

[0028] Each R 9 Independently, it is hydrogen, C1-C4 alkyl, methoxy, CH2-methoxy, hydroxyl, CH2F, CF2, CF3, C-CN, cyclopropyl, or two Rs on the same or different carbon atoms. 9 Connect to form C1-C2 alkylene bridges or spirorings;

[0029] Each R 10 It is a bond, halogen, CH2F, CHF2, CF3, C1-C3 alkyl, cyclopropyl, OR 12 or N(R) 12 )2;

[0030] Each R 11 It is a halogen or a C1-C3 alkyl group.

[0031] R 12 It is a C1-C3 alkyl group, and

[0032] R 13 It is H or forms a ring with A.

[0033] In another aspect of the invention, a pharmaceutical composition is provided comprising a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0034] In another aspect of the invention, a method for inhibiting the activity of KRas G12S and / or KRas G12C in cells is provided, the method comprising contacting cells with a compound of formula (Ia) or (Ib) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one embodiment, the contact is performed in vitro. In one embodiment, the contact is performed in vivo.

[0035] This article also provides methods for inhibiting cell proliferation in vitro or in vivo, the methods comprising contacting cells with an effective amount of a compound of formula (Ia) or (Ib) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0036] A method for treating a patient with cancer is also provided, the method comprising administering to a patient in need a therapeutically effective amount of the compound or pharmaceutical composition of the present invention or a pharmaceutically acceptable salt thereof.

[0037] This article also provides methods for treating diseases or disorders associated with KRas G12S and / or KRas G12C in patients requiring treatment, the methods comprising administering to the patient a therapeutically effective amount of a compound of formula (Ia) or (Ib) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0038] This document also provides compounds of formula (Ia) or (Ib) as described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for therapeutic purposes.

[0039] This article also provides compounds of formula (Ia) or (Ib) as described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment of cancer.

[0040] This article also provides compounds of formula (Ia) or (Ib) or pharmaceutically acceptable salts thereof for the inhibition of KRasG12S and / or KRasG12C.

[0041] This document also provides compounds of formula (Ia) or (Ib) as described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment of diseases or disorders associated with KRas G12S and / or KRas G12C.

[0042] This article also provides the use of compounds of formula (Ia) or (Ib) as described herein, or pharmaceutically acceptable salts thereof, in the preparation of medicaments for the treatment of cancer.

[0043] This document also provides the use of compounds of formula (Ia) or (Ib) as described herein, or pharmaceutically acceptable salts thereof, in the preparation of medicaments for inhibiting the activity of KRas G12S and / or KRas G12C.

[0044] This document also provides for the use of compounds of formula (Ia) or (Ib) as described herein, or pharmaceutically acceptable salts thereof, in the preparation of medicaments for the treatment of diseases or disorders associated with KRas G12S and / or KRas G12C.

[0045] This article also provides a method for treating cancer in patients in need, the method comprising (a) determining that the cancer is associated with a KRas G12S mutation (i.e., cancer associated with KRas G12S) or with a KRas G12C mutation (i.e., cancer associated with KRas G12C); and (b) administering to the patient a therapeutically effective amount of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0046] This article also provides methods for preparing compounds of formula (Ia) or (Ib) or pharmaceutically acceptable salts thereof.

[0047] This article also provides compounds of formula (Ia) or (Ib) or pharmaceutically acceptable salts thereof obtained by the methods for preparing compounds described herein. Invention Details

[0049] This invention relates to inhibitors of KRas G12S and / or KRas G12C. In particular, this invention relates to compounds that inhibit the activity of KRas G12S and / or KRas G12C, pharmaceutical compositions comprising a therapeutically effective amount of the compounds, and methods of using the compounds.

[0050] definition

[0051] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. All patents, patent applications, and publications mentioned herein are incorporated herein by reference.

[0052] As used in this article, "KRas G12S" refers to a mutant form of the mammalian KRas protein in which the amino acid 12 is replaced by serine instead of glycine. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence P01116 identified in the UniProtKB / Swiss-Prot database: variant p.Gly12Asp.

[0053] As used herein, "KRas G12S inhibitor" refers to the compounds of the present invention represented by formula (Ia) or (Ib) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12S.

[0054] As used herein, “KRas G12S-related disease or disorder” means a disease or disorder that is associated with, mediated by, or has a KRas G12S mutation. A non-limiting example of a KRas G12S-related disease or disorder is a KRas G12S-related cancer.

[0055] As used in this article, "KRas G12C" refers to a mutant form of the mammalian KRas protein in which amino acid position 12 is replaced by cysteine ​​instead of glycine. The assignment of amino acid codons and residue positions for human KRas is based on the amino acid sequence P01116 identified in the UniProtKB / Swiss-Prot database: variant p.Gly12Cys.

[0056] As used herein, "KRas G12C inhibitor" refers to the compounds of the present invention represented by formula (Ia) or (Ib) as described herein. These compounds are capable of negatively regulating or inhibiting all or part of the enzymatic activity of KRas G12C.

[0057] As used herein, “KRas G12C-related disease or disorder” means a disease or disorder that is associated with, mediated by, or has a KRas G12C mutation. A non-limiting example of a KRas G12C-related disease or disorder is a KRas G12C-related cancer.

[0058] As used herein, the interchangeable terms “subject,” “individual,” or “patient” refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, a patient is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of a disease or condition to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed with cancer having a KRasG12S or KRasG12C mutation (e.g., as determined using a regulatory-approved assay or kit, such as an FDA-approved assay). In some embodiments, the subject has a KRas G12S or KRas G12C mutation-positive tumor (e.g., as determined using a regulatory-approved assay or kit). A subject may be a subject with a KRas G12S or KRasG12C mutation-positive tumor (e.g., identified as positive using a regulatory-approved assay or kit, such as an FDA-approved assay). Subjects may be those whose tumors have KRas G12S or KRas G12C mutations (e.g., where a regulatory-approved, such as FDA-approved, kit or assay is used to identify the tumor). In some embodiments, the subject is suspected of having cancer associated with the KRas G12S gene or cancer associated with the KRas G12C gene. In some embodiments, the subject has a clinical record indicating that the subject has a tumor with a KRas G12S or KRas G12C mutation (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein).

[0059] In some embodiments of any of the methods or uses described herein, determinations of whether a patient has a KRas G12S or KRas G12C mutation may include, for example, a biological sample or biopsy sample (such as a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having KRas G12S- or KRas G12C-related cancer, a patient with one or more symptoms of KRas G12S- or KRas G12C-related cancer, and / or a patient with an increased risk of developing KRas G12S- or KRas G12C-related cancer). These determinations may include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, fragment FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR, quantitative real-time RT-PCR). As is known in the art, the determination is typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

[0060] The term "regulatory agency" refers to the agency in a country that approves the medical use of a pharmaceutically active agent within that country. For example, a non-restrictive example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0061] The term "acetyl" refers to -C(O)CH3.

[0062] As used herein, the terms "C1-C6 alkyl", "C1-C4 alkyl", and "C1-C3 alkyl" refer to straight-chain or branched aliphatic groups having 1-6 carbon atoms, 1-4 carbon atoms, or 1-3 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.

[0063] The terms “C1-C3 haloalkyl” and “C1-C4 haloalkyl” refer to C1-C3 or C1-C4 alkyl chains as described herein, wherein one or more hydrogen atoms are replaced by halogens. Examples include trifluoromethyl, difluoromethyl, and fluoromethyl.

[0064] "C1-C4 alkylene" groups are C1-C4 alkyl groups as described herein, which are located between and serve to connect the other two chemical groups. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, 2-2-dimethylethylene, propylene, and butylene.

[0065] The terms “C1-C3 alkoxy” and “C1-C4 alkoxy” refer to -OC1-C3 alkyl and -OC1-C4 alkyl, respectively, wherein the alkyl part is as described above.

[0066] The term "cycloalkyl" includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons (e.g., 3 to 8 carbons) and, as another example, 3 to 6 carbons, wherein the cycloalkyl group is optionally further reinforced by one or more R groups as described herein. X Group substitution. Cycloalkyl groups can be monocyclic, bicyclic, spirocyclic, or bridged cyclic systems. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term "cycloalkyl" also includes bridged cycloalkyl groups, such as bicyclic [1.1.1]pentyl.

[0067] As used herein, the terms “C1-C3 hydroxyalkyl” and “C1-C4 hydroxyalkyl” refer to -C1-C3 alkylene-OH and -C1-C4 alkylene-OH, respectively.

[0068] As used herein, the term “C2-C4 hydroxyalkynyl” refers to -C2-C4 ynynyl-OH.

[0069] "Aryl" is a C6-C group containing one to three aromatic rings. 14 The aromatic moiety is optionally substituted with one or more substituents as described herein. As one embodiment, the aryl group is C6-C. 10 Aryl. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, fluorenyl, and dihydrobenzofuranyl. "Aryl" also refers to bicyclic or tricyclic ring systems, wherein one or both rings of the aryl ring system may be saturated or partially saturated, and wherein if the ring system comprises two saturated rings, the saturated rings may be fused or spirocyclic. Examples of aryl ring systems comprising two saturated rings and wherein these rings are spirocyclic include the following ring systems: .

[0070] The term "aryl C1-C6 alkyl" or "aralkyl" group comprises an aryl group covalently linked to an alkyl group, wherein the alkyl and aryl groups may be independently and optionally substituted or unsubstituted. Examples of aralkyl groups are (C6-C6 alkyl groups). 10 Aryl (C1-C6)alkyl, including but not limited to benzyl, phenethyl, and naphthylmethyl. Examples of substituted aryl C1-C6 alkyl groups are those in which the alkyl group is replaced by a hydroxyalkyl group.

[0071] A "heterocyclic group" or "heterocyclic group" is a ring structure having 3 to 12 atoms, for example 4 to 8 atoms, wherein one or more atoms are selected from N, O, and S, wherein the ring N atom can be oxidized to NO, and the ring S atom can be oxidized to SO or SO2, and the remaining ring atoms are carbon. The heterocyclic group can be a monocyclic, bicyclic, spirocyclic, or bridged ring system. The heterocyclic group is optionally separated from one or more R atoms at one or more positions. 6 Replace, where R 6As defined in Formula I. The heterocyclic group is also independently and optionally substituted at the nitrogen atom of the ring with an alkyl, aralkyl, or alkylcarbonyl group, or at the sulfur atom with a lower alkyl group. Examples of heterocyclic groups include, but are not limited to, epoxy, aziridine, aziridinepropyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolylalkyl, pyrrolidone, piperidinyl, piperazinyl, imidazoalkyl, imidazopyridinyl, thiazoalkyl, dithiohexyl, trithiohexyl, dioxazolidinyl, oxazolidinyl, decahydroquinolinyl, piperidinone, 4-piperidinone, quininecycloyl, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, morpholinyl, aziridineheptyl, oxazaaziridineheptyl, azirbiscyclohexyl, azirbiscycloheptyl, azirbiscyclooctyl, azirbiscyclononyl (e.g., Octahydroinzazinyl), azaspirohepyl, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolazine], hexahydro-1H-pyrrolazinyl, tetrahydro-1H-pyrrolazinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroinzazinyl, oxazaspirononyl, oxazaspironoctyl, diazaspirononyl, oxazabicycloheptyl, hexahydropyrrolazinyl 4(1H)-oxide, tetrahydro-2H-thiaranyl 1-oxide, and tetrahydro-2H-thiaranyl 1,1-dioxide. Compounds having adjacent ring O and / or S atoms are specifically excluded from the scope of this term.

[0072] 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 a total of 6, 10, or 14 π electrons in its cyclic structure; and, in addition to carbon atoms, each ring contains one to three heteroatoms selected from N, O, and S. Examples of heteroaryl groups include acridinel, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenel, benzooxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolel, benzoisooxazolyl, benzoisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbazolinyl, chromanyl, chromenyl, cinnamyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanyl, and furanyl. Zanyl, imidazolinyl, imidazolyl, 1H-indolenyl, indolenyl, dihydroindoleyl, indazinyl, indoleyl, 3H-indoleyl, isobenzofuranyl, isobenzodihydropyranyl, isoindoleyl, isodihydroindoleyl, isoindoleyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthidyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolylalkyl, oxazolyl, oxazolylalkyl, pyrimidine yl, phenanthrene, o-diazaphenanthyl, phenazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purine, pyranyl, pyrazinyl, pyrazolylyl, pyrazolyl, pyridazinyl, pyridoxazole, pyridothiazole, pyridinyl, pyridinyl, pyrimidinyl, pyrrolinyl, 2H-pyrroleyl, pyrroleyl, quinazolinyl, quinolinyl, 4H-quinazinyl The following groups are listed: quinoxalinyl, quininecycloyl, tetrahydroisoquinoline, tetrahydroquinoline, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianyl, thiazolyl, thiophene, thieno-thiazolyl, thieno-oxazolyl, thieno-imidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthonyl. "Heteroaryl" also refers to bicyclic systems where, in addition to a carbon atom, each ring has one to three heteroatoms selected from N, O, and S, and one of the ring systems can be saturated or partially saturated.

[0073] As used herein, the “effective amount” of a compound refers to an amount sufficient to negatively regulate or inhibit the activity of KRas G12S and / or KRas G12C. This amount may be administered as a single dose or according to a prescribed regimen, as long as it is effective.

[0074] As used herein, a "therapeuticly effective amount" of a compound is an amount sufficient to improve or reduce symptoms of the disease in some way, or to stop or reverse the progression of the disease, or to negatively regulate or inhibit the activity of KRas G12S and / or KRas G12C. This amount may be administered as a single dose or according to a prescribed regimen, as long as it is effective.

[0075] As used herein, treatment means in any way to alleviate or otherwise improve the symptoms or pathological condition of a symptom, disorder, or disease. Treatment also includes any pharmaceutical use of the compositions described herein.

[0076] As used herein, relief of symptoms of a particular disorder by administration of a particular pharmaceutical composition means any reduction caused by or related to the administration of the composition, whether permanent or temporary, lasting or transient.

[0077] compound

[0078] In one aspect of the invention, compounds represented by formula (Ia) or (Ib) are provided:

[0079]

[0080] Or its pharmaceutically acceptable salt, wherein:

[0081] A is selected from: , , , , , , , , , , and ;

[0082] B is selected from:

[0083] , , , ;

[0084] X is a bond, N, methylene, ethylene, or propylene;

[0085] D is either CO or SO2;

[0086] E is N or CR 10 ;

[0087] Y represents a bond, O, or NR. 5 ;

[0088] Z is a bond, a C1-C4 alkyl group, a heterocyclic group, a heteroaryl group, or an aryl group, wherein Z is optionally substituted by 1-3 substituents selected from halogens, C1-C4 alkyl groups, C1-C4 haloalkyl groups, oxoalkyl groups, and OR groups. 12 、N(R 12 2. COR 12 and cyano;

[0089] Each R 2 Independently, it is hydrogen, hydroxyl, halogen, C1-C3 alkyl, spirocyclopropyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, CHF2, HC(=O)-, -OC(O)N(R) 5 )2、-CO2R 5 -CO2N(R) 5 )2、=CH2、=CHR 11 or = C(R) 11 )2, where R 2 Optionally by one or more R 4 replace;

[0090] R 3 It is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally surrounded by one or more R groups. 8 replace;

[0091] R 4 It is a bond, halogen, or C1-C3 alkyl;

[0092] Each R 5 It is independently hydrogen or C1-C3 alkyl;

[0093] Each R 6 It is independently hydrogen, hydroxyl, C1-C4 alkyl, C1-C4 hydroxyalkyl or heteroaryl, or two R 6 Linkage forms C3-C6 cycloalkyl or heterocyclic rings;

[0094] Each R 8 It is independently a halogen, cyano, hydroxyl, cycloalkyl, C1-C3 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 or -S-C1-C3 haloalkyl;

[0095] Each R 9 Independently, it is hydrogen, C1-C4 alkyl, methoxy, CH2-methoxy, hydroxyl, CH2F, CF2, CF3, C-CN, cyclopropyl, or two Rs on the same or different carbon atoms. 9 Connect to form C1-C2 alkylene bridges or spirorings;

[0096] Each R 10 It is a bond, halogen, CH2F, CHF2, CF3, C1-C3 alkyl, cyclopropyl, OR 12 or N(R) 12 )2;

[0097] Each R 11 It is a halogen or a C1-C3 alkyl group.

[0098] R 12 It is a C1-C3 alkyl group, and

[0099] R 13 It is H or forms a ring with A.

[0100] In some such implementations, equation (Ia) is equation IA:

[0101] .

[0102] In other such implementations, equation (Ia) is equation IB:

[0103] .

[0104] In some implementations, X is methylene.

[0105] In some implementations, X is ethylene.

[0106] In some implementations, X is a key.

[0107] In some implementations, X is propylidene.

[0108] In one implementation, Y is NR 5 .

[0109] In one implementation, Y is the key.

[0110] In one implementation, Y is O.

[0111] In one implementation, Z is hydrogen.

[0112] In another embodiment, Z is a C1-C4 alkyl group optionally substituted with 1-3 halogens.

[0113] In yet another embodiment, Z is an aryl group optionally substituted with 1-3 halogens, cyano groups, or C1-C4 haloalkyl groups. In one aspect of this embodiment, the aryl group is a phenyl group.

[0114] In yet another embodiment, Z is a heteroaryl group optionally substituted with 1-2 C1-C4 alkyl groups. In one aspect of this embodiment, the heteroaryl group is pyrazolyl or pyridinyl.

[0115] In another embodiment of the invention, Z is a heterocyclic group optionally substituted with oxygen. In one aspect of this embodiment, the heterocyclic group is an oxazolidine.

[0116] In one implementation scheme, two R 9 The connection forms a methylene bridge, or two R 9 The connection forms an ethylene bridge.

[0117] In some implementations, R 5 It is hydrogen.

[0118] In some implementations, R 5 It is a C1-C3 alkyl group. In some of these embodiments, the C1-C3 alkyl group is methyl.

[0119] In one implementation, R 2 It is a halogen. In one aspect of this implementation, R 2 It's fluorine.

[0120] In another implementation, R 2 Yes = CHR 11 .

[0121] In yet another implementation scheme, R 2 =C(R) 11 )2.

[0122] In one embodiment of a compound of formula (Ia) or (Ib), formula (IA) and / or formula (IB), R 3 It is arbitrarily controlled by one or more R 8 Substituted aryl group. In some embodiments, the aryl group is selected from the group consisting of phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and 2,3-dihydro-1H-indenyl, wherein each is optionally substituted with one or more R 8 replace.

[0123] In one embodiment, the aryl group is reacted with one or more R groups. 8 A phenyl group substituted with a radical. In one embodiment, the aryl group is substituted with one or more R groups. 8 A phenyl group substituted with a radical, wherein the R 8 The phenyl group is independently selected from halogens, C1-C3 alkyl groups, and cycloalkyl groups. In some embodiments, the phenyl group is formed by two R groups. 8 Group substitution. In some embodiments, the phenyl group is replaced by two R groups. 8 Group substitution, one of which R 8 The group is halogen, and the other R 8 The group is C1-C3 alkyl or cycloalkyl.

[0124] In one embodiment, the aryl group is optionally surrounded by one or more R groups. 8 The aryl group is substituted with an R group. In one embodiment, the aryl group is optionally replaced with an R group. 8 Substituted 2,3-dihydro-1H-indenyl. In one embodiment, R 8 It is a C1-C alkyl group.

[0125] In one embodiment, the aryl group is reacted with one or more R groups. 8 A naphthyl group substituted with a group. In one embodiment, the aryl group is substituted with one or more R groups. 8 The group-substituted naphthyl group, said R 8 It is independently selected from halogen, cyano, hydroxy, C1-C3 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, cycloalkyl, triazolyl, C1-C3 haloalkyl and -O-C1-C3 haloalkyl.

[0126] In one embodiment, the aryl group is a naphthyl group substituted with a hydroxyl group. In one embodiment, the aryl group is a naphthyl group substituted with a halogen. In some embodiments, the halogen is chlorine, fluorine, or bromine. In other embodiments, the halogen is chlorine. In other embodiments, the halogen is fluorine.

[0127] In one embodiment, the aryl group is a naphthyl group substituted with a C1-C3 alkyl group, wherein the C1-C3 alkyl group is methyl or ethyl.

[0128] In one embodiment, the aryl group is a naphthyl group substituted with a C2-C4 alkenyl group. In some embodiments, the C2-C4 alkenyl group is a prop-2-alkenyl group.

[0129] In one embodiment, the aryl group is a naphthyl group substituted with a C2-C4 ynyl group. In some embodiments, the C2-C4 ynyl group is acetylene or prop-2-ynyl.

[0130] In one embodiment, the aryl group is a naphthyl group substituted with a cycloalkyl group. In some embodiments, the cycloalkyl group is a cyclopropyl group.

[0131] In one embodiment, the aryl group is formed by one or two R groups. 8 Substituted naphthyl groups, wherein each R 8 It is a halogen, cyano, hydroxyl, C1-C3 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 ynyl, C2-C4 hydroxyynyl, C1-C3 cyanoalkyl, or triazolyl. In one embodiment, the aryl group is formed by two R groups. 8 The group-substituted naphthyl group, said R 8The radical is independently selected from halogen, hydroxyl, C1-C3 alkyl, and C2-C4 alkynyl. In another embodiment, an R... 8 It's a hydroxyl group, another R 8 It is a C1-C3 alkyl, halogen, or C2-C4 alkynyl, or an R 8 It's halogen, another R 8 It is a C1-C3 or C2-C4 alkynyl group.

[0132] In one embodiment, the aryl group is composed of three R groups. 8 Group-substituted naphthyl groups, wherein the first R 8 The group is halogen, the second R 8 The group is hydroxyl, and the third R is... 8 The group is C1-C3 alkyl or C2-C4 ynyl.

[0133] In one embodiment of a compound of formula (Ia) or (Ib), formula (IA) and / or formula (IB), R 3 It is arbitrarily controlled by one or more R 8 Substituted heteroaryl groups. In one embodiment, the heteroaryl group is isoquinolinyl, indazole, or benzo[d][1,3]dioxanepentyl, optionally substituted with one or more R... 8 Replacement. In one embodiment, the heteroaryl group is optionally replaced by one or more R... 8 Substituted indazole group. In one embodiment, the heteroaryl group is an indazole group optionally substituted with a C1-C3 alkyl group or a C1-C3 alkyl group and a halogen. In other embodiments, the heteroaryl group is optionally substituted with one or more R groups. 8 Substituted isoquinolinyl group. In other embodiments, the heteroaryl group is an isoquinolinyl group optionally substituted with a halogen or a C2-C4 alkynyl group. In some embodiments, the heteroaryl group is optionally substituted with two R groups. 8 A benzo[d][1,3]dioxane-pentyl group substituted with a radical. In some embodiments, the heteroaryl group is optionally replaced by two R groups. 8 Benzo[d][1,3]dioxanepentyl substituted with groups, wherein each R 8 The groups are independently chosen halogens. In one embodiment, both halogens are gem-difluoro substituted. In another embodiment, R3 is substituted with two R groups. 8 Substituted indazole group, one of which R 8 It's halogen, another R 8 It is a C1-C3 alkyl group.

[0134] In one embodiment of a compound of formula (Ia) or (Ib), formula (IA) and / or formula (IB), R 4 It is hydrogen.

[0135] In one embodiment of a compound of formula (Ia) or (Ib), formula (IA) and / or formula (IB), R 4 It is a halogen. In one implementation, R 4 It is fluorine. In one implementation, R 4 It is chlorine.

[0136] In one embodiment of a compound of formula (Ia) or (Ib), formula (IA) and / or formula (IB), R 4 It is a C1-C3 alkyl group. In one embodiment, R 4 It is a methyl group.

[0137] Non-limiting examples of compounds of formula (Ia) or (Ib), formula (IA) and / or formula (IB) are selected from the following group:

[0138]

[0139] And its pharmaceutically acceptable salts.

[0140] In one embodiment, the compounds of formula (Ia) or (Ib), formula (IA), and / or formula (IB) include dihydrochloride, formate, diformate, trihydrochloride, trifluoroacetate, bis(trifluoroacetate), and tri(trifluoroacetate) salts of the above compounds. The compounds of formula (Ia) or (Ib) or pharmaceutically acceptable salts thereof can be formulated into pharmaceutical compositions.

[0141] Pharmaceutical Composition

[0142] In another aspect, the present invention provides pharmaceutical compositions comprising KRasG12S and / or KRas G12C inhibitors according to the present invention, and pharmaceutically acceptable carriers, excipients, or diluents. The compounds of the present invention can be formulated by any method well known in the art and can be prepared for administration via any route, including but not limited to parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, and rectal administration. In some embodiments, the compounds of the present invention are administered intravenously in a hospital setting. In one embodiment, administration can be via an oral route.

[0143] 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 biological systems (such as cells, cell cultures, tissues, or organisms) and does not interfere with the effectiveness of the bioactivity of the active ingredient. Therefore, in addition to inhibitors, compositions according to the invention may also contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. Preparation of pharmaceutically acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th edition, edited by A. Gennaro, Mack Publishing Co., Easton, Pennsylvania, 1990.

[0144] As used herein, the term pharmaceutically acceptable salt refers to a salt that retains the desired biological activity of the compound and exhibits minimal or no undesirable toxicological effects. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and salts formed with organic acids (e.g., acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pyric acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid). These compounds can also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, particularly including quaternary ammonium salts of the formula -NR+Z-, where R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methanesulfonate, sulfonate, phosphate, or carboxylate ions (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelic acid, benzylloate, and diphenylacetate).

[0145] The active compound is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective dose to a patient without causing serious toxicity in the treated patient. In one embodiment, the dose of the active compound for all the above-described conditions ranges from about 0.01 to 100 mg / kg, for example, 0.1 to 50 mg / kg daily, and as another example, from 0.5 to about 25 mg / kg of recipient body weight / day. In a suitable carrier, the typical local dose range is 0.01%–3% wt / wt. The effective dose range of a pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound to be delivered. If the derivative itself exhibits activity, the effective dose can be estimated as described above using the weight of the derivative or by other means known to those skilled in the art.

[0146] Pharmaceutical compositions comprising the compounds of the present invention can be used in the methods of use described herein.

[0147] How to use

[0148] In another aspect, the present invention provides a method for inhibiting KRas G12S and / or KRas G12C activity in cells, the method comprising contacting cells for which KRas G12S activity needs to be inhibited with an effective amount of a compound of formula (Ia) or (Ib), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the contact is performed in vitro. In one embodiment, the contact is performed in vivo.

[0149] As used herein, the term "contact" means bringing the components into contact with each other in an in vitro or in vivo system. For example, "contacting" KRas G12S with a compound provided herein includes administering the compound provided herein to an individual or patient (e.g., a human having KRas G12S), and, for example, introducing the compound provided herein into a sample containing cells or a purified formulation containing KRas G12S. For example, "contacting" KRas G12C with a compound provided herein includes administering the compound provided herein to an individual or patient (e.g., a human having KRas G12C), and, for example, introducing the compound provided herein into a sample containing cells or a purified formulation containing KRas G12C.

[0150] In one embodiment, cells requiring inhibition of KRas G12S and / or KRas G12C activity are contacted with an effective amount of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof to negatively regulate the activity of KRas G12S and / or KRas G12C.

[0151] The methods described herein are designed to inhibit undesirable cell proliferation resulting from enhanced intracellular KRas G12S and / or KRas G12C activity by negatively modulating the activity of KRas G12S and / or KRas G12C. Cells can be exposed to a single dose or multiple doses depending on a specific treatment regimen to influence the desired negative modulation of KRas G12S and / or KRas G12C. The ability of a compound to bind KRas G12S and / or KRas G12C can be monitored in vitro using well-known methods, including those described in Examples A and B below. Furthermore, the inhibitory activity of exemplary compounds in cells can be monitored, for example, by measuring the amount of phosphorylated ERK to assess the inhibitory effect on KRas G12S and / or KRas G12C activity, using, for example, the method described in Example C below.

[0152] On the other hand, a method for treating cancer in a patient in need is provided, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof.

[0153] The compositions and methods provided herein can be used to treat KRas G12S-associated cancers and / or KRas G12C-associated cancers in patients in need. The methods include administering to the patient a therapeutically effective amount of a compound of formula (Ia) or (Ib), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the KRas G12S-associated cancer is lung cancer. In one embodiment, the KRas G12C-associated cancer is lung cancer.

[0154] The compositions and methods provided herein can be used to treat a variety of cancers, including tumors such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, and testicular cancer. More specifically, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, the following tumor types: astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, and sarcoma. More specifically, these compounds can be used to treat the following diseases: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor). Tumors), vasoactive intestinal peptide tumors (vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminomatous seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal tumor). Hepatocellular carcinoma, fibroma, fibroadenoma, adenoma-like tumor, lipoma; Liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bile duct: gallbladder cancer, ampullary cancer, bile duct cancer; Bone: osteoblastoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor;Nervous system: Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma; Gynecology: Uterus (endometrial cancer), cervix (cervical cancer, precancerous cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors. Tumors: dysgerminoma, malignant teratoma; vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma); vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma); fallopian tube (cancer); hematologic system: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal glands: neuroblastoma.

[0155] In some implementations, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer. In some implementations, the cancer is non-small cell lung cancer.

[0156] The concentration and route of administration to the patient will vary depending on the cancer being treated. Compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions containing such compounds and salts may also be administered co-administered with other antitumor compounds (e.g., chemotherapy) or in combination with other treatments (e.g., radiation or surgical interventions) as adjuncts before or after surgery.

[0157] This document also provides compounds of formula (Ia) or (Ib) as described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for therapeutic purposes.

[0158] This article also provides compounds of formula (Ia) or (Ib) as described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment of cancer.

[0159] This article also provides compounds of formula (Ia) or (Ib) or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof for the inhibition of KRas G12S and / or KRas G12C.

[0160] This document also provides compounds of formula (Ia) or (Ib) as described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment of diseases or disorders associated with KRas G12S and / or KRas G12C.

[0161] This article also provides the use of compounds of formula (Ia) or (Ib) as described herein, or pharmaceutically acceptable salts thereof, in the preparation of medicaments for the treatment of cancer.

[0162] This document also provides the use of compounds of formula (Ia) or (Ib) as described herein, or pharmaceutically acceptable salts thereof, in the preparation of medicaments for inhibiting the activity of KRas G12S and / or KRas G12C.

[0163] This document also provides for the use of compounds of formula (Ia) or (Ib) as described herein, or pharmaceutically acceptable salts thereof, in the preparation of medicaments for the treatment of diseases or disorders associated with KRas G12S and / or KRas G12C.

[0164] This article also provides a method for treating cancer in patients in need, the method comprising (a) determining that the cancer is associated with a KRas G12S mutation or a KRas G12C mutation (e.g., cancer associated with KRas G12S or cancer associated with KRas G12C) (e.g., identified using a regulatory-approved assay or kit, such as an FDA-approved assay); and (b) administering to the patient a therapeutically effective amount of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0165] Those skilled in the art will recognize that in vivo and in vitro assays using appropriate, known and generally accepted cell and / or animal models can predict the ability of a test compound to treat or prevent a given disorder.

[0166] Those skilled in the art will further recognize that human clinical trials (including first-in-human, dose-range, and efficacy trials) in healthy patients and / or patients with a given disability can be conducted using methods well known in the clinical and medical fields.

[0167] Example

[0168] The compounds of the present invention can be prepared using the synthetic methods and reaction schemes described herein, or from commercially available reagents using other reagents and conventional methods well known to those skilled in the art.

[0169] The following examples are intended to further illustrate certain embodiments of the present invention and are not intended to limit the scope of the invention.

[0170] reagent abbreviations

[0171]

[0172] Example 1

[0173]

[0174] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone

[0175]

[0176] Step A. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-methyl-1H-pyrazole-1-yl) methyl ketone: 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (50 mg, 1.0 equivalent) and 3-methyl-1H-pyrazole (10.0 mg, 1.5 equivalent) in DCM (1 DMAP (12.3 mg, 1.2 equivalents) and EDCI (19.3 mg, 1.2 equivalents) were added to a solution in mL. The reaction was stirred at 25 °C for 12 h. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 5 µm; A: water (FA), B: ACN, B%: 15%–45% B, 10 min] to give the title compound (12.1 mg, 22% yield) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 8.96 (s, ¹H), 8.16 (d, J = 2.8 Hz, 1H), 7.54 (dd, J=5.6, 8.8 Hz, 1H), 7.23-7.12 (m, 2H), 7.09-6.96 (m, 1H), 6.29 (d, J = 2.8 Hz,1H), 5.44-5.21 (m, 1H), 4.71-4.54 (m, 2H), 4.42-4.23 (m, 2H), 4.01 (dt, J =5.2, 10.4 Hz, 1H), 3.63-3.11 (m, 6H), 3.08-2.94 (m, 1H), 2.46 (br d, J = 7.6Hz, 1H), 2.36 (s, 3H), 2.24-1.99 (m, 10H), 0.83-0.74 (m, 3H); LCMS (ESI, M+1): m / z = 686.4.

[0177] Example 2

[0178]

[0179] 3-(1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carbonyl)oxazolidin-2-one

[0180]

[0181] Step A. 2-(8-fluoronaphthyl-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane: Potassium acetate (11.8 g, 3.0 equivalent) and [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (2.93 g, 0.10 equivalent) were added to a solution of 1-bromo-8-fluoronaphthalene (9.00 g, 1.0 equivalent) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyl-2-yl)-1,3,2-dioxaborhecyl) dioxane (100 mL). The reaction mixture was degassed and purged three times with nitrogen. The reaction mixture was stirred at 90 °C for 1 hour. The mixture was diluted with H₂O (100 mL) and extracted with dichloromethane (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1] to give the title compound (8.50 g, 78% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 8.04 (td, J= 2.4, 8.0 Hz, 1H), 7.79(d, J = 8.0 Hz, 1H), 7.64-7.56 (m, 2H), 7.52 (dt, J = 5.2, 8.0 Hz, 1H), 7.35(dd, J = 8.0, 12.0 Hz, 1H), 1.36 (s, 12H).

[0182] Step B. 2,7-Dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: At 25°C, t-BuONa (4.19 g, 1.1 equivalents) was added in portions to a solution of 2,2,2-trifluoroethanol (4.36 g, 1.1 equivalents) in THF (50 mL). The reaction was stirred at 25°C for 1 hour. At -40°C, the mixture was added to a solution of 2,4,7-trichloro-8-fluoropyridyl[4,3-d]pyrimidine (10.0 g, 1.0 equivalents) in THF (100 mL). The reaction was stirred at 0°C for 1 hour. The mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 30 / 1 to 1 / 1] to give the title compound (7.10 g, 80% yield) as a white solid; LCMS (ESI, M+1): m / z = 315.0.

[0183] Step C: 7-Chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethyl) (Oxy)pyrido[4,3-d]pyrimidine: To 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3- d Pyrimidine (7.00 g, 1.0 equivalent) and 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol (3.13 g, 1.0 equivalent) were added to a solution of Na₂CO₃ (7.04 g, 3.0 equivalent) in THF (70 mL). The reaction was stirred at 40 °C for 3 h. The mixture was diluted with H₂O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO₂, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1] to give the title compound (8.50 g, 83% yield) as a white solid; LCMS (ESI, M+1): m / z = 421.1.

[0184] Step D: 8-Fluoro-7-(8-Fluoronaphth-1-yl)-2-((Tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2, 2,2-Trifluoroethoxy)pyrido[4,3-d]pyrimidine:To a solution of 7-chloro-8-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (5.00 g, 1.0 equivalent) in CPME (5.0 mL), 2-(8-fluoro-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (3.23 g, 1.0 equivalent), Cs₂CO₃ (23.8 mL, 3.0 equivalent), and CataCXium A Pd G₃ (865 mg, 0.1 equivalent) were added. The reaction mixture was degassed and purged three times with nitrogen. The reaction was stirred at 90 °C for 1 hour. The mixture was diluted with H₂O (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 10 / 1] to give the title compound (4.60 g, 67% yield) as a white solid. 1 H NMR(400 MHz, DMSO-d6) δ = 9.20 (s, 1H), 8.22-8.18 (m, 1H), 7.95 (d, J = 8.0 Hz,1H), 7.78-7.73 (m, 1H), 7.65 (d, J = 6.4 Hz, 1H), 7.60 (dt, J = 5.2, 8.0 Hz, 1H), 7.32 (dd, J = 7.6, 13.2 Hz, 1H), 5.43-5.31 (m, 2H), 4.18 (s, 2H), 3.01-2.89 (m, 2H), 2.61-2.53 (m, 2H), 1.95-1.87 (m, 2H), 1.84-1.75 (m, 4H), 1.64-1.56 (m, 2H); LCMS (ESI, M+1): m / z =531.4.

[0185] Step E. 1-(8-Fluoro-7-(8-Fluoronaphth-1-yl)-2-((Tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy) tert-butyl pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate:N-ethyl-N,N-diisopropylamine (1.10 g, 9.0 equivalent) and 4Å molecular sieve (75.0 mg) were added to a solution of 8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (500 mg, 1.0 equivalent) and piperidine-4-carboxylic acid tert-butyl ester (627 mg, 3.0 equivalent) in DMF (10 mL). The reaction was stirred at 50 °C for 16 h. The mixture was diluted with water (80 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative TLC [(SiO2, dichloromethane / methanol) = 12 / 1] to give the title compound (400 mg, 69% yield) as a pale yellow solid; LCMS (ESI, M+1): m / z = 616.4.

[0186] Step F. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine Aceto[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid: At 0 °C, TFA (1.8 mL) was added to a solution of 1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid tert-butyl ester (100 mg, 1.0 equivalent) in DCM (5.5 mL). The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated to give the title compound (90.0 mg, crude) as a pale yellow oil; LCMS (ESI, M+1): m / z = 560.3.

[0187] Step G. 3-(1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy) (4,3-d)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carbonyl)oxazolidin-2-oneDMAP (13.6 mg, 1.2 equivalents) and EDCI (21.4 mg, 1.2 equivalents) were added to a solution of 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (50.0 mg, 1.0 equivalent) and oxazolidin-2-one (8.56 mg, 1.1 equivalent) in DCM (0.5 mL). The reaction was stirred at 30 °C for 12 h. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 µm; A: water (FA), B: ACN, B%: 22%–52% B, 9 min] and preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 µm; A: water (FA), B: ACN, B%: 20%–50% B, 9 min] to give the title compound (7.42 mg, 13% yield) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 9.04 (s, ¹H), 7.99 (br d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.68-7.58 (m, 2H), 7.45(dt, J = 4.8, 8.0 Hz, 1H), 7.12 (dd, J = 7.6, 12.8 Hz, 1H), 4.77-4.63 (m,2H), 4.57-4.43 (m, 4H), 4.07 (t, J = 8.0 Hz, 2H), 4.02-3.91 (m, 1H), 3.60-3.42 (m, 4H), 2.79 (td, J = 6.6, 10.8 Hz, 2H), 2.26 (td, J LCMS (ESI, M+1): m / z = 629.3.

[0188] Example 3

[0189]

[0190] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-(pyridin-2-yl)piperidin-4-carboxamide

[0191]

[0192] Step A. 1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-(pyridin-2-yl)piperidin-4-carboxamide: Add HATU (272 mg, 2 equivalents), DIEA (277 mg, 6.0 equivalents), and pyridine-2-amine (37 mg, 1.1 equivalents) to a solution of 1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (200 mg, 1.0 equivalents) in DMF (2 mL). Stir the reaction at 25 °C for 1 hour. The mixture was purified by preparative HPLC [Waters Xbridge 150 × 25 mm × 5 µm; A: water (NH4HCO3), B: ACN, B%: 34%–64% B, 9 min] to give the title compound (7.46 mg, 3.2% yield) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 9.05 (s, ¹H), 8.31 (dd, J = 0.8, 4.8 Hz, 1H), 8.24 (d, J = 8.4Hz, 1H), 8.14 (s, 1H), 8.01 (td, J = 1.8, 7.6 Hz, 1H), 7.78-7.71 (m, 2H), 7.68-7.60 (m, 2H), 7.46 (dt, J = 5.2, 7.8 Hz, 1H), 7.17-7.05 (m, 2H), 4.71(br d, J = 13.6 Hz, 2H), 4.27 (s, 2H), 3.53-3.39 (m, 2H), 3.16 (td, JLCMS (ESI, M+1): m / z = 636.3.

[0193] Example 4

[0194]

[0195] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(1H-pyrazol-1-yl)methyl ketone

[0196]

[0197] Step A. Methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: Add K3PO4 (1.0 g, 1.0 equivalent) to a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (1.0 g, 1.0 equivalent) and methyl piperidine-4-carboxylate (290 mg, 1.2 equivalent) in a DMAC (10 mL). (g, 3.0 equivalents). The reaction was stirred at 60 °C for 0.5 h. The mixture was quenched with water (15 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over Na2SO4 and concentrated to give the title compound (1.2 g, crude), as a yellow oil.

[0198] Step B. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid: LiOH was added to a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (1.2 g, 1.0 equivalent) in MeOH (4.0 mL). H₂O (2 M, 3.78 mL, 4.0 equivalents). The reaction was stirred at 20 °C for 0.5 h. The mixture was filtered and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (0.8 g, 65.8% yield) as a white solid; LCMS (ESI, M+1): m / z = 622.3.

[0199] Step C. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(1H-pyrazol-1-yl) methyl ketone: Add EDCI to a solution of 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (100 mg, 1.0 equivalent) and TEA (81.4 mg, 5.0 equivalent) in DMF (2.0 mL). (38.5 mg, 1.25 equivalents) and HOBt (2.17 mg, 0.10 equivalents). The reaction was stirred at 25 °C for 0.5 h, then 1H-pyrazole (43.8 mg, 4.0 equivalents) was added. The reaction was stirred at 25 °C for 48 h. The mixture was filtered and purified twice by preparative HPLC [column: Waters Xbridge 150 × 25 mm × 5 µm; A: water (NH4HCO3), B: ACN; B%: 48%–78%, 9 min]. The desired fractions were extracted with DCM (3 × 7.0 mL). The combined organic layers were dried over Na2SO4 and concentrated to give the title compound (11.3 mg, 9.89% yield) as a white solid. 1¹H NMR (400 MHz, chloroform-d) δ = 8.96 (s, ¹H), 8.27 (d, ¹H) J = 2.8 Hz, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.58-7.50 (m, 1H), 7.22-7.14 (m,2H), 7.06-6.94 (m, 1H), 6.50 (dd, J = 1.2, 2.8 Hz, 1H), 5.41-5.20 (m, 1H), 4.74-4.53 (m, 2H), 4.44-4.23 (m, 2H), 4.14-3.98 (m, 1H), 3.61-3.10 (m, 5H), 3.08-2.94 (m, 1H), 2.56-2.39 (m, 1H), 2.38-2.27 (m, 1H), 2.26-2.04 (m, 7H), 2.00-1.89 (m, 3H), 0.82 (br t, J = 7.6 Hz, 3H); LCMS (ESI, M+1): m / z = 672.3.

[0200] Example 5

[0201]

[0202] (1R,5S,6r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]hept-6-carboxylic acid 2,6-difluorophenyl ester

[0203] Example 6

[0204]

[0205] (1R,5S,6s)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]hept-6-carboxylic acid 2,6-difluorophenyl ester

[0206]

[0207] Step A. (1R,5S,6s)-3-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]hept-6-carboxylic acid 2,6-difluorophenyl ester and (1R,5S,6r)-3-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin) 2,6-Difluorophenyl ester of 3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]hept-6-carboxylic acid (150 mg, 1.0 equivalent), EDCI (75.5 mg, 1.5 equivalent), and DMAP (48.1 mg, 1.5 equivalent) in DCM (2 mL) was added to a solution of 3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]hept-6-carboxylic acid (150 mg, 1.0 equivalent), EDCI (75.5 mg, 1.5 equivalent), and DMAP (48.1 mg, 1.5 equivalent). The reaction was stirred at 25 °C for 4 hours. The mixture was concentrated. The residue was diluted with H2O (2 mL) and extracted with EtOAc (3 × 2 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [column: YMC-ActusTriart C18 150 × 30 mm × 7 µm; A: water (FA), B: ACN; B%: 20%–50% B, 10 min] and lyophilized to give two isomers.

[0208] (1R,5S,6r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]hept-6-carboxylic acid 2,6-difluorophenyl ester (Example 5, 2.61 mg, 1.3% yield), is a yellowish-white solid; 1 ¹H NMR (400 MHz, chloroform-d) δ = 9.48–9.43 (m, ¹H), 8.02–7.98 (m, ¹H), 7.77–7.73 (m, ¹H), 7.66–7.60 (m, 2H), 7.48–7.41 (m, ¹H), 7.24–7.17 (m, ¹H), 7.12 (dd, J= 7.6, 12.8 Hz, 1H), 7.02 (s, 2H), 4.66-4.56 (m, 2H), 4.50 (s, 4H), 3.75-3.63 (m, 2H), 3.23 (br d, J = 6.0 Hz, 2H), 3.08 (d, J = 5.6 Hz, 1H), 2.96-2.89 (m, 2H), 2.36 (br dd, J = 6.4, 12.8 Hz,2H), 2.21-2.13 (m, 2H), 2.13-2.04 (m, 3H), 1.95 (br dd, J = 6.8, 13.2 Hz,2H), 1.66 (br dd, J = 6.0, 10.0 Hz, 1H); LCMS (ESI, M+1): m / z = 684.4.

[0209] (1R,5S,6s)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]hept-6-carboxylic acid 2,6-difluorophenyl ester (Example 6, 3.51 mg, 1.8% yield), is a yellow solid; 1 ¹H NMR (400 MHz, chloroform-d) δ = 9.50–9.43 (m, ¹H), 8.03–7.93 (m, ¹H), 7.73 (d, ¹H) J = 8.0 Hz, 1H), 7.66-7.59 (m, 2H), 7.48-7.41 (m, 1H), 7.17-7.07 (m, 2H), 6.95-6.86 (m, 2H), 4.82-4.66 (m, 2H), 4.63-4.53 (m, 2H), 4.37-4.26 (m, 2H), 3.74-3.59 (m, 2H), 3.58-3.48 (m, 1H), 3.23-3.13 (m, 2H), 2.99-2.86 (m, 2H), 2.37-2.33 (m, 2H), 2.16-2.09 (m, 2H), 2.09-2.04 (m, 2H), 2.01 (br d, J = 4.0 Hz, 1H), 1.92 (br dd, J= 6.8, 13.2 Hz, 2H), 1.67 (d, J = 10.0 Hz, 1H); LCMS (ESI, M+1): m / z = 684.4.

[0210] Example 7

[0211]

[0212] (1R,5S,6r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]hept-6-carboxylic acid 4-fluorophenyl ester

[0213] Example 8

[0214]

[0215] (1R,5S,6s)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]hept-6-carboxylic acid 4-fluorophenyl ester

[0216]

[0217] Step A. Methyl 3-azabicyclo[3.1.1]hept-6-carboxylate: HCl was added to a mixture of 6-methyl 3-(tert-butyl)-3-heptacyclo[3.1.1]hept-3,6-dicarboxylic acid ester (950 mg, 1.0 equivalent) in MeCN (10 mL). Dioxane (10 mL, 4 M). The reaction was stirred at 0 °C for 1 hour. The mixture was concentrated and diluted with MeOH (10 mL). The pH of the mixture was adjusted to 7 with NaHCO3 solid, filtered, and concentrated to give the title compound (570 mg, 99% yield) as a white solid.

[0218] Step B. 3-(8-Fluoro-7-(8-Fluoronaphth-1-yl)-2-((Tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine Methyl pyrimidin-4-yl)-3-azabicyclo[3.1.1]hept-6-carboxylate:K3PO4 (2.34 g, 3.0 equivalent) was added to a mixture of 8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.95 g, 1.0 equivalent) and methyl 3-azabicyclo[3.1.1]hept-6-carboxylate (570 mg, 1.0 equivalent) in a DMAC (10 mL). The reaction was stirred at 60 °C for 12 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (750 mg, 35% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 586.4;

[0219] Step C. 3-(8-Fluoro-7-(8-Fluoronaphth-1-yl)-2-((Tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine Pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]hept-6-carboxylic acid: LiOH was added to a solution of methyl 3-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]hept-6-carboxylate (100 mg, 1.0 equivalent) in MeOH (1 mL) and H2O (1 mL). H2O (179 mg, 25 equivalents). The reaction was stirred at 25 °C for 4 hours. The mixture was concentrated and adjusted to pH 7 with HCl (4 M). The mixture was filtered to give the title compound (70.0 mg, 72% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 572.4;

[0220] Step D. (1R,5S,6S)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazine-7a(5H)- 4-fluorophenyl ester of hept-6-carboxylic acid and (1R, )methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]hept-6-carboxylic acid 5S,6r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4, 3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]hept-6-carboxylic acid 4-fluorophenyl ester:Add 4-fluorophenol (13.7 mg, 2.0 equivalent) to a solution of 3-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]hept-6-carboxylic acid (35 mg, 1.0 equivalent), EDCI (17.6 mg, 1.5 equivalent), and DMAP (11.2 mg, 1.5 equivalent) in DCM (1 mL). Stir the reaction at 25 °C for 4 hours. Concentrate the mixture. Dilute the residue with H2O (2 mL) and extract with EtOAc (3 × 2 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [column: Welch Xtimate C18 150 × 25 mm × 5 µm; A: water (FA), B: ACN; B%: 30%-50% B, 10 min] to obtain two isomers.

[0221] (1R,5S,6r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]hept-6-carboxylic acid 4-fluorophenyl ester (Example 7, 2.05 mg, 4.7% yield), is a yellowish-white solid; 1 ¹H NMR (400 MHz, chloroform-d) δ = 9.50–9.43 (m, 1H), 8.04–7.96 (m, 1H), 7.78–7.72 (m, 1H), 7.67–7.58 (m, 2H), 7.50–7.42 (m, 1H), 7.16–7.11 (m, 3H), 7.10 (d, J = 2.4 Hz, 2H), 4.90-4.81 (m, 2H), 4.57-4.47 (m,4H), 3.96-3.84 (m, 2H), 3.24-3.15 (m, 2H), 3.03-2.93 (m, 3H), 2.86-2.78 LCMS (ESI, M+1): m / z = 666.4

[0222] (1R,5S,6s)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.1]hept-6-carboxylic acid 4-fluorophenyl ester (Example 8, 2.38 mg, 5.5% yield), is a beige solid; 1 ¹H NMR (400 MHz, chloroform-d) δ = 9.49–9.43 (m, ¹H), 8.03–7.96 (m, ¹H), 7.77–7.71 (m, ¹H), 7.67–7.57 (m, ²H), 7.49–7.41 (m, ¹H), 7.11 (dd, ) J = 7.6, 12.8 Hz, 1H), 7.00 (s, 2H), 6.93-6.84 (m, 2H), 4.91-4.62(m, 4H), 4.44-4.26 (m, 2H), 3.98-3.72 (m, 2H), 3.47 (br d, J = 2.8 Hz, 1H),3.23-3.07 (m, 2H), 3.02-2.84 (m, 2H), 2.44-2.29 (m, 3H), 2.26-2.15 (m, 2H),2.14-2.05 (m, 2H), 2.04-1.91 (m, 2H), 1.66 (br s, 1H); LCMS (ESI, M+1): m / z =666.4.

[0223] Example 9

[0224]

[0225] (3,5-Dimethyl-1H-pyrazol-1-yl)(1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methyl ketone

[0226]

[0227] Step A. (3,5-Dimethyl-1H-pyrazol-1-yl)(1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-) Pyrrolazine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methyl ketoneAdd 3,5-dimethyl-1H-pyrazole (25.8 mg, 3.0 equivalent), EDCI (25.7 mg, 1.5 equivalent), and DMAP (16.4 mg, 1.5 equivalent) to a solution of 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (50 mg, 1.0 equivalent) in DCM (0.5 mL). Stir the reaction at 25 °C for 1 hour. Concentrate the mixture. Dilute the residue with water (1 mL), neutralize with solid NaHCO3, and extract with ethyl acetate (2 × 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Phenomenex lunaC18 150 × 25 mm × 10 µm; A: water (FA); B: ACN, B%: 30%–60%, 7 min] to give the title compound (16.4 mg, 28% yield, HCOOH salt) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ= 9.11 (s, 1H), 8.19 (br d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.78-7.72 (m, 1H), 7.65 (d, J = 6.8 Hz, 1H), 7.59 (dt, J = 5.2, 8.0 Hz, 1H), 7.32(dd, J = 7.6, 13.2 Hz, 1H), 6.23 (s, 1H), 4.58 (br d, J = 13.2 Hz, 2H), 4.08(s, 2H), 4.07-3.99 (m, 1H), 3.57 (br t, J = 12.8 Hz, 2H), 2.98-2.90 (m, 2H), 2.59-2.53 (m, 2H), 2.49 (s, 3H), 2.23 (s, 3H), 2.18-2.09 (m, 2H), 1.99-1.87(m, 4H), 1.85-1.71 (m, 4H), 1.63-1.54 (m, 2H); LCMS (ESI, M+1): m / z = 638.4.

[0228] Example 10

[0229]

[0230] (1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone

[0231]

[0232] Step A. (1-(8-Fluoro-7-(8-Fluoronaphth-1-yl)-2-((Tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy) Pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone Add 5-methyl-1H-pyrazole (22.0 mg, 3.0 equivalent), EDCI (25.7 mg, 1.5 equivalent), and DMAP (16.4 mg, 1.5 equivalent) to a solution of 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (50 mg, 1.0 equivalent) in DCM (0.5 mL). Stir the reaction at 25 °C for 1 hour. Concentrate the mixture. Dilute the residue with water (1 mL), neutralize with solid NaHCO3, and extract with ethyl acetate (2 × 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Phenomenex luna C18150 × 25 mm × 10 µm; A: water (FA); B: ACN, B%: 28%–58% B, 7 min] to give the title compound (15.1 mg, 27% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.12 (s,1H), 8.32 (d, J = 2.8 Hz, 1H), 8.19 (br d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.0Hz, 1H), 7.79-7.72 (m, 1H), 7.65 (d, J = 6.4 Hz, 1H), 7.59 (dt, J = 5.2, 7.6Hz, 1H), 7.32 (dd, J = 7.6, 13.2 Hz, 1H), 6.50 (d, J = 2.8 Hz, 1H), 4.59 (brd, J= 13.2 Hz, 2H), 4.08 (s, 2H), 4.05-3.95 (m, 1H), 3.59 (br t, J = 12.8Hz, 2H), 2.99-2.88 (m, 2H), 2.58-2.53 (m, 2H), 2.31 (s, 3H), 2.19-2.11 (m,2H), 2.01-1.86 (m, 4H), 1.86-1.71 (m, 4H), 1.63-1.53 ​​(m, 2H); LCMS (ESI, M+1): m / z = 624.4.

[0233] Example 11

[0234]

[0235] (1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(1H-pyrazol-1-yl)methyl ketone

[0236]

[0237] Step A. (1-(8-Fluoro-7-(8-Fluoronaphth-1-yl)-2-((Tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy) Pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(1H-pyrazol-1-yl)methyl ketone To a solution of 1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (150 mg, 1.0 equivalent) in DCM (1.5 mL), 1H-pyrazole (54.7 mg, 3.0 equivalent), EDCI (77.1 mg, 1.5 equivalent), and DMAP (49.1 mg, 1.5 equivalent) were added. The reaction was stirred at 25 °C for 1 hour. The mixture was diluted with water (5 mL) and extracted with DCM (10 mL). The combined organic layers were dried over sodium sulfate, concentrated, and purified by preparative HPLC. The purified compound was then purified by preparative HPLC [Phenomenex luna C18 150 × 25 mm × 10 µm; A: water (FA); B: ACN, B%: 18%–48% B, 10 min] to give the title compound (14.4 mg, 8% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ = 9.10 (s, 1H), 8.29 (d, J = 4.8 Hz, 1H), 7.99 (d, J= 7.6 Hz, 1H), 7.77-7.73 (m, 2H), 7.63-7.59 (m, 3H), 7.50-7.40 (m, 1H), 7.14-7.09 (m, 1H), 6.52 (s, 1H), 4.76-4.72 (m, 2H), 4.29 (s, 2H), 4.15-4.00 (m, 1H), 3.51 (br t, J = 12.0 Hz, 2H), 3.20-3.18 (m, 2H), 2.69-2.68 (m,2H), 2.23-2.22 (m, 2H), 2.16-2.12 (m, 4H), 1.93-1.88 (m, 4H), 1.71-1.60 (m,2H); LCMS (ESI, M+1): m / z = 610.4.

[0238] Example 12

[0239]

[0240] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid 2,4,6-trifluorophenyl ester

[0241]

[0242] Step A. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine Methyl pyrimidin-4-yl)piperidine-4-carboxylate K3PO4 (2.40 g, 3.0 equivalent) and methyl piperidine-4-carboxylate (1.62 g, 3.0 equivalent) were added to a solution of 8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.00 g, 1.0 equivalent) in DMAC (20 mL). The reaction was stirred at 60 °C for 1 h. The mixture was filtered, concentrated, and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (2.07 g, 92% yield) as a white solid; LCMS (ESI, M+1): m / z = 574.3.

[0243] Step B. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine Aceto[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acidLiOH was added to a solution of methyl 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylate (2.07 g, 1.0 equivalent) in MeOH (21 mL). H2O (757 mg, 5.0 equivalents) and H2O (7 mL). The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (1.49 g, 68% yield) as a white solid; LCMS (ESI, M+1): m / z = 560.3.

[0244] Step C. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine 2,4,6-trifluorophenyl ester of pyrimidin-4-yl)piperidin-4-carboxylic acid DMAP (26.2 mg, 1.5 equivalent) and EDCI (41.1 mg, 1.5 equivalent) were added to a solution of 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (80.0 mg, 1.0 equivalent) and 2,4,6-trifluorophenol (63.5 mg, 3.0 equivalent) in DCM (2 mL). The reaction was stirred at 30 °C for 1 hour. The mixture was concentrated and purified by preparative HPLC [column: Welch Ultimate XB-SiOH 250 × 50 mm × 10 µm; A: hexane, B: EtOH, B%: 5%–45% B, 15 min] and preparative HPLC [column: Welch Ultimate C18 150 × 25 mm × 5 µm; A: water (FA), B: ACN, B%: 25%–55% B, 10 min] to give the title compound (3.52 mg, 3.3% yield) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 9.06 (s, ¹H), 8.01 (brd, J = 7.6 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.69-7.57 (m, 2H), 7.47 (dt, J = 4.8, 8.0 Hz, 1H), 7.14 (dd, J = 7.6, 12.8 Hz, 1H), 6.90-6.74 (m, 2H), 4.55(br dd, J= 4.0, 13.2 Hz, 2H), 4.36 (s, 2H), 3.77-3.57 (m, 2H), 3.34-3.22 (m,2H), 3.20-3.05 (m, 1H), 2.83-2.64 (m, 2H), 2.44-2.28 (m, 2H), 2.27-2.09 (m,4H), 2.07-1.87 (m, 4H), 1.83-1.66 (m, 2H); LCMS (ESI, M+1): m / z = 690.3.

[0245] Example 13

[0246]

[0247] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid 2,4-difluorophenyl ester

[0248]

[0249] Step A. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine 2,4-difluorophenyl ester of pyrimidin-4-yl)piperidin-4-carboxylic acid To a solution of 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 2,4-difluorophenol (34.9 mg, 3.0 equivalent) in DCM (1 mL), DMAP (16.4 mg, 1.5 equivalent) and EDCI (25.7 mg, 1.5 equivalent) were added. The reaction was stirred at 30 °C for 1 hour. The mixture was quenched with water (5.0 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were concentrated and purified by preparative TLC (dichloromethane:methanol = 8 / 1) and preparative HPLC [column: Welch Xtimate C18 150 × 25 mm × 5 µm; A: water (FA), B: ACN, B%: 23%–53% B, 10 min] to give the title compound (2.19 mg, 3.6% yield) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 9.05 (s, ¹H), 8.05–7.95 (m, ¹H), 7.75 (d, ¹H) J= 8.0 Hz, 1H), 7.68-7.57 (m, 2H), 7.50-7.41 (m, 1H), 7.18-7.07 (m,2H), 7.01-6.84 (m, 2H), 4.55 (br dd, J = 4.4, 9.2 Hz, 2H), 4.39-4.23 (m, 2H), 3.68-3.54 (m, 2H), 3.29-3.01 (m, 3H), 2.77-2.61 (m, 2H), 2.38-2.25 (m, 2H), 2.24-2.07 (m, 4H), 1.96-1.87 (m, 4H), 1.74-1.66 (m, 2H); LCMS (ESI, M+1): m / z= 672.3.

[0250] Example 14

[0251]

[0252] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid 4-fluorophenyl ester

[0253]

[0254] step A. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyr 4-fluorophenyl ester of pyrimidin-4-yl)piperidine-4-carboxylic acidTo a solution of 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (200 mg, 1.0 equivalent) and 4-fluorophenol (80.1 mg, 2.0 equivalent) in DCM (2 mL), DMAP (65.5 mg, 1.5 equivalent) and EDCI (103 mg, 1.5 equivalent) were added. The reaction was stirred at 30 °C for 1 hour. The mixture was quenched with water (5.0 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were concentrated and purified by preparative HPLC [column: Phenomenexluna C18 150 × 25 mm × 10 µm; A: water (FA), B: ACN, B%: 30%–60% B, 9 min], preparative TLC (dichloromethane:methanol = 8 / 1), and preparative HPLC [column: Welch Xtimate C18 150 × 25 mm × 5 µm; A: water (FA), B: ACN, B%: 20%–50% B, 10 min] to give the title compound (2.88 mg, 1.2% yield) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 9.05 (s, ¹H), 8.00 (brd, J = 7.6 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.68-7.59 (m, 2H), 7.45 (dt, J = 4.8, 8.0 Hz, 1H), 7.13 (br d, J = 12.4 Hz, 1H), 7.09 (d, J = 2.4 Hz, 2H),7.08 (s, 2H), 4.66-4.54 (m, 2H), 4.34 (s, 2H), 3.63-3.49 (m, 2H), 3.32-3.19(m, 2H), 3.07-2.95 (m, 1H), 2.70 (td, J = 7.2, 10.4 Hz, 2H), 2.30 (br dd, J=2.8, 13.6 Hz, 2H), 2.22-2.07 (m, 5H), 1.95-1.91 (m, 4H), 1.78-1.69 (m, 2H); LCMS (ESI, M+1): m / z = 654.2.

[0255] Example 15

[0256]

[0257] 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxaldehyde

[0258]

[0259] Step A. 4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol DIEA (131 mg, 3.0 equivalent) was added to a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (200 mg, 1.0 equivalent), 4-(dimethoxymethyl)piperidine (161 mg, 3.0 equivalent), and 4Å molecular sieve (20 mg) in DMF (1 mL). The reaction was stirred at 60 °C for 2 h. The mixture was filtered and the filtrate was purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (150 mg, 65% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 652.4.

[0260] Step B. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolazine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxaldehydeTFA (420 mg, 20 equivalents) was added to a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (120 mg, 1 equivalent) in DCM (100 μL). The reaction was stirred at 25 °C for 2 hours. The mixture was concentrated. The residue was diluted with saturated NaHCO3 aqueous solution (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [YMC Triart 30 × 150 mm × 7 µm; A: water (FA); B: ACN, B%: 25%–55%, 8 min] and preparative HPLC [C18 150 × 30 mm; A: water (FA); B: ACN, B%: 20%–50%, 7 min] to give the title compound (85.0 mg, 75% yield, HCOOH salt) as a white solid. 1 HNMR (400 MHz, methanol-d4) δ 9.09–9.02 (m, 1H), 7.68 (dd, J = 5.6, 8.8 Hz, 1H),7.33-7.29 (m, 1H), 7.28-7.21 (m, 1H), 7.08-7.03 (m, 1H), 5.51-5.30 (m, 1H),4.79-4.68 (m, 2H), 4.51-4.38 (m, 2H), 4.38-4.32 (m, 1H), 3.61-3.37 (m, 5H), 3.24-3.14 (m, 1H), 2.56-2.33 (m, 3H), 2.29-2.08 (m, 4H), 2.07-1.88 (m, 4H),1.69-1.53 ​​(m, 2H), 0.85-0.76 (m, 3H); LCMS (ESI, M+1): m / z = 606.3.

[0261] Example 16

[0262]

[0263] 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid methyl ester

[0264]

[0265] Step A. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid methyl ester DIEA (65.4 mg, 3.0 equivalent) was added to a mixture of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (100 mg, 1.0 equivalent), methyl piperidinium-4-carboxylate (48.3 mg, 2.0 equivalent), and 4Å molecular sieve (20 mg) in DMSO (1 mL). The reaction was stirred at 40 °C for 12 h. The mixture was filtered and the filtrate was purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] and preparative HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3), B: ACN, B: 48%–78%, 9 min] to give the title compound (22.4 mg, 21% yield) as a white solid. 1 HNMR (400 MHz, methanol-d4) δ 9.04 (s, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.30(d, J = 2.4 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H),5.40-5.21 (m, 1H), 4.64-4.53 (m, 2H), 4.35-4.22 (m, 2H), 3.72 (s, 3H), 3.67-3.54 (m, 2H), 3.29-3.16 (m, 3H), 3.06-2.97 (m, 1H), 2.91-2.81 (m, 1H), 2.54-2.40 (m, 1H), 2.39-2.09 (m, 6H), 2.04-1.84 (m, 5H), 0.85-0.74 (m, 3H); LCMS(ESI, M+1): m / z = 636.4.

[0266] Example 17

[0267]

[0268] (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carbaldehyde

[0269]

[0270] Step A. (1R,5S,8r)-3-((benzyloxy)carbonyl)-3-azabicyclic[3.2.1]octyl-8-carboxylic acid: At 0 °C, Cb2Cl (1.07 g, 1.2 equivalent) was added to a mixture of (1R,5S,8r)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid (780 mg, 1.0 equivalent) and NaOH (221 mg, 1.1 equivalent) in H2O (10.0 mL). The reaction was stirred at 0–10 °C for 16 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated, and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (503 mg, 20% yield) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform-d): δ = 7.37–7.30 (m, 5H), 5.14 (s, 2H), 4.72 (s, 1H), 4.07–3.88 (m, 2H), 3.05–2.91 (m, 2H), 2.69–2.56 (m, 2H), 1.88–1.75 (m, 2H), 1.65–1.45 (m, 2H); LCMS (ESI, M+1): m / z = 290.0

[0271] Step B. (1R,5S,8r)-8-(hydroxymethyl)-3-azabicyclo[3.2.1] octyl-3-carboxylic acid benzyl ester: At 0 °C, BH3 was added to a solution of (1R,5S,8r)-3-((benzyloxy)carbonyl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid (300 mg, 1.0 equivalent) in THF (3.00 mL). Me₂S (10 M, 3.0 equivalents). The reaction was stirred at 0 °C for 2 h. The mixture was quenched with MeOH (5.00 mL) and concentrated under vacuum. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated, and purified by preparative HPLC [column: YMC-GelSiL-HG 250 mm × 70 mm × 10 µm; A: hexane, B: EtOH, B%: 5%–45%, 15 min] to give the title compound (190 mg, 60% yield) as a colorless oil; LCMS (ESI, M+1): m / z = 276.1

[0272] Step C. ((1R,5S,8r)-3-azabicyclo[3.2.1]oct-8-yl)methanol: Under a nitrogen atmosphere, Pd / C (20 mg, 10% purity) was added to a solution of (1R,5S,8r)-8-(hydroxymethyl)-3-azabicyclo[3.2.1]octyl-3-carboxylic acid benzyl ester (170 mg, 1.0 equivalent) in MeOH (5.00 mL). The suspension was degassed and purged three times with H2. The reaction was stirred at 30 °C for 2 hours under H2 (15 Psi). The mixture was filtered and concentrated to give the title compound (60 mg, crude) as a white solid; LCMS (ESI, M+1): m / z = 142.1

[0273] Step D. ((1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazine-7a(5H)- (3,2,1) methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-8-yl)methanol: K3PO4 (156 mg, 3.0 equivalent) and 4 Å molecular sieve (20 mg) were added to a mixture of 8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (130 mg, 1.0 equivalent) and ((1R,5S,8r)-3-azabicyclo[3.2.1]oct-8-yl)methanol (51.9 mg, 1.5 equivalent) in DMF (3.00 mL). The reaction was stirred at 40 °C for 2 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (45 mg, 30% yield) as a white solid; LCMS (ESI, M+1): m / z = 572.4

[0274] Step E. (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazine-7a(5H)- (4,3-d)pyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-8-carbaldehyde:At 0 °C, DMP (22.3 mg, 1.5 equivalents) was added to a solution of ((1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-8-yl)methanol (20.0 mg, 1.0 equivalent) in DCM (1.00 mL). The reaction was stirred at 0 °C for 2 hours. The mixture was quenched with saturated NaHCO3 solution (10.0 mL) and extracted with ethyl acetate (2 × 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (7.41 mg, 33% yield, CF3COOH salt) as a white solid. 1 ¹H NMR (400 MHz, methanol-d⁴) δ = 9.07 (s, ¹H), 8.11 (br d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.74-7.67 (m, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.53 (dt, J = 5.2, 8.0 Hz, 1H), 7.25-7.14 (m, 1H), 4.83-4.70(m, 2H), 4.40 (s, 2H), 4.25 (d, J = 8.4 Hz, 1H), 3.68-3.55 (m, 2H), 2.97-2.84(m, 2H), 2.50 (br s, 2H), 2.23-2.11 (m, 2H), 2.11-1.93 (m, 5H), 1.92-1.82 (m,2H), 1.82-1.72 (m, 2H), 1.65-1.52 (m, 2H); LCMS (ESI, M+1): m / z = 570.3.

[0275] Example 18

[0276]

[0277] (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid 2,2,2-trifluoroethyl ester

[0278]

[0279] Step A. (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazine-7a(5H)- 2,2,2-trifluoroethyl pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-8-carboxylic acid DMAP (15.6 mg, 1.5 eq) and EDCI (24.5 mg, 1.5 eq) were added to a solution of (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid (50.0 mg, 1.0 eq) and 2,2,2-trifluoroethanol (25.6 mg, 3.0 eq) in DCM (1 mL). The reaction was stirred at 30 °C for 2 h. The reaction mixture was concentrated and purified by preparative HPLC [Phenomenex Luna C18 150 × 25 mm × 10 µm; A: water (TFA); B: ACN; B%: 15%–45%, 9 min]. The desired fraction was collected. The mixture was adjusted to pH 7 with saturated NaHCO3 (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by preparative HPLC [Phenomenex Luna C18 150 × 25 mm × 10 µm; A: water (FA); B: ACN; B%: 28%–58%, 9 min] to give the title compound (19.1 mg, 31% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.22-9.08 (m, 1H), 8.19 (dd, J = 8.0 Hz, 1H), 7.94 (t, J = 7.6 Hz, 1H), 7.81-7.71(m, 1H), 7.68-7.55 (m, 2H), 7.36-7.27 (dd, J = 7.2, 13.2 Hz, 2H), 4.82 (q, J = 9.2 Hz, 2H), 4.63 (br d, J = 10.0 Hz, 2H), 4.13 (s, 2H), 3.68 (br d, J=12.8 Hz, 2H), 3.15 (s, 1H), 3.07-2.92 (m, 2H), 2.74 (br s, 2H), 2.67-2.60 (m,2H), 2.00-1.89 (m, 2H), 1.88-1.74 (m, 4H), 1.74-1.50 (m, 6H); LCMS (ESI, M+1): m / z = 668.4.

[0280] Example 19

[0281]

[0282] (1R,5S,8s)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]methyl octyl-8-carboxylate

[0283]

[0284] Step A. (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazine-7a(5H)- Methyl octyl-8-carboxylate (4,3-d)pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylate DMAP (28.2 mg, 1.5 equivalent) was added to a solution of (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid (90 mg, 1.0 equivalent), 4-hydroxybenzyl nitrile (36.6 mg, 2.0 equivalent), and EDCI (44.2 mg, 1.5 equivalent) in DCM (2.00 mL). The reaction was stirred at 40 °C for 1 hour. MeOH (1 mL, 160 equivalent) was added to the mixture. The reaction was stirred at 60 °C for 2 hours. The mixture was diluted with water (30 mL) and extracted with DCM (2 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated, and purified by preparative HPLC [column: Welch Ultimate XB-SiOH 250 × 50 × 10 µm; A: hexane-EtOH; B: 10%–50%, 15 min] to give the title compound (23.7 mg, 25% yield) as a white solid. 1 ¹H NMR (400 MHz, methanol-d⁴) δ = 9.14–9.07 (m, ¹H), 8.18 (br d, J = 8.4 Hz, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.77-7.70 (m, 1H), 7.65-7.62 (m,1H), 7.58 (dt, J = 5.2, 8.0 Hz, 1H), 7.31 (dd, J = 7.6, 13.2 Hz, 1H), 4.59(br d, J = 12.4 Hz, 2H), 4.07 (s, 2H), 3.64 (s, 4H), 3.62 (s, 1H), 2.99-2.91(m, 3H), 2.70 (br s, 2H), 2.61-2.52 (m, 2H), 1.96-1.86 (m, 2H), 1.85-1.71 (m,4H), 1.70-1.64 (m, 2H), 1.59 (br dd, J = 7.2, 12.4 Hz, 2H), 1.55-1.47 (m,2H); LCMS (ESI, M+1): m / z = 600.3.

[0285] Example 20

[0286]

[0287] (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid 4-cyanophenyl ester

[0288]

[0289] Step A. (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazine-7a(5H)- 4-cyanophenyl octyl-8-carboxylic acid ester (4,3-d)pyrimidin-4-yl)-3-azabicyclo[3.2.1]EDCI (24.6 mg, 1.5 equivalent) was added to a solution of (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid (50 mg, 1.0 equivalent), 4-hydroxybenzyl nitrile (30.5 mg, 3.0 equivalent), and DMAP (15.6 mg, 1.5 equivalent) in DCM (1.00 mL). The reaction was stirred at 10 °C for 16 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex Luna C18 150 × 25 mm × 10 µm; A: water (TFA), B: ACN, B%: 30%–60%, 9 min] to give the title compound (25.5 mg, 42% yield) as a white solid. 1 ¹H NMR (400 MHz, methanol-d⁴) (400 MHz, DMSO-d⁶) δ = 9.15 (s, ¹H), 8.18 (br d, J = 8.4 Hz, 1H),7.99-7.90 (m, 3H), 7.78-7.70 (m, 1H), 7.66-7.62 (m, 1H), 7.61-7.55 (m, 1H),7.45-7.39 (m, 2H), 7.31 (dd, J = 7.2, 13.2 Hz, 1H), 4.66 (br d, J = 12.0 Hz,2H), 4.07 (s, 2H), 3.71 (br d, J = 12.4 Hz, 2H), 2.93 (td, J LCMS (ESI, M+1): m / z = 687.3.

[0290] Example 21

[0291]

[0292] (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid 2-cyanophenyl ester

[0293]

[0294] Step A. (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazine-7a(5H)- 2-Cyanophenyl octyl-8-carboxylic acid ester (Pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid ester To a solution of (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid (50.0 mg, 1.0 eq) and 2-hydroxybenzyl nitrile (30.5 mg, 3.0 eq) in DCM (1 mL), DMAP (15.6 mg, 1.5 eq) and EDCI (24.5 mg, 1.5 eq) were added. The reaction was stirred at 30 °C for 2 h. The mixture was concentrated and purified by preparative HPLC [Phenomenex Luna C18 150 × 25 mm × 10 µm; A: water (TFA); B: ACN; B%: 32%–62%, 9 min], followed by purification by preparative HPLC [Phenomenex Luna C18 150 × 25 mm × 10 µm; A: water (FA); B: ACN; B%: 33%–53%, 10 min] to give the title compound (11.0 mg, 18% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.20 (s, 1H), 8.19 (br d, J = 8.8 Hz,1H), 8.01-7.92 (m, 2H), 7.83 (m, 1H), 7.78-7.71 (t, J = 7.6 Hz, 1H), 7.68-7.56 (m, 2H), 7.55-7.46 (m, 2H), 7.32 (dd, J = 7.2, 13.2 Hz, 1H), 4.89-4.59(m, 2H), 4.53-4.32 (m, 2H), 3.78 (br t, JLCMS (ESI, M+1): m / z = 687.3.

[0295] Example 22

[0296]

[0297] (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid 3-cyanophenyl ester

[0298]

[0299] Step A. (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazine-7a(5H)- 3-cyanophenyl octyl-8-carboxylic acid ester (3.2.1)-(methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid ester DMAP (15.6 mg, 1.5 eq) and EDCI (24.5 mg, 1.5 eq) were added to a solution of (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid (50.0 mg, 1.0 eq) and 3-hydroxybenzyl nitrile (30.5 mg, 3.0 eq) in DCM (1 mL). The reaction was stirred at 30 °C for 2 h. The mixture was concentrated and purified by preparative HPLC [Phenomenex Luna C18 150 × 25 mm × 10 µm; A: water (TFA); B: ACN; B%: 30%–60%, 9 min] and preparative HPLC [Phenomenex Luna C18 150 × 25 mm × 10 µm; A: water (FA); B: ACN; B%: 25%–55%, 10 min], and then purified by preparative HPLC [YMC-Actus Triart C18 150 × 30 mm × 7 µm; A: water (FA); B: ACN; B%: 30%–60%, 10 min] to give the title compound (14.5 mg, 24% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.15 (s, 1H), 8.18 (brd, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.84-7.71 (m, 3H), 7.69-7.62(m, 2H), 7.61-7.53 (m, 2H), 7.32 (dd, J = 7.2, 13.2 Hz, 1H), 4.66 (br d, J =10.8 Hz, 2H), 4.10 (s, 2H), 3.72 (br d, J = 12.4 Hz, 2H), 3.30 (s, 1H), 3.01-2.92 (m, 2H), 2.87 (br s, 2H), 2.58 (td, J = 6.8, 9.8 Hz, 2H), 1.91 (m, 2H), 1.87-1.73 (m, 6H), 1.66-1.55 (m, 4H); LCMS (ESI, M+1): m / z = 687.3.

[0300] Example 23

[0301]

[0302] (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid 3,4-difluorophenyl ester

[0303]

[0304] Step A. (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazine-7a(5H)- 3,4-difluorophenyl octyl-8-carboxylic acid ester (3,2.1)-methoxy-pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acidEDCI (54.0 mg, 1.5 equivalent) was added to a solution of (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid (110 mg, 1.0 equivalent), 3,4-difluorophenol (48.9 mg, 2.0 equivalent), and DMAP (34.4 mg, 1.5 equivalent) in DCM (1.00 mL). The reaction was stirred at 40 °C for 1 hour. The mixture was diluted with water (20 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by preparative TLC (dichloromethane:methanol = 8 / 1), followed by purification by preparative HPLC [column: YMC Triart C18 150 × 25 mm × 5 µm; A: water (FA), B: ACN, B%: 32%–62%, 2 min] to give the title compound (2.90 mg, 2% yield, HCOOH salt) as a white solid. 1 ¹H NMR (400 MHz, methanol-d⁴) δ = 9.06 (s, ¹H), 8.00 (br d, J =7.6 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.67-7.58 (m, 2H), 7.50-7.42 (m, 1H), 7.24-7.17 (m, 1H), 7.17-7.09 (m, 1H), 7.03-6.95 (m, 1H), 6.88-6.82 (m, 1H),4.91-4.80 (m, 1H), 4.80-4.71 (m, 1H), 4.28 (br s, 2H), 3.67-3.51 (m, 2H),3.31-3.14 (m, 2H), 3.04 (s, 1H), 2.97-2.86 (m, 2H), 2.77-2.61 (m, 2H), 2.22-2.10 (m, 2H), 1.99-1.88 (m, 6H), 1.80-1.67 (m, 4H); LCMS (ESI, M+1): m / z =698.3.

[0305] Example 24

[0306]

[0307] (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid 2,6-difluorophenyl ester

[0308]

[0309] Step A. (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazine-7a(5H)- 2,6-difluorophenyl octyl-8-carboxylic acid ester (2,6-difluorophenyl ester) of pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid EDCI (24.5 mg, 1.5 equivalent) was added to a solution of (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid (50.0 mg, 1.0 equivalent), 2,6-difluorophenol (33.3 mg, 3.0 equivalent), and DMAP (15.6 mg, 1.5 equivalent) in DCM (1.00 mL). The reaction was stirred at 10 °C for 4 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex Luna C18 150 × 25 mm × 10 µm; A: water (TFA), B: ACN, B%: 65%, 9 min] to give the title compound (8.80 mg, 17% yield) as a white solid; 1 ¹H NMR (400 MHz, methanol-d⁴) δ = 9.16 (s, ¹H), 8.13 (br d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H),7.76-7.68 (m, 1H), 7.62 (d, J = 6.4 Hz, 1H), 7.54 (dt, J = 5.2, 8.0 Hz, 1H), 7.32 (tt, J = 6.0, 8.4 Hz, 1H), 7.20 (dd, J = 7.6, 13.2 Hz, 1H), 7.15-7.08(m, 2H), 4.89 (br s, 2H), 4.68 (s, 2H), 3.82 (br d, J= 12.4 Hz, 2H), 3.76-3.65 (m, 2H), 3.41 (s, 1H), 3.30-3.26 (m, 2H), 2.98 (br s, 2H), 2.42-2.32 (m,2H), 2.30-2.07 (m, 6H), 2.03-1.92 (m, 2H), 1.76-1.65 (m, 2H); LCMS (ESI, M+1): m / z = 698.5.

[0310] Example 25

[0311]

[0312] (1R,5S,8s)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid 2-fluorophenyl ester

[0313]

[0314] Step A. (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazine-7a(5H)- 2-fluorophenyl octyl-8-carboxylic acid ester (Pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid ester EDCI (24.5 mg, 1.5 equivalent) was added to a solution of (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid (50.0 mg, 1.0 equivalent), 2-fluorophenol (28.7 mg, 3.0 equivalent), and DMAP (15.6 mg, 1.5 equivalent) in DCM (1.00 mL). The reaction was stirred at 10 °C for 4 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex Luna C18 150 × 25 mm × 10 µm; A: water (TFA), B: ACN, B%: 36%–66%, 9 min] to give the title compound (8.88 mg, 17% yield) as a white solid. 1 ¹H NMR (400 MHz, methanol-d⁴) δ = 9.16 (s, ¹H), 8.13 (d, ¹H) J = 8.4 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.75-7.68(m, 1H), 7.62 (dd, J= 1.2, 7.2 Hz, 1H), 7.54 (dt, J = 5.2, 8.0 Hz, 1H),7.33-7.23 (m, 2H), 7.23-7.17 (m, 3H), 4.91-4.86 (m, 2H), 4.68 (s, 2H), 3.81(br d, J = 12.8 Hz, 2H), 3.76-3.66 (m, 2H), 3.34 (s, 1H), 3.30-3.26 (m, 2H), 2.97 (br s, 2H), 2.41-2.31 (m, 2H), 2.29-2.17 (m, 3H), 2.17-2.07 (m, 3H), 2.02-1.94 (m, 2H), 1.73-1.65 (m, 2H); LCMS (ESI, M+1): m / z = 680.5.

[0315] Example 26

[0316]

[0317] (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1] octyl-8-carboxylic acid phenyl ester

[0318]

[0319] Step A. (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazine-7a(5H)- (4,3-d)pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid Add 8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.40 g, 1.0 equivalent) to a mixture of (1R,5S,8r)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid (1.01 g, 2.0 equivalent, HCl), K3PO4 (1.68 g, 3.0 equivalent), and 4Å molecular sieve (50.0 mg) in DMF (20.0 mL). Stir the reaction mixture at 60 °C for 2 hours. Filter the mixture and test the filtrate by reversed-phase rapid chromatography [C18, 0.1% NH3]. Purification under H2O conditions yielded the title compound (1.1 g, 69% yield) as a brown solid; LCMS (ESI, M+1): m / z = 586.4.

[0320] Step B. (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazine-7a(5H)- phenyl octyl-8-carboxylic acid ester (Pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid ester EDCI (24.5 mg, 1.5 equivalent) was added to a solution of (1R,5S,8r)-3-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid (50.0 mg, 1.0 equivalent), phenol (24.1 mg, 3.0 equivalent), and DMAP (15.6 mg, 1.5 equivalent) in DCM (1.00 mL). The reaction was stirred at 10 °C for 4 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex LunaC18 150 × 25 mm × 10 µm; A: water (TFA), B: ACN, B%: 35%–65%, 9 min] to give the title compound (10.0 mg, 18% yield) as a white solid. 1 ¹H NMR (400 MHz, methanol-d⁴) δ = 9.15 (s, ¹H), 8.13 (br d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.74-7.68 (m,1H), 7.62 (d, J = 6.4 Hz, 1H), 7.54 (dt, J = 5.2, 8.0 Hz, 1H), 7.45-7.38 (m,2H), 7.29-7.24 (m, 1H), 7.20 (dd, J = 7.6, 12.8 Hz, 1H), 7.10 (d, J = 8.0 Hz,2H), 4.90-4.86 (m, 2H), 4.62 (s, 2H), 3.79 (br d, J = 12.8 Hz, 2H), 3.66-3.56(m, 2H), 3.28 (s, 1H), 3.25-3.17 (m, 2H), 2.95 (br s, 2H), 2.37-2.27 (m, 2H), 2.25-2.01 (m, 6H), 1.99-1.90 (m, 2H), 1.73-1.63 (m, 2H); LCMS (ESI, M+1): m / z= 662.6.

[0321] Example 27

[0322]

[0323] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid 2-cyanophenyl ester

[0324] Step A. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d] (Pyrimidin-4-yl)piperidine-4-carboxylic acid To a mixture of 8-fluoro-7-(8-fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolazin-8-ylmethoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equivalent) and 4 Å molecular sieve (100 mg) in DMF (3.0 mL), K3PO4 (600 mg, 5.0 equivalent) and piperidine-4-carboxylic acid (281 mg, 3.0 equivalent, HCl) were added. The reaction was stirred at 60 °C for 1.5 h. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by preparative TLC [petroleum ether / ethyl acetate = 3 / 1] to give the title compound (250 mg, 72% yield) as a white solid; LCMS (ESI, M+1): m / z = 560.3.

[0325] Step B. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid 2-cyanophenyl ester DMAP (16.4 mg, 1.5 equivalent) and EDCI (25.7 mg, 1.5 equivalent) were added to a mixture of 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 2-hydroxybenzyl nitrile (31.9 mg, 3.0 equivalent) in DCM (2.00 mL). The reaction was stirred at 25 °C for 4 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 37%–67% B, 9 min] to give the title compound (9.96 mg, 14.6% yield) as a beige solid; 1HNMR (400 MHz, DMSO-d6) δ = 10.26 (br s, 1H), 9.19 (s, 1H), 8.20 (br d, J =8.4 Hz, 1H), 7.96 (t, J = 8.4 Hz, 2H), 7.83 (t, J = 8.0 Hz, 1H), 7.76 (t, J =7.6 Hz, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.60 (br d, J = 5.2 Hz, 1H), 7.54-7.49(m, 2H), 7.32 (dd, J = 7.6, 13.1 Hz, 1H), 4.58 (s, 4H), 3.73-3.64 (m, 2H), 3.52 (br dd, J = 5.6, 11.6 Hz, 2H), 3.26-3.18 (m, 2H), 2.33-2.27 (m, 2H),2.19 (br dd, J = 5.6, 11.6 Hz, 2H), 2.10 (br d, J = 6.4 Hz, 2H), 2.07-1.94(m, 7H); LCMS (ESI, M+1): m / z =661.3.

[0326] Example 28

[0327]

[0328] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid 3-cyanophenyl ester

[0329]

[0330] Step A. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acidK3PO4 (600 mg, 5.0 equivalent) and piperidine-4-carboxylic acid (281 mg, 3.0 equivalent, HCl) were added to a mixture of 8-fluoro-7-(8-fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolazin-8-ylmethoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equivalent) and 4 Å molecular sieve (100 mg) in DMF (3.00 mL). The reaction was stirred at 60 °C for 1.5 h. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by preparative TLC [petroleum ether / ethyl acetate = 3 / 1] to give the title compound (250 mg, 72% yield) as a white solid; LCMS (ESI, M+1): m / z = 560.3.

[0331] Step B. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid 3-cyanophenyl ester DMAP (16.4 mg, 1.5 equivalent) and EDCI (25.7 mg, 1.5 equivalent) were added to a mixture of 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 3-hydroxybenzyl nitrile (31.9 mg, 3.0 equivalent) in DCM (2.00 mL). The reaction was stirred at 25 °C for 4 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 25%-55% B, duration 10 min] and preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 37%-67% B, duration 9 min] to give the title compound (7.3 mg, 11% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 10.23 (br s, 1H), 9.18(s, 1H), 8.20 (br d, J = 8.4 Hz, 1H), 7.95 (d, J= 8.0 Hz, 1H), 7.81-7.73 (m,3H), 7.70-7.63 (m, 2H), 7.62-7.54 (m, 2H), 7.32 (s, 1H), 4.57 (s, 2H), 3.28-3.16 (m, 4H), 2.27-1.97 (m, 13H), 1.23 (br s, 2H), 1.05 (t, J = 7.2 Hz, 2H); LCMS (ESI, M+1): m / z =661.4.

[0332] Example 29

[0333]

[0334] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid 4-cyanophenyl ester

[0335]

[0336] Step A. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid K3PO4 (600 mg, 5.0 equivalent) and piperidine-4-carboxylic acid (281 mg, 3.0 equivalent, HCl) were added to a mixture of 8-fluoro-7-(8-fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolazin-8-ylmethoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equivalent) and 4 Å molecular sieve (100 mg) in DMF (3.0 mL). The reaction was stirred at 60 °C for 1.5 h. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over Na₂SO₄, concentrated, and purified by preparative TLC [petroleum ether / ethyl acetate = 3 / 1] to give the title compound (250 mg, 72% yield) as a white solid; LCMS (ESI, M+1): m / z = 560.3

[0337] Step B. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid 4-cyanophenyl esterDMAP (16.4 mg, 1.5 equivalent) and EDCI (25.7 mg, 1.5 equivalent) were added to a mixture of 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 4-hydroxybenzyl nitrile (31.9 mg, 3.0 equivalent) in DCM (2.00 mL). The reaction was stirred at 25 °C for 4 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 36%-66% B, 9 min] to give the title compound (20.3 mg, 33% yield) as a beige solid; 1 H NMR(400 MHz, DMSO-d6) δ = 10.24 (br s, 1H), 9.18 (s, 1H), 8.20 (br d, J = 8.8Hz, 1H), 7.98-7.93 (m, 3H), 7.75 (d, J = 8.0 Hz, 1H), 7.66-7.57 (m, 2H), 7.42(d, J = 8.4 Hz, 2H), 7.32 (dd, J = 7.6, 13.1 Hz, 1H), 4.60-4.53 (m, 4H), 3.69-3.45 (m, 4H), 2.33-2.22 (m, 3H), 2.18 (br dd, J = 5.6, 11.4 Hz, 2H),2.10 (br d, J = 6.4 Hz, 2H), 2.07-1.93 (m, 8H); LCMS (ESI, M+1): m / z =661.3.

[0338] Example 30

[0339]

[0340] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid 2,6-difluorophenyl ester

[0341] Step A. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d] (Pyrimidin-4-yl)piperidine-4-carboxylic acid To a mixture of 8-fluoro-7-(8-fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolazin-8-ylmethoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equivalent) and 4 Å molecular sieve (100 mg) in DMF (3.0 mL), K3PO4 (600 mg, 5.0 equivalent) and piperidine-4-carboxylic acid (281 mg, 3.0 equivalent, HCl) were added. The reaction was stirred at 60 °C for 1.5 h. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by preparative TLC [petroleum ether / ethyl acetate = 3 / 1] to give the title compound (250 mg, 72% yield) as a white solid; LCMS (ESI, M+1): m / z = 560.3.

[0342] Step B. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid 2,6-difluorophenyl ester DMAP (16.4 mg, 1.5 equivalent) and EDCI (25.7 mg, 1.5 equivalent) were added to a mixture of 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 2,6-difluorophenol (34.8 mg, 3.0 equivalent) in DCM (2.0 mL). The reaction was stirred at 25 °C for 4 hours. The reaction mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 27%-57% B, duration 10 min] and preparative HPLC [column: Phenomenex luna C18 150 × 40 mm × 15 μm; mobile phase: [water (TFA)-ACN]; gradient: 35%-65% B, duration 10 min] to give the title compound (5.6 mg, 9% yield) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ = 10.21 (br s,1H), 9.19 (s, 1H), 8.20 (br d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.76 (t, J= 7.6 Hz, 1H), 7.67-7.56 (m, 2H), 7.45-7.37 (m, 1H), 7.36-7.28 (m,3H), 4.61-4.51 (m, 4H), 3.43 (s, 2H), 3.22 (br dd, J = 4.4, 11.2 Hz, 2H),2.34-2.23 (m, 3H), 2.18 (br dd, J = 6.0, 11.6 Hz, 2H), 2.15-2.08 (m, 2H), 2.04-1.95 (m, 6H), 1.07-1.03 (m, 2H); LCMS (ESI, M+1): m / z =672.3.

[0343] Example 31

[0344]

[0345] 2,2,2-trifluoroethyl 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid

[0346]

[0347] Step A. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid K3PO4 (600 mg, 5.0 equivalent) and piperidine-4-carboxylic acid (281 mg, 3.0 equivalent, HCl) were added to a mixture of 8-fluoro-7-(8-fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolazin-8-ylmethoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equivalent) and 4 Å molecular sieve (100 mg) in DMF (3.00 mL). The reaction was stirred at 60 °C for 1.5 h. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by preparative TLC [petroleum ether / ethyl acetate = 3 / 1] to give the title compound (250 mg, 72% yield) as a white solid; LCMS (ESI, M+1): m / z = 560.3.

[0348] Step B. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid 2,2,2-trifluoroethyl esterDMAP (16.37 mg, 1.5 equivalent) and EDCI (25.69 mg, 1.5 equivalent) were added to a mixture of 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 2,2,2-trifluoroethanol (26.8 mg, 3.0 equivalent) in DCM (2.0 mL). The reaction was stirred at 25 °C for 4 hours. The reaction mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 24%-54% B, 10 min] to give the title compound (16.7 mg, 28% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.09 (s, 1H), 8.25 (s, 1H), 8.18(br d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.79-7.70 (m, 1H), 7.66-7.54 (m, 2H), 7.31 (dd, J = 7.6, 13.2 Hz, 1H), 4.80 (q, J = 9.2 Hz, 2H), 4.46(br d, J = 13.2 Hz, 2H), 4.08 (s, 2H), 3.52 (br t, J LCMS (ESI, M+1): m / z =642.3.

[0349] Example 32

[0350]

[0351] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid pyridin-3-yl ester

[0352]

[0353] Step A. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid To a mixture of 8-fluoro-7-(8-fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolazin-8-ylmethoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equivalent) and 4 Å molecular sieve (100 mg) in DMF (3.0 mL), K3PO4 (600 mg, 5.0 equivalent) and piperidine-4-carboxylic acid (281 mg, 3.0 equivalent, HCl) were added. The reaction was stirred at 60 °C for 1.5 h. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over Na₂SO₄, concentrated, and purified by preparative TLC [petroleum ether / ethyl acetate = 3 / 1] to give the title compound (250 mg, 72% yield) as a white solid; LCMS (ESI, M+1): m / z = 560.3

[0354] Step B. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid pyridin-3-yl ester DMAP (16.4 mg, 1.5 equivalent) and EDCI (25.7 mg, 1.5 equivalent) were added to a mixture of 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (50.0 mg, 1.0 equivalent) and pyridine-3-ol (25.49 mg, 3.0 equivalent) in DCM (2.0 mL). The reaction was stirred at 25 °C for 4 hours. The reaction mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 28%-58% B, 10 min] to give the title compound (27.4 mg, 47% yield) as a white solid. 1 HNMR (400 MHz, DMSO-d6) δ = 9.19 (s, 1H), 8.55-8.45 (m, 2H), 8.20 (br d, J =8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.79-7.73 (m, 1H), 7.72-7.56 (m, 4H), 7.52 (dd, J= 4.8, 8.4 Hz, 1H), 7.32 (dd, J = 7.6, 13.2 Hz, 1H), 4.60-4.54(m, 4H), 3.66 (br d, J = 13.2 Hz, 2H), 3.52 (br d, J = 5.6 Hz, 2H), 2.27 (brd, J = 11.0 Hz, 3H), 2.18 (br dd, J = 5.6, 11.2 Hz, 2H), 2.10 (br d, J = 6.4Hz, 2H), 2.06-1.97 (m, 7H); LCMS (ESI, M+1): m / z =637.3.

[0355] Example 33

[0356]

[0357] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid 3,5-difluorophenyl ester

[0358]

[0359] Step A. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid To a mixture of 8-fluoro-7-(8-fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolazin-8-ylmethoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equivalent) and 4 Å molecular sieve (100 mg) in DMF (3.0 mL), K3PO4 (600 mg, 5.0 equivalent) and piperidine-4-carboxylic acid (281 mg, 3.0 equivalent, HCl) were added. The reaction was stirred at 60 °C for 1.5 h. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over Na₂SO₄, concentrated, and purified by preparative TLC [petroleum ether / ethyl acetate = 3 / 1] to give the title compound (250 mg, 72% yield) as a white solid; LCMS (ESI, M+1): m / z = 560.3

[0360] Step B. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid 3,5-difluorophenyl esterTo a solution of 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 3,5-difluorophenol (34.9 mg, 3.0 equivalent) in DCM (2.00 mL), DMAP (16.37 mg, 1.5 equivalent) and EDCI (25.69 mg, 1.5 equivalent) were added. The reaction was stirred at 25 °C for 4 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 30%-60% B, 10 min] to give the title compound (8.30 mg, 14% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.11 (s, 1H), 8.31 (s, 1H), 8.18 (br d, J = 8.0Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.78-7.70 (m, 1H), 7.65-7.56 (m, 2H), 7.31(dd, J = 7.6, 13.2 Hz, 1H), 7.26-7.18 (m, 1H), 7.09 (dd, J = 2.0, 7.6 Hz,2H), 4.49 (br d, J = 13.2 Hz, 2H), 4.08 (s, 2H), 3.64-3.57 (m, 2H), 3.19-3.10(m, 2H), 2.96-2.91 (m, 2H), 2.21 (br dd, J = 3.2, 13.2 Hz, 2H), 2.05-1.97 (m,2H), 1.93-1.87 (m, 2H), 1.78 (td, J = 6.0, 12.0 Hz, 4H), 1.59 (br dd, J =7.6, 12.0 Hz, 2H), 1.23 (br s, 1H); LCMS (ESI, M+1): m / z =672.3.

[0361] Example 34

[0362]

[0363] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid 2,3-difluorophenyl ester

[0364] Step A. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4, 3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid K3PO4 (600 mg, 5.0 equivalent) and piperidine-4-carboxylic acid (281 mg, 3.0 equivalent, HCl) were added to a mixture of 8-fluoro-7-(8-fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolazin-8-ylmethoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equivalent) and 4 Å molecular sieve (100 mg) in DMF (3.00 mL). The reaction was stirred at 60 °C for 1.5 h. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by preparative TLC [petroleum ether / ethyl acetate = 3 / 1] to give the title compound (250 mg, 72% yield) as a white solid; LCMS (ESI, M+1): m / z = 560.3.

[0365] Step B. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid 2,3-difluorophenyl ester To a solution of 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (50 mg, 1.0 equivalent) and 2,3-difluorophenol (34.8 mg, 3.0 equivalent) in dichloromethane (2.00 mL), 4-dimethylaminopyridine (16.4 mg, 1.5 equivalent) and EDCI (25.7 mg, 1.5 equivalent) were added. The mixture was stirred at 25 °C for 4 hours. The reaction mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 28%-58% B, 10 min] to give the title compound (14.3 mg, 23% yield) as a yellow solid; 1 H NMR (400 MHz, DMSO-d6) δ = 9.12 (s, 1H), 8.29 (s, 1H), 8.18 (br d, J= 8.4 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.78-7.71 (m, 1H), 7.66-7.56 (m, 2H), 7.48-7.36 (m, 1H), 7.35-7.26 (m, 2H), 7.22 (br dd, J =1.6, 6.8 Hz, 1H), 4.50 (br d, J = 13.6 Hz, 2H), 4.08 (s, 2H), 3.64-3.56 (m,2H), 3.26-3.21 (m, 1H), 2.97-2.91 (m, 2H), 2.24 (br d, J = 10.4 Hz, 2H),2.09-1.72 (m, 10H), 1.59 (br dd, J = 7.6, 12.0 Hz, 2H); LCMS (ESI, M+1): m / z=672.3.

[0366] Example 35

[0367]

[0368] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid 2-fluorophenyl ester

[0369]

[0370] Step A. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido [4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acidK3PO4 (600 mg, 5.0 equivalent) and piperidine-4-carboxylic acid (281 mg, 3.0 equivalent, HCl) were added to a mixture of 8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (300 mg, 1.0 equivalent) and 4Å molecular sieve (100 mg) in DMF (3.00 mL). The reaction was stirred at 60 °C for 1.5 h. The mixture was diluted with H2O (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by preparative TLC [petroleum ether / ethyl acetate = 3 / 1] to give the title compound (250 mg, 72% yield) as a white solid; LCMS (ESI, M+1): m / z = 560.3.

[0371] Step B. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine 2-fluorophenyl ester of pyrimidin-4-yl)piperidine-4-carboxylic acid DMAP (16.4 mg, 1.5 equivalent) and EDCI (25.7 mg, 1.5 equivalent) were added to a solution of 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 2-fluorophenol (30.0 mg, 3.0 equivalent) in dichloromethane (2.0 mL). The reaction was stirred at 25 °C for 4 hours. The mixture was concentrated and purified by preparative HPLC [column: Phenomenex luna C18 250 × 50 mm × 15 μm; mobile phase: [water (FA)-ACN]; gradient: 38%-68% B, 9 min] to give the title compound (11.2 mg, 19% yield) as a white solid. 1 HNMR (400 MHz, DMSO-d6) δ = 9.12 (s, 1H), 8.35 (s, 1H), 8.18 (br d, J = 8.2Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.77-7.72 (m, 1H), 7.64 (dd, J = 0.8, 7.2Hz, 1H), 7.59 (br dd, J = 2.8, 8.0 Hz, 1H), 7.40-7.26 (m, 5H), 4.49 (br d, J= 13.6 Hz, 2H), 4.08 (s, 2H), 3.64-3.58 (m, 2H), 3.21 (br s, 2H), 2.96-2.90(m, 2H), 2.27-2.21 (m, 2H), 1.99 (br d, J = 10.8 Hz, 2H), 1.93-1.87 (m, 2H),1.79 (br dd, J = 5.2, 11.2 Hz, 4H), 1.62-1.55 (m, 2H), 1.23 (br s, 1H); LCMS(ESI, M+1): m / z =654.3.

[0372] Example 36

[0373]

[0374] (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidin-4-carboxylic acid 3,4-difluorophenyl ester

[0375] Example 37

[0376]

[0377] (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidin-4-carboxylic acid 3,4-difluorophenyl ester

[0378]

[0379] Step A. 3-Oxoperidin-4-carboxylic acid ethyl ester: HCl was added to a solution of 40.0 g (1.0 equivalent) of 4-ethyl 1-(tert-butyl) 3-oxopiperidinium-1,4-dicarboxylic acid in MeOH (150 mL). MeOH (4 M, 250 mL). The reaction was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure to give the title compound (40.0 g, crude) as a yellow solid; LCMS (ESI, M+1): m / z = 172.3.

[0380] Step B. 3-O-piperidine-1,4-dicarboxylic acid 1-benzyl ester 4-ethyl ester:At 0 °C, TEA (88.7 g, 5.0 equivalent) was added to a mixture of ethyl 3-oxopiperidin-4-carboxylate (30.0 g, 1.0 equivalent) and CbzCl (35.9 g, 1.2 equivalent) in DCM (300 mL). The reaction was stirred at 20 °C for 2 hours. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 20 / 1 to 5 / 1] to give the title compound (23.0 g, 43% yield) as a colorless oil. 1 ¹H NMR (400 MHz, chloroform-d) δ = 12.09 (s, 1H), 7.39–7.32 (m, 5H), 5.16 (s, 2H), 4.24 (q, 1H) J = 7.2 Hz, 2H), 4.12 (br s, 2H), 3.58 (t, J =5.6 Hz, 2H), 2.36 (br s, 2H), 1.31 (t, J = 7.2 Hz, 3H).

[0381] Step C. 3-Hydroxypiperidine-1,4-dicarboxylic acid 1-benzyl ester 4-ethyl ester: At 0 °C, NaBH4 (1.95 g, 1.6 equivalent) was added to a solution of 1-benzyl 4-ethyl 3-oxopiperidinium-1,4-dicarboxylic acid (10.0 g, 1.0 equivalent) in THF (100 mL). The reaction was stirred at 0 °C for 1 hour. The mixture was diluted with saturated NH4Cl (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1] to give the title compound (4.60 g, 46% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.40-7.28 (m, 5H), 5.14 (br s, 2H), 4.36-4.09 (m, 5H), 3.04 (br s, 1H), 2.97-2.84 (m, 1H), 2.56 (br d, J = 10.4Hz, 1H), 2.21-2.01 (m, 1H), 1.87-1.70 (m, 1H), 1.28 (t, J= 7.2 Hz, 3H); LCMS(ESI, M+1): m / z = 308.3.

[0382] Step D. (3R,4R)-3-hydroxypiperidine-1,4-dicarboxylic acid 1-benzyl ester 4-ethyl ester and (3S,4S)-3-hydroxypiperidine 1-Benzyl ester of 1,4-dicarboxylic acid, 4-ethyl ester: The residue was purified by SFC [column: DAICL CHIRALPAK IG (250 mm × 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 40%, isocratic elution mode] to give the title compound (1.50 g, 33% yield) and (1.50 g, 33% yield).

[0383] Step E. (3R,4R)-3-hydroxypiperidine-4-carboxylic acid ethyl ester: Under a nitrogen atmosphere, Pd / C (1.00 g, 10% purity) was added to a solution of (3R,4R)-3-hydroxypiperidine-1,4-dicarboxylic acid 1-benzyl ester 4-ethyl ester (700 mg, 1.0 equivalent) in ethyl acetate (8.00 mL). The reaction mixture was degassed and purged three times with H2. The reaction was stirred at 25 °C under H2 (50 psi) for 4 hours. The mixture was filtered and concentrated to give the title compound (300 mg, crude) as a yellow solid. 1 ¹H NMR (400MHz, chloroform-d) δ = 4.18 (q, J = 7.2 Hz, 2H), 4.07 (br s, 1H), 3.13-3.04 (m,2H), 2.80-2.66 (m, 3H), 2.59 (dt, J = 2.8, 12.4 Hz, 1H), 2.54-2.47 (m, 1H), 2.02-1.88 (m, 1H), 1.71 (br dd, J = 3.6, 13.2 Hz, 1H), 1.27 (t, J = 7.2 Hz, 3H).

[0384] Step F. (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)) Ethyl methoxypyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylate:To a mixture of 8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (200 mg, 1.0 equivalent) and K3PO4 (240 mg, 3.0 equivalent) in DMF (3.00 mL), ethyl (3R,4R)-3-hydroxypiperidin-4-carboxylate (261 mg, 4.0 equivalent) and 4 Å molecular sieve (50.0 mg) were added. The reaction was stirred at 60 °C for 2 h. The mixture was filtered and purified by preparative HPLC [FA conditions] to give the title compound (180 mg, 80% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 604.3.

[0385] Step G. (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)) (Methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylic acid: To a solution of (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidin-4-carboxylic acid ethyl ester (90.0 mg, 1.0 equivalent) in THF (1.50 mL), NaOH (2 M, 224 μL, 3.0 equivalent) was added. The reaction was stirred at 25 °C for 3 h. The pH of the mixture was adjusted to 6. The mixture was washed with ethyl acetate (2 × 20.0 mL). The aqueous layer was lyophilized to give the title compound (60.0 mg, crude) as a beige solid; LCMS (ESI, M+1): m / z = 576.3.

[0386] Step H. (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)) 3,4-difluorophenyl ester of methoxypyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylic acid:To a solution of (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidin-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 3,4-difluorophenol (33.9 mg, 3.0 equivalent) in DCM (1.00 mL), DMAP (15.9 mg, 1.5 equivalent) and EDCI (25.0 mg, 1.5 equivalent) were added. The reaction was stirred at 20 °C for 4 hours. The mixture was diluted with water (20.0 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, concentrated, and purified by preparative HPLC [column: Phenomenexluna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 19%-49% B, 10 min] to give the title compound (Example 36, 2.00 mg, 3.2% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.26 (d, J = 7.2 Hz, 1H), 8.30 (br d, J = 4.4 Hz, 1H), 8.18 (brd, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.67-7.61 (m, 1H), 7.60-7.54 (m, 1H), 7.54-7.47 (m, 1H), 7.38-7.28 (m, 2H), 7.08-7.00 (m, 1H), 4.71-4.54 (m, 2H), 4.47 (br s, 1H), 4.09 (s, 2H), 3.74 (br dd, J = 4.8, 13.6 Hz, 2H), 3.29-3.17 (m, 3H), 3.02-2.91 (m, 2H), 2.56 (br d, J =9.6 Hz, 2H), 2.30 (br d, J = 13.2 Hz, 1H), 1.91 (br dd, J= 6.0, 11.6 Hz, 3H), 1.82-1.75 (m, 3H), 1.63-1.56 (m, 2H); LCMS (ESI, M+1): m / z = 688.3.

[0387] Step I. (3S,4S)-3-hydroxypiperidine-4-carboxylic acid ethyl ester: Under a nitrogen atmosphere, Pd / C (1.00 g) was added to a solution of (3S,4S)-3-hydroxypiperidine-1,4-dicarboxylic acid 1-benzyl ester 4-ethyl ester (700 mg, 1.0 equivalent) in EtOAc (8.00 mL). The reaction mixture was degassed and purged three times with H2. The reaction was stirred at 25 °C under H2 (50 psi) for 4 hours. The mixture was filtered and concentrated to give the title compound (300 mg, crude) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 4.15 (q, J = 7.2 Hz, 2H), 4.05 (br s, 1H), 3.06 (td, J = 3.2, 12.8 Hz, 2H), 2.78 (br s, 2H), 2.67 (dd, J = 1.6, 13.2 Hz, 1H), 2.56 (dt, J = 2.8, 12.4 Hz,1H), 2.51-2.41 (m, 1H), 1.92 (dq, J = 4.4, 12.8 Hz, 1H), 1.74-1.64 (m, 1H),1.24 (t, J = 7.2 Hz, 3H).

[0388] Step J. (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)) Ethyl methoxypyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylate: To a mixture of 8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (250 mg, 1.0 equivalent) and K3PO4 (300 mg, 3.0 equivalent) in DMF (3.00 mL), ethyl (3S,4S)-3-hydroxypiperidin-4-carboxylate (245 mg, 3.0 equivalent) and 4Å molecular sieve (50.0 mg) were added. The reaction was stirred at 60 °C for 2 h. The mixture was filtered and purified by preparative HPLC [FA conditions] to give the title compound (220 mg, 77% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 604.3.

[0389] Step K. (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)) (Methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylic acid: To a solution of (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidin-4-carboxylic acid ethyl ester (90.0 mg, 1.0 equivalent) in THF (1.50 mL), NaOH (2 M, 224 μL, 3.0 equivalent) was added. The reaction was stirred at 25 °C for 3 h. The pH of the mixture was adjusted to 6. The mixture was washed with ethyl acetate (2 × 20.0 mL). The aqueous layer was lyophilized to give the title compound (60.0 mg, crude) as a beige solid; LCMS (ESI, M+1): m / z = 576.3.

[0390] Step L. (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)) 3,4-difluorophenyl ester of methoxypyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylic acid: DMAP (15.9 mg, 1.5 equivalent) and EDCI (25.0 mg, 1.5 equivalent) were added to a mixture of (3S,4S)-1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidin-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 3,4-difluorophenol (33.9 mg, 3.0 equivalent) in DCM (1.00 mL). The reaction was stirred at 20 °C for 4 hours. The mixture was diluted with water (20.0 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, concentrated, and purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 19%-49% B, 10 min] to give the title compound (Example 37, 2.00 mg, 3.2% yield) as a white solid. 1 HNMR (400 MHz, DMSO-d6) δ = 9.27 (d, J = 7.2 Hz, 1H), 8.27 (br s, 1H), 8.19(br d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.64 (dd, J= 7.6, 12.0 Hz, 1H), 7.61-7.56 (m, 1H), 7.55-7.48 (m, 1H), 7.39-7.29 (m, 2H), 7.09-7.00 (m, 1H), 4.73-4.55 (m, 2H), 4.48 (br s, 1H), 4.11 (s,2H), 3.74 (br dd, J = 4.8, 13.2 Hz, 2H), 3.36-3.18 (m, 3H), 3.01-2.93 (m,2H), 2.64-2.54 (m, 2H), 2.31 (br d, J = 13.2 Hz, 1H), 1.97-1.87 (m, 3H), 1.81(br dd, J = 6.0, 11.2 Hz, 3H), 1.65-1.56 (m, 2H); LCMS (ESI, M+1): m / z =688.3.

[0391] Example 38

[0392]

[0393] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxaldehyde

[0394]

[0395] Step A. (1-(8-Fluoro-7-(8-Fluoronaphth-1-yl)-2-((Tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy) Pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methanolTo a solution of 8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (100 mg, 1.0 equivalent) and piperidin-4-ylmethanol (65.1 mg, 3.0 equivalent) in DMF (1.00 mL), 4 Å molecular sieve (20.0 mg) and DIEA (73.1 mg, 3.0 equivalent) were added. The reaction was stirred at 50 °C for 12 h. The mixture was purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; gradient: 17%–47% B, 10 min] to give the title compound (60.0 mg, 56% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 546.3.

[0396] Step B. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine Aceto[4,3-d]pyrimidin-4-yl)piperidine-4-carboxaldehyde Add Dys-Martin reagent (77.7 mg, 2.0 equivalent) to a solution of (1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methanol (50.0 mg, 1.0 equivalent) in DCM (1.00 mL). Stir the reaction at 20 °C for 2 hours. Quench the mixture with Na₂SO₃ (20.0 mL, at 0 °C) and extract with ethyl acetate (3 × 20.0 mL). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, concentrated, and purified by preparative HPLC [column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (ammonium hydroxide v / v)-ACN]; gradient: 31%-61% B, 9 min] to give the title compound (5.60 mg, 11% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.67 (s, 1H), 9.08 (s, 1H), 8.18 (br d, J = 7.6 Hz, 1H), 7.93 (d, J =8.0 Hz, 1H), 7.78-7.70 (m, 1H), 7.66-7.55 (m, 2H), 7.31 (br dd, J= 7.2, 13.6Hz, 1H), 4.64-4.50 (m, 1H), 4.40-4.34 (m, 1H), 4.05 (s, 2H), 3.62-3.54 (m,1H), 2.96-2.89 (m, 2H), 2.85-2.73 (m, 1H), 2.56 (br s, 2H), 2.15-2.02 (m,2H), 1.94-1.71 (m, 9H), 1.60-1.53 ​​(m, 2H); LCMS (ESI, M+1): m / z = 544.3.

[0397] Example 39

[0398]

[0399] 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid phenyl ester

[0400]

[0401] Step A. 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid phenyl ester DMAP (63.3 mg, 1.5 equivalent) and EDCI (99.3 mg, 1.5 equivalent) were added to a mixture of 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (230 mg, 1.0 equivalent) and phenol (65.0 mg, 2.0 equivalent) in DCM (2.0 mL). The reaction was stirred at 25 °C for 2 hours. The mixture was concentrated and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (170 mg, 65.7% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 742.4.

[0402] Step B. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolazine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid phenyl esterHCl was added to a solution of 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid phenyl ester (150 mg, 1.0 equivalent) in MeCN (1.0 mL). Dioxane (4 M, 39 equivalents). The reaction was stirred at 25 °C for 0.5 h. The mixture was concentrated. The residue was diluted with water (2.0 mL). The mixture was adjusted to pH = 7 with saturated aqueous NaHCO3 solution. The mixture was extracted with ethyl acetate (3 × 5.0 mL). The combined organic layers were dried over sodium sulfate, concentrated, and purified by preparative HPLC [Phenomenex luna C18 150 × 25 mm × 10 µm; A: water (FA); B: ACN, B%: 25%–55%, 8 min] to give the title compound (103 mg, 66% yield, 0.33 HCOOH) as a white solid. 1 ¹H NMR (400 MHz, dimethyl sulfoxide-d6) δ = 10.12–9.77 (m, ¹H), 9.12 (s, ¹H), 7.77 (dd, 1H) J = 6.0, 9.2 Hz, 1H), 7.51-7.39 (m, 2H), 7.38-7.31 (m, 2H), 7.30-7.25(m, 1H), 7.20-7.13 (m, 2H), 7.03 (d, J = 2.4 Hz, 1H), 5.42-5.20 (m, 1H), 4.60-4.43 (m, 2H), 4.19 (dd, J = 4.4, 10.4 Hz, 1H), 4.14-4.05 (m, 1H), 3.70-3.53 (m, 2H), 3.20-3.04 (m, 4H), 2.93-2.80 (m, 1H), 2.41-2.31 (m, 1H), 2.23(br d, J = 10.4 Hz, 2H), 2.19-2.07 (m, 3H), 2.06-1.92 (m, 3H), 1.91-1.75 (m,3H), 0.73 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 698.3.

[0403] Example 40

[0404]

[0405] 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid 3,4-difluorophenyl ester

[0406]

[0407] Step A. 1-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid methyl ester: At -40 °C, methyl piperidine-4-carboxylate (408 mg, 0.80 equivalent) was added to a solution of 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (900 mg, 1.0 equivalent) and DIEA (921 mg, 2.0 equivalent) in DCM (18.0 mL). The reaction was stirred at -40 °C for 0.5 h. The mixture was diluted with water (30.0 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to give the title compound (600 mg, 42% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 359.1.

[0408] Step B. 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy) Methyl pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: Methyl 1-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)piperidine-4-carboxylate (500 mg, 1.0 equivalent) in DMSO (0.5 mL) was mixed with ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (665 mg, 3.0 equivalent). The mixture was stirred at 100 °C for 3 h. The mixture was filtered and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (600 mg, 88% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 482.2.

[0409] Step C. 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid methyl ester:Methyl 1-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (500 mg, 1.0 equivalent) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (561 mg, 1.5 equivalent) in methoxycyclopentane (9.0 mL) and water (3.0 mL) were added to a mixture of [2-(2-aminophenyl)phenyl]palladium bis(1-adamantyl)butylphosphine methanesulfonate (75.5 mg, 0.10 equivalent) and Cs2CO3 (1.01 g, 3.0 equivalent). The reaction mixture was degassed and purged three times with nitrogen. The reaction was stirred at 90°C for 5 hours. The mixture was filtered, concentrated, and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (650 mg, 90% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 680.5.

[0410] Step D. 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid: Methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (500 mg, 1.0 equivalent) was added to a mixture of water (1.5 mL) and THF (4.5 mL) with NaOH (2 M aqueous solution, 4.0 equivalent). The reaction was stirred at 25 °C for 2 h. The mixture was adjusted to pH = 7 with HCl (2 M) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the title compound (480 mg, 96% yield) as a yellow oil; LCMS (ESI, M+1): m / z = 666.3.

[0411] Step E. 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid 3,4-di Fluorophenyl esters:To a mixture of 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (200 mg, 1.0 equivalent) and 3,4-difluorophenol (78.2 mg, 2.0 equivalent) in DCM (2 mL), DMAP (55.1 mg, 1.5 equivalent) and EDCI (86.4 mg, 1.5 equivalent) were added. The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (200 mg, 81% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 778.4.

[0412] Step F. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid 3,4-difluorophenyl ester: HCl was added to a mixture of 1,4-difluorophenyl ester (100 mg, 1.0 equivalent) of 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid in MeCN (0.5 mL). Dioxane (4 M, 31 equivalents). The reaction was stirred at 25 °C for 0.5 h. The mixture was concentrated. The residue was diluted with water (2.0 mL). The mixture was adjusted to pH 7 with saturated aqueous NaHCO3 solution and extracted with ethyl acetate (3 × 5.0 mL). The combined organic layers were dried over sodium sulfate, concentrated, and purified by preparative HPLC [Phenomenex luna C18 150 × 25 mm × 10 µm; A: water (FA); B: ACN, B%: 28%–58%, 10 min] to give the title compound (42.6 mg, 41% yield, 0.28 HCOOH) as a white solid. 1 ¹H NMR (400 MHz, dimethyl sulfoxide-d6) δ = 10.19–9.69 (m, ¹H), 9.10 (s, ¹H), 7.77 (dd, J = 6.0, 9.2 Hz, 1H), 7.59-7.50 (m, 1H), 7.49-7.41 (m,1H), 7.39-7.27 (m, 2H), 7.11-7.05 (m, 1H), 7.03 (d, J= 2.4 Hz, 1H), 5.45-5.14 (m, 1H), 4.62-4.43 (m, 2H), 4.16 (dd, J = 4.0, 10.4 Hz, 1H), 4.10-4.02(m, 1H), 3.69-3.54 (m, 2H), 3.16-2.99 (m, 4H), 2.87-2.76 (m, 1H), 2.43-2.30(m, 1H), 2.26-2.17 (m, 2H), 2.17-2.08 (m, 2H), 2.08-1.92 (m, 4H), 1.90-1.72(m, 3H), 0.80-0.65 (m, 3H); LCMS (ESI, M+1): m / z = 734.2.

[0413] Example 41

[0414]

[0415] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid methyl ester

[0416]

[0417] Step A: 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine Methyl pyrimidin-4-yl)piperidine-4-carboxylate N-ethyl-N,N-diisopropylamine (73.2 mg, 6.0 equivalent) and 4Å molecular sieve (10.0 mg) were added to a solution of 8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (50.1 mg, 1.0 equivalent) and piperin-4-carboxylate (27.0 mg, 2.0 equivalent) in DMF (1 mL). The reaction was stirred at 50 °C for 16 h. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (2 × 15 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Phenomenex luna C18 150 × 25 mm × 10 μm; A: water (FA), B: ACN, B%: 22%–52%, 7 min] to give the title compound (11.4 mg, 20% yield, 0.6 HCCOH) as a white solid. 1¹H NMR (400 MHz, methanol-d⁴) δ = 9.08 (s, ¹H), 8.12 (br d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.76-7.66 (m, 1H), 7.65-7.58 (m, 1H), 7.54 (dt, J = 5.2, 8.0 Hz, 1H), 7.19 (dd, J = 7.6, 13.2Hz, 1H), 4.62 (br d, J = 13.6 Hz, 2H), 4.52 (s, 2H), 3.79-3.70 (m, 3H), 3.69-3.60 (m, 2H), 3.50-3.42 (m, 2H), 3.12-3.02 (m, 2H), 2.92-2.83 (m, 1H), 2.28-2.02 (m, 8H), 2.02-1.90 (m, 4H); LCMS (ESI, M+1): m / z =574.5.

[0418] Example 42

[0419]

[0420] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid 4-(trifluoromethyl)phenyl ester

[0421]

[0422] Step A. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine 4-(trifluoromethyl)phenyl ester of pyrimidin-4-yl)piperidin-4-carboxylic acidTo a solution of 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (45.0 mg, 1.0 equivalent) and 4-(trifluoromethyl)phenol (39.1 mg, 3.0 equivalent) in DCM (5 mL), 4-dimethylaminopyridine (19.7 mg, 2.0 equivalent) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (30.8 mg, 2.0 equivalent) were added. The reaction was stirred at 40 °C for 16 hours. The mixture was concentrated and purified by preparative HPLC [Phenomenexluna C18 150 × 25 mm × 10 μm, A: water (FA), B: ACN, B%: 35%–65%, 7 min] to give the title compound (23.5 mg, 39% yield, 0.1 HCOOH) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.18 (s, 1H), 8.20 (br d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.79-7.72 (m, 1H), 7.67-7.56 (m, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.32 (dd, J = 7.2, 13.2 Hz, 1H), 4.64-4.46 (m, 4H), 3.64 (brt, J = 12.4 Hz, 2H), 3.51-3.40 (m, 2H), 3.24-3.10 (m, 3H), 2.26 (br d, J =10.4 Hz, 2H), 2.15 (br dd, J = 6.0, 12.0 Hz, 2H), 2.09-1.91 (m, 8H); LCMS(ESI, M+1): m / z = 704.4.

[0423] Example 43

[0424]

[0425] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid 3,4-difluorophenyl ester

[0426]

[0427] Step A. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine 3,4-difluorophenyl ester of pyrimidin-4-yl)piperidine-4-carboxylic acid To a solution of 1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 3,4-difluorophenol (34.9 mg, 3.0 equivalent) in DCM (3 mL), 4-dimethylaminopyridine (21.8 mg, 2.0 equivalent) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (34.3 mg, 2.0 equivalent) were added. The reaction was stirred at 35 °C for 16 hours. The mixture was concentrated and purified by preparative HPLC [Phenomenex luna C18150 × 25 mm × 10 μm; A: water (FA), B: ACN, B%: 32%–62%, 7 min] to give the title compound (21.5 mg, 33% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.17 (s,1H), 8.20 (br d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.82-7.72 (m,1H), 7.66-7.62 (m, 1H), 7.61-7.56 (m, 1H), 7.55-7.48 (m, 1H), 7.48-7.41 (m,1H), 7.32 (dd, J = 7.6, 13.2 Hz, 1H), 7.12-7.04 (m, 1H), 4.62-4.41 (m, 4H), 3.69-3.57 (m, 2H), 3.38 (br s, 2H), 3.18-3.04 (m, 3H), 2.23 (br d, J = 10.4Hz, 2H), 2.13 (br dd, J= 6.4, 11.6 Hz, 2H), 2.08-1.88 (m, 8H); LCMS (ESI, M+1): m / z = 672.2.

[0428] Example 44

[0429]

[0430] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid phenyl ester

[0431]

[0432] Step A. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine Phenylaceto[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid phenyl ester To a solution of 1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (50.0 mg, 1.0 equivalent) and phenol (25.2 mg, 3.0 equivalent) in DCM (5 mL), 4-dimethylaminopyridine (21.8 mg, 2.0 equivalent) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (34.3 mg, 2.0 equivalent) were added. The reaction was stirred at 40 °C for 16 hours. The mixture was concentrated and purified by preparative HPLC [Phenomenex luna C18 150 × 25 mm × 10 μm; A: water (FA), B: ACN, B%: 30%–50%, 10 min] to give the title compound (2.07 mg, 3.6% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.19 (s, 1H), 8.21-8.17 (m,1H), 7.98-7.89 (m, 1H), 7.81-7.70 (m, 1H), 7.68-7.56 (m, 2H), 7.50-7.39 (m,2H), 7.36-7.25 (m, 2H), 7.17 (d, J= 8.0 Hz, 2H), 4.60-4.44 (m, 2H), 4.28-4.15 (m, 2H), 3.66-3.57 (m, 2H), 3.15-3.04 (m, 3H), 2.80-2.68 (m, 2H), 2.28-2.20 (m, 2H), 2.03-1.79 (m, 8H), 1.73-1.63 (m, 2H); LCMS (ESI, M+1): m / z =636.5.

[0433] Example 45

[0434]

[0435] (3R,4S)-1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylic acid methyl ester

[0436]

[0437] Step A. methyl 3-oxopiperidin-4-carboxylate HCl was added to a solution of 2.00 g (1.0 equivalent) of 4-methyl 1-(tert-butyl) 3-oxopiperidinium-1,4-dicarboxylic acid in 20 mL of ACN. Dioxane (4 M, 1.94 mL, 1.0 equivalent). The reaction was stirred at 0 °C for 1 hour. The mixture was concentrated to give the title compound (1.20 g, crude), a white oil.

[0438] Step B. 3-O-piperidine-1,4-dicarboxylic acid 1-benzyl ester 4-methyl ester At 0 °C, TEA (1.08 g, 1.4 equivalent) was added to a solution of methyl 3-oxopiperidin-4-carboxylate (1.20 g, 1.0 equivalent) and benzyl chloroformate (1.56 g, 1.2 equivalent) in THF (12 mL). The reaction was stirred at 25 °C for 2 h. The mixture was quenched with water (15 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over sodium sulfate, concentrated, and purified by preparative HPLC (column: Phenomenex luna C18 250 × 50 mm × 10 µm; A: water (FA), B: ACN, B%: 38%–68% B, after 21 min) to give the title compound (1.27 g, 57% yield) as a red oil; LCMS (ESI, M+1): m / z = 292.2.

[0439] Step C. 4-Methyl 1-benzyl ester of 3-hydroxypiperidine-1,4-dicarboxylic acid At 0 °C, 1.00 g (1.00 equivalent) of 1-benzyl ester 4-methyl 3-oxopiperidinium-1,4-dicarboxylic acid in EtOH (10 mL) was added to a solution of NaBH4 (64.9 mg, 0.5 equivalent). The reaction was stirred at 0 °C for 5 min. The mixture was quenched with saturated NH4Cl solution (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over sodium sulfate, concentrated, and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (500 mg, 44% yield) as a colorless oil; LCMS (ESI, M+1): m / z = 293.9.

[0440] Step D. methyl 3-hydroxypiperidine-4-carboxylate Pd / C (100 mg, 10% purity) was added to a solution of 4-methyl 1-benzyl 3-hydroxypiperidine-1,4-dicarboxylic acid (500 mg, 1.0 equivalent) in isopropanol (5 mL). The reaction mixture was degassed and purged three times with H2. The reaction was stirred at 25 °C under H2 (15 psi) for 1 hour. The mixture was filtered and concentrated to give the title compound (270 mg, crude) as a yellow oil.

[0441] Step E. (3R,4S)-1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)) Methyl methoxypyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylate DIEA (164 mg, 5.0 equivalent) and 8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (135 mg, 1.0 equivalent) were added to a solution of methyl 3-hydroxypiperidine-4-carboxylate (135 mg, 3.3 equivalent) in DMF (1 mL). The reaction was stirred at 40 °C for 12 h. The mixture was filtered and purified by preparative HPLC [column: Phenomenex luna C18 150 × 40 mm × 15 µm; A: water (FA), B: ACN, B%: 12%–42% B, 11 min] and SFC [column: ChiralPak IH, 250 × 50 mm, 10 µm; A: CO2, B: MeOH (0.1% NH3H2O), B%: 40%–40% B, 5.1 min] to give the title compound (1.39 mg, 0.86% yield) as a yellow solid. 1 ¹H NMR (400 MHz, methanol-d⁴) δ = 9.12 (s, ¹H), 8.12 (br d, J= 8.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.75-7.66 (m, 1H), 7.63-7.49 (m,2H), 7.19 (dd, J = 7.6, 12.8 Hz, 1H), 4.63 (br d, J = 4.4 Hz, 1H), 4.55-4.49(m, 1H), 4.41 (s, 2H), 4.15-4.06 (m, 1H), 3.75 (s, 3H), 3.69-3.58 (m, 1H), 3.50-3.34 (m, 2H), 2.96-2.84 (m, 2H), 2.74 (ddd, J = 4.4, 8.8, 10.8 Hz, 1H), 2.25-2.13 (m, 3H), 2.08-1.80 (m, 8H); LCMS (ESI, M+1): m / z = 590.5.

[0442] Example 46

[0443]

[0444] (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylic acid methyl ester

[0445] Example 47

[0446]

[0447] (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylic acid methyl ester

[0448]

[0449] Step A. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine Methyl pyrimidin-4-yl)-3-hydroxypiperidine-4-carboxylate and (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)- 2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-cis-hydroxypiperidine- Methyl 4-formateDIEA (164 mg, 5.0 equivalent) and 8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (135 mg, 1.0 equivalent) were added to a solution of methyl 3-hydroxypiperidine-4-carboxylate (135 mg, 3.3 equivalent) in DMF (1 mL). The reaction was stirred at 40 °C for 12 h. The mixture was filtered and purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 µm; A: water (FA), B: ACN, B%: 18%-48% B, 9 min] and SFC [column: DAICELCHIRALCEL OX, 250 × 30 mm, 10 µm; A: CO2, B: MeOH (0.1 % NH3H2O), B%: 50%-50% B, 3.7 min] to obtain two isomers.

[0450] (3S,4S)-1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidin-4-carboxylate (Example 46, 3.42 mg, 2.0% yield, HCOOH salt), as a beige solid; SFC: 94.4% ee. Column: Lux 3um Cellulose-4 50 × 4.6 mm ID, 3 µm; mobile phase: 40% (MeOH:ACN=4:1) (0.05% DEA); flow rate: 3 mL / min; detector: 220 nm, t R 2.211 minutes; 1 H NMR (400 MHz, methanol-d4) δ = 9.24 (d, J = 11.2 Hz, 1H), 8.11 (brd, J = 8.0 Hz, 1H), 7.92-7.79 (m, 1H), 7.73-7.66 (m, 1H), 7.64-7.48 (m, 2H), 7.26-7.13 (m, 1H), 4.82 (br d, J = 2.4 Hz, 1H), 4.74 (br d, J= 13.6 Hz, 1H),4.45 (br s, 1H), 4.41-4.35 (m, 2H), 3.76-3.66 (m, 4H), 3.28-3.21 (m, 2H),2.98-2.80 (m, 3H), 2.44-2.28 (m, 1H), 2.20-2.10 (m, 2H), 2.07-1.76 (m, 8H); LCMS (ESI, M+1): m / z = 590.6;

[0451] (3R,4R)-1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-hydroxypiperidin-4-carboxylate (Example 47, 6.40 mg, 4.1% yield, HCOOH salt), was a white solid; SFC: 94.4% ee. Column: Lux 3um Cellulose-4 50 × 4.6 mm ID, 3 µm; mobile phase: 40% (MeOH:ACN=4:1) (0.05% DEA); flow rate: 3 mL / min; detector: 220 nm, t R 2.719 minutes; 1 ¹H NMR (400 MHz, methanol-d⁴) δ = 9.25 (d, J = 11.2 Hz, 1H), 8.11 (brd, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.73-7.67 (m, 1H), 7.63-7.49(m, 2H), 7.19 (dd, J = 7.6, 13.2 Hz, 1H), 4.83-4.78 (m, 1H), 4.74 (br d, J =13.6 Hz, 1H), 4.49-4.36 (m, 3H), 3.77-3.65 (m, 4H), 3.29-3.25 (m, 1H), 2.98-2.85 (m, 3H), 2.44-2.28 (m, 1H), 2.23-2.12 (m, 2H), 2.11-1.93 (m, 6H), 1.92-1.82 (m, 3H); LCMS (ESI, M+1): m / z = 590.5.

[0452] Example 48

[0453]

[0454] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-4-carboxylic acid 3,4-difluorophenyl ester

[0455]

[0456] Step A: 4-Ethyl 1-benzyl ester of 5-hydroxyazacycloheptan-1,4-dicarboxylic acid At 0 °C, NaBH4 (1.39 g, 1.1 equivalent) was added to a solution of 1-benzyl 4-ethyl 5-oxazonicycloheptan-1,4-dicarboxylic acid (11.0 g, 1.0 equivalent) in THF (110 mL). The reaction was stirred at 0 °C for 1 h. At 0 °C, the mixture was quenched with saturated NH4Cl solution (100 mL) and extracted with ethyl acetate (3 × 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1] to give the title compound (5.00 g, 44% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ = 7.37-7.27(m, 5H), 5.06 (s, 2H), 4.81-4.72 (m, 1H), 4.11-3.95 (m, 2H), 3.57-3.37 (m,3H), 3.33-3.21 (m, 1H), 2.47-2.40 (m, 1H), 2.11-1.99 (m, 1H), 1.95-1.77 (m,2H), 1.75-1.61 (m, 1H), 1.17 (dt, J = 2.4, 7.2 Hz, 3H).

[0457] Step B: 5-((methanesulfonyl)oxy)azacycloheptan-1,4-dicarboxylic acid 1-benzyl ester 4-ethyl esterTEA (6.61 g, 9.1 mL, 3.0 equivalent) and MsCl (6.47 g, 2.6 equivalent) were added to a solution of 1-benzyl ester 4-ethyl 5-hydroxyazine-1,4-dicarboxylic acid (7.00 g, 1.0 equivalent) in DCM (70 mL). The reaction was stirred at 25 °C for 1 hour. The mixture was slowly quenched with ice water (50 mL) at 0 °C. The mixture was diluted with water (20 mL) and extracted with DCM (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 (10.0 g, crude) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ = 7.38-7.25 (m,5H), 5.33-5.23 (m, 1H), 5.07 (s, 2H), 4.16-3.96 (m, 2H), 3.57-3.35 (m, 4H),3.13 (d, J = 3.6 Hz, 2H), 3.10-3.05 (m, 1H), 2.92 (br d, J = 10.0 Hz, 1H), 2.32-2.22 (m, 1H), 2.10-1.90 (m, 3H), 1.20-1.14 (m, 3H).

[0458] Step C: 2,3,6,7-Tetrahydro-1H-azacycloheptane-1,4-dicarboxylic acid 1-benzyl ester 4-ethyl ester: DBU (6.86 g, 2.0 equivalent) was added to a solution of 1-benzyl 4-ethyl 5-((methanesulfonyl)oxy)azacycloheptan-1,4-dicarboxylic acid ester (9.00 g, 1.0 equivalent) in THF (90 mL). The reaction was stirred at 80 °C for 1 h. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1] to give the title compound (4.00 g, 54% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ = 7.40-7.27 (m,5H), 7.02 (br d, J = 1.6 Hz, 1H), 5.10 (s, 2H), 4.10 (q, J = 7.2 Hz, 2H),3.51 (br s, 4H), 2.64-2.58 (m, 2H), 2.44 (br d,J = 5.2 Hz, 2H), 1.21 (t, J =7.2 Hz, 3H).

[0459] Step D: Ethyl heptane-4-carboxylate Pd / C (700 mg, 10% purity) was added to a solution of 1-benzyl 4-ethyl 2,3,6,7-tetrahydro-1H-azacycloheptane-1,4-dicarboxylic acid 4-benzyl ester (3.00 g, 1.0 equivalent) in THF (50 mL). The reaction mixture was degassed and purged three times with H2. The reaction mixture was stirred at 40 °C under H2 (50 Psi) for 6 hours. The mixture was filtered and concentrated to give the title compound (1.50 g, 88% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6)δ = 4.03 (q, J = 7.2 Hz, 2H), 2.83-2.71 (m, 2H), 2.71-2.58 (m, 2H), 2.57-2.52(m, 1H), 1.91-1.79 (m, 2H), 1.72-1.57 (m, 3H), 1.54-1.39 (m, 1H), 1.16 (t, J = 7.2 Hz, 3H).

[0460] Step E: 8-Fluoro-7-(8-Fluoronaphth-1-yl)-2-((Tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2, 2,2-Trifluoroethoxy)pyrido[4,3-d]pyrimidine: To a mixture of 8-fluoro-7-(8-fluoro-1-naphthyl)-2-(1,2,3,5,6,7-hexahydropyrrolazin-8-ylmethoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1.00 g, 1.0 equivalent) and 4 Å molecular sieve (1.00 g) in DMF (20 mL), K3PO4 (731 mg, 1.8 equivalent) and ethyl azaheptan-4-carboxylate (1.61 g, 5.0 equivalent) were added. The reaction was stirred at 50 °C for 1 h. The mixture was filtered, concentrated, and purified by reversed-phase rapid chromatography [water (0.1 % FA) / ACN] to give the title compound (730 mg, 61% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.15 (s, 1H), 8.17 (br d, J= 8.4 Hz, 1H),7.97-7.91 (m, 1H), 7.77-7.70 (m, 1H), 7.66-7.53 (m, 2H), 7.35-7.26 (m, 1H),4.19-4.08 (m, 2H), 4.06-4.03 (m, 3H), 3.95-3.83 (m, 2H), 2.99-2.87 (m, 2H), 2.68-2.60 (m, 1H), 2.57-2.52 (m, 2H), 2.29-2.17 (m, 1H), 2.07 (br d, J = 11.6Hz, 2H), 1.98-1.84 (m, 5H), 1.83-1.65 (m, 5H), 1.56 (td, J = 7.2, 12.0 Hz, 2H), 1.16-1.12 (m, 3H).

[0461] Step F: 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine Aceto[4,3-d]pyrimidin-4-yl)azacycloheptane-4-carboxylic acid: To a solution of ethyl 1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptan-4-carboxylate (390 mg, 1.0 equivalent) in THF (4.0 mL) and MeOH (4.0 mL), a solution of NaOH (648 μL, 2.0 equivalent, 2 M) was added. The reaction was stirred at 25 °C for 1 hour. The mixture was quenched with HCl (3 M) and concentrated to give the title compound (500 mg, HCl) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.15 (s, 1H), 8.53-8.50 (m,1H), 8.54 (s, 1H), 8.17-7.76 (m, 1H), 7.66-7.55 (m, 2H), 7.30 (dd, J = 7.6,12.8 Hz, 1H), 4.21-4.08 (m, 2H), 3.92-3.82 (m, 2H), 2.95-2.87 (m, 2H), 2.56-2.53 (m, 2H), 2.47-2.36 (m, 1H), 1.94 (br s, 5H), 1.88 (br dd, J = 5.6, 12.0Hz, 3H), 1.83-1.69 (m, 5H), 1.60-1.52 (m, 3H).

[0462] Step G: 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine 3,4-difluorophenyl ester of pyrimidin-4-yl(aziridine-4-yl)-heptan-4-carboxylic acid: To a solution of 1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-4-carboxylic acid (95.0 mg, 1.0 equivalent) and 3,4-difluorophenol (64.6 mg, 3.0 equivalent) in DCM (1.0 mL), DMAP (40.5 mg, 2.0 equivalent) and EDCI (63.5 mg, 2.0 equivalent) were added. The reaction was stirred at 50 °C for 1 hour. The mixture was concentrated and purified by preparative HPLC [column: YMC-Actus Triart C18 150 × 30 mm × 7 μm; mobile phase: [water (FA)-ACN]; gradient: 30%-60% B, duration 10 min] and preparative HPLC [column: YMC-Actus Triart C18 150 × 30 mm × 7 μm; mobile phase: [water (FA)-ACN]; gradient: 30%-60% B, duration 10 min] to give the title compound (19.5 mg, 17% yield, 0.2 HCOOH) as a beige solid; 1 H NMR (400MHz, DMSO-d6) δ = 9.21-9.16 (m, 1H), 8.18 (br d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.77-7.70 (m, 1H), 7.67-7.55 (m, 2H), 7.49 (br d, J = 9.2 Hz,1H), 7.42-7.26 (m, 2H), 7.05-6.98 (m, 1H), 4.31-4.19 (m, 2H), 4.13-4.05 (m,2H), 4.03-3.84 (m, 2H), 3.75-3.62 (m, 1H), 3.61-3.46 (m, 2H), 2.94 (br dd, J LCMS (ESI, M+1): m / z =686.4.

[0463] Example 49

[0464]

[0465] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-4-carboxylic acid methyl ester

[0466]

[0467] Step A. Methyl 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-4-carboxylate: At 0 °C, oxaloyl chloride (22.1 mg, 2.0 equivalent) and dimethylformamide (6.37 mg, 1.0 equivalent) were added to a solution of 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-4-carboxylic acid (50.0 mg, 1.0 equivalent) in dichloromethane (1 mL). The reaction was stirred at 0 °C for 0.5 h. The mixture was concentrated. Methanol (27.9 mg, 10.0 equivalents) was added dropwise to the residue at 0 °C. The reaction was stirred at 25 °C for 4 hours. The mixture was filtered and the filtrate was passed through a preparative HPLC system [YMC-Actus Triart C18 150]. 30 mm 7 μm; mobile phase: [water (FA)-ACN]; B%: 23%-53%, duration 4 min] purification to give the title compound (5.79 mg, 11% yield, 0.3 HCOOH) as a white solid; 1 H NMR (400 MHz, DMSO+D2O) δ = 9.12 (s, 1H), 8.15 (br d, J = 8.4Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.72 (br t, J = 8.0 Hz, 1H), 7.64-7.52 (m,2H), 7.32-7.24 (m, 1H), 4.22-4.14 (m, 3H), 4.11-4.07 (m, 1H), 3.54 (br d, J =6.0 Hz, 3H), 3.02 (br d, J= 4.4 Hz, 2H), 2.67-2.63 (m, 4H), 2.22-2.18 (m,1H), 2.08-2.04 (m, 2H), 2.01-1.87 (m, 4H), 1.86-1.81 (m, 2H), 1.80-1.72 (m,3H), 1.67-1.59 (m, 3H); LCMS (ESI, M+1): m / z =588.5

[0468] Example 50

[0469]

[0470] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-4-carboxylic acid 4-(trifluoromethyl)phenyl ester

[0471]

[0472] Step A. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine 4-(trifluoromethyl)phenyl ester of pyrimidin-4-yl)azheptan-4-carboxylic acid ([4,3-d]pyrimidin-4-yl)azheptan-4-carboxylic acid To a solution of 1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-4-carboxylic acid (60.0 mg, 1.0 equivalent) in dichloromethane (1.0 mL), 4-(trifluoromethyl)phenol (50.9 mg, 3.0 equivalent), 4-dimethylaminopyridine (25.6 mg, 2.0 equivalent), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (40.1 mg, 2.0 equivalent) were added. The reaction was stirred at 25 °C for 4 hours. The mixture was concentrated and analyzed by preparative HPLC [YMC-Actus Triart C18 150]. 30 mm 7 μm; mobile phase: [water(FA)-ACN]; B%: 33%-63%, duration 4 min] Purification to give the title compound (34.9 mg, 46% yield, 0.6 HCOOH) as a white solid; 1 H NMR (400MHz, DMSO+D2O) δ = 9.18 (s, 1H), 8.16 (br d, J = 8.0 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.79-7.71(m, 3H), 7.62-7.54 (m, 2H), 7.32-7.24 (m, 3H), 4.33-4.25(m, 3H), 4.14 (br s, 1H), 4.07-3.91 (m, 3H), 3.16 (br d, J = 4.8 Hz, 1H),3.00-2.96 (m, 1H), 2.83-2.79 (m, 2H), 2.28-2.12 (m, 4H), 2.03-1.95 (m, 3H),1.91 (br dd, J = 6.0, 12.0 Hz, 2H), 1.86-1.78(m, 3H), 1.78-1.72 (m, 2H); LCMS(ESI, M+1): m / z =718.3.

[0473] Example 51

[0474]

[0475] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylic acid phenyl ester

[0476]

[0477] Step A. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine Methyl pyrimidin-4-yl)piperidine-3-carboxylate K3PO4 (1.20 g, 3.0 equivalent) and methyl piperidine-3-carboxylate (270 mg, 1.0 equivalent) were added to a solution of 8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (1 g, 1.0 equivalent) in DMAC (10 mL). The reaction was stirred at 60 °C for 1 h. The mixture was purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (677 mg, 32% yield) as a red solid; LCMS (ESI, M+1): m / z = 574.3.

[0478] Step B. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine Aceto[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylic acidLiOH was added to a solution of methyl 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-carboxylate (567 mg, 1.0 equivalent) in EtOH (3 mL) and H2O (1 mL). H2O (207 mg, 5.0 equivalents). The reaction was stirred at 25 °C for 1 hour. The mixture was purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (300 mg, 48% yield) as a white solid; LCMS (ESI, M+1): m / z = 560.2.

[0479] Step C. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine Phenylaceto[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylic acid phenyl ester Phenol (25.2 mg, 1.5 equivalents), EDCI (51.4 mg, 1.5 equivalents), and DMAP (32.8 mg, 1.5 equivalents) were added to a solution of 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-carboxylic acid (100 mg, 1.0 equivalent) in DCM (1 mL). The reaction was stirred at 25 °C for 1 hour. The mixture was then concentrated. The residue was purified by preparative HPLC [Phenomenex luna C18 150 × 25 mm × 10 µm; A: water (FA), B: ACN, B%: 30%–60%, 7 min] to give the title compound (20.9 mg, 33% yield, HCOOH salt) as a white solid; 1 H NMR (400MHz, DMSO-d6) δ = 9.18 (d, J = 2.4 Hz, 1H), 8.19 (br d, J = 8.0 Hz, 1H), 7.94(d, J= 8.0 Hz, 1H), 7.78-7.70 (m, 1H), 7.68-7.54 (m, 2H), 7.45-7.38 (m, 2H), 7.3-7.22 (m, 2H), 7.13-7.06 (m, 2H), 4.62-4.49 (m, 1H), 4.27-4.15 (m, 1H), 4.15-4.06 (m, 2H), 4.03-3.91 (m, 1H), 3.80-3.67 (m, 1H), 3.24-3.16 (m, 1H), 2.98-2.88 (m, 2H), 2.60-2.55 (m, 1H), 2.23 (br d, J = 7.2 Hz, 1H), 2.08-1.70(m, 10H), 1.64-1.53 ​​(m, 2H); LCMS (ESI, M+1): m / z = 636.4.

[0480] Example 52

[0481]

[0482] 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-carboxylic acid 2-fluorophenyl ester

[0483]

[0484] Step A. 1-(8-fluoro-7-(8-fluoronaphth-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyridine Phenylaceto[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylic acid phenyl ester : To a solution of 1-(8-fluoro-7-(8-fluoronaphthyl-1-yl)-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-carboxylic acid (50 mg, 1.0 equivalent) in DCM (0.5 mL), 2-fluorophenol (15.0 mg, 1.5 equivalent), EDCI (25.7 mg, 1.5 equivalent), and DMAP (16.4 mg, 1.5 equivalent) were added. The reaction was stirred at 25 °C for 1 hour. The mixture was then concentrated. The residue was purified by preparative HPLC [Phenomenex luna C18 150 × 25 mm × 10 µm; A: water (FA); B: ACN, B%: 30%–60%, 7 min] to give the title compound (20.9 mg, 33% yield, HCOOH salt) as a white solid. 1¹H NMR (400 MHz, chloroform-d) δ = 9.11 (d, J = 4.4 Hz, 1H), 8.01 (br d, J = 7.6Hz, 1H), 7.82-7.71 (m, 1H), 7.68-7.58 (m, 2H), 7.46 (dt, J = 4.8, 8.0 Hz,1H), 7.25-7.10 (m, 5H), 4.7-4.62 (m, 1H), 4.59-4.48 (m, 2H), 4.46-4.32 (m,1H), 4.05-3.86 (m, 1H), 3.77-3.60 (m, 1H), 3.51 (br d, J = 4.0 Hz, 2H), 3.25-3.15 (m, 1H), 2.84-2.77 (m, 2H), 2.43-2.36 (m, 1H), 2.26 (br dd, J = 6.0,12.8 Hz, 2H), 2.14-1.91 (m, 7H), 1.88-1.77 (m, 2H); LCMS (ESI, M+1): m / z =654.4.

[0485] Example 53

[0486]

[0487] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-4-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone

[0488]

[0489] Step A. Azacyclooctane-4-carboxylic acid: 1-(tert-butoxycarbonyl)azacyclooctane-4-carboxylic acid (300 mg, 1 equivalent) was dissolved in HCl. The solution in dioxane (2 M, 11.7 mL, 20 equivalents) was stirred at 25 °C for 1 hour. The mixture was concentrated. The residue was diluted with methanol (2.0 mL) and neutralized with solid NaHCO3. The mixture was filtered and the filtrate was concentrated to give the title compound (180 mg, 88% yield) as a yellow oil. 1¹H NMR (400 MHz, methanol-d⁴) δ 3.39–3.32 (m, 1H), 3.27–3.10 (m, 3H), 2.77–2.64 (m, 1H), 2.15–2.06 (m, 2H), 1.99–1.85 (m, 4H), 1.80–1.67 (m, 2H).

[0490] Step B. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-4-carboxylic acid: Add DIEA (244 mg) to a solution of 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (280 mg, 1.0 equivalent) and aazacyclooctane-4-carboxylic acid (148 mg, 2.0 equivalent) in DMF (2.5 mL). 20 mg (4 equivalents) and 4 Å molecular sieve (20 mg). The reaction was stirred at 60 °C for 2 h. Azacyclooctane-4-carboxylic acid (150 mg, 1.6 equivalents, HCl salt) and DIEA (244 mg, 4.0 equivalents) were added to the resulting mixture. The reaction was stirred at 60 °C for 2 h. The mixture was filtered and purified by reversed-phase rapid chromatography [water (0.1% FA) / acetonitrile] to give the title compound (260 mg, 82% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 650.4.

[0491] Step C. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-4-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone: to 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-4-carboxylic acid (50 mg, 1 equivalent) and EDCI (22.1 mg, 1.5 equivalent) in DMF (0.5 HOBt (12.5 mg, 1.2 equivalents) and TEA (31.1 mg, 4.0 equivalents) were added to a solution in mL. The reaction was stirred at 25 °C for 12 hours. The mixture was filtered and the filtrate was purified by preparative HPLC [Phenomenex Luna C18 150 × 25 mm × 10 µm; A: water (NH4HCO3), B: ACN, B%: 56%–86%, 10 min] to give the title compound (4.97 mg, 8.5% yield) as a yellow solid. 1 HNMR (400 MHz, DMSO-d6) δ 9.97-9.88 (m, 1H), 9.21-9.16 (m, 1H), 8.25-8.19 (m,1H), 7.81-7.71 (m, 1H), 7.38-7.29 (m, 2H), 6.98 (s, 1H), 6.44-6.38 (m, 1H), 5.37-5.13 (m, 1H), 4.35-4.07 (m, 4H), 4.05-3.97 (m, 2H), 3.91-3.81 (m, 1H), 3.11-2.95 (m, 3H), 2.87-2.75 (m, 1H), 2.31-2.25 (m, 1H), 2.16-2.00 (m, 9H), 1.98-1.92 (m, 1H), 1.91-1.65 (m, 8H), 0.76-0.65 (m, 3H); LCMS (ESI, M+1): m / z= 714.5.

[0492] Example 54

[0493]

[0494] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-5-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone

[0495]

[0496] Step A. Methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-5-carboxylate: Add DIEA (699 mg) to a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (1 g, 1.0 equivalent) and methyl azacyclooctane-5-carboxylate (309 mg, 1.0 equivalent) in DMF (10 mL). The reaction mixture was prepared by stirring at 25 °C for 10 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (2 × 2 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (700 mg, 52% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 708.4.

[0497] Step B. Methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-5-carboxylate: Add HCl to a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-5-carboxylate (650 mg, 1.0 equivalent) in MeOH (2 mL). MeOH (4 M, 2.00 mL, 8.7 equivalents). The reaction was stirred at 0 °C for 0.5 h. The mixture was concentrated. The residue was diluted with water (5 mL), neutralized with solid NaHCO3, and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (2 × 2 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (600 mg, 86% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 664.4.

[0498] Step C. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-5-carboxylic acid: LiOH was added to a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-5-carboxylic acid (550 mg, 1.0 equivalent) in MeOH (6 mL). H2O (2 M, 1.81 mL, 4.4 equivalents). The reaction was stirred at 25 °C for 0.5 h. The mixture was purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (390 g, 72% yield) as a white solid; LCMS (ESI, M+1): m / z = 650.4.

[0499] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-5-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone: to 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-5-carboxylic acid (60 mg, 1.0 equivalent) and 3-methyl-1H-pyrazole (22.7 mg, HATU (70.2 mg, 2.0 equivalent) and DIEA (35.8 mg, 3.0 equivalent) were added to a solution of HATU (70.2 mg, 2.0 equivalent) in DMF (0.5 mL). The reaction was stirred at 25 °C for 0.5 h. The mixture was purified by reversed-phase rapid chromatography [C18, neutral conditions] to give the title compound (14.4 mg, 21% yield) as a white solid. 1 H (400 MHz, chloroform-d) δ = 9.08 (d, J = 12.0 Hz, 1H), 8.13 (d, J = 2.8 Hz,1H), 7.58-7.48 (m, 1H), 7.22-7.07 (m, 3H), 6.25 (d, J = 2.8 Hz, 1H), 5.39-5.17 (m, 1H), 4.23 (br d, J = 3.2 Hz, 4H), 4.02-3.78 (m, 3H), 3.38-3.09 (m,3H), 3.04-2.93 (m, 1H), 2.61-2.50 (m, 1H), 2.27 (s, 4H), 2.24-2.04 (m, 10H),2.02-1.83 (m, 4H), 0.85 (br t, J = 6.8 Hz, 3H); LCMS (ESI, M+1): m / z = 714.5.

[0500] Example 55

[0501]

[0502] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-3-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone

[0503]

[0504] Step A. Ethyl 3-(but-3-en-1-ylamino)propionate K₂CO₃ (87.5 g, 3.0 equivalent) was added to a solution of ethyl 3-aminopropionate hydrochloride (49.5 g, 1.5 equivalent) in ACN (1000 mL). The reaction was stirred at 25 °C for 1 hour. 4-Bromobut-1-ene (28.5 g, 1.0 equivalent) was added. The reaction was stirred at 45 °C for 17 hours. The reaction mixture was concentrated to give the title compound (48.3 g, crude product) as a colorless oil. 1 ¹H NMR (400 MHz, chloroform-d) δ = 5.91–5.64 (m, 1H), 5.16–4.89 (m, 1H), 4.21–3.97 (m, 2H), 3.00–2.75 (m, 2H), 2.66 (t, J = 6.8 Hz, 1H), 2.56-2.34 (m, 2H), 2.29-2.09 (m, 1H), 1.34-1.14 (m, 3H).

[0505] Step B. Ethyl 3-(but-3-en-1-yl(tert-butoxycarbonyl)amino)propionate TEA (51.1 g, 2.0 equivalent) and Boc₂O (82.7 g, 1.5 equivalent) were added to a solution of ethyl 3-(but-3-enylamino)propionate (43.3 g, 1.0 equivalent) in DCM (450 mL). The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated and purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 20:1) to give the title compound (40.2 g, 59% yield) as a yellow oil.

[0506] Step C. 2-((but-3-en-1-yl(tert-butoxycarbonyl)amino)methyl)pent-4-enoic acid ethyl esterA solution of ethyl 3-(but-3-en-1-yl(tert-butoxycarbonyl)amino)propionate (20.0 g, 1.0 equivalent) in THF (200 mL) was degassed and purged three times with nitrogen. LDA (2 M, 1.5 equivalent) was slowly added at -65 °C, and the reaction was stirred at -40 °C for 1 h. 3-Iodoprop-1-ene (13.6 g, 1.1 equivalent) was added at -65 °C. The reaction was stirred at -40 °C for 0.5 h. The mixture was quenched with water (100 mL) at 0 °C and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 20:1) to give the title compound (3.90 g, 15% yield) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform-d) δ = 5.81–5.64 (m, 2H), 5.11–4.95 (m, 4H), 4.16–4.06 (m, 2H), 3.50–3.21 (m, 3H), 3.17–3.05 (m, 1H), 2.95–2.68 (m, 1H), 2.39–2.11 (m, 4H), 1.44 (s, 9H), 1.23 (t, J = 7.2 Hz, 3H).

[0507] Step D. (Z)-3,4,7,8-Tetrahydroazacyclooctane-1,3(2H)-dicarboxylic acid 1-(tert-butyl) ester 3-ethyl ester Grubbs catalyst (265 mg, 0.10 equivalent) was added to a solution of ethyl 2-((but-3-en-1-yl(tert-butoxycarbonyl)amino)methyl)pent-4-enoate (1.00 g, 1.0 equivalent) in DCM (150 mL). The reaction was purged with nitrogen three times. The reaction was stirred at 40 °C for 1.5 h. The mixture was filtered, concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to give the title compound (650 mg, 71% yield) as a brown oil. 1 ¹H NMR (400 MHz, chloroform-d) δ = 5.96–5.59 (m, 2H), 4.20–4.06 (m, 3H), 3.91–3.75 (m, 1H), 3.42–3.05 (m, 1H), 3.01–2.89 (m, 1H), 2.83–2.58 (m, 1H), 2.49–2.21 (m, 3H), 2.19–2.06 (m, 1H), 1.47 (d, J = 3.2 Hz, 9H), 1.26 (td,J = 7.2, 10.3 Hz, 3H).

[0508] Step E. Azacyclooctane-1,3-dicarboxylic acid 1-(tert-butyl) ester 3-ethyl ester Add (Z)-3,4,7,8-tetrahydroazacyclooctane-1,3(2H)-dicarboxylic acid 1-(tert-butyl) ester 3-ethyl ester (650 mg, 1.0 equivalent) to a mixture of Pd / C (200 mg, 10% purity) in EtOH (20 mL). Degas the suspension under vacuum and purge several times with H2. Stir the reaction at 25 °C for 1 hour under H2 (15 psi). Filter and concentrate the mixture to give the title compound (381 mg, crude) as a brownish-brown oil. 1 ¹H NMR (400 MHz, chloroform-d) δ = 4.20–4.05 (m, 2H), 3.94–3.60 (m, 2H), 3.16 (ddd, J = 6.8, 11.2, 14.4 Hz, 1H), 3.03-2.80 (m, 2H), 1.98-1.82 (m,1H), 1.77-1.59 (m, 5H), 1.49-1.42 (m, 10H), 1.29-1.20 (m, 4H).

[0509] Step F. Ethyl aziridine-3-carboxylate 381 mg, 1.0 equivalent, of 1-(tert-butyl) 1,3-dicarboxylic acid ester 3-ethyl ester was dissolved in HCl. The solution in MeOH (2 M, 6.7 equivalents) was stirred at 25°C for 0.5 hours. The mixture was concentrated, diluted with MeOH (3 mL), and the pH was adjusted to 8 with NaHCO3 solid. The mixture was filtered and concentrated to give the title compound (236 mg, crude product) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform-d) δ = 4.18–3.99 (m, 2H), 3.31–3.22 (m, 1H), 3.19–3.13 (m, 2H), 3.02–2.89 (m, 2H), 2.17–2.06 (m, 1H), 1.96–1.81 (m, 4H), 1.68 (br s, 3H), 1.20 (t, J = 7.2 Hz, 3H).

[0510] Step G. 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-3-carboxylate: to 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (500 mg, 1.0 equivalent), azacyclooctane-3-carboxylate (207 mg, 1.2 equivalent) and DIEA (349 mg, HATU (514 mg, 1.5 equivalent) was added to a solution of DMF (5 mL). The reaction was stirred at 25 °C for 2 hours. The mixture was filtered, concentrated, and purified by preparative HPLC [C18 150 × 30 mm; A: water (FA), B: ACN, B%: 35%–65%, 7 min] to give the title compound (120 mg, 12%, HCOOH) as a white solid; LCMS (ESI, M+1): m / z = 722.4.

[0511] Step H. Ethyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-3-carboxylate: Ethyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-3-carboxylate (170 mg, 1.0 equivalent, FA) was prepared in HCl The solution in MeOH (2 M, 45 equivalents) was stirred at 25°C for 1 hour. The mixture was concentrated, diluted with MeOH (3 mL), adjusted to pH 8 with NaHCO3 solid, filtered, and concentrated to give the title compound (200 mg, crude) as a yellow oil; LCMS (ESI, M+1): m / z = 678.4.

[0512] Step I. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-3-carboxylic acid: LiOH was added to a solution of ethyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-3-carboxylic acid (180 mg, 1.0 equivalent) in MeOH (5 mL). H2O (2 M, 38 equivalents). The reaction was stirred at 25 °C for 0.5 h. The mixture was filtered, concentrated, and purified by preparative HPLC [C18 150 × 30 mm; A: water (FA), B: FA, B%: 25%–55%, 7 min] to give the title compound (65.0 mg, 35%, HCOOH) as a white solid.

[0513] Step J. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-3-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone: to 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclooctane-3-carboxylic acid (30.0 mg, 1.0 equivalent, HCOOH) and 3-methyl-1H-pyrazole (10.6 mg, DIEA (22.3 mg, 4.0 equivalent) was added to a solution of DMF (1 mL). The reaction was stirred at 25 °C for 10 min. HATU (32.8 mg, 2.0 equivalent) was added. The reaction was stirred at 25 °C for 0.5 h. The mixture was filtered and purified by preparative HPLC [Waters Xbridge 150 × 25 mm × 5 µm; A: water (NH4HCO3), B: ACN, B%: 58%–88%, 9 min] to give the title compound (6.57 mg, 21%) as a beige solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 9.17–8.93 (m, ¹H), 8.17 (t, ¹H) J= 3.2 Hz, 1H), 7.51 (td, J = 5.6, 9.2 Hz, 1H), 7.13 (br s, 3H),6.32-6.23 (m, 1H), 5.36-5.12 (m, 1H), 4.85-4.62 (m, 1H), 4.59-4.31 (m, 2H),4.09-3.99 (m, 1H), 3.96-3.72 (m, 1H), 3.70-3.52 (m, 1H), 3.30-2.99 (m, 3H), 2.97-2.87 (m, 1H), 2.64-2.37 (m, 2H), 2.34-2.22 (m, 4H), 2.19-2.07 (m, 3H),2.04-1.98 (m, 2H), 1.97-1.73 (m, 9H), 0.86-0.79 (m, 3H); LCMS (ESI, M+1): m / z= 714.4.

[0514] Example 56

[0515]

[0516] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-yl)(3-methyl-1H-pyrazole-1-yl)methyl ketone

[0517]

[0518] Step A. Methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylate: Add DIEA (1.40 g, 1.0 equivalent) to a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (1.00 g, 1.0 equivalent) and PyBOP (1.41 g, 1.5 equivalent) in DMF (10 mL). 6.0 equivalents) and methyl pyrrolidine-3-carboxylate (448 mg, 1.5 equivalents, HCl). The reaction was stirred at 40 °C for 12 h. The mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (1.20 g, 98% yield) as a yellow solid; 1 H NMR (400 MHz, DMSO-d6) δ = 9.30-9.22 (m, 1H), 7.93-7.85 (m,1H), 7.69-7.64 (m, 1H), 7.46-7.39 (m, 1H), 7.27-7.10 (m, 4H), 5.39-5.19 (m,3H), 4.24-3.89 (m, 6H), 3.69 (s, 3H), 3.45-3.41 (m, 4H), 3.14-3.08 (m, 2H),3.07-3.06 (m, 1H), 2.89-2.79 (m, 1H), 2.44-2.31 (m, 2H), 2.29 (s, 2H), 2.19-2.11 (m, 2H), 2.09-1.98 (m, 2H), 1.91-1.75 (m, 4H); LCMS (ESI, M+1): m / z =666.4.

[0519] Step B. Methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylate: Add HCl to a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylate (1.10 g, 1.0 equivalent) in MeOH (10 mL). MeOH (4 M, 24 equivalents). The reaction was stirred at 25 °C for 12 hours. The mixture was concentrated, diluted with MeOH (10 mL), adjusted to pH approximately 8 with NaHCO3 solid, filtered, and concentrated to give the title compound (1.00 g, crude) as a yellow solid.

[0520] Step C. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid: LiOH was added to a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid (900 mg, 1.0 equivalent) in MeOH (6 mL) and H₂O (2 mL). H₂O (911 mg, 15 equivalents). The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated and adjusted to pH 4 with HCl (12 M), and filtered to give the title compound (800 mg, 88% yield, HCl) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 10.75-9.69 (m, 1H), 9.35-9.22 (m, 1H), 7.75(dd, J= 6.0, 8.8 Hz, 1H), 7.39-7.29 (m, 2H), 7.10-7.02 (m, 1H), 5.50-5.29(m, 1H), 4.40-4.25 (m, 2H), 4.06-3.91 (m, 2H), 3.55-3.21 (m, 4H), 3.16 (s,1H), 3.04-2.96 (m, 3H), 2.36-2.09 (m, 6H), 1.97-1.86 (m, 2H), 1.73-1.69 (m,2H), 0.80-0.66 (m, 3H); LCMS (ESI, M+1): m / z =608.3.

[0521] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone: to 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)pyrrolidine-3-carboxylic acid (200 mg, 1.0 equivalent), EDCI (94.7 mg, 1.5 equivalent) in DCM (2 DMAP (60.3 mg, 1.5 equivalents) and 3-methyl-1H-pyrazole (50.1 mg, 2.0 equivalents) were added to a solution in mL. The reaction was stirred at 25 °C for 12 hours. The mixture was filtered and purified by preparative HPLC [Waters Xbridge Prep OBD C18 150 × 40 mm × 10 µm; A: water (NH4HCO3), B: ACN, B%: 40%–70%, 20 min] to give the title compound (42.3 mg, 18%) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ = 9.18-9.02 (m, 1H), 8.21-8.10 (m, 1H), 7.48-7.41(m, 1H), 7.15-7.08 (m, 1H), 7.07-7.02 (m, 1H), 6.99-6.83 (m, 1H), 6.33-6.27(m, 1H), 5.39-5.15 (m, 1H), 4.41-4.17 (m, 5H), 4.11-3.87 (m, 2H), 3.42-3.24(m, 2H), 3.23-3.12 (m, 1H), 2.99 (br d, J = 5.6 Hz, 1H), 2.50-2.38 (m, 2H), 2.34 (s, 3H), 2.33-2.17 (m, 3H), 2.16-2.09 (m, 2H), 2.00-1.88 (m, 3H), 0.83-0.74 (m, 3H); LCMS (ESI, M+1): m / z =672.4.

[0522] Example 57

[0523]

[0524] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(4-methyl-1H-pyrazol-1-yl)methyl ketone

[0525]

[0526] Step A. Methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: Add DIEA (7.0 g, 1.0 equivalent) to a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (10 g, 1.0 equivalent) and methyl piperidine-4-carboxylate (7.7 g, 3.0 equivalent) in DMF (30 mL). 3.0 equivalents) and PyBOP (14.1 g, 1.5 equivalents). The reaction was stirred at 25 °C for 25 h. The mixture was diluted with H2O (100 ml) and extracted with ethyl acetate (200 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (10 g, 80% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 680.4.

[0527] Step B. Methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: 10 g (1 equivalent) of methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate and HCl A solution of MeOH (2 M, 30 mL, 4.08 equivalents) was stirred at 25 °C for 1 hour. The mixture was concentrated. The residue was alkalized with saturated NaHCO3 solution (25 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (2 × 2 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (5 g, 41% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 636.4.

[0528] Step C. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid: LiOH was added to a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (5 g, 1.0 equivalent) in MeOH (15 mL). H2O (2 M, 15.7 mL, 4 equivalents). The reaction was stirred at 25 °C for 1 hour. The mixture was purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (3 g, 57% yield) as a white solid; LCMS (ESI, M+1): m / z = 622.4.

[0529] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(4-methyl-1H-pyrazol-1-yl) methyl ketone: to 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (200 mg, 1.0 equivalent), DIEA (208 mg, 5.0 equivalent) and HATU (147 mg, 1.2 equivalents) of 4-methyl-1H-pyrazole (79.2 mg, 3.0 equivalents) was added to a solution in DMF (3.0 mL). The reaction was stirred at 30 °C for 2 hours. The mixture was filtered and purified by reversed-phase rapid chromatography [C18, H2O conditions], followed by purification by [column: Phenomenex Luna 150 × 25 mm × 10 µm; A: water (NH4HCO3), B: ACN; B%: 54%–84%, 10 min] to give the title compound (11.0 mg, 4.8% yield) as a white solid. 1 ¹H NMR (400 MHz, methanol-d⁴) δ = 9.09–9.05 (m, ¹H), 8.09 (s, ¹H), 7.71–7.64 (m, 2H), 7.33–7.21 (m, 2H), 7.06 (d, 2H) J= 2.4 Hz, 1H),5.46-5.22 (m, 1H), 4.79-4.66 (m, 2H), 4.41-4.25 (m, 2H), 4.14-4.03 (m, 1H),3.773.61 (m, 2H), 3.28-3.17 (m, 2H), 3.11-3.00 (m, 1H), 2.58-2.45 (m, 1H), 2.40-2.18 (m, 5H), 2.13 (s, 4H), 2.11-2.01 (m, 4H), 2.00-1.86 (m, 2H), 0.81(br t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 686.4.

[0530] Example 58

[0531]

[0532] (3-(dimethylamino)-1H-pyrazole-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methyl ketone

[0533]

[0534] Step A. N,N-Dimethyl-1H-pyrazole-3-amine: AcOH (361 mg, 1.0 equivalent) was added to a solution of 1H-pyrazole-3-amine (500 mg, 1.0 equivalent) and formaldehyde (542 mg, 3.0 equivalent) in MeOH (5 mL). The reaction was stirred at 25 °C for 0.5 h. NaBH3CN (227 mg, 0.6 equivalent) was added to the mixture. The reaction was stirred at 25 °C for 1 h. The mixture was concentrated. The residue was diluted with water (10 mL), neutralized with solid NaHCO3, and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to give the title compound (150 mg, 19% yield) as a colorless oil.

[0535] Step B. (3-(dimethylamino)-1H-pyrazole-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methyl ketone: to 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (200 mg, 1.0 equivalent) and N,N-dimethyl-1H-pyrazole-3-amine (53.6 mg, HATU (245 mg, 2.0 equivalent) and DIEA (125 mg, 3.0 equivalent) were added to a solution of DMF (1 mL). The reaction was stirred at 25 °C for 0.5 h. The mixture was purified by preparative HPLC [Waters Xbridge 150 × 25 mm × 5 µm; A: water (ammonium hydroxide v / v)-ACN; B: ACN, B%: 45%-75%, 10 min] to give the title compound (36.8 mg, 15% yield) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 8.96 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 3.2Hz, 1H), 7.57-7.49 (m, 1H), 7.21-7.12 (m, 2H), 7.07-6.96 (m, 1H), 6.03 (d, J = 3.2 Hz, 1H), 5.40-5.18 (m, 1H), 4.60 (br d, J = 12.4 Hz, 2H), 4.33-4.22 (m,2H), 3.98-3.85 (m, 1H), 3.57-3.42 (m, 2H), 3.38-3.12 (m, 3H), 2.98 (s, 6H), 2.55-2.42 (m, 1H), 2.40-2.04 (m, 9H), 2.00-1.87 (m, 3H), 0.83 (br t, J = 7.6Hz, 3H); LCMS (ESI, M+1): m / z = 715.4.

[0536] Example 59

[0537]

[0538] ((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-8-yl)(1H-pyrazol-1-yl)methyl ketone

[0539]

[0540] Step A. (1R,5S,8r)-3-azabicyclo[3.2.1]octyl-3,8-dicarboxylic acid 3-benzyl ester 8-methyl ester: At 0 °C, TMSCHN2 (2 M, 7.95 mL, 4.0 equivalent) was added dropwise to a solution of (1R,5S,8r)-3-((benzyloxy)carbonyl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid (1.15 g, 1.0 equivalent) in DCM (10 mL) and MeOH (10 mL). The reaction was stirred at 20 °C for 3 h. The mixture was quenched with CH3COOH (10 mL) at 0 °C. The mixture was concentrated and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 100 / 1 to 2 / 1] to give the title compound (1.1 g, 44% yield, 96% purity) as a colorless oil; LCMS (ESI, M+1): m / z = 304.2.

[0541] Step B. (1R,5S,8s)-3-azabicyclo[3.2.1]octyl-3,8-dicarboxylic acid 3-benzyl ester 8-methyl ester: (1R,5S,8r)-3-azabicyclo[3.2.1]octyl-3,8-dicarboxylic acid 3-benzyl ester 8-methyl ester (1.1 g, 1.0 equivalent) was purified by SFC [column: DAICL CHIRALPAK IK (250 mm × 30 mm, 10 μm); mobile phase: CO2-i-PrOH; B%: 30%, isocratic elution mode] to obtain two peaks.

[0542] Peak 1: (1R,5S,8S)-3-azabicyclo[3.2.1]octyl-3,8-dicarboxylic acid 3-benzyl ester 8-methyl ester (652 mg, crude), a colorless oil; SFC: Column: Chiralpak IC-3 50 × 4.6 mm ID, 3 μm; Mobile phase: Phase A: CO2, Phase B: IPA (0.05% DEA); Gradient elution: IPA (0.05% DEA) in CO2, 5% to 40%; Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35°C; Back pressure: 100 bar. tR: 1.533 min.

[0543] Peak 2: (1R,5S,8r)-3-azabicyclo[3.2.1]octyl-3,8-dicarboxylic acid 3-benzyl ester 8-methyl ester (400 mg, crude product, RT = 1.773 min), a colorless oil; t R 1.777 minutes.

[0544] Step C. (1R,5S,8r)-3-azabicyclo[3.2.1]methyl octyl-8-carboxylate: Under a nitrogen atmosphere, Pd / C (100 mg, 10% purity) was added to a solution of (1R,5S,8s)-3-azabicyclo[3.2.1]octyl-3,8-dicarboxylic acid 3-benzyl ester 8-methyl ester (652 mg, 1.0 equivalent) in MeOH (10 mL). The reaction was degassed and purged three times with H2. The reaction was stirred at 20 °C under H2 (15 psi) for 2 hours. The mixture was filtered through a diatomaceous earth mat and concentrated to give the title compound (310 mg, crude) as a colorless oil.

[0545] Step D. (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1] methyl octyl-8-carboxylate: to 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (300 mg, 1.0 equivalent of methyl octyl-8-carboxylate (128 mg, 1.5 equivalent) and (1R,5S,8r)-3-azabicyclo[3.2.1]octyl-8-carboxylate were added to a solution of DIEA (261 mg, 4.0 equivalent) in a DMAC (1 mL). The reaction was stirred at 80 °C for 2 h. The mixture was purified by reversed-phase rapid chromatography [0.1 % FA conditions] to give the title compound (275 mg, 61% yield) as a beige solid; LCMS (ESI, M+1): m / z = 662.3.

[0546] Step E. (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid: to (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octyl-8-carboxylic acid methyl ester (255 mg, Add LiOH to a solution of MeOH (1.0 equivalent) in 1 mL. H2O (2 M H2O solution, 433 µL, 3.0 equivalents). The mixture was stirred at 20 °C for 2 h. The pH of the mixture was adjusted to 8 with 1N HCl at 0 °C. The mixture was purified by reversed-phase rapid chromatography [0.1% FA conditions] to give the title compound (180 mg, 70% yield) as a beige solid; LCMS (ESI, M+1): m / z = 648.4.

[0547] Step F. ((1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-8-yl)(1H-pyrazol-1-yl) methyl ketone: to (1R,5S,8S)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]oct-8-carboxylic acid (60 TEA (75 mg, 8.0 equivalent), HOBt (19 mg, 1.5 equivalent), and EDCI (27 mg, 1.5 equivalent) were added to a solution of 1H-pyrazole (50 mg, 8.0 equivalent) in DMF (1 mL). The reaction was stirred at 40 °C for 12 h. The mixture was purified by preparative HPLC [column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: water (NH4HCO3)-ACN; gradient: 50%-80% B, duration 53 min] to give the title compound (9.1 mg, 13.6% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ =9.11 (s, 1H), 8.35 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 1.2 Hz, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.30 (d, J = 2.8 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 7.08-7.03 (m, 1H), 6.56 (dd, J = 1.6, 2.8 Hz, 1H), 5.40-5.23 (m, 1H), 4.40-4.21(m, 2H), 4.15-4.02 (m, 1H), 3.99-3.62 (m, 2H), 3.29-3.12 (m, 3H), 3.07-2.96(m, 1H), 2.93-2.76 (m, 2H), 2.61-2.09 (m, 6H), 2.08-1.75 (m, 6H), 1.74-1.58(m, 2H), 0.80 (dt, J = 2.0, 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 698.4.

[0548] Example 60

[0549]

[0550] (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)(1H-pyrazol-1-yl)methyl ketone

[0551]

[0552] Step A. 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine:At -40 °C, POCl3 (356 g, 5.0 equivalent) and DIEA (132 g, 2.2 equivalent) were added to a solution of 7-chloro-8-fluoro-pyrido[4,3-d]pyrimidin-2,4-diol (100 g, 1.0 equivalent) in toluene (300 mL). The reaction was stirred at 110 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was quenched at 0 °C by adding saturated NaHCO3 (2000 mL). The mixture was filtered and the filter cake was dissolved in ethyl acetate (1000 mL). The organic phase was washed with saturated NaHCO3 (1000 mL), dried with Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was ground with petroleum ether (500 mL) at 25 °C for 30 min to give the title compound (50 g, 81% yield) as a yellow solid.

[0553] Step B. 2,7-Dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: At 25 °C, t-BuONa (2 M, 261 mL, 1.1 equivalents) was added to a solution of 52 g, 1.1 equivalents of 2,2,2-trifluoroethanol in 200 mL of THF. The reaction was stirred at 25 °C for 1 hour. At -40 °C, the mixture was added to a solution of 120 g, 1.0 equivalents of 2,4,7-trichloro-8-fluoro-pyrido[4,3-d]pyrimidine in 1200 mL of THF. The reaction was stirred at 0 °C for 1 hour. The mixture was quenched with 500 mL of H₂O and extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with 400 mL of brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was ground with n-heptane (200 ml) and MTBE (20 mL) at 25 °C for 60 min to give the title compound (120 g, crude product), a yellow solid; LCMS (ESI, M+1): m / z = 315.9.

[0554] Step C. 7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-4-(2, 2,2-Trifluoroethoxy)pyrido[4,3-d]pyrimidine:To a solution of 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (120 g, 1.0 equivalent) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methanol (66.5 g, 1.1 equivalent) in THF (1200 mL), Na₂CO₃ (121 g, 3.0 equivalent) was added. The reaction was stirred at 40 °C for 12 h. The mixture was filtered and purified by reversed-phase rapid chromatography [water (FA, 0.1 %) / acetonitrile] to give the title compound (100 g, two steps: 57% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 439.1.

[0555] Step D. 5-Ethyl-6-fluoro-4-(8-fluoro-2-((((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol: to 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidinyl (28.4 g, 1.0 equivalent), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)naphth-2-ol (25.6 g, 1.25 equivalent) and Cs2CO3 (1.5 g). A solution of M in H₂O (129 mL, 3.0 equivalents) was added to a solution of Ad₂nBuP-Pd-G₃ (7.07 g, 0.15 equivalents) in methoxycyclopentane (300 mL). The reaction mixture was degassed and purged three times with nitrogen. The reaction was stirred at 100 °C for 3 hours. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reversed-phase rapid chromatography [water (0.1 % FA) / acetonitrile] to give the title compound (16.8 g, 40% yield) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 9.19 (d, J = 10.4 Hz, 1H), 7.54 (dd, J= 5.6, 8.8 Hz, 1H), 7.26-7.21 (m,1H), 7.16-7.11 (m, 1H), 6.96-6.84 (m, 1H), 5.46-5.22 (m, 1H), 5.05-4.71 (m,2H), 4.56-4.32 (m, 2H), 3.48-3.21 (m, 3H), 3.13-3.01 (m, 1H), 2.47-2.32 (m,4H), 2.32-2.08 (m, 4H), 0.78 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z =593.2.

[0556] Step E. 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol: 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (1.00 g, 1.0 equivalent) was added to a solution of piperazine (727 mg, 5.0 equivalent) in DMF (10 mL). The reaction was stirred at 25 °C for 2 hours. The mixture was purified by reversed-phase rapid chromatography [water (neutral) / acetonitrile = 1 / 1] to give the title compound (914 mg, 90% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 579.4.

[0557] Step F. (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)(1H-pyrazol-1-yl) methyl ketone: At 0 °C, bis(trichloromethyl) carbonate (120 mg, 1.4 equivalents) was added to a mixture of 1H-pyrazole (20.0 mg, 1.0 equivalent) and DIEA (151 mg, 4.0 equivalent) in DCM (0.3 mL). The reaction was stirred at 0 °C for 1 hour. At 0 °C, 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(piperazin-1-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (153 mg, 0.9 equivalent) and DIEA (56.9 mg, 1.5 equivalent) in DCM (0.7 mL) were added dropwise to the mixture. The reaction was stirred at 20 °C for 14 hours. The mixture was quenched with saturated aqueous NaHCO3 solution (5 mL) and extracted with DCM (4 × 3 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [column: Waters Xbridge 150 × 25 mm × 5 µm; mobile phase: water (ammonium hydroxide v / v)-acetonitrile; gradient: 42%-72% B, 10 min] to give the title compound (75.7 mg, 38% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.95 (br s, 1H),9.18 (s, 1H), 8.28 (d, J = 2.4 Hz, 1H), 7.82 (s, 1H), 7.77 (dd, J = 6.0, 9.0Hz, 1H), 7.40-7.30 (m, 2H), 7.02 (d, J = 1.6 Hz, 1H), 6.53 (br d, J= 1.6 Hz,1H), 5.39-5.17 (m, 1H), 4.24-3.97 (m, 10H), 3.12-3.03 (m, 2H), 3.02-2.90 (m,1H), 2.85-2.79 (m, 1H), 2.42-2.30 (m, 1H), 2.20-2.09 (m, 2H), 2.08-1.95 (m,2H), 1.89-1.71 (m, 3H), 0.73 (br t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z =673.2.

[0558] Example 61

[0559]

[0560] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-methoxy-1H-pyrazol-1-yl)methyl ketone

[0561]

[0562] Step A. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-methoxy-1H-pyrazole-1-yl) methyl ketone; to 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (350 mg, 1.0 equivalent) and 3-methoxy-1H-pyrazole (55.2 mg, 1.0 equivalent) in DMF HATU (428 mg, 2.0 equivalent) and DIEA (364 mg, 5.0 equivalent) were added to a solution in 4 mL. The reaction was stirred at 25 °C for 3 hours. The mixture was diluted with water (4 mL) and extracted with ethyl acetate (4 mL). The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by preparative HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3), B: ACN, B%: 54%–84%, 9 min] to give the title compound (15.5 mg, 4% yield) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 8.97 (s, ¹H), 8.08 (d, ¹H) J = 3.2 Hz, 1H), 7.60-7.51 (m, 1H), 7.23-7.16 (m, 2H), 7.06-6.97 (m, 1H), 6.02 (d, J = 2.8 Hz, 1H), 5.35 (br s, 1H), 4.69-4.55 (m, 2H), 4.29 (br d, J = 6.4 Hz, 2H), 3.99 (s, 3H), 3.90 (br dd, J = 5.2, 10.1 Hz, 1H), 3.59-3.43 (m, 2H), 3.36-3.14 (m, 3H), 3.05 (s, 1H), 2.56-2.40 (m, 2H), 2.27-2.06 (m, 7H), 1.99-1.87 (m, 3H), 0.83 (br t, J = 7.2Hz, 3H) LCMS (ESI, M+1): m / z =702.4.

[0563] Example 62

[0564]

[0565] 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-N-(pyridin-2-yl)piperidin-4-carboxamide

[0566]

[0567] Step A. Methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: Add PyBOP to a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (2.00 g, 1.0 equivalent) and methyl piperidine-4-carboxylate (1.03 g, 2.0 equivalent) in DMF (20 mL). (2.82 g, 1.5 equivalents) and DIEA (1.40 g, 3.0 equivalents). The reaction was stirred at 25 °C for 3 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (2.1 g, 74% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 680.3.

[0568] Step B. 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid: LiOH was added to a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (2.0 g, 1.0 equivalent) in MeOH (6.2 mL). H2O (2 M H2O solution, 6.2 mL, 4.2 equivalents). The reaction was stirred at 25 °C for 0.5 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (600 mg, 30% yield) as a white solid; LCMS (ESI, M+1): m / z = 666.4.

[0569] Step C. 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-N-(pyridin-2-yl)piperidin-4-carboxamide: to 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (300 mg, 1.0 equivalent) and N-methylpyridin-2-amine (195 mg, 460 mg of 2-chloro-1-methylpyridinium iodide and DIEA (349 mg, 6.0 equivalents) were added to a solution of 2-chloro-1-methylpyridinium iodide in 3 mL of THF. The reaction was stirred at 25 °C for 12 h. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (ammonium hydroxide), B: ACN, B%: 40%–70%, 10 min] to give the title compound (112 mg, 32% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 756.4.

[0570] Step D. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-N-(pyridin-2-yl)piperidine-4-carboxamide: to 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N-methyl-N-(pyridin-2-yl)piperidine-4-carboxamide (112 mg, 1.0 equivalent) in MeOH (1 Add HCl to the solution in mL) MeOH (4 M, 1 mL, 27 equivalents). The reaction was stirred at 25 °C for 0.5 h. The mixture was concentrated, alkalized with saturated NaHCO3 solution (6 mL), and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (FA), B: ACN, B%: 15%–45%, 10 min] to give the title compound (71.4 mg, 67% yield, 0.23 HCOOH) as a yellow solid. 1 ¹H NMR (400MHz, chloroform-d) δ = 8.86 (s, ¹H), 8.56–8.50 (m, ¹H), 7.82 (br t, J = 7.8 Hz,1H), 7.52-7.43 (m, 1H), 7.32-7.27 (m, 1H), 7.24 (s, 1H), 7.17-7.08 (m, 2H),7.02-6.90 (m, 1H), 5.42-5.16 (m, 1H), 4.59-4.41 (m, 2H), 4.39-4.21 (m, 2H), 3.52 (br d, J = 14.0 Hz, 1H), 3.36 (s, 3H), 3.33-2.94 (m, 5H), 2.86-2.71 (m,1H), 2.48-1.83 (m, 12H), 0.77 (br t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z =712.4.

[0571] Example 63

[0572]

[0573] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-4-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone

[0574]

[0575] Step A. Methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptan-4-carboxylate: to 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (400 mg, 1.0 equivalent) and benzotriazol-1-yloxy-tris-(pyrrolidine-1-yl)-hexafluorophosphate (751 mg, TEA (301 μL, 3.0 equivalent) and methyl aziridine-4-carboxylate (340 mg, 3.0 equivalent) were added to a mixture in DMSO (4 mL). The reaction was stirred at 35 °C for 12 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (380 mg, 76% yield) as a yellow oil; LCMS (ESI, M+1): m / z = 694.4.

[0576] Step B. Methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-4-carboxylate: At 0 °C, HCl was added to a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-4-carboxylate (260 mg, 1.0 equivalent) in ACN (2 mL). Dioxane (4 M, 3.5 mL, 37 equivalents). The reaction was stirred at 15 °C for 1 hour. The mixture was adjusted to pH 7 with saturated NaHCO3 (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (300 mg, crude) as a yellow oil.

[0577] Step C. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-4-carboxylic acid: Add LiOH (2 M, 923 μL, 4.0 equivalents) to a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-4-carboxylic acid (300 mg, 1.0 equivalents) in MeOH (3 mL). The reaction was stirred at 15 °C for 2 hours. The mixture was adjusted to pH 8 with HCl (1 M) and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (190 mg, 64% yield) as a white solid; LCMS (ESI, M+1): m / z = 636.4.

[0578] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-4-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone: to 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-4-carboxylic acid (30.0 mg, 1.0 equivalent) and 3-methyl-1H-pyrazole (7.75 mg, HATU (35.9 mg, 2.0 equivalent) and TEA (19.7 μL, 3.0 equivalent) were added to a solution of DMF (0.3 mL). The reaction was stirred at 25 °C for 1 hour. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [column: Waters Xbridge 150 × 25 mm × 10 µm; A: water (NH4HCO3), B: ACN; B%: 53%–73%, 8 min] to give the title compound (9.07 mg, 27% yield) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ = 9.18 (d, J = 2.4 Hz, 1H), 8.19(t, J = 3.2 Hz, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.34-7.19 (m, 2H), 7.07(dd, J = 2.4, 7.6 Hz, 1H), 6.37 (d, J = 1.2 Hz, 1H), 5.37-5.20 (m, 1H), 4.49-4.22 (m, 4H), 4.14 (br s, 1H), 4.02 (br d, J = 9.2 Hz, 1H), 3.88 (br s, 1H), 3.21 (br d, J= 19.8 Hz, 3H), 3.08-2.96 (m, 1H), 2.57-2.41 (m, 2H), 2.39-2.31(m, 1H), 2.31-2.10 (m, 10H), 2.05-1.94 (m, 2H), 1.92-1.77 (m, 2H), 0.87-0.77(m, 3H); LCMS (ESI, M+1): m / z = 700.4.

[0579] Example 64

[0580]

[0581] (4-(dimethylamino)-1H-pyrazole-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methyl ketone

[0582]

[0583] Step A. 4-(dimethylamino)-1H-pyrazole-1-carboxylic acid tert-butyl ester: AcOH (164 mg, 1.0 equivalent) was added to a solution of tert-butyl 4-aminopyrazole-1-carboxylate (500 mg, 1.0 equivalent) and formaldehyde (2.22 g, 37% purity, 10 equivalent) in MeOH (10 mL). The reaction was stirred at 25 °C for 0.5 h. Sodium cyanoborohydride (514 mg, 3.0 equivalent) was added to the reaction mixture. The reaction was stirred at 25 °C for 0.5 h. The mixture was concentrated, alkalized with NaHCO3 (10 mL), and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (2 × 2 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give the title compound (500 mg, 81% yield) as a white oil; LCMS (ESI, M-99, M-55): m / z = 112.0, 156.0

[0584] Step B. N,N-Dimethyl-1H-pyrazole-3-amine:TFA (767 mg, 5.7 equivalents) was added to a solution of tert-butyl 4-(dimethylamino)-1H-pyrazole-1-carboxylate (250 mg, 1 equivalent) in DCM (0.5 mL). The reaction was stirred at 25 °C for 0.5 h. The mixture was concentrated. The residue was alkalized with NaHCO3 (2 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (2 × 2 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (130 mg, 99% yield) as a colorless oil.

[0585] Step C. (3-(dimethylamino)-1H-pyrazole-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl) methyl ketone: to 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (150 mg, 1.0 equivalent) and N,N-dimethyl-1H-pyrazole-4-amine (53.6 mg, HATU (183 mg, 2.0 equivalent) and DIEA (93.5 mg, 3.0 equivalent) were added to a solution of HATU (1 mL) in DMF. The reaction was stirred at 25 °C for 0.5 h. The mixture was purified by reversed-phase rapid chromatography [C18, water / ACN] to give the title compound (10.3 mg, 5% yield) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 8.94 (d, J = 7.2 Hz, 1H), 7.53-7.46 (m,3H), 7.19-7.08 (m, 2H), 7.06-6.94 (m, 1H), 5.39-5.19 (m, 1H), 4.60 (br dd, J = 4.4, 8.4 Hz, 2H), 4.34-4.23 (m, 2H), 4.05-3.95 (m, 1H), 3.54-3.08 (m, 6H), 3.05-2.95 (m, 1H), 2.80 (s, 6H), 2.51-2.03 (m, 9H), 2.00-1.88 (m, 3H), 0.86-0.78 (m, 3H); LCMS (ESI, M+1): m / z = 715.3.

[0586] Example 65

[0587]

[0588] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone

[0589]

[0590] Step A. Methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylic acid: to 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (300 mg, 1.0 equivalent), TEA (164 mg, Methyl piperidine-3-carboxylate (155 mg, 2.0 equivalent) was added to a solution of benzotriazol-1-yloxy-tris-(pyrrolidine-1-yl)-β-hexafluorophosphate (422 mg, 1.5 equivalent) in DMSO (3 mL). The reaction was stirred at 30 °C for 6 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (300 mg, 81% yield) as a yellow oil; LCMS (ESI, M+1): m / z = 680.4.

[0591] Step B. Methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylate: Add HCl to a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylate (150 mg, 1.0 equivalent) in MeCN (0.5 mL). Dioxane (4 M, 1.0 mL). The reaction was stirred at 0 °C for 0.5 h. At 0 °C, the mixture was adjusted to pH > 8 with saturated aqueous NaHCO3 solution (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (120 mg, crude) as a yellow solid; LCMS (ESI, M+1): m / z = 636.3.

[0592] Step C. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylic acid: LiOH was added to a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-3-carboxylic acid (70.0 mg, 1.0 equivalent) in THF (0.2 mL) and MeOH (0.3 mL). H₂O (13.9 mg, 3.0 equivalents) in a H₂O (0.2 mL) solution. The reaction was stirred at 20 °C for 1 hour. The mixture was adjusted to pH ≈ 6 with HCl (4 M, 0.8 mL) at 0 °C and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (50.0 mg, 72% yield) as a white solid; LCMS (ESI, M+1): m / z = 622.3.

[0593] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone: to 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-3-carboxylic acid (80.0 mg, 1.0 equivalent), EDCI (37.0 mg, 1.5 equivalent), HOBt (26.1 mg, 3-methylpyrazole (21.1 mg, 2.0 equivalent) was added to a mixture of 1.5 equivalents of DIEA and 49.9 mg (3.0 equivalents) in DMF (1.0 mL). The reaction was stirred at 20 °C for 12 hours.

[0594] The mixture was filtered and purified by reversed-phase rapid chromatography [C18, neutral conditions] to give the title compound (18.5 mg, 20% yield) as a yellow solid; 1 H NMR (400 MHz, DMSO-d6) δ = 9.94 (br d, J =5.2 Hz, 1H), 9.30 (d, J = 5.6 Hz, 1H), 8.31-8.30 (m, 1H), 7.79-7.50 (m, 1H), 7.45-7.26 (m, 2H), 7.07-6.98 (m, 1H), 6.48-6.46 (m, 1H), 5.40-5.14 (m, 1H),4.73-4.68 (m, 1H), 4.45-4.42 (m, 1H), 4.17-4.09 (m, 1H), 4.07-4.03 (m, 1H),3.76-3.65 (m, 1H), 3.56-3.43 (m, 2H), 3.12-3.04 (m, 2H), 3.00 (br s, 1H),2.85-2.78 (m, 1H), 2.33 (br s, 1H), 2.27 (d, J = 10.4 Hz, 3H), 2.21-2.10 (m,3H), 2.05 (br s, 2H), 1.95 (br d, J= 8.8 Hz, 2H), 1.88-1.72 (m, 4H), 0.75-0.67 (m, 3H); LCMS (ESI, M+1): m / z = 686.4.

[0595] Example 66

[0596]

[0597] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-vinyl-1H-pyrazol-1-yl)methyl ketone

[0598]

[0599] Step A. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-vinyl-1H-pyrazol-1-yl) methyl ketone:

[0600] To a solution of 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (300 mg, 1.0 equivalent) and 3-vinyl-1H-pyrazole (300 mg, 6.6 equivalent) in DMF (3 mL), HATU (367 mg, 2.0 equivalent) and DIEA (312 mg, 5.0 equivalent) were added. The mixture was stirred at 25 °C for 0.5 h. The mixture was filtered and purified by preparative HPLC [Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; A: water (NH4HCO3), B: ACN, B%: 45%–75%, 20 min] to give the title compound (4.94 mg, 1.4% yield) as an orange solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 8.98 (s, ¹H), 8.20 (d, ¹H) J = 3.0 Hz, 1H), 7.63-7.51 (m, 1H), 7.23-7.13 (m, 2H), 7.03 (dd,J = 2.4, 18.6 Hz, 1H), 6.77 (dd, J = 11.2, 17.8 Hz, 1H), 6.63 (d, J = 2.8 Hz, 1H), 5.91 (d, J = 17.8 Hz, 1H), 5.58 (d, J = 11.3 Hz, 1H), 5.41-5.19 (m, 1H), 4.70-4.58 (m, 2H), 4.36-4.21(m, 2H), 4.09-3.96 (m, 1H), 3.61-3.42 (m, 2H), 3.37-3.12 (m, 3H), 3.05-2.94(m, 1H), 2.57-2.40 (m, 1H), 2.31 (br s, 1H), 2.28-2.06 (m, 7H), 2.02-1.92 (m,3H), 0.83 (br t, J = 7.4 Hz, 3H); LCMS (ESI, M+1): m / z = 698.4.

[0601] Example 67

[0602]

[0603] (1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone

[0604]

[0605] Step A. 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine:To a solution of POCl3 (187 g, 5.0 equivalents) in toluene (150 mL), 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (52.6 g, 1.0 equivalents) and DIEA (69.4 g, 2.2 equivalents) were added. The reaction was stirred at 110 °C for 27 h. The solvent was concentrated under vacuum. The mixture was poured into an ice-cold saturated NaHCO3 solution (2.5 L) and kept at pH 8, then filtered. The filter cake was dissolved in ethyl acetate (1.5 L) and washed with saturated NaHCO3 aqueous solution (1 L) and saturated brine (1 L). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound (50 g, 81% yield) as a brown solid.

[0606] Step B. 2,7-Dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: At 0 °C, NaH (7.98 g, 60% purity, 1.2 equivalents) was added to a solution of 2,2,2-trifluoroethanol (15.0 g, 0.9 equivalents) in THF (150 mL). The mixture was stirred at 0 °C for 0.5 h. Then, at -40 °C, the mixture was added to a solution of 2,4,7-trichloro-8-fluoropyridyl[4,3-d]pyrimidine (42.0 g, 1.0 equivalents) in THF (840 mL). The reaction was stirred at -40 °C for 1 h. The mixture was quenched with H2O (500 mL) and extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate 10 / 1 to 5 / 1] to give the title compound (34.4 g, 53% yield) as a yellow solid; LCMS [ESI, M+1]: 315.9.

[0607] Step C. 7-Chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-4-(2, 2,2-Trifluoroethoxy)pyrido[4,3-d]pyrimidine: To 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (33.3 g, 1.0 equivalent), DIEA (54.5 g, 4.0 equivalent), and 4 Molecular sieve (4.0 g) was added to a mixture of (2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methanol (20.1 g, 1.2 equivalents) in THF (340 mL). The reaction mixture was stirred at 40 °C for 14 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated under vacuum, and purified by reversed-phase rapid chromatography [water (FA, 0.1 %) / acetonitrile] to give the title compound (28.8 g, 62% yield) as a yellow solid.1 ¹H NMR (400 MHz, chloroform-d) δ 8.98 (s, ¹H), 5.40–5.19 (m, ¹H), 5.02 (q, δ) J LCMS [ESI, M+1]: 439.1.

[0608] Step D. 8-Fluoro-7-(7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine: to 7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine (2.20 g, A solution of 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (3.85 g, 1.5 equivalent) in methoxycyclopentane (25 mL) was reacted with CataCxium (R) A Pd G3 (365 mg, 0.1 equivalent) and Cs2CO3 (1.5 M aqueous solution, 2.5 equivalent). The reaction was stirred at 100 °C under N2 atmosphere for 3 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (40 mL). The organic layer was dried over sodium sulfate, concentrated, and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (2.80 g, 64% yield) as a brown solid. LCMS (ESI, M+1): m / z =789.4.

[0609] Step E. Methyl 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: At 25°C, to 8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidinyl (1.20 g, DIEA (590 mg, 3.0 equivalent) and 4 Å molecular sieve (1.00 g) were added to a solution of methyl piperidine-4-carboxylate (653 mg, 3.0 equivalent) in DMF (12 mL). The reaction was stirred at 70 °C for 12 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate, concentrated, and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (800 mg, 56% yield) as a yellow solid. LCMS (ESI, M+1): m / z = 832.5.

[0610] Step F. Methyl 1-(8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: At 0 °C, methyl 1-(8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (1.00 g, 1.0 equivalent) was added to MeOH HCl / MeOH (2 M, 20 mL, 33.28 equivalents) was added to the solution in 10 mL. The reaction was stirred at 0 °C for 0.5 h. The mixture was concentrated under vacuum. The mixture was alkalized with NaHCO3 (10 mL) and extracted with ethyl acetate (10 mL). The combined organic layers were dried over sodium sulfate and concentrated to give the title compound (900 mg, crude) as a yellow solid. LCMS (ESI, M+1): m / z = 788.4.

[0611] Step G. Methyl 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: Add CsF (2.26 g, 13 equivalents) to a solution of methyl 1-(8-fluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (900 mg, 1.0 equivalent) in DMF (9 mL). The reaction was stirred at 40 °C for 14 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was dried over sodium sulfate and concentrated to give the title compound (900 mg, crude) as a yellow solid. LCMS (ESI, M+1): m / z = 632.3.

[0612] Step H. 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid: Add LiOH·H2O (1.5 M aqueous solution, 2.11 mL, 4.0 equivalents) to a solution of methyl 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (500 mg, 1.0 equivalents) in MeOH (5 mL). The reaction was stirred at 25 °C for 0.5 h. The mixture was concentrated, diluted with water (5 mL), and extracted with ethyl acetate (7 mL). The organic layer was dried over sodium sulfate, concentrated, and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (300 mg, 58% yield) as a yellow solid. LCMS (ESI, M+1): m / z = 618.2.

[0613] Step I. (1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone: to 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (150 mg, 242.87 μmol, 1 eq EDCI (69.8 mg, 1.5 equivalent) and DMAP (44.5 mg, 1.5 equivalent) were added to a solution of 3-methyl-1H-pyrazole (39.9 mg, 2.0 equivalent) in DCM (0.5 mL). The reaction was stirred at 25 °C for 12 h. The mixture was concentrated, diluted with water (5 mL), and extracted with ethyl acetate (7 mL). The combined organic layers were dried over sodium sulfate, concentrated, and purified by preparative HPLC [Waters Xbridge Prep OBD C18 150 × 40 mm × 10 µm; A: water (10 mM NH4HCO3), B: ACN, B%: 38%–68%, 20 min] to give the title compound (31.5 mg, 18% yield) as an orange solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 8.94 (d, J = 4.4 Hz, 1H), 8.15(d, J = 2.8 Hz, 1H), 7.68-7.56 (m, 1H), 7.24-7.09 (m, 3H), 6.29 (d, J = 2.8Hz, 1H), 5.40-5.13 (m, 1H), 4.64 (br d, J = 13.2 Hz, 2H), 4.31-4.19 (m, 2H), 4.07-3.97 (m, 1H), 3.52 (br t, J = 11.2 Hz, 2H), 3.33-3.10 (m, 3H), 3.04-2.90(m, 1H), 2.80 (s, 1H), 2.35 (s, 3H), 2.33-2.27 (m, 1H), 2.21 (br d, J= 10.0Hz, 3H), 2.11 (br d, J = 12.8 Hz, 3H), 2.03-1.90 (m, 3H); LCMS (ESI, M+1): m / z =682.4.

[0614] Example 68

[0615]

[0616] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-3-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone

[0617]

[0618] Step A. Methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptan-3-carboxylate: Add TEA (456 mg, 5.0 equivalent) and PyBOP (938 mg, 5.0 equivalent) to a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (500 mg, 1.0 equivalent) in DMSO (5 mL). 2.0 equivalents). The reaction was stirred at 30 °C for 0.5 h. Then, methyl aziridine-3-carboxylate (262 mg, 1.5 equivalents, HCl) was added to the mixture. The reaction was stirred at 30 °C for 12 h. The mixture was filtered and washed with DMSO (1 mL), and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (265 mg, 41% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 694.3.

[0619] Step B. Methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-3-carboxylate: Add HCl to a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-3-carboxylate (143 mg, 1.0 equivalent) in ACN (1 mL). Dioxane (4 M, 2 mL, 39 equivalents). The reaction was stirred at 20 °C for 0.5 h. The mixture was adjusted to pH 8 with saturated NaHCO3 aqueous solution (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (160 mg, crude) as a yellow solid; LCMS (ESI, M+1): m / z = 650.4.

[0620] Step C. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-3-carboxylic acid: At 0 °C, methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-3-carboxylic acid (160 mg, 1.0 equivalent) was added to a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-3-carboxylic acid in THF (0.6 mL), MeOH (0.4 mL), and H₂O (0.6 mL) with LiOH. H2O (31.0 mg, 3.0 equivalents). The reaction was stirred at 20 °C for 2 hours. The mixture was filtered and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (100 mg, 63% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 636.3.

[0621] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-3-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone: to 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacycloheptane-3-carboxylic acid (100 mg, 1.0 equivalent), DIEA (61.0 mg, 3.0 equivalent), HOBt (31.9 mg, 3.0 equivalent). 3-methyl-1H-pyrazole (25.8 mg, 2.0 equivalent) was added to a solution of EDCI (45.2 mg, 1.5 equivalent) in DMF (0.5 mL). The reaction was stirred at 20 °C for 12 h. The mixture was filtered and purified by reversed-phase rapid chromatography [C18, H2O conditions] to give the title compound (17.6 mg, 15% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.93 (s, 1H), 9.26 (s, 1H), 8.34 (d, J = 2.7 Hz, 1H), 7.76 (dd, J = 6.0, 8.8 Hz, 1H), 7.43-7.28(m, 2H), 7.01 (dd, J = 2.4, 14.0 Hz, 1H), 6.50 (d, J = 2.8 Hz, 1H), 5.30-5.04(m, 1H), 4.63-4.48 (m, 1H), 4.26-4.06 (m, 3H), 4.01-3.70 (m, 3H), 3.05-2.87(m, 3H), 2.75 (br s, 1H), 2.40-2.31 (m, 1H), 2.26 (s, 3H), 2.20-2.13 (m, 1H), 2.12-2.01 (m, 3H), 1.97-1.89 (m, 2H), 1.88-1.49 (m, 7H), 0.73 (td, J = 7.6,17.2 Hz, 3H); LCMS (ESI, M+1): m / z = 700.3.

[0622] Example 69

[0623]

[0624] (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-diazacycloheptane-1-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone

[0625]

[0626] Step A. 4-(4-(1,4-diazacycloheptane-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol: Add 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthyl-2-ol (400 mg, 1.0 equivalent) to a solution of 1,4-diazacycloheptane (169 mg, 2.5 equivalent) in DMF (3.5 mL). The reaction was stirred at 25 °C for 2 hours. The mixture was purified by reversed-phase rapid chromatography [water (0.1% formic acid) / acetonitrile = 1 / 4] to give the title compound (370 mg, 85.7% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 593.3.

[0627] Step B. (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-diazacycloheptane-1-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone: At 0 °C, bis(trichloromethyl) carbonate (320 mg, 2.9 equivalents) was added to a solution of 5-methyl-1H-pyrazole (30.0 mg, 1.0 equivalent) and DIEA (189 mg, 4.0 equivalent) in DCM (0.5 mL). The reaction was stirred at 0 °C for 1 hour. At 0 °C, 4-(4-(1,4-diazacycloheptane-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-ol (195 mg, 0.9 equivalents) and DIEA (70.8 mg, 1.5 equivalents) were added, and the reaction was stirred at 20 °C for 14 hours. The mixture was quenched with saturated aqueous NaHCO3 solution (10 mL) and extracted with DCM (4 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reversed-phase rapid chromatography [water (0.1% formic acid) / acetonitrile = 1 / 1] and preparative HPLC [column: Waters Xbridge 150 × 25 mm × 5 µm; mobile phase: (water (ammonium hydroxide v / v) - acetonitrile); gradient: 46%-76% B, 10 min] to give the title compound (23.1 mg, 9% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.90 (br s, 1H), 9.18 (s, 1H), 7.98(s, 1H), 7.76 (dd, J = 6.0, 9.2 Hz, 1H), 7.39-7.29 (m, 2H), 7.02 (d, J = 2.4Hz, 1H), 6.25 (d, J= 2.4 Hz, 1H), 5.37-5.16 (m, 1H), 4.41-4.26 (m, 2H), 4.25-4.00 (m, 6H), 3.97-3.69 (m, 2H), 3.14-3.02 (m, 2H), 3.00 (s, 1H), 2.86-2.76 (m, 1H), 2.39-2.26 (m, 1H), 2.22-1.93 (m, 9H), 1.89-1.67 (m, 3H), 0.76-0.64 (m, 3H); LCMS (ESI, M+1): m / z = 701.5.

[0628] Example 70

[0629]

[0630] (S,Z)-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone

[0631]

[0632] Step A. 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidine- 2,4-Diol: To a mixture of 7-chloro-8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol (150 g, 1.0 equivalent) and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (263 g, 1.1 equivalent) in dimethylformamide (1500 mL) and water (300 mL), cataCXium® A Pd G3 (25.3 g, 0.05 equivalent) and potassium phosphate (295 g, 2.0 equivalent) were added. The reaction mixture was degassed and purged three times with nitrogen, and stirred at 100 °C under a nitrogen atmosphere for 12 hours. The mixture was filtered, and the filter cake was washed with dimethylformamide (300 mL). The filtrate was concentrated, ground with water (2000 mL), filtered, and washed with water (1000 mL) and ethanol (500 mL). The crude product was ground with methyl tert-butyl ether (600 mL), filtered, and washed with methyl tert-butyl ether (200 mL) to give 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol (102 g, 34.0% yield), as a yellow solid; 1H NMR (400 MHz, DMSO- d 6) δ = 12.29-11.37 (m, 2H), 8.84 (s, 1H), 7.90(dd, J = 6.0, 8.8 Hz, 1H), 7.68 (d, J = 2.8 Hz, 1H), 7.44 (t, J = 9.2 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 5.34 (s, 2H), 3.42 (s, 3H), 2.42-2.29 (m, 1H), 2.25-2.12 (m, 1H), 0.79 (t, J = 7.2 Hz, 3H).

[0633] Step B. 2,4-Dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyrido[4, 3-d]pyrimidine: At 0 °C, POCl3 (3.34 g, 5.0 equivalent) and DIEA (2.28 mL, 3.0 equivalent) were added dropwise to a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2,4-diol (1.80 g, 1.0 equivalent) in toluene (30.0 mL). The reaction was stirred at 100 °C for 1 hour. The mixture was concentrated and then poured into a saturated NaHCO3 solution (100 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over sodium sulfate, concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate 20 / 1 to 5 / 1) to give the title compound (1.60 g, 81% yield) as a yellow oil. 1 ¹H NMR (400 MHz, chloroform-d) δ = 9.54 (s, ¹H), 7.73 (dd, ¹H) J = 6.0, 9.2 Hz, 1H), 7.59 (d, J = 2.8 Hz, 1H), 7.30 (t, J = 9.2 Hz, 1H), 7.20 (d, J = 2.8 Hz, 1H), 5.31 (d, J = 2.0 Hz, 2H), 3.53 (s, 3H), 2.48-2.35(m, 1H), 2.21-2.07 (m, 1H), 0.81 (t, J = 7.4 Hz, 3H).

[0634] Step C. Methyl 1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: At -40 °C, TEA (411 mg, 3 equivalents) was added to a solution of 2,4-dichloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidinyl (610 mg, 1.0 equivalent) in DCM (12 mL). At -40 °C, a solution of methyl piperidine-4-carboxylate (155 mg, 0.8 equivalent) in DCM (3 mL) was added dropwise to the mixture. The reaction was stirred at -40 °C for 1 hour. The mixture was diluted with water (20 mL) and extracted with dichloromethane (2 × 20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (petroleum ether / ethyl acetate 20 / 1 to 2 / 1) to give the title compound (940 mg, 56% yield) as a yellow solid. 1 ¹H NMR (400 MHz, methanol-d⁴) δ 9.18 (s, ¹H), 7.84–7.76 (m, ¹H), 7.63 (d, ¹H) J = 2.8 Hz, 1H), 7.32 (t, J = 9.2 Hz, 1H), 7.23 (d, J = 2.8 Hz, 1H), 5.33 (s, 2H), 4.68-4.59 (m, 2H), 3.73 (s, 3H), 3.72-3.63 (m, 2H), 3.50 (s, 3H), 2.93-2.83 (m,1H), 2.54-2.40 (m, 1H), 2.27-2.13 (m, 3H), 2.02-1.89 (m, 2H), 0.81 (t, J =7.6 Hz, 3H).

[0635] Step D. Methyl (S,Z)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: At 0 °C, NaH (89.8 mg, 60% purity, 2.5 equivalents) was added to a solution of (S,Z)-(2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (169 mg, 1.1 equivalents) in THF (10 mL). The reaction was stirred at 0 °C for 10 min. Methyl 1-(2-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylate (500 mg, 1 equivalent) was added to the mixture. The reaction was stirred at 0–20 °C for 1 hour. The mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (300 mg, 43% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 692.4.

[0636] Step E. Methyl (S,Z)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate: Add HCl dropwise to a mixture of (S,Z)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (350 mg, 1 equivalent) in ACN (1.25 mL). Dioxane (2 M, 5.06 mL, 20 equivalents). The reaction was stirred at 25 °C for 1 h. The mixture was concentrated. The residue was alkalized with saturated NaHCO3 solution (6 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (300 mg, 82% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 648.4.

[0637] Step F. (S,Z)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid: Add a solution of NaOH (92.6 mg, 5 equivalents) in H2O (1.5 mL) to a solution of (S,Z)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid methyl ester (300 mg, 1.0 equivalent) in EtOH (4.5 mL). The reaction was stirred at 25°C for 1 hour. The mixture was filtered and subjected to reversed-phase rapid chromatography [water (NH3)] Purification with H2O / acetonitrile yielded the title compound (200 mg, 67% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 634.3.

[0638] Step G. (S,Z)-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone: to (S,Z)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-((2-(fluoromethylene)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (100 mg, 1 equivalent) and EDCI (45.4 mg, 1.5 equivalent) in DMF (1 HOBt (25.6 mg, 1.2 equivalents) and TEA (63.9 mg, 4.0 equivalents) were added to a solution in mL, followed by 3-methyl-1H-pyrazole (38.9 mg, 3.0 equivalents). The reaction was stirred at 25 °C for 12 hours. The mixture was filtered and purified by preparative HPLC [Phenomenex Luna C18 150 × 25 mm × 10 µm; A: water (NH4HCO3), B: ACN, B%: 56%–86%, 10 min], followed by purification by preparative HPLC [Phenomenex Luna C18 150 × 25 mm × 10 µm; A: water (FA), B: ACN, B%: 20%–50%, 1 min]. The desired fraction was diluted with water (60 mL) and extracted with dichloromethane (2 × 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound (2.50 mg, 2.2% yield) as a white solid. 1HNMR (400 MHz, chloroform-d3) δ 9.03-8.96 (m, 1H), 8.19-8.14 (m, 1H), 7.61-7.54 (m,1H), 7.25-7.19 (m, 2H), 7.08-7.02 (m, 1H), 6.65-6.37 (m, 1H), 6.33-6.28 (m,1H), 4.72-4.61 (m, 2H), 4.36-4.19 (m, 2H), 4.09-3.99 (m, 1H), 3.98-3.85 (m,1H), 3.61-3.49 (m, 2H), 3.48-3.40 (m, 1H), 3.30-3.15 (m, 1H), 2.82-2.72 (m,1H), 2.72-2.62 (m, 1H), 2.56-2.45 (m, 1H), 2.40-2.32 (m, 4H), 2.28-2.06 (m,7H), 1.98-1.91 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z =698.5.

[0639] Example 71

[0640]

[0641] ((3S,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-4-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone

[0642]

[0643] Step A. (3S,4R)-3-methylpiperidin-4-carboxylic acid: HCl was added to a solution of (3S,4R)-1-(tert-butoxycarbonyl)-3-methylpiperidin-4-carboxylic acid (250 mg, 1.0 equivalent) in ACN (0.5 mL). Dioxane (2 M, 0.5 mL, 1.0 equivalent). The reaction was stirred at 25 °C for 0.5 h. The mixture was concentrated to give the title compound (120 mg, 73% yield) as a white solid; MS (ESI, M+1): m / z = 144.4

[0644] Step B. (3S,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-4-carboxylic acid: to 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (130 mg, 1.0 equivalent) in DMF (1.5 (3S,4R)-3-methylpiperidin-4-carboxylic acid (62.8 mg, 2.0 equivalent) and K3PO4 (279 mg, 6.0 equivalent) were added to a solution in mL. The reaction was stirred at 60 °C for 0.5 h. The mixture was purified by preparative HPLC [Phenomenex luna C18150 × 25 mm × 10 µm; A: water (FA)-ACN; B: ACN, B%: 15%–45%, 9 min] to give the title compound (35 mg, 24% yield) as a white solid; LCMS (ESI, M+1): m / z = 636.4.

[0645] Step C. ((3S,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-4-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone: to (3S,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-4-carboxylic acid (30 mg, HATU (35.9 mg, 2.0 equivalent) and DIEA (18.3 mg, 3.0 equivalent) were added to a solution of 1.0 equivalent of 3-methyl-1H-pyrazole (11.6 mg, 3.0 equivalent) in DMF (0.5 mL). The reaction was stirred at 25 °C for 0.5 h. The mixture was purified by reversed-phase rapid chromatography [C18, water / ACN] to give the title compound (18.0 mg, 54% yield) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 8.97 (d, J = 5.6 Hz, 1H), 8.20 (d, J= 2.8 Hz, 1H), 7.62-7.52 (m, 1H), 7.25-7.17 (m, 2H), 7.05 (dd, J =2.8, 6.4 Hz, 1H), 6.33 (d, J = 2.8 Hz, 1H), 5.40-5.21 (m, 1H), 4.77-4.69 (m,1H), 4.64-4.55 (m, 1H), 4.29 (d, J = 3.6 Hz, 2H), 3.84 (tt, J = 3.6, 11.2 Hz,1H), 3.43-3.34 (m, 1H), 3.33-3.16 (m, 3H), 3.15-3.04 (m, 1H), 3.04-2.96 (m,1H), 2.55-2.36 (m, 5H), 2.36-2.29 (m, 1H), 2.27-2.18 (m, 3H), 2.17-2.11 (m,1H), 2.01-1.90 (m, 4H), 1.01 (t, J = 7.2 Hz, 3H), 0.88-0.80 (m, 3H); LCMS(ESI, M+1): m / z = 700.4.

[0646] Example 72

[0647]

[0648] (4-(tert-butyl)-1H-pyrazole-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methyl ketone

[0649]

[0650] Step A. (4-(tert-butyl)-3H-2l4-pyrazole-2-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methyl ketone: to 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (50.0 mg, 1.0 equivalent) and 4-tert-butyl-1H-pyrazole (20.0 mg, EDCI (23.1 mg, 1.5 equivalent), HOBt (5.43 mg, 0.5 equivalent), and TEA (24.4 mg, 3.0 equivalent) were added to a solution of DMF (1 mL). The reaction was stirred at 25 °C for 1 hour. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 mL). The combined organic layers were dried over sodium sulfate, concentrated, and purified by preparative HPLC [Waters Xbridge C18 150 × 25 mm × 5 µm; A: water (10 mM NH4HCO3), B: ACN, B%: 62%–92%, 9 min] to give the title compound (11.8 mg, 19% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 9.93 (s, 1H), 9.10 (s, 1H), 8.16 (d, J = 0.4 Hz, 1H), 7.97 (d, J = 0.4 Hz, 1H), 7.76 (dd, J = 6.0, 9.2Hz, 1H), 7.37-7.30 (m, 2H), 7.02 (d, J = 2.4 Hz, 1H), 5.41-5.14 (m, 1H), 4.63-4.52 (m, 2H), 4.20-4.11 (m, 1H), 4.09-3.95 (m, 2H), 3.67-3.50 (m, 2H), 3.16-2.98 (m, 4H), 2.87-2.77 (m, 1H), 2.14 (br d, J= 10.0 Hz, 4H), 2.08-1.97(m, 3H), 1.97-1.88 (m, 2H), 1.86-1.75 (m, 3H), 1.26 (s, 9H), 0.72 (t, J = 7.2Hz, 3H) LCMS (ESI, M+1): m / z = 728.5.

[0651] Example 73

[0652]

[0653] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3,4,5-trimethyl-1H-pyrazol-1-yl)methyl ketone

[0654]

[0655] Step A. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3,4,5-trimethyl-1H-pyrazole-1-yl) methyl ketone: to 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (50 mg, 1.0 equivalent) and 3,4,5-trimethyl-1H-pyrazole (26.6 mg, HATU (61.2 mg, 2.0 equivalent) and DIEA (31.2 mg, 3.0 equivalent) were added to a solution of DMF (1 mL). The reaction was stirred at 25 °C for 0.5 h. The mixture was purified by preparative HPLC [Waters Xbridge 150 × 25 mm × 5 µm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 50%-80% B, 15 min] to give the title compound (6.31 mg, 11% yield) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 8.99 (s, ¹H), 7.61–7.53 (m, ¹H), 7.25–7.18 (m, ²H), 7.06 (dd, ¹H) J= 2.8, 16.8 Hz, 1H), 5.41-5.20 (m, 1H), 4.65 (br d, J = 13.2 Hz,2H), 4.34-4.21 (m, 2H), 4.15-4.05 (m, 1H), 3.60-3.44 (m, 2H), 3.33-3.13 (m,3H), 3.05-2.95 (m, 1H), 2.49 (s, 4H), 2.31 (br d, J = 6.0 Hz, 1H), 2.24 (s,4H), 2.21-2.12 (m, 3H), 2.11-2.02 (m, 3H), 2.01-1.92 (m, 6H), 0.84 (t, J =7.6 Hz, 3H); LCMS (ESI, M+1): m / z = 714.4.

[0656] Example 74

[0657]

[0658] (3,5-Dimethyl-1H-pyrazole-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methyl ketone

[0659]

[0660] Step D. (3,5-Dimethyl-1H-pyrazole-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methyl ketone: to 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (100 mg, 1.0 equivalent) and 3,5-dimethyl-1H-pyrazole (46.4 mg, HATU (122 mg, 2.0 equivalent) and DIEA (62.4 mg, 3.0 equivalent) were added to a solution of HATU (1 mL) in DMF. The reaction was stirred at 25 °C for 0.5 h. The mixture was purified by reversed-phase rapid chromatography [C18, neutral conditions] to give the title compound (28.3 mg, 24% yield) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 8.99 (s, 1H), 7.64–7.51 (m, 1H), 7.25–7.18 (m, 2H), 7.10–7.00 (m, 1H), 6.02 (s, 1H), 5.41–5.20 (m, 1H), 4.71–4.61 (m, 2H), 4.34–4.21 (m, 2H), 4.17–4.03 (m, 1H), 3.59–3.46 (m, 2H), 3.35–3.14 (m, 3H), 3.06–2.95 (m, 1H), 2.57 (s, 3H), 2.54–2.44 (m, 1H). 2.33-2.27 (m, 4H), 2.26-2.12 (m, 5H), 2.11-2.04 (m, 2H), 2.01-1.87 (m, 3H), 0.84 (t, J = 7.6 Hz, 3H); LCMS (ESI, M+1): m / z = 700.4.

[0661] Example 75

[0662]

[0663] (3-(tert-butyl)-1H-pyrazole-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)methyl ketone

[0664]

[0665] Step A. (3-(tert-butyl)-1H-pyrazole-1-yl)(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl) methyl ketone: to 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (100 mg, 1.0 equivalent) and 3-tert-butyl-1H-pyrazole (59.9 mg, HATU (91.7 mg, 1.5 equivalent) and DIEA (62.4 mg, 3.0 equivalent) were added to a solution of DMF (1 mL). The reaction was stirred at 25 °C for 1 hour. The mixture was filtered and purified by preparative HPLC [column: Waters Xbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3), B: ACN, B%: 54%–84%, 15 min]. The aqueous solution was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (27.0 mg, 23% yield) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 8.99 (s, ¹H), 8.15 (d, ¹H) J = 2.8 Hz, 1H), 7.57 (dd, J =5.6, 9.2 Hz, 1H), 7.24-7.17 (m, 2H), 7.08-7.00 (m, 1H), 6.39 (d, J= 2.8 Hz,1H), 5.41-5.20 (m, 1H), 4.70-4.57 (m, 2H), 4.34-4.22 (m, 2H), 4.09-3.98 (m,1H), 3.62-3.46 (m, 2H), 3.42-3.10 (m, 3H), 3.06-2.94 (m, 1H), 2.56-2.43 (m,1H), 2.38-2.29 (m, 1H), 2.28-2.20 (m, 3H), 2.20-2.07 (m, 4H), 2.02-1.90 (m,3H), 1.35 (s, 9H), 0.83 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 728.4.

[0666] Example 76

[0667]

[0668] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-isopropyl-1H-pyrazole-1-yl)methyl ketone

[0669]

[0670] Step A. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(3-isopropyl-1H-pyrazole-1-yl) methyl ketone: to 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (100 mg, 1.0 equivalent) and 3-isopropyl-1H-pyrazole (53.2 mg, HATU (91.7 mg, 1.5 equivalent) and DIEA (62.4 mg, 3.0 equivalent) were added to a solution of DMF (1 mL). The reaction was stirred at 25 °C for 2 hours. The mixture was filtered and purified by preparative HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3), B: ACN, B%: 50%–80%, 15 min] to give the title compound (13.9 mg, 12% yield) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 8.97 (s, ¹H), 8.16 (d, ¹H) J = 2.8 Hz, 1H), 7.58-7.51 (m,1H), 7.22-7.14 (m, 2H), 7.07-6.96 (m, 1H), 6.34 (d, J = 2.8 Hz, 1H), 5.41-5.18 (m, 1H), 4.70-4.55 (m, 2H), 4.36-4.24 (m, 2H), 4.10-3.95 (m, 1H), 3.60-3.45 (m, 2H), 3.40-3.11 (m, 3H), 3.09-2.94 (m, 2H), 2.55-2.43 (m, 1H), 2.38-2.28 (m, 1H), 2.27-2.17 (m, 4H), 2.17-2.08 (m, 3H), 2.00-1.90 (m, 3H), 1.31(d, J = 6.8 Hz, 6H), 0.82 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 714.3.

[0671] Example 77

[0672]

[0673] (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone

[0674]

[0675] Step A. Methyl 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptan-6-carboxylate: At 25°C, slowly add DIEA (70.0 mg, 1.0 equivalent) to a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (100 mg, 1.0 equivalent) in DMF (2 mL). The reaction was carried out with 3.0 equivalents of PyBOP and 141 mg (1.5 equivalents) at 25 °C and stirred for 20 min. Then, methyl 1,4-oxazetane-6-carboxylate (34.4 mg, 1.2 equivalents) was slowly added at 25 °C. The reaction was stirred at 25 °C for 2 h. The mixture was filtered, concentrated, and purified by preparative HPLC [C18 150 × 25 mm × 10 µm; A: water (ammonium hydroxide v / v), B: ACN, B%: 40%–70%, 10 min] to give the title compound (96.0 mg, 77% yield) as a white solid; LCMS (ESI, M+1): m / z = 696.5.

[0676] Step B. Methyl 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-carboxylate: At 0 °C, a solution of methyl 4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-carboxylate (50.0 mg, 1.0 equivalent) in MeOH (0.9 mL) was added to HCl. MeOH (2 M, 2 mL, 111 equivalents). The reaction was stirred at 25 °C for 1 hour. The mixture was concentrated, diluted with MeOH (3 mL), adjusted to pH 7 with NaHCO3 solid, filtered, and concentrated to give the title compound (45.0 mg, 78% yield) as a white solid; LCMS (ESI, M+1): m / z = 652.3.

[0677] Step C. 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-carboxylic acid: Add LiOH to a solution of methyl 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-carboxylic acid (35.0 mg, 1.0 equivalent) in MeOH (1 mL). H2O (2 M, 1 mL, 37 equivalents). The reaction was stirred at 25 °C for 1 h. The mixture was filtered and purified by reversed-phase rapid chromatography (0.1 % FA conditions) to give the title compound (18.0 mg, 48% yield, HCOOH) as a white solid; LCMS (ESI, M+1): m / z = 638.2.

[0678] Step D. (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone: to 4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-1,4-oxazacycloheptane-6-carboxylic acid (16.0 mg, 1.0 equivalent, HATU (17.8 mg, 2.0 equivalent) was added to a solution of HCOOH, 3-methyl-1H-pyrazole (5.76 mg, 3.0 equivalent), and DIEA (15.1 mg, 5.0 equivalent) in DMF (0.5 mL). The reaction was stirred at 25 °C for 2 hours. The mixture was filtered and purified by preparative HPLC [Waters Xbridge 150 × 25 mm × 5 µm; A: water (NH4HCO3), B: ACN, B%: 40%–70%, 9 min] to give the title compound (4.65 mg, 26%) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 8.83 (t, J = 3.6 Hz, 1H), 8.11-7.98 (m, 1H), 7.67-7.52 (m, 1H), 7.23-7.09 (m, 2H), 6.84-6.62 (m, 1H), 6.29-6.17 (m, 1H), 5.43-5.20 (m, 2H), 4.51-4.31 (m, 1H), 4.28-4.17 (m, 1H), 4.04-3.85 (m, 2H), 3.83-3.54 (m, 4H), 3.43-3.14 (m, 3H), 3.09-2.98 (m, 1H), 2.53-2.38 (m, 2H), 2.36-2.31 (m, 2H), 2.30-2.23 (m, 3H), 2.22-2.08 (m, 5H), 2.02-1.99 (m, 2H), 0.82-0.72 (m, 3H); LCMS (ESI, M+1): m / z = 702.2.

[0679] Example 78

[0680]

[0681] (7-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]oct-4-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone

[0682]

[0683] Step A. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octyl-4-carboxylic acid tert-butyl ester: to 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (500 mg, 1.0 equivalent) in DMF (6 4,7-diazaspiro[2.5]octyl-4-carboxylic acid tert-butyl ester (627 mg, 3.5 equivalents) and DIEA (218 mg, 2.0 equivalents) were added to the mixture in mL. The reaction was stirred at 35 °C for 10 h. The mixture was filtered and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (450 mg, 74% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 705.4.

[0684] Step B. 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4,7-diazaspiro[2.5]oct-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol: At 0 °C, HCl was added to a solution of tert-butyl 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]oct-4-carboxylic acid (150 mg, 1.0 equivalent) in MeOH (1 mL). MeOH (2 M, 3 mL). The reaction was stirred at 0 °C for 1 hour. The mixture was adjusted to pH 7 with saturated NaHCO3 (10 mL) and extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (120 mg, crude) as a white solid.

[0685] Step C. (7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]oct-4-yl)(3-methyl-1H-pyrazol-1-yl) ketone: Add bis(trichloromethyl) carbonate (120 mg, 1.7 equivalents) to a solution of 3-methyl-1H-pyrazole (20.0 mg, 1.0 equivalent) and DIEA (126 mg, 4.0 equivalent) in DCM (0.5 mL). Stir the reaction at 0 °C for 1 hour. At 0 °C, 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(4,7-diazaspiro[2.5]oct-7-yl)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (118 mg, 0.8 equivalent) and DIEA (47.2 mg, 1.5 equivalent) in DCM (0.5 mL) were added to the mixture. The reaction was stirred at 20 °C for 12 hours. The mixture was quenched with saturated aqueous NaHCO3 solution (10 mL) and extracted with DCM (4 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and passed by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 µm; A: water (FA), B: ACN; B%: 20%–50%, duration 10 min] and SFC [column: DAICEL CHIRALCEL OX (250 mm × 30 mm, 10 µm); A: CO2-ACN, B: MeOH (0.1% NH3)]. [H2O); B%: 40%, isocratic elution mode] Two peaks were obtained after purification.

[0686] Peak 1: (7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]oct-4-yl)(5-methyl-1H-pyrazol-1-yl) methyl ketone: The residue was purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 µm; A: water (FA), B: ACN; B%: 22%–52%, 10 min] to give the title compound (6.63 mg, 3.8% yield) as a beige gel. 1 H NMR (400 MHz, DMSO-d6) δ = 10.00 (s, 1H),9.16 (s, 1H), 7.77 (dd, J = 6.0, 9.2 Hz, 1H), 7.54 (s, 1H), 7.41-7.29 (m,2H), 7.04 (d, J = 2.4 Hz, 1H), 6.26 (s, 1H), 5.59-5.34 (m, 1H), 4.41-4.14 (m,6H), 3.89 (br d, J = 3.6 Hz, 2H), 3.46 (br d, J = 6.8 Hz, 2H), 2.44-1.84 (m,13H), 1.02-0.78 (m, 4H), 0.71 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 713.3; SFC: 96.3% de; Column: Chiralcel OX-3 50 × 4.6 mm ID, 3 µm; Mobile phase: Phase A is CO2, Phase B is MeOH + ACN (0.05% DEA); Gradient elution: 30% MeOH + ACN (0.05% DEA) in CO2; Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35°C; Back pressure: 100 bar, t R 2.315 minutes.

[0687] Peak 2: (7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]oct-4-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone: The residue was purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 µm; A: water (FA), B: ACN; B%: 22%–52%, 10 min] to give the title compound (11.8 mg, 6.6% yield) as a beige gel; 1 H NMR (400 MHz, DMSO-d6) δ = 10.03 (br s,1H), 9.13 (s, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.76 (dd, J = 6.0, 8.8 Hz, 1H),7.39-7.28 (m, 2H), 7.05 (s, 1H), 6.31 (d, J = 2.4 Hz, 1H), 5.47-5.26 (m, 1H), 4.32-4.08 (m, 8H), 2.97 (br d, J = 5.2 Hz, 2H), 2.33 (br s, 2H), 2.26-1.76(m, 11H), 1.05-0.95 (m, 2H), 0.90 (br s, 2H), 0.71 (br t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 713.3; SFC: 97.3% DE; Column: Chiralcel OX-3 50 × 4.6 mm I.D., 3 µm; Mobile phase: Phase A is CO2, Phase B is MeOH + ACN (0.05% DEA); Gradient elution: 30% MeOH + ACN (0.05% DEA) in CO2; Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35°C; Back pressure: 100 bar, t R 2.765 minutes.

[0688] Example 79

[0689]

[0690] ((3R,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-4-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone

[0691]

[0692] Step A. cis-(3R,4R)-3-methylpiperidine-1,4-dicarboxylic acid 1-benzyl ester 4-methyl ester: Benzyl chloroformate (1.04 g, 1.2 equivalent) was added to a solution of methyl cis-(3R,4R)-3-methylpiperidin-4-carboxylate (800 mg, 1.0 equivalent) and TEA (1.54 g, 3.0 equivalent) in DCM (16 mL). The reaction was stirred at 0 °C for 1 h. The mixture was concentrated and purified by silica gel chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give the title compound (1.1 g, 69% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 7.46-7.23 (m, 5H),5.07 (s, 2H), 3.91 (br d, J = 13.2 Hz, 1H), 3.72 (br d, J = 12.0 Hz, 1H),3.61 (s, 3H), 3.23-3.06 (m, 1H), 3.02-2.80 (m, 1H), 2.71 (td, J = 4.8, 10.0Hz, 1H), 2.15 (br dd, J = 3.6, 6.8 Hz, 1H), 1.73-1.50 (m, 2H), 0.75 (d, J =6.8 Hz, 3H).

[0693] Step B. (3R,4R)-3-methylpiperidine-1,4-dicarboxylic acid 1-benzyl ester 4-methyl ester: Methyl (3R,4R)-3-methylpiperidin-4-carboxylate (1.3 g, 1.0 equivalent) was purified by SFC separation [column: DAICL CHIRALPAK AD, 250 mm × 50 mm, 10 µm; A: CO2, B: MeOH (0.2% NH3H2O), B%: 15% B, time 6.3 min] to obtain two isomers.

[0694] Peak 1: (3R,4R)-3-methylpiperidine-1,4-dicarboxylic acid 1-benzyl ester 4-methyl ester(700 mg, 50% yield), white solid; LCMS (ESI, M-44): m / z = 248.4; SFC >99% ee; Column: Chiralpak AD-350 × 4.6 mm ID, 3 µm; Mobile phase: 5% to 40% MeOH (0.05% DEA), in CO2; Flow rate: 3 mL / min; Detector: PDA, t R 1.054 minutes.

[0695] Peak 2: (3S,4S)-3-methylpiperidine-1,4-dicarboxylic acid 1-benzyl ester 4-methyl ester (700 mg, 51% yield), white solid; LCMS (ESI, M-44): m / z = 248.4; SFC >99% ee; Column: Chiralpak AD-350 × 4.6 mm ID, 3 µm; Mobile phase: 5% to 40% MeOH (0.05% DEA), in CO2; Flow rate: 3 mL / min; Detector: PDA, t R 1.162 minutes.

[0696] Step C. (3R,4R)-3-methylpiperidine-4-carboxylic acid methyl ester: Pd / C (60 mg, 10% purity) was added to a solution of (3R,4R)-3-methylpiperidin-1,4-dicarboxylic acid 1-benzyl ester 4-methyl ester (600 mg, 1.0 equivalent) in MeOH (12 mL). The reaction mixture was degassed and purged three times with nitrogen. The reaction was stirred at 25 °C under a H2 atmosphere (15 Psi) for 2 hours. The mixture was filtered and concentrated to give the title compound (300 mg, crude) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ = 3.58 (s, 3H), 2.87 (td, J = 4.0, 12.2 Hz, 1H), 2.66 (br dd, J = 3.6, 6.0 Hz, 2H), 2.56 (td, J = 4.4, 10.8 Hz, 1H), 2.45-2.34 (m, 1H), 2.03-1.91(m, 1H), 1.66-1.38 (m, 2H), 0.85 (d, J = 6.8 Hz, 3H).

[0697] Step D. (3R,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidine-4-carboxylate: to 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (150 mg, 1.0 equivalent) and (3R,4R)-3-methylpiperidine-4-carboxylate (47.8 mg, 1.2 equivalents) of K3PO4 (161 mg, 3.0 equivalents) and 4 Å molecular sieve (30.0 mg) were added to a solution in DMAC (2 mL). The reaction was stirred at 60 °C for 0.5 h. The mixture was filtered and the filtrate was diluted with H2O (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (200 mg, crude) as a yellow solid; LCMS (ESI, M+1): m / z = 650.4.

[0698] Step E. (3R,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-4-carboxylic acid: Add LiOH to a solution of (3R,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-4-carboxylic acid methyl ester (200 mg, 1.0 equivalent) in MeOH (2 mL). H2O (2 M, 2.00 mL, 13 equivalents). The reaction was stirred at 25 °C for 0.5 h. The mixture was purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (100 mg, 44% yield) as a white solid; LCMS (ESI, M+1): m / z = 636.5.

[0699] Step F. ((3R,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-4-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone: to (3R,4R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-4-carboxylic acid (90.0 mg, 1.0 equivalent) and HATU 3-Methyl-1H-pyrazole (17.4 mg, 1.5 equivalent) and DIEA (91.5 mg, 5.0 equivalent) were added to a solution of 3-methyl-1H-pyrazole in DMF (1 mL). The reaction was stirred at 25 °C for 1 hour. The mixture was filtered and purified by preparative HPLC [Waters Xbridge 150 × 25 mm × 5 µm; A: water (NH4HCO3); B: ACN, B%: 55%–85%, 9 min] to give the title compound (10 mg, 10% yield) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 9.00 (br d, J = 4.0 Hz, 1H), 8.22-8.13 (m, 1H), 7.64-7.50 (m, 1H), 7.23-7.16 (m, 2H), 7.13-6.95 (m, 1H), 6.36-6.18 (m, 1H), 5.48-5.12 (m, 1H), 4.49-4.23 (m, 3H), 4.21-4.13 (m, 1H), 3.91(br dd, J = 2.4, 12.8 Hz, 1H), 3.83-3.65 (m, 1H), 3.46-3.09 (m, 3H), 3.06-2.91 (m, 1H), 2.75-2.57 (m, 1H), 2.56-2.40 (m, 1H), 2.39-2.29 (m, 4H), 2.24(br s, 1H), 2.14 (br dd, J = 3.8, 8.2 Hz, 2H), 2.00-1.84 (m, 6H), 1.04-0.92(m, 3H), 0.82 (q, J= 7.6 Hz, 3H); LCMS (ESI, M+1): m / z = 700.5.

[0700] Example 80

[0701]

[0702] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(4-isopropyl-1H-pyrazole-1-yl)methyl ketone

[0703]

[0704] Step A. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl)(4-isopropyl-1H-pyrazole-1-yl) methyl ketone: to 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)piperidin-4-carboxylic acid (80.0 mg, 1.0 equivalent) and 4-isopropyl-1H-pyrazole (42.5 mg, HATU (73.4 mg, 1.5 equivalent) and DIEA (49.9 mg, 3.0 equivalent) were added to a solution of DMF (1 mL). The reaction was stirred at 25 °C for 0.5 h. The mixture was filtered and purified by preparative HPLC [column: Waters Xbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3), B: ACN, B%: 62%–92%, 15 min]. The aqueous phase was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (4.79 mg, 15% yield) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 8.99 (s, ¹H), 8.01 (s, ¹H), 7.64 (s, ¹H), 7.58 (dd, ¹H) J = 5.6, 9.2 Hz, 1H), 7.24-7.18 (m, 2H), 7.05 (dd, J= 2.4, 18.4 Hz, 1H),5.43-5.20 (m, 1H), 4.73-4.58 (m, 2H), 4.35-4.27 (m, 2H), 4.10-3.98 (m, 1H),3.58-3.46 (m, 2H), 3.41-3.14 (m, 3H), 3.08-2.95 (m, 1H), 2.91-2.83 (m, 1H), 2.57-2.44 (m, 1H), 2.39-2.30 (m, 1H), 2.27-2.08 (m, 7H), 2.04-1.92 (m, 3H),1.26 (d, J = 6.8 Hz, 6H), 0.83 (t, J = 6.8 Hz, 3H); LCMS (ESI, M+1): m / z =714.4.

[0705] Example 81

[0706]

[0707] ((2S,6R)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,6-dimethylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone

[0708]

[0709] Step A. (3R,5S)-3,5-dimethyl-4-(3-methyl-1H-pyrazole-1-carbonyl)piperazine-1-carboxylic acid tert-butyl ester: At 0 °C, bis(trichloromethyl) carbonate (410 mg, 0.59 equivalent) and TEA (472 mg, 2.0 equivalent) were slowly added to a solution of 3-methyl-1H-pyrazole (192 mg, 1.0 equivalent) in DCM (3 mL). The reaction was stirred at 0 °C for 2 hours. At 0 °C, (3R,5S)-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.0 equivalent) and TEA (472 mg, 2.0 equivalent) were added to DCM (3 mL). The reaction was stirred at 40 °C for 2 hours. The mixture was poured into water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to give the title compound (500 mg, 88%) as a white oil.1 ¹H NMR (400 MHz, chloroform-d) δ = 8.00 (d, J = 2.4 Hz, 1H), 6.14 (d, J = 2.4Hz, 1H), 4.82 (br d, J = 2.4 Hz, 2H), 4.06-3.81 (m, 2H), 3.29-3.03 (m, 2H), 2.30 (s, 3H), 1.50 (s, 9H), 1.38 (d, J = 7.2 Hz, 6H); LCMS (ESI, M+23): m / z =345.1.

[0710] Step B. ((2R,6S)-2,6-dimethylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone: (3R,5S)-3,5-dimethyl-4-(3-methyl-1H-pyrazole-1-carbonyl)piperazine-1-carboxylic acid tert-butyl ester (400 mg, 1.0 equivalent) was dissolved in HCl. The solution in MeOH (2 M, 8.00 mL, 12.9 equivalents) was stirred at 25 °C for 1 hour. The mixture was concentrated, dissolved in MeOH (5 mL), adjusted to pH = 7 with NaHCO3 solid, and concentrated to dryness under reduced pressure. The mixture was dissolved in DCM (5 mL) and filtered. The filtrate was concentrated to dryness under reduced pressure to give the title compound (300 mg, crude) as a white oil; LCMS (ESI, M+1): m / z = 223.2.

[0711] Step C. ((2R,6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,6-dimethylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone: Add PYBOP to a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (600 mg, 1.0 equivalent) in DMF (6 mL). (845 mg, 1.5 equivalents) and DIEA (420 mg, 3.0 equivalents). The reaction was stirred at 25 °C for 0.5 h. ((2R,6S)-2,6-dimethylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone (289 mg, 1.2 equivalents) was added to the mixture. The reaction was stirred at 25 °C for 1.5 h. The reaction mixture was quenched at 0 °C by adding water (15 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with saturated brine (3 × 20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative HPLC [Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; A: water (NH4HCO3), B%: ACN, B%: 55%–85%, 20 min] to give the title compound (500 mg, 99% yield) as a white solid; LCMS (ESI, M+1): m / z = 759.4.

[0712] Step D. ((2R,6S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,6-dimethylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone: ((2R...) ,6S)-4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2,6-dimethylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone (150 mg, 1.0 equivalent) in HCl The solution in MeOH (2 M, 3.00 mL, 30 equivalents) was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (3 mL), adjusted to pH = 7 with NaHCO3 solid, filtered, concentrated, and purified by preparative HPLC [WatersXbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3), B%: ACN, B%: 52%–82%, 9 min] to give the title compound (55.3 mg, 96% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ= 9.92 (s, 1H), 9.22 (s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.77 (dd, J = 6.0,9.2 Hz, 1H), 7.43-7.29 (m, 2H), 7.02 (d, J = 2.4 Hz, 1H), 6.33 (d, J = 2.8Hz, 1H), 5.42-5.13 (m, 1H), 4.66 (br s, 2H), 4.36-4.21 (m, 2H), 4.20-4.14 (m,1H), 4.12-3.98 (m, 3H), 3.15-2.96 (m, 3H), 2.88-2.76 (m, 1H), 2.40-2.31 (m,1H), 2.25 (s, 3H), 2.18-1.98 (m, 4H), 1.77 (br s, 3H), 1.54-1.37 (m, 6H), 0.73 (t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 715.4.

[0713] Example 82

[0714]

[0715] (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone

[0716]

[0717] Step A. 3-Methyl-4-(3-methyl-1H-pyrazole-1-carbonyl)piperazine-1-carboxylic acid tert-butyl ester: At 0 °C, bis(trichloromethyl) carbonate (490 mg, 0.66 equivalent) and TEA (505 mg, 2.0 equivalent) were added to a solution of 3-methyl-1H-pyrazole (205 mg, 1.0 equivalent) in DCM (3 mL). The reaction was stirred at 0 °C for 3 h. At 0 °C, tert-butyl 3-methylpiperazine-1-carboxylate (500 mg, 1.0 equivalent) and TEA (505 mg, 2.0 equivalent) were added to DCM (3 mL). The reaction was stirred at 40 °C for 2 h. The mixture was quenched with water (5 mL) and extracted with dichloromethane (3 × 10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give the title compound (280 mg, 34% yield) as a colorless oil. 1 ¹H NMR (400 MHz, chloroform-d) δ = 8.05–7.92 (m, ¹H), 6.13 (d, J = 2.8 Hz, 1H), 4.78 (br s, 1H), 4.41 (br d, J= 12.4 Hz, 1H), 4.18-4.03 (m, 1H), 3.95-3.74 (m, 1H), 3.32 (dt, J = 3.6, 12.0Hz, 1H), 3.21-2.88 (m, 2H), 2.28 (s, 3H), 1.46 (s, 9H), 1.30 (d, J = 6.8 Hz, 3H); LCMS (ESI, M+23): m / z = 331.1.

[0718] Step B. (3-Methyl-1H-pyrazole-1-yl)(2-methylpiperazin-1-yl)methyl ketone: 3-Methyl-4-(3-methyl-1H-pyrazole-1-carbonyl)piperazine-1-carboxylic acid tert-butyl ester (230 mg, 1.0 equivalent) was dissolved in HCl. The solution in MeOH (2 M, 4.6 mL, 12.3 equivalents) was stirred at 25 °C for 2 hours. The mixture was concentrated, diluted with MeOH (3 mL), adjusted to pH 7 with NaHCO3 solid, filtered, and concentrated to give the title compound (153 mg, 97% yield) as a white solid; LCMS (ESI, M+1): m / z = 209.2.

[0719] Step C. (4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone: At 25°C, slowly add DIEA (266 mg, 1.0 equivalent) to a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (380 mg, 1.0 equivalent) in DMF (6 mL). 3.0 equivalents) and PyBOP (535 mg, 1.5 equivalents) were added, and the reaction was stirred at 25 °C for 20 min. (3-methyl-1H-pyrazole-1-yl)(2-methylpiperazin-1-yl) methyl ketone (150 mg, 1.0 equivalents) was slowly added at 25 °C. The reaction was stirred at 25 °C for 2 h. The mixture was filtered and purified by reversed-phase rapid chromatography (0.1 % FA conditions) to give the title compound (700 mg, crude, HCOOH) as a colorless oil; LCMS (ESI, M+1): m / z = 745.4.

[0720] Step D. (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone: (4-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl)(3-methyl-1H-pyrazol-1-yl) methyl ketone (300 mg, 1.0 equivalent, HCOOH) in HCl The solution in MeOH (2 M, 5 mL, 26 equivalents) was stirred at 25 °C for 2 hours. The mixture was concentrated, diluted with MeOH (3 mL), adjusted to pH 7 with NaHCO3 solid, filtered, concentrated, and purified by preparative HPLC [Waters Xbridge Prep OBD C18 150 × 40 mm × 10 µm; A: water (NH4HCO3), B: ACN, B%: 40%–70%, 20 min] to give the title compound (81.0 mg, 30% yield, two-step process) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 10.04-9.82 (m, 1H), 9.20 (s, 1H), 8.13 (t, J = 2.4 Hz, 1H), 7.77 (dd, J = 6.0, 9.2Hz, 1H), 7.43-7.28 (m, 2H), 7.13-6.94 (m, 1H), 6.33 (d, J = 2.8 Hz, 1H),5.44-5.16 (m, 1H), 4.85-4.65 (m, 1H), 4.51-4.39 (m, 1H), 4.39-4.25 (m, 2H),4.21-3.97 (m, 3H), 3.96-3.83 (m, 2H), 3.30-3.24 (m, 1H), 3.15-3.06 (m, 2H), 2.89-2.74 (m, 1H), 2.43-2.32 (m, 1H), 2.25 (s, 3H), 2.19-1.96 (m, 4H), 1.77(br s, 3H), 1.37 (dd, J = 6.8, 10.0 Hz, 3H), 0.79-0.65 (m, 3H); LCMS (ESI, M+1): m / z = 701.3.

[0721] Example 83

[0722]

[0723] (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-yl)(3-methyl-1H-pyrazol-1-yl)methyl ketone

[0724]

[0725] Step A. 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-carboxylate: methyl 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-ol (2.3 g, 1.0 equivalent) and methyl 4-methylpiperidin-4-carboxylate (1.0 g, 1.2 equivalent, HCl salt) in DMF (20 PyBOP (3.24 g, 1.5 equivalents) and DIEA (5.36 g, 10 equivalents) were added to a solution in mL. The reaction was stirred at 25 °C for 12 h. The mixture was filtered and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (3.4 g, 87% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 694.4.

[0726] Step B. Methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidine-4-carboxylate: Add HCl to a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidine-4-carboxylate (3.4 g, 1.0 equivalent) in MeOH (15 mL). MeOH (2 M, 30 mL, 12 equivalents). The reaction was stirred at 25 °C for 4 hours. The mixture was concentrated. The residue was alkalized with saturated NaHCO3 solution (80 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and analyzed by reversed-phase rapid chromatography [C18, 0.1% NH3]. Purification under H2O conditions yielded the title compound (1.9 g, 55% yield) as a white solid; LCMS (ESI, M+1): m / z = 650.4.

[0727] Step C. 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-carboxylic acid: LiOH was added to a solution of methyl 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-carboxylic acid (1.9 g, 1.0 equivalent) in MeOH (15 mL). H2O (2 M H2O solution, 15 mL, 10 equivalents). The reaction was stirred at 25 °C for 4 hours. The mixture was filtered and the filtrate was purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (1.12 g, 34% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 636.4.

[0728] Step D. (1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-yl)(3-methyl-1H-pyrazole-1-yl) methyl ketone: to 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-4-methylpiperidin-4-carboxylic acid (300 mg, 1.0 equivalent) and 3-methyl-1H-pyrazole (58.1 mg, HATU (359 mg, 2.0 equivalent) and DIEA (366 mg, 6.0 equivalent) were added to a solution of DMF (3 mL) in 1.5 equivalents. The reaction was stirred at 25 °C for 12 hours. The mixture was filtered and purified by preparative HPLC [Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; A: water (NH4HCO3), B: ACN, B%: 52%–82%, 20 min] to give the title compound (8.22 mg, 2.4% yield) as a yellow solid. 1 ¹H NMR (400 MHz, chloroform-d) δ = 8.93 (d, J = 2.1 Hz, 1H), 8.19(d, J= 2.8 Hz, 1H), 7.56-7.48 (m, 1H), 7.20-7.10 (m, 2H), 7.01-6.88 (m, 1H), 6.22 (d, J = 2.8 Hz, 1H), 5.40-5.17 (m, 1H), 4.34-4.18 (m, 4H), 3.75-3.59 (m,2H), 3.36-3.11 (m, 3H), 3.04-2.93 (m, 1H), 2.89-2.76 (m, 2H), 2.50-2.41 (m,1H), 2.33 (s, 3H), 2.27-2.12 (m, 4H), 1.97-1.89 (m, 5H), 1.64 (br d, J = 1.1Hz, 3H), 0.81 (t, J = 7.4 Hz, 3H); LCMS (ESI, M+1): m / z = 700.4.

[0729] Example 84

[0730]

[0731] 2-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclobut-3-yl)-1-(3-methyl-1H-pyrazol-1-yl)ethyl-1-one

[0732]

[0733] Step A. 2-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)azacyclobut-3-yl)acetic acid: Add 20 mg of 4 Å molecular sieve to a solution of 2-(azacyclobut-3-yl)acetic acid (154 mg, 2 equivalents, HCl) and DIEA (327 mg, 5.0 equivalents) in DMF (3.00 mL). Stir the reaction at 25 °C for 10 min. Then, 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7-yl)naphth-2-ol (300 mg, 1.0 equivalent) was added. The reaction was stirred at 40 °C for 3 hours. The mixture was filtered and purified by reversed-phase rapid chromatography [C18, 0.1% formic acid conditions] to give the title compound (320 mg, 96% yield, HCOOH) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.25-9.58 (m, 1H),8.93 (s, 1H), 7.76 (dd, J = 6.0, 9.2 Hz, 1H), 7.41-7.27 (m, 2H), 7.00 (d, J =2.4 Hz, 1H), 5.46-5.22 (m, 1H), 5.06-4.89 (m, 1H), 4.62-4.38 (m, 2H), 4.28-3.96 (m, 4H), 3.23-3.08 (m, 5H), 2.95-2.85 (m, 1H), 2.76 (br d, J = 7.2 Hz,2...

Claims

1. Compounds of formula (Ia) or (Ib): Or its pharmaceutically acceptable salt, wherein: A is selected from: , , , , , , , , , , and B is selected from: 、 、 、 ； X is a bond, N, methylene, ethylene, or propylene; D is either CO or SO2; E is N or CR 10 ; Y represents a bond, O, or NR. 5 ; Z is a bond, a C1-C4 alkyl group, a heterocyclic group, a heteroaryl group, or an aryl group, wherein Z is optionally substituted by 1-3 substituents selected from halogens, C1-C4 alkyl groups, C1-C4 haloalkyl groups, oxoalkyl groups, and OR groups. 12 、N(R 12 2. COR 12 and cyano; Each R 2 Independently, it is hydrogen, hydroxyl, halogen, C1-C3 alkyl, spirocyclopropyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, CHF2, HC(=O)-, -OC(O)N(R) 5 )2、-CO2R 5 -CO2N(R) 5 )2、=CH2、=CHR 11 or = C(R) 11 )2, where R 2 Optionally by one or more R 4 replace; R 3 It is an aryl or heteroaryl group, wherein the aryl or heteroaryl group is optionally surrounded by one or more R groups. 8 replace; R 4 It is a bond, halogen, or C1-C3 alkyl; Each R 5 It is independently hydrogen or C1-C3 alkyl; Each R 6 It is independently hydrogen, hydroxyl, C1-C4 alkyl, C1-C4 hydroxyalkyl or heteroaryl, or two R 6 Linkage forms C3-C6 cycloalkyl or heterocyclic rings; Each R 8 It is independently a halogen, cyano, hydroxyl, cycloalkyl, C1-C3 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 or -S-C1-C3 haloalkyl; Each R 9 Independently, it is hydrogen, C1-C4 alkyl, methoxy, CH2-methoxy, hydroxyl, CH2F, CF2, CF3, C-CN, cyclopropyl, or two Rs on the same or different carbon atoms. 9 Connect to form C1-C2 alkylene bridges or spirorings; Each R 10 It is a bond, halogen, CH2F, CHF2, CF3, C1-C3 alkyl, cyclopropyl, OR 12 or N(R) 12 )2; Each R 11 It is a halogen or a C1-C3 alkyl group. R 12 It is a C1-C3 alkyl group, and R 13 It is H or forms a ring with A.

2. The compound or salt according to claim 1, wherein formula (Ia) is formula IA: (Formula IA).

3. The compound or salt according to claim 1, wherein formula (Ia) is formula IB: (Formula IB) 4. The compound or salt according to any one of claims 1-3, wherein B is: 。 5. The compound or salt according to any one of claims 1-4, wherein X is a methylene group.

6. The compound or salt according to any one of claims 1-4, wherein X is an ethylene.

7. The compound or salt according to any one of claims 1-4, wherein X is a bond.

8. The compound or salt of any one of claims 1-4, wherein X is propylidene.

9. The compound or salt according to any one of claims 1-8, wherein Y is O.

10. A compound or salt according to any one of claims 1-8, wherein Y is NR. 5 .

11. The compound or salt according to any one of claims 1-8, wherein Y is a bond.

12. A compound or salt according to any one of claims 1-8, wherein Z is hydrogen.

13. A compound or salt according to any one of claims 1-8, wherein Z is a C1-C4 alkyl group optionally substituted with 1-3 halogens.

14. A compound or salt according to any one of claims 1-8, wherein Z is an aryl group optionally substituted with 1-3 halogens, cyano groups or C1-C4 haloalkyl groups.

15. The compound or salt of claim 14, wherein the aryl group is phenyl.

16. A compound or salt according to any one of claims 1-8, wherein Z is a heteroaryl group optionally substituted with 1-2 C1-C4 alkyl groups.

17. The compound or salt of claim 16, wherein the heteroaryl group is pyrazolyl or pyridyl.

18. A compound or salt according to any one of claims 1-8, wherein Z is an optional heterocyclic group substituted with oxygen.

19. The compound or salt of claim 18, wherein the heterocyclic group is an oxazolidine.

20. A compound or salt according to any one of claims 1-8, wherein the two Rs 9 The connection forms a methylene bridge.

21. A compound or salt according to any one of claims 1-8, wherein the two Rs 9 The connection forms an ethylene bridge.

22. The compound or salt of claim 4, wherein R 2 It's fluorine.

23. The compound or salt of claim 19, wherein R 2 Yes = CHR 11 .

24. The compound or salt of claim 19, wherein R 2 =C(R) 11 )2.

25. The compound or salt according to any one of claims 1-24, wherein R 3 It is arbitrarily controlled by one or more R 8 Substituted aryl groups.

26. The compound or salt of claim 25, wherein the aryl group is optionally surrounded by one or more R 8 Substituted naphthyl group.

27. The compound or salt of claim 26, wherein the naphthyl group is surrounded by an R 8 Replace, wherein one of the R 8 It is hydroxyl, halogen, C1-C3 alkyl, C1-C3 haloalkyl, cycloalkyl, C2-C4 alkenyl or C2-C4 alkynyl.

28. The compound or salt of claim 26, wherein the naphthyl group is affected by two R groups. 8 Replace, one of the R 8 It's a hydroxyl group, another R 8 It is a C1-C3 alkyl, halogen, or C2-C4 alkynyl, or an R 8 It's halogen, another R 8 It is a C1-C3 alkyl or C2-C4 alkynyl.

29. The compound or salt of claim 26, wherein the naphthyl group is surrounded by three R groups. 8 Replace, where the first R 8 It's a hydroxyl group, the second R 8 It's halogen, the third R 8 It is a C1-C3 alkyl or C2-C4 alkynyl.

30. The compound or salt of claim 26, wherein the aryl group is optionally surrounded by one or more R groups. 8 Substituted phenyl groups.

31. The compound or salt of claim 30, wherein the phenyl group is affected by an R 8 Replace, where R 8 It is a C1-C3 alkyl group.

32. The compound or salt of claim 30, wherein the phenyl group is affected by two R groups. 8 Replace, one of the R 8 It's halogen, another R 8 It is a C1-C3 alkyl group.

33. The compound or salt of claim 30, wherein the phenyl group is affected by two R groups. 8 Replace, one of the R 8 It's halogen, another R 8 It is a cycloalkyl group.

34. The compound or salt according to any one of claims 1-24, wherein R 3 It is a heteroaryl group.

35. The compound or salt of claim 34, wherein the heteroaryl group is optionally surrounded by one or more R 8 Substituted indazole group.

36. The compound or salt of claim 35, wherein the indazole group is surrounded by two R groups. 8 Replace, one of the R 8 It's halogen, another R 8 It is a C1-C3 alkyl group.

37. The compound or salt according to any one of claims 1-36, wherein R 4 It is halogen.

38. The compound or salt of claim 37, wherein the halogen is fluorine.

39. The compound or salt of claim 1, wherein the compound is selected from: And its pharmaceutically acceptable salts.

40. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-39 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

41. A method for inhibiting the activity of KRas G12S and / or KRas G12C in cells, the method comprising contacting cells for which the activity of KRas G12S and / or KRas G12C to be inhibited with an effective amount of a compound according to any one of claims 1-39 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 40.

42. A method of treating cancer, the method comprising administering to a patient suffering from cancer a therapeutically effective amount of a compound according to any one of claims 1-39 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 40.

43. The method of claim 42, wherein the therapeutically effective amount of the compound is between about 0.01 and 100 mg / kg per day.

44. The method of claim 43, wherein the therapeutically effective amount of the compound is between about 0.1 and 50 mg / kg per day.

45. The method of claim 42, wherein the cancer is selected from the group consisting of: heart; sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma. Lungs: Bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, hamartoma, mesothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); urogenital system The following are cancer-related cancers: kidneys (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminomatous seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma-like tumor, lipoma); liver: hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract cancer: gallbladder cancer, ampullary cancer, bile duct cancer; Bone: Osteoblastic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondrogenic exostosis), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma, and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord neurofibroma, meningioma, glioma, sarcoma; Gynecology: Uterus (endometrium) Cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granular theca cell tumor, Sertoli-stromal cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer); hematologic system: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, and adrenal glands: neuroblastoma.

46. ​​The method of claim 42, wherein the cancer is a cancer associated with KRas G12S.

47. The method of claim 42, wherein the cancer is a cancer associated with KRas G12C.

48. The method of any one of claims 46 or 47, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

49. A method for treating cancer in a patient in need, the method comprising (a) determining that the cancer is associated with a KRasG12S mutation or a KRasG12C mutation (e.g., cancer associated with KRasG12S or cancer associated with KRasG12C); and (b) administering to the patient a therapeutically effective amount of a compound of any one of claims 1-39 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 40.

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