Tetrahydropyridopyrimidine pan-KRas inhibitors

Abstract

The present invention relates to compounds that inhibit at least one of KRas wild-type, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and KRas Q61H, pharmaceutical compositions containing the compounds, and methods of use therefor.

Description

[Technical Field]

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

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

[0003] The role of activated KRas in malignant tumors was observed more than 30 years ago (see, for example, Non-Patent Document 2). Aberrant expression of KRas accounts for up to 20% of all cancers and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas. KRas mutations at codons 12, 13, 61, and other positions in the KRas primary amino acid sequence are present in 88% of all pancreatic adenocarcinoma patients, 50% of all colorectal adenocarcinoma patients, and 32% of lung adenocarcinoma patients (see, for example, Non-Patent Document 3). Recent papers have shown that wild-type Kras inhibition inhibits KRas WT It has also been suggested that this may be a viable therapeutic strategy for treating addictive cancers (see, for example, Non-Patent Document 4).

[0004] The well-known role of KRas in malignancies and the discovery of these frequent mutations in KRas in various tumor types have made KRas a very attractive target for the pharmaceutical industry for cancer therapy. Despite 30 years of extensive research to develop KRas inhibitors for the treatment of cancer, no KRas inhibitor has yet proven sufficiently safe and / or effective to gain regulatory approval (see, e.g., Non-Patent Document 5).

[0005] Compounds that inhibit KRas activity, including those that disrupt effectors such as guanine nucleotide exchange factors, remain highly desirable and under investigation (see, e.g., Non-Patent Document 6), and recent progress has been made in covalently targeting the allosteric pocket of KRas G12C (see, e.g., Non-Patent Document 7 and Non-Patent Document 8). Clearly, there is ongoing interest in developing inhibitors of KRas, particularly inhibitors of activating KRas mutants.

[0006] Therefore, there is a need to develop novel pan-KRas inhibitors that demonstrate sufficient efficacy for treating KRas-mediated cancers. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Alamgeer et al.,(2013)Current Opin Pharmcol.13:394-401 [Non-patent document 2] Santos et al.,(1984)Science 223:661-664 [Non-patent document 3] Prior et al.,(2020)Cancer Res 80:2969-74 [Non-patent document 4] Bery et al.,(2020)Nat.Commun.11:3233 [Non-patent document 5] McCormick(2015)Clin Cancer Res.21(8):1797-1801 [Non-patent document 6] Sun et al.,(2012)Agnew Chem Int Ed Engl.51(25):6140-6143 doi:10.1002 / anie201201358 [Non-Patent Document 7] Ostrem et al.,(2013)Nature 503:548-551 [Non-patent document 8] Fell et al.,(2018)ACS Med.Chem.Lett.9:1230-1234 Summary of the Invention [Means for solving the problem]

[0008] In one aspect of the invention, compounds that inhibit KRas activity are provided.

[0009] In one aspect of the invention, a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: A is an aryl or heteroaryl, and the aryl or heteroaryl is selected from 1 to 4 R 1 optionally replaced by; B is [ka] is selected from Y 1 is 1 to 4 R 8 L-hydrogen, hydroxy, halogen, 1 to 4 R optionally substituted with 9 L-C3-C6 cycloalkyl optionally substituted with 1 to 4 R 9 LS(O)N(R 5 )2, 1 to 4 R 8L-heteroaryl optionally substituted with 1 to 4 R 8 and L-aryl optionally substituted with 1-2 oxo (=O) or oxo-containing substituents and 1-2 heteroaryl-R 8 or R 8 is an L-heterocycle optionally further substituted with Y 2 is hydrogen or C1-C4 alkyl; Or Y 1 and Y 2 together, [ka] Forming wherein X is selected from a bond, -S-, -O-, -N<bond to a fused ring, -CH2-, -CH2-NH-, -CH2-NH-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, -O-CH2-, and -S-CH2-; Each R 1 are independently halogen, cyano, hydroxy, C1-C4 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, -CH2C(=O)N(R 5 )2, -C3-C4 alkynyl (NR 5 )2, -N(R 5 )2, deutero C2-C4 alkynyl, (C1-C3 alkoxy)haloC1-C3 alkyl- or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with halogen or C1-C3 alkyl; Each R 2 are independently hydrogen, hydroxy, halogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, -OC(O)N(R 5 )2, -CH2OC(O)N(R 5 )2, -CH2NR 5 -SO2-N(R5 )2, -CO2R 5 , -CO2N(R 5 )2, =CH2, =CHR 11 or =C(R 11 )2; Each R 3 are independently hydrogen, hydroxy, halogen, L-C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, -OC(O)N(R 5 )2, -CH2OC(O)N(R 5 )2, -CH2NR 5 -SO2-N(R 5 )2, -CO2R 5 , -CO2N(R 5 )2;=CH2,=CHR 11 or =C(R 11 )2; In the formula, R 2 and R 3 At least one of the following is =CH2, =CHR 11 or =C(R 11 )2; R 4 is hydrogen, halogen or C1-C3 alkyl; Each R 5 are independently hydrogen, cyclopropyl, or C1-C3 alkyl; Each R 6 are independently hydrogen, hydroxy, C1-C4 hydroxyalkyl, or heteroaryl, or two R 6 together form a C3-C6 cycloalkyl or heterocycle; Each R 7are independently hydrogen, C1-C3 alkyl, hydroxy, halogen, halo-C1-C3 alkyl, di-halo-C1-C3 alkyl, tri-halo-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -O-CH2-C(O)NH2, LC(O)NH2, -C(O)NH(C1-C3 alkyl), -NHC(O)(C1-C3 alkyl), -C(O)N(C1-C3 alkyl) -C(O)NH(C-C4 cycloalkyl) and -NHC(O)(C-C3 alkyl); Two R on the same atom 7 optionally taken together form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, said spirocyclic ring optionally substituted with 1 to 2 substituents selected from oxo (=O), halogen, hydroxy, C1-C3 alkyl and -O-(C1-C3 alkyl); Two R on adjacent atoms 7 are optionally taken together to form a bond or 1 to 4 R 8 C3-C6 cycloalkyl optionally substituted with 1 to 4 R 8 heteroaryl optionally substituted with 1 to 4 R 8 aryl optionally substituted with and 1 to 4 R 8 forming a fused ring selected from heterocycles optionally substituted with Two R on non-adjacent atoms 7 optionally, taken together, form 1-2 carbon bridges; Each R 8are independently C1-C3 alkyl, L-hydroxy, halogen, halo-C1-C3 alkyl, di-halo-C1-C3 alkyl, tri-halo-C1-C3 alkyl, -N(R 5 )2, oxo(=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OR 5 , -C(O)B', -C(OR 5 )(R 5 )2, -(C1-C3 alkyl)C(O)N(R 5 )2, -C(O)N(R 5 )2, -C(O)N(R 10 )2, -CN, LL-heteroaryl, or L-heterocycle (each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, -CH2-S-CH3, -S(O)2NH2, or -S(O)2(C1-C3 alkyl); Each R 9 are independently C1-C3 alkyl, hydroxy, halogen, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2, L-heteroaryl, or -CN; 2 R's 9 together form a bond or -S(O)(CH3)2; Each R 10 are independently hydrogen, C1-C3 alkyl, halogen, or R 7 Or another R 10 together to form a heterocyclic ring; Each R 11 are independently halogen; Each L is independently a bond; -C1-C4 alkylene-, -NR 5 - or -C(O)-; each n is 0 to 3; o is 1 to 6; p is 1 to 8; q is between 0 and 1).

[0010] In another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] In another aspect of the invention, a method for inhibiting the activity of wild-type KRas or cells containing one or more KRas mutations, such as KRas mutations G12A, G12C, G12D, G12R, G12S, G12V, G13D, or Q61H, in a cell comprises contacting the cell with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0012] Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[0013] Also provided is a method for treating cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutical composition or a pharmaceutically acceptable salt thereof.

[0014] Also provided herein is a method of treating a disease or disorder associated with KRas wild-type or associated with KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein.

[0015] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, for use in therapy.

[0016] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, for use in the treatment of cancer.

[0017] Also provided herein are compounds of Formula (I) or pharmaceutically acceptable salts thereof for use in inhibiting wild-type KRas or multiple types of KRas mutations, such as KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations.

[0018] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of a disease or disorder associated with wild-type KRas or KRas mutations G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H.

[0019] There is also provided herein the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of cancer.

[0020] Also provided herein is the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of the activity of wild-type KRas or mutant forms of KRas, including the mutations: G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H.

[0021] Also provided herein is the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with wild-type KRas or associated with KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H.

[0022] Also provided herein are methods for treating cancer in a patient in need thereof, the methods comprising: (a) determining that the cancer is associated with wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutation (i.e., a cancer associated with wild-type KRas or associated with KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61HG12X); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0023] One potential utility of the pan-KRas inhibitors described herein, including pan-KRas inhibitors such as (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (Example 5 of 63 / 125,776), is for the treatment of cancers that develop resistance after long-term treatment with a KRas G12C inhibitor. Accordingly, embodiments of the present invention include those in which a patient suffering from cancer is treated with a pan-KRas inhibitor described herein after treatment with a G12C inhibitor has become ineffective or less effective due to the emergence of resistance-conferring mutations.

[0024] Treatment of KRas G12C mutant cancers with covalent KRas G12C inhibitors, such as adagrasib (MRTX849) or sotorasib (AMG510), can result in the incorporation of additional mutations that confer resistance to adagrasib. These mutations can confer resistance through a number of mechanisms.

[0025] Mutations that change the mutant cysteine at codon 12 to another amino acid render currently available covalent KRas G12C inhibitors ineffective because they create a covalent bond with the mutant cysteine amino acid side chain. Similarly, in patients with a KRas G12C-mutant allele and one wild-type KRas allele, mutations at the wild-type codon 12 glycine to another codon allow bypass signaling in these tumors through novel mutant proteins. The repertoire of codon 12 mutations that can arise from single nucleotide substitutions in the wild-type gene (glycine codon) includes mutations commonly observed in cancer, such as G12S, G12V, G12R, and G12C. The repertoire of codon 12 mutations that can arise from single nucleotide base substitutions at cysteine codon 12 includes G12S and G12R, as well as mutations less frequently observed in cancer, such as G12Y, G12F, and G12W.

[0026] Secondary site mutations elsewhere in the KRas G12C mutant gene can also occur, conferring resistance to KRas G12C inhibitor treatment. These mutations may confer resistance through different mechanisms. RAS proteins are small GTPases that normally cycle between an active GTP-bound state and an inactive GDP-bound state. RAS proteins are loaded with GTP through guanine nucleotide exchange factors (GEFs; e.g., SOS1) activated by upstream receptor tyrosine kinases, leading to subsequent interaction with effector proteins that activate RAS-dependent signaling. RAS proteins hydrolyze GTP to GDP through their intrinsic GTPase activity, which is dramatically enhanced by GTPase-activating proteins (GAPs). Mutations at codons 12 and 13 in the RAS protein impair GTP hydrolysis stimulated by GAPs, leaving RAS primarily in the GTP-bound, active state. Covalent KRas G12C inhibitors currently in clinical development bind only to the GDP-bound form of KRas G12C. Mutations such as the Q61 codon mutation, which may or may not occur on the same allele as the G12C mutation, may represent a mechanism of resistance to KRas G12C inhibitor treatment by reducing the intrinsic GTPase activity of KRas and shifting KRas to a GTP-loaded state that is less susceptible to covalent inhibition. Concomitant mutations such as R68, H95, and Y96 may coexist with the KRas G12C mutation and reduce the binding affinity of KRas G12C inhibitors to the Switch II binding pocket.

[0027] The pan-KRas inhibitors described herein may exhibit activity against common as well as uncommon codon 12 mutations or mutations occurring in the KRAS protein that reduce binding of the KRas G12C inhibitor to the KRAS protein.

[0028] Also provided herein are processes for preparing compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0029] Also provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof obtained by the process for preparing a compound as defined herein. DETAILED DESCRIPTION OF THE INVENTION

[0030] The present invention relates to inhibitors of wild-type KRas or multiple mutant forms of KRas, such as the KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations. In particular, the present invention relates to compounds that inhibit the activity of wild-type KRas or KRas mutants such as G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H, pharmaceutical compositions comprising therapeutically effective amounts of the compounds, and methods of use thereof.

[0031] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, and publications mentioned herein are incorporated by reference.

[0032] As used herein, "KRas G12A" refers to a mutant form of a mammalian KRas protein containing an alanine-to-glycine amino acid substitution at amino acid position 12. The amino acid codon and residue position assignment for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G12A inhibitor" refers to a compound of the present invention represented by Formula (I), as described herein. These compounds are capable of negatively modulating or inhibiting all or part of the enzymatic activity of KRas G12A. As used herein, "KRas G12A-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G12A mutation. A non-limiting example of a KRas G12A-associated disease or disorder is KRas G12A-associated cancer.

[0033] As used herein, "KRas G12C" refers to a mutant form of a mammalian KRAS protein containing an amino acid substitution of cysteine for glycine at amino acid position 12. The amino acid codon and residue position assignment for human KRas is based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G12C inhibitors" refer to compounds of the present invention represented by Formula (I) as described herein. These compounds are capable of negatively modulating or inhibiting all or part of the enzymatic activity of KRas G12C. As used herein, "KRas G12C-associated diseases or disorders" refers to diseases or disorders associated with, mediated by, or having a KRas G12C mutation. A non-limiting example of a KRas G12C-associated disease or disorder is KRas G12CD-associated cancer.

[0034] As used herein, "KRas G12D" refers to a mutant form of a mammalian KRas protein containing an amino acid substitution of aspartic acid for glycine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G12D inhibitors" refer to compounds of the present invention represented by Formula (I) as described herein. These compounds are capable of negatively modulating or inhibiting all or part of the enzymatic activity of KRas G12D. As used herein, "KRas G12D-associated diseases or disorders" refers to diseases or disorders associated with, mediated by, or having a KRas G12D mutation. A non-limiting example of a KRas G12D-associated disease or disorder is KRas G12D-associated cancer.

[0035] As used herein, "KRas G12R" refers to a mutant form of a mammalian KRAS protein containing an arginine-to-glycine amino acid substitution at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G12R inhibitors" refer to compounds of the present invention represented by Formula (I) as described herein. These compounds are capable of negatively modulating or inhibiting all or part of the enzymatic activity of KRas G12R. As used herein, "KRas G12R-associated diseases or disorders" refers to diseases or disorders associated with, mediated by, or having a KRas G12R mutation. A non-limiting example of a KRas G12R-associated disease or disorder is KRas G12R-associated cancer.

[0036] As used herein, "KRas G12S" refers to a mutant form of a mammalian KRAS protein containing a serine-to-glycine amino acid substitution at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G12S inhibitors" refer to compounds of the present invention represented by Formula (I) as described herein. These compounds are capable of negatively modulating or inhibiting all or part of the enzymatic activity of KRas G12S. As used herein, "KRas G12S-associated diseases or disorders" refers to diseases or disorders associated with, mediated by, or having a KRas G12S mutation. A non-limiting example of a KRas G12S-associated disease or disorder is KRas G12S-associated cancer.

[0037] As used herein, "KRas G12V" refers to a mutant form of a mammalian KRAS protein containing an amino acid substitution of valine for glycine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G12V inhibitors" refer to compounds of the present invention represented by Formula (I) as described herein. These compounds are capable of negatively modulating or inhibiting all or part of the enzymatic activity of KRas G12V. As used herein, "KRas G12V-associated diseases or disorders" refers to diseases or disorders associated with, mediated by, or having a KRas G12V mutation. A non-limiting example of a KRas G12V-associated disease or disorder is KRas G12V-associated cancer.

[0038] As used herein, "KRas G13D" refers to a mutant form of a mammalian KRAS protein containing an amino acid substitution of aspartic acid for glycine at amino acid position 13. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G13D inhibitors" refer to compounds of the present invention represented by Formula (I) as described herein. These compounds are capable of negatively modulating or inhibiting all or part of the enzymatic activity of KRas G13D. As used herein, "KRas G13D-associated diseases or disorders" refers to diseases or disorders associated with, mediated by, or having a KRas G13D mutation. A non-limiting example of a KRas G13D-associated disease or disorder is KRas G13D-associated cancer.

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

[0040] As used herein, the terms "subject," "individual," or "patient," used interchangeably, refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or disorder being treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer with wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation (e.g., as determined using a regulatory agency-approved assay or kit). The subject can be a subject with a tumor that is positive for wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation (e.g., as identified using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may be one whose tumor has wild-type KRas or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations (e.g., where the tumor is identified using a kit or assay approved by a regulatory agency, e.g., approved by the FDA). In some embodiments, the subject is suspected of having a cancer associated with wild-type KRas or associated with the KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H genes.In some embodiments, the subject has clinical records indicating that the subject has a tumor with wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutation (and optionally, the clinical records indicate that the subject should be treated with any of the compositions provided herein).

[0041] In some embodiments of any of the methods or uses described herein, a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a cancer associated with wild-type KRas or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H, a patient with one or more symptoms of a cancer associated with wild-type KRas or associated with KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H, and / or a patient at increased risk of developing a cancer associated with wild-type KRas or associated with KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H) is used to determine whether the patient has wild-type KRas or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H. Assays used to determine whether a patient has the G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations can include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time T-PCR). As is well known in the art, assays are generally performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

[0042] The term "regulatory authority" refers to a national agency responsible for the approval of pharmaceuticals for medical use by a nation. For example, a non-limiting example of a regulatory authority is the US Food and Drug Administration (FDA).

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

[0044] The terms "C1-C6 alkyl," "C1-C4 alkyl," and "C1-C3 alkyl," as used herein, refer to straight-chain and branched-chain aliphatic groups having 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms, respectively. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

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

[0046] A "C1-C4 alkylene" group is a C1-C4 alkyl group, as defined herein above, that is positioned between and serves to link two other chemical groups. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

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

[0048] The term "cycloalkyl," as used herein, includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, for example, 3 to 8 carbons, and as a further example, 3 to 6 carbons, which cycloalkyl groups may optionally further include one or more R groups, as defined herein. 8 or R 9The cycloalkyl group is substituted with a cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term "cycloalkyl" also includes bridged cycloalkyls, such as bicyclo[1.1.1]pentanyl.

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

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

[0051] An "aryl" group is a C6-C14 aromatic moiety containing one to three aromatic rings, which are optionally substituted with one or more substituents as defined herein and in Formula I. In one embodiment, the aryl group is a C6-C10 aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl. "Aryl" also refers to bicyclic or tricyclic ring systems in which one or two rings of each of the aryl ring systems can be saturated or partially saturated, and when the ring system contains two saturated rings, the saturated rings can be fused or spirocyclic. Examples of aryl ring systems containing two saturated rings in which the rings are spirocyclic include the following ring systems: [ka] Examples include:

[0052] An "aralkyl" or "arylalkyl" group comprises an aryl group covalently bonded to an alkyl group, either of which can independently be optionally substituted or unsubstituted. Examples of aralkyl groups are (C-C)aryl(C-C)alkyl-, including, but not limited to, benzyl, phenethyl, and naphthylmethyl. Examples of substituted aralkyl groups are those in which the alkyl group is substituted with hydroxyalkyl.

[0053] A "heterocyclyl" or "heterocyclic" group is a saturated or partially unsaturated ring structure having 3 to 12 atoms, e.g., 4 to 8 atoms, where one or more atoms are selected from the group consisting of N, O, and S, where the ring N atom can be oxidized to NO, the ring S atom can be oxidized to SO or SO, and the remainder of the ring atoms are carbon. A heterocyclyl can be a monocyclic, bicyclic, spirocyclic, or bridged ring system. A heterocyclic group is optionally substituted on ring carbon or ring nitrogen at one or more positions as defined herein and in Formula I. A heterocyclic group is also independently optionally substituted on ring nitrogen atoms by alkyl, aralkyl, alkylcarbonyl, or on sulfur atoms by lower alkyl. Examples of heterocyclic groups include epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 dioxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyl, azabicycloheptanyl, azabicyclooctanyl, azabicyclononanyl (e.g., octahydroindolinyl), and the like. oxazinyl), azaspiroheptanyl, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolidine], hexahydro-1H-pyrrolidinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyl, oxaazaspirooctanyl, diazaspirononanyl, oxazabioctoheptanyl, hexahydropyrrolidinyl 4(1H)-oxide, tetrahydro-2H-thiopyranyl 1-oxide, and tetrahydro-2H-thiopyranyl 1,1-dioxide. Specifically excluded from the scope of this term are compounds having adjacent ring O and / or S atoms.

[0054] As used herein, the term "heteroaryl" refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic array; and having, in addition to carbon atoms, 1 to 3 heteroatoms per ring or 1 to 3 heteroatoms in at least one ring selected from the group consisting of N, O, and S.Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazoyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanyl, furazanyl, imidazolinyl, and imidazolyl. , 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, Oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidyl nyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl."Heteroaryl" also refers to bicyclic ring systems having, in addition to carbon atoms, 1 to 3 heteroatoms per ring selected from the group consisting of N, O, and S, wherein one ring system can be saturated or partially saturated.

[0055] As used herein, an "effective amount" of a compound is an amount sufficient to negatively modulate or inhibit the activity of wild-type KRas or one or more of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H. Such an amount may be administered as a single dose or according to a regimen to be effective.

[0056] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to ameliorate or alleviate symptoms to some extent, or to halt or reverse the progression of a condition, or to negatively modulate or inhibit the activity of wild-type KRas or one or more of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H. Such an amount may be administered as a single dose or according to a regimen whereby it is effective.

[0057] As used herein, treatment means any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also includes any pharmaceutical use of the compositions herein.

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

[0059] compound A particular embodiment of the present invention is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein A is an aryl or heteroaryl, and the aryl or heteroaryl optionally contains 1 to 4 R 1 is replaced by; B is [ka] is selected from Y 1 is 1 to 4 R 8 L-hydrogen, hydroxy, halogen, 1 to 4 R optionally substituted with 9 L-C3-C6 cycloalkyl optionally substituted with 1 to 4 R 9 LS(O)N(R 5 )2, 1 to 4 R 8 L-heteroaryl optionally substituted with 1 to 4 R 8 and L-aryl optionally substituted with 1-2 oxo (=O) or oxo-containing substituents and 1-2 heteroaryl-R 8 or R 8 is an L-heterocycle optionally further substituted with Y 2 is hydrogen or C1-C4 alkyl; Or Y 1 and Y 2 together, [ka] Forming wherein X is selected from a bond, -S-, -O-, -N<bond to a fused ring, -CH2-, -CH2-NH-, -CH2-NH-CH2-, -CH2-CH2-CH2-, -CH2-CH2-, -O-CH2-, and -S-CH2-; Each R 1are independently halogen, cyano, hydroxy, C1-C4 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, -CH2C(=O)N(R 5 )2, -C3-C4 alkynyl (NR 5 )2, -N(R 5 )2, deutero C2-C4 alkynyl, (C1-C3 alkoxy)haloC1-C3 alkyl- or C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted with halogen or C1-C3 alkyl; Each R 2 are independently hydrogen, hydroxy, halogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, -OC(O)N(R 5 )2, -CH2OC(O)N(R 5 )2, -CH2NR 5 -SO2-N(R 5 )2, -CO2R 5 , -CO2N(R 5 )2, =CH2, =CHR 11 or =C(R 11 )2; Each R 3 are independently hydrogen, hydroxy, halogen, L-C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, -OC(O)N(R 5 )2, -CH2OC(O)N(R5)2, -CH2NR 5 -SO2-N(R 5 )2, -CO2R 5 , -CO2N(R 5 )2;=CH2,=CHR 11 or =C(R 11 )2; In the formula, R 2 and R 3 At least one of the following is =CH2, =CHR 11 or =C(R 11 )2; R 4 is hydrogen, halogen or C1-C3 alkyl; Each R 5 are independently hydrogen, cyclopropyl, or C1-C3 alkyl; Each R 6 are independently hydrogen, hydroxy, C1-C4 hydroxyalkyl, or heteroaryl, or two R 6 together form a C3-C6 cycloalkyl or heterocycle; Each R 7 are independently hydrogen, C1-C3 alkyl, hydroxy, halogen, halo-C1-C3 alkyl, di-halo-C1-C3 alkyl, tri-halo-C1-C3 alkyl, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -O-CH2-C(O)NH2, LC(O)NH2, -C(O)NH(C1-C3 alkyl), -NHC(O)(C1-C3 alkyl), -C(O)N(C1-C3 alkyl) -C(O)NH(C-C4 cycloalkyl) and -NHC(O)(C-C3 alkyl); Two R on the same atom 7 optionally taken together form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, said spirocyclic ring optionally substituted with 1 to 2 substituents selected from oxo (=O), halogen, hydroxy, C1-C3 alkyl and -O-(C1-C3 alkyl); Two R on adjacent atoms 7 optionally, taken together, represent a bond or 1 to 4 R 8C3-C6 cycloalkyl optionally substituted with 1 to 4 R 8 heteroaryl optionally substituted with 1 to 4 R 8 aryl optionally substituted with and 1 to 4 R 8 forming a fused ring selected from heterocycles optionally substituted with Two R on non-adjacent atoms 7 optionally, taken together, form 1-2 carbon bridges; Each R 8 are independently C1-C3 alkyl, L-hydroxy, halogen, halo-C1-C3 alkyl, di-halo-C1-C3 alkyl, tri-halo-C1-C3 alkyl, -N(R 5 )2, oxo(=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OR 5 , -C(O)B', -C(OR 5 )(R 5 )2, -(C1-C3 alkyl)C(O)N(R 5 )2, -C(O)N(R 5 )2, -C(O)N(R 10 )2, -CN, LL-heteroaryl, or L-heterocycle (each optionally substituted with C1-C3 alkyl, C1-C3 haloalkyl, -CH2-S-CH3, -S(O)2NH2, or -S(O)2(C1-C3 alkyl); Each R 9 are independently C1-C3 alkyl, hydroxy, halogen, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2, L-heteroaryl, or -CN; 2 R's 9 together form a bond or -S(O)(CH3)2; Each R 10 are independently hydrogen, C1-C3 alkyl, halogen, or R 7 Or another R 10 together to form a heterocyclic ring; Each R11 are independently halogen; Each L is independently a bond; -C1-C4 alkylene-, -NR 5 - or -C(O)-; each n is 0 to 3; o is 1 to 6; p is 1 to 8; q is between 0 and 1).

[0060] A particular embodiment of the present invention is a compound of formula q is 1; A is naphthyl; B: [ka] The present invention includes compounds or salts thereof,

[0061] A particular embodiment of the present invention comprises: q is 1; A is naphthyl; B: [ka] The present invention includes compounds or salts thereof,

[0062] A particular embodiment of the present invention is 1 is hydrogen, hydroxy, halogen or 1 to 4 R 8 and Y is an L-heteroaryl optionally substituted with 2 is hydrogen or C1-C4 alkyl.

[0063] A particular embodiment of the present invention is 1 and Y 2 Together, [ka] This includes compounds or salts that form:

[0064] A particular embodiment of the invention is where X is -CH-NH- and two R 7Together, 1 to 4 R 8 and one R8 is substituted with -C(O)N(R 10 )2) includes compounds or salts which form a fused heteroaryl ring.

[0065] A particular embodiment of the invention is when the fused heteroaryl ring is pyrazolyl and one R 8 -C(O)N(R 10 )2 and one R 8 is halogen or C1-C3 alkyl.

[0066] A particular embodiment of the invention is where X is a bond and two R 7 taken together to form a fused heterocyclyl ring optionally substituted by one or two oxo.

[0067] A particular embodiment of the invention is where X is -CH- and two R 7 taken together to form a spirocyclic heterocyclyl ring substituted with one or two oxo groups.

[0068] Certain embodiments of the present invention are directed to at least one R 1 is C1-C4 alkyl.

[0069] Certain embodiments of the present invention are directed to at least one R 1 is a halogen.

[0070] Particular embodiments of the present invention include compounds or salts wherein said halogen is fluorine.

[0071] Certain embodiments of the present invention are directed to at least one R 1 is hydroxy.

[0072] Certain embodiments of the present invention are 2 is C1-C4 alkyl.

[0073] Certain embodiments of the present invention are directed to at least one R 2 is a halogen.

[0074] Particular embodiments of the present invention include compounds or salts wherein said halogen is fluorine.

[0075] Certain embodiments of the present invention are directed to at least one R 2 is hydroxy.

[0076] Certain embodiments of the present invention are directed to at least one R 3 is C1-C4 alkyl.

[0077] Certain embodiments of the present invention are directed to at least one R 3 is a halogen.

[0078] Particular embodiments of the present invention include compounds or salts wherein said halogen is fluorine.

[0079] Certain embodiments of the present invention are directed to at least one R 2 But =CH2, =CHR 11 or =C(R 11 )2.

[0080] A particular embodiment of the present invention is 11 This includes compounds or salts in which:

[0081] Certain embodiments of the present invention are directed to at least one R 3 is hydroxy.

[0082] Certain embodiments of the present invention are directed to at least one R 3 But =CH2, =CHR 11 or =C(R 11 )2.

[0083] A particular embodiment of the present invention is 11 This includes compounds or salts in which:

[0084] A particular embodiment of the present invention is 4 is a halogen.

[0085] Particular embodiments of the present invention include compounds or salts wherein said halogen is fluorine.

[0086] Certain embodiments of the present invention are directed to at least one R 5 is C1-C4 alkyl.

[0087] Certain embodiments of the present invention are directed to at least one R 5 is hydrogen.

[0088] Certain embodiments of the present invention may be embodied in one or both R 6 is hydrogen or C1-C4 alkyl.

[0089] Certain embodiments of the present invention are 6 taken together to form a C3-C6 cycloalkyl or heterocycle.

[0090] A particular embodiment of the present invention is 1 is L-C3-C6 cycloalkyl, L-heteroaryl, L-aryl or L-heterocycle, and L is a bond, C1-C4 alkyl, NH or N(C1-C3)alkyl.

[0091] A particular embodiment of the present invention is 1 is L-heteroaryl.

[0092] Particular embodiments of the present invention include compounds or salts wherein heteroaryl is thietanedioxide, isothiazolidinedioxide, imidazopyrazine, pyridine, or pyrimidine.

[0093] A particular embodiment of the present invention is 1 is L-C3-C6 cycloalkyl.

[0094] Particular embodiments of the present invention include compounds or salts wherein cycloalkyl is cyclobutane, cyclopentane, cyclohexane, or cycloheptane.

[0095] A particular embodiment of the present invention is 1 is an L-heterocycle.

[0096] Particular embodiments of the present invention include compounds or salts wherein the heterocycle is a pyrrolidinone.

[0097] A particular embodiment of the present invention is 2 is hydrogen.

[0098] A particular embodiment of the present invention is 2 is C1-C4 alkyl.

[0099] Certain embodiments of the present invention are directed to at least one R 8 is C1-C4 alkyl.

[0100] Certain embodiments of the present invention are directed to at least one R 8 is hydroxy or C1-C3 alkyl-hydroxy.

[0101] Certain embodiments of the present invention are 8 is oxo (=O).

[0102] Certain embodiments of the present invention are directed to at least one R 8 is aryl or heteroaryl.

[0103] Certain embodiments of the present invention are directed to at least one R 8 is C(O)OH.

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

[0105] Certain embodiments of the present invention are directed to at least one R 8 is —NH2, —NH(C1-C3 alkyl); —N(C1-C3 alkyl)2.

[0106] Certain embodiments of the present invention are directed to at least one R 9 is C1-C4 alkyl.

[0107] Certain embodiments of the present invention are directed to at least one R 9 is hydroxy or C1-C3 alkyl-hydroxy.

[0108] Certain embodiments of the present invention are 9 is oxo (=O).

[0109] Certain embodiments of the present invention are directed to at least one R 9 is aryl or heteroaryl.

[0110] Certain embodiments of the present invention are directed to at least one R 9 is C(O)OH.

[0111] Certain embodiments of the present invention are directed to at least one R 9 is -C(O)NH2, -C(O)NH(C1-C3 alkyl) or -C(O)N(C1-C3 alkyl) 2 The present invention includes compounds or salts thereof,

[0112] A particular embodiment of the present invention is 1 and Y 2 taken together to form piperidine, azepane, azocane, thiazepine, diazepane, oxazepane, azetidine, pyrrolidine, piperazine (attached to the fused ring via the nitrogen) or thiomorpholine.

[0113] Certain embodiments of the present invention include two R 7 taken together form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, wherein the spirocyclic ring is optionally substituted with one or more substituents selected from oxo (=O), halogen, hydroxy, C1-C3 alkyl, and -O-(C1-C3 alkyl).

[0114] Certain embodiments of the present invention are directed to two R 7 are joined together to form a bond or 1 to 4 R 8 optionally substituted C3-C6 cycloalkyl; 1-4 R 8 heteroaryl optionally substituted with 1 to 4 R 8 aryl optionally substituted with and 1 to 4 R 8 The present invention also includes compounds or salts which form a fused ring selected from heterocycles optionally substituted with:

[0115] Certain embodiments of the present invention are directed to two R 7 together form a 1-2 carbon bridge.

[0116] Certain embodiments of the present invention are 10 is hydrogen, C1-C3 alkyl or halogen, and another R 10R 7 and a compound or salt thereof which, when taken together with the above, forms a heterocycle.

[0117] Certain embodiments of the present invention are 10 taken together to form a heterocycle.

[0118] Certain embodiments of the present invention are 10 are independently hydrogen, C1-C3 alkyl or halogen.

[0119] Particular embodiments of the present invention include compounds or salts where q is 1. It is preferred that q is 1.

[0120] Non-limiting examples of compounds of formula (I) are: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0121] In one embodiment, compounds of formula (I) include the bishydrochloride, trishydrochloride, trifluoroacetate, bistrifluoroacetate, and tris-trifluoroacetate salts of the above compounds. The compounds of formula (I) or pharmaceutically acceptable salts thereof can be formulated into pharmaceutical compositions.

[0122] Pharmaceutical Composition In another aspect, the present invention provides pharmaceutical compositions comprising a KRas wild-type, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H inhibitor according to the present invention and a pharmaceutically acceptable carrier, excipient, or diluent. The compounds of the present invention can be formulated by any method known in the art and prepared for administration by any route, including, but not limited to, parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal, intramuscular, intravitreal, intravenous, intraarterial, oral, buccal, sublingual, transdermal, topical, intranasal, intratracheal, rectal, subcutaneous, and local administration. In certain embodiments, the compounds of the present invention are administered intravenously in a hospital setting. In one embodiment, administration can be by the oral route. In some embodiments, provided pharmaceutical compositions can be administered to a subject in need of treatment systemically by injection, for example, by intravenous injection; or by injection or application to an appropriate site, for example, by direct injection via a syringe or by direct application to the site if the site is exposed by surgery; or by local administration.

[0123] Parenteral administration may be by bolus injection or continuous infusion. Pharmaceutical compositions for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.

[0124] The provided pharmaceutical compositions can also be formulated as depot preparations. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or intramuscular injection. Thus, for example, the formulation can be modified with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as sparingly soluble salts.

[0125] The pharmaceutical compositions may be optionally presented in a vial, pack, or medical device, including, but not limited to, a dispenser device, which may contain one or more unit dosage forms containing the active ingredient. In one embodiment, the dispenser device may contain a syringe with a single dose of the liquid formulation for immediate injection. The syringe may be accompanied by instructions for administration.

[0126] The characteristics of the carrier depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with a biological system, such as a cell, cell culture, tissue, or organ, and does not interfere with the effectiveness of the biological activity of the active ingredient. Thus, in addition to the inhibitor, the composition according to the present invention may contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other substances well known in the art. The preparation of pharmaceutically acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0127] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the above-identified compounds and exhibits minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenedisulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, specifically including quaternary ammonium salts of the formula -NRZ-, where R is hydrogen, alkyl, or benzyl, and Z is a counterion that includes chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphonate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).

[0128] The active compound is included in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing significant toxic effects in the treated patient. In one embodiment, the dose of the active compound for all of the above conditions is in the range of about 0.01 to 300 mg / kg, e.g., 0.1 to 100 mg / kg / day, and further example, 0.5 to about 25 mg / kilogram of host body weight / day. Typical topical dosages range from 0.01 to 3% wt / wt in a suitable carrier. The effective dosage range of pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative is active itself, the effective dosage can be estimated as above using the weight of the derivative or by other means known to those skilled in the art.

[0129] Pharmaceutical compositions containing the compounds of the present invention can be used in the methods of use described herein.

[0130] How to use In another aspect, the present invention provides a method for inhibiting wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, and / or KRas Q61H activity in a cell, the method comprising contacting wild-type KRas or a cell in which inhibition of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, and / or Q61H activity is desired with an effective amount of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0131] As used herein, the term "contacting" refers to bringing together specified moieties in an in vitro system or an in vivo system. For example, "contacting" wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H with a compound provided herein includes administering a compound provided herein to an individual or patient, e.g., a human, having wild-type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H mutation; This involves introducing into a sample containing a cellular or purified preparation containing a G13D or KRas Q61H mutation.

[0132] In one embodiment, a cell in which inhibition of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H activity is desired is contacted with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to negatively modulate the activity of one or more of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and KRas Q61H.

[0133] By negatively modulating the activity of one or more of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and KRas Q61H, the methods described herein are designed to inhibit undesired cell proliferation that results from enhanced wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H activity in cells. The cells may be contacted in a single dose or multiple doses according to a particular treatment regimen to affect the desired negative modulation of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H. The ability of a compound to bind to one or more of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and KRas Q61H may be monitored in vitro using well-known methods, including those described in Examples A and B below. Additionally, the inhibitory activity of representative compounds in cells can be monitored by measuring the amount of phosphorylated ERK, inhibition of one or more of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H activity, for example, using the methods described in Example C below.

[0134] In another aspect, there is provided a method of treating cancer in a patient in need thereof, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof.

[0135] Compositions and methods provided herein can be used to treat cancers associated with wild-type KRas or associated with KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer associated with wild-type KRas or associated with KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H is lung cancer.

[0136] The compositions and methods provided herein can be used to treat a wide variety of cancers, including tumors of the lung, prostate, breast, brain, skin, cervical cancer, testicular cancer, etc. More specifically, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid carcinomas and sarcomas. More specifically, these compounds may be used to treat: cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; pulmonary: bronchogenic lung carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, 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 system: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), sperm Neoplasia (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibrocarcinoma, adenomatous tumor, lipoma); Liver: Hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: Gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma Osteochronoma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma);Gynecological: Uterus (endometrial carcinoma), Cervix (cervical cancer, precancerous cervical dysplasia), Ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), Vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), Vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)), Fallopian tubes (carcinoma); Hematological: Blood (myeloid leukemia (acute and chronic), acute leukemia) lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi lentigo, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer. In certain embodiments, the cancer is non-small cell lung cancer.

[0137] The concentration and route of administration to the patient will vary depending on the cancer being treated. The present compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing such compounds and salts may also be co-administered with other anti-neoplastic compounds, such as chemotherapeutic agents, or used in combination with other treatments, such as radiation or surgical intervention, either as adjuvant therapy before or after surgery.

[0138] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein for use in therapy.

[0139] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein, for use in the treatment of cancer.

[0140] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for use in inhibiting wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H.

[0141] Also provided herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as defined herein for use in the treatment of a disease or disorder in which wild-type KRas is associated or in which KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H is associated.

[0142] There is also provided herein the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein in the manufacture of a medicament for the treatment of cancer.

[0143] Also provided herein is the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of the activity of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H.

[0144] Also provided herein is the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with wild-type KRas or associated with KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H.

[0145] Also provided herein are methods for treating cancer in a patient in need thereof, the methods comprising: (a) determining that the cancer is associated with wild-type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H mutation (e.g., as determined using a regulatory agency approved, e.g., FDA approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0146] Those skilled in the art will recognize that both in vivo and in vitro testing using appropriate, known, and generally accepted cellular and / or animal models will predict the ability of a test compound to treat or prevent certain disorders.

[0147] Those skilled in the art will further recognize that human clinical trials, including first-in-human dose-ranging and efficacy studies in healthy patients and / or patients suffering from certain disorders, can be completed according to methods well known in the clinical and medical arts.

[0148] Reaction Schemes and Examples The compounds of the invention can be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and conventional methods well known to those skilled in the art. For example, the compounds of the invention can be prepared according to the reaction schemes and examples outlined below.

[0149] The compounds of the present invention may have one or more asymmetric centers and may be synthesized as stereoisomeric mixtures, isomers of identical constitution but differing in the arrangement of their atoms in space. The compounds may be used as mixtures, or the individual components / isomers may be separated using commercially available reagents and conventional methods for isolating stereoisomers and enantiomers well known to those skilled in the art, for example, using a CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatography HPLC column according to the manufacturer's instructions. Alternatively, the compounds of the present invention may be synthesized using optically pure and chiral reagents to prepare individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Unless otherwise indicated, whenever this specification, including the claims, refers to a compound of the present invention, the term "compound" should be understood to encompass all chiral (enantiomers and diastereomers) and racemic forms.

[0150] The compounds of the present invention may be in anhydrous, solvated or hydrated form, and all such forms are embraced within the scope of the present invention.

[0151] Example 233 [ka] (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(1,6-diazaspiro[3.3]heptan-6-yl)methanone [ka]

[0152] Step A. 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid: 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2 To a mixture of 1,5-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl-4-methylbenzenesulfonate (150 mg, 1.0 equiv) and 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (50.0 mg, 1.1 equiv, HCl salt) was added 4 Å molecular sieves (30 mg, 1.0 equiv) and N,N-diethylpropan-2-amine (279 mg, 10 equiv). The reaction was stirred at 40° C. for 12 hours. The mixture was filtered and purified by reverse phase flash chromatography [water (FA, 0.1%) / acetonitrile] to give the title compound (100 mg, 65% yield) as a yellow solid; LCMS (ESI, M+1): m / z=704.4.

[0153] Step B. tert-Butyl 6-(5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carbonyl)-1,6-diazaspiro[3.3]heptane-1-carboxylate: 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carbonyl)-1,6-diazaspiro[3.3]heptane-1-carboxylate in DMF (0.5 mL) To a mixture of 2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (70.0 mg, 1.0 equiv), HATU (75.6 mg, 2.0 equiv), N,N-diethylpropan-2-amine (38.6 mg, 3.0 equiv), and tert-butyl 1,6-diazaspiro[3.3]heptane-1-carboxylate (49.3 mg, 2.5 equiv). The reaction was stirred at 20 °C for 0.5 h. The mixture was filtered, purified by prep-HPLC [Welch Ultimate C18 150 × 25 mm × 5 μm; A: water (FA), B: ACN; B%: 29%-59% over 30 min], and lyophilized to give the title compound (52 mg, 58% yield) as a yellow solid.

[0154] Step C. (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(1,6-diazaspiro[3.3]heptan-6-yl)methanone: tert-Butyl 6-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(1,6-diazaspiro[3.3]heptan-6-yl)methanone in DCM (0.5 mL) To a mixture of 1,6-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carbonyl)-1,6-diazaspiro[3.3]heptane-1-carboxylate (34.0 mg, 1.0 equiv) was added TFA (770 mg, 175 equiv). The reaction was stirred at 0 °C for 1 hour. The mixture was concentrated, dissolved in methanol (3.0 mL), neutralized with solid NaHCO, filtered, purified by prep-HPLC [Phenomenex luna 150 × 25 mm × 10 μm; A: water (FA), B: ACN; B%: 7%-37% over 9 min], and lyophilized to give the title compound (1.91 mg, 5.7% yield, FA [formate] salt) as a yellow solid.1H NMR (400MHz, dimethyl sulfoxide-d6 + heavy water-d2) δ=7.57(dd,J=6.0,9.2Hz,1H),7.32-7.15(m,1H),6.98(s,2H),6.58(s,1H),5.35 -5.13(m,1H),5.03-4.92(m,1H),4.77-4.67(m,1H),4.63-4.38(m,4H),4.25-4.03(m,3H),3.98-3.84(m,2H),3.55(br d,J=17.2Hz,1H),3.48-3.38(m,3H),3.34-3.16(m,3H),3.15-2.93(m,5H),2.88-2.73(m,1H),2. 65-2.57(m,1H),2.45-2.36(m,1H),2.22-1.96(m,4H),1.96-1.63(m,6H),1.07-0.99(m,3H);19F NMR (400MHz, dimethyl sulfoxide-d6+heavy water-d2) δ=-121.055,-171.774; LCMS (ESI, M+1): m / z=740.5.

[0155] Example 234 [ka] 3,6-Diazabicyclo[3.2.1]octan-3-yl(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone [ka] Prepared according to Example 233, except using HCl instead of TFA in the final step. The title compound was obtained as an orange solid (FA salt). 1H NMR (400MHz, dimethyl sulfoxide-d6+heavy water-d2)δ=7.56(dd,J=6.0,8.8Hz,1H),7.22(t,J=9.6Hz,1H),7.05-6.89(m,2H),6.61-6.44(m,1H),5.33-5.12(m,1 H),5.08-4.88(m,1H),4.81-4.65(m,1H),4.61-4.40(m,3H),4.35-4.07( m,2H),4.00-3.87(m,2H),3.76-3.65(m,1H),3.62-3.50(m,1H),3.41(br d,J=7.6Hz,1H),3.14(br s,2H),3.13-3.00(m,5H),2.99-2.82(m,3H),2.81-2.72(m,1H),2.69-2.60(m,1H),2.55(br 19F NMR (400MHz, dimethyl sulfoxide-d6 + heavy water-d2) δ=-121.048,-171.624; LCMS (ESI, M+1): m / z=754.6.

[0156] Example 235 [ka] 2,6-Diazabicyclo[3.2.1]octan-2-yl(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone [ka] The synthesis was carried out according to Example 233, except that HCl was used instead of TFA in the final step. The title compound was obtained as a yellow solid (FA salt). 1H NMR (400 MHz, dimethylsulfoxide-d6 + D2O-d2) δ = 7.61-7.51 (m, 1H), 7.28-7.18 (m, 1H), 7.03-6.92 (m, 2H), 6.63-6.53 (m, 1H), 5.22 (br d,J=13.8Hz,2H),5.04-4.93(m,1H),4.80-4.68(m,1H),4.65-4.15(m,4H),4.13-4.05(m,2H),3.97-3.90(m, 1H),3.87-3.77(m,2H),3.60-3.52(m,1H),3.52-3.29(m,4H),3.28-3.09(m,6H),3.08-2.98(m,1H),2.91(br s,1H),2.63(br s, 1H), 2.23-2.07 (m, 3H), 2.05-1.80 (m, 7H), 1.78-1.66 (m, 2H), 1.07-0.95 (m, 3H); 19F NMR (400 MHz, dimethyl sulfoxide-d6 + D2O-d2) δ = -120.845, -171.812; LCMS (ESI, M+1): m / z = 754.6.

[0157] Example 236 [ka] 5-Ethyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2-(methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol [ka]

[0158] Step A. 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine: 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine in DMF (0.65 mL) To a solution of -(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (130 mg, 1 equiv) and N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (60 mg, 1.93 equiv) was added N,N-diethylpropan-2-amine (48.3 mg, 2 equiv) and 4 Å molecular sieves (20 mg). The mixture was stirred at 40° C. for 24 hours. The reaction was filtered and purified by reverse-phase flash chromatography [water (FA, 0.1%) / acetonitrile=3 / 2] to give the title compound (100 mg, 76.81% yield) as a black-brown solid; LCMS (ESI, M+1): m / z=689.5.

[0159] Step B. 5-Ethyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2-(methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol: 5-(7-(8-ethyl-7-fluoro)-2-fluoro-4-(2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2-(methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol in MeOH (1 mL) To a solution of -3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (100 mg, 1 equiv) was added HCl / MeOH (4 M, 1 mL). The mixture was stirred at 0 °C for 2 h. The reaction was concentrated under reduced pressure to give a residue. The mixture was diluted with HO (10 mL) and extracted with ethyl acetate (5 mL x 4).The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by prep-HPLC [column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: water (FA)-ACN; B%: 15%-45%, 2 min] and [column: Waters Xbridge 150×25 mm×5 μm; mobile phase: water (NH4HCO3)-ACN; B%: 40%-70%, 9 min] to give the title compound (18.89 mg, 19.37% yield) as a yellow solid; 1H NMR (400 MHz, methanol-d4) δ = 7.51 (dd, J = 5.6, 9.2 Hz, 1H), 7.14 (t, J = 9.4 Hz, 1H), 6.96 (s, 2H), 5.54 (d, J = 2.8 Hz, 1H), 5.35-5.14 (m, 1H), 4.83 (s, 1H), 4.66 (br d, J = 16.4 Hz, 1H), 4.24 (br d,J=4.4Hz,2H),4.17-3.98(m,4H),3.96-3.83(m,1H),3.68(dd,J=2.0,17.6Hz,1H),3.55-3.34(m,3H),3.25-3.10(m,5H),2.98 (dt,J=5.6,9.6Hz,1H),2.74(s,3H),2.72-2.65(m,1H),2.32-1.77(m,8H),1.12(t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=645.4.

[0160] Example 237 [ka] 7-(8-Ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((methylsulfamoyl)methylamino)methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine [ka]

[0161] Step A. tert-Butyl 2-((methyl(N-methylsulfamoyl)amino)methyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a mixture of tert-butyl 2-((methylamino)methyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (200 mg, 1.0 equiv) and TEA (217 mg, 3.0 equiv) in DCM (2.0 mL) was added methylsulfamoyl chloride (92.4 mg, 1.0 equiv). The reaction was stirred at 20° C. for 2 h. The mixture was concentrated and purified by reverse-phase flash chromatography (0.1% FA condition) to give the title compound (120 mg, 45% yield) as a white oil; LCMS (ESI, M+1): m / z=374.1.

[0162] Step B. 2-[[Methyl(methylsulfamoyl)amino]methyl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine: A mixture of tert-butyl 2-((methyl(N-methylsulfamoyl)amino)methyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (90.0 mg, 1.0 equiv)in in HCl·MeOH (4 M, 1.5 mL, 25 equiv) was stirred for 1 hour at 20° C. The mixture was concentrated in vacuo to give the title compound (110 mg, crude) as a white solid, which was used in the next step without further purification.

[0163] Step C. 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((methylsulfamoyl)methylamino)methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine: 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R To a mixture of (115 mg, 1 equiv)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (1.0 equiv) and 2-[[methyl(methylsulfamoyl)amino]methyl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine (90.0 mg, 2.0 equiv) was added N,N-diethylpropan-2-amine (213 mg, 10 equiv) and 4 Å molecular sieves (10.0 mg). The reaction was stirred at 90 °C for 7 hours. The reaction was filtered and purified by reverse-phase flash chromatography (C18, 0.1% FA conditions) to give the title compound (80.0 mg, 36% yield) as a yellow solid; LCMS (ESI, M+1): m / z=796.5.

[0164] Step D. 7-(8-Ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((methylsulfamoyl)methylamino)methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine: 7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((methylsulfamoyl)methylamino)methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine in HCl·MeOH (4 M, 1.5 mL, 68 equiv) A mixture of 1,4-dimethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((methylsulfamoyl)methylamino)methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (70.0 mg, 1.0 equiv) was stirred at 20° C. for 0.5 h. The mixture was concentrated, basified with saturated NaHCO solution to pH 7, and extracted with ethyl acetate (2×3 mL). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure, and purified by prep-HPLC (column: Phenomenex luna C18 15 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; B%: 15%-45%, 10 min) to give the title compound (20.5 mg, 30% yield, FA salt) as an orange solid. 1H NMR (400MHz, methanol-d4) δ=7.51(dd,J=5.6,8.8Hz,1H),7.15(t,J=9.6Hz,1H),6.97(s,2H),6.31(s,1H),5.46-5.25(m,1H),5.05-4.94(m,2H),4.46(br s,2H),4.30-4.12(m,5H),4.06(br d,J=16.8Hz,2H),3.72-3.63(m,1H),3.57-3.50(m,1H),3.39(br d,J=8.4Hz,5H),3.29-3.09(m,3H),2.79-2.68(m,4H),2.60(s,3H),2.44-2.14(m,4H),2.13-1.92(m,4H),1.12(br t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=752.6.

[0165] Example 238 [ka] 4-(4-(1-cyclopropyl-7,8-dihydropyrazolo[4,3-c]azepin-5(1H,4H,6H)-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol [ka]

[0166] Step A. tert-Butyl 2-cyclopropyl-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(2H)-carboxylate: To a mixture of tert-butyl 4,6,7,8-tetrahydro-1H-pyrazolo[4,3-c]azepine-5-carboxylate (800 mg, 1.0 equiv), cyclopropylboronic acid (579 mg, 2.0 equiv), 4 Å molecular sieves (400 mg), NaCO (715 mg, 2 equiv), and 2-(2-pyridyl)pyridine (526 mg, 1 equiv) in DCE (8 mL) was added Cu(OAc) (612 mg, 1.0 equiv). The reaction was degassed and purged with O three times and stirred at 100 °C under an O atmosphere for 3 h. The mixture was added to ice-water (10 mL), extracted with ethyl acetate (3×30 mL), washed with brine (50 mL), dried over NaSO, concentrated, and purified by prep-HPLC (YMC Triart C18 150×25 mm×5 um; A: water [(FA)-ACN]; B: ACN, B%: 35%-65% over 10 min), followed by SFC separation (DAICEL CHIRALPAK IC (250 mm×30 mm, 5 um); A: [0.1% NH3HO MeOH]; B: ACN, B%: 25%-25%, 4.5 min) to give two regioisomers: tert-Butyl 1-cyclopropyl-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxylate (400 mg, 23% yield) as a colorless oil; 1H NMR (400 MHz, chloroform-d) δ = 7.27-7.07 (m, 1H), 4.42-4.22 (m, 2H), 3.71-3.58 (m, 2H), 3.31-3.26 (m, 1H), 3.01-2.93 (m, 2H), 1.89 (br s, 2H), 1.48-1.36 (m, 9H), 1.14-1.08 (m, 2H), 1.07-1.00 (m, 2H); LCMS (ESI, M+1): m / z = 278.2 tert-Butyl 2-cyclopropyl-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(2H)-carboxylate (420 mg, 29% yield) as a colorless oil; 1H NMR (400 MHz, chloroform-d) δ = 7.31-7.08 (m, 1H), 4.36-4.17 (m, 2H), 3.63 (br s, 2H), 3.47 (br s, 1H), 2.94-2.80 (m, 2H), 1.79 (br s, 2H), 1.42 (br s, 9H), 1.09-1.01 (m, 2H), 1.00-0.92 (m, 2H); LCMS (ESI, M+1): m / z = 278.2.

[0167] Step B. 1-Cyclopropyl-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine: To a solution of tert-butyl 1-cyclopropyl-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxylate (100 mg, 1.0 equiv) in DCM (1 mL) was added TFA (1.54 g, 37 equiv). The reaction was stirred at 0-25 °C under a N atmosphere for 10 min. The mixture was diluted with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated to give the title compound (60.0 mg, 94% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 178.1.

[0168] Step C. 1-Cyclopropyl-5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine: 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine in DMF (0.3 mL) To a mixture of S-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (150 mg, 1.0 equiv), N,N-diethylpropan-2-amine (41.8 mg, 1.5 equiv), and 4 Å molecular sieves (30 mg, 1.0 equiv) was added 1-cyclopropyl-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine (60 mg, 1.57 equiv). The reaction was degassed and purged with N three times and stirred at 40 °C under a N atmosphere for 12 h. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2 × 30 mL). The combined layers were washed with brine (40 mL), dried over sodium sulfate, concentrated, and purified by reverse-phase column (C18, A: water [(0.1% FA)-ACN]; B%: 45%-65% over 25 min) to give the title compound (140 mg, 93% yield) as a yellow oil; LCMS (ESI, M+1): m / z=700.2.

[0169] Step D. 4-(4-(1-cyclopropyl-7,8-dihydropyrazolo[4,3-c]azepin-5(1H,4H,6H)-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol: 1-Cyclopropyl-5-(7-( To a solution of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine (100 mg, 1.0 equiv) was added HCl·MeOH (4 M, 350 μL 10 equiv). The reaction was stirred at 25 °C for 0.5 h. The mixture was concentrated and purified by reverse phase column (Column: Phenomenex luna C18 150 × 25 mm × 10 um; A: water [(FA)-ACN]; B%: 18%-48% over 2 min) to give the title compound (140 mg, 93% yield, FA salt) as a pale yellow solid. 1H NMR (400MHz, methanol-d4)δ=8.49(s,1H),7.50(dd,J=6.0,8.8Hz,1H),7.35(d,J =2.8Hz,1H),7.24-7.06(m,1H),6.96(s,2H),5.57-5.27(m,1H),4.83-4.58(m, 2H),4.38-4.21(m,2H),4.20-3.96(m,3H),3.68-3.46(m,5H),3.43-3.33(m,3 H),3.24(dt,J=5.5,9.9Hz,2H),3.18-3.09(m,2H),3.08-2.97(m,1H),2.73(br d,J=14.8Hz,1H),2.55-2.34(m,2H),2.33-2.22(m,1H),2.22-2.10(m,3H),2.08-1.86(m,2H),1.16-0.96(m,7H).LCMS(ESI,M+1):m / z=656.3

[0170] Example 239 [ka] 4-(4-(2-cyclopropyl-7,8-dihydropyrazolo[4,3-c]azepin-5(2H,4H,6H)-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol [ka]

[0171] Step A. 2-Cyclopropyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine: To a solution of tert-butyl 2-cyclopropyl-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(2H)-carboxylate (100 mg, 1.0 equiv) in DCM (1 mL) was added TFA (1.54 g, 37 equiv). The reaction was stirred at 0-25 °C under a N atmosphere for 10 min. The mixture was diluted with saturated NaHCO (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated to give the title compound (60.0 mg, 94% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 178.1.

[0172] Step B. 2-Cyclopropyl-5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine: 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7 To a solution of aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (150 mg, 1.0 equiv), N,N-diethylpropan-2-amine (41.85 mg, 1.5 equiv), and 4 Å molecular sieves (30 mg, 1.0 equiv) was added 2-cyclopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[4,3-c]azepine (60 mg, 1.6 equiv). The reaction was stirred at 40 °C for 12 h under a N atmosphere. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, concentrated, and purified by reverse-phase column (C18, A: water [(0.1% FA)-ACN]; B: ACN, B%: 45%-65%, 25 min) to give the title compound (140 mg, 93% yield) as a yellow oil; LCMS (ESI, M+1): m / z=700.2.

[0173] Step C. 4-(4-(2-cyclopropyl-7,8-dihydropyrazolo[4,3-c]azepin-5(2H,4H,6H)-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol: 2-Cyclopropyl-5-(7-( To a solution of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine (100 mg, 1 equiv) was added HCl·MeOH (4 M, 350 μL 10 equiv). The reaction was stirred at 25 °C for 0.5 h. The mixture was concentrated under reduced pressure and purified by prep-HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; A: water [(FA)-ACN]; B%: 18%-48% over 2 min) to give the title compound (140 mg, 93% yield, FA salt) as a pale yellow solid. 1H NMR (400MHz, methanol-d4)δ=7.55(s,1H),7.53-7.48(m,1H),7.14(t,J=9.2Hz,1H),6.96 (s,2H),5.44-5.26(m,1H),4.65(s,2H),4.31-4.16(m,1H),4.15-3.96(m,4H),3.66(br d,J=18.0Hz,1H),3.55-3.48(m,2H),3.43-3.34(m,5H),3.20(br s,3H),2.95-2.81(m,2H),2.81-2.64(m,1H),2.43-2.22(m,2H),2.21-2.13(m,1H),2.12-2.00(m,3H),1.99-1.81(m,2H),1.10(br d,J=2.0Hz,3H),1.01(br s,4H);LCMS(ESI,M+1):m / z=656.3.

[0174] Example 240 [ka] 4-(4-(1-cyclobutyl-7,8-dihydropyrazolo[4,3-c]azepin-5(1H,4H,6H)-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol [ka]

[0175] Step A. tert-Butyl 2-cyclobutyl-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(2H)-carboxylate: To a mixture of tert-butyl 4,6,7,8-tetrahydro-1H-pyrazolo[4,3-c]azepine-5-carboxylate (850 mg, 1.0 equiv) and CsCO (2.33 g, 2.0 equiv) in DMF (10 mL) was added iodocyclobutane (1.30 g, 2.0 equiv). The reaction was stirred at 100 °C under a N atmosphere for 3 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, concentrated, and purified by prep-HPLC (column: YMC Triart C18 150 x 25 mm x 5 um; A: water [(FA)-ACN]; B: ACN, B%: 42%-72% over 10 min) and SFC separation (column: DAICEL CHIRALPAK IC (250 mm x 30 mm, 5 um); A,: [0.1% NH3HO MeOH]; B, ACN, B%: 25%-25% over 4.0 min) to give two regioisomers: tert-Butyl 1-cyclobutyl-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxylate (250 mg, 24% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ = 7.39-7.28 (m, 1H), 4.66 (quin, J = 8.4 Hz, 1H), 4.43-4.26 (m, 2H), 3.71-3.56 (m, 2H), 2.81-2.76 (m, 2H), 2.67 (br t, J = 9.2 Hz, 2H), 2.42-2.33 (m, 2H), 1.93-1.81 (m, 4H), 1.46-1.37 (m, 9H). tert-Butyl 2-cyclobutyl-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(2H)-carboxylate (250 mg, 24% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ = 7.48-7.31 (m, 1H), 4.70 (br d, J = 8.4 Hz, 1H), 4.49-4.25 (m, 2H), 3.72 (br s, 2H), 3.03-2.81 (m, 2H), 2.69-2.35 (m, 4H), 1.88 (br s, 4H), 1.59-1.40 (m, 9H).

[0176] Step B. 1-Cyclobutyl-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine: To a solution of tert-butyl 1-cyclobutyl-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxylate (100 mg, 1.0 equiv) in DCM (1 mL) was added TFA (1.54 g, 39 equiv). The reaction was stirred at 0-25 °C under a N atmosphere for 10 minutes. The mixture was diluted with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated to give the title compound (60.0 mg, 91% yield) as a yellow solid. LCMS (ESI, M+1): m / z = 192.1.

[0177] Step C. 1-Cyclobutyl-5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine: 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7 To a mixture of aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (160 mg, 1.0 equiv), N,N-diethylpropan-2-amine (44.6 mg, 1.5 equiv), and 4 Å molecular sieves (30 mg, 1.0 equiv) was added 2-cyclobutyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine (60 mg, 1.4 equiv). The reaction was stirred at 40 °C for 12 h under a N atmosphere. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, concentrated, and purified by reverse-phase column (C18, mobile phase: [water (0.1% FA)-ACN]; B%: 45%-65%, 25 min) to give the title compound (140 mg, 85.1% yield) as a yellow oil; LCMS (ESI, M+1): m / z = 714.2.

[0178] Step D. 4-(4-(1-cyclobutyl-7,8-dihydropyrazolo[4,3-c]azepin-5(1H,4H,6H)-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol: 1-Cyclobutyl-5-(7- To a solution of (8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine (100 mg, 1 equiv) was added HCl·MeOH (4 M, 350 μL 10 equiv). The reaction was stirred at 25 °C for 0.5 h under a N atmosphere. The mixture was concentrated and purified by prep-HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 μm; A: water [(FA)-ACN]; B: ACN, B%: 18%-48% over 2 min) to give the title compound (33.1 mg, 35.3% yield, FA salt) as a pale yellow solid; 1H NMR (400 MHz, methanol-d4) δ = 7.56-7.48 (m, 1H), 7.44 (d, J = 3.2 Hz, 1H), 7.20-7.07 (m, 1H), 6.96 (s, 2H), 5.55-5.26 (m, 1H), 4.84-4.58 (m, 3H), 4.36-4.17 (m, 2H), 4.13-3.94 (m, 3H), 3.62 (br d,J=17.6Hz,1H),3.59-3.44(m,4H),3.40-3.33(m,2H),3.28-3.17(m,2H),3.16-3.03(m,1H),3.02-2.90(m,1H),2.89-2.78(m,1H),2.72(br d,J=14.6Hz,1H),2.65-2.53(m,2H),2.43-2.27(m,4H),2.26-2.08(m,4H),2.07 -1.93(m,2H),1.92-1.79(m,2H),1.17-1.06(m,3H)LCMS(ESI,M+1):m / z=670.4.

[0179] Example 241 [ka] 4-(4-(2-cyclobutyl-7,8-dihydropyrazolo[4,3-c]azepin-5(2H,4H,6H)-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol [ka]

[0180] Step A. 2-Cyclobutyl-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine: To a solution of tert-butyl 2-cyclobutyl-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(2H)-carboxylate (100 mg, 1.0 equiv) in DCM (1 mL) was added TFA (1.54 g, 39 equiv). The reaction was stirred at 0-25 °C for 10 minutes under a N atmosphere. The mixture was diluted with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated to give the title compound (60.0 mg, 91% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 192.1.

[0181] Step B. 2-Cyclobutyl-5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine: 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7 To a mixture of aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (160 mg, 1.0 equiv), N,N-diethylpropan-2-amine (44.6 mg, 1.5 equiv), and 4 Å molecular sieves (30 mg, 1.0 equiv) was added 2-cyclobutyl-5,6,7,8-tetrahydro-4H-pyrazolo[4,3-c]azepine (60 mg, 1.4 equiv). The reaction was stirred at 40 °C for 12 hours under a N atmosphere. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, concentrated, and purified by reverse-phase column (C18, mobile phase: [water (0.1% FA)-ACN]; B%: 45%-65%, 25 min) to give the title compound (140 mg, 85% yield) as a yellow oil; LCMS (ESI, M+1): m / z=714.2.

[0182] Step C. 4-(4-(2-cyclobutyl-7,8-dihydropyrazolo[4,3-c]azepin-5(2H,4H,6H)-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol: 2-Cyclobutyl-5-(7- To a solution of (8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine (100 mg, 1.0 equiv) was added HCl·MeOH (4 M, 350 μL 10 equiv). The reaction was stirred at 25 °C for 0.5 h under a N atmosphere. The mixture was concentrated and purified by prep-HPLC (Phenomenex luna C18 150 x 25 mm x 10 um; A: water [(FA)-ACN]; B: ACN, B%: 18%-48% over 2 min) to give the title compound (33.1 mg, 35% yield, FA salt) as a pale yellow solid; 1H NMR (400MHz, methanol-d4)δ=7.67-7.56(m,1H),7.50(dd,J=5.6,8.8Hz,1H),7.20-7.08(m,1H),6.95(s,2H),5.42-5.19(m, 1H),4.80-4.62(m,3H),4.28-4.14(m,1H),4.00(s,4H),3.70-3.61(m,1H),3.57-3.40(m,2H),3.39-3.33(m,3H),3.26(br s,1H),3.24-3.11(m,2H),3.10-3.01(m,1H),2.99-2.84(m,2H),2.81-2.65(m,1H),2.54-2.36(m,4H),2 .35-2.17(m,2H),2.17-1.97(m,4H),1.96-1.78(m,4H),1.15-1.01(m,3H);LCMS(ESI,M+1):m / z=670.4.

[0183] Example 242 [ka] 5-Ethyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2-(oxetan-3-yl)-7,8-dihydropyrazolo[4,3-c]azepin-5(2H,4H,6H)-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol [ka]

[0184] Step A. tert-Butyl 2-(oxetan-3-yl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(2H)-carboxylate: A mixture of tert-butyl 4,6,7,8-tetrahydro-1H-pyrazolo[4,3-c]azepine-5-carboxylate (600 mg, 1.0 equiv), 3-iodooxetane (559 mg, 1.2 equiv), and CsCO (822 mg, 2.0 equiv) in DMF (6 mL) was degassed and purged with N three times. The reaction was stirred at 100 °C under a N atmosphere for 1 h. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, concentrated, and purified by prep-HPLC (column: YMC Triart C18 150*25 mm*5 um; mobile phase: [water (FA)-ACN]; B%: 28%-58%, 10 min) and SFC separation (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 5 um); mobile phase: [0.1% NH3H2OMeOH]; B%: 35%-35%, 3.5 min) to give two regioisomers: tert-Butyl 2-(oxetan-3-yl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(2H)-carboxylate (220 mg, 30% yield) as a colorless oil; 1H NMR (400 MHz, chloroform-d) δ = 7.48-7.32 (m, 1H), 5.44-5.22 (m, 1H), 5.15-4.90 (m, 4H), 4.48-4.19 (m, 2H), 3.66 (br s, 2H), 3.12-2.80 (m, 2H), 1.90-1.75 (m, 2H), 1.42 (br s, 9H). tert-Butyl 1-(oxetan-3-yl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxylate (120 mg, 16% yield) as a colorless oil; 1H NMR (400 MHz, chloroform-d) δ = 7.47-7.35 (m, 1H), 5.40-5.38 (m, 1H), 5.24-5.11 (m, 2H), 5.06-4.92 (m, 2H), 4.45-4.25 (m, 2H), 3.74-3.58 (m, 2H), 2.82-2.70 (m, 2H), 1.93-1.84 (m, 2H), 1.41 (brs, 9H).

[0185] Step B. 2-(Oxetan-3-yl)-2,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine: To a solution of tert-butyl 2-(oxetan-3-yl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(2H)-carboxylate (100 mg, 1.0 equiv) in DCM (1 mL) was added TFA (1.54 g, 39.6 equiv). The reaction was degassed and purged with N2 three times, then stirred under N2 atmosphere at 0-25 °C for 10 min. The mixture was concentrated to give the title compound (60.0 mg, 91% yield) as a yellow solid. LCMS (ESI, M+1): m / z = 194.0.

[0186] Step C. 7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate: To a solution of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (140 mg, 1.0 equiv) in DCM (2 mL) was added TFA (770 mg, 33.5 equiv). The reaction was stirred at 0-25°C for 1.5 hours. The mixture was quenched with saturated NaHCO3 (20 mL). The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, concentrated, and purified by reverse-phase column (C18, mobile phase: [water (0.1% FA)-ACN]; B%: 45%-65%, 25 min) to give the title compound (90 mg, 68% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 651.2.

[0187] Step D. 5-Ethyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2-(oxetan-3-yl)-7,8-dihydropyrazolo[4,3-c]azepin-5(2H,4H,6H)-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol: 7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)- To a solution of 2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (90 mg, 1.0 equiv), N,N-diethylpropan-2-amine (26.8 mg, 1.5 equiv), and 4 Å molecular sieves (20 mg, 1.0 equiv) was added 2-(oxetan-3-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[4,3-c]azepine (90 mg, 3.4 equiv). The reaction was degassed and purged with N three times, then stirred at 40 °C for 12 h under a N atmosphere. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, concentrated and purified by reverse phase column (Column: Waters Xbridge 150*25 mm*5 um; Mobile phase: [water (NH4HCO3)-ACN]; B%: 46%-76%, 8 min) to give the title compound (13.2 mg, 7% yield) as a pale red solid.1H NMR (400MHz, methanol-d4)δ=7.56(s,1H),7.51(dd,J=5.6,9.2Hz,1H),7.14(t,J=9.2Hz,1H),6.96(s,2H),5.68-5.55(m,1H),5.40- 5.22(m,1H),5.08-5.05(m,2H),5.01-4.96(m,4H),4.84-4.76(m,1H),4.70-4.62(m,1H),4.60(s,1H),4.21-4.06(m,3H),4.01(br d,J=17.9Hz,1H),3.70-3.56(m,1H),3.56-3.46(m,1H),3.36(br d,J=7.5Hz,3H),3.25(br s,1H),3.24-3.11(m,2H),3.10-3.00(m,1H),2.96-2.82(m,2H),2.78-2.66(m,1H),2.35-2 .10(m,4H),2.07-1.86(m,4H),1.10(dt,J=1.5,7.2Hz,3H);LCMS(ESI,M+1):m / z=:672.4.

[0188] Example 243 [ka] 5-Ethyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(1-(oxetan-3-yl)-7,8-dihydropyrazolo[4,3-c]azepin-5(1H,4H,6H)-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol [ka]

[0189] Step A. 1-(Oxetan-3-yl)decahydropyrazolo[4,3-c]azepine: To a solution of tert-butyl 1-(oxetan-3-yl)-4,6,7,8-tetrahydropyrazolo[4,3-c]azepine-5(1H)-carboxylate (100 mg, 1.0 equiv) in DCM (1 mL) was added TFA (1.54 g, 39.6 equiv). The reaction was stirred at 0-25 °C for 10 min under a N atmosphere. The mixture was concentrated to give the title compound (60.0 mg, 91% yield) as a yellow solid. LCMS (ESI, M+1): m / z = 194.2.

[0190] Step B. 5-Ethyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(1-(oxetan-3-yl)-7,8-dihydropyrazolo[4,3-c]azepin-5(1H,4H,6H)-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol: 7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluoro)naphthalen-2-ol in DMF (0.3 mL) To a mixture of 1-(oxetan-3-yl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine (30 mg, 0.56 equiv) was added 1-(oxetan-3-yl)-1,4,5,6,7,8-hexahydropyrazolo[4,3-c]azepine (30 mg, 0.56 equiv) and 40°C (1.0 equiv) diisopropyl ether. The reaction was stirred at 40°C for 12 hours under a N2 atmosphere. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, and purified by prep-HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (10 mM NH4HCO3), B: ACN, B%: 46%-76% over 8 min] to give the title compound (13.2 mg, 7% yield) as a pale red solid.1H NMR (400MHz, methanol-d4) δ=7.65(d,J=3.2Hz,1H),7.58-7.44(m,1H),7.22-7.07( m,1H),7.03-6.86(m,2H),5.42(quin,J=6.8Hz,1H),5.36-5.17(m,1H),5.00(br dd,J=4.8,7.2Hz,4H),4.97-4.93(m,2H),4.82-4.66(m,3H),4.26-4.15( m,1H),4.08-3.96(m,3H),3.73-3.64(m,1H),3.51-3.46(m,1H),3.23(br s,2H),3.20-3.09(m,3H),3.06-2.93(m,3H),2.78-2.68(m,1H),2.23-2.03 (m,4H),2.02-1.80(m,4H),1.16-1.01(m,3H);LCMS(ESI,M+1):m / z=672.4.

[0191] Example 244 [ka] 4-(4-(2-amino-3-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol [ka]

[0192] Step A. 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine: 3-Methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine in DMF (5 mL). To a solution of 4]diazepin-2-amine (105 mg, 2.0 equiv, HCl) was added N,N-diethylpropan-2-amine (167 mg, 5.0 equiv) and 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (180 mg, 1.0 equiv). The mixture was stirred at 40°C for 14 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over sodium sulfate, concentrated, and purified by reverse-phase HPLC (C18, 0.1% FA conditions) to give the title compound (150 mg, 65% yield) as a yellow solid; LCMS (ESI, M+1): m / z=689.3.

[0193] Step B. 4-(4-(2-amino-3-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol: 5-(7-(8-ethyl-7-fluoro-3-(meth)amino)-2-methyl-3-(methyl)-2-methyl ... To a solution of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (19 mg, 1.0 equiv) was added HCl / MeOH (4 M, 2 mL, 290 equiv) at 0° C. The mixture was stirred at 0° C. for 0.5 h. The mixture was concentrated and purified by prep-HPLC (Phenomenex Luna C18 150 × 25 mm × 10 μm; mobile phase: A: water (FA), B: ACN; B%: 15%-45% over 10 min) to give the title compound (5.01 mg, 26% yield, FA salt) as a yellow solid; 1H NMR (400 MHz, methanol-d4) δ = 7.52 (dd, J = 6.0, 9.2 Hz, 1H), 7.15 (t, J = 9.2 Hz, 1H), 7.02-6.93 (m, 2H), 5.53-5.30 (m, 1H), 4.69-4.56 (m, 2H), 4.32-4.13 (m, 4H), 4.12-3.98 (m, 2H), 3.95-3.83 (m, 1H), 3.71- 3.61(m,1H),3.59-3.47(m,3H),3.46-3.37(m,2H),3.25-3.11(m,3H),2.78-2.65(m,1H),2.50-2.3 1(m,2H),2.29-1.97(m,7H),1.97-1.90(m,3H),1.10(t,J=6.8Hz,3H).LCMS(ESI,M+1):m / z=645.5.

[0194] Example 245 [ka] 2-((1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)azepan-3-yl)methoxy)-N-methylacetamide [ka]

[0195] Step A: tert-Butyl 3-((2-(methylamino)-2-oxoethoxy)methyl)azepane-1-carboxylate: To a solution of tert-butyl 3-(hydroxymethyl)azepane-1-carboxylate (300 mg, 1.0 equiv) in THF (5.0 mL) was added NaH (157 mg, 60% purity, 3.0 equiv) slowly at 0° C. The mixture was stirred at 0° C. for 1 h. Then, 2-bromo-N-methyl-acetamide (238 mg, 1.2 equiv) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 5 h. The reaction was quenched with water (20 mL) at 0° C. and extracted with EtOAc (2×30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1] to give the title compound (200 mg, 51% yield) as a yellow oil.

[0196] Step B: 2-(Azepan-3-ylmethoxy)-N-methylacetamide: To a solution of tert-butyl 3-((2-(methylamino)-2-oxoethoxy)methyl)azepane-1-carboxylate (100 mg, 1 equiv) in EtOAc (1.0 mL) was added HCl / EtOAc (1.0 mL, 4.0 M, 6.0 equiv). The mixture was stirred at 25° C. for 1 h. The reaction was concentrated to give the title compound (60 mg, 90% yield).

[0197] Step C: 2-((1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)azepan-3-yl)methoxy)-N-methylacetamide: 2-(azepan-3-ylmethoxy)-N-methylacetamide (57 mg, To a solution of 4.0 equiv) was added N,N-diethylpropan-2-amine (93.0 mg, 10 equiv) and 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (50.0 mg, 1.0 equiv). The mixture was stirred at 40°C for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (40 mL). The organic phase was dried over Na2SO4, concentrated, and purified by prep-TLC [DCM / MeOH=10 / 1] to give the title compound (40 mg, 60% yield) as a yellow solid. LCMS (ESI, M+1): m / z = 723.3

[0198] Step D: 2-((1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)azepan-3-yl)methoxy)-N-methylacetamide ... in MeCN (1.0 mL) To a solution of 40.0 mg (1 equiv) of 2-((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)azepan-3-yl)methoxy)-N-methylacetamide (40.0 mg, 1 equiv) was added HCl / dioxane (1.0 mL, 4.0 M, 10 equiv). The mixture was stirred at 0° C. for 1 hour. The reaction mixture was concentrated and purified by prep-HPLC [column: Phenomenex C18 75 × 30 mm × 3 μm; mobile phase: [water (FA)-ACN]; B%: 18%-48%, 7 min] and prep-HPLC [column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 48%-78%, 9 min] to give the title compound (12.4 mg, 32% yield) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ=9.70(d,J=7.0Hz,1H),7.58(br d,J=6.2Hz,2H),7.23(t,J=9.2Hz,1H),7.02-6.97(m,2H),5.46-5.22(m,1H),4.03(br s,3H),3.84(br d,J=6.6Hz,4H),3.58(br d,J=17.6Hz,2H),3.38(br s,2H),3.21-3.06(m,5H),2.91(br s,1H),2.75-2.65(m,1H),2.60(dd,J=2.0,4.6Hz,3H),2.39-1.60(m,13H),1.54-1.20(m,3H),1.07-1.01(m,3H);LCMS(ESI,M+1):m / z=679.2.

[0199] Example 246 [ka] 5-Ethyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-(hydroxymethyl)-7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepin-5(6H)-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol [ka]

[0200] Step A. (5,6,7,8-Tetrahydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepin-3-yl)methanol: To a solution of tert-butyl 3-(hydroxymethyl)-7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (220 mg, 1.0 equiv) in MeCN (1 mL) was added HCl·dioxane (2 mL, 9.8 equiv). The reaction was stirred at 25 °C for 0.5 h. The mixture was concentrated to give the title compound (240 mg, crude, HCl) as a yellow solid, which was used in the next step without further purification.

[0201] Step B. (5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepin-3-yl)methanol: 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(( To a mixture of (2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (80.0 mg, 1.0 equiv) and (5,6,7,8-tetrahydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepin-3-yl)methanol (38.7 mg, 2.0 equiv) was added N,N-diethylpropan-2-amine (149 mg, 10 equiv) and 4 Å molecular sieves (10 mg). The reaction was stirred at 40 °C for 12 hours. The mixture was filtered and purified by reverse-phase flash chromatography [C18, water (FA, 0.1%) / acetonitrile] to give the title compound (70.0 mg, 87% yield) as a yellow solid. LCMS (ESI, M+1): m / z = 691.4.

[0202] Step C. 5-Ethyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-(hydroxymethyl)-7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepin-5(6H)-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol: (5-(7- A mixture of (8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepin-3-yl)methanol (50.0 mg, 1.0 equiv) was stirred at 25° C. for 0.5 hours. The mixture was concentrated, basified with NaHCO to pH=7, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; B%: 15%-45%, 10 min) to give the title compound (30 mg, 63% yield, 0.53 FA) as an off-white solid.1H NMR (400MHz, acetic acid-d4) δ=7.53(dd,J=6.0,9.2Hz,1H),7.17(t,J=9.2Hz,1H),7.11-7.01(m, 2H),5.69-5.45(m,1H),5.27-4.99(m,2H),4.94-4.78(m,3H),4.78-4.59(m,2H),4.51(br dd,J=12.0,14.0Hz,1H),4.33-4.14(m,3H),4.13-3.95(m,2H),3.88(br dd,J=7.6,18.4Hz,1H),3.76(br t,J=16.0Hz,1H),3.54-3.33(m,4H),3.30-3.13(m,2H),2.85-2.62(m,2H),2.57-2.41(m,2H),2.27(br s,5H),1.14(br t,J=7.2Hz,3H).LCMS(ESI,M+1):m / z=647.4.

[0203] Example 247 [ka] (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone Prepared according to Example 233, except using HCl instead of TFA in the final step. The title compound was obtained as an orange solid (FA salt). 1H NMR (400MHz, dimethyl sulfoxide-d6 + heavy water-d2) δ=7.56(dd,J=6.0,8.8Hz,1H),7.23(t,J=9.6Hz,1H),6.98(s,2H),6.59(s,1H),5.38-5.18(m,1H),5.11(br s,1H),5.00(br dd,J=10.4,15.6Hz,1H),4.82-4.67(m,1H),4.54(br d,J=6.0Hz,1H),4.47(br d,J=5.2Hz,2H),4.26-4.11(m,1H),4.05-3.88(m,2H),3.87-3.77(m,2H),3.56(br d,J=17.6Hz,1H),3.47-3.39(m,1H),3.29-3.03(m,7H),2.93-2.82(m,1H),2. 72-2.61(m,3H),2.20-2.03(m,8H),2.00-1.63(m,9H),1.08-0.98(m,3H);19F NMR (400MHz, dimethyl sulfoxide-d6 + heavy water-d2) δ=-121.048,-171.962; LCMS (ESI, M+1): m / z=768.5.

[0204] Example 248 [ka] 5-Ethyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-vinyl-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol [ka]

[0205] Step A. 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-vinyl-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine: 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R, To a mixture of (7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (44.9 mg, 1.0 equiv) and 3-vinyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (60.0 mg, 5.0 equiv, HCl) was added N,N-diethylpropan-2-amine (83.5 mg, 10 equiv) and 4 Å molecular sieves (10.0 mg). The reaction was stirred at 50 °C for 12 h. The mixture was filtered and purified by reverse-phase HPLC (0.1% FA condition) to give the title compound (27.0 mg, 62% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 672.4.

[0206] Step B. 5-Ethyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-vinyl-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol: 7-(8-ethyl-7-fluoro-3-(methoxy))-2-(2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-vinyl-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol in MeOH (0.3 mL) To a solution of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(3-vinyl-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (27.0 mg, 1.0 equiv) was added HCl·MeOH (4 M, 0.5 mL, 50 equiv). The reaction was stirred at 20 °C for 0.5 h. The reaction was concentrated under reduced pressure to remove the solvent. The residue was added saturated aqueous NaHCO3 to adjust the pH to approximately 7 and extracted with ethyl acetate (2 × 3 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC (column: Welch Ultimate C18 150*25mm*5um; mobile phase: [water (FA)-ACN]; B%: 10%-40%, 10 min) to give the title compound (7.30 mg, 26% yield) as an off-white solid.1H NMR (400MHz, methanol-d4)δ=7.57-7.46(m,1H),7.15(br t,J=9.6Hz,1H),6.99(br d,J=5.2Hz,2H),6.90(s,1H),6.71(dd,J=11.2,17.6Hz,1H),6.04(d,J=17. 6Hz,1H),5.57-5.33(m,2H),4.83-4.75(m,2H),4.43-4.19(m,5H),4.13(br d,J=17.6Hz,1H),3.89-3.78(m,1H),3.72(br d,J=17.6Hz,1H),3.58(br d,J=18.4Hz,4H),3.38(br d,J=4.8Hz,2H),3.24(br d,J=8.4Hz,3H),2.77(br d,J=12.4Hz,1H),2.55-2.34(m,2H),2.32-2.13(m,3H),2.10-1.98(m,1H),1.12(br t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=628.5.

[0207] Example 249 [ka] 5-Ethyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(1,6-dioxa-9-azaspiro[3.6]decan-9-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol The synthesis was carried out according to Example 248, except that TFA was used instead of HCl in Step C. The title compound was obtained as a yellow solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 8.54 (s, 1H), 7.50 (dd, J = 5.9, 8.8 Hz, 1H), 7.13 (t, J = 9.2 Hz, 1H), 7.01-6.93 (m, 2H), 5.37-5.19 (m, 1H), 4.59 (br s, 2H), 4.52-4.42 (m, 2H), 4.17-3.96 (m, 6H), 3.95-3.74 (m, 4H), 3.70-3.45 (m, 3H), 3.42-3.34 (m, 2H), 3.26-3.21 (m, 2H), 3.17 (br s,1H),3.05-2.96(m,1H),2.71-2.61(m,1H),2.59-2.48(m,1H),2.34-2.15(m,2H),2.14-2.05 (m,1H),2.02-1.93(m,2H),1.89-1.78(m,1H),1.12-1.03(m,3H).LCMS(ESI,M+1):m / z=622.5.

[0208] Example 250 [ka] 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-4-thioxo-1,3,7-triazaspiro[4.5]decan-2-one [ka]

[0209] Step A. Benzyl 2-oxo-4-thioxo-1,3,7-triazaspiro[4.5]decane-7-carboxylate: To a solution of benzyl 2,4-dioxo-1,3,7-triazaspiro[4.5]decane-7-carboxylate (1.00 g, 1.0 equiv) in THF (10 mL) was added Lawesson's reagent (4.00 g, 3.0 equiv). The reaction was stirred at 60° C. for 6 hours. Upon completion, the reaction was concentrated under reduced pressure to remove the solvent. MeOH (30 mL) was added to the residue and filtered to obtain a filter cake. The filter cake was washed with EtOAc (30 mL) to give the title compound (360 mg, 34% yield) as a white solid; 1H NMR (400 MHz, DMSO-d6) δ = 12.54 (br s, 1H), 10.73 (s, 1H), 9.25 (br s, 1H), 8.70-8.35 (m, 1H), 7.59-7.10 (m, 5H), 5.06 (br s, 2H), 4.17-3.63 (m, 2H), 3.27-2.71 (m, 2H), 2.15-1.88 (m, 1H), 1.83-1.50 (m, 3H).

[0210] Step B. 4-Thioxo-1,3,7-triazaspiro[4.5]decan-2-one: To a solution of benzyl 2-oxo-4-thioxo-1,3,7-triazaspiro[4.5]decane-7-carboxylate (400 mg, 1.0 equiv) in DCM (4 mL) at 0 °C was added trimethylsilyl iodide (1.47 g, 5.9 equiv). The reaction was stirred at 0-20 °C for 0.5 h. The mixture was diluted with HO (10 mL) and washed with DCM (10 × 10 mL). The aqueous phase was lyophilized to afford the title compound (400 mg, crude) as a yellow solid; LCMS (ESI, M+1): m / z = 186.0.

[0211] The last two steps were carried out according to Example 248. The title compound was obtained as a white solid (FA salt). 1H NMR (400 MHz, methanol-d4) δ = 7.52 (dd, J = 5.6, 9.2 Hz, 1H), 7.15 (t, J = 9.2 Hz, 1H), 7.03-6.92 (m, 2H), 5.52-5.32 (m, 1H), 4.45-4.22 (m, 4H), 4.18-4.05 (m, 2H), 3.71-3.58 (m, 2H), 3.56-3.38 (m ,5H),3.22-3.14(m,3H),3.07-2.93(m,1H),2.84-2.68(m,1H),2.40-2.23(m,3H),2.19-2.10 (m,2H),2.09-1.98(m,2H),1.95-1.77(m,3H),1.17-1.05(m,3H);LCMS(ESI,M+1):m / z=664.6.

[0212] Example 251 [ka] 2-((1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)azepan-3-yl)methoxy)-N,N-dimethylacetamide [ka]

[0213] Step A. Benzyl 3-(hydroxymethyl)azepane-1-carboxylate: To a mixture of azepan-3-ylmethanol (4.00 g, 1.0 equiv) and K2CO3 (12.8 g, 3.0 equiv) in THF (40 mL) and water (20 mL), CbzCl (10.5 g, 2.0 equiv) was added dropwise at 0 °C, and the reaction was stirred at 0-10 °C for 17 h. The mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by column chromatography to give the title compound (7 g, 55% yield) as a yellow solid.

[0214] Step B. Benzyl 3-[(2-ethoxy-2-oxo-ethoxy)methyl]azepane-1-carboxylate: To a solution of benzyl 3-(hydroxymethyl)azepane-1-carboxylate (1.00 g, 1.0 equiv) in THF (15 mL) was added NaH (303 mg, 60% purity, 2.0 equiv). The reaction was stirred at 0 °C for 0.5 h, and then ethyl 2-bromoacetate (761 mg, 1.2 equiv) was added. The reaction was stirred at 15 °C for 6 h. The mixture was quenched with water (50 mL) at 0 °C and extracted with ethyl acetate (20 mL × 3). The organic layer was dried over Na SO , filtered, concentrated, and purified by column chromatography (SiO , petroleum ether / ethyl acetate = 10 / 1 to 2 / 1) to give the title compound (630 mg, 17% yield) as a yellow solid.

[0215] Step C. 2-[(1-benzyloxycarbonylazepan-3-yl)methoxy]acetic acid: A mixture of benzyl 3-[(2-ethoxy-2-oxo-ethoxy)methyl]azepane-1-carboxylate (500 mg, 1.0 equiv) in a solution of LiOH (2 M, 10.00 mL, 13.9 equiv) was stirred at 15 °C for 1 hour. The mixture was acidified with HCl (1 M, 20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried, filtered, and concentrated to give the title compound (560 mg, 84% yield) as a yellow solid.

[0216] Step D Benzyl 3-[[2-(dimethylamino)-2-oxo-ethoxy]methyl]azepane-1-carboxylate: A mixture of 2-[(1-benzyloxycarbonylazepan-3-yl)methoxy]acetic acid (165 mg, 1.0 equiv), N,N-diethylpropan-2-amine (199 mg, 3.0 equiv) and HATU (292 mg, 1.5 equiv) in DCM (2 mL) was stirred at 30° C. for 2 hours, and then dimethylamine hydrochloride (50.2 mg, 1.2 equiv) was added. The reaction was stirred at 30° C. for 2 hours. The mixture was concentrated to give the title compound (560 mg, 84% yield) as a white solid.

[0217] Step E 2-(Azepan-3-ylmethoxy)-N,N-dimethyl-acetamide: A mixture of benzyl 3-[[2-(dimethylamino)-2-oxo-ethoxy]methyl]azepane-1-carboxylate (180 mg, 1.0 equiv) and Pd / C (15 mg, 60% purity, 0.1 equiv) in MeOH (5 mL) was stirred under a H atmosphere (15 Psi) at 20° C. for 2 h. The mixture was filtered and concentrated to give the title compound (200 mg, 54% yield) as a white solid.

[0218] The last two steps were carried out according to Example 248. The title compound was obtained as a brown solid. 1H NMR(400MHz,DMSO-d6)δ=9.68(br d,J=4.4Hz,1H),7.59(dd,J=6.0,8.8Hz,1H),7.23(t,J=9.6Hz,1H),6.98(d,J=4.0Hz,2H),5.33-5.14(m,1H),4.10(br d,J=4.4Hz,3H),3.98-3.74(m,4H),3.69-3.44(m,2H),3.30(s,6H),3.13-3.01(m,4H),2.97(br s,1H),2.90(d,J=7.6Hz,3H),2.78(d,J=3.6Hz,4H),2.67(br s,1H),2.33(s,1H),2.12-1.90(m,4H),1.84-1.62(m,6H),1.35-1.23(m,2H),1.03(q,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=693.3.

[0219] Example 252 [ka] 2-((1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)azepan-3-yl)methoxy)-N,N-dimethylpropanamide [ka]

[0220] Synthesized according to Example 251. The title compound was obtained as a white solid. NMR (400MHz, methanol-d4) δ=7.50(dd,J=6.0,8.8Hz,1H),7.13(t,J=9.2Hz,1H),7.0 2-6.89(m,2H),5.43-5.10(m,1H),4.49-3.95(m,6H),3.75-3.57(m,1H),3.56-3. 32(m,5H),3.30-3.13(m,7H),3.10(dd,J=1.2,6.0Hz,3H),3.03-2.96(m,1H),2.9 4-2.88(m,3H),2.85-2.66(m,1H),2.39-2.25(m,1H),2.23-1.63(m,10H),1.42(br dd,J=5.6,8.8Hz,2H),1.34-1.26(m,3H),1.17-1.03(m,3H);LCMS(ESI,M+1):m / z=707.5.

[0221] Example 253 [ka] N-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-P,P-dimethylphosphinic acid amide [ka]

[0222] Step A. 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine: 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(( To a mixture of (2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (7.50 g, 1.0 equiv) and 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (2.46 g, 1.5 equiv) was added N,N-diethylpropan-2-amine (8.37 g, 6.0 equiv) and 4 Å molecular sieves (2.00 g). The reaction was stirred at 40° C. for 6 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated to give the title compound (7.20 g, 98% yield) as a yellow solid; LCMS (ESI, M+1): m / z=675.6.

[0223] Step B. 4-(4-(2-amino-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol: 5-(7-(8-ethyl-7-fluoro-3-( To a mixture of (2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (100 mg, 1.0 equiv) was added HCl·MeOH (1.0 mL, 27 equiv). The reaction was stirred at 20° C. for 0.5 h. The mixture was concentrated and purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (78 mg, 83% yield) as an orange solid; LCMS (ESI, M+1): m / z = 631.4.

[0224] Step CN-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-P,P-dimethylphosphinic acid amide: 4-(4-(2-a)-2-hydroxybenzoyl)-4-methyl ... To a mixture of 1,4-amino-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol (78.0 mg, 1.0 equiv.) was added dimethylphosphinic chloride (34.8 mg, 2.5 equiv.) and THF (0.8 mL). The reaction was stirred at 20° C. for 2 hours. The mixture was concentrated, purified by prep-HPLC [Phenomenex C18 150 × 25 mm × 10 μm; A: water (NH4HCO3), B: ACN; B%: 28%-58% over 8 min], and lyophilized to give the title compound (5.59 mg, 7.3% yield) as an off-white solid.1H NMR (400MHz, dimethyl sulfoxide-d6) δ=9.73(br s,1H),7.66-7.54(m,1H),7.39(d,J=7.2Hz,1H),7.24(t,J=9.6Hz,1H),7.06-6.91(m,2H),5.68(s,1H),5.35-5.16(m,1H),4.87(br d,J=16.4Hz,1H),4.61(br d,J=16.0Hz,1H),4.26(br d,J=4.8Hz,2H),4.05(br dd,J=2.8,13.2Hz,1H),3.96-3.72(m,4H),3.62(br d, J = 17.6 Hz, 1H), 3.14-2.95 (m, 6H), 2.84-2.76 (m, 1H), 2.70-2.57 (m, 2H), 2.20-2.06 (m, 2H), 2.05-1.88 (m, 4H), 1.87-1.79 (m, 1H), 1.78-1.69 (m, 2H), 1.48 (d, J = 14.4 Hz, 6H), 1.08 (t, J = 7.2 Hz, 3H); F NMR (400 MHz, dimethyl sulfoxide-d) δ = -121.333, -171.984; LCMS (ESI, M+1): m / z = 707.5.

[0225] Example 254 [ka] 1-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-1,3-dimethylurea [ka]

[0226] Step A-N-(5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)formamide: 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)formamide To a flask containing ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (1.00 g, 1.0 equiv) was added ethyl formate (2.76 g, 25.2 equiv) and formamide (3.39 g, 50.8 equiv). The reaction was stirred at 90° C. for 5 hours. The mixture was concentrated and triturated with HO (50 mL) to give the title compound (0.80 g, 77% yield) as a yellow solid; LCMS (ESI, M+1): m / z=703.4.

[0227] Step B. 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine: N-(5-(7-(8-ethyl-7-fluoro-3- To a mixture of (methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)formamide (0.30 g, 1.0 equiv) was added DIBAL-H (1 M, 1.28 mL, 3.0 equiv) at 0 °C under nitrogen. The reaction was stirred at -78 °C for 3 h. The mixture was diluted with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase chromatography [C18, 0.1% formic acid] to give the title compound (0.10 g, 34% yield) as a yellow solid. LCMS (ESI, M+1): m / z = 689.2.

[0228] Step C. 1-(5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-1,3-dimethylurea: 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-1,3-dimethylurea in THF (0.5 mL) To a mixture of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (100 mg, 1.0 equiv.) was added pyridine (490 mg, 42.7 equiv.) and methylcarbamic acid chloride (33.9 mg, 2.5 equiv.). The reaction was stirred at 20° C. for 2 hours. The mixture was concentrated and purified by reverse phase chromatography [C18, 0.1% formic acid conditions] to give the title compound (100 mg, 89% yield) as a yellow oil; LCMS (ESI, M+1): m / z=746.7.

[0229] Step D. 1-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-1,3-dimethylurea: 1-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-1,3-dimethylurea in ACN (220 μL) To a mixture of 1,3-dimethylurea (90.0 mg, 1 equiv.) and 3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-1,3-dimethylurea (90.0 mg, 1 equiv.) was added HCl·MeOH (4 M, 452 μL, 15 equiv.). The reaction was stirred at 20 °C for 1 h. The mixture was concentrated, dissolved in methanol (1 mL), neutralized with solid NaHCO, filtered, and purified by prep-HPLC [Phenomenex luna 150 × 25 mm × 10 μm; A: water (FA), B: ACN; B%: 19%-49% over 10 min] and lyophilized to give a residue. The residue was triturated with acetonitrile (2 mL) for 15 min at 20 °C and purified by prep-HPLC [Welch Ultimate C18 150 × 25 mm × 5 μm; A: water (FA), B: ACN; B%: 18%-48% over 10 min] and lyophilized to give the title compound (11.8 mg, 14% yield, 0.24 equiv FA) as an off-white solid.1H NMR (400MHz, dimethyl sulfoxide-d6) δ = 9.79-9.62 (m, 1H), 7.87-7.77 (m, 1H), 7.61-7.55 (m, 1H), 7.28-7.18 (m, 1H), 7.02-6.95 (m, 2H), 6.07-6.00 (m, 1H), 5.34-5.11 (m, 1H), 4.96-4.83 (m, 1H), 4.77-4.65 (m, 1H), 4.41-4.29 (m, 2H), 4.12-4.00 (m, 1H), 3.94 -3.76(m,4H),3.65-3.57(m,1H),3.18-3.08(m,6H),3.07-2.90(m,4H),2.84-2.76(m,1H),2.74-2.64(m,4H),2.45-2.35(m ,1H),2.24-2.11(m,1H),2.09-2.01(m,1H),2.00-1.88(m,3H),1.86-1.77(m,1H),1.77-1.62(m,2H),1.10-1.00(m,3H);19F NMR (400 MHz, dimethyl sulfoxide-d6) δ = -121.341, -172.090; LCMS (ESI, M+1): m / z = 702.5.

[0230] Example 255 [ka] 3-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)propanamide [ka]

[0231] Step A. tert-Butyl 2-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of 5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (8.5 g, 1.0 equiv) in THF (150 mL) was added BH THF (1.0 M, 121 mL, 4.0 equiv) at 0 °C under N. The reaction was stirred at 60 °C under a N atmosphere for 12 h. The reaction was quenched with MeOH (200 mL) at 0 °C. The mixture was concentrated and purified by prep-HPLC (column: 120 g flash column Welch Ultimate XB_C18 20-40 μm; 120 A; mobile phase: MeCN / HO; flow rate: 85 mL / min; gradient: B 5-40% in 20 min; 40% in 5 min) to give the title compound (5.7 g, 70.6% yield, N / A purity) as a colorless oil. H NMR (400 MHz, DMSO-d) δ = 8.13 (s, 1H), 6.06 (s, 1H), 4.92 (br s, 1H), 4.50-4.23 (m, 6H), 3.62 (br s, 2H), 1.71 (br s, 2H), 1.34 (br s, 9H). LCMS (ESI, M+1): m / z = 268.2.

[0232] Step B. tert-Butyl 2-formyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of tert-butyl 2-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (1.0 g, 1.0 equiv) in DCM (10 mL) was added Dess-Martin reagent (2.38 g, 1.5 equiv). The reaction was stirred at 25 °C for 2 h. The mixture was filtered and purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give the title compound (800 mg, 80.6% yield) as a white solid. LCMS (ESI, M+1): m / z = 266.2.

[0233] Step C. (E)-tert-butyl 2-(3-methoxy-3-oxoprop-1-en-1-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of ethyl 2-(diethoxyphosphoryl)acetate (659 mg, 1.2 equiv) in THF (10.0 mL) was added NaH (181 mg, 60% purity, 1.5 equiv) and the mixture was stirred at 0° C. for 0.5 h. Tert-butyl 2-formyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (800 mg, 3.02 mmol, 1.0 equiv) was added at 0° C. The reaction was stirred at 25° C. for 2.5 h. The mixture was quenched with NH4Cl.aq (50 mL) at 0°C and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give the title compound (700 mg, 72.2% yield) as a white solid. LCMS (ESI, M+1): m / z = 322.1

[0234] Step D. tert-Butyl 2-(3-methoxy-3-oxopropyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of (E)-tert-butyl 2-(3-methoxy-3-oxoprop-1-en-1-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (700 mg, 1.0 equiv) in EtOH (10.0 mL) was added Pd / C (100 mg, 10% purity) under a N atmosphere. The suspension was degassed and purged with H three times. The reaction was stirred under H (15 Psi) at 20 °C for 1 h. The mixture was filtered and concentrated to give the title compound (600 mg, crude) as a yellow oil. LCMS (ESI, M+1): m / z = 324.3

[0235] Step E. 3-(5-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)propanoic acid: To a solution of tert-butyl 2-(3-methoxy-3-oxopropyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (600 mg, 1.0 equiv) in MeOH (10.0 mL) and water (2.0 mL) was added NaOH (223 mg, 3.0 equiv). The reaction was stirred at 60° C. for 2 hours. The mixture was quenched with citric acid (2 M, 10 mL) at 20° C. and then extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the title compound (700 mg, crude) as a yellow oil. LCMS (ESI, M+1): m / z = 310.3

[0236] Step F. tert-Butyl 2-(3-amino-3-oxopropyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of 3-(5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)propanoic acid (300 mg, 1.0 equiv) in THF (6.0 mL) was added HATU (553 mg, 1.5 equiv), N,N-diethylpropan-2-amine (376 mg, 3.0 equiv), and NH4Cl (77.8 mg, 1.5 equiv). The mixture was stirred at 20°C for 2 h. The reaction was diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (20 mL × 3), dried over NaSO, concentrated, and purified by prep-HPLC [column: Phenomenex luna C18 150 × 40 mm × 15 μm; mobile phase: [water (FA)-ACN]; B%: 15%-45%, 10 min] to give the title compound (100 mg, 33% yield) as a white solid. LCMS (ESI, M+1): m / z = 309.1

[0237] Step G. 3-(5,6,7,8-Tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)propanamide: To a solution of tert-butyl 2-(3-amino-3-oxopropyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (500 mg, 1 equiv) in DCM (2.0 mL) was added TFA (2.00 mL). The mixture was stirred at 20° C. for 1 hour. The reaction was concentrated to give the title compound (300 mg, crude) as a yellow oil. LCMS (ESI, M+1): m / z=209.1

[0238] The last two steps were carried out according to Example 248. The title compound was obtained as a yellow solid (FA salt). 1H NMR (400MHz, methanol-d4) δ=8.53(s,1H),7.51(dd,J=6.0,8.8Hz,1H),7.15(t,J=9.2Hz ,1H),7.03-6.92(m,2H),6.07(s,1H),5.41-5.21(m,1H),4.78-4.74(m,1H),4.41(br s,2H),4.21-4.16(m,1H),4.13-4.09(m,2H),4.08-3.95(m,2H),3.70(br d,J=18.0Hz,1H),3.50(br s,1H),3.44-3.34(m,3H),3.28(br s,1H),3.17(br d,J=8.4Hz,2H),3.07(br d,J=5.6Hz,1H),2.87-2.81(m,2H),2.70(br d,J=12.8Hz,1H),2.51(t,J=7.6Hz,2H),1.99(br d,J=6.4Hz,8H),1.96-1.85(m,1H),1.12(br t,J=6.8Hz,3H);LCMS(ESI,M+1):m / z=687.5.

[0239] Example 256 [ka] 5-Ethyl-6-fluoro-4-(2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol [ka]

[0240] Synthesized according to Example 248, except that TFA was used instead of HCl in the final step. The title compound was obtained as a yellow solid. LCMS (ESI, M+1): m / z=606.5

[0241] Example 257 [ka] (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methanone [ka] Prepared according to Example 233, except using HCl instead of TFA in the final step, to obtain the title compound as a yellow solid. 1H NMR (400MHz, methanol-d4) δ=7.51(dd,J=8.8,5.6Hz,1H)7.14(t,J=9.2Hz,1H)6.96(s,2H)6.58-6.60(m,1H)5.17-5.35(m,1H)5.00(br d,J=16.8Hz,1H)4.77-4.84(m,1H)4.71(br s,1H)4.59(br s,1H)4.53(br d,J=5.2Hz,2H)4.34(br s,1H)3.99-4.14(m,4H)3.62-3.71(m,1H)3.50(br d,J=17.6Hz,1H)3.35-3.45(m,3H)3.13-3.26(m,5H)3.08(br s,1H)2.94-3.03(m,3H)2.72(br d,J=13.2Hz,H)2.23-2.41(m,4H)2.12-2.22(m,3H)2.07(br d,J=9.2Hz,3H)1.82-2.01(m,4H)1.10(br t,J=6.8Hz,3H);LCMS(ESI,M+1):m / z=784.4.

[0242] Example 258 [ka] 3,8-Diazabicyclo[3.2.1]octan-8-yl(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone [ka] This was synthesized according to Example 233, except that HCl was used instead of TFA in the final step. The title compound was obtained as a yellow solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 7.55-7.48 (m, 1H), 7.19-7.10 (m, 1H), 7.00-6.93 (m, 2H), 6.77-6.69 (m, 1H), 5.53-5.28 (m, 2H), 5.04-4.90 (m, 2H), 4.64-4.47 (m, 3H), 4.36-4.16 (m, 3H), 4.13-4.00 (m, 2H). ),3.72-3.63(m,1H),3.62-3.46(m,4H),3.45-3.35(m,2H),3.22-3.03(m,4H),3.01-2.92(m,2H), 2.80-2.70(m,1H),2.56-2.33(m,2H),2.33-2.09(m,5H),2.09-1.86(m,6H),1.16-1.05(m,3H);19F NMR (400MHz, methanol-d4) δ=-122.917,-173.733; LCMS (ESI, M+1): m / z=754.3.

[0243] Example 259 [ka] (1,4-Diazabicyclo[3.2.1]octan-4-yl)(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone [ka] This was synthesized according to Example 233, except that HCl was used instead of TFA in the final step. The title compound was obtained as a brown solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 7.55-7.48 (m, 1H), 7.18-7.11 (m, 1H), 7.00-6.93 (m, 2H), 6.69-6.61 (m, 1H), 5.69-5.24 (m, 2H), 5.04-4.95 (m, 1H), 4.73-4.63 (m, 1H), 4.63-4.45 (m, 3H), 4.34-4.18 (m, 3H), 4.12-4.00 (m, 2H), 3.76-3. .62(m,2H),3.61-3.47(m,4H),3.43-3.35(m,2H),3.24-3.12(m,5H),3.11-3.01(m,1H),3.00-2.82(m,2H),2.79 19F NMR (400MHz, methanol-d4) δ=-122.932,-173.906; LCMS (ESI, M+1): m / z=754.5.

[0244] Example 260 [ka] (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(5-methyl-2,5-diazabicyclo[2.2.2]octan-2-yl)methanone [ka] The synthesis was carried out according to Example 233, except that HCl was used instead of TFA in the final step. The title compound was obtained as a yellow solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 7.55-7.48 (m, 1H), 7.15 (t, J = 9.2 Hz, 1H), 6.97 (s, 2H), 6.75-6.66 (m, 1H), 5.52-5.32 (m, 1H), 5.23-4.92 (m, 2H), 4.60-4.49 (m, 2H), 4.43-4.14 (m, 4H), 4.11 (br s, 2H), 4.02-3.91 (m, 1H), 3.73-3.64 (m, 1H), 3.63-3.47 (m, 5H), 3.37 (br dd,J=5.4,8.3Hz,2H),3.25-3.08(m,6H),2.79-2.70(m,1H),2.63(s,3H),2.54-2.34(m,2H),2. 34-2.20(m,3H),2.19-2.13(m,2H),2.10-1.98(m,3H),1.92-1.75(m,2H),1.16-1.06(m,3H);19F NMR (400MHz, methanol-d4) δ=-122.947,-173.906; LCMS (ESI, M+1): m / z=768.5.

[0245] Example 261 [ka] (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)methanone [ka] This was synthesized according to Example 233, except that HCl was used instead of TFA in the final step. The title compound was obtained as a yellow solid (FA salt). 1H NMR (400 MHz, dimethylsulfoxide-d6 + deuterium oxide-d2) δ = 7.57 (dd, J = 6.0, 8.8 Hz, 1H), 7.23 (t, J = 9.2 Hz, 1H), 6.98 (s, 2H), 6.69-6.54 (m, 1H), 5.49-5.38 (m, 0.5H), 5.37-5.16 (m, 1H), 5.08-4.93 (m, 1H), 4.74 (br s,1.5H),4.56-4.41(m,2H),4.26-4.10(m,1H),4.06-3.96(m,1H),3.96-3. 78(m,5H),3.61-3.37(m,3H),3.30-3.11(m,5H),3.10-2.93(m,4H),2.84(br d,J=5.6Hz,1H),2.69-2.59(m,1H),2.54(br d,J=3.6Hz,3H),2.24-2.08(m,2H),2.06-1.90(m,4H),1.89-1.67(m,4H),1.10-0.98(m,3H);19F NMR (400 MHz, dimethyl sulfoxide-d₆ + deuterium oxide-d₂) δ = −121.070, −171.887; LCMS (ESI, M+1): m / z = 754.6.

[0246] Example 262 [ka] (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)methanone [ka] The synthesis was carried out according to Example 233, except that HCl was used instead of TFA in the final step. The title compound was obtained as a brown solid (FA salt). 1H NMR (400MHz, dimethylsulfoxide-d6 + deuterium oxide-d2) δ = 7.57 (dd, J = 6.0, 8.8 Hz, 1H), 7.23 (t, J = 9.2 Hz, 1H), 6.98 (s, 2H), 6.64 (d, J = 2.0 Hz, 1H), 5.35-5.14 (m, 1H), 5.08-4.95 (m, 1H), 4.74 (br d, J = 16.8 Hz, 1H), 4.57-4.42 (m, 2H), 4.26-4.03 (m, 3H), 3.83 (br d, J = 16.4 Hz, 5H), 3.59 (br s, 1H), 3.55 (br s,1H),3.47-3.38(m,1H),3.30-3.17(m,3H),3.13-2.98(m,4H),2.86-2.76(m,1H),2.69-2.61(m,2H),2.33(br s,1H),2.28-2.10(m,3.5H),2.06(br d,J=0.8Hz,1H),2.01-1.88(m,3.5H),1.85-1.63(m,4H),1.57-1.45(m,1H),1.10-0.99(m,3H);19F NMR (400 MHz, dimethyl sulfoxide-d₆ + deuterium oxide-d₂) δ = −121.130, −171.827; LCMS (ESI, M+1): m / z = 754.3.

[0247] Example 263 [ka] 4-(4-(2-(1-(dimethylamino)-2,2-difluoroethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol [ka]

[0248] Step A: tert-Butyl 2-[1-(tert-butylsulfinylamino)-2,2-difluoro-ethyl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate: A solution of tert-butyl 2-[(E)-tert-butylsulfinyliminomethyl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (350 mg, 1.0 equiv) in THF (6.00 mL) was cooled to −78° C. Next, t-BuOK (1 M, 2.85 mL, 3.0 equiv) and difluoromethyl(trimethyl)silane (354 mg, 3.0 equiv) were added sequentially to the reaction, which was then allowed to warm slowly to 0° C. over 2 hours. The reaction was diluted with water (40.0 mL) and extracted with ethyl acetate (40.0 mL). The combined organic layers were washed, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-TLC [SiO, petroleum ether / ethyl acetate=1 / 1] to give the title compound (280 mg, 47% yield, 67% purity) as a yellow oil; LCMS (ESI, M+1): m / z=421.2.

[0249] Step B: tert-Butyl 2-(1-amino-2,2-difluoro-ethyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate: To a solution of tert-butyl 2-[1-(tert-butylsulfinylamino)-2,2-difluoro-ethyl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (280 mg, 1.0 equiv) in HO (0.20 mL) in THF (1.0 mL) was added I (50.7 mg, 0.3 equiv). The mixture was stirred at 50 °C for 2 hours. The reaction was cooled to 15 °C and then quenched with 15% aqueous sodium bicarbonate (0.3 mL). The reaction mixture was extracted with an aqueous solution of sodium thiosulfate (40.0 mL) and ethyl acetate (45.0 mL). The combined organic layers were filtered and concentrated to give the title compound (130 mg, crude). LCMS (ESI, M+1): m / z=317.1

[0250] Step C: tert-Butyl 2-[1-(dimethylamino)-2,2-difluoro-ethyl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate: To a solution of tert-butyl 2-(1-amino-2,2-difluoro-ethyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (130 mg, 1.0 equiv) in dichloromethane (2.0 mL) was first added ethanoic acid (12.3 mg, 0.5 equiv), followed by the addition of HCHO (1.67 g, 1.53 mL, 37% purity, 50.0 equiv) and NaBHCN (129 mg, 5.0 equiv). The mixture was stirred at 40° C. for 4 hours. The reaction was quenched at 25° C. by the addition of saturated aqueous ammonium chloride (0.50 mL), then diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by prep-TLC [SiO, ethyl acetate / methanol=20 / 1] to give the title compound (100 mg, 50% yield, 70% purity) as a yellow oil; LCMS (ESI, M+1): m / z=345.1.

[0251] Step D: 2,2-Difluoro-N,N-dimethyl-1-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)ethanamine: To a solution of tert-butyl 2-[1-(dimethylamino)-2,2-difluoro-ethyl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (100 mg, 1 equiv) in HCl / dioxane (0.50 mL) and MeCN (0.50 mL). The mixture was stirred at 25° C. for 1 hour. The reaction was filtered and concentrated under reduced pressure to give the title compound (70 mg, crude); LCMS (ESI, M+1): m / z=245.1.

[0252] The last two steps were carried out according to Example 248. The title compound was obtained as a white solid (FA salt). 1H NMR (400 MHz, DMSO-d6) δ = 9.86-9.59 (m, 1H), 8.24 (s, 1H), 7.59 (dd, J = 6.0, 8.8 Hz, 1H), 7.24 (t, J = 9.6 Hz, 1H), 7.00-6.97 (m, 2H), 6.47-6.18 (m, 1H), 6.15 (d, J = 2.8 Hz, 1H), 5.31-5.15 (m, 1H), 4.95 (br dd, J = 6.8, 16.0 Hz, 1H), 4.73 (br dd, J = 4.0, 16.2 Hz, 1H), 4.44 (br d,J=4.0Hz,2H),4.11-4.01(m,1H),3.93-3.76(m,6H),3.60(br dd,J=2.4,17.4Hz,1H),3.40(br d,J=4.4Hz,2H),3.12-3.04(m,4H),2.98(br s,1H),2.83-2.77(m,1H),2.64(br d,J=13.6Hz,1H),2.14(s,6H),2.04-1.70(m,8H),1.06(t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=723.5

[0253] Example 264 [ka] 2,5-Diazabicyclo[2.2.2]octan-2-yl(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone [ka] This was synthesized according to Example 233, except that HCl was used instead of TFA in the final step. The title compound was obtained as an off-white solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 7.55-7.49 (m, 1H), 7.14 (t, J = 9.6Hz, 1H), 6.97 (s, 2H), 6.76-6.69 (m, 1H), 5.41-5.26 (m, 1H), 5.07-4.95 (m, 1H), 4.76 (br d, J = 4.4Hz, 1H), 4.55 (br s,2H),4.28-3.96(m,6H),3.90-3.81(m,1H),3.75-3.68(m,2H),3.66-3.5 9(m,1H),3.57-3.52(m,1H),3.49-3.34(m,6H),3.23-3.05(m,3H),2.74(br d,J=14.4Hz,1H),2.43-2.23(m,3H),2.19-1.91(m,10H),1.15-1.07(m,3H);19F NMR (400MHz, methanol-d4) δ=-122.962,-173.613; LCMS (ESI, M+1): m / z=754.4.

[0254] Example 265 [ka] 3,8-Diazabicyclo[3.2.1]octan-3-yl(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone [ka] Synthesized according to Example 233, except using HCl instead of TFA in the final step. The title compound was obtained as an off-white solid (FA salt). 1H NMR (400MHz, methanol-d4)δ=7.57-7.47(m,1H),7.14(t,J=9.6Hz,1H),6.97(s,2H),6.68(s, 1H),5.50-5.27(m,1H),5.10-4.96(m,2H),4.66-4.42(m,4H),4.33-4.14(m,3H),4.05(br d,J=17.6Hz,2H),3.97-3.80(m,2H),3.67(br d,J=17.6Hz,1H),3.57-3.37(m,7H),3.22-3.10(m,3H),2.75(br d,J=14.0Hz,1H),2.48-2.25(m,3H),2.23-2.17(m,1H),2.14-1.80(m,9H),1.18-1.03(m,3H);19F NMR(400MHz, methanol-d4)δ=-123.000,-173.698;LCMS(ESI,M+1):m / z=754.2

[0255] Example 266 [ka] N-Decyl-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [ka]

[0256] Step A. tert-Butyl 2-(decylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of 5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (1.00 g, 1.0 equiv) and decan-1-amine (839 mg, 1.5 equiv) in DMF (6 mL) was added HATU (2.70 g, 2.0 equiv) and N,N-diethylpropan-2-amine (1.38 g, 3.0 equiv). The mixture was stirred at 20 °C for 18 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The organic layer was washed with brine (10 mL) and dried over Na SO . The solvent was concentrated and the residue was purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (1.40 g, 94% yield) as a yellow solid; LCMS (ESI, M+1): m / z=421.3.

[0257] Step B. tert-Butyl 2-(decyl(methyl)carbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of tert-butyl 2-(decyl(methyl)carbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (643 mg, 1.0 equiv) in THF (6 mL) was added NaH (122 mg, 60% purity, 2.0 equiv) slowly at 0 °C. The mixture was stirred at 25 °C for 20 min. To the mixture was added CHI (2.39 g, 11 equiv) slowly at 0 °C. The mixture was stirred at 25 °C for 12 h. The mixture was quenched with saturated aqueous NH Cl (10 mL) at 0 °C and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine (20 mL) and dried over NaSO. The solvent was concentrated and purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (500 mg, 74% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 435.4.

[0258] Step CN-Decyl-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of tert-butyl 2-(decyl(methyl)carbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (500 mg, 1.0 equiv) in MeOH (2.5 mL) was added HCl·MeOH (4 M, 5 mL, 17 equiv) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. The mixture was concentrated, and the residue was dissolved in MeOH (5 mL). NaHCO (200 mg) was added, and the mixture was stirred at 25 °C for 0.5 h. The mixture was filtered and concentrated to give the title compound (300 mg, crude) as a yellow solid.

[0259] The last two steps were done according to Example 248 (Steps B and C). The title compound was obtained as a pale red solid (FA salt). 1H NMR (400MHz, methanol-d4)δ=7.50(dd,J=6.0,8.8Hz,1H),7.13(t,J=9.2Hz,1H),6 .96(s,2H),6.61-6.56(m,1H),5.40-5.20(m,1H),5.07-4.92(m,1H),4.85-4.76 (m,1H),4.60-4.45(m,2H),4.27-3.95(m,5H),3.75-3.60(m,2H),3.58-3.44(m, 2H),3.37(dt,J=2.4,6.8Hz,3H),3.30-3.12(m,5H),3.11-2.98(m,3H),2.72(br d,J=13.6Hz,1H),2.39-2.17(m,3H),2.17-1.95(m,4H),1.90(br dd,J=6.0,13.6Hz,1H),1.63(br s,2H),1.40-1.17(m,14H),1.15-1.05(m,3H),0.91-0.83(m,3H);LCMS(ESI,M+1):m / z=813.5.

[0260] Example 267 [ka] N-Decyl-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [ka]

[0261] Step A-N - Decyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of tert-butyl 2-(decylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (321 mg, 1.0 equiv) in MeOH (2 mL) at 0 °C was added HCl·MeOH (4 M, 4 mL, 21 equiv). The mixture was stirred at 0 °C for 0.5 h. The mixture was concentrated to give the title compound (200 mg, crude) as a yellow oil; LCMS (ESI, M+1): m / z = 321.4.

[0262] The last two steps were carried out according to Example 248 (Steps A and B). The title compound was obtained as a pale red solid. 1H NMR (400MHz, methanol-d4) δ=7.51(dd,J=5.6,9.2Hz,1H),7.14(t,J=9.2Hz,1H),7.02-6.95(m,2H),6.69(s,1 H),5.44-5.22(m,1H),5.05-4.92(m,3H),4.63-4.45(m,2H),4.27-4.10(m,3H),4.09-3.96(m,2H),3.65(br d,J=17.6Hz,1H),3.54(br d,J=9.4Hz,1H),3.42-3.32(m,6H),3.28-3.21(m,1H),3.18(br dd,J=2.3,10.8Hz,1H),3.15-3.06(m,1H),2.73(br d,J=14.8Hz,1H),2.45-2.21(m,3H),2.16(br d,J=9.2Hz,1H),2.12-1.99(m,3H),1.98-1.85(m,1H),1.58(br t,J=7.2Hz,2H),1.43-1.22(m,14H),1.15-1.06(m,3H),0.92-0.89(m,1H),0.94-0.82(m,2H);LCMS(ESI,M+1):m / z=799.5.

[0263] Example 268 [ka] (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)methanone [ka]

[0264] Step A. tert-Butyl 2-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octane-3-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: 5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate in DMF (100 mL) To a mixture of 2-azolo[1,5-a][1,4]diazepine-2-carboxylic acid (5.00 g, 1.0 equiv.), N,N-diethylpropan-2-amine (6.89 g, 3.0 equiv.), HATU (13.5 g, 2.0 equiv.), and (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (4.52 g, 2.0 equiv.) was added. The mixture was stirred at 20 °C for 12 h. The residue was filtered, washed with DMF (1 mL), and purified by reverse-phase flash chromatography (C18, 0.1% formic acid) to give the title compound (5.00 g, 71% yield) as a white solid; LCMS (ESI, M+1): m / z = 391.2.

[0265] Step B. ((1R,5R,6R)-6-Hydroxy-3-azabicyclo[3.2.1]octan-3-yl)(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone: To a solution of tert-butyl 2-((1R,5R,6R)-6-hydroxy-3-azabicyclo[3.2.1]octane-3-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (5.00 g, 1.0 equiv) in MeCN (10 mL) at 0 °C was added HCl·dioxane (4 M, 20 mL, 6.2 equiv). The mixture was stirred at 0 °C for 0.5 h. The reaction was concentrated. The residue was adjusted to pH 8 with 20% aqueous NaOH (5 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (3.50 g, 94% yield) as a white solid.

[0266] The last two steps were carried out according to Example 248. The title compound was obtained as a pale red solid. 1H NMR (400MHz, methanol-d4) δ = 7.51 (dd, J = 6.0, 9.2 Hz, 1H), 7.14 (t, J = 9.2 Hz, 1H), 6.97 (s, 2H), 6.69-6.47 (m, 1H), 5.51-5.26 (m, 1H), 5.00-4.91 (m, 1H), 4.79-4.63 (m, 1H), 4.60-4.33 (m, 4H), 4.30-4.19 (m, 3H), 4.18-4.03 (m, 3H), 3.68 (br d,J=17.6Hz,1H),3.60-3.44(m,4H),3.41-3.34(m,2H),3.29-3.11(m,4H),3.02-2.85(m,1H),2.73(br d,J=13.2Hz,1H),2.50-2.15(m,7H),2.15-1.88(m,5H),1.78-1.65(m,2H),1.17-1.01(m,3H);LCMS(ESI,M+1):m / z=769.5.

[0267] Example 269 [ka] 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-(methoxymethyl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [ka]

[0268] Step A: 5-tert-butyl 2-methyl-3-vinyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate: A mixture of 5-tert-butyl 2-methyl-3-iodo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate (2.80 g, 1.0 equiv), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.05 g, 2.0 equiv), CataCXium A Pd G3 (968 mg, 0.2 equiv), and NaHCO3 (1.68 g, 3.0 equiv) in dioxane (30 mL) and HO (6 mL) was degassed and purged with N2 three times. The mixture was then stirred at 80° C. under a N atmosphere for 3 hours. The mixture was diluted with HO (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous NaSO, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (2.1 g, 92% yield) as a yellow solid; LCMS (ESI, M+1): m / z=322.1.

[0269] Step B: 5-tert-butyl 2-methyl 3-formyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate: To a solution of 5-tert-butyl 2-methyl 3-vinyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate (2.1 g, 1.0 equiv) in THF (25 mL) and HO (25 mL) was slowly added KOsO·2HO (120 mg, 0.05 equiv) and NaIO (2.80 g, 2.0 equiv) at 0–5 °C. The mixture was stirred at 20 °C for 3 h. The mixture was diluted with HO (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (1.8 g, 72% yield) as a yellow solid. LCMS (ESI, M+1): m / z = 324.2.

[0270] Step C: 5-tert-butyl 2-methyl 3-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate: To a solution of 5-tert-butyl 2-methyl 3-formyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate (1.5 g, 1.0 equiv) in EtOH (20 mL) was added NaBH (180 mg, 1.0 equiv) slowly under a N atmosphere. The reaction was stirred at 0 °C for 2 h. The solution was diluted with HO (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (1.5 g, 99% yield) as a yellow oil.

[0271] Step D: tert-Butyl 3-oxo-6,7,8,10-tetrahydro-1H-furo[3',4':3,4]pyrazolo[1,5-a][1,4]diazepine-9(3H)-carboxylate: To a solution of 5-tert-butyl 2-methyl 3-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate (1.5 g, 1 equiv) in THF (90 mL) was added t-BuONa (691 mg, 2 equiv) at 0 °C. The mixture was stirred at 20 °C for 2 h. The mixture was diluted with HO (100 mL) and extracted with ethyl acetate (4 × 50 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (0.8 g, 75% yield) as a yellow oil. LCMS (ESI, M+1): m / z = 294.1.

[0272] Step E: tert-Butyl 2-(dimethylcarbamoyl)-3-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of tert-butyl 3-oxo-6,7,8,10-tetrahydro-1H-furo[3',4':3,4]pyrazolo[1,5-a][1,4]diazepine-9(3H)-carboxylate (0.45 g, 1.0 equiv) and N-methylmethanamine (2 M, 1.53 mL, 2.0 equiv) in DMF (4.5 mL) was added HATU (1.17 g, 2.0 equiv) and N,N-diethylpropan-2-amine (595 mg, 3.0 equiv). The mixture was stirred at 20 °C for 12 hours. The mixture was purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (0.23 g, 42% yield) as a yellow oil.

[0273] Step F: tert-Butyl 2-(dimethylcarbamoyl)-3-(methoxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of tert-butyl 2-(dimethylcarbamoyl)-3-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (180 mg, 1.0 equiv) in THF (2 mL) was added NaH (31.9 mg, 60% purity, 1.5 equiv) under N at 0-5 °C. The mixture was stirred at 0 °C for 0.5 h, and then MeI (151 mg, 2.0 equiv) was added. The mixture was stirred at 20 °C for 1 h. The mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% NH3·H2O] to give the title compound (165 mg, 88% yield) as a white solid.

[0274] Step G: 3-(Methoxymethyl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of tert-butyl 2-(dimethylcarbamoyl)-3-(methoxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (100 mg, 1.0 equiv) in DCM (0.5 mL) was added HCl dioxane (4 M, 2.0 mL, 17.1 equiv) in ACN (2 mL) at 0 °C. The mixture was stirred at 20 °C for 1 h. The solution was concentrated to give the title compound (120 mg, HCl salt, crude) as a yellow solid.

[0275] The last two steps were carried out according to Example 248. The title compound was obtained as a yellow solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 7.51 (dd, J = 6.0, 8.8Hz, 1H), 7.14 (t, J = 9.2Hz, 1H), 7.00-6.92 (m, 2H), 5.47-5.24 (m, 1H), 5.03-4.95 (m, 2H), 4.86-4.79 (m, 1H), 4.57-4.38 (m, 4H), 4.21-3.98 (m, 5H), 3.74-3.65 (m, 1H), 3.52-3.45 (m, 1H), 3.45- 3.36(m,4H),3.35-3.32(m,1H),3.26-3.22(m,3H),3.21-3.13(m,3H),3.13-3.06(m,6H),2.74-2.60(m,1H),2.43-2.2 2(m,3H),2.21-2.11(m,2H),2.10-2.00(m,2H),1.99-1.86(m,1H),1.11(t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=731.4.

[0276] Example 270 [ka] (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methanone [ka] Synthesized according to Example 233, except using HCl instead of TFA in the final step. The title compound was obtained as a yellow solid (FA salt). 1H NMR (400MHz, dimethyl sulfoxide-d6 + heavy water-d2) δ=7.55(dd,J=6.0,9.2Hz,1H),7.21(t,J=9.2Hz,1H),6.97(br d,J=2.4Hz,2H),6.56(s,1H),5.46-5.22(m,1H),4.98(br t,J=18.8Hz,1H),4.81-4.67(m,1H),4.55-4.39(m,3H),4.28-4.12(m,2H),4.11-3.97(m,2H),3.81(br d,J=16.8Hz,2H),3.60-3.49(m,2H),3.44(br s,3H),3.36-3.12(m,6H),3.09-2.91(m,3H),2.65(br d,J=14.8Hz,1H),2.40(s,3H),2.26-2.10(m,3H),2.00(br s,3H),1.96-1.72(m,4H),1.67-1.49(m,2H),1.01(br d,J=3.6Hz,3H);19F NMR (400MHz, dimethyl sulfoxide-d6 + heavy water-d2) δ=-123.905,-171.962; LCMS (ESI, M+1): m / z=768.5.

[0277] Example 271 [ka] (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)methanone [ka] This was synthesized according to Example 233, except that HCl was used instead of TFA in the final step. The title compound was obtained as a yellow solid (FA salt). 1H NMR (400MHz, dimethylsulfoxide-d6 + deuterium oxide-d2) δ = 7.55 (dd, J = 6.0, 9.2 Hz, 1H), 7.21 (t, J = 9.2 Hz, 1H), 7.02-6.91 (m, 2H), 6.63 (dd, J = 3.6, 6.4 Hz, 1H), 5.51-5.30 (m, 1H), 5.05-4.82 (m, 2H), 4.81-4.65 (m, 1H), 4.49-4.30 (m, 3H), 4.26-4.12 (m, 3H), 3.80 (br d,J=16.8Hz,2H),3.62-3.35(m,5H),3.26-2.98(m,7H),2.93-2.72(m,2H),2.70-2.62(m,1H),2.47-2.41(m,1H),2 .37-2.31(m,1H),2.26(s,4H),2.18-2.08(m,2H),2.07-1.95(m,2H),1.93-1.81(m,3H),1.00(q,J=6.8Hz,3H);19F NMR (400MHz, dimethyl sulfoxide-d6 + heavy water-d2) δ=-120.659,-172.172; LCMS (ESI, M+1): m / z=754.4.

[0278] Example 272 [ka] 1-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-1,3,3-trimethylurea [ka]

[0279] Step A. 1-(5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-1,3,3-trimethylurea: 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-1,3,3-trimethylurea in THF (1 mL) To a mixture of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (100 mg, 1.0 equiv) and dimethylcarbamic chloride (39.0 mg, 2.5 equiv) was added pyridine (4.90 g, 427 equiv). The reaction was stirred at 20° C. for 2 hours. The mixture was concentrated and purified by reverse phase chromatography [C18, 0.1% formic acid conditions] to give the title compound (97.0 mg, 87% yield) as a purple solid; LCMS (ESI, M+1): m / z=760.2.

[0280] Step B. 1-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-1,3,3-trimethylurea: 1-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-1,3,3-trimethylurea in ACN (215 μL) To a mixture of 1,3,3-trimethyl-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-1,3,3-trimethylurea (87.0 mg, 1.0 equiv.) was added HCl·MeOH (4 M, 429 μL, 15 equiv.). The reaction was stirred at 20 °C for 1 h. The mixture was concentrated, dissolved in methanol (1 mL), neutralized with solid NaHCO, filtered, purified by prep-HPLC [Phenomenex luna C18 150 × 25 mm × 10 μm; A: water (FA), B: ACN; B%: 20%-50% over 10 min], and lyophilized to give the title compound (20.8 mg, 23% yield, 0.48 equiv FA) as a yellow solid.1H NMR (400MHz, methanol-d4) δ=7.55-7.48(m,1H),7.19-7.11(m,1H),7.00-6.95(m,2H),5.99-5.95(m,1H),5.46-5.27(m,1H),4.97(br d,J=16.8Hz,1H),4.80-4.73(m,1H),4.43-4.37(m,2H),4.29-4.14(m,3H),4.09-4.02( m,1H),3.99-3.90(m,1H),3.73-3.65(m,1H),3.56-3.51(m,1H),3.51-3.43(m,2H),3.43 -3.39(m,2H),3.24-3.17(m,2H),3.14(s,4H),2.77-2.73(m,6H),2.73-2.68(m,1H),2.34(br s,1H),2.32-2.23(m,2H),2.16(br d,J=10.8Hz,5H),1.99-1.90(m,1H),1.10(dt,J=1.6,7.2Hz,3H);19F NMR(400MHz,methanol-d4)δ=-122.925,-173.818;LCMS(ESI,M+1):m / z=716.5.

[0281] Example 273 [ka] (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone [ka] Synthesized according to Example 233, except using HCl instead of TFA in the final step. The title compound was obtained as an off-white solid (FA salt). 1H NMR (400MHz, methanol-d4) δ=7.56-7.48(m,1H),7.15(t,J=9.6Hz,1H),6.97(s,2H),6.73(s,1H),5.46-5.40(m,0.5H),5.29(br s,0.5H),5.05-4.94(m,1H),4.77(br s,1H),4.59-4.52(m,2H),4.30-4.08(m,6H),4.08-4.00(m,2H),3.92-3.8 2(m,1H),3.74-3.63(m,2H),3.60-3.47(m,4H),3.43-3.35(m,4H),3.21(br s,2H),3.16(br s,2H),2.80-2.70(m,1H),2.30(br dd,J=9.2,12.6Hz,2H),2.22-2.16(m,1H),2.13-2.00(m,4H),1.97-1.90(m,1H),1.33(br s,1H),1.30(br s,1H),1.12(br t,J=7.2Hz,3H);19F NMR(400MHz,methanol-d4)δ=-122.969,-173.801;LCMS(ESI,M+1):m / z=754.4.

[0282] Example 274 [ka] 1-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-1-methylurea [ka]

[0283] Step A. 1-(5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-1-methylurea: 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-1-methylurea in methanol (2 mL) To a mixture of (2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (100 mg, 1.0 equiv) was added sodium cyanate (28.3 mg, 3.0 equiv) in AcOH (2.10 g, 241 equiv). The reaction was stirred at 50° C. for 2 hours. The mixture was concentrated, dissolved in methanol (2 mL), neutralized with solid NaHCO, and concentrated.The residue was diluted with water (5 mL), extracted with EtOAc (3 x 5 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound as a yellow oil (100 mg, 92% yield); 1H NMR (400 MHz, chloroform-d) δ = 7.61-7.52 (m, 1H), 7.24-7.16 (m, 2H), 7.05-7.00 (m, 1H), 5.95-5.89 (m, 1H), 5.44-5.20 (m, 3H), 4.95-4.77 (m, 2H), 4.68-4.52 (m, 1H), 4.46-4.30 (m, 2H), 4.27-4.16 (m, 2H), 4.10-3.99 (m, 1H), 3.92-3.73 (m, 2H), 3.72-3.66. (m,3H),3.63-3.56(m,1H),3.55-3.51(m,3H),3.51-3.47(m,1H),3.45-3.31(m,2H),3.28-3.23(m,3H),3.23-3.10(m,2H),3 .08-2.97(m,1H),2.69-2.32(m,2H),2.32-2.22(m,2H),2.06-1.98(m,4H),1.18-1.03(m,3H);LCMS(ESI,M+1):m / z=732.6.

[0284] Step B. 1-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-1-methylurea: 1-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-1-methylurea in ACN (230 μL) To a mixture of 1-(3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-1-methylurea (90.0 mg, 1.0 equiv.) was added HCl·MeOH (4 M, 461 μL, 15 equiv.). The reaction was stirred at 20 °C for 1 h. The mixture was concentrated, dissolved in methanol (1 mL), neutralized with solid NaHCO, filtered, purified by prep-HPLC [Phenomenex luna 150 × 25 mm × 10 μm; A: water (FA), B: ACN; B%: 18%-48% over 10 min], and lyophilized to give the title compound (30.5 mg, 34% yield, 0.34 equiv FA) as an orange solid. 1H NMR (400MHz, methanol-d4)δ=7.55-7.47(m,1H),7.19-7.10(m,1H),7.01-6.92(m,2H),6.16-6.08(m,1H),5.44-5.26(m ,1H),4.98-4.93(m,1H),4.83-4.77(m,1H),4.47-4.33(m,2H),4.26-4.20(m,1H),4.19-4.12(m,2H),4.11-4.04(m,1 H),4.03-3.94(m,1H),3.73-3.64(m,1H),3.57-3.50(m,1H),3.49-3.36(m,5H),3.25-3.22(m,3H),3.21-3.07(m,3H) ),2.80-2.71(m,1H),2.44-2.25(m,3H),2.20-2.13(m,1H),2.12-2.01(m,3H),2.00-1.86(m,1H),1.15-1.06(m,3H); 19 F NMR (400 MHz, methanol-d₄) δ = −122.955, −173.765; LCMS (ESI, M+1): m / z = 688.0.

[0285] Example 275 [ka] (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(2,6-diazaspiro[4.5]decan-2-yl)methanone [ka] This was synthesized according to Example 233, except that HCl was used instead of TFA in the final step. The title compound was obtained as an off-white solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 7.56-7.48 (m, 1H), 7.18-7.11 (m, 1H), 7.00-6.91 (m, 2H), 6.77-6.70 (m, 1H), 5.45-5.26 (m, 1H), 5.06-4.96 (m, 2H), 4.61-4.53 (m, 2H), 4.47-4.29 (m, 1H), 4.28-4.12 (m, 4H), 4.11-3.97 (m, 3H), 3.93-3. .81(m,1H),3.76-3.61(m,2H),3.60-3.51(m,1H),3.46-3.37(m,4H),3.24-3.01(m,5H),2.79-2.68(m,1H),2.44 19F NMR (400MHz, methanol-d4) δ=-122.940,-173.652; LCMS (ESI, M+1): m / z=782.5.

[0286] Example 276 [ka] (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(1,7-diazaspiro[4.4]nonan-7-yl)methanone [ka] This was synthesized according to Example 233, except that HCl was used instead of TFA in the final step. The title compound was obtained as a yellow solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 7.56-7.48 (m, 1H), 7.19-7.11 (m, 1H), 7.00-6.93 (m, 2H), 6.78-6.71 (m, 1H), 5.46-5.26 (m, 1H), 5.09-4.98 (m, 2H), 4.62-4.51 (m, 2H), 4.45-4.30 (m, 1H), 4.29-4.11 (m, 4H), 4.09-4.00 (m, 2H). ,3.99-3.74(m,2H),3.74-3.60(m,2H),3.59-3.46(m,2H),3.45-3.35(m,4H),3.26-3.17(m,2H),3.16-3.09 (m,1H),2.79-2.69(m,1H),2.45-2.26(m,4H),2.24-2.01(m,10H),2.00-1.87(m,1H),1.18-1.07(m,3H);19F NMR (400MHz, methanol-d4) δ=-122.940,-173.532; LCMS (ESI, M+1): m / z=768.9.

[0287] Example 277 [ka] (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(2,5-diazaspiro[3.4]octan-2-yl)methanone [ka] Synthesized according to Example 233, except using HCl instead of TFA in the final step. The title compound was obtained as a yellow solid (FA salt). 1H NMR (400MHz, methanol-d4) δ=7.52(dd,J=6.0,9.2Hz,1H),7.15(t,J=9.2Hz,1H),6.98(s,2H),6.74(s,1H),5.53-5.32(m,1H),4.97(br d,J=9.6Hz,2H),4.70-4.59(m,2H),4.58-4.47(m,2H),4.37-4.15(m,5H),4.05(br d,J=17.6Hz,2H),3.67(br d,J=17.2Hz,1H),3.63-3.47(m,4H),3.37(br dd,J=5.6,7.2Hz,2H),3.29-3.17(m,3H),3.14(dt,J=2.8,7.2Hz,2H),2.75(br 19F NMR (400MHz, methanol-d4) δ=-122.910,-173.743, LCMS (ESI, M+1): m / z=754.1.

[0288] Example 278 [ka] (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(1,6-diazaspiro[3.4]octan-6-yl)methanone [ka] The synthesis was carried out according to Example 233, except that HCl was used instead of TFA in the final step. The title compound was obtained as a yellow solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 7.52 (dd, J = 5.6, 8.8 Hz, 1H), 7.14 (t, J = 9.2 Hz, 1H), 6.97 (s, 2H), 6.80-6.70 (m, 1H), 5.48-5.25 (m, 1H), 5.06-4.97 (m, 1H), 4.83-4.75 (m, 1H), 4.66- 4.49(m,2H),4.35-4.11(m,4H),4.10-3.72(m,6H),3.70-3.50(m,3H),3.48-3.34(m,5H ),3.26-3.08(m,3H),2.80-2.50(m,4H),2.46-2.16(m,5H),2.14-1.90(m,4H),1.12(br t,J=7.2Hz,3H),19F NMR(400MHz,methanol-d4)δ=-122.947,-173.375,LCMS(ESI,M+1):m / z=754.1.

[0289] Example 279 [ka] 4-(4-(5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol [ka] Synthesized according to Example 248. The title compound was obtained as a brown solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 7.78-7.68 (m, 1H), 7.58-7.47 (m, 1H), 7.22-7.12 (m, 1H), 7.03-6.96 (m, 2H), 6.89 (br s,1H),5.60-5.38(m,1H),4.67-4.55(m,1H),4.52-4.33(m,3H),4.32- 4.20(m,2H),4.18-4.07(m,1H),3.90-3.67(m,5H),3.60-3.47(m,1H),3 .45-3.35(m,2H),3.28-3.17(m,3H),2.83-2.73(m,1H),2.64-2.40(m, 2H),2.37-2.00(m,5H),1.17-1.06(m,3H);LCMS(ESI,M+1):m / z=602.4.

[0290] Example 280 [ka] 4-(4-(2-(1-(dimethylamino)-2,2,2-trifluoroethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol [ka]

[0291] Step A: tert-Butyl (E)-2-(((tert-butylsulfinyl)imino)methyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of tert-butyl 2-formyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (200 mg, 1.0 equiv) in THF (8.0 mL) was added 2-methylpropane-2-sulfinamide (184 mg, 2.0 equiv). The mixture was stirred at 0° C. for 6 hours. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography [SiO, petroleum ether / ethyl acetate = 5 / 1 to 3 / 1] to give the title compound (200 mg, 68% yield, 95% purity). LCMS (ESI, M+1): m / z = 369.1

[0292] Step B: tert-Butyl 2-(1-((tert-butylsulfinyl)amino)-2,2,2-trifluoroethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: A solution of tert-butyl (E)-2-(((tert-butylsulfinyl)imino)methyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (300 mg, 1.0 equiv) in THF (6.0 mL) was cooled to −78° C. t-BuOK (1.00 M, 2.44 mL, 3.0 equiv) and TMSCF (347 mg, 3.0 equiv) were then added sequentially to the reaction, which was allowed to warm slowly to 0° C. over 2 h. The reaction mixture was partitioned between ethyl acetate (20.0 mL) and water (10.0 mL). The residue was purified by prep-TLC [ethyl acetate / petroleum = 1 / 1] to give the title compound (160 mg, 40% yield, 90% purity). LCMS (ESI, M+1): m / z = 439.3

[0293] Step C: tert-Butyl 2-(1-amino-2,2,2-trifluoroethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of tert-butyl 2-(1-((tert-butylsulfinyl)amino)-2,2,2-trifluoroethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (450 mg, 1.00 equiv) in THF (1.00 mL) and water (0.20 mL) was added (1-(pyrrolidin-1-ylmethyl)cyclopropyl)methanol (43.4 mg, 0.50 equiv). The mixture was stirred at 50° C. for 2 hours. The reaction was partitioned between ethyl acetate (20.0 mL) and a saturated solution of sodium thiosulfate (10.0 mL). The organic phase was separated and concentrated to give a residue to give the title compound (100 mg, 70% yield, 92% purity). LCMS (ESI, M+1): m / z=335.1

[0294] Step D: tert-Butyl 2-(1-(dimethylamino)-2,2,2-trifluoroethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of tert-butyl 2-(1-amino-2,2,2-trifluoroethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (100 mg, 1 equiv), paraformaldehyde (1.21 g), and acetic acid (8.98 mg) in DCE (1.00 mL) was added NaBHCN (94.0 mg). The mixture was stirred at 40° C. for 4 hours. The reaction was partitioned between ethyl acetate (20.0 mL) and water (10.0 mL). The residue was purified by prep-TLC [SiO2, petroleum ether / ethyl acetate = 0 / 1] to give the title compound (60.0 mg, 55% yield, 70% purity). LCMS (ESI, M+1): m / z = 363.2

[0295] Step E: 2,2,2-Trifluoro-N,N-dimethyl-1-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)ethan-1-amine: To a solution of tert-butyl 2-(1-(dimethylamino)-2,2,2-trifluoroethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (50.0 mg, 1.0 equiv) in MeCN (0.50 mL) was added HCl / dioxane (0.50 mL). The mixture was stirred at 20° C. for 1 hour. The reaction was concentrated to give the title compound (30.0 mg, 83% yield, 90% purity). LCMS (ESI, M+1): m / z=263.1

[0296] The last two steps were carried out according to Example 248. The title compound was obtained as a yellow solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 8.54-8.51 (m, 1H), 7.51 (dd, J = 5.8, 8.8Hz, 1H), 7.15 (t, J = 9.6Hz, 1H), 7.01-6.95 (m, 2H), 6.35-6.28 (m, 1H), 5.43-5.23 (m, 1H), 5.16-4.99 (m, 1H), 4.99-4.89 (m, 1H), 4.85-4.73 (m, 1H), 4.60-4.45 (m, 2H), 4.32-4.18 (m, 3H), 4.17-4.10 (m, 1H), 4.05 (br dd,J=8.7,18.4Hz,1H),3.98-3.87(m,1H),3.65(br dd,J=10.1,17.6Hz,1H),3.57-3.48(m,1H),3.46-3.34(m,4H),3.29-3.23(m,1H),3.21-3.15(m,1H),3.13-3.05(m,1H),2.74(br d,J=16.0Hz,1H),2.43-2.33(m,1H),2.30(d,J=7.2Hz,7H),2.26-2.20(m,1H),2.13(br d,J=10.8Hz,1H),2.10-1.99(m,3H),1.98-1.87(m,1H),1.16-1.06(m,3H);LCMS(ESI,M+1):m / z=741.4

[0297] Example 281 [ka] (4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,4-oxazepan-6-yl)dimethylphosphine oxide [ka]

[0298] Step A. tert-Butyl 6-(dimethylphosphoryl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate: A mixture of tert-butyl 6-(((trifluoromethyl)sulfonyl)oxy)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate (350 mg, 1 equiv), methylphosphonoylmethane (86.5 mg, 1.1 equiv), Pd(PPh3)4 (58.2 mg, 0.05 equiv) and Et3N (204 mg, 2.0 equiv) in MeCN (10 mL) was stirred at 90 °C under a N2 atmosphere for 10 h. The reaction mixture was concentrated and purified by prep-HPLC (Waters Xbridge 150 x 25 mm x 5 μm column; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 12%-42%, 9 min) to give the title compound. 1H NMR (400 MHz, chloroform-d) δ = 7.51 (d, J = 15.6 Hz, 1H), 4.35 (br d, J = 7.6 Hz, 2H), 3.99-3.84 (m, 4H), 1.59 (s, 3H), 1.55 (s, 3H), 1.52 (s, 9H).

[0299] Step B. tert-Butyl 6-(dimethylphosphoryl)-1,4-oxazepane-4-carboxylate: A mixture of tert-butyl 6-(dimethylphosphoryl)-2,3-dihydro-1,4-oxazepine-4(7H)-carboxylate (100 mg, 1.0 equiv) and Pd / C (50 mg, 60% purity, 1.0 equiv) in MeOH (1.0 mL) was degassed and purged with H three times, then the mixture was stirred under an atmosphere of H for 2 h at 25° C. The reaction was filtered with MeOH (20 mL) and concentrated under reduced pressure to give the title compound (100 mg) as a white solid.

[0300] Step C. Dimethyl(1,4-oxazepan-6-yl)phosphine oxide: To a solution of tert-butyl 6-(dimethylphosphoryl)-1,4-oxazepan-4-carboxylate (100 mg, 1.0 equiv) in DCM (2.0 mL) was added TFA (411 mg, 10.0 equiv). The mixture was stirred at 25° C. for 1 hour. The reaction was concentrated under reduced pressure to give the title compound (50 mg) as a yellow oil.

[0301] The last two steps were carried out according to Example 248. The title compound was obtained as a pale red solid. 1H NMR(400MHz,DMSO-d6)δ=9.70-9.65(m,1H),7.59(dd,J=6.2,8.5Hz,1H),7.24(t ,J=9.2Hz,1H),7.03-6.93(m,2H),5.34-5.15(m,1H),4.53-4.22(m,1H),4.06(br d,J=16Hz,1H),3.95-3.82(m,6H),3.75-3.57(m,3H),3.50-3.39(m,2H),3.15-3.01(m,4H),2.98(s,1H),2.80(br d,J=7.6Hz,1H),2.67(br dd,J=2,3.7Hz,2H),2.16-1.88(m,4H),1.87-1.66(m,4H),1.49-1.42(m,6H),1.08-1.01(m,3H),LCMS(ESI,M+1):m / z=656.1.

[0302] Example 282 [ka] ((3S,5S)-3,5-Dimethylpiperazin-1-yl)(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone [ka] This was synthesized according to Example 233, except that HCl was used instead of TFA in the final step. The title compound was obtained as a white solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 7.52 (dd, J = 5.6, 8.8 Hz, 1H), 7.14 (t, J = 9.2 Hz, 1H), 6.97 (s, 2H), 6.70 (s, 1H), 5.50-5.31 (m, 1H), 5.06-4.87 (m, 2H), 4.54 (br d, J = 7.2 Hz, 2H), 4.39-4.18 (m, 4H), 4.17-3.97 (m, 4H), 3.92 (br dd, J = 3.2, 10.4 Hz, 1H), 3.68 (br d,J=17.6Hz,1H),3.60-3.47(m,6H),3.43-3.34(m,2H),3.24-3.13(m,3H),2.75(br d,J=14.0Hz,1H),2.52-2.20(m,4H),2.17-1.97(m,4H),1.29(brs,6H),1.11(t,J=7.2Hz,3H);19F NMR (400MHz, methanol-d4) δ=-122.947,-173.718; LCMS (ESI, M+1): m / z=756.6.

[0303] Example 283 [ka] 3,6-Diazabicyclo[3.1.1]heptan-3-yl(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone [ka] Prepared according to Example 233, except using HCl instead of TFA in the final step. The title compound was obtained as a white solid (FA salt). 1H NMR (400MHz, methanol-d4) δ=7.51(dd,J=5.2,8.4Hz,1H),7.14(t,J=9.2Hz,1H),6.97 (d,J=2.4Hz,2H),6.81-6.73(m,1H),5.49-5.26(m,1H),5.07-4.95(m,1H),4.90(br dd,J=3.6,6.4Hz,1H),4.68-4.62(m,1H),4.57(br d,J=2.8Hz,2H),4.44-4.33(m,1H),4.28-4.13(m,6H),4.11-4.01(m,2H),3.98-3.87(m,1H),3.68(br dd,J=2.4,17.2Hz,1H),3.55(br d,J=9.2Hz,1H),3.50-3.36(m,5H),3.23-3.07(m,3H),2.97-2.87(m,1H),2.74(br d,J=14.4Hz,1H),2.48-2.15(m,4H),2.12-1.90(m,4H),1.86-1.77(m,1H),1.16-1.05(m,3H),19F NMR (400MHz, methanol-d4) δ=-122.939,-173.651, LCMS (ESI, M+1): m / z=740.6.

[0304] Example 284 [ka] 4-(4-(3-bromo-7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepin-5(6H)-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol [ka]

[0305] Step A. tert-Butyl 7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a mixture of 5,6,7,8-tetrahydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepine (1.00 g, 1 equiv) and BocO (3.16 g, 2 equiv) in DCM (8.0 mL) was added DMAP (88.4 mg, 0.10 equiv) and TEA (2.20 g, 3 equiv). The reaction was stirred at 20 °C for 12 h. The mixture was filtered and purified by reverse-phase HPLC (0.1% FA condition) to give the title compound (1.09 g, 63% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 239.0.

[0306] Step B. tert-Butyl 3-bromo-7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a mixture of tert-butyl 7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (650 mg, 1.0 equiv) in MeCN (6.0 mL) was added NBS (1.46 g, 3.0 equiv). The reaction was stirred at 90° C. for 4 hours. The reaction 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 column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) and reverse-phase HPLC [water (FA, 0.1%) / acetonitrile] to give the title compound (640 mg, 72% yield) as a yellow oil. LCMS (ESI, M+1, M+3): m / z = 316.9, 318.9.

[0307] Step C. 3-Bromo-5,6,7,8-tetrahydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepine: To a solution of tert-butyl 3-bromo-7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (100 mg, 1.0 equiv) in MeCN (1.0 mL) was added HCl / dioxane (4 M, 1.0 mL, 13 equiv). The reaction was stirred at 20° C. for 0.5 h. The mixture was concentrated in vacuo to give the title compound (110 mg, crude) as a white solid, which was used in the next step without further purification.

[0308] The last two steps were carried out according to Example 248. The title compound was obtained as an off-white solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 7.51 (dd, J = 5.6, 8.8 Hz, 1H), 7.15 (t, J = 9.2 Hz, 1H), 7.03-6.92 (m, 2H), 5.49-5.27 (m, 1H), 4.92 (br s, 1H), 4.83-4.72 (m, 2H), 4.66-4.58 (m, 1H), 4.24-4.02 (m, 5H), 3.69 (br d, J = 18.0 Hz, 1H), 3.55-3.46 (m, 2H), 3.46-3.37 (m, 4H), 3.28-3.12 (m, 3H), 2.71 (br d,J=14.4Hz,1H),2.46-2.24(m,3H),2.23-2.14(m,2H),2.13-2.03(m,2H),2 .01-1.89(m,1H),1.11(t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=695.0,697.0.

[0309] Example 285 [ka] N-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N-isopropylmethanesulfonamide [ka]

[0310] Step A-N-(5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanesulfonamide: 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanesulfonamide in pyridine (4 mL) To a mixture of 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (300 mg, 1.0 equiv) and 7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (300 mg, 1.0 equiv) was added MsO (116 mg, 1.5 equiv) in an ice bath. The reaction was warmed to 20 °C and stirred for 4 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (300 mg, 86% yield) as a yellow solid; 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ = 9.74 (br s, 1H), 7.76-7.69 (m, 1H), 7.36-7.28 (m, 2H), 7.17-7.11 (m, 1H), 5.96 (s, 1H), 5.35-5.16 (m, 3H), 4.98-4.64 (m, 2H), 4.35 (br d, J = 5.6 Hz, 2H), 3.94-3.75 (m, 4H), 3.64 (br d,J=17.6Hz,1H),3.42(s,3H),3.29-3.26(m,3H),3.19-3.12(m,2H),3.10-3.03(m,2H),3.01-2.94(m,4H),2.83-2.76(m,1H),2.15(br s,2H),2.01(br s,2H),1.93(br d,J=1.2Hz,2H),1.86-1.66(m,4H),1.07(t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=753.2.

[0311] Step B N-(5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N-isopropylmethanesulfonamide: N-(5-(7-( To a mixture of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanesulfonamide (80 mg, 1.0 equiv) was added methylsulfonyl methanesulfonate (68 mg, 3.5 equiv). The reaction was stirred at 20° C. for 4 hours.The mixture was filtered and purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (50 mg, 54% yield) as an orange solid; 1H NMR (400 MHz, chloroform-d) δ = 7.60-7.51 (m, 1H), 7.24-7.16 (m, 2H), 7.05-6.98 (m, 1H), 6.18-5.97 (m, 1H), 5.36-5.15 (m, 3H), 4.93-4.53 (m, 2H), 4.52-4.35 (m, 3H), 4.26-4.15 (m, 1H), 4.15-4.04 (m, 1H), 4.03-3.80 (m, 3H), 3.79-3.69 (m, 1H), 3.59-3.70 (m, 3H). .51(m,3H),3.50-3.45(m,1H),3.43-3.31(m,2H),3.30-3.20(m,2H),3.18-3.11(m,2H),3.11-3.04(m,3H),3.03-2.89(m, 1H),2.69-2.56(m,1H),2.35-2.04(m,5H),2.00-1.79(m,3H),1.73-1.64(m,1H),1.29-1.16(m,6H),1.16-1.08(m,3H);19F NMR (400 MHz, chloroform-d) δ = -119.247, -173.073; LCMS (ESI, M+1): m / z = 795.1.

[0312] Step CN-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N-isopropylmethanesulfonamide: N-(5-(7-( To a mixture of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N-isopropylmethanesulfonamide (45 mg, 1.0 equiv.) was added HCl·MeOH (4 M, 15 equiv.). The mixture was stirred at 20°C for 1 hour. The reaction was filtered and purified by prep-HPLC [Phenomenex luna C18 150 x 25 mm x 10 μm; A: water (FA), B: ACN; B%: 27%-57% over 10 min] to give the title compound (7.96 mg, 18% yield, 0.22 equiv FA) as an orange solid.1H NMR(400MHz,ジメチルスルホキシド-d6)δ=9.80-9.55(m,1H),7.64-7.54( m,1H),7.28-7.19(m,1H),7.04-6.93(m,2H),6.15-6.08(m,1H), 5.35-5.11(m,1H),4.98-4.84(m,1H),4.79-4.67(m,1H),4.51-4.36(m,2H),4.27-4.13(m,1H),4.09-3.97(m,1H),3.96-3.77(m ,4H),3.65-3.54(m,1H),3.45-3.37(m,2H),3.25-3.21(m,1H),3.17-3.11(m,1H),3.10-3.02(m,6H),3.01-2.95(m,1H),2.86-2 1H NMR (400 MHz, dimethyl sulfoxide-d6+heavy water-d2) δ = 7.61-7.52 (m, 1H), 7.27-7.19 (m, 1H), 7.03-6.92 (m, 2H), 6.15-6.07 (m, 1H), 5.34-5.12 (m, 1H), 4.94-4.83 (m, 1H), 4.77-4.67 (m, 1H), 4.47-4.33 (m, 2H), 4.24-4.11 (m, 1H), 4.11-4.00 (m, 1H), 3.99-3.77 (m, 4H), 3.59-3.52 (m,1H),3.45-3.34(m,1H),3.33-3.19(m,2H),3.19-3.13(m,1H),3.12-3.06(m,3H),3.05-3.04(m,3H),3.03-2.97(m,1H),2.87-2 19F NMR (400 MHz, dimethicone-d6 + deuterium oside-d2) δ = -121.213, -171.797; LCMS (ESI, M+1): m / z = 751.7.

[0313] Example 286 [ka] 6-Azabicyclo[3.1.1]heptan-6-yl(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone [ka] The synthesis was carried out according to Example 233, except that HCl was used instead of TFA in the final step. The title compound was obtained as a yellow solid. 1H NMR (400MHz, methanol-d4) δ = 7.51 (dd, J = 5.6, 8.8 Hz, 1H), 7.14 (t, J = 9.4 Hz, 1H), 7.01-6.93 (m, 2H), 6.71-6.65 (m, 1H), 5.36-5.16 (m, 1H), 5.01 (td, J = 3.2, 6.0 Hz, 2H), 4.56-4.44 (m, 3H), 4.27-4.15 (m, 1H), 4.11-3.96 (m, 4H), 3.71-3.61 (m, 1H), 3.54 (br dd,J=2.4,8.8Hz,1H),3.44-3.38(m,2H),3.27-3.10(m,6H),3.02-2.92(m,1H),2.78-2.68(m,1H),2.66-2.56(m,1H),2. 39-2.18(m,4H),2.15-2.02(m,4H),1.98-1.82(m,5H),1.75-1.64(m,2H),1.17-1.05(m,3H);LCMS(ESI,M+1):m / z=739.4

[0314] Example 287 [ka] N-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N-isopropylacetamide [ka]

[0315] Step A. tert-Butyl 2-((tert-butoxycarbonyl)(isopropyl)amino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a mixture of tert-butyl 2-((tert-butoxycarbonyl)amino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (100 mg, 1.0 equiv) in THF (1 mL) was added NaH (56.7 mg, 60% purity, 5.0 equiv). The reaction was stirred at 25° C. for 1 hour. 2-Iodopropane (482 mg, 10 equiv) was added to the above mixture. The reaction was stirred at 60° C. for 12 hours. The mixture was quenched with HO (3 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to give the title compound (50.0 mg, 40% yield) as a yellow oil; LCMS (ESI, M+1): m / z = 395.2.

[0316] Step B N-Isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine: To a solution of tert-butyl 2-((tert-butoxycarbonyl)(isopropyl)amino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (50.0 mg, 1 equiv) in MeCN (0.5 mL) was added HCl·dioxane (4.0 M, 2.0 mL). The reaction was stirred at 0 °C for 1 h. The pH of the mixture was adjusted to 8 with saturated aqueous NaHCO (3.0 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (23.0 mg, 89% yield) as a yellow oil; LCMS (ESI, M+1): m / z=195.2.

[0317] Step C. 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N-isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine: tert-Butyl 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N-isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine in DMF (0.5 mL) To a mixture of (((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl 4-methylbenzenesulfonate (50.0 mg, 1.0 equiv) and N-isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (21.0 mg, 1.5 equiv) was added DIEA (27.9 mg, 3.0 equiv). The reaction was stirred at 40° C. for 12 hours. The mixture was filtered and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to give the title compound (40.0 mg, 73% yield) as a yellow oil; LCMS (ESI, M+1): m / z=717.5.

[0318] Step DN-(5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N-isopropylacetamide: 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N-isopropylacetamide in THF (2 mL) To a mixture of (2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N-isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (60 mg, 1.0 equiv) was added DMF (285 mg, 46 equiv) and NaH (5.02 mg, 60% purity, 1.5 equiv) at 0° C. The reaction was stirred at 20° C. for 30 minutes. To the resulting mixture was added AcO (17.1 mg, 2.0 equiv) in THF (1 mL) at 0° C. The reaction was stirred at 20° C. for 2 hours. The mixture was diluted with saturated aqueous NaHCO3 (5 mL) and extracted with EtOAc (3 x 10 mL).The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (50 mg, 77% yield) as a white solid; 1H NMR (400MHz, chloroform-d) δ = 7.60-7.55 (m, 1H), 7.23-7.17 (m, 2H), 7.03-7.00 (m, 1H), 5.96-5.92 (m, 1H), 5.35-5.14 (m, 3H), 4.93-4.80 (m, 2H), 4.65-4.55 (m, 1H), 4.55-4.40 (m, 2H), 4.26-4.17 (m, 1H), 4.14-4.03 (m, 1H), 4.02-3.93 (m, 2H), 3.91-3.81 (m, 1H), 3.80-3.93 (m, 3H). .71(m,1H),3.56-3.51(m,3H),3.49-3.43(m,1H),3.42-3.31(m,2H),3.30-3.19(m,2H),3.18-3.05(m,3H),3.02-2.92(m,1H),2.65 19F NMR (400 MHz, chloroform-d) δ = -119.097, -173.140; LCMS (ESI, M+1): m / z = 759.1.

[0319] Step E-N-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N-isopropylacetamide: N-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N-isopropylacetamide in ACN (112 μL) To a mixture of 45 mg (1.0 equiv) of 4-(3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N-isopropylacetamide (4.0 equiv) was added HCl·MeOH (4 M, 0.2 mL, 1.5 equiv). The reaction was stirred at 20°C for 1 hour. The mixture was concentrated, dissolved in MeOH (1 mL), neutralized with solid NaHCO, filtered, and purified by prep-HPLC [Phenomenex luna C18 150 × 25 mm × 10 μm; A: water (FA), B: ACN; B%: 21%-51% over 10 min] to give the title compound (42 mg, 96% yield, 0.3 equiv FA) as a yellow solid.1H NMR (400MHz, dimethyl sulfoxide-d6) δ = 10.75-8.99 (m, 1H), 7.63-7.56 (m, 1H), 7.29-7.19 (m, 1H), 7.02-6.95 (m, 2H), 6.08-6.02 (m, 1H), 5.33-5.12 (m, 1H), 4.96-4.84 (m, 1H), 4.80-4.70 (m, 1H), 4.68-4.58 (m, 1H), 4.52-4.38 (m, 2H), 4.09-3.97 (m, 1H), 3.96-3.89 (m, 1H), 3.88-3.77 (m, 3H), 3.59 (br d,J=16.0Hz,2H),3.48-3.38(m,2H),3.18-3.07(m,2H),3.07-3.01(m,2 H),3.00-2.91(m,1H),2.84-2.75(m,1H),2.65-2.58(m,1H),2.29-2.15( m,1H),2.07-2.01(m,1H),2.00-1.86(m,3H),1.85-1.76(m,1H),1.76-1 .66(m,2H),1.65-1.52(m,3H),1.10-1.01(m,3H),1.00-0.84(m,6H);19F NMR (400 MHz, dimethyl sulfoxide-d6) δ = -121.409, -172.099; LCMS (ESI, M+1): m / z = 715.5.

[0320] Example 288 [ka] 1-((5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methyl)-1,3,3-trimethylurea [ka]

[0321] Step A. tert-Butyl 2-((1,3,3-trimethylureido)methyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a mixture of tert-butyl 2-((methylamino)methyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (80.0 mg, 1.0 equiv) and N,N-diethylpropan-2-amine (742 mg, 20 equiv) in DCM (0.5 mL) was added dimethylcarbamyl chloride (61.4 mg, 2.0 equiv). The reaction was stirred at 25° C. for 2 hours. The mixture was concentrated and purified by reverse-phase flash chromatography [water (FA, 0.1%) / acetonitrile] to give the title compound (40 mg, 39% yield) as a yellow oil. LCMS (ESI, M+1): m / z=352.1.

[0322] Step B. 1,1,3-Trimethyl-3-((5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methyl)urea: A mixture of tert-butyl 2-((1,3,3-trimethylureido)methyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (30.0 mg, 1.0 equiv) in HCl / dioxane (4 M, 1.0 mL, 47 equiv) was stirred at 20° C. for 0.5 hours. The mixture was concentrated in vacuo to give the title compound (24.0 mg) as a white oil, which was used in the next step without further purification.

[0323] The last two steps were carried out according to Example 248. The title compound was obtained as a yellow solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 7.52 (dd, J = 5.6, 8.8 Hz, 1H), 7.15 (t, J = 9.6 Hz, 1H), 6.97 (s, 2H), 6.17 (s, 1H), 5.44 (s, 1H), 5.10-4.96 (m, 1H), 4.76 (br dd, J = 3.6, 16.4 Hz, 2H), 4.51-4.37 (m, 2H), 4.34-4.15 (m, 4H), 4.13-4.00 (m, 2H), 3.98-3.84 (m, 1H), 3.69 (br d,J=17.6Hz,1H),3.57-3.47(m,1H),3.46-3.34(m,3H),3.27-3.14(m,3H),3.12-3.01(m,1H),2.93-2.53(m,1 0H),2.41-2.18(m,3H),2.17-1.97(m,4H),1.95-1.83(m,1H),1.18-1.01(m,3H).LCMS(ESI,M+1):m / z=730.3.

[0324] Example 289 [ka] 7-(8-Ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((dimethylsulfamoyl)methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine [ka]

[0325] Step A. 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((dimethylsulfamoyl)methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine: 5-(7-(8-ethyl-7-fluoro)-3-(methoxymethoxy)-1-naphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((dimethylsulfamoyl)methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine in pyridine (490 mg, 21 equiv) To a mixture of 5,6,7,8-tetrahydro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (200 mg, 1.0 equiv) was added dimethylsulfamoyl chloride (104 mg, 2.5 equiv) and THF (0.50 mL). The reaction was stirred at 20° C. for 2 hours. The mixture was concentrated and purified by reverse-phase flash chromatography (C18, 0.1% formic acid) to give the title compound (77.0 mg, 31% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 796.5.

[0326] Step B. 7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((dimethylsulfamoyl)methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine: 7-(8-ethyl-7-fluoro-3-(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((dimethylsulfamoyl)methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine in ACN (0.50 mL) To a mixture of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((dimethylsulfamoyl)methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (77.0 mg, 1.0 equiv) was added HCl·MeOH (4 M, 1.0 mL, 41 equiv). The reaction was stirred at 20 °C for 0.5 h. The mixture was concentrated, dissolved in methanol (3.0 mL), neutralized with solid NaHCO, filtered, purified by prep-HPLC [Phenomenex Luna C18 250 × 50 mm × 15 μm; A: water (FA), B: ACN; B%: 22%-52% over 15 min], and lyophilized to give the title compound (72.0 mg, 98% yield, FA salt) as a yellow solid.1H NMR (400MHz, dimethyl sulfoxide-d6 + heavy water-d2) δ=7.58(dd,J=6.0,8.8Hz,1H),7.23(t,J=9.2Hz,1H),6.99(s,2H),6.13(s,1H),5.35-5.14(m,1H),4.90(br d,J=16.4Hz,1H),4.69(br d,J=16.4Hz,1H),4.36(br s,2H),4.10(br d,J=12.8Hz,1H),4.00-3.74(m,4H),3.59(br s,1H),3.41(br d,J=8.0Hz,1H),3.34-3.22(m,2H),3.15(s,4H),3.13-3.07(m,3H),3.03(br s,1H),2.87-2.78(m,1H),2.66(s,7H),2.22-2.10(m,1H),2.09-1.97(m,2H),1.96-1.86(m,2H),1.84-1.66(m,3H),1.05(br t,J=7.2Hz,3H);19F NMR(400MHz,dimethylsulfoxide-d6+heavy water-d2)δ=-121.273,-171.969;LCMS(ESI,M+1):m / z=752.5.

[0327] Example 290 [ka] 7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((methylsulfamoyl)methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine [ka]

[0328] Step A. 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((methylsulfamoyl)methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine: 5-(7-(8-ethyl-7-fluoro)-3-(methoxymethoxy)-1-naphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((methylsulfamoyl)methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine in pyridine (490 mg, 35 equiv) To a mixture of N-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (120 mg, 1.0 equiv) was added methylsulfamoyl chloride (56.4 mg, 2.5 equiv) and THF (0.50 mL). The reaction was stirred at 20° C. for 2 hours. The mixture was concentrated and purified by reverse-phase flash chromatography (C18, 0.1% formic acid) to give the title compound (52.0 mg, 38% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 782.4.

[0329] Step B. 7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((methylsulfamoyl)methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine: 7-(8-ethyl-7-fluoro-3-(methyl)amino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((methylsulfamoyl)methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine in ACN (0.50 mL) To a mixture of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((methylsulfamoyl)methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (52.0 mg, 1.0 equiv) was added HCl·MeOH (4 M, 1.0 mL, 60 equiv). The reaction was stirred at 20 °C for 0.5 h. The mixture was concentrated, dissolved in methanol (3.0 mL), neutralized with solid NaHCO, filtered, purified by prep-HPLC [Phenomenex Luna C18 150 × 25 mm × 10 μm; A: water (FA), B: ACN; B%: 23%-53% over 58 min], and lyophilized to give the title compound (12.2 mg, 24% yield, FA salt) as an off-white solid.1H NMR (400MHz, dimethyl sulfoxide-d6) δ=9.84-9.58(m,1H),7.59(dd,J=6.0,8.8Hz,1H),7.52-7.37(m,1H) ),7.24(t,J=9.2Hz,1H),6.99(s,2H),6.15(s,1H),5.35-5.14(m,1H),4.98-4.85(m,1H),4.68(br d,J=16.0Hz,1H),4.42-4.29(m,2H),4.10(br dd,J=2.4,12.0Hz,1H),3.96-3.76(m,4H),3.59(br d,J=17.6Hz,1H),3.42(br d,J=7.2Hz,2H),3.16-3.01(m,7H),2.98(s,1H),2.87-2.75(m,1H),2.70-2.62(m,1H),2.45(d,J=4.8Hz,3H),2.15(br dd,J=6.8,7.6Hz,1H),2.06(br d,J=7.6Hz,1H),2.04-1.91(m,3H),1.77(br s,2H),1.76-1.65(m,2H),1.06(t,J=7.2Hz,3H);19F NMR (400MHz, dimethyl sulfoxide-d6) δ=-121.371,-171.962; LCMS (ESI, M+1): m / z=738.4.

[0330] Example 291 [ka] 7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((sulfamoyl)methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine [ka]

[0331] Step A. 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((sulfamoyl)methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine: 5-(7-(8-ethyl-7-fluoro)-3-(methoxymethoxy)-1-naphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((sulfamoyl)methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine in pyridine (490 mg, 35 equiv) To a mixture of -3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (120 mg, 1.0 equiv) was added sulfamoyl chloride (50.3 mg, 2.5 equiv) in THF (0.50 mL). The reaction was stirred at 20° C. for 2 hours. The mixture was concentrated and purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (46.0 mg, 34% yield) as a yellow solid; LCMS (ESI, M+1): m / z=768.4.

[0332] Step B. 7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((sulfamoyl)methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine: 7-(8-ethyl-7-fluoro-3-( To a mixture of (2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((sulfamoyl)methylamino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (46.0 mg, 1.0 equiv) was added HCl·MeOH (1.0 mL, 66 equiv). The reaction was stirred at 20° C. for 0.5 h. The mixture was concentrated, dissolved in methanol (3.0 mL), neutralized with solid NaHCO, filtered, purified by prep-HPLC [Phenomenex Luna C18 150 × 25 mm × 10 μm; A: water (FA), B: ACN; B%: 20%-50% over 58 min], and lyophilized to give the title compound (12.4 mg, 27% yield, FA salt) as an orange solid.1H NMR (400MHz, dimethyl sulfoxide-d6 + heavy water-d2) δ=7.57(dd,J=6.0,8.8Hz,1H),7.23(br t,J=9.2Hz,1H),6.98(s,2H),6.17(s,1H),5.41-5.17(m,1H),4.94-4.83(m,1H),4.68(br d,J=16.0Hz,1H),4.32(br s,2H),4.14-4.06(m,1H),4.06-3.94(m,2H),3.93-3.77(m,3H),3.42(br d,J=9.2Hz,1H),3.27-3.10(m,6H),3.06(s,3H),2.91-2.83(m,1H),2.66(br d,J=4.4Hz,1H),2.13(br d,J=4.0Hz,2H),2.06(br s,1H),2.02-1.96(m,1H),1.95-1.71(m,5H),1.04(br t,J=7.2Hz,3H);19F NMR (400MHz, dimethyl sulfoxide-d6+heavy water-d2) δ=-121.153,-171.917; LCMS (ESI, M+1): m / z=724.6.

[0333] Example 292 [ka] N-Cyclopropyl-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N,3-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [ka]

[0334] Step A. 5-tert-Butyl 2-methyl 7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate: To a solution of 5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (5.0 g, 1.0 equiv) in MeOH (25 mL) was added diazomethyl(trimethyl)silane (2 M, 18 mL, 2.0 equiv). The mixture was stirred at 25 °C for 0.5 h. The reaction was filtered and concentrated to give the title compound (2.40 g, 81% yield) as a yellow solid. LCMS (ESI, M+1): m / z = 296.2.

[0335] Step B. 5-tert-butyl 2-methyl 3-iodo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate: To a solution of 5-tert-butyl 2-methyl 7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate (2.40 g, 1.0 equiv) in CHCOOH (25 mL) was added NIS (3.70 g, 2.0 equiv). The mixture was stirred at 80 °C for 0.5 h. The reaction was quenched at 0 °C with saturated NaHCO solution (80 mL). The filtrate was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to give the title compound (2.05 g, 59% yield) as a yellow solid; LCMS (ESI, M+1): m / z=422.1.

[0336] Step C. 5-tert-butyl 2-methyl 3-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate: A mixture of 5-tert-butyl 2-methyl 3-iodo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate (2.0 g, 1.0 equiv), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (4.80 g, 50% purity, 4.0 equiv), Pd(dppf)Cl (347 mg, 0.1 equiv), and KCO (2.0 g, 3.0 equiv) in DMF (20 mL) was degassed and purged with N three times. The mixture was stirred at 100° C. for 5 hours under a N atmosphere. The reaction was filtered, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (1.20 g, 82% yield) as a white solid; LCMS (ESI, M+1): m / z=310.2.

[0337] Step D. 5-(tert-Butoxycarbonyl)-3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid: To a solution of 5-tert-butyl 2-methyl-3-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate (3.0 g, 1.0 equiv) in THF (15 mL) was added LiOH·HO (1.20 g, 3.0 equiv), MeOH (7.5 mL), and HO (15 mL). The mixture was stirred at 25 °C for 1 h. The reaction was concentrated. The residue was adjusted to pH 8 with HCl (2.5 mL, 2 M). The residue was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (2.50 g, crude) as a white solid; LCMS (ESI, M+1): m / z=296.2.

[0338] Step E. tert-Butyl 2-(cyclopropyl(methyl)carbamoyl)-3-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of 5-(tert-butoxycarbonyl)-3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (1.0 g, 1.0 equiv) in DMF (10 mL) was added HATU (2.0 g, 1.5 equiv), N-methylcyclopropanamine (1.20 g, 3.0 equiv, HCl), and N,N-diethylpropan-2-amine (3.50 g, 8.0 equiv). The mixture was stirred at 25° C. for 12 hours. The reaction was filtered. The filtrate was purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (1.10 g, 93% yield) as a white solid; LCMS (ESI, M+1): m / z=349.2.

[0339] Step F: N-Cyclopropyl-N,3-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of tert-butyl 2-(cyclopropyl(methyl)carbamoyl)-3-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (1.10 g, 1.0 equiv) in ACN (12 mL) was added HCl·dioxane (4 M, 11 mL) at 0° C. The mixture was stirred at 25° C. for 1 h. The reaction was concentrated. The residue was adjusted to pH 10 with saturated NaOH solution (10 mL) at 0° C. The reaction was extracted with DCM (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (877 mg, crude) as a yellow solid; LCMS (ESI, M+1): m / z=249.1.

[0340] The last two steps were carried out according to Example 248. The title compound was obtained as a yellow solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 8.51 (s, 1H), 7.51-7.48 (m, 1H), 7.13 (t, J = 9.4Hz, 1H), 6.96 (s, 2H), 5.46-5.30 (m, 1H), 4.75 (d, J = 7.4Hz, 1H), 4.53-4.36 (m, 2H), 4.25-3.94 (m, 5H), 3.68-3.63 (m, 1H), 3.55 -3.36(m,6H),3.26-3.12(m,3H),3.11-3.03(m,3H),2.89(s,1H),2.68(d,J=14.8Hz,1H),2.51-2.2 1(m,4H),2.21-1.85(m,8H),1.08(t,J=7.2Hz,3H),0.88-0.34(m,4H);LCMS(ESI,M+1):m / z=727.5.

[0341] Example 293 [ka] N-Cyclopropyl-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [ka]

[0342] Step A. tert-Butyl 2-(cyclopropylcarbamoyl)-3-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of 5-(tert-butoxycarbonyl)-3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (1.0 g, 1.0 equiv) in DMF (10 mL) was added HATU (1.9 g, 1.5 equiv), cyclopropanamine (0.966 g, 5.0 equiv), and N,N-diethylpropan-2-amine (1.31 g, 3.0 equiv). The mixture was stirred at 25° C. for 12 hours. The reaction was filtered. The filtrate was purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (1.00 g, 87% yield) as a white solid.

[0343] Step B N-Cyclopropyl-3-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of tert-butyl 2-(cyclopropylcarbamoyl)-3-methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (1.00 g, 1 equiv) in ACN (10 mL) was added HCl·dioxane (4 M, 10 mL) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction was concentrated. The residue was adjusted to pH 10 with saturated NaOH solution (10 mL) at 0 °C. The reaction was extracted with DCM (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (650 mg, crude) as a yellow solid.

[0344] The last two steps were carried out according to Example 248. The title compound was obtained as a white solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 8.53-8.49 (m, 1H), 7.54-7.47 (m, 1H), 7.18-7.10 (m, 1H), 6.99-6.90 (m, 2H), 5.46-5.24 (m, 1H), 4.87-4.81 (m, 1H), 4.75-4.64 (m, 1H), 4.53-4.43 (m, 1H), 4.43-4.33 (m, 1H), 4.19-4.02 (m, 4H), 4.00-3.90 (m, 1H), 3 .69-3.59(m,1H),3.36(s,6H),3.27-3.09(m,3H),2.81-2.65(m,2H),2.45-2.33(m,1H),2.32(s,3H),2.23(s,2H),2.16 -2.01(m,4H),1.96-1.86(m,1H),1.14-1.05(m,3H),0.82-0.73(m,2H),0.62-0.54(m,2H);LCMS(ESI,M+1):m / z=713.2.

[0345] Example 294 [ka] 3-Cyclopropyl-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [ka]

[0346] Step A. 5-tert-butyl 2-methyl 3-cyclopropyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate: To a solution of 5-tert-butyl 2-methyl 3-iodo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate (3.0 g, 1 equiv) in DMF (48 mL) was added cyclopropylboronic acid (1.22 g, 2 equiv) and KCO (2.95 g, 3 equiv), followed by degassing and purging with a N atmosphere. To the reaction was added Pd(dppf)Cl (521 mg, 0.1 equiv) under N. The reaction was stirred at 100 °C for 4 h. The reaction mixture was filtered through Celite, diluted with water (500 mL), and extracted with ethyl acetate (4 x 150 mL). The organic phase was dried over NaSO, concentrated, and purified by column chromatography (SiO, petroleum ether / ethyl acetate = 30 / 1 to 1 / 2). This was then concentrated and purified by reverse-phase chromatography [0.1% FA condition] to give the title compound (1.9 g, 79% yield) as a brown oil; LCMS (ESI, M+1): m / z = 349.1.

[0347] Step B. 5-(tert-Butoxycarbonyl)-3-cyclopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid: To a solution of 5-tert-butyl 2-methyl 3-cyclopropyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate (1.8 g, 1.0 equiv) in MeOH (18 mL) was added NaOH (1 M, 10.7 mL, 2.0 equiv) at 0 °C. The mixture was stirred at 25 °C for 1 hour. The pH of the mixture was adjusted to 3 with 1 M aqueous HCl at 0 °C. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phase was dried over Na2SO4 and concentrated to give the title compound (1.6 g) as a brown solid; LCMS (ESI, M+1): m / z = 322.1.

[0348] Step C. tert-Butyl 3-cyclopropyl-2-(dimethylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of 5-(tert-butoxycarbonyl)-3-cyclopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (1.4 g, 1.0 equiv) in DMF (5 mL) was added EDCI (1.67 g, 2.0 equiv), HOBt (706 mg, 1.2 equiv), TEA (4.4 g, 10 equiv), and N-methylmethanamine (2 M, 11 mL, 5.0 equiv). The mixture was stirred at 40° C. for 66 hours. The reaction was filtered and purified by reverse phase flash chromatography {0.1% FA conditions} to give the title compound (1.3 g, 88% yield) as a brown oil; LCMS (ESI, M+1): m / z=349.1.

[0349] Step D. 3-Cyclopropyl-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of tert-butyl 3-cyclopropyl-2-(dimethylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (200 mg, 1.0 equiv) in ACN (1 mL) was slowly added HCl·dioxane (4 M, 3.00 mL, 21 equiv) at 0 °C. The reaction was stirred at 0 °C for 1 h. The reaction was concentrated at 0 °C. MeOH (4 mL) and NaHCO were then slowly added to the crude product at 0 °C (pH = 8), followed by filtration and concentration. The residue was dissolved in DCM:MeOH = 10:1 (5 mL) and stirred for 10 min. The mixture was filtered, and the filter cake was washed with DCM:MeOH=10:1 (2×5 mL). The organic phase was concentrated to give the title compound (120 mg, crude) as a brown oil; LCMS (ESI, M+1): m / z=249.1.

[0350] The last two steps were carried out according to Example 248. The title compound was obtained as a white solid (FA salt). 1H NMR (400MHz, methanol-d4) δ=8.53(s,1H),7.51(dd,J=5.8,8.8Hz,1H),7.15(t,J=9.2Hz,1H),6.93(br d,J=2.8Hz,2H),5.41-5.22(m,1H),5.07(br d,J=16.4Hz,1H),4.82(br d,J=16.4Hz,1H),4.51-4.34(m,2H),4.22-4.08(m,3H),4.06-3.91(m,2H),3.79-3.70(m,1H),3.53-3.32(m,5H),3.28(br s,1H),3.24-3.13(m,2H),3.13-3.03(m,4H),3.00(s,3H),2.78-2.66(m,1H),2.38-2.09(m,5H),2.08-1.83(m,3 H),1.68-1.58(m,1H),1.08(t,J=7.2Hz,3H),0.86-0.59(m,2H),0.53-0.20(m,2H);LCMS(ESI,M+1):m / z=727.5.

[0351] Example 295 [ka] 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-isopropyl-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [ka]

[0352] Step A. 5-tert-butyl 2-methyl 3-(prop-1-en-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate: A mixture of 5-tert-butyl 2-methyl 3-iodo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate (2 g, 1 equiv), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.60 g, 2 equiv) and CsCO (4.64 g, 3 equiv) in dioxane (12 mL) and HO (3 mL) was degassed and purged with N three times. Pd(dppf)Cl (347 mg, 0.1 equiv) was added, and the mixture was stirred at 90 °C for 12 hours under a N atmosphere. The mixture was diluted with H O (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous Na SO , concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (1.35 g, 84% yield) as a yellow oil; LCMS (ESI, M+1): m / z = 336.1.

[0353] Step B. 5-tert-Butyl 2-methyl 3-isopropyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate: Pd / C (200 mg, 10% purity) was added to MeOH (10 mL) under a N atmosphere. 5-tert-Butyl 2-methyl 3-(prop-1-en-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate (1.8 g, 1 equiv) was added, and the mixture was degassed and purged with H three times. The mixture was stirred under a H atmosphere (15 Psi) at 25 °C for 12 h. The mixture was filtered through a pad of Celite. The filter cake was washed with MeOH (50 mL). The filtrate was concentrated to give the title compound (1.75 g, crude) as a pale yellow oil; LCMS (ESI, M+1): m / z=338.2.

[0354] Step C. 5-(tert-Butoxycarbonyl)-3-isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid: To a solution of 5-tert-butyl 2-methyl 3-isopropyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate (1.65 g, 1 equiv) in MeOH (10 mL) was added NaOH (998 mg, 5 equiv). The mixture was stirred at 25° C. for 12 hours. The pH of the mixture was adjusted to 3 with 1 M HCl at below 10° C. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (1.5 g, 94% yield) as a white solid; LCMS (ESI, M+1): m / z = 324.1.

[0355] Step D. tert-Butyl 2-(dimethylcarbamoyl)-3-isopropyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of 5-(tert-butoxycarbonyl)-3-isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (500 mg, 1 equiv) and MeNH (2 M in THF, 2.32 mL, 3 equiv) in DMF (4 mL) was added HATU (1.18 g, 2 equiv) and N,N-diethylpropan-2-amine (400 mg, 2 equiv). The mixture was stirred at 25 °C for 2 h. The mixture was diluted with HO (10 mL) and extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (450 mg, 82% yield) as a red oil; LCMS (ESI, M+1): m / z = 351.2.

[0356] Step E. 3-Isopropyl-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of tert-butyl 2-(dimethylcarbamoyl)-3-isopropyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (250 mg, 1 equiv) in MeOH (2 mL) was added HCl·MeOH (4 M, 2 mL). The mixture was stirred at 25 °C for 2 h. The reaction was concentrated. The residue was dissolved in MeOH (3 mL). NaHCO (1 g) was added and the mixture was stirred for 0.5 h. The mixture was filtered. The filter cake was washed with MeOH (10 mL). The filtrate was concentrated to give the title compound (150 mg, crude) as a red oil; LCMS (ESI, M+1): m / z=251.1.

[0357] The last two steps were carried out according to Example 248. The title compound was obtained as a white solid. 1H NMR (400 MHz, methanol-d4) δ = 7.50 (dd, J = 5.6, 9.2 Hz, 1H), 7.14 (t, J = 9.4 Hz, 1H), 6.99-6.94 (m, 2H), 5.39-5.33 (m, 1H), 5.33-5.17 (m, 1H), 4.58 (br dd,J=4.4,16.2Hz,1H),4.52-4.39(m,2H),4.16-4.01(m,4H),3.76(ddd,J=3.2,10.0,14.0Hz,1H),3.69-3.61(m,1 H),3.48-3.35(m,3H),3.26-3.16(m,3H),3.16-3.11(m,2H),3.08(s,3H),3.04-2.97(m,2H),2.95(s,3H),2.63(br d,J=12.8Hz,1H),2.32-1.78(m,9H),1.21(d,J=7.2Hz,3H),1.17(d,J=7.2Hz,3H),1.11(t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=729.3.

[0358] Example 296 [ka] 4-(4-(2-amino-3-bromo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol [ka]

[0359] Step A. 5-tert-Butyl 2-methyl 7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate: To a solution of 5-tert-butoxycarbonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (2.00 g, 1.0 equiv) in MeOH (10 mL) and DCM (20 mL) was added diazomethyl(trimethyl)silane (2 M, 2.0 equiv). The mixture was washed with saturated NaHCO3 solution (50 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (1.92 g, 90% yield) as a white solid. LCMS (ESI, M+1): m / z = 296.1

[0360] Step B. 5-tert-Butyl 2-methyl 3-bromo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate: To a solution of 05-tert-butyl 02-methyl 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2,5-dicarboxylate (1.00 g, 1 equiv) in AcOH (10 mL) and ACN (5 mL) was added NBS (1.21 g, 2 equiv). The mixture was stirred at 40 °C for 5 h. NaHCO3 solution was slowly added dropwise to the mixture (200 mL), followed by extraction with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (SiO, petroleum ether / ethyl acetate=1 / 0 to petroleum ether / ethyl acetate=0 / 1) to give the title compound (1.20 mg, 92% yield) as a yellow oil; LCMS (ESI, M+1): m / z=374.0.

[0361] Step C. 3-Bromo-5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid: To a solution of O5-tert-butyl O2-methyl 3-bromo-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2,5-dicarboxylate (1.20 g, 1 equiv) in MeOH (12 mL) and HO (4 mL) was added LiOH (384 mg, 5 equiv). The mixture was stirred at 20 °C for 16 h. The reaction mixture was washed with EtOAc (20 mL × 2). The aqueous phase was acidified with 2 M HCl solution (50 mL) and then extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated to give the title compound (803 mg, 69% yield) as a white solid. LCMS (ESI, M+1): m / z=360.0

[0362] Step D. tert-Butyl 3-bromo-2-((tert-butoxycarbonyl)amino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a mixture of 3-bromo-5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (703 mg, 1.0 equiv) in toluene (6 mL) was added 4 Å molecular sieves (200 mg, 1.0 equiv), TEA (815 μL, 3.0 equiv), DPPA (1.5 equiv) and 2-methylpropan-2-ol (4.34 g, 30 equiv) and stirred under nitrogen at 110° C. for 16 hours. The mixture was filtered, and the filtrate was diluted with HO (30 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [Column SiO: Welch Ultimate XB-SiOH 250 × 50 × 10 μm; A: hexane, B: EtOH (0.1% FA), B%: 1%-30% over 15 min] to give the title compound (366 mg, 43% yield) as a yellow oil.

[0363] Step E. 3-Bromo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine: To a solution of tert-butyl 3-bromo-2-(tert-butoxycarbonylamino)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (200 mg, 1.0 equiv) in MeOH (1 mL) was added HCl·MeOH (4 M, 5 mL). The mixture was stirred at 25 °C for 1 h. The reaction was concentrated to give the title compound (803 mg, 69% yield) as a white solid; 1H NMR (400 MHz, methanol-d4) δ = 7.46-7.32 (m, 1H), 7.29-7.14 (m, 1H), 4.61-4.47 (m, 4H), 3.66-3.57 (m, 2H), 2.20 (br s, 2H).

[0364] The last two steps were carried out according to Example 248. The title compound was obtained as a yellow solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 7.50 (dd, J = 5.6, 9.2 Hz, 1H), 7.14 (t, J = 9.2 Hz, 1H), 7.00-6.93 (m, 2H), 5.45-5.26 (m, 1H), 4.78-4.63 (m, 2H), 4.07 (s, 5H), 4.01-3.84 (m, 2H) ),3.73-3.60(m,1H),3.52-3.44(m,2H),3.43-3.35(m,4H),3.20-3.06(m,2H),2.7 4-2.63(m,1H),2.47-1.85(m,9H),1.15-1.07(m,3H);LCMS(ESI,M+1):m / z=711.3;

[0365] Example 297 [ka] 3-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N,N-dimethylpropanamide [ka]

[0366] Step A. tert-Butyl 2-(3-(dimethylamino)-3-oxopropyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of 3-(5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)propanoic acid (300 mg, 1.0 equiv) in THF (6.0 mL) was added HATU (553 mg, 1.5 equiv), N,N-diethylpropan-2-amine (376 mg, 3.0 equiv), and (CH)NH (727 μL, 2.0 M, 1.5 equiv). The mixture was stirred at 20 °C for 2 h. The reaction was diluted with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, concentrated, and purified by prep-HPLC [column: Phenomenex luna C18 150 × 40 mm × 15 μm; mobile phase: [water (FA)-ACN]; B%: 23%-53%, 10 min] to obtain the title compound (100 mg, 31% yield) as a white solid. LCMS (ESI, M+1): m / z = 337.1.

[0367] Step B N,N-Dimethyl-3-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)propanamide: To a solution of tert-butyl 2-(3-(dimethylamino)-3-oxopropyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (100 mg, 1.0 equiv) was added HCl / MeOH (4.0 mL, 4.0 M). The mixture was stirred at 20° C. for 1 hour. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC [Column: Waters Xbridge 150 × 25 mm × 5 μm; Mobile phase: [water (NH4HCO3)-ACN]; B%: 2%-32%, 8 min] to give the title compound (50.0 mg, 71% yield) as a white solid. LCMS (ESI, M+1): m / z = 237.1.

[0368] The last two steps were carried out according to Example 248. The title compound was obtained as a white solid. 1H NMR (400MHz, methanol-d4) δ = 7.51 (dd, J = 6.0, 9.2 Hz, 1H), 7.14 (t, J = 9.2 Hz, 1H), 7.00-6.87 (m, 2H), 6.05 (d, J = 1.6 Hz, 1H), 5.35-5.17 (m, 1H), 4.95 (br d, J = 16.0 Hz, 1H), 4.78-4.69 (m, 1H), 4.47-4.34 (m, 2H), 4.26-3.82 (m, 5H), 3.70 (br d,J=18.8Hz,1H),3.56-3.34(m,3H),3.24-3.09(m,5H),3.03-2.95(m,4H),2.90(s,3H),2.82(br d,J=8.0Hz,2H),2.74-2.63(m,3H),2.32-2.12(m,3H),2.09-1.82(m,5H),1.18-1.05(m,3H);LCMS(ESI,M+1):m / z=715.4.

[0369] Example 298 [ka] 2-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N-methylacetamide [ka]

[0370] Step A. tert-Butyl 2-(2-(methylamino)-2-oxoethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of 2-(5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)acetic acid (200 mg, 1.0 equiv) in THF (6.0 mL) was added HATU (386 mg, 1.5 equiv), N,N-diethylpropan-2-amine (262 mg, 3.0 equiv), and MeNH (8.37 mL, 2.0 M, 25 equiv). The mixture was stirred at 20 °C for 2 h. The reaction was quenched with NH4Cl solution (20 mL) at 20 °C and then extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated to give the title compound (200 mg, crude) as a yellow oil. LCMS (ESI, M+1): m / z = 309.1.

[0371] Step B N-Methyl-2-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)acetamide: To a solution of tert-butyl 2-(2-(methylamino)-2-oxoethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (200 mg, 1.0 equiv) in MeOH (2.0 mL) was added HCl / MeOH (1.33 mL, 4.0 M). The mixture was stirred at 20° C. for 1 hour. The reaction was concentrated to give the title compound (200 mg, crude) as a yellow oil. LCMS (ESI, M+1): m / z=209.1.

[0372] The last two steps were carried out according to Example 248. The title compound was obtained as a white solid. 1H NMR (400MHz, methanol-d4) δ = 7.51 (dd, J = 6.0, 8.8 Hz, 1H), 7.15 (t, J = 9.2 Hz, 1H), 6.96 (br d, J = 4.4 Hz, 2H), 6.15 (s, 1H), 5.33-5.19 (m, 1H), 5.00-4.93 (m, 2H), 4.80-4.72 (m, 2H), 4.64-4.55 (m, 2H), 4.50-4.34 (m, 2H), 4.27-3.86 (m, 5H), 3.76-3.62 (m, 1H), 3.56-3.36 (m, 5H), 3.14 (br s,1H),3.25-3.13(m,1H),3.03-2.94(m,1H),2.73(s,3H),2.28(br s,5H),2.00-1.84(m,3H),1.11(br t,J=6.8Hz,3H);LCMS(ESI,M+1):m / z=687.5

[0373] Example 299 [ka] 2-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)acetamide [ka] Synthesized according to Example 298, except that NH4Cl was used instead of MeNH2 in the first step. The title compound was obtained as a yellow solid. 1H NMR (400MHz, methanol-d4) δ=7.51(dd,J=6.0,8.8Hz,1H),7.14(t,J=9.2Hz,1H),6.96(br d,J=5.2Hz,2H),6.19(s,1H),5.40-5.23(m,1H),4.84-4.73(m,2H),4.44(br s,2H),4.24-3.99(m,5H),3.69(br d,J=18.4Hz,1H),3.54-3.34(m,6H),3.27(br s,1H),3.18(br d,J=8.8Hz,2H),3.07(br d,J=5.6Hz,1H),2.72(br d,J=10.0Hz,1H),2.44-1.81(m,9H),1.11(br t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=673.4.

[0374] Example 300 [ka] 4-(4-(6-(1H-1,2,3-triazol-1-yl)-1,4-oxazepan-4-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol [ka]

[0375] Step A. tert-Butyl 6-((methylsulfonyl)oxy)-1,4-oxazepane-4-carboxylate: To a solution of tert-butyl 6-hydroxy-1,4-oxazepane-4-carboxylate (2 g, 1.0 equiv) and TEA (2.33 g, 2.5 equiv) in THF (20 mL) was added MsCl (2.9 g, 2.8 equiv) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 h. The resulting mixture was quenched with saturated aqueous NaHCO (5 mL) at 0 °C, diluted with HO (40 mL), and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 2] to give the title compound (2.8 g, 98% yield) as an off-white solid; 1H NMR (400 MHz, DMSO-d6) δ = 4.84 (br d, J = 4.4 Hz, 1H), 3.99-3.34 (m, 8H), 3.20 (s, 3H), 1.42 (s, 9H).

[0376] Step B. tert-Butyl 6-azido-1,4-oxazepane-4-carboxylate: To a solution of tert-butyl 6-methylsulfonyloxy-1,4-oxazepane-4-carboxylate (1.8 g, 1.0 equiv) in DMF (18 mL) was slowly added NaN (2.46 g, 6.2 equiv). The mixture was stirred at 70 °C for 12 h. To the reaction at 0 °C was added saturated aqueous NaCO until the pH reached approximately 9. The reaction was quenched by the addition of HO (40 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with HO (40 mL), dried over NaSO, filtered, concentrated, and purified by column chromatography [SiO, petroleum ether / ethyl acetate = 100 / 0 to 8 / 1] to give the title compound (1.3 g, 84% yield) as a brown oil; H NMR (400 MHz, DMSO-d) δ = 3.85-3.35 (m, 9H), 1.41 (d, J = 6.4 Hz, 9H).

[0377] Step C. tert-Butyl 6-(5-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)-1,4-oxazepane-4-carboxylate: To a solution of tert-butyl 6-azido-1,4-oxazepane-4-carboxylate (1.2 g, 1.0 equiv) in THF (12 mL) under N2 atmosphere was added CuI (94 mg, 0.1 equiv), TEA (200 mg, 0.4 equiv), and ethynyl(trimethyl)silane (1.95 g, 4.0 equiv) under N2 atmosphere. The reaction was stirred at 50 °C for 12 h under N2 atmosphere. The reaction was filtered through Celite. The resulting mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 x 20 mL). The organic phase was dried over Na2SO4, filtered, concentrated, and purified by reverse phase [0.1% FA conditions] to give the title compound (1.55 g, 80% yield) as a brown oil; 1H NMR (400 MHz, methanol-d4) δ = 8.08 (s, 1H), 3.92-3.41 (m, 9H), 1.53-1.43 (m, 9H), 0.31 (s, 9H).

[0378] Step D. tert-Butyl 6-(1H-1,2,3-triazol-1-yl)-1,4-oxazepane-4-carboxylate: To a solution of tert-butyl 6-(5-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)-1,4-oxazepane-4-carboxylate (1.3 g, 1.0 equiv) in THF (5 mL) was added TBAF (1 M, 15.27 mL, 4.0 equiv). The reaction was stirred at 45 °C for 2 h. The reaction was diluted with water (40 mL) and extracted with ethyl acetate (3 × 20 mL). The organic phase was dried over NaSO, concentrated, and purified by reverse-phase flash chromatography {0.1% FA condition} to give the title compound (0.68 g, 66% yield) as a brown solid; LCMS (ESI, M+1): m / z = 269.1.

[0379] Step E. 6-(1H-1,2,3-Triazol-1-yl)-1,4-oxazepane: To a solution of tert-butyl 6-(triazol-1-yl)-1,4-oxazepane-4-carboxylate (0.68 g, 1.0 equiv) in ACN (3 mL) was slowly added HCl·dioxane (4 M, 7 mL, 11 equiv) at 0 °C. The reaction was stirred at 0 °C for 1 h. The reaction was concentrated. The crude product was dissolved in MeOH (4 mL). NaHCO (0.5 g) was added and the mixture was stirred for 0.2 h. The mixture was filtered, concentrated, and dissolved in [DCM:MeOH=10:1 (3 × 5 mL)]. The mixture was filtered and concentrated to give the title compound (420 mg, 98.5% yield) as a brown oil.

[0380] The last two steps were carried out according to Example 248. The title compound was obtained as a pale red solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 8.52 (s, 1H), 8.21-8.14 (m, 1H), 7.81-7.75 (m, 1H), 7.56-7.46 (m, 1H), 7.15 (t, J = 9.2Hz, 1H), 7.03-6.93 (m, 2H), 5.70-5.56 (m, 1H), 5.51-5.32 (m, 1H), 4.81-4.66 (m, 1H), 4.60-4.42 (m, 1H), 4.40-4.14 (m, 5H), 4.09-3.95 (m, 3H), 3. 93-3.74(m,2H),3.68-3.58(m,1H),3.56-3.46(m,3H),3.38(dt,J=2.4,7.2Hz,2H),3.26-3.05(m,3H),2.81-2.68(m,1H),2.53- 2.30(m,2H),2.29-2.19(m,1H),2.17-2.07(m,2H),2.06-1.94(m,1H),1.11(dt,J=2.8,7.2Hz,3H);LCMS(ESI,M+1):m / z=647.5.

[0381] Example 301 [ka] N-Ethyl-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazocine-2-carboxamide [ka]

[0382] Step A. tert-Butyl 2-(ethylcarbamoyl)-6,7,8,9-tetrahydropyrazolo[1,5-a][1,4]diazocine-5(4H)-carboxylate: To a solution of 5-tert-butoxycarbonyl-6,7,8,9-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazocine-2-carboxylic acid (100 mg, 1.0 equiv) and ethanamine (15.3 mg, 1.0 equiv) in DMF (3.0 mL) was added HATU (3.0 mg, 3.0 equiv) and DIEA (438 mg, 10 equiv). The mixture was stirred at 40° C. for 12 hours. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide a residue. The residue was purified by prep-TLC (SiO 2 , petroleum ether / ethyl acetate=0:1) to give the title compound (20 mg, 18% yield) as a colorless oil; LCMS (ESI, M+1): m / z=323.2.

[0383] Step B N-Ethyl-4,5,6,7,8,9-hexahydropyrazolo[1,5-a][1,4]diazocine-2-carboxamide: A solution of tert-butyl 2-(ethylcarbamoyl)-6,7,8,9-tetrahydropyrazolo[1,5-a][1,4]diazocine-5(4H)-carboxylate (20 mg, 1.0 equiv) in MeCN (1.0 mL) and HCl / dioxane (4 M, 1.0 mL) was stirred for 1 hour at 25° C. The reaction was concentrated to give the title compound (50 mg, crude), LCMS (ESI, M+1): m / z = 223.2.

[0384] The last two steps were carried out according to Example 248. The title compound was obtained as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ = 9.71 (br s, 1H), 8.08 (t, J = 6.0 Hz, 1H), 7.59 (dd, J = 6.0, 8.8 Hz, 1H), 7.24 (t, J = 9.2 Hz, 1H), 6.98 (s, 2H), 6.52 (s, 1H), 5.32-5.13 (m, 1H), 4.97 -4.82(m,2H),4.55-4.35(m,2H),3.94-3.76(m,3H),3.68-3.58(m,3H),3.44-3.37(m,1H),3.31-3.17(m,4H),3.10-2.95(m,4H),2.82- 2.74(m,1H),2.61-2.55(m,2H),2.32(s,1H),2.06-1.67(m,9H),1.56-1.41(m,1H),1.06(q,J=6.8Hz,6H);LCMS(ESI,M+1):m / z=701.3.

[0385] Example 302 [ka] 3-Azabicyclo[3.2.1]octan-3-yl(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone [ka] Synthesized according to Example 233, except using HCl instead of TFA in the final step. The title compound was obtained as an off-white solid (FA salt). 1H NMR (400MHz, methanol-d4) δ=7.53(dd,J=5.6,9.2Hz,1H),7.16(t,J=9.6Hz,1H), 6.99(s,2H),6.66-6.51(m,1H),5.49-5.25(m,1H),5.11-4.95(m,1H),4.90(br s,1H),4.86-4.83(m,1H),4.62-4.52(m,2H),4.42(br t,J=13.6Hz,1H),4.36-4.13(m,4H),4.07(br dd,J=5.2,17.2Hz,2H),3.68(br d,J=17.6Hz,1H),3.61-3.53(m,1H),3.41(br d,J=4.0Hz,4H),3.31-3.19(m,3H),3.18-3.09(m,1H),2.88(br d,J=12.4Hz,1H),2.82-2.71(m,1H),2.44-2.15(m,6H),2.13-1.87(m,4H),1.79-1.50(m,6H),1.13(br dd,J=2.4,4.4Hz,3H).LCMS(ESI,M+1):m / z=753.7.

[0386] Example 303 [ka] ((3S,5R)-3,5-Dimethylpiperazin-1-yl)(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone [ka] This was synthesized according to Example 233, except that HCl was used instead of TFA in the final step. The title compound was obtained as a white solid. 1H NMR (400MHz, dimethylsulfoxide-d6) δ = 9.68 (s, 1H), 7.66-7.52 (m, 1H), 7.24 (t, J = 9.6 Hz, 1H), 6.99 (s, 2H), 6.48 (s, 1H), 5.34-5.12 (m, 1H), 5.00 (br d, J = 15.2 Hz, 1H), 4.74 (br d, J = 17.2 Hz, 1H), 4.62-4.43 (m, 3H), 4.41-4.29 (m, 1H), 4.24-4.06 (m, 1H), 3.95-3.76 (m, 4H), 3.60 (br d,J=16.8Hz,1H),3.51-3.39(m,1H),3.31-3.24(m,4H),3.22-3.13(m,1H),3.12-3.01(m,3H),2.97(br s,1H),2.85-2.74(m,1H),2.64-2.59(m,2H),2.27-2.10(m,3H),2.08-2.03(m,1H),2.00-1.90(m,3H),1.83-1.68(m,3H),1.06(br t,J=6.8Hz,3H),0.99(br d,J=2.8Hz,3H),0.92(br s,3H);19F NMR (376 MHz, dimethyl sulfoxide-d6) δ = -121.318, -171.999; LCMS (ESI, M+1): m / z = 756.2.

[0387] Example 304 [ka] 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azepine-2-carboxamide [ka]

[0388] Step A. 5-Benzyl 2-ethyl 7,8-dihydro-4H-thiazolo[5,4-c]azepine-2,5(6H)-dicarboxylate: To a solution of benzyl 3-bromo-4-oxoazepane-1-carboxylate (1.50 g, 1.0 equiv) in EtOH (15 mL) was added ethyl 2-amino-2-thioxoacetate (1.22 g, 2.0 equiv). The reaction was stirred at 80 °C for 24 hours. The mixture was filtered and purified by prep-HPLC (column: UniSil 10-120 C18 50 × 250 mm; mobile phase: [water (FA)-ACN]; B%: 35%-65%, 22 min) to give the title compound (300 mg, 34% yield) as a yellow oil; LCMS (ESI, M+1): m / z = 361.2.

[0389] Step B. 5-((Benzyloxy)carbonyl)-5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azepine-2-carboxylic acid: To a solution of O5-benzyl O2-ethyl 4,6,7,8-tetrahydrothiazolo[5,4-c]azepine-2,5-dicarboxylate (620 mg, 1.0 equiv) in THF (5 mL) and HO (1.5 mL) was added NaOH (688 mg, 10 equiv). The reaction was stirred at 20 °C for 0.5 h. Upon completion, the pH of the residue was adjusted to 4 with HCl (2 M). The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with saturated aqueous NaCl (2 × 15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound (540 mg, 94% yield) as a yellow oil.

[0390] Step C. Benzyl 2-(chlorocarbonyl)-7,8-dihydro-4H-thiazolo[5,4-c]azepine-5(6H)-carboxylate: To a solution of 5-benzyloxycarbonyl-4,6,7,8-tetrahydrothiazolo[5,4-c]azepine-2-carboxylic acid (500 mg, 1.0 equiv) in DCM (1 mL) and DMF (0.1 mL) was added oxalyl dichloride (382 mg, 2.0 equiv) in DCM (1 mL). The reaction was stirred at 25° C. for 5 minutes. The reaction was concentrated to give the title compound (520 mg, 98% yield) as a yellow oil.

[0391] Step D. Benzyl 2-(dimethylcarbamoyl)-7,8-dihydro-4H-thiazolo[5,4-c]azepine-5(6H)-carboxylate: To a solution of benzyl 2-(chlorocarbonyl)-7,8-dihydro-4H-thiazolo[5,4-c]azepine-5(6H)-carboxylate (560 mg, 1.0 equiv) in DCM (5 mL) was added dimethylamine (2 M, 1.60 mL, 2.0 equiv). The reaction was stirred at 20 °C for 10 minutes. The reaction was concentrated and purified by reverse-phase HPLC (0.1% FA condition) to give the title compound (210 mg, 37% yield) as a yellow oil; LCMS (ESI, M+1): m / z = 360.6.

[0392] Step E-N, N-dimethyl-5,6,7,8-tetrahydro-4H-thiazolo[5,4-c]azepine-2-carboxamide: To a solution of benzyl 2-(dimethylcarbamoyl)-7,8-dihydro-4H-thiazolo[5,4-c]azepine-5(6H)-carboxylate (30.0 mg, 1.0 equiv) in DCM (0.5 mL) was added TMSI (735 mg, 44 equiv) at 0° C. The reaction was stirred at 20° C. for 1 hour. The mixture was diluted with water (5 mL) and washed with DCM (2×5 mL). The aqueous solution was lyophilized to afford the title compound (55.0 mg, crude) as a yellow solid.

[0393] The last two steps were carried out according to Example 248. The title compound was obtained as an orange solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 7.51 (dd, J = 5.6, 8.8 Hz, 1H), 7.14 (t, J = 9.2 Hz, 1H), 6.97 (d, J = 3.2 Hz, 2H), 5.45-5.21 (m, 1H), 5.10 (br dd, J = 11.2, 16.0 Hz, 1H), 4.82-4.75 (m, 1H), 4.67-4.47 (m, 1H), 4.26-4.10 (m, 3H), 4.09-4.00 (m, 2H), 3.65 (br d, J = 17.6 Hz, 1H), 3.59-3.47 (m, 4H), 3.38 (br d,J=5.8Hz,2H),3.29-3.14(m,5H),3.13-2.99(m,5H),2.75(br d,J=14.0Hz,1H),2.32-2.09(m,4H),2.07-1.85(m,4H),1.11(t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=704.3.

[0394] Example 305 [ka] N-((5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methyl)methanesulfonamide [ka]

[0395] Step A. tert-Butyl 2-(methylsulfonamidomethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a mixture of tert-butyl 2-(aminomethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (100 mg, 1.0 equiv) and TEA (114 mg, 3.0 equiv) in DCM (1 mL) was added methanesulfonyl chloride (0.370 g, 8.6 equiv) at 0 °C. The reaction was stirred at 20 °C for 1 h. The mixture was quenched with ice water (10 mL) and extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated and purified by reverse-phase flash chromatography [water (FA 0.1%) / acetonitrile] to give the title compound (80 mg, 62% yield) as a yellow solid; LCMS (ESI, M+1): m / z=344.9.

[0396] Step B N-((5,6,7,8-Tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methyl)methanesulfonamide: To a mixture of tert-butyl 2-(methylsulfonamidomethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (118 mg, 1.0 equiv) in MeCN (1 mL) was added HCl·dioxane (4 M, 5.8 mL, 67 equiv). The reaction was stirred at 25 °C for 1 h. The mixture was concentrated to give the title compound (80.6 mg, crude) as a yellow solid, which was used in the next step without further purification.

[0397] The last two steps were carried out according to Example 248. The title compound was obtained as an off-white solid. 1H NMR (400MHz, methanol-d4) δ = 7.49 (br d, J = 1.2 Hz, 1H), 7.16-7.08 (m, 1H), 6.94 (s, 2H), 6.28 (d, J = 2.8 Hz, 1H), 5.38-5.12 (m, 1H), 4.94-4.87 (m, 2H), 4.51-4.38 (m, 2H), 4.17 (s, 2H), 4.13-3.98 (m, 5H), 3.72 (br d,J=2.0Hz,1H),3.54-3.45(m,1H),3.44-3.34(m,2H),3.25-3.09(m,5H),2.98(dt,J=5.6,9.2Hz,1H),2.83(d,J=1.2Hz,3H),2.7 5-2.65(m,1H),2.30-2.11(m,3H),2.11-1.91(m,4H),1.89-1.78(m,1H),1.12(dt,J=2.0,7.2Hz,3H),LCMS(ESI,M+1):m / z=723.3.

[0398] Example 306 [ka] 3-Oxa-6-azabicyclo[3.2.1]octan-6-yl(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone [ka] The synthesis was carried out according to Example 233, except that HCl was used instead of TFA in the final step. The title compound was obtained as a yellow solid. 1H NMR (400MHz, methanol-d4) δ = 7.51 (dd, J = 6.0, 8.8 Hz, 1H), 7.14 (t, J = 9.2 Hz, 1H), 6.97 (s, 2H), 6.78-6.70 (m, 1H), 5.46-5.27 (m, 1H), 4.96 (br d, J = 18.8 Hz, 2H), 4.62-4.39 (m, 3H), 4.32-3.89 (m, 7H), 3.81-3.62 (m, 4H), 3.55 (br t, J = 11.6 Hz, 2H), 3.49-3.33 (m, 5H), 3.28-3.09 (m, 3H), 2.73 (br d,J=14.4Hz,1H),2.46-2.17(m,5H),2.14-1.88(m,6H),1.11(q,J=6.8Hz,3H);LCMS(ESI,M+1):m / z=755.9.

[0399] Example 307 [ka] 2-Azabicyclo[2.2.1]heptan-2-yl(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone [ka] Prepared according to Example 233, except using HCl instead of TFA in the final step. The title compound was obtained as an orange solid (FA salt). 1H NMR (400MHz, methanol-d4) δ=7.53(dd,J=5.6,8.8Hz,1H),7.16(t,J=9.2Hz,1H),6.99(s,2H),6.68(br dd,J=3.2,6.0Hz,1H),5.48-5.24(m,1H),5.21-4.86(m,2H),4.74-4.67(m,1H),4.60-4.49(m,2H),4.29-3.97( m,5H),3.87-3.61(m,2H),3.59-3.46(m,2H),3.45-3.36(m,3H),3.25-2.95(m,5H),2.83-2.70(m,1H),2.66(br s,1H),2.47-2.14(m,4H),2.12-1.88(m,4H),1.85-1.62(m,4H),1.59-1.44(m,2H),1.13(br d,J=7.2Hz,3H).LCMS(ESI,M+1):m / z=739.5.

[0400] Example 308 [ka] 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [ka] Prepared according to Example 233, except using HCl instead of TFA in the final step. The title compound was obtained as a white solid (FA salt). 1H NMR (400MHz, methanol-d4) δ=7.53(dd,J=5.6,8.8Hz,1H),7.16(t,J=9.6Hz,1H),6.93(s,2H),6.74(s,1H),5.49-5.27(m,1H),5.04-4.94(m,1H),4.84(br s,1H),4.64-4.47(m,2H),4.29-3.99(m,5H),3.68(br d,J=17.6Hz,1H),3.56(br d,J=9.2Hz,1H),3.49(br s,5H),3.29-3.09(m,3H),2.76(br d,J=14.0Hz,1H),2.48-2.18(m,4H),2.15-1.90(m,4H),1.13(t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=659.5.

[0401] Example 309 [ka] 1-((5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methyl)-1,3-dimethylurea [ka]

[0402] Step A. tert-Butyl 2-(methylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of 5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (20.0 g, 1.0 equiv) in DMF (20 mL) was added HATU (5.41 g, 2.0 equiv), methanamine (960 mg, 2.0 equiv, HCl), and N,N-diethylpropan-2-amine (2.76 g, 3.0 equiv). The reaction was stirred at 20° C. for 2 hours. The mixture was filtered and purified by reverse-phase HPLC (0.1% FA condition) to give the title compound (1.28 mg, 59% yield) as a white solid; LCMS (ESI, M+1): m / z=295.1.

[0403] Step B. tert-Butyl 2-((methylamino)methyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of tert-butyl 2-(methylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (1.00 g, 1.0 equiv) in THF (10 mL) was added BH MeS (10 M, 3.4 mL, 10 equiv) at 0 °C. The reaction was stirred at 80 °C for 2 h. The mixture was quenched with HCl (2 M) and stirred at 40 °C for 0.5 h. The mixture was concentrated and purified by reverse-phase HPLC (0.1% FA condition) to give the title compound (270 mg, 25% yield) as a white solid; LCMS (ESI, M+1): m / z=281.1.

[0404] Step C. tert-Butyl 2-((1,3-dimethylureido)methyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of tert-butyl 2-((methylamino)methyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (60.0 mg, 1.0 equiv) in DCM (0.5 mL) was added TEA (65.0 mg, 3.0 equiv) and methylcarbamic acid chloride (40.0 mg, 2.0 equiv). The reaction was stirred at 20° C. for 10 min. The mixture was concentrated and purified by reverse-phase HPLC (0.1% FA condition) to give the title compound (50.0 mg, 65% yield) as a white solid; LCMS (ESI, M+1): m / z=338.0.

[0405] Step D. 1,3-Dimethyl-1-((5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methyl)urea: A solution of tert-butyl 2-((1,3-dimethylureido)methyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (40.0 mg, 1.0 equiv) in HCl·dioxane (4 M, 1.00 mL, 67 equiv) was stirred at 20° C. for 0.5 h. The reaction was concentrated to give the title compound (35.0 mg, crude, HCl) as a white solid.

[0406] The last two steps were carried out according to Example 248. The title compound was obtained as a white solid (FA salt); 1H NMR (400 MHz, methanol-d4) δ = 7.51 (dd, J = 5.6, 8.8 Hz, 1H), 7.19-7.11 (m, 1H), 6.98-6.93 (m, 2H), 6.11 (s, 1H), 5.39-5.20 (m, 1H), 5.02-4.92 (m, 1H), 4.73 (br d,J=4.8Hz,1H),4.48-4.39(m,3H),4.37-4.29(m,1H),4.20-4.12(m,2H),4.11-4.04(m, 2H),4.01-3.90(m,1H),3.73-3.65(m,1H),3.54-3.46(m,1H),3.43-3.36(m,2H),3.24(br s,2H),3.18(br d,J=8.4Hz,2H),3.05(td,J=4.4,9.6Hz,1H),2.84-2.73(m,6H),2.71(br d,J=11.6Hz,1H),2.32-2.23(m,2H),2.23-2.17(m,1H),2.14-1.94(m,5H),1.92-1.84(m,1H),1.15-1.09(m,3H);LCMS(ESI,M+1):m / z=716.6.

[0407] Example 310 [ka] (3,3-Dimethylpiperazin-1-yl)(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone [ka] This was synthesized according to Example 233, except that HCl was used instead of TFA in the final step. The title compound was obtained as an orange solid. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ = 9.69 (s, 1H), 7.69-7.53 (m, 1H), 7.24 (t, J = 9.2 Hz, 1H), 6.99 (s, 2H), 6.61-6.32 (m, 1H), 5.33-5.11 (m, 1H), 5.09-4.91 (m, 1H), 4.74 (br d, J = 16.4 Hz, 1H), 4.60-4.38 (m, 2H), 4.16 (br d, J = 2.4 Hz, 1H), 3.94-3.73 (m, 5H), 3.65-3.51 (m, 2H), 3.44 (br d,J=12.0Hz,2H),3.28-3.14(m,3H),3.13-3.02(m,3H),2.97(br s,1H),2.86-2.77(m,1H),2.73(br t,J=4.8Hz,2H),2.63(br 19F NMR (376 MHz, dimethyl sulfoxide-d6) δ = -121.333, -171.977; LCMS (ESI, M+1): m / z = 756.7.

[0408] Example 311 [ka] 6-Oxa-3-azabicyclo[3.2.1]octan-3-yl(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone [ka] The synthesis was carried out according to Example 233, except that HCl was used instead of TFA in the final step. The title compound was obtained as a white solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 7.53 (dd, J = 5.6, 8.8 Hz, 1H), 7.16 (t, J = 9.2 Hz, 1H), 6.99 (s, 2H), 6.64-6.57 (m, 1H), 5.44-5.22 (m, 1H), 5.11-4.90 (m, 2H), 4.68-4.31 (m, 4H), 4.24-3.78 (m, 7H), 3.69 (br d, J = 17.6 Hz, 2H), 3.56 (br d,J=9.2Hz,1H),3.48-3.34(m,6H),3.30-2.86(m,5H),2.67-2.50(m,1H),2.41- 2.22(m,4H),2.21-1.91(m,6H),1.19-1.06(m,3H);LCMS(ESI,M+1):m / z=755.6.

[0409] Example 312 [ka] 4-(4-(2-amino-3-fluoro-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-ethyl-6-fluoronaphthalen-2-ol [ka]

[0410] Step A. tert-Butyl 2-((tert-butoxycarbonyl)amino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (1.00 g, 1.0 equiv) was dissolved in (Boc)O (10 mL) and the mixture was stirred at 60° C. for 2 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (2×8 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give the title compound (2.20 g, 93% yield) as a white solid; LCMS (ESI, M+1, M-55): m / z = 353.2, 297.2.

[0411] Step B. tert-Butyl 2-((tert-butoxycarbonyl)(methoxymethyl)amino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of tert-butyl 2-((tert-butoxycarbonyl)amino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (2.00 g, 1.0 equiv) in THF (50 mL) was added NaH (454 mg, 60% purity, 2.0 equiv) slowly in portions at 0° C. The mixture was stirred at 0° C. for 30 minutes, and then bromo(methoxy)methane (1.06 g, 1.5 equiv) was added dropwise slowly at 0° C. The mixture was stirred at 25° C. for 30 minutes. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give the title compound (1.60 g, 67% yield) as a white solid; 1H NMR (400 MHz, chloroform-d) δ = 6.36-6.08 (m, 1H), 5.15 (s, 2H), 4.38 (br s, 2H), 4.32-4.28 (m, 2H), 3.68 (br s, 2H), 3.41 (s, 3H), 1.92 (br s, 2H), 1.51 (s, 9H), 1.43 (s, 9H). LCMS (ESI, M+1, M-55): m / z = 397.2, 341.2.

[0412] Step C. tert-Butyl 2-((tert-butoxycarbonyl)(methoxymethyl)amino)-3-fluoro-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of tert-butyl 2-((tert-butoxycarbonyl)(methoxymethyl)amino)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (1.50 g, 1.0 equiv) in acetonitrile (5 mL) was added Select F (1.34 g, 1.0 equiv). The mixture was stirred at 40° C. for 2 hours. The reaction was filtered and washed with methanol (50 mL). The filtrate was concentrated to dryness under reduced pressure. The mixture was purified by prep-HPLC (column: Phenomenex luna C18 150 x 40 mm x 15 μm; A: [water (FA)]; B: ACN, B%: 45%-75%, 10 min) and (column: Phenomenex luna C18 150 x 40 mm x 15 μm; mobile phase: [water (FA)-ACN]; B%: 45%-75%, 10 min)) to give the title compound (600 mg, 38% yield) as a white solid. LCMS (ESI, M+23): m / z = 437.2.

[0413] Step D. 3-Fluoro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine: To a solution of tert-butyl 2-((tert-butoxycarbonyl)(methoxymethyl)amino)-3-fluoro-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (500 mg, 1.0 equiv) in methanol (12.5 mL) was added HCl·MeOH (4 M, 12.5 mL). The mixture was stirred at 0° C. for 0.5 h. The reaction was concentrated to dryness under reduced pressure. The residue was dissolved in methanol (3 mL) and adjusted to pH=8 with NaHCO3. The mixture was stirred for 0.5 h with methanol (2 mL) and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was diluted with dichloromethane / methanol (10 / 1, 3 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound (140 mg, 68% yield) as a white solid.

[0414] The last two steps were carried out according to Example 248. The title compound was obtained as a white solid. 1H NMR (400MHz, methanol-d4) δ = 7.51 (dd, J = 5.6, 9.2Hz, 1H), 7.14 (t, J = 9.2Hz, 1H), 7.02-6.92 (m, 2H), 5.34 (br s, 1H), 4.80-4.60 (m, 1H), 4.24-4.16 (m, 2H), 4.12-3.96 (m, 4H), 3.66 (br d, J = 17.2Hz, 1H), 3.56-3.44 (m, 2H), 3.44-3.36 (m, 3H), 3.24-3.12 (m, 4H), 3.04-2.92 (m, 1H), 2.72 (br d,J=14.0Hz,1H),2.332-2.16(m,3H),2.12-2.04(m,2H),2.04-1.76(m,4H),1.11(t,J=7.2Hz,3H)LCMS(ESI,M+1):m / z=649.4.

[0415] Example 313 [ka] 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N,N-dimethylazepane-3-carboxamide [ka]

[0416] Step A. tert-Butyl 3-(dimethylcarbamoyl)azepane-1-carboxylate: To a solution of 1-(tert-butoxycarbonyl)azepane-3-carboxylic acid (100 mg, 1.0 equiv) in DCM (0.1 mL) was added HATU (234 mg, 1.5 equiv), N,N-diethylpropan-2-amine (159 mg, 3.0 equiv), and N-methylmethanamine (50.2 mg, 1.5 equiv). The mixture was stirred at 20 °C for 12 h. The reaction was concentrated and purified by flash silica gel chromatography [ISCO®; 4 g SepaFlash® silica flash column, 20–80% ethyl acetate / petroleum ether gradient elution @ 15 mL / min] to afford the title compound (105 mg, 95% yield) as a yellow gum. 1H NMR (400 MHz, chloroform-d) δ = 4.02-3.75 (m, 2H), 3.16-3.08 (m, 3H), 3.06-2.96 (m, 2H), 2.95-2.90 (m, 3H), 1.95-1.79 (m, 2H), 1.78-1.57 (m, 3H), 1.47 (d, J = 2.0 Hz, 9H), 1.44-1.32 (m, 1H).

[0417] Step B N,N-Dimethylazepane-3-carboxamide: To a solution of tert-butyl 3-(dimethylcarbamoyl)azepane-1-carboxylate (100 mg, 1.0 equiv) in dioxane (0.5 mL) was added HCl / dioxane (0.5 mL, 4.0 M, 5.4 equiv). The mixture was stirred at 20° C. for 12 hours. The reaction was concentrated to give the title compound (60 mg, crude) as a yellow gum. 1H NMR (400 MHz, methanol-d4) δ = 3.47-3.32 (m, 3H), 3.30-3.23 (m, 1H), 3.19-3.13 (m, 1H), 3.11 (s, 3H), 2.95 (s, 3H), 2.18-2.06 (m, 1H), 2.05-1.93 (m, 1H), 1.93-1.81 (m, 2H), 1.80-1.65 (m, 2H).

[0418] The last two steps were carried out according to Example 248. The title compound was obtained as a yellow solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 8.50 (br s, 1H), 7.56-7.44 (m, 1H), 7.35 (br d, J = 8.0Hz, 1H), 7.28-7.22 (m, 1H), 7.14 (t, J = 9.2Hz, 1H), 7.03-6.91 (m, 2H), 5.51-5.27 (m, 1H), 4.45-3.97 (m, 5H), 3.78-3.59 (m, 2H), 3.57-3.43 (m, 5H), 3.42-3.33 (m, 2H), 3.23 (br d,J=3.2Hz,1H),3.19(s,3H),3.16-3.07(m,2H),2.96(s,3H),2.81-2.69(m,1H),2.49-2.25(m,2H),2.23-2.06(m ,3H),2.02-1.83(m,4H),1.83-1.62(m,2H),1.60-1.22(m,2H),1.09(q,J=6.4Hz,3H);LCMS(ESI,M+1):m / z=649.4.

[0419] Example 314 [ka] 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N-methylazepane-3-carboxamide [ka]

[0420] Step A. tert-Butyl 3-(methylcarbamoyl)azepane-1-carboxylate: To a solution of 1-(tert-butoxycarbonyl)azepane-3-carboxylic acid (100 mg, 1.0 equiv) in DCM (1.0 mL) was added HATU (234 mg, 1.5 equiv), N,N-diethylpropan-2-amine (159 mg, 3.0 equiv), and methanamine (36.1 mg, 1.3 equiv). The mixture was stirred at 20 °C for 12 h. The reaction was concentrated and purified by flash silica gel chromatography [ISCO®; 4 g SepaFlash® silica flash column, eluent: 0 to 100% ethyl acetate / petroleum ether; gradient: 15 mL / min] to afford the title compound (100 mg, 76% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ = 7.07 (br d, J = 3.6 Hz, 1H), 3.64-3.45 (m, 2H), 3.25 (ddd, J = 5.2, 9.2, 14.0 Hz, 1H), 2.78 (br s, 3H), 2.67-2.55 (m, 1H), 1.98-1.80 (m, 2H), 1.79-1.54 (m, 3H), 1.47 (s, 9H), 1.42-1.34 (m, 1H).

[0421] Step B N-Methylazepane-3-carboxamide: To a solution of tert-butyl 3-(methylcarbamoyl)azepane-1-carboxylate (100 mg, 1.0 equiv) in dioxane (0.5 mL) was added HCl / dioxane (0.5 mL, 4.0 M, 5.4 equiv). The mixture was stirred at 20° C. for 12 hours. The reaction was concentrated to give the title compound (60 mg, crude) as a yellow gum. 1H NMR (400 MHz, methanol-d4) δ = 3.46-3.38 (m, 1H), 3.28 (br d, J = 4.4 Hz, 1H), 3.15 (ddd, J = 4.0, 8.8, 13.2 Hz, 1H), 2.86 (s, 5H), 2.84-2.79 (m, 1H), 2.12-2.00 (m, 1H), 1.98-1.78 (m, 4H), 1.77-1.64 (m, 1H).

[0422] The last two steps were carried out according to Example 248. The title compound was obtained as a yellow solid. 1H NMR (400MHz, methanol-d4) δ = 8.53 (s, 1H), 7.60-7.40 (m, 1H), 7.14 (t, J = 9.2Hz, 1H), 7.06-6.87 (m, 2H), 5.42-5.25 (m, 1H), 4.68-4.62 (m, 1H), 4.45-4.24 (m, 1H), 4.24-3.89 (m, 4H), 3.78-3.64 (m, 1H), 3.64-3.57 (m, 3H), 3.56- 3.35(m,5H),3.28-2.92(m,4H),2.76-2.73(m,3H),2.44-2.17(m,2H),2.15-1.99(m,3H),1.99-1.84(m,4H),1. 73(q,J=12.0Hz,2H),1.55-1.33(m,1H),1.18(t,J=7.2Hz,3H),1.14-1.05(m,3H);LCMS(ESI,M+1):m / z=635.4.

[0423] Example 315 [ka] 1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)azepane-3-carboxamide [ka]

[0424] Step A. tert-Butyl 3-carbamoylazepane-1-carboxylate: To a solution of 1-(tert-butoxycarbonyl)azepane-3-carboxylic acid (100 mg, 1.0 equiv) in DCM (1.0 mL) was added HATU (234 mg, 1.5 equiv), N,N-diethylpropan-2-amine (159 mg, 3.0 equiv), and NH4Cl (28.6 mg, 1.3 equiv). The mixture was stirred at 20°C for 12 hours. The reaction was concentrated to give the title compound (90 mg, 90% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=13.80(br s,1H),8.76(dd,J=1.2,4.4Hz,1H),8.53(dd,J=1.2,8.4Hz,1H),7.31(br d,J=16.0Hz,1H),6.76(br s,1H),3.75-3.42(m,3H),3.20-2.94(m,3H),1.79-1.60(m,3H),1.59-1.44(m,2H),1.39(s,9H).

[0425] Step B. Azepane-3-carboxamide: To a solution of tert-butyl 3-carbamoylazepane-1-carboxylate (90.0 mg, 1.0 equiv) in dioxane (0.5 mL) was added HCl / dioxane (0.5 mL, 4.0 M, 5.4 equiv). The mixture was stirred at 20° C. for 12 hours. The reaction was concentrated to give the title compound (60 mg, crude) as a yellow gum. 1H NMR (400 MHz, methanol-d4) δ = 8.50 (dd, J = 1.2, 4.4 Hz, 1H), 8.16 (dd, J = 1.2, 8.4 Hz, 1H), 7.31 (dd, J = 4.4, 8.4 Hz, 1H), 3.07-3.00 (m, 4H), 2.91 (d, J = 8.4 Hz, 2H), 2.60-2.51 (m, 4H).

[0426] The last two steps were carried out according to Example 248. The title compound was obtained as a brown solid. 1H NMR (400 MHz, methanol-d4) δ = 7.59-7.49 (m, 1H), 7.18 (t, J = 9.2 Hz, 1H), 7.11-6.99 (m, 2H), 5.69-5.47 (m, 1H), 4.72-4.60 (m, 1H), 4.52-4.38 (m, 1H), 4.33-4.09 (m, 2H), 4.06-3.82 (m, 5H), 3.80 (br s,1H),3.59-3.33(m,5H),3.29-2.73(m,4H),2.72-2.50(m,2H),2.48-2.17(m,4H),2 .10-1.93(m,4H),1.81-1.44(m,2H),1.23-1.08(m,3H);LCMS(ESI,M+1):m / z=621.4.

[0427] Example 316 [ka] 4-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N,N-dimethylbutanamide [ka]

[0428] Step A. (E)-4-(5-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)but-3-enoic acid: To a mixture of tert-butyl 2-formyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (500 mg, 1.0 equiv) and 2-carboxyethyl(triphenyl)phosphonium bromide (860 mg, 1.1 equiv) in THF (12 mL) was added t-BuOK (3.77 mL, 1.0 M, 2.0 equiv) at 0° C. over 1 h. The mixture was degassed and purged with N three times, then stirred under a N atmosphere at 20° C. for 16 h. The reaction mixture was concentrated and purified by prep-HPLC [column: Phenomenex luna C18 150 × 40 mm × 15 μm; mobile phase: [water (FA)-ACN]; B%: 23%-53%, 10 min] to give the title compound (100 mg, 17% yield) as a white solid. LCMS (ESI, M+1): m / z = 322.2.

[0429] Step B. 4-(5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)butanoic acid: To a solution of (£)-4-(5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)but-3-enoic acid (100 mg, 1.0 equiv) in EtOH (4.0 mL) was added Pd / C (30 mg) under N atmosphere. The mixture was degassed and purged with H three times. The mixture was stirred under H (15 Psi) at 20 °C for 1 h. The reaction was filtered and concentrated to give the title compound (100 mg, crude) as a yellow oil. LCMS (ESI, M+1): m / z = 324.1

[0430] Step C. tert-Butyl 2-(4-(dimethylamino)-4-oxobutyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of 4-(5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)butanoic acid (100 mg, 1.0 equiv) in THF (2.0 mL) was added HATU (176 mg, 1.5 equiv), N,N-diethylpropan-2-amine (120 mg, 3.0 equiv), and (CH)NH (309 μL, 2.0 M, 2.0 equiv). The mixture was stirred at 20 °C for 1 h. The reaction was diluted with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated to give the title compound (100 mg, crude) as a yellow oil. LCMS (ESI, M+1): m / z = 351.2.

[0431] Step DN, N-Dimethyl-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)butanamide: To a solution of tert-butyl 2-(4-(dimethylamino)-4-oxobutyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (100 mg, 1.0 equiv) was added HCl / MeOH (2.0 mL, 4.0 M). The mixture was stirred at 20 °C for 1 h. The reaction was concentrated and purified by prep-HPLC [Column: Waters Xbridge 150 × 25 mm × 5 μm; Mobile phase: [water (NH4HCO3)-ACN]; B%: 1%-30%, 10 min] to give the title compound (50.0 mg, 70% yield) as a white solid. LCMS (ESI, M+1): m / z = 251.2.

[0432] The last two steps were carried out according to Example 248. The title compound was obtained as a white solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 8.64-8.42 (m, 1H), 7.51 (dd, J = 5.8, 9.2 Hz, 1H), 7.15 (t, J = 9.2 Hz, 1H), 6.98-6.91 (m, 2H), 6.07 (s, 1H), 5.44-5.25 (m, 1H), 4.80-4.72 (m, 2H), 4.41 (br d, J = 4.4 Hz, 2H), 4.26-4.13 (m, 3H), 4.08 (br d, J = 17.6 Hz, 1H), 4.00-3.89 (m, 1H), 3.70 (br d,J=17.6Hz,1H),3.55-3.48(m,1H),3.47-3.33(m,5H),3.18(br d,J=8.8Hz,2H),2.99(d,J=1.6Hz,3H),2.90(s,3H),2.72(br s,1H),2.62-2.55(m,2H),2.45-2.05(m,9H),1.95-1.84(m,3H),1.11(br t,J=6.8Hz,3H);LCMS(ESI,M+1):m / z=729.5.

[0433] Example 317 [ka] 2-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N,N-dimethylacetamide [ka]

[0434] Step A. tert-Butyl 2-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a mixture of 5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (8.5 g, 1.0 equiv) in THF (150 mL) was added BH.THF (121 mL, 1.0 M, 4.0 equiv) under N at 0° C. The mixture was stirred at 60° C. under N for 12 hours. The reaction was quenched with MeOH (200 mL) at 0 °C, concentrated, and purified by prep-HPLC [Column: 120 g flash column WelchUltimate XB_C18 20-40 μm; 120A; Mobile phase: MeCN / HO; Flow rate: 85 mL / min; Gradient B%: 5-40%, 20 min; 40% 5 min] to give the title compound (5.7 g, 71% yield) as a colorless oil. 1H NMR(400MHz,DMSO-d6)δ=8.13(s,1H),6.06(s,1H),4.92(br s,1H),4.50-4.23(m,6H),3.62(br s,2H),1.71(br s,2H),1.34(br s,9H);LCMS(ESI,M+1):m / z=268.2.

[0435] Step B. tert-Butyl 2-(chloromethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: A mixture of tert-butyl 2-(hydroxymethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (2.50 g, 1.0 equiv), MsCl (4.05 g, 3.8 equiv), and TEA (2.84 g, 3.0 equiv) in DCM (30 mL) was degassed and purged with N three times at 0 °C. The mixture was stirred under a N atmosphere at 20 °C for 3 h. The reaction was quenched at 0 °C with NaHCO solution (50 mL) and then extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated to give the title compound (2.80 g, crude) as a yellow oil. LCMS (ESI, M+1): m / z = 286.1.

[0436] Step C. tert-Butyl 2-(cyanomethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of tert-butyl 2-(chloromethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (2.80 g, 1.0 equiv) in DMF (30 mL) was added NaCN (1.55 g, 3.2 equiv). The mixture was stirred at 60° C. for 3 hours. At 0° C., the reaction was diluted with water (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1] to give the title compound (1.40 g, 52% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 6.12 (s, 1H), 4.42 (s, 2H), 4.38-4.31 (m, 2H), 3.88 (s, 2H), 3.62 (br s, 2H), 1.72 (br s, 2H), 1.33 (br s, 9H); LCMS (ESI, M+1): m / z = 277.1.

[0437] Step D. 2-(5-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)acetic acid: To a solution of tert-butyl 2-(cyanomethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (700 mg, 1.0 equiv) in EtOH (15 mL) and water (3 mL) was added NaOH (203 mg, 2.0 equiv). The mixture was stirred at 90 °C for 3 h. The reaction was then diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated to afford the title compound (700 mg, 94% yield) as a yellow solid. LCMS (ESI, M+1): m / z = 296.1.

[0438] Step E. tert-Butyl 2-(2-(dimethylamino)-2-oxoethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of 2-(5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)acetic acid (200 mg, 1.0 equiv) in THF (6 mL) was added N,N-diethylpropan-2-amine (262 mg, 3.0 equiv), HATU (386 mg, 1.5 equiv), and (CH)NH (677 μL, 2 M, 2.0 equiv). The mixture was stirred at 20 °C for 2 h. The reaction was diluted with water (30 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated to give the title compound (200 mg, crude) as a yellow oil. LCMS (ESI, M+1): m / z = 323.2.

[0439] Step F N,N-Dimethyl-2-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)acetamide: To a solution of tert-butyl 2-(2-(dimethylamino)-2-oxoethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (200 mg, 1.0 equiv) in MeOH (3.0 mL) was added HCl / MeOH (3.0 mL, 4.0 M, 19 equiv). The mixture was stirred at 20° C. for 1 hour. The reaction was concentrated to give the title compound (200 mg, crude) as a yellow oil. LCMS (ESI, M+1): m / z=223.2.

[0440] The last two steps were carried out according to Example 248. The title compound was obtained as a white solid (FA salt). 1H NMR (400MHz, methanol-d4) δ = 7.52 (dd, J = 6.0, 9.2Hz, 1H), 7.15 (t, J = 9.2Hz, 1H), 6.99-6.91 (m, 2H), 6.13 (s, 1H), 5.46-5.26 (m, 1H), 4.83-4.77 (m, 2H), 4.47-4.39 (m, 2H), 4.28-4.20 (m, 1H), 4.20-4.12 (m, 2H), 4 .11-3.98(m,2H),3.75-3.63(m,3H),3.55-3.36(m,6H),3.23-3.13(m,3H),3.10(s,3H),2.95(s,3H),2 .78-2.63(m,1H),2.45-2.17(m,4H),2.14-1.94(m,4H),1.14-1.05(m,3H);LCMS(ESI,M+1):m / z=701.4.

[0441] Example 318 [ka] (3-chloro-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(4-methylpiperazin-1-yl)methanone [ka]

[0442] Step A: tert-Butyl 2-(4-methylpiperazine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of 5-tert-butoxycarbonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (1.00 g, 1.0 equiv) in DMF (10.0 mL) was added 1-methylpiperazine (356 mg, 1.0 equiv), HATU (4.05 g, 3.0 equiv), and N,N-diethylpropan-2-amine (4.59 g, 10.0 equiv). The mixture was stirred at 20° C. for 1 hour. The reaction mixture was then diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography [SiO2, dichloromethane / methanol = 10 / 1] to give the title compound (1.20 g, 90% yield, 97% purity) as a red solid. LCMS (ESI, M+1): m / z = 364.3.

[0443] Step B: tert-Butyl 3-chloro-2-(4-methylpiperazine-1-carbonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of tert-butyl 2-(4-methylpiperazine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (1.20 g, 1.0 equiv) in DMF (15.0 mL) was added NCS (553 mg, 1.3 equiv). The mixture was stirred at 20° C. for 24 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL×2). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (SiO2, dichloromethane / methanol = 20 / 1 to 10 / 1) to give the title compound (400 mg, 32% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 4.53 (s, 2H), 4.46-4.39 (m, 2H), 3.67 (br s, 2H), 3.27-2.90 (m, 4H), 2.80-2.60 (m, 4H), 2.52 (br s, 3H), 1.82 (br s, 2H), 1.36 (s, 9H). LCMS (ESI, M+1): m / z = 398.2.

[0444] Step C: (3-Chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(4-methylpiperazin-1-yl)methanone: A solution of tert-butyl 3-chloro-2-(4-methylpiperazine-1-carbonyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (400 mg, 1.0 equiv) in MeCN (4.0 mL) and HCl / dioxane (4 M, 4.00 mL, 15.9 equiv) was stirred at 20° C. for 1 hour. The reaction was concentrated to give the title compound (500 mg, crude) as a colorless oil. LCMS (ESI, M+1): m / z = 298.1.

[0445] The last two steps were carried out according to Example 248. The title compound was obtained as a yellow solid. 1H NMR (400MHz, CD3OD) δ = 7.51 (dd, J = 6.0, 8.8 Hz, 1H), 7.15 (t, J = 9.6 Hz, 1H), 7.00-6.93 (m, 2H), 5.37-5.19 (m, 1H), 5.05-4.89 (m, 2H), 4.83-4.56 (m, 2H), 4.55-4.38 (m, 2H), 4.15-3.95 (m, 5H), 3.80-3.62 (m, 5H), 3.56-3.36 (m, 4H), 3.25-3.12 (m, 4H), 3.05-2.96 (m, 1H), 2.71 (br d,J=15.2Hz,1H),2.55-2.43(m,4H),2.30-1.80(m,8H),1.40-1.25(m,1H),1.10(t,J=6.8Hz,3H);LCMS(ESI,M+1):m / z=776.3.

[0446] Example 319 [ka] 8-Bromo-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one [ka] Synthesized according to Example 248, except using TFA instead of HCl in the final step. The title compound was obtained as a white solid (TFA salt). 1H NMR (400MHz, methanol-d4)δ=7.52(dd,J=5.6,8.8Hz,1H),7.28-7.10(m,5H),7.02-6.90(m,2H),5.66-5.42(m,1H),5.12-5.02(m,2H),4.60 -4.59(m,1H),4.66(d,J=5.6Hz,3H),4.05-3.67(m,6H),3.62-3.44(m,2H),3.27-3.07(m,2H),2.89-2.07(m,8H),0.93(q,J=7.6Hz,3H);1 LCMS(ESI,M+1):m / z=721.2

[0447] Example 320 [ka] 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3-methoxy-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [ka]

[0448] Step A. 5-tert-Butyl 2-ethyl 7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate: To a solution of ethyl 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (8.40 g, 1.0 equiv, HCl) in DCM (100 mL) was added TEA (10.4 g, 3.0 equiv) and BocO (14.9 g, 2.0 equiv). The reaction was stirred at 25 °C for 1 h. The mixture was diluted with water (50 mL) and extracted with DCM (2 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give the title compound (9.90 g, 92% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 310.0.

[0449] Step B. 5-tert-Butyl 2-ethyl 3-iodo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate: To a solution of 5-tert-butyl 2-ethyl 7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate (4.00 g, 1.0 equiv) in AcOH (40 mL) was added 1-iodopyrrolidine-2,5-dione (5.82 g, 2.0 equiv). The reaction was stirred at 80 °C for 1 hour. The reaction was neutralized with saturated aqueous NaHCO (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with Na2SO3 (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase HPLC (0.1% FA condition) to give the title compound (4.70 g, 82% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 436.0.

[0450] Step C. 5-tert-Butyl 2-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate: To a solution of O5-tert-butyl O2-ethyl 3-iodo-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2,5-dicarboxylate (1.80 g, 1.0 equiv) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.29 g, 10 equiv) in MeCN (18 mL) was added bis(triphenylphosphine)palladium(II) chloride (303 mg, 0.10 equiv) and TEA (1.26 g, 3.0 equiv). The reaction was stirred for 12 hours at 40° C. The mixture was filtered and purified by reverse-phase HPLC (0.1% FA condition) to give the title compound (1.00 g, 50% yield) as a white solid; LCMS (ESI, M-137): m / z=297.8.

[0451] Step D. 5-tert-Butyl 2-ethyl 3-hydroxy-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate: To a solution of 5-tert-butyl 2-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate (970 mg, 1.0 equiv) in THF (10 mL) and HO (3 mL) was added HO (1.10 g, 30% purity, 4.3 equiv) and NaOH (178 mg, 2.0 equiv). The reaction was stirred at 20 °C for 1 h. The reaction was quenched with saturated NaSO solution (10 mL) and extracted with DCM (10 × 3 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (550 mg, 26% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 326.1.

[0452] Step E 5-tert-butyl 2-ethyl 3-methoxy-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate: To a solution of 5-tert-butyl 2-ethyl 3-hydroxy-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate (540 mg, 1.0 equiv) in DMF (5 mL) was added KCO (688 mg, 3.0 equiv) and MeI (2.36 g, 10 equiv). The reaction was stirred at 20 °C for 4 h. The reaction was quenched at 20 °C by the addition of aqueous NHCl (4 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase HPLC (0.1% FA condition) to give the title compound (260 mg, 40% yield) as a yellow solid.

[0453] Step F. 5-(tert-Butoxycarbonyl)-3-methoxy-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid: To a solution of 5-tert-butyl 2-ethyl 3-methoxy-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-2,5(6H)-dicarboxylate (100 mg, 1.0 equiv) in THF (1 mL) and HO (0.3 mL) was added NaOH (118 mg, 10 equiv). The reaction was stirred at 20 °C for 12 h. The pH of the residue was adjusted to 4 with HCl (2 M). The mixture was extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous sodium sulfate and concentrated to give the title compound (70.0 mg, 65% yield) as a yellow solid; LCMS (ESI, M-73): m / z = 237.7.

[0454] Step G. tert-Butyl 3-methoxy-2-(methylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of 5-tert-butoxycarbonyl-3-methoxy-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (60.0 mg, 1.0 equiv) and methanamine (65.0 mg, 5.0 equiv) in DCM (1 mL) was added HATU (110 mg, 1.5 equiv) and N,N-diethylpropan-2-amine (199 mg, 8.0 equiv). The reaction was stirred at 20° C. for 1 hour. The mixture was filtered and purified by reverse-phase HPLC (0.1% FA condition) to give the title compound (60.0 mg, 96% yield) as a white solid; LCMS (ESI, M+1): m / z=325.3.

[0455] Step H. 3-Methoxy-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: A mixture of tert-butyl 3-methoxy-2-(methylcarbamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (50.0 mg, 1.0 equiv) in HCl·dioxane (4 M, 1 mL, 26 equiv) was stirred for 0.5 h at 20° C. The mixture was concentrated to give the title compound (50 mg, crude, HCl) as a white solid.

[0456] The last two steps were carried out according to Example 248. The title compound was obtained as an off-white solid. 1H NMR (400 MHz, methanol-d4) δ = 7.57-7.48 (m, 1H), 7.15 (t, J = 9.6 Hz, 1H), 6.97 (s, 2H), 5.66-5.45 (m, 1H), 5.04-4.93 (m, 1H), 4.71 (br t,J=14.8Hz,1H),4.54-4.36(m,4H),4.32-4.21(m,1H),4.11-3.96(m,2H),3.9 1-3.77(m,6H),3.70(d,J=17.6Hz,1H),3.59-3.47(m,1H),3.40-3.34(m,3H),3 .28-3.12(m,2H),2.88(s,3H),2.80-2.50(m,3H),2.48-2.37(m,1H),2.36-2.1 2(m,4H),2.07-1.95(m,1H),1.10(t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=703.3.

[0457] Example 321 [ka] N-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N-methylpropane-2-sulfonamide [ka]

[0458] Step A-N-(5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N-methylpropane-2-sulfonamide: 5-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N-methylpropane-2-sulfonamide in pyridine (138 mg, 12 equiv) To a mixture of (fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (100 mg, 1.0 equiv) was added propane-2-sulfonyl chloride (62.1 mg, 3.0 equiv) in THF (141 μL). The reaction was stirred at 20 °C for 4 h. The mixture was concentrated and purified by reverse-phase flash chromatography [C18, 0.1% formic acid conditions] to give the title compound (64.0 mg, 55% yield) as a yellow solid; LCMS (ESI, M+1): m / z=795.6.

[0459] Step B N-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N-methylpropane-2-sulfonamide: N-(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N-methylpropane-2-sulfonamide in ACN (0.50 mL) To a mixture of 59.0 mg (1 equiv) of 5-(3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N-methylpropane-2-sulfonamide (3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)-N-methylpropane-2-sulfonamide was added HCl·MeOH (4 M, 1.0 mL, 54 equiv). The reaction was stirred at 20 °C for 0.5 h. The mixture was concentrated, dissolved in methanol (3.0 mL), neutralized with solid NaHCO, filtered, purified by prep-HPLC [Phenomenex Luna C18 150 × 25 mm × 10 μm; A: water (FA), B: ACN; B%: 20%-50% over 10 min], and lyophilized to give the title compound (18.0 mg, 31% yield) as an orange solid (FA salt).1H NMR (400MHz, dimethyl sulfoxide-d6) δ=9.83-9.60(m,1H),7.59(dd,J=6.0,8.8Hz,1H ),7.24(t,J=9.6Hz,1H),6.99(s,2H),6.15(s,1H),5.38-5.09(m,1H),4.91(br d,J=16.4Hz,1H),4.69(br d,J=16.0Hz,1H),4.47-4.26(m,2H),4.16-4.01(m,1H),3.97-3.75(m,4H),3.59(br d,J=17.6Hz,1H),3.54-3.46(m,1H),3.41(br d,J=7.6Hz,2H),3.22(s,3H),3.18-3.03(m,4H),3.02-2.95(m,1H),2.86-2.75(m,1H),2.64(br d,J=13.6Hz,1H),2.16(br s,1H),2.11-1.84(m,5H),1.83-1.65(m,3H),1.20-1.14(m,6H),1.07(br t,J=7.2Hz,3H);19F NMR (376MHz, dimethyl sulfoxide-d6) δ=-121.393,-172.014; LCMS (ESI, M+1): m / z=751.5.

[0460] Example 322 [ka] 2-Oxa-6-azabicyclo[3.2.1]octan-6-yl(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone [ka] Synthesized according to Example 233, except that HCl was used instead of TFA in the final step. The title compound was obtained as a white solid (31.7 mg, 21% yield); 1H NMR (400 MHz, methanol-d4) δ = 7.51 (dd, J = 6.0, 8.8 Hz, 1H), 7.20-7.09 (m, 1H), 7.01-6.88 (m, 2H), 6.78-6.68 (m, 1H), 5.34-5.01 (m, 2H), 5.00-4.87 (m, 1H), 4.64-4.44 (m, 4H), 4.33-3.90(m, 6H), 3.86-3.62(m, 4H), 3.58-3.50(m, 1H), 3.44-3.38(m, 1H), 3 .24-3.11(m, 6H), 3.02-2.89(m, 1H), 2.79-2.65(m, 1H), 2.42-2.03(m, 5H), 1.99(br s, 7H), 1.20-0.99(m, 3H); LCMS(ESI,M+1): m / z=755.7.

[0461] Example 323 [ka] (2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone [ka] Synthesized according to Example 233. The title compound was obtained as a yellow solid. 15(t,J=12.0Hz,1H),7.03-6.93(m,2H),6.73(d,J=8.0Hz,1H),5.35-5.20(m,1H),5.10-4.95(m,1H),4.69(br d,J=4.0Hz,1H),4.60-4.50(m,2H),4.33-4.17(m,1H),4.16-3.97(m,5H),3.95-3.86(m,3H),3.73 -3.64(m,1H),3.61-3.52(m,2H),3.45-3.38(m,2H),3.27-3.11(m,5H),3.03-2.94(m,1H),2.74(br d,J=16.0Hz,1H),2.44-2.02(m,6H),2.01-1.83(m,5H),1.19-1.06(m,3H);LCMS(ESI,M+1):m / z=741.6.

[0462] Example 324 [ka] 7-(8-Ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2-((methylsulfamoyl)amino)methyl-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine [ka]

[0463] Step A. tert-Butyl 2-(((N-methylsulfamoyl)amino)methyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a solution of tert-butyl 2-(aminomethyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (140 mg, 1.0 equiv) and methylsulfamoyl chloride (102 mg, 1.5 equiv) in DCM (2.0 mL) was added TEA (159 mg, 3.0 equiv). The reaction was stirred at 20° C. for 1 h. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×6 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase HPLC (0.1% FA condition) to give the title compound (115 mg, 60% yield) as a white oil; LCMS (ESI, M+1): m / z=360.0.

[0464] Step B. 2-[(Methylsulfamoylamino)methyl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine: To a solution of tert-butyl 2-(((N-methylsulfamoyl)amino)methyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (95.0 mg, 1.0 equiv) in MeCN (1.0 mL) was added HCl / dioxane (4 M, 1.0 mL, 15 equiv). The reaction was stirred at 25° C. for 0.5 h. The mixture was concentrated in vacuo to afford the title compound (110 mg, crude) as a white solid, which was used in the next step without further purification.

[0465] The last two steps were carried out according to Example 248. The title compound was obtained as an off-white solid. 1H NMR (400MHz, methanol-d4) δ=7.51(dd,J=5.6,8.8Hz,1H),7.19-7.10(m,1H),6.96(br d,J=6.4Hz,2H),6.29(s,1H),5.37-5.19(m,1H),4.85(br d,J=7.2Hz,2H),4.47-4.37(m,2H),4.16-3.99(m,7H),3.73-3.64(m,1H),3.55 -3.47(m,1H),3.45-3.34(m,2H),3.25-3.12(m,5H),3.05-2.96(m,1H),2.72(br d,J=11.6Hz,1H),2.55(s,3H),2.32-2.13(m,3H),2.12-1.93(m,4H),1.91-1.83(m,1H),1.13(br t,J=6.8Hz,3H);LCMS(ESI,M+1):m / z=738.4.

[0466] Example 325 [ka] 3-Oxa-6-azabicyclo[3.1.1]heptan-6-yl(5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone [ka] This was synthesized according to Example 233, except that HCl was used instead of TFA in the final step. The title compound was obtained as an off-white solid. 1H NMR (400MHz, methanol-d4) δ = 7.51 (dd, J = 5.6, 8.8 Hz, 1H), 7.14 (t, J = 9.2 Hz, 1H), 7.01-6.95 (m, 2H), 6.72 (s, 1H), 5.36-5.14 (m, 1H), 5.09 (br s, 1H), 5.05-4.92 (m, 1H), 4.51 (br s, 3H), 4.28-4.14 (m, 3H), 4.11-3.97 (m, 4H), 3.91 (br dd,J=10.0,16.4Hz,2H),3.71-3.61(m,1H),3.57-3.50(m,1H),3.49-3.35(m,2H),3.24-3.12 (m,5H),3.01-2.93(m,1H),2.80-2.69(m,2H),2.38-2.04(m,5H),2.03-1.70(m,5H),1.12(br s,3H);LCMS(ESI,M+1):m / z=741.4.

[0467] Example 326 [ka] 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-sulfonamide [ka]

[0468] Step A. Benzyl 2-amino-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a mixture of 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-amine (500 mg, 1.0 equiv, HCl), TEA (1.07 g, 4.0 equiv) in THF (10 mL) was added CbzCl (452 mg, 1.0 equiv) at 0 °C. The reaction was stirred at 20 °C for 2 h. To the mixture was added aqueous NaHCO (20 mL), and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (450 mg, 56% yield) as a yellow oil; 1H NMR (400 MHz, chloroform-d) δ = 7.39-7.29 (m, 5H), 5.67-5.45 (m, 1H), 5.13-5.09 (m, 2H), 4.46-4.39 (m, 2H), 4.23-4.18 (m, 2H), 3.77-3.71 (m, 2H), 1.97-1.85 (m, 2H).

[0469] Step B. Benzyl 2-(chlorosulfonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: To a mixture of benzyl 2-amino-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (500 mg, 1.0 equiv) in ACN (40 mL) at 0 °C was added a solution of HCl (2.55 g, 37% purity, 14.8 equiv) in HO (0.9 mL), followed by an aqueous solution of NaNO (241 mg, 2.0 equiv) in HO (0.8 mL). After stirring at 0 °C for 45 min, AcOH (945 mg, 9.0 equiv), CuCl (86.4 mg, 0.5 equiv), and CuCl (141 mg, 0.6 equiv) were added to the mixture, and the reaction was purged with SO gas for 25 min at 0 °C. The reaction was stirred at 0-15 °C for 12 h. The mixture was poured into ice water (10 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (600 mg, crude) as a dark green oil.

[0470] Step C. Benzyl 2-(N,N-dimethylsulfamoyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate: A mixture of benzyl 2-(chlorosulfonyl)-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepine-5(6H)-carboxylate (200 mg, 1.0 equiv) in N-methylmethanamine (2 M in THF, 6.67 mL, 24 equiv) was stirred for 2 hours at 20° C. The mixture was concentrated, diluted with saturated aqueous NH4Cl (5 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (80 mg, 38% yield) as a yellow oil; 1H NMR (400 MHz, chloroform-d) δ = 7.41-7.29 (m, 5H), 6.67-6.44 (m, 1H), 5.14-5.08 (m, 2H), 4.61-4.56 (m, 1H), 4.56-4.48 (m, 3H), 3.86-3.79 (m, 2H), 2.83-2.77 (m, 6H), 2.05-1.94 (m, 2H); LCMS (ESI, M+1): m / z = 378.9.

[0471] Step D-N, N-Dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-sulfonamide: To a mixture of benzyl 2-(N,N-dimethylsulfamoyl...

Claims

1. Equation (I): 【Chemistry 1】 (In the formula, A is an aryl or heteroaryl, and the aryl or heteroaryl has 1 to 4 R １ It is optionally replaced by; B is, 【Chemistry 2】 Selected from, Y １ is L-hydrogen, hydroxy, halogen, L-C3-C6 cycloalkyl optionally substituted with 1 to 4 R ８ , L-S(O) ９ optionally substituted with 1 to 4 R ９ , L-N(R ２ ), L-heteroaryl optionally substituted with 1 to 4 R ５ ), L-aryl optionally substituted with 1 to 4 R ２ and is a L-heterocycle substituted with 1 to 2 oxo(=O) or oxo-containing substituents and optionally further substituted with 1 to 2 heteroaryl-R ８ or R ８ ; ８ or R ８ ; Y ２ is hydrogen or a C1-C4 alkyl group; Or, Y １ and Y ２ They came together, 【Transformation 3】 Forming, Here, X is a bond, -S-, -O-, -N < bond to the fused ring, -CH ２ -ien-CH ２ -NH-, -CH ２ -NH-CH ２ -ien-CH ２ -CH ２ -CH ２ -ien-CH ２ -CH ２ -, -O-CH ２ - and -S-CH ２ - Selected from; Each R １ These are independently halogen, cyano, hydroxy, C1-C4 alkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, -CH ２ C(=O)N(R) ５ ) ２ ,-C3-C4 alkynyl (NR ５ ) ２ , -N(R ５ ) ２ , deutero C2-C4 alkynyl, (C1-C3 alkoxy)halo C1-C3 alkyl- or C3-C6 cycloalkyl, where the C3-C6 cycloalkyl is optionally substituted with a halogen or C1-C3 alkyl; Each R ２ These are independently hydrogen, hydroxyl, halogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, -OC(O)N(R) ５ ) ２ ien-CH ２ OC(O)N(R) ５ ) ２ ien-CH ２ NR ５ -SO ２ -N(R) ５ ) ２ , -CO ２ R ５ , -CO ２ N(R) ５ ) ２ ❖ = CH ２ ¶=CHR １１ or = C(R １１ ) ２ And; Each R ３ These are independently hydrogen, hydroxyl, halogen, L-C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, -OC(O)N(R) ５ ) ２ ien-CH ２ OC(O)N(R) ５ ) ２ ien-CH ２ NR ５ -SO ２ -N(R) ５ ) ２ , -CO ２ R ５ , -CO ２ N(R) ５ ) ２ ;=CH ２ ¶=CHR １１ or = C(R １１ ) ２ And; In the formula, R ２ and R ３ At least one of them is = CH ２ ¶=CHR １１ or = C(R １１ ) ２ And; R ４ is hydrogen, halogen, or C1-C3 alkyl; Each R ５ These are independently hydrogen, cyclopropyl, or C1-C3 alkyl; Each R ６ These are independently hydrogen, hydroxyl, C1-C4 hydroxyalkyl or heteroaryl, or two R ６ These combine to form a C3-C6 cycloalkyl or heterocycle; Each R ７ is independently hydrogen, C1-C3 alkyl, hydroxy, halogen, halo-C1-C3 alkyl, di-halo-C1-C3 alkyl, tri-halo-C1-C3 alkyl, -NH ２ , -NH(C1-C3 alkyl), -N(C1-C3 alkyl) ２ , oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -O-CH ２ -C(O)NH ２ , L-C(O)NH ２ , -C(O)NH(C1-C3 alkyl), -NHC(O)(C1-C3 alkyl), -C(O)N(C1-C3 alkyl) ２ , -CN, aryl, dialkylphosphine oxide, -S(O) ２ NH(CH ３ ), sulfone or an L-heterocycle optionally substituted with 1-2 substituents selected from L-hydroxy, oxo (=O), C1-C3 alkyl and C3 cycloalkyl or an L-heteroaryl optionally substituted with 1-2 substituents selected from L-hydroxy, -NH ２ , C1-C3 alkyl, C1-C3 haloalkyl, C3 cycloalkyl, -C(O)NH(C3-C4 cycloalkyl) and -NHC(O)(C1-C3 alkyl). Two R atoms on the same atom ７ These elements are optionally combined to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocyclic rings, and the spirocyclic ring is optionally substituted with one or two substituents selected from oxo (=O), halogen, hydroxyl, C1-C3 alkyl and -O-(C1-C3 alkyl). Two Rs on adjacent atoms ７ may optionally together form a fused ring selected from a C3-C6 cycloalkyl optionally substituted with 1 to 4 Rs, a heteroaryl optionally substituted with 1 to 4 Rs, an aryl optionally substituted with 1 to 4 Rs, and a heterocycle optionally substituted with 1 to 4 Rs, or a bond ８ a C3-C6 cycloalkyl optionally substituted with 1 to 4 Rs ８ a heteroaryl optionally substituted with 1 to 4 Rs ８ an aryl optionally substituted with 1 to 4 Rs ８ a heterocycle optionally substituted with 1 to 4 Rs Two R atoms on non-neighboring atoms ７ They optionally combine to form one or two carbon bridges; Each R ８ These are independently C1-C3 alkyl, L-hydroxy, halogen, halo-C1-C3 alkyl, dihalo-C1-C3 alkyl, trihalo-C1-C3 alkyl, -N(R) ５ ) ２ , oxo(=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OR ５ , -C (OR ５ ) (Caution ５ ) ２ ,-(C1-C3 alkyl)C(O)N(R ５ ) ２ , -C(O)N(R ５ ) ２ , -C(O)N(R １０ ) ２ -CN, L-L-heteroaryl or L-heterocyclic (each being C1-C3 alkyl, C1-C3 haloalkyl, -CH2-S-CH3, -S(O) ２ NH ２ or -S(O) ２ (It is optionally substituted with C1-C3 alkyl groups); Each R ９ These are independently C1-C3 alkyl, hydroxy, halogen, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH ２ -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl) ２ , L-heteroaryl or -CN, Two R ９ They come together and bond or -S(O)(CH ３ ) ２ Forming; Each R １０ Independently, are hydrogen, C1-C3 alkyl, halogen, or R ７ Or another R １０ Together with it, it forms a complex ring; Each R １１ These are halogens independently; Each L is independently bonded; -C1-C4 alkylene-, -NR ５ - or -C(O)-; Each n is between 0 and 3; o is 1 to 6; p is 1 to 8; (q is between 0 and 1) The compound indicated by or a pharmaceutically acceptable salt thereof.

2. q is 1; A is naphthyl; B: 【Chemistry 4】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. q is 1; A is naphthyl; B 【Transformation 5】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. Y １ However, hydrogen, hydroxyl, halogen, or 1 to 4 R ８ It is an L-heteroaryl that is optionally substituted, Y ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or a C1-C4 alkyl group.

5. Y １ and Y ２ They came together, 【Transformation 6】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof that forms a compound.

6. X is -CH2-NH-, and there are two R ７ These come together to form 1 to 4 R ８ A condensed heteroaryl ring is formed by substitution with one R. ８ ga-C(O)N(R) １０ ) ２ The compound according to claim 5 or a pharmaceutically acceptable salt thereof.

7. The aforementioned condensed heteroaryl ring is pyrazolyl, and one R ８ ga-C(O)N(R) １０ ) ２ And one R ８ The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein is a halogen or a C1-C3 alkyl group.

8. X is a bond, and two R ７ The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the compounds combine to form a condensed heterocyclyl ring which is optionally substituted with one or two oxos.

9. X is -CH2-, and there are two R ７ The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the compounds together form a spirocyclic heterocyclyl ring substituted with one or two oxos.

10. at least one R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a C1-C4 alkyl group.

11. at least one R １ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the halogen is...

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein the halogen is fluorine.

13. at least one R １ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is hydroxyl.

14. One R ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a C1-C3 alkyl group.

15. at least one R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the halogen is...

16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein the halogen is fluorine.

17. at least one R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is hydroxyl.

18. at least one R ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a C1-C4 alkyl group.

19. at least one R ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the halogen is...

20. The compound according to claim 19 or a pharmaceutically acceptable salt thereof, wherein the halogen is fluorine.

21. at least one R ２ However, =CH ２ ¶=CHR １１ or = C(R １１ ) ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

22. R １１ The compound according to claim 21 or a pharmaceutically acceptable salt thereof, wherein F is present.

23. at least one R ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is hydroxyl.

24. at least one R ３ However, =CH ２ ¶=CHR １１ or = C(R １１ ) ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

25. R １１ The compound according to claim 24 or a pharmaceutically acceptable salt thereof, wherein F is present.

26. R ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the halogen is...

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

28. at least one R ５ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a C1-C3 alkyl group.

29. at least one R ５ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

30. One or both R ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen or a C1-C4 hydroxyalkyl group.

31. Two R ６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein these elements combine to form a C3-C6 cycloalkyl or heterocycle.

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

33. Y １ The compound according to claim 32 or a pharmaceutically acceptable salt thereof, wherein is L-heteroaryl.

34. The compound according to claim 33 or a pharmaceutically acceptable salt thereof, wherein the heteroaryl is thietanedioxide, isothiazolidinedioxide, imidazopyrazine, pyridine, or pyrimidine.

35. Y １ The compound according to claim 32, or a pharmaceutically acceptable salt thereof, wherein is L-C3 to C6 cycloalkyl.

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

37. Y １ The compound according to claim 32 or a pharmaceutically acceptable salt thereof, wherein is an L-heterocyclic ring.

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

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

40. Y ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a C1-C4 alkyl group.

41. at least one R ８ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a C1-C3 alkyl group.

42. at least one R ８ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydroxyl or C1-C3 alkyl-hydroxyl.

43. One or two R ８ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is oxo (=O).

44. at least one R ８ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is aryl or heteroaryl.

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

46. at least one R ８ However, -C(O)NH ２ -C(O)NH(C1-C3 alkyl) or -C(O)N(C1-C3 alkyl) ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

47. at least one R ８ However, -NH ２ -NH(C1-C3 alkyl); -N(C1-C3 alkyl) ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

48. at least one R ９ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a C1-C3 alkyl group.

49. at least one R ９ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is hydroxyl or C1-C3 alkyl-hydroxyl.

50. One or two R ９ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is oxo (=O).

51. at least one R ９ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a heteroaryl compound.

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

53. at least one R ９ However, -C(O)NH ２ -C(O)NH(C1-C3 alkyl) or -C(O)N(C1-C3 alkyl) ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

54. Y １ and Y ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein these compounds combine to form piperidine, azepane, azocane, thiazepine, diazepane, oxazepane, azetidine, pyrrolidine, piperazine (bonded to a condensed ring via nitrogen), or thiomorpholine.

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

56. Two R atoms on adjacent atoms ７ They come together and bond or 1 to 4 R ８ C3-C6 cycloalkyl groups optionally substituted with; 1-4 R groups ８ A heteroaryl that is optionally substituted with 1 to 4 R ８ aryls and 1 to 4 Rs are optionally substituted. ８ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein a fused ring is formed by selecting a heterocycle that is optionally substituted.

57. Two R atoms on non-neighboring atoms ７ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein these together form one or two carbon bridges.

58. One R １０ is hydrogen, C1-C3 alkyl or halogen, and another R １０ R ７ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which together with to form a heterocycle.

59. Two R １０ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compounds combine to form a heterocycle.

60. Each R １０ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the elements are independently hydrogen, a C1-C3 alkyl group, or a halogen. 【Request Item 61】 【Chemistry 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Transformation 58】 【Chemistry 59】 【Transformation 60】 【Chemistry 61】 【Transformation 62】 【Transformation 63】 【Chemistry 64】 【Transformation 65】 【Chemical Formula 66】 【Transformation 67】 【Transformation 68】 【Transformation 69】 【Transformation 70】 【Chemistry 71】 【Chemistry 72】 【Transformation 73】 【Chemistry 74】 【Chemistry 75】 【Transformation 76】 compounds selected from and its pharmaceutically acceptable salts.

62. A pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 61, and a pharmaceutically acceptable excipient.

63. The pharmaceutical composition according to claim 62 for inhibiting wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H activity in cells.

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

65. The pharmaceutical composition according to claim 64, wherein the therapeutically effective dose of the compound is about 0.01 to 100 mg / kg / day.

66. The pharmaceutical composition according to claim 65, wherein the therapeutically effective dose of the compound is about 0.1 to 50 mg / kg / day.

67. The aforementioned cancers include: cardiac sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchogenic lung cancer (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, cartilaginous hamartoma, mesothelioma; Gastrointestinal tract: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagon-producing tumor, gastrin-producing tumor, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); genitourinary tract: kidney (Adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibrocarcinoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder carcinoma, ampulla carcinoma, cholangiocarcinoma; Bone: Osteogenosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfloma (osteochondral exostosoma), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid and giant cell tumor; Nervous system: Skull (osteoma, blood vessels) Tumors, granulomas, xanthomas, osteoosteitis), meninges (meningioma, meningiosarcoma, gliomas), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas); gynecological system: uterus (endometrial carcinoma (serous cystadenoma, mucinous cystadenoma, undifferentiated) A pharmaceutical composition according to claim 64, selected from the group consisting of: (types of carcinomas), granulosa-encapsular cell tumors, Sertoli-Leydig cell tumors, undifferentiated germ cell tumors, malignant teratomas), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (embryonic rhabdomyosarcoma), fallopian tubes (carcinoma); hematological: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentigo dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

68. The pharmaceutical composition according to claim 67, wherein the cancer is a cancer associated with KRas G12A, a cancer associated with KRas G12C, a cancer associated with KRas G12D, a cancer associated with KRas G12R, a cancer associated with KRas G12S, a cancer associated with KRas G12V, a cancer associated with KRas G13D, a cancer associated with KRas Q61H, or a cancer associated with wild-type KRas.

69. The pharmaceutical composition according to claim 67, wherein the cancer is associated with KRas wild type or at least one of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H.

70. The pharmaceutical composition according to claim 64, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, or pancreatic cancer.

71. The pharmaceutical composition according to claim 62 for treating cancer determined to be associated with KRas wild-type or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H mutations.

72. The pharmaceutical composition according to claim 64, administered via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, synovial, subarachnoid, intramuscular, intravitreous, intravenous, intra-arterial, oral, buccal, sublingual, transdermal, topical, intratracheal, intrarectal, subcutaneous, and local administration.

73. The pharmaceutical composition according to claim 72, wherein the administration route is oral, intravenous, or intramuscular, or the administration route utilizes a delivery device, or the administration is performed in a hospital.

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