Quinazoline pan-KRas inhibitors

Abstract

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

Description

[Technical Field]

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

[0002] Kirsten rat sarcoma 2 viral oncogene homolog (KRas) is a small GTPase and a member of the Ras family of oncogenes. KRas functions as a molecular switch, cycling between inactive (GDP-bound) and active (GTP-bound) states, transducing upstream cellular signals received from multiple tyrosine kinases to downstream effectors to regulate various processes, including cell proliferation (see, e.g., Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0003] The role of activated KRas in malignant tumors was observed more than 30 years ago (see, e.g., Santos et al., (1984) Science 223:661-664). Aberrant expression of KRas stabilizes GTP binding and accounts for up to 20% of all cancers and oncogenic KRas mutations, which result in 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, e.g., Prior et al., (2020) Cancer Res 80:2969-74). Recent publications have also demonstrated that wild-type Kras inhibition inhibits KRas WT It has been suggested that this may be a viable therapeutic strategy for treating addictive cancers (see, for example, Bery et al., (2020) Nat. Commun. 11:3233).

[0004] The well-known role of KRas in malignancies and the discovery of these frequent mutations in KRas in various tumor types have made KRas a highly attractive target for the pharmaceutical industry for cancer therapy. Despite 30 years of extensive discovery efforts to develop inhibitors of KRas to treat cancer, KRas inhibitors have yet to demonstrate sufficient safety and / or efficacy to gain regulatory approval (see, e.g., McCormick (2015) Clin Cancer Res. 21(8):1797-1801).

[0005] Compounds that inhibit KRas activity remain highly desirable and under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors (e.g., Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143 doi:10.1002 / anie 201201358), and recent advances in covalently targeting the allosteric pocket of KRas G12C (see, e.g., Ostrem et al., (2013) Nature 503:548-551 and Fell et al., (2018) ACS Med. Chem. Lett. 9:1230-1234). Clearly, there is still ongoing interest and effort in developing inhibitors of KRas, particularly inhibitors that activate KRas mutants.

[0006] Therefore, there is a need to develop new pan-KRas inhibitors that are sufficiently effective to treat 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 all.,(2020)Cancer Res 80:2969-74 [Non-patent document 4] Bery et al.,(2020)Nat.Commun.11:3233 [Non-Patent Document 5] McCormick(2015)Clin Cancer Res.21(8):1797-1801 [Non-patent document 6] Sun et al.,(2012)Agnew Chem Int Ed Engl.51(25):6140-6143 doi:10.1002 / anie 201201358 [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

[0008] In one aspect of the invention, a compound of formula (I):

[0009] [ka] or a pharmaceutically acceptable salt thereof, wherein: A is aryl or heteroaryl, and the aryl or heteroaryl is selected from 1 to 4 R 1 is optionally replaced by; B is

[0010] [ka] and; Y 1 is hydrogen, hydroxy, halogen, C1-C4 alkyl, 1 to 4 R 9L-C3-C6 cycloalkyl optionally substituted with 1 to 4 R 8 L-heteroaryl optionally substituted with 1 to 4 R 8 L-aryl optionally substituted with LC(O)-NH2, and 1-2 oxo (=O) or oxo-containing substituents, and further 1-2 R 8 an L-heterocycle optionally substituted with Y 2 is hydrogen or C1-C4 alkyl; Or, Y 1 and Y 2 is combined

[0011] [ka] wherein X forms a bond, -S-, -O-, -N<, -CH2-N<, -CH2-CH2-N<, -CH-, -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, deuteroC2-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 2are independently hydrogen, deuterium, hydroxy, halogen, C1-C3 alkyl, ═CH2, ═CH(halogen), ═C(halogen)2, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(═O)—, —OC(O)N(R 5 )2, -CO2R 5 , or -CO2N(R 5 )2; Each R 3 are independently hydrogen, deuterium, hydroxy, halogen, C1-C3 alkyl, ═CH2, ═CH(halogen), ═C(halogen)2, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(═O)—, —COC(O)N(R 5 )2, -CO2R 5 , or -CO2N(R 5 )2; R 4 is hydrogen, halogen, or C1-C3 alkyl; Each R 5 are independently hydrogen or C1-C3 alkyl; Each R 6 are independently hydrogen, hydroxy, C1-C4 hydroxyalkyl, or heteroaryl; Each R 7 are independently hydrogen, C-C alkyl, hydroxy, halogen, C-C haloalkyl, —NH, —NH(C-C alkyl), —N(C-C alkyl), oxo (═O), —O—(C-C alkyl), —(C-C alkyl)-OH, —C(O)OH, —C(O)O(C-C alkyl), —C(O)NH, —C(O)NH(C-C alkyl), —C(O)N(C-C alkyl), —CN, aryl, —CH—S(O)NH, or heteroaryl independently optionally substituted with 1 to 2 C-C alkyl, —CN, or C(O)NH; Two R on the same atom 7are optionally joined to form a spirocyclic ring selected from C-C cycloalkyl and heterocycle, wherein the spirocyclic ring is optionally substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, hydroxy, C-C alkyl, and -O-(C-C alkyl); Two R on adjacent atoms 7 are optionally joined to form a bond or 1 to 4 R 8 C-C 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 are optionally joined to form a bridge containing 1 to 3 members selected from (i) —CH— optionally substituted with 1 to 2 substituents selected from hydroxy, cyano, -halogen, C-C alkyl, and NH, (ii) up to one —O—, (iii) up to one —S—, and (iv) up to one —NH—; Each R 8 are independently C1-C3 alkyl, hydroxy, halogen, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2, -C(O)-pyrrolidine or -CN; Each R 9 are independently C1-C3 alkyl, hydroxy, halogen, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2 or -CN; R 10is absent, hydrogen, deuterium, hydroxy, halogen, C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C3 alkenyl, deuterated C2-C3 alkenyl or C3-C6 cycloalkyl; L is a bond, -C1-C4 alkyl-, -NH-, -N(C1-C3 alkyl)-, or cyclopropyl-CH2-; Z is C or O, where when Z is C the six-membered ring containing Z is aromatic, and when Z is O the six-membered ring containing Z is oxane; each n is 0 to 3; o is 1 to 6; and p is 1 to 8.

[0012] 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.

[0013] In yet another aspect of the present invention, there is provided 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, and / or Q61H, in a cell, the method comprising contacting the cell with a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0014] Also provided herein are methods for inhibiting cell proliferation in vitro or in vivo, the methods comprising contacting a cell with an effective amount of a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0015] Also provided is a method for treating cancer in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the invention, or a pharmaceutically acceptable salt thereof.

[0016] Also provided herein is a method of treating a wild-type, KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H associated disease or disorder in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0017] Also provided herein is a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in therapy.

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

[0019] Also provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof for use in inhibiting KRas wild-type or multiple types of KRas mutations, for example, KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations.

[0020] Also provided herein is a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of a disease or disorder associated with wild-type KRas or a disease or disorder associated with KRas mutations G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H.

[0021] There is also provided herein 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 cancer.

[0022] 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 inhibiting the activity of wild-type forms of KRas or mutant forms of KRas, including the mutations: G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H.

[0023] Also provided herein is the use of a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a KRas wild-type associated disease or disorder or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H associated disease or disorder.

[0024] 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 KRas wild-type or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H mutations (i.e., KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-associated cancer); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0025] One potential utility of the pan-KRas inhibitors described herein, including pan-KRas inhibitors such as 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (Example 23 herein), is for the treatment of cancers that develop resistance after long-term treatment with a KRas G12C inhibitor. Thus, embodiments of the present invention include those in which patients afflicted with cancer are treated with a pan-KRas inhibitor, such as Example 5 described herein, after treatment with the G12C inhibitor has become ineffective or less effective due to the emergence of resistance-conferring mutations.

[0026] Treatment of KRas G12C-mutated cancers with covalent KRas G12C inhibitors, such as adagrasib (MRTX849) or sotorasib (AMG510), can lead to the incorporation of additional mutations that confer resistance to adagrasib. These mutations can confer resistance through multiple mechanisms.

[0027] Because current inhibitors form a covalent bond with the mutant cysteine ​​amino acid side chain, mutations that change the mutant cysteine ​​at codon 12 to another amino acid render current covalent KRas G12C inhibitors ineffective. Similarly, in patients with one wild-type KRas allele in addition to the KRas G12C-mutant allele, mutation of the wild-type codon 12 glycine to another codon allows bypass signaling in these tumors via a novel mutant protein. The repertoire of codon 12 mutations that can arise with 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 with single-nucleotide base substitutions at cysteine ​​codon 12 includes, in addition to G12S and G12R, mutations that are not frequently observed in cancer, such as G12Y, G12F, and G12W.

[0028] Second-site mutations can also occur elsewhere in the KRas G12C mutant gene, conferring resistance to treatment with KRas G12C inhibitors. These mutations may confer resistance via 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 via guanine nucleotide exchange factors (GEFs; e.g., SOS1), which are activated by upstream receptor tyrosine kinases and trigger subsequent interactions with effector proteins that activate RAS-dependent signaling. RAS proteins hydrolyze GTP to GDP through their intrinsic GTPase activity, which is dramatically enhanced by GTPase-activating proteins (GAPs). Mutations at codons 12 and 13 in RAS proteins impair GAP-stimulated GTP hydrolysis, rendering RAS primarily in the GTP-bound, active state. Covalent KRas G12C inhibitors currently in clinical development bind only to GDP-bound KRas G12C. Mutations such as the Q61 codon mutation, which may or may not occur on the same allele as the G12C mutation, may represent a mechanism of resistance to KRas G12C inhibitor treatment by reducing the intrinsic GTPase activity of KRas and shifting KRas to a GTP-loaded state that is insensitive to covalent inhibition. Co-mutations such as R68, H95, and Y96 may also exist with the KRas G12C mutation and may reduce the binding affinity of KRas G12C inhibitors to the switch II binding pocket.

[0029] The pan-KRas inhibitors described herein may exhibit activity against common and non-common codon 12 mutations or mutations occurring in the KRas protein that reduce binding of the KRas G12C inhibitor to the KRas protein.

[0030] Also provided herein are processes for preparing compounds of formula (I), or pharmaceutically acceptable salts thereof.

[0031] Also provided herein are compounds of formula (I), or pharmaceutically acceptable salts thereof, obtainable by the process for preparing the compounds defined herein. DETAILED DESCRIPTION OF THE INVENTION

[0032] The present invention relates to inhibitors of wild-type KRas and / or multiple mutant forms of KRas, such as the KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations. In particular, the present invention relates to compounds that inhibit the activity of wild-type KRas and / or mutant KRas, such as the G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations, pharmaceutical compositions containing therapeutically effective amounts of the compounds, and methods of use thereof.

[0033] 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.

[0034] The compounds described herein comprise both their natural isotopic abundance and non-natural abundance atoms.The disclosed compounds can be isotopically labeled or isotopically substituted compounds that are identical to those described, except that one or more atoms are replaced by atoms with atomic mass or mass number different from the atomic mass or mass number that is typically found in nature.The examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F and 36The compounds further include prodrugs thereof, and pharmaceutically acceptable salts of the compounds or prodrugs that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, e.g. 3 H and 14 Incorporating radioactive isotopes such as 1C are useful in drug and / or substrate tissue distribution assays. 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, deuterium, i.e. 2 Substitution with heavier isotopes, such as H, can confer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopically labeled compounds of the invention and prodrugs thereof can generally be prepared by performing the following procedure by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0035] As used herein, "wild-type KRas" refers to the non-mutated form of mammalian KRas protein. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "wild-type KRas inhibitor" refers to the compounds of the present invention represented by Formula (I) described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of wild-type KRas G12A. As used herein, "wild-type KRas-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having wild-type KRas. A non-limiting example of a wild-type KRas-associated disease or disorder is wild-type KRas-associated cancer.

[0036] As used herein, "KRas G12A" refers to a mutant mammalian KRas protein containing a glycine to alanine 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 G12A inhibitor" refers to a compound of the present invention represented by Formula (I) described herein. These compounds can negatively regulate or inhibit all or 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.

[0037] As used herein, "KRas G12C" refers to a mutant mammalian KRas protein containing a glycine to cysteine ​​amino acid substitution at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G12C inhibitors" refer to compounds of the present invention represented by Formula (I) described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12C. As used herein, "KRas G12C-associated diseases or disorders" refer 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.

[0038] As used herein, "KRas G12D" refers to a mutant form of a mammalian KRas protein containing an amino acid substitution of aspartic acid for glycine at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G12D inhibitors" refer to compounds of the present invention represented by Formula (I) described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12D. As used herein, "KRas G12D-associated diseases or disorders" refer 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.

[0039] As used herein, "KRas G12R" refers to a mutant mammalian KRas protein containing a glycine to arginine 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 inhibitor" refers to a compound of the present invention represented by Formula (I) described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12R. As used herein, "KRas G12R-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRas G12R mutation. A non-limiting example of a KRas G12R-associated disease or disorder is KRas G12R-associated cancer.

[0040] As used herein, "KRas G12S" refers to a mutant mammalian KRas protein containing a glycine to serine amino acid substitution at amino acid position 12. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G12S inhibitors" refer to compounds of the present invention represented by Formula (I) described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12S. As used herein, "KRas G12S-associated diseases or disorders" refer 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.

[0041] As used herein, "KRas G12V" refers to a mutant mammalian KRas protein containing a glycine to valine 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 G12V inhibitors" refer to compounds of the present invention represented by Formula (I) described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G12V. As used herein, "KRas G12V-associated diseases or disorders" refer 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.

[0042] As used herein, "KRas G13D" refers to a mutant mammalian KRas protein containing an amino acid substitution from glycine to aspartic acid at amino acid position 13. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas G13D inhibitors" refer to compounds of the present invention represented by Formula (I) described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas G13D. As used herein, "KRas G13D-associated diseases or disorders" refer 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.

[0043] As used herein, "KRas Q61H" refers to a mutant mammalian KRas protein containing a glutamine-to-histidine amino acid substitution at amino acid position 61. The amino acid codon and residue position assignments for human KRas are based on the amino acid sequence identified by UniProtKB / Swiss-Prot P01116:Variantp.Gly12Asp. As used herein, "KRas Q61H inhibitors" refer to compounds of the present invention represented by Formula (I) described herein. These compounds can negatively regulate or inhibit all or part of the enzymatic activity of KRas Q61H. As used herein, "KRas Q61H-associated diseases or disorders" refer 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.

[0044] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the patient is human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of a disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer with wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation (e.g., as determined using 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 KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations (e.g., determined using a regulatory agency-approved assay or kit). The subject can have a tumor that is positive for wild-type KRas or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject may have a tumor with wild-type KRas or a KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutation (e.g., if the tumor is identified as such using a regulatory approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having wild-type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H gene-associated cancer.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).

[0045] In some embodiments of any of the methods or uses described herein, a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample)) from a patient (e.g., a patient suspected of having a wild-type KRas-related or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-related cancer, a patient with one or more symptoms of a wild-type KRas-related or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-related cancer, and / or a patient at increased risk of developing a wild-type KRas-related or KRas G12A, G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-related cancer) is used to determine whether the patient has wild-type KRas or KRas G12C, G12D, G12R, G12S, G12V, G13D and / or Q61H-related cancer. Assays can be used to determine whether a patient has the G12A, G12C, G12D, G12R, G12S, G12V, G13D, and / or Q61H mutations, and can include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR).As is well known in the art, assays are typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof.

[0046] The term "regulatory authority" refers to a national agency that approves the medical use of pharmaceutical agents in that country. For example, a non-limiting example of a regulatory authority is the U.S. Food and Drug Administration (FDA).

[0047] The term "acyl" refers to C(O)CH3.

[0048] As used herein, the terms "C1-C6 alkyl," "C1-C4 alkyl," and "C1-C3 alkyl" refer to straight-chain and branched-chain aliphatic groups having 1 to 6 carbon atoms, or 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.

[0049] The terms "C-C haloalkyl" and "C-C haloalkyl" refer to a C-C alkyl chain or a C-C alkyl chain, respectively, as defined herein, in which one or more hydrogens have been replaced with halogen. Examples include trifluoromethyl, difluoromethyl, and fluoromethyl.

[0050] A "C1-C4 alkylene" group, as defined herein above, is a C1-C4 alkyl group that is positioned between and serves to connect two other chemical groups. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0051] 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.

[0052] 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, where a cycloalkyl group can be selected from one or more R 8 or R 9 and optionally substituted with a group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term "cycloalkyl" also includes bridged cycloalkyls, such as bicyclo[1.1.1]pentanyl.

[0053] As used herein, the terms "C1-C3 hydroxyalkyl" and "C1-C4 hydroxyalkyl" refer to -C1-C3 alkylene-OH and -C1-C4 alkylene-OH, respectively.

[0054] As used herein, the term "C2-C4 hydroxyalkynyl" refers to -C2-C4 alkynylene-OH.

[0055] An "aryl" group is a C6-C aryl group containing one to three aromatic rings. 14 an aromatic moiety, as defined herein, containing one or more R 8 or R 9 In one embodiment, the aryl group is optionally substituted with C-C 10 It is an aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, and dihydrobenzofuranyl. "Aryl" also refers to a bicyclic or tricyclic ring system, where one or two rings of the aryl ring system can be saturated or partially saturated, respectively, 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, where the rings are spirocyclic, include the following ring systems:

[0056] [ka]

[0057] An "araC1-C6 alkyl" or "arylalkyl" group comprises an aryl group covalently bonded to an alkyl group, either of which independently can be optionally substituted or unsubstituted. Examples of aralkyl groups include (C6-C 10 )aryl(C1-C6)alkyl-, including, but not limited to, benzyl, phenethyl, and naphthylmethyl. An example of a substituted araC1-C6 alkyl is when the alkyl group is substituted with hydroxyalkyl.

[0058] A "heterocyclyl" or "heterocyclic" group is a ring structure having 3 to 12 atoms, e.g., 4 to 8 atoms, in which 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 can have one or more R on a ring carbon or ring nitrogen at one or more positions. 8 or R 9 optionally substituted with a group, where R 6is as defined for Formula I. Heterocyclic groups are also independently optionally substituted on the ring nitrogen atom with alkyl, aralkyl, alkylcarbonyl, or on the sulfur with lower alkyl. Examples of heterocyclic groups include, but are not limited to, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorpholinyl 1,1 oxide, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyl, azabicycloheptanyl, azabicyclooctanyl, azabicyclononanyl (e.g., octahydroquinolinyl), and the like. Indolizinyl), azaspiroheptanyl, dihydro-1H,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrrolizidine], hexahydro-1H-pyrrolidinyl, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyl, oxaazaspirooctanyl, diazaspirononanyl, oxazabioctoheptanyl, hexahydropyrrolidinyl 4(1H)-oxide, tetrahydro-2H-thiopyranyl 1-oxide, and tetrahydro-2H-thiopyranyl 1,1-dioxide. Specifically excluded from the scope of this term are compounds with adjacent ring O and / or S atoms.

[0059] As used herein, the term "heteroaryl" refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; groups having 6, 10, or 14 pi electrons shared in a cyclic array; and groups having, in addition to carbon atoms, 1 to 3 heteroatoms per ring selected from the group consisting of N, O, and S, or 1 to 3 heteroatoms in at least one ring.Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, ox Sazolidinyl, 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, quinuclidinyl , 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 a bicyclic ring system having, in addition to carbon atoms, one to three heteroatoms per ring selected from the group consisting of N, O, and S, where one ring system can be saturated or partially saturated.

[0060] As used herein, an "effective amount" of a compound is an amount sufficient to negatively regulate or inhibit the activity of one or more of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H. Such an amount can be administered as a single dose or according to a regimen, and is thereby effective.

[0061] As used herein, a "therapeutically effective amount" of a compound is an amount sufficient to improve or in some manner reduce symptoms, or to stop or reverse the progression of a condition, or to negatively regulate or inhibit the activity of one or more of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H. Such an amount can be administered as a single dose or according to a regimen, and is thereby effective.

[0062] 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.

[0063] As used herein, amelioration of symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any relief, permanent or temporary, lasting or transient, that can result from or be associated with administration of the composition.

[0064] compound In one embodiment of the present invention, a compound of formula (I):

[0065] [ka] or a pharmaceutically acceptable salt thereof, wherein: A is aryl or heteroaryl, and the aryl or heteroaryl is selected from 1 to 4 R 1 is optionally replaced by; B is

[0066] [ka] and; Y 1 is hydrogen, hydroxy, halogen, C1-C4 alkyl, 1 to 4 R 9 L-C3-C6 cycloalkyl optionally substituted with 1 to 4 R 8 L-heteroaryl optionally substituted with 1 to 4 R 8 L-aryl optionally substituted with LC(O)-NH2, and 1-2 oxo (=O) or oxo-containing substituents, and further 1-2 R 8 an L-heterocycle optionally substituted with Y 2 is hydrogen or C1-C4 alkyl; Or, Y 1 and Y 2 is combined

[0067] [ka] wherein X forms a bond, -S-, -O-, -N<, -CH2-N<, -CH2-CH2-N<, -CH-, -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, deuteroC2-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, deuterium, hydroxy, halogen, C1-C3 alkyl, ═CH2, ═CH(halogen), ═C(halogen)2, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(═O)—, —OC(O)N(R 5 )2, -CO2R 5 , or -CO2N(R 5 )2; Each R 3 are independently hydrogen, deuterium, hydroxy, halogen, C1-C3 alkyl, ═CH2, ═CH(halogen), ═C(halogen)2, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(═O)—, —COC(O)N(R 5 )2, -CO2R 5 , or -CO2N(R 5 )2; R 4 is hydrogen, halogen, or C1-C3 alkyl; Each R 5 are independently hydrogen or C1-C3 alkyl; Each R 6 are independently hydrogen, hydroxy, C1-C4 hydroxyalkyl, or heteroaryl; Each R 7are independently hydrogen, C-C alkyl, hydroxy, halogen, C-C haloalkyl, —NH, —NH(C-C alkyl), —N(C-C alkyl), oxo (═O), —O—(C-C alkyl), —(C-C alkyl)-OH, —C(O)OH, —C(O)O(C-C alkyl), —C(O)NH, —C(O)NH(C-C alkyl), —C(O)N(C-C alkyl), —CN, aryl, —CH—S(O)NH, or heteroaryl independently optionally substituted with 1 to 2 C-C alkyl, —CN, or C(O)NH; Two R on the same atom 7 are optionally joined to form a spirocyclic ring selected from C-C cycloalkyl and heterocycle, wherein the spirocyclic ring is optionally substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, hydroxy, C-C alkyl, and -O-(C-C alkyl); Two R on adjacent atoms 7 are optionally joined to form a bond or 1 to 4 R 8 C-C 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 are optionally joined to form a bridge containing 1 to 3 members selected from (i) —CH— optionally substituted with 1 to 2 substituents selected from hydroxy, cyano, -halogen, C-C alkyl, and NH, (ii) up to one —O—, (iii) up to one —S—, and (iv) up to one —NH—; Each R 8are independently C1-C3 alkyl, hydroxy, halogen, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2, -C(O)-pyrrolidine or -CN; Each R 9 are independently C1-C3 alkyl, hydroxy, halogen, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2 or -CN; R 10 is absent, hydrogen, deuterium, hydroxy, halogen, C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C3 alkenyl, deuterated C2-C3 alkenyl or C3-C6 cycloalkyl; L is a bond, -C1-C4 alkyl-, -NH-, -N(C1-C3 alkyl)-, or cyclopropyl-CH2-; Z is C or O, where when Z is C the six-membered ring containing Z is aromatic, and when Z is O the six-membered ring containing Z is oxane; each n is 0 to 3; o is 1 to 6; and p is 1 to 8.

[0068] Such embodiments can include compounds or salts of the formula: A is aryl, and the aryl is 1 to 4 R 1 is optionally replaced by; Y 1 and Y 2 is combined

[0069] [ka] wherein X forms a bond, -S-, -O-, -N<, -CH2-N<, -CH2-CH2-N<, -CH-, -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(=Os)N(R 5 )2, -C3-C4 alkynyl (NR 5 )2, -N(R 5 )2, or (C1-C3 alkoxy)haloC1-C3 alkyl-; Each R 6 are independently hydrogen, hydroxy, C1-C4 hydroxyalkyl, or heteroaryl; Each R 7 are independently hydrogen, C-C alkyl, hydroxy, halogen, C-C haloalkyl, —NH, —NH(C-C alkyl), —N(C-C alkyl), oxo (═O), —O—(C-C alkyl), —(C-C alkyl)-OH, —C(O)OH, —C(O)O(C-C alkyl), —C(O)NH, —C(O)NH(C-C alkyl), —C(O)N(C-C alkyl), —CN, or —CH—S(O)NH; Two R on the same atom 7 are optionally joined to form a spirocyclic ring selected from C-C cycloalkyl and heterocycle, wherein the spirocyclic ring is optionally substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, hydroxy, C-C alkyl, and -O-(C-C alkyl); Two R on adjacent atoms 7 are optionally joined to form a bond or 1 to 4 R 8C-C 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 are optionally joined to form a bridge containing 1 to 3 members selected from (i) —CH— optionally substituted with 1 to 2 substituents selected from hydroxy, cyano, -halogen, C-C alkyl, and NH, (ii) up to one —O—, (iii) up to one —S—, and (iv) up to one —NH—; Each R 8 are independently C1-C3 alkyl, hydroxy, halogen, -NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH2, -C(O)NH(C1-C3 alkyl), -C(O)N(C1-C3 alkyl)2, -C(O)-pyrrolidine or -CN; R 10 is absent, hydrogen, deuterium, hydroxy, halogen, C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C3 alkenyl, deuterated C2-C3 alkenyl or C3-C6 cycloalkyl; L is a bond, -C1-C4 alkyl-, -NH-, -N(C1-C3 alkyl)-, or cyclopropyl-CH2-; Z is C or O, where when Z is C the six-membered ring containing Z is aromatic, and when Z is O the six-membered ring containing Z is oxane; each n is 0 to 3; and p is 1 to 8.

[0070] In some embodiments described herein, B is

[0071] [ka] is.

[0072] In some embodiments described herein, B is dimethylamino.

[0073] In some embodiments, A is naphthyl.

[0074] In certain embodiments, -LB is

[0075] [ka] is.

[0076] In certain embodiments, A is indazolyl.

[0077] In certain embodiments, A is benzothiophenyl.

[0078] In some embodiments described herein, at least one R 1 is C1-C4 alkyl.

[0079] In certain embodiments described herein, at least one R 1 is a halogen, preferably fluorine.

[0080] In some embodiments described herein, at least one R 1 is hydroxy.

[0081] In some embodiments described herein, at least one R 2 is a halogen, preferably fluorine.

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

[0083] In certain embodiments of the present invention, at least one R 3 is selected from the group consisting of ethenyl, fluoroethenyl, and difluoroethenyl.

[0084] In certain embodiments of the present invention, R 4 is a halogen, preferably fluorine.

[0085] In certain embodiments of the invention, one or both R 6 is C1-C4 alkyl.

[0086] In certain embodiments of the invention, one or both R 6 is hydrogen.

[0087] In certain embodiments of the invention described herein, two R 7 are joined to form a spirocyclic ring selected from C-C cycloalkyl and heterocycle, wherein the spirocyclic ring is optionally substituted with one or more substituents selected from oxo (=O), halogen, hydroxy, C-C alkyl, and -O-(C-C alkyl).

[0088] In certain embodiments of the invention described herein, two R on adjacent atoms 7 is bonded to 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 and forming a fused ring selected from optionally substituted heterocycles.

[0089] In certain embodiments of the present invention, two R on non-adjacent atoms 7are linked to form a bridge containing 1 to 3 members selected from: (i) -CH- optionally substituted with 1 to 2 substituents selected from hydroxy, cyano, -halogen, C-C alkyl, and NH; (ii) up to one -O-; (iii) up to one -S-; and (iv) up to one -NH-.

[0090] In certain embodiments of the present invention, at least one R 8 is C1-C4 alkyl.

[0091] In certain embodiments of the present invention, at least one R 8 is hydroxy or C1-C3 alkyl-hydroxy.

[0092] In certain embodiments of the present invention, one or two R 8 is oxo (=O).

[0093] In certain embodiments of the present invention, Y 1 and Y 2 combine to form piperidine, azepane, azocane, thiazepine, diazepane, oxazepane, azetidine, pyrrolidine, piperazine attached to the fused ring through the nitrogen or thiomorpholine.

[0094] Non-limiting examples of compounds of formula (I) are selected from the group consisting of:

[0095] [ka]

[0096] [ka]

[0097] [ka]

[0098]

change

[0099]

change

[0100]

change

[0101]

change

[0102]

change

[0103]

change

[0104]

change

[0105]

change

[0106]

change

[0107]

change

[0108]

change

[0109] [ka]

[0110] [ka]

[0111] [ka]

[0112] [ka]

[0113] [ka]

[0114] [ka]

[0115] [ka]

[0116] [ka]

[0117] [ka] and pharmaceutically acceptable salts thereof.

[0118] In one embodiment, compounds of formula (I) include the bis-hydrochloride, tris-hydrochloride, trifluoroacetic acid, bis-trifluoroacetic acid, and tris-trifluoroacetic acid salts of the above compounds. The compounds of formula (I) or pharmaceutically acceptable salts thereof can be formulated into pharmaceutical compositions.

[0119] Pharmaceutical Composition In another aspect, the present invention provides pharmaceutical compositions comprising a wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H inhibitor according to the present invention and a pharmaceutically acceptable carrier, excipient, or diluent. The compounds of the present invention can be formulated by any method known in the art and prepared for administration by any route, including, but not limited to, parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal, intramuscular, intravitreal, intravenous, intraarterial, oral, buccal, sublingual, transdermal, topical, intranasal, intratracheal, rectal, subcutaneous, and local administration. In certain embodiments, the compounds of the present invention are administered intravenously in a hospital setting. In one embodiment, administration can be oral. In some embodiments, provided pharmaceutical compositions can be administered to a subject in need of treatment by systemic injection, such as intravenous injection; or by injection or application to the relevant site, for example, by direct injection via a syringe, or by direct application to the site if the site is exposed in a surgical procedure; or by local administration.

[0120] Parenteral administration may be by bolus injection or continuous infusion. Pharmaceutical compositions for injection may be presented in unit dosage form, eg, in ampoules or in multi-dose containers, with an added preservative.

[0121] Provided pharmaceutical compositions can also be formulated as depot preparations.Such long-acting preparations can be administered by implantation (for example, subcutaneous or intramuscular) or by intramuscular injection.Therefore, for example, preparations can be modified with suitable polymer or hydrophobic material (for example, as emulsion in acceptable oil) or ion exchange resin, or as poorly soluble derivatives, for example, as poorly soluble salts.

[0122] The pharmaceutical composition may be provided in a vial, a pack, or a medical device, including, but not limited to, a dispenser device, which may contain one or more unit dosage forms containing the active ingredient, if desired. In one embodiment, the dispenser device may include a syringe with a single dose of the liquid formulation ready for injection. The syringe may be accompanied by instructions for administration.

[0123] The characteristics of the carrier depend on the route of administration. As used herein, the term "pharmaceutically acceptable" refers to a non-toxic material that is compatible with a biological system, such as a cell, cell culture, tissue, or organism, and does not interfere with the effectiveness of the biological activity of the active ingredient. Thus, in addition to the inhibitor, the composition according to the present invention may contain diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials 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.

[0124] As used herein, the term pharmaceutically acceptable salt refers to the salt that maintains the desired biological activity of the compound identified above and shows minimal or no undesired toxicological effects.Examples of such salt include but are not limited to the acid addition salt formed with inorganic acid (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid etc.), and the salt formed with organic acid such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known to those of skill 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, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamate, mandelate, benzilate, and diphenylacetate).

[0125] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount to the patient without causing significant toxic effects to the patient being treated. In one embodiment, the dose of the active compound for all of the above conditions ranges from about 0.01 to 300 mg / kg per day, e.g., 0.1 to 100 mg / kg, and as a further example, from 0.5 to about 25 mg per kilogram of recipient body weight per day. Typical topical dosages will range from 0.01 to 3% weight / weight in a suitable carrier. The effective dosage range of pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative is active in itself, the effective dosage can be estimated as described above using the weight of the derivative or by other means known to those skilled in the art.

[0126] Pharmaceutical compositions containing the compounds of the present invention can be used in the methods of use described herein.

[0127] How to use In yet another aspect, the present invention provides a method for inhibiting wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, and / or KRas Q61H activity in a cell, the method comprising contacting a cell in which inhibition of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, and / or Q61H activity is desired with an effective amount of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0128] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or an in vivo system. For example, "contacting" wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H with a compound provided herein refers to 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, as well as 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, or KRas Q61H mutation. This involves introducing a compound provided herein into a sample containing a cell preparation or purified preparation containing the Q61H mutation.

[0129] In one embodiment, a cell in which inhibition of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H activity is desired is contacted with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to negatively regulate the activity of wild-type KRas or one or more of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and KRas Q61H.

[0130] By negatively modulating the activity of wild-type KRas or one or more of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and KRas Q61H, the methods described herein are designed to inhibit unwanted cell proliferation resulting from enhanced wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H activity in cells. Cells may be contacted with a single dose or multiple doses according to a particular treatment regimen to affect the desired negative regulation of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H. The ability of a compound to bind to wild-type KRas or one or more of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and KRas Q61H can be monitored in vitro using well-known methods, including those described in Examples A and B below. Additionally, the inhibitory activity of exemplary compounds in cells can be monitored, for example, by measuring the amount of phosphorylated ERK inhibition of one or more of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H activity using, for example, the methods described in Example C below.

[0131] In another aspect, there is provided a method of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt.

[0132] Compositions and methods provided herein can be used to treat wild-type KRas-related or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H-related cancer in a patient in need 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 wild-type KRas-related or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and / or KRas Q61H-related cancer is lung cancer.

[0133] The compositions and methods provided herein can be used to treat a wide variety of cancers, including tumors such as lung, prostate, breast, brain, skin, cervical, and testicular cancers. More specifically, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid cancers and sarcomas. More specifically, these compounds can be used to treat: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrohamartoma, 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, carcinoma) Posi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, breast fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder carcinoma, oncogenic carcinoma Neck cancer, bile duct cancer; 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 (osteochondroma), benign chondroma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), pleomorph Glioblastoma, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma; Gynecological: uterine cancer (endometrial cancer), cervix (cervical carcinoma, atypical cervical preneoplasia), ovary (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, botulismoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer);Hematological: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentigo dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer, small cell lung cancer, colon cancer, rectal cancer, or pancreatic cancer. In certain embodiments, the cancer is non-small cell lung cancer.

[0134] The concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions containing such compounds and salts can also be co-administered with other anti-tumor compounds, such as chemotherapy, or used as adjuvants either before or after surgery in combination with other treatments, such as radiation or surgical intervention.

[0135] Also provided herein is a compound of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in therapy.

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

[0137] 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.

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

[0139] There is also provided herein 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 cancer.

[0140] 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 inhibiting the activity of wild-type KRas or KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and / or KRas Q61H.

[0141] Also provided herein is the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the 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.

[0142] 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 approved, e.g., FDA-approved, kit or assay); 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.

[0143] Those skilled in the art will recognize that both in vivo and in vitro tests using suitable, known, and generally accepted cellular and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0144] 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 afflicted with a given disorder, can be completed according to methods well known in the clinical and medical arts. [Example]

[0145] Reaction Schemes and Examples The compounds of the present invention can be prepared from commercially available reagents using the synthetic methods and reaction schemes described herein, or using other reagents and conventional methods known to those skilled in the art. For example, the compounds of the present invention can be prepared according to the following reaction schemes and examples outlined below.

[0146] The compounds of the present invention may have one or more chiral centers and may be synthesized as stereoisomeric mixtures, isomers of identical constitution that differ in the arrangement of their atoms in space. The compounds may be used as mixtures, or the individual components / isomers may be separated using 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 chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Unless otherwise specified, whenever the specification, including the claims, refers to a compound of the present invention, the term "compound" should be understood to encompass all chiral (enantiomers and diastereomers) and racemic forms.

[0147] 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.

[0148] The following examples are intended to illustrate further certain embodiments of the present invention and are not intended to limit the scope of the invention.

[0149] Example 1

[0150] [ka] (1R,5R,6R)-3-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol

[0151] [ka]

[0152] Step A. 7-Bromo-2-chloro-8-fluoro-4-(2,2,2-trifluoroethoxy)quinazoline: To a solution of 2,2,2-trifluoroethanol (3.45 g, 1.2 equiv.) in THF (36 mL) was added NaH (1.38 g, 60% purity, 1.2 equiv.) at 0° C. The mixture was stirred at 0° C. for 0.5 h. Next, the mixture was added to a solution of 7-bromo-2,4-dichloro-8-fluoroquinazoline (8.50 g, 1.0 equiv.) in THF (64 mL) at −40° C. The mixture was stirred at −40° C. for 1 h. The mixture was diluted with saturated aqueous NH4Cl (80 mL) and extracted with EtOAc (100 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) and concentrated under vacuum to give the title compound (9.10 g, yield 88%) as a yellow solid; 1 H NMR(400MHz,CDCl3-d)δ=7.87(dd,J=1.2,8.8Hz,1H),7.77(dd,J=6.0,8.8Hz,1H),5.02(q,J=8.0Hz,2H)

[0153] Step B. 1-[1-[[7-Bromo-8-fluoro-4-(2,2,2-trifluoroethoxy)quinazolin-2-yl]oxymethyl]cyclopropyl]-N,N-dimethyl-methanamine: To a solution of 7-bromo-2-chloro-8-fluoro-4-(2,2,2-trifluoroethoxy)quinazoline (1.00 g, 1.0 equiv.) and [1-[(dimethylamino)methyl]cyclopropyl]methanol (395 mg, 1.1 equiv.) in dioxane (10 mL) was added Na2CO3 (884 mg, 3.0 equiv.). The mixture was stirred at 40 °C for 12 hours. The mixture was diluted with water (3 mL) and extracted with EtOAc (5 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 0 / 1) and concentrated to give the title compound (650 mg, 52% yield) as a yellow oil; LCMS (ESI, M+3): m / z = 454.1.

[0154] Step C. 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4-2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: 1-[1-[[7-bromo-8-fluoro-4-(2,2,2-trifluoroethoxy)quinazolin-2-yl]oxymethyl]cyclo in CPME (7 mL) To a solution of [propyl]-N,N-dimethylmethanamine (750 mg, 1.0 equiv.) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (629 mg, 1.2 equiv.), CsCO (1.5 M, 3.3 mL, 3.0 equiv.) and Ad2nBup-Pd-G (242 mg, 0.2 equiv.) were added. The mixture was stirred at 100 °C under a N atmosphere for 2 hours. The mixture was diluted with water (5 mL) and extracted with EtOAc (8 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 0 / 1) and concentrated to give the title compound (740 mg, 79% yield) as a brown solid; LCMS (ESI, M+1): m / z = 562.0.

[0155] Step D. (1S,5S,6S)-3-[2-[[1-[(dimethylamino)methyl]cyclopropyl]methoxy]-7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-quinazolin-4-yl]-3-azabicyclo[3.2.1]octan-6-ol: 4-(2-((1-((dimethylamino)methyl))-2-((1-((dimethylamino)methyl))) in DMF (1 mL) and ACN (1 mL) To a solution of (1S,5S,6S)-3-azabicyclo[3.2.1]octan-6-ol (68.0 mg, 1.2 equiv.) was added KPO (283 mg, 3.0 equiv.). The mixture was stirred at 40°C for 12 hours. The mixture was diluted with water (3 mL) and extracted with EtOAc (3 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC [Phenomenex Synergi C18 150 × 25 mm × 10 μm; A: water (FA), B: ACN, B%: 23% to 53% over 10 min] and concentrated to remove ACN. The aqueous phase was adjusted to pH = 7 with saturated aqueous NaHCO3 and extracted with DCM (20 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated. The impurities were further purified by preparative HPLC [Phenomenex luna C18 150 x 25 mm x 10 um; A: water (FA), B: ACN, B%: 17% to 47% over 12 min] and lyophilized to give the title compound (53.06 mg, 19% yield) as a white solid; SFC: Rt = 0.660 min, 1.511 min; Column: Chiralpak IC-3 50 x 4.6 mm ID, 3 um; Mobile phase: Phase A for CO2 and Phase B for EtOH (0.05% DEA); Gradient elution: 50% EtOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35 °C; Back pressure: 100 bar. 1H NMR(400MHz,DMSO-d6)δ=8.22-8.08(m,2H),7.75(dd,J=6.0,8.8Hz,1H),7.34(t,J=9.4Hz,1H),7.29(d,J=1.6Hz,1H),7.22(br t,J=7.6Hz,1H),6.93(d,J=2.4Hz,1H),4.63-4.48(m,2H),4.26-4.13(m,3H),3.52(br t,J=10.2Hz,1H),3.28(br dd,J=7.2,12.4Hz,1H),2.40-2.25(m,6H),2.21(s,6H),2.13-2.03(m,2H),1.76-1.60(m,2H),1.36(br d,J=13.2Hz,1H),0.74-0.67(m,3H),0.66-0.61(m,2H),0.41(s,2H);LCMS(ESI,M+1):m / z=589.3.

[0156] Example 2

[0157] [ka] (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

[0158] [ka]

[0159] Step A. (R)-1-(7-Bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol: To a solution of 7-bromo-2,4-dichloro-8-fluoroquinazoline (1.60 g, 1.0 equiv.), DIEA (2.23 g, 3.19 equiv.), and 4 Å molecular sieves (100 mg) in DCM (20 mL) was added (3R)-3-methylpiperidin-3-ol (1.0 g, 1.61 equiv.) in DCM (5 mL). The mixture was stirred at 0-15 °C for 16 h. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (4 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) and TLC (PE / EA = 1 / 1, Rf = 0.49) to give the title compound (1.0 g, 46% yield) as a red solid; LCMS (ESI, M+1): m / z = 374.0.

[0160] Step B. (R)-1-(7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3R)-1-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-3-methyl-piperidin-3-ol (400 mg, 1.0 equiv.), [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol (512 mg, 3.01 equiv.) in dioxane (2.0 mL), DIEA (415 mg, 3.01 equiv.) and 4 Å molecular sieves (80 mg) were added. The mixture was stirred at 95° C. for 42 hours. The mixture was filtered. The filtrate was purified by reverse phase flash [water (FA, 0.1%)] to give the title compound (260 mg, 43% yield) as a yellow solid; LCMS (ESI, M+1): m / z=499.2.

[0161] Step C. (R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol: (R)-1-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3 in methoxycyclopentane (1.0 mL) A mixture of 5-methylpiperidin-3-ol (100 mg, 1.0 equiv.), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (96.0 mg, 1.51 equiv.) was degassed and purged with N2 three times; [2-(2-aminophenyl)phenyl]palladium(1+); bis(1-adamantyl)-butyl-phosphane; and methanesulfonate (14.6 mg, 0.1 equiv.) were added, and the mixture was stirred at 95 °C under a N2 atmosphere for 3 hours. Upon completion, the mixture was diluted with water (3 mL) and extracted with ethyl acetate (4 × 4 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse-phase flash [C18, 0.1% formic acid condition] and preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: water (0.225% FA)-ACN; B%: 15% to 45% over 10 min] to give the title compound (44.1 mg, 35% yield) as a white solid; 1H NMR (400MHz, methanol-d4) δ=7.99(dd,J=1.6,8.4Hz,1H),7.65(dd,J=6.0,9.2Hz,1H),7.33(ddd,J=2.0,6.8,8.8Hz ,1H),7.27-7.19(m,2H),6.95(d,J=2.4Hz,1H),5.54-5.37(m,1H),4.58-4.52(m,1H),4.51-4.45(m,1H),4.32(br d,J=12.8Hz,1H),4.15(br d,J=13.2Hz,1H),3.84-3.68(m,1H),3.53-3.52(m,1H),3.84-3.52(m,2H),3.51-3.42(m,1H),3.28(br d,J=4.4Hz,1H),2.65-2.38(m,1H),2.50-2.38(m,3H),2.36-2.27(m,1H),2.26-2.12(m ,3H),2.10-1.99(m,1H),1.90-1.72(m,3H),1.27(d,J=13.1Hz,3H),0.82-0.73(m,3H). LCMS (ESI, M+1): m / z=607.4.

[0162] Example 3

[0163] [ka] 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

[0164] [ka]

[0165] Step A. 7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline: To a solution of 7-bromo-2-chloro-8-fluoro-4-(2,2,2-trifluoroethoxy)quinazoline (5.00 g, 1.0 equiv.) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol (2.44 g, 1.1 equiv.) in dioxane (50 mL) was added Na2CO3 (4.42 g, 3.0 equiv.). The mixture was stirred at 110° C. for 12 hours. The mixture was filtered and washed with EtOAc (10 mL × 2). The organic layer was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) and concentrated under vacuum to give the title compound (5.30 g, yield 79%) as a yellow solid; 1 H NMR(400MHz,CDCl3-d)δ=7.75(dd,J=1.6,8.8Hz,1H),7.51(dd,J=6.0,8.8Hz,1H),5.36(br d,J=1.6Hz,1H),5.23(br d,J=1.6Hz,1H),4.97(q,J=8.4Hz,2H),4.36-4.22(m,2H),3.33-3.22(m,2H),3.18(s,1 H),3.00(dt,J=5.6,9.2Hz,1H),2.30-2.24(m,1H),2.19-2.09(m,2H),2.02-1.91(m,3H)

[0166] Step B. 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)naphthalen-2-ol: 7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a(5H)-yl)quinazolin-7-yl)naphthalen-2-ol in CPME (20 mL) To a solution of (2,2,2-trifluoroethoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (2.00 g, 1.0 equiv.) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (1.57 g, 1.2 equiv.) was added CsCO (1.5 M, 8.3 mL, 3.0 equiv.) and Ad2nBup-Pd-G (604 mg, 0.2 equiv.). The mixture was stirred at 100° C. under a nitrogen atmosphere for 2 hours. The mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) and concentrated under vacuum to give the title compound (1.50 g, yield 61%) as a brown solid; 1 H NMR(400MHz,CDCl3-d)δ=7.89-7.83(m,1H),7.58(dd,J=5.6,8.8Hz,1H),7.34-7.28(m,1H),7.25-7.18(m,2H),6.92(dd,J=2.4,15.2Hz,1H),5.44-5 .19(m,1H),5.02-4.84(m,2H),4.40-4.30(m,2H),3.36-3.23(m,2H),3.07 -2.96(m,1H),2.51-2.09(m,6H),2.03-1.87(m,4H),1.27(t,J=6.8Hz,3H)

[0167] Step C. 5-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione: To a solution of 2,3,3a,6a-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-4,6-dione (35.5 mg, 2.0 equiv.) in DMF (0.5 mL) and ACN (0.5 mL) was added KPO (134 mg, 5.0 equiv.) and stirred at 25° C. for 0.5 h. Then, 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)naphthalen-2-ol (75.0 mg, 1.0 equivalent) was added to the reaction solution and stirred at 25°C for 1.5 hours. The mixture was filtered to remove insoluble matter, and the filtrate was extracted with DCM (50 mL). The organic layer was concentrated in vacuo. The crude product was purified by preparative HPLC [Waters Xbridge 150 x 25 mm x 5 um; A: water (NH4HCO3), B: ACN, B%: 40% to 70% over 8 minutes] to give the title compound (18.1 mg, 23% yield) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ=11.38(br d,J=5.6Hz,1H),9.92(s,1H),8.06(d,J=8.8Hz,1H),7.79-7.75(m,1H),7.38-7.34(m,1H),7.31(br d,J=2.8Hz,2H),6.94(d,J=2.4Hz,1H),5.36-5.21(m,1H),4.43(br d,J=11.2Hz,2H),4.21-4.15(m,2H),4.11-4.00(m,2H),3.68-3.64(m,2H),3.10(br d,J=12.8Hz,2H),3.02(brs,1H),2.83(br d,J=6.0Hz,1H),2.37-2.33(m,2H),2.19-2.00(m,4H),1.79(br d,J=3.6Hz,2H),0.74-0.69(m,3H);LCMS(ESI,M+1):m / z=632.3.

[0168] Example 4

[0169] [ka] 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-azaspiro[3.5]nonan-2-ol

[0170] [ka]

[0171] Step A. 6-(7-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-azaspiro[3.5]nonan-2-ol: To a solution of 6-azaspiro[3.5]nonan-2-ol (45.0 mg, 3.0 equiv., HCl) in DMF (0.5 mL) was added KPO (89.7 mg, 5.0 equiv.). The mixture was stirred at 25 °C for 0.5 h. Then, 5-ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)naphthalen-2-ol (50.0 mg, 1.0 equivalent) was added. The mixture was stirred at 40°C for 2 hours. The mixture was filtered to remove insoluble matter. The crude product was purified by preparative HPLC [Phenomenex Synergi Polar-RP 100 x 25 mm x 4 um; A: water (TFA), B: ACN, B%: 31% to 51% over 7 minutes] to give the title compound (4.19 mg, 7.6% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ=10.17-9.60(m,1H),7.94(d,J=8.4Hz,1H),7.77(dd,J=6.0,9.2Hz,1H),7.51-7.45(m,1H),7.39-7.31(m,2 H),6.94(d,J=2.4Hz,1H),5.46(td,J=6.8,17.6Hz,1H),5.36(brs,1H),4.19-4.07(m,2H),3.14-3.07(m,2H),3.02(s,1H),2.83(br d,J=6.0Hz,1H),2.76(br d,J=10.8Hz,2H),2.69-2.65(m,2H),2.36-2.32(m,2H),2.12-1.94(m,6H),1.89-1.73(m,4H),1.68-1.60(m,2H),1.51-1.43(m,2H),0.70(br t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=633.5.

[0172] Example 5

[0173] [ka] 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one

[0174] [ka]

[0175] Step A. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one: 5-ethyl-6-fluoro-4-(8-fluoro)-3-hydroxynaphthalen-1-yl in DMF (0.1 mL) and ACN (0.1 mL) To a solution of 1-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)naphthalen-2-ol (50.0 mg, 1.0 equiv.) and 1,3,7-triazaspiro[4.5]decan-2-one (15.7 mg, 1.2 equiv.) was added KPO (53.8 mg, 3.0 equiv.). The mixture was stirred at 60° C. for 12 hours. The mixture was diluted with water (2 mL) and extracted with EtOAc (2 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC [Unisil 3-100 C18 Ultra 150×50mm×3um; A: water (FA), B: ACN, B%: 15%-45% over 7 minutes] and lyophilized. The impurities were further purified by preparative HPLC [Waters Xbridge 150×25mm×5um; A: water (NH4HCO3), B: ACN, B%: 37%-67% over 8 minutes] and lyophilized to give the title compound (3.25mg, 5.8% yield) as a white solid. 1H NMR (400MHz, methanol-d4) δ=7.89(dd,J=2.8,8.8Hz,1H),7.66(dd,J=6.0,9.2Hz,1H),7.37-7.30(m,1H),7.27-7.18(m,2H),6.95(d,J= 2.4Hz,1H),5.51-5.27(m,1H),4.50-4.27(m,2H),4.02-3.81(m,4H),3.42(ddd,J=2.8,9.2,14.0Hz,4H),3.30-3.27(m,1H),3.14(br dd,J=1.6,6.4Hz,1H),2.53-2.29(m,4H),2.28-2.17(m,1H),2.13-1.86(m,7H),0.82-0.72(m,3H);LCMS(ESI,M+1):m / z=647.4.

[0176] Example 6

[0177] [ka] 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[4.5]decane-1,3-dione

[0178] [ka]

[0179] Step A. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[4.5]decane-1,3-dione: 5-ethyl-6-fluoro-4-(8- To a solution of fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)naphthalen-2-ol (70.0 mg, 1.0 equiv.) and 2,7-diazaspiro[4.5]decane-1,3-dione (36.3 mg, 1.8 equiv.) was added KPO (75.4 mg, 3.0 equiv.). The mixture was stirred at 40 °C for 12 h. The mixture was quenched by adding water (2 mL) and then extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by preparative HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (10 mM NH4HCO3), B: ACN, B%: 41% to 71% over 8 min] and lyophilized to give the title compound (10.0 mg, 11% yield) as a white solid; 1 H NMR (400MHz, methanol-d4)δ=7.83(br d,J=8.4Hz,1H),7.70-7.60(m,1H),7.35-7.28(m,1H),7.27-7.18(m,2H),6.95(s,1H),5.41-5.36(m,1H),5.24(br d,J=1.2Hz,1H),4.63-4.47(m,1H),4.43-4.33(m,1H),4.30-4.17(m,2H),3.71-3. 54(m,2H),3.23(brs,2H),3.08-2.84(m,2H),2.68(dd,J=2.0,18.0Hz,1H),2.56(br d,J=5.6Hz,3H),2.29-2.11(m,3H),2.06-1.85(m,6H),1.30(br dd,J=1.6,3.2Hz,1H),0.87-0.66(m,3H). LCMS (ESI, M+1): m / z=660.4.

[0180] Example 7

[0181] [ka] 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl-1,3,7-triazaspiro[4.5]decane-2,4-dione

[0182] [ka]

[0183] Step A. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: 5-ethyl-6-fluoro-4-(8-fluoro)-3-hydroxynaphthalen-1-yl in DMF (0.5 mL) and ACN (0.5 mL). To a solution of fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)naphthalen-2-ol (150 mg, 1.0 equiv.) and 1,3,7-triazaspiro[4.5]decane-2,4-dione (51.5 mg, 1.2 equiv.) was added KPO (161 mg, 3.0 equiv.). The mixture was stirred at 40 °C for 12 h. The mixture was diluted with water (2 mL) and extracted with EtOAc (2 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified twice by preparative HPLC [Phenomenex Synergi C18 150×25mm×10um; A: water (FA), B: ACN, B%: 15%-45% over 10min] to give the title compound (8.08mg, yield 4.5%, FA) as a yellow solid; 1H NMR(400MHz,DMSO-d6)δ=10.83(br d,J=1.2Hz,1H),8.70(d,J=7.6Hz,1H),8.18(brs,1H),7.84(br dd,J=3.6,8.4Hz,1H),7.76(dd,J=6.0,9.2Hz,1H),7.39-7.27(m,3H),6.96-6.90(m,1H) ),5.40-5.16(m,1H),4.30-4.17(m,2H),4.14-4.07(m,1H),4.05-3.98(m,1H),3.46(br d,J=13.2Hz,2H),3.36-3.33(m,1H),3.09(br d,J=12.4Hz,2H),2.86-2.78(m,1H),2.38-2.31(m,2H),2.15-1.97(m,5H),1.91-1.74(m,5H),0.71(br t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=661.3.

[0184] Example 8

[0185] [ka] 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide

[0186] [ka]

[0187] Step A. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide: 5-ethyl-6-fluoro-4-(8-fluoro)-3-hydroxynaphthalen-1-yl in DMF (0.5 mL) and ACN (0.5 mL). To a solution of fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)naphthalen-2-ol (200 mg, 1.0 equiv.) and 2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide (70.0 mg, 1.1 equiv.) was added KPO (215 mg, 3.0 equiv.). The mixture was stirred at 40 °C for 12 h. The mixture was diluted with water (2 mL) and extracted with EtOAc (2 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified twice by preparative HPLC [Phenomenex Synergi C18 150×25mm×10um; A: water (FA), B: ACN, B%: 16%-46% over 10min] to give the title compound (16.39mg, yield 6.7%) as a pale yellow solid; 1 H NMR(400MHz,DMSO-d6)δ=9.92(brs,1H),7.85(dd,J=8.8,13.6Hz,1H),7.76(dd,J=6.4,8.4Hz,1H),7.38-7. 26(m,4H),7.24-7.13(m,1H),6.92(s,1H),5.43-5.12(m,1H),4.15-3.93(m,3H),3.87-3.75(m,1H),3.73-3 .43(m,2H),3.32-3.27(m,1H),3.14-3.06(m,3H),3.01(brs,1H),2.88-2.77(m,1H),2.42-2.31(m,2H),2.1 3(brs,1H),2.08-1.96(m,3H),1.90-1.74(m,6H),0.71(dt,J=2.4,7.2Hz,3H);LCMS(ESI,M+1):m / z=683.3.

[0188] Example 9

[0189] [ka] 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0190] [ka]

[0191] Step A. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 5-ethyl-6-fluoro-4-(8-fluoro)-3-hydroxynaphthalen-1-yl in DMF (0.1 mL) and ACN (0.1 mL). To a solution of 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)naphthalen-2-ol (55.0 mg, 1.0 equiv.) and N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (23.2 mg, 1.2 equiv.) was added KPO (59.2 mg, 3.0 equiv.). The mixture was stirred at 60° C. for 12 hours. The mixture was diluted with water (2 mL) and extracted with EtOAc (2 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified twice by preparative HPLC [Unisil 3-100 C18 Ultra 150×50mm×3um; A: water (FA), B: ACN, B%: 17% to 47% over 7 min] to give the title compound (3.80 mg, 5.7% yield) as a white solid; 1 H NMR (400 MHz, methanol-d4) δ = 7.95 (d, J = 8.4 Hz, 1H), 7.65 (dd, J = 5.6, 9.2 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.27-7.19 (m, 2H), 6.95 (d, J = 2.4 Hz, 1H), 6.71 (s, 1H), 5.45-5.27 (m, 1H), 5.24-5.10 (m, 2H),4.56-4.50(m,2H),4.45-4.24(m,4H),3.52-3.33(m,6H),3.14-3.06(m,4H),2.49-2.31(m ,5H),2.29-2.14(m,2H),2.12-1.89(m,3H),0.76(t,J=6.8Hz,3H);LCMS(ESI,M+1):m / z=700.3.

[0192] Example 10

[0193] [ka] (3R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol

[0194] [ka]

[0195] Step A. (R)-1-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol: To a solution of 7-bromo-2,4-dichloro-6,8-difluoroquinazolin-4-yl (300 mg, 1 eq.) and 4 Å MS (1.5 mg) in DCM (0.5 mL) was added DIEA (370 mg, 3 eq.) and (R)-3-methylpiperidin-3-ol (132 mg, 1.2 eq.). The mixture was stirred at 0° C. for 0.5 h. Upon completion, the residue was extracted with DCM (10 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the residue. The residue was purified by reverse-phase HPLC (0.1% FA condition) to give the title compound (170 mg, 45% yield) as a yellow solid. LCMS (ESI, M+1, M+3): m / z=391.9, 393.9.

[0196] Step B. (R)-1-(7-Bromo-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol: To a solution of (3R)-1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methyl-piperidin-3-ol (165 mg, 1 eq.) and 4 Å MS (1.5 mg) in dioxane (1 mL) was added DIEA (217 mg, 4 eq.) and (1-((dimethylamino)methyl)cyclopropyl)methanol (271 mg, 5 eq.). The mixture was stirred at 90° C. for 48 hours. Upon completion, the reaction mixture was filtered and purified by reverse-phase HPLC (0.1% FA condition) to afford the title compound (67 mg, 33% yield) as a yellow oil. LCMS (ESI, M+1, M+3): m / z=484.9, 486.9.

[0197] Step C. (3R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol: (R)-1-(7-bromo-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (62 mg, 1 mL) in THF (1 mL). A mixture of 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (69.3 mg, 2 equiv.), methanesulfonato(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (7.98 mg, 0.1 equiv.), and CsCO (107 mg, 3 equiv.) was degassed and purged with N three times. The mixture was then stirred at 60 °C under a N atmosphere for 12 h. Upon completion, the mixture was extracted with EtOAc (10 mL × 3). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 × 30 mm × 5 μm; mobile phase: [water (FA)-ACN]; B%: 17% to 47%, 8 min) to give the title compound (18.4 mg, yield 26%) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ = 7.88-7.77 (m, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.33-7.20 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 4.43-4.34 (m, 2H), 4.32-4.21 (m, 1H), 4.08 (br d,J=13.6Hz,1H),3.54-3.42(m,1H),3.42-3.35(m,1H),2.86(brs,2H),2.69-2.50(m,7H),2.49-2.41(m,1H),2.20-2.0 9(m,1H),1.88-1.71(m,3H),1.28(d,J=11.2Hz,3H),0.88-0.76(m,5H),0.73-0.61(m,2H);LCMS(ESI,M+1):m / z=595.3.

[0198] Example 11

[0199] [ka] (R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-((R)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol

[0200] Example 12

[0201] [ka] (R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-((S)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol

[0202] [ka]

[0203] Step A. (R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-((R)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol: (3R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (35.0 mg, 1 equiv.) was purified by SFC [Column: DAICEL CHIRALPAK AD 250 mm × 30 mm × 10 μm; Mobile phase: 0.1% NH₃·H₂O in IPA; B%: 45%–45%, 3.3 min] (t RPurification by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: water (FA)-ACN]; B%: 20% to 50%, 2 min] gave two peaks.

[0204] Peak 1 (Example 11) (35.0 mg, 1 equivalent) was purified by SFC [column: DAICEL CHIRALPAK AD (250 mm × 30 mm × 10 μm); mobile phase: 0.1% NH₃·H₂O in IPA; B%: 45%–45%, 3.3 min] (t R : 1.944 min) and purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: water (FA)-ACN]; B%: 20% to 50%, 2 min] to give the title compound (6.74 mg, yield 18%, 0.22 FA) as a white solid; 1 H NMR (400MHz, methanol-d4)δ=7.83(dd,J=1.6,10.0Hz,1H),7.68(dd,J=6.0,9.2Hz,1H),7. 29(d,J=2.8Hz,1H),7.25(t,J=9.2Hz,1H),6.98(d,J=2.8Hz,1H),4.38(s,2H),4.24(br d,J=13.6Hz,1H),4.07(br d,J=13.2Hz,1H),3.48-3.34(m,2H),2.79(brs,2H),2.57(brs,6H),2.53-2.31(m,2H),2.24-2.07(m,1H),1.91-1.6 9(m,3H),1.29(s,3H),0.90-0.75(m,5H),0.65(brs,2H);LCMS(ESI,M+1):m / z=595.4;HPLC:>99%ee,Column: Chiralpak AD-3 50×4.6mm ID, 3 μm, Mobile phase: Phase A for CO2 and Phase B for IPA (0.05% DEA), Gradient elution: 5% to 40% IPA (0.05% DEA) in CO2, Flow rate: 3 mL / min, Detector: 220 nm, t R :1.942 minutes.

[0205] Peak 2 (Example 12) (13.5 mg, 36% yield, 0.4 FA) as a white solid; 1H NMR (400MHz, methanol-d4)δ=7.80(br d,J=9.6Hz,1H),7.68(dd,J=6.0,9.2Hz,1H),7.29(d,J=2.8Hz,1H),7.25(t,J=9.6Hz,1H),6.98(d,J=2.8Hz,1H),4.44-4.33(m,2H),4.27(br d,J=12.8Hz,1H),4.07(br d,J=13.2Hz,1H),3.51(d,J=13.2Hz,1H),3.45-3.35(m,1H),2.89-2.70(m,2H),2.67-2.53(m,6H),2.53-2.32(m,2H),2.23-2.08( m,1H),1.91-1.68(m,3H),1.26(s,3H),0.90-0.74(m,5H),0.66(brs,2H);LCMS(ESI,M+1):m / z=595.4;HPLC:99%ee,Column:Chiralpak AD-3 50×4.6mm ID, 3 μm, Mobile phase: Phase A against CO2 and Phase B against IPA (0.05% DEA), Gradient elution: 5% to 40% IPA (0.05% DEA) in CO2, Flow rate: 3 mL / min, Detector: 220 nm, t R :2.227 minutes.

[0206] Example 13

[0207] [ka] (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

[0208] [ka]

[0209] Step A. (R)-1-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol: To a mixture of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (2 g, 1.0 equiv.), 4 Å MS (600 mg), and DIPEA (3.29 g, 4.4 mL, 4.0 equiv.) in DCM (20 mL) was added (R)-3-methylpiperidin-3-ol (660 mg, 0.9 equiv.) in DCM (3 mL) dropwise at 0° C. The mixture was stirred at 25° C. for 0.5 h. The mixture was filtered, diluted with water (30 mL), extracted with DCM (3×30 mL), washed with brine (50 mL), dried over NaSO, and concentrated. The residue was purified by reverse phase flash [C18, 0.1% formic acid conditions] to give the title compound (1.4 g, 55% yield) as a yellow solid; LCMS [ESI, M+3]: 393.7.

[0210] Step B. (R)-1-(7-Bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (230 mg, 1.0 equiv.) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (102 mg, 1.1 equiv.) in dioxane (2 mL) was added DIPEA (227 mg, 306 μL, 1.1 equiv.) and 4 Å MS (50 mg). The mixture was stirred at 100° C. for 72 hours. The reaction mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (4 x 5 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by reverse-phase flash [C18, 0.1% formic acid] to give the title compound (86 mg, 27% yield) as a yellow solid; LCMS [ESI, M+3]: 517.2.

[0211] Step C. (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol: (R)-1-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl) in THF (1 mL) A mixture of 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (70.0 mg, 1.0 equiv.), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (85.9 mg, 2.0 equiv.), Ad2nBuP-Pd-G3 (9.89 mg, 0.1 equiv.), and Cs2CO3 (1.5 M, 272 μL, 3.0 equiv.) was degassed and purged with N2 three times. The mixture was then stirred at 60 °C under a N2 atmosphere for 2 h. The mixture was filtered, diluted with water (10 mL), and extracted with ethyl acetate (4 × 10 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by reverse-phase flash [C18, 0.1% formic acid condition] and preparative HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3), B: ACN; B%: 50% to 80% over 10 min] to give the title compound (11 mg, 12% yield) as a white solid; 1H NMR (400 MHz, methanol-d4) δ = 7.80-7.77 (m, 1H), 7.67 (dd, J = 5.6, 9.2 Hz, 1H), 7.31-7.21 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 5.39-5.23 (m1H), 4.63-4.59 (m, 1H), 4.35-4.18 (m, 3H), 4.05 (br d,J=13.2Hz,1H),3.55-3.37(m,2H),3.24-3.17(m,2H),3.08-2.95(m,1H),2.62-2.50(m,1H),2.49-2.26(m, 2H),2.25-2.10(m,3H),2.03-1.70(m,6H),1.27(d,J=12.0Hz,3H),0.81(q,J=7.2Hz,3H);SFC[Column: Chiralpak AD-3 50×4.6mm ID, 3 μm Mobile phase: Phase A against CO2 and Phase B against IPA (0.05% DEA); gradient elution of IPA (0.05% DEA) in CO2 from 5% to 40%, flow rate: 3 mL / min; detector: PDA; column temperature: 35 °C; back pressure: 100 bar]; LCMS (ESI, M+1): m / z = 625.3.

[0212] Example 14

[0213] [ka] (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol

[0214] [ka]

[0215] Step A. (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro- A solution of (1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (150 mg, 1.0 equiv.), (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (156 mg, 5.0 equiv.), and DIEA (371 mg, 11.7 equiv.), 4 Å molecular sieves (10 mg) was stirred at 40°C to 60°C for 72 hours. After completion, the mixture was filtered and purified by preparative HPLC (column: Phenomenex Luna C18 150 * 25mm * 10 μm; Mobile phase: [water (FA)-ACN]; B%: 20%-50%, 10 min) and (Column: Welch Xtimate C18 150 * 25mm * 5 um; mobile phase: [water (NH3H2O)-ACN]; B%: 45%-75%, 8 min) to afford the title compound (7.57 mg, 4.8% yield) as a white solid. 1H NMR (400MHz, methanol-d4)δ=8.04-7.96(m,1H),7.69(dd,J=5.6,8.8Hz,1H),7.33-7 .20(m,2H),6.99(d,J=2.4Hz,1H),5.44-5.22(m,1H),4.77-4.67(m,1H),4.61(br d,J=11.2Hz,1H),4.41-4.34(m,1H),4.32(d,J=10.4Hz,1H),4.25-4.19(m,1H),3.63-3.55(m,1H),3.47(br d,J=12.4Hz,1H),3.40-3.35(m,1H),3.30-3.14(m,3H),3.09-2.99(m,1H),2.66-2.53(m,1H),2.48-2.41(m,1H),2.38(br d,J=4.0Hz,1H),2.28(brs,1H),2.27-2.24(m,1H),2.24-2.14(m,2H),2. 08-1.97(m,2H),1.96-1.81(m,3H),1.60-1.45(m,1H),0.87-0.78(m,3H). LCMS (ESI, M+1): m / z=637.3.

[0216] Example 15

[0217] [ka] (6S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0218] [ka]

[0219] Step A. (6S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro) in DMF (1 mL) A mixture of (S)-6-methyl-1,4-oxazepan-6-ol (226 mg, 7.0 equiv.), (S)-6-methyl-1,4-oxazepan-6-ol (226 mg, 7.0 equiv.), and DIEA (191 mg, 6.0 equiv.) with 4 Å molecular sieves (10.0 mg) was stirred at 80° C. for 72 hours. After completion, the mixture was filtered and purified by preparative HPLC (column: Phenomenex Luna C18 150 * 25mm * 10 um; mobile phase: [water (FA)-ACN]; B%: 20%-50%, 10 min) to give the title compound (16.1 mg, 9% yield) as an off-white solid; 1 H NMR (400MHz, methanol-d4)δ=8.25-8.07(m,1H),7.68(dd,J=6.0,8.8Hz,1H),7.31-7.21(m,2H),6.98(dd,J=2.4,8. 8Hz,1H),5.54-5.32(m,1H),4.55-4.37(m,4H),4.13-3.97(m,2H),3.94-3.82(m,2H),3.75-3.56(m,3H),3.50(br dd,J=7.2,9.6Hz,2H),3.23-3.16(m,1H),2.61-2.33(m,4H),2.29-2.21(m,1H),2.18-2.08(m, 2H),2.04-1.93(m,1H),1.26(d,J=8.4Hz,3H),0.84-0.71(m,3H);LCMS(ESI,M+1):m / z=641.1.

[0220] Example 16

[0221] [ka] 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

[0222] [ka]

[0223] Step A. (3aR,6aS)-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione: 4-(6,8-difluoro-2-(((2R, A mixture of (7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (100 mg, 1.0 equiv.), (3aR,6aS)-tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (161 mg, 7.0 equiv.) and 4 Å molecular sieves (5 mg) was stirred at 80° C. for 48 hours. Upon completion, the mixture was filtered and purified by preparative HPLC (column: Phenomenex Luna C18 150 * 25mm * 10 μm; Mobile phase: [water (NH4HCO3)-ACN]; B%: 35%-65%, 8 min) and preparative HPLC (column: Phenomenex luna C18 150 * 25mm * The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 μm; mobile phase: [water (FA)-ACN]; B%: 18%-48%, 10 min). The desired fractions were collected and lyophilized. * 25mm* 10 um; mobile phase: [water (FA)-ACN]; B%: 18%-48%, 10 min) to give the title compound (6.27 mg, yield 5%) as a white solid; 1 H NMR (400MHz, methanol-d4) δ=7.88(br d,J=10.0Hz,1H),7.68(dd,J=6.0,9.2Hz,1H),7.34-7.18(m,2H),6.99(d,J=2.4Hz,1H),5.53-5.33(m,1H),4.66(br d,J=12.0Hz,2H),4.52-4.36(m,2H),4.28-4.08(m,2H),3.69(br d,J=7.6Hz,2H),3.73-3.45(m,2H),3.26-3.18(m,1H),2.59-2.33(m,4H),2.31-2.24(m,1H),2.22-2.11(m,2H),2.08-1.99(m,1H),0.79(br t,J=6.8Hz,3H);LCMS(ESI,M+1):m / z=650.1.

[0224] Example 17

[0225] [ka] 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one

[0226] [ka]

[0227] Step A. 6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one: A mixture of 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (150 mg, 1 equiv.), 1,6-diazaspiro[3.5]nonan-2-one (68.9 mg, 2 equiv.), and DIEA (191 mg, 6 equiv.) in DMF (1 mL) was stirred at 40° C. for 12 h. After completion, the mixture was purified by preparative HPLC using Phenomenex Luna C18 150 * 25mm * 10 μm; mobile phase: [water (FA)-ACN]; B%: 20%-50%, 10 min to obtain the title compound (53.8 mg, 33% yield) as a white solid; 1 H NMR (400MHz, methanol-d4)δ=7.75-7.60(m,2H),7.35-7.19(m,2H),6.98(s,1H),5.55-5.30(m,1H),4.55-4.37(m,2H),4.22-4.07(m ,2H),3.91-3.77(m,1H),3.74-3.53(m,4H),2.90-2.71(m,2H),2.61-2.35(m,4H),2.33-2.26(m,1H),2.22-1.86(m,8H),0.80(br t,J=7.2Hz,3H). LCMS (ESI, M+1): m / z=650.6.

[0228] Example 18

[0229] [ka] (2S,4s)-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-6-azaspiro[3.5]nonan-2-ol

[0230] Example 19

[0231] [ka] (2R,4r)-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-6-azaspiro[3.5]nonan-2-ol

[0232] [ka]

[0233] Step A. 7-Bromo-2-chloro-6,8-difluoro-4-(2,2,2-trifluoroethoxy)quinazoline: To a solution of 2,2,2-trifluoroethanol (2.39 g, 1.0 equiv.) in THF (80 mL) was added NaH (1.05 g, 1.1 equiv.) at 0° C. After completion, the mixture was stirred at 10° C. for 0.5 h, and the mixture was added to a solution of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (7.5 g, 1.0 equiv.) in THF (80 mL) with stirring at −40° C. The mixture was stirred at −40° C. for 1 h and then at 25° C. for 2 h. The reaction mixture was quenched by the addition of HO (100 mL) at 0° C. and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase flash [C18, water (FA, 0.1%) / acetonitrile] to give the title compound (5 g, 54.3% yield). LCMS (ESI, M+1, M+3): m / z = 376.7, 378.7.

[0234] Step B. 7-Bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline: To a mixture of 7-bromo-2-chloro-6,8-difluoro-4-(2,2,2-trifluoroethoxy)quinazoline (4.9 g, 1.0 equiv.) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (5.37 g, 2.6 equiv.) in THF (50 mL) was added NaCO (4.13 g, 3.0 equiv.). The mixture was stirred at 40° C. for 24 hours and at 60° C. for an additional 16 hours. Upon completion, the mixture was filtered to remove NaCO. The residue was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250 × 50 mm × 10 μm; mobile phase: [water (FA)-ACN]; B%: 25% to 55%, 30 min) to give the title compound (3.3 g, 50% yield) as a white solid. LCMS (ESI, M+1, M+3): m / z = 499.9, 501.9.

[0235] Step C. 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: 7-Bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol in methoxycyclopentane (35 mL). To a solution of (2,2,2-trifluoroethoxy)quinazoline (3.3 g, 1.0 equiv.) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (2.50 g, 1.2 equiv.) was added CsCO (1.5 M, 3.0 equiv.) at 25 °C. The suspension was degassed under vacuum and purged twice with N. Methanesulfonato(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (480 mg, 0.1 equiv.) was added, and the suspension was degassed under vacuum and purged three times with N. The mixture was stirred at 90 °C for 2 h. After completion, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250 × 50 mm × 10 um; mobile phase: [water (FA)-ACN]; B%: 20% to 50%, 22 min) to give the title compound (2.9 g, 71.4% yield) as a white solid. LCMS (ESI, M+1): m / z = 610.5.

[0236] Step D. (2S,4s)-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-6-azaspiro[3.5]nonan-2-ol and trans-(2R,4r)-6-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-6-azaspiro[3.5]nonan-2-ol A mixture of 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (100 mg, 1.0 equiv.), 6-azaspiro[3.5]nonan-2-ol (43.7 mg, 1.5 equiv., HCl), 4 Å molecular sieves (50.0 mg, 1.0 equiv.), and KPO (104 mg, 3.0 equiv.) in DMF (0.5 mL) and ACN (0.5 mL) was degassed and purged with N three times, after which the mixture was stirred under a N atmosphere at 40 °C for 12 h. Upon completion, the mixture was filtered. The reaction mixture was cooled to room temperature. Ethyl acetate (40 mL) and water (40 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined extracts were washed with brine (40 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by preparative TLC (SiO2, dichloromethane / methanol = 10 / 1 column: Phenomenex Luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; B%: 22% to 52%, 10 min) to give two peaks.

[0237] Example 18 (25.1 mg, 46.5% yield) as a white solid: 11H NMR (400 MHz, CD3OD) δ = 8.53 (br s, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.63 (br d, J = 10.0 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 5.46 - 5.22 (m, 1H), 4.41 - 4.21 (m, 3H), 3.88 (s, 2H), 3.85 - 3.74 (m, 2H), 3.41 (br d, J = 2.0 Hz, 3H), 3.14 - 2.99 (m, 1H), 2.66 - 2.51 (m, 1H), 2.48 - 2.25 (m, 3H), 2.25 - 2.14 (m, 3H), 2.11 - 1.99 (m, 2H), 1.98 - 1.90 (m, 1H), 1.89 - 1.68 (m, 6H), 0.81 (br t, J = 7.2 Hz, 3H); LCMS (ESI, M+1): m / z = 651.4。

[0238] Example 19 as a white solid (10.3 mg, yield 18.7%): 1 1H NMR (400 MHz, METHANOL-d4) δ = 8.54 (br s, 1H), 7.68 (dd, J = 5.8, 9.2 Hz, 1H), 7.60 (br d, J = 9.8 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.25 (t, J = 9.4 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 5.54 - 5.20 (m, 1H), 4.43 - 4.29 (m, 2H), 4.24 (br t, J = 7.3 Hz, 1H), 3.97 - 3.73 (m, 4H), 3.53 - 3.35 (m, 3H), 3.17 - 3.02 (m, 1H), 2.66 - 2.52 (m, 1H), 2.50 - 2.37 (m, 2H), 2.36 - 2.28 (m, 2H), 2.27 - 2.16 (m, 2H), 2.13 - 2.02 (m, 2H), 2.01 - 1.90 (m, 1H), 1.80 (br s, 4H), 1.69 (td, J = 7.3, 11.7 Hz, 2H), 0.81 (br t, J = 7.4 Hz, 3H); LCMS (ESI, M+1): m / z = 651.4

[0239] Example 20

[0240] [Chemical formula] 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one

[0241] [ka]

[0242] Step A. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one: 4-(6,8-difluoro-2-(((2R,7aS)-2-fluoro)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one in DMF (0.2 mL) To a mixture of (hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (150 mg, 1.0 equiv.), 1,3,7-triazaspiro[4.5]decan-2-one (76.4 mg, 2.0 equiv.), DIEA (318 mg, 10 equiv.) and 4 Å molecular sieves (10 mg) were added. The mixture was stirred at 60° C. for 12 hours. Upon completion, the mixture was filtered and purified by preparative HPLC (column: Phenomenex Luna C18 150 * 25mm * 10 μm; Mobile phase: [water (FA)-ACN]; B%: 18%-48%, 10 min) and (Column: Welch Xtimate C18 150 * 25mm * 5 um; mobile phase: [water (NH3H2O)-ACN]; B%: 30%-60%, 8 min) to give the title compound (16.7 mg, 10% yield) as a white solid. 1H NMR (400MHz, methanol-d4) δ=7.74-7.57(m,2H),7.36-7.12(m,2H),6.98(brs,1H),5.44-5.20(m,1H),4.37-4.17(m,2H),3.95-3.73(m,4 H),3.43(ddd,J=2.4,6.8,9.2Hz,1H),3.30-3.13(m,4H),3.06-2.95(m,1H),2.60-2.11(m,4H),2.06-1.84(m,7H),0.88-0.71(m,3H). LCMS (ESI, M+1): m / z=665.2.

[0243] Example 21

[0244] [ka] 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

[0245] [ka]

[0246] Step A. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione in DMF (0.5 mL) To a solution of (2-hydroxy-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (100 mg, 1.0 equiv.) and 1,3,9-triazaspiro[4.5]decane-2,4-dione (55.51 mg, 2.0 equiv.), 4 Å MS (20 mg) and DIEA (63.6 mg, 3.0 equiv.) were added. The mixture was stirred at 40 °C for 24 h. The reaction mixture was filtered and purified by preparative HPLC [column: Phenomenex C18 75 × 30 mm × 3 μm; mobile phase: (water (FA)-ACN]; B%: 18% to 48%, 7 min] to give the title compound (32.7 mg, 29% yield) as a white solid. 1 H NMR (400MHz, methanol-d4)δ=7.77-7.66(m,2H),7.36-7.22(m,2H),7.01(d,J=2.4Hz,1H),5.56-5.35(m,1H),4.56-4.31(m,4H),3.74-3.4 9(m,5H),3.30-3.21(m,1H),2.64-2.37(m,4H),2.35-2.15(m,4H),2.12-1.94(m,4H),0.88-0.76(m,3H));LCMS(ESI,M+1):m / z=679.6.

[0247] Example 22

[0248] [ka] 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide

[0249] [ka]

[0250] Step A. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide: 4-(6,8-difluoro-2-(((2R,7aS)-2- To a solution of (fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (150 mg, 1 equiv.), DIEA (254 mg, 8 equiv.), 4 Å molecular sieves (5 mg), and 2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide (94.1 mg, 2 equiv.) were added. The mixture was stirred at 40 °C for 72 h. After completion, the mixture was filtered and purified by Phenomenex Luna C18 150 × 25 mm × 10 μm column (mobile phase: [water (FA)-ACN]; B%: 20% to 50%, 10 min) to give the title compound (9.9 mg, 5.4% yield) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ = 8.57-8.46 (m, 1H), 7.74-7.64 (m, 2H), 7.29 (d, J = 2.8 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 7.00-6.94 (m, 1H), 5.51-5.32 (m, 1H), 4.51-4.28 (m, 3H), 4.25-4.14 (m, 1H), 3.75-3.45 (m, 5H), 3.42 (br d,J=11.6Hz,1H),3.25-3.17(m,2H),2.63-2.33(m,4H),2.32-2.22(m,1H),2.17-1.98(m,5H),1.95-1.81(m,2H),0.81(br t,J=7.2Hz,3H). LCMS (ESI, M+1): m / z=701.3.

[0251] Example 23

[0252] [ka] 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0253] [ka]

[0254] Step A. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide in DMF (1.5 mL) To a solution of (150 mg, 1.0 equiv.) hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol was added DIEA (254 mg, 8.0 equiv.), 4 Å molecular sieves (5 mg), and N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (102 mg, 2.0 equiv.). The mixture was stirred at 40° C. for 72 h. After completion, the mixture was filtered and purified by (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; B%: 22%-52%, 10 min) and preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (NH3H2O)-ACN]; B%: 32%-62%, 8 min) to give the title compound (12.9 mg, 7.1% yield) as a yellow solid; 1 H NMR (400MHz, methanol-d4)δ=7.84-7.63(m,2H),7.35-7.20(m,2H),6.98(brs,1H),6.71(s,1H),5.56-5.31(m,1H),5.24-5.06(m,2H) ,4.61-4.28(m,6H),3.70-3.45(m,3H),3.35(s,3H),3.03(s,4H),2.71-2.48(m,2H),2.46-2.24(m,5H),2.22-1.96(m,3H),0.80(br t,J=6.8Hz,3H);LCMS(ESI,M+1):m / z=718.3.

[0255] Example 24

[0256] [ka] (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

[0257] [ka]

[0258] Step A. (R)-1-(7-Bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol: To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (723 mg, 1.0 equiv.) and DIEA (1.41 g, 5.0 equiv.), 4 Å MS (100 mg) in DCM (10 mL) was added (R)-3-methylpiperidin-3-ol (302 mg, 1.2 equiv.) in DCM (1 mL) dropwise at 0 °C. The reaction was stirred at 0-15 °C for 0.5 h. Upon completion, the reaction mixture was diluted with HO (10 mL) and extracted with DCM (20 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give the title compound (541 mg, yield 59%, purity 98.7%) as a yellow solid; LCMS (ESI, M+1): m / z = 409.9.

[0259] Step B. (R)-1-(7-Bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol: (R)-1-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (478 mg, 1.0 equiv.), (((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (558 mg, 3 To a mixture of 1.0 eq. DIEA (755 mg, 5.0 eq.) and 4 Å molecular sieves (50 mg) was added DIEA (755 mg, 5.0 eq.). The reaction was stirred at 90 °C for 16 h. Upon completion, the reaction mixture was diluted with HO (10 mL) and extracted with ethyl acetate (10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The crude was purified by reverse-phase flash (0.1% FA condition) to give the title compound (214 mg, 32% yield, 93.0% purity) as a pale yellow solid; LCMS (ESI, M+1): m / z = 533.1.

[0260] Step C. (3R)-1-(6-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol: (R)-1-(7-bromo-6-chloro-8-fluoro-2-(((2 To a mixture of R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (100 mg, 1.0 equiv.), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (71.3 mg, 1.2 equiv.), KCO (77.9 mg, 3.0 equiv.), RuPhos Pd G (15.7 mg, 0.1 equiv.) and RuPhos (8.77 mg, 0.1 equiv.) were added under N under N. The reaction was stirred at 80 °C for 1.5 h. Upon completion, the reaction mixture was diluted with HO (2 mL) and extracted with ethyl acetate (4 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude material was purified by reverse-phase flash (0.1% FA condition) and preparative HPLC (Phenomenex Synergi C18 150 x 25 mm x 10 μm; A: water (0.225% FA), B: ACN, B%: 19%-49% over 10 min) to give the title compound (4.42 mg, 3% yield) as a white solid. 1H NMR (400MHz, methanol-d4): δ=8.57-8.48(m,1H),8.17-8.09(m,1H),7.67(dd,J=6.0,9.2Hz,1H),7.28(d,J=2.8Hz,1H),7.24 (t,J=9.6Hz,1H),6.89(d,J=2.8Hz,1H),5.47-5.29(m,1H),4.60(brs,1H),4.45-4.38(m,1H),4.36-4.31(m,1H),4.10(br d,J=14.0Hz,1H),3.57(d,J=13.2Hz,1H),3.52-3.34(m,4H),3.18-3.10(m,1H),2.68-2.54(m,1H),2.52-2.04( m,7H),2.01-1.92(m,1H),1.88-1.71(m,3H),1.32-1.25(m,3H),0.84-0.74(m,3H);LCMS(ESI,M+1):m / z=641.2.

[0261] Example 25

[0262] [ka] 5-(6-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0263] [ka]

[0264] Step A. 5-(7-Bromo-2,6-dichloro-8-fluoro-quinazolin-4-yl)-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (400 mg, 1.0 equiv.) in DCM (4 mL) was added DIEA (782 mg, 5.0 equiv.) at 0° C. To the mixture was added N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (385 mg, 1.3 equiv., HCl) and stirred at 25° C. for 0.5 h. The reaction mixture was extracted with dichloromethane (2 x 10 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (515 mg, crude) as a white solid. LCMS (ESI, M+1): m / z = 503.1.

[0265] Step B. 5-(7-bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 5-(7-bromo-2,6-dichloro-8- To a solution of (fluoro-quinazolin-4-yl)-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (515 mg, 1.0 equivalents) was added DIEA (398 mg, 3.0 equivalents) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol (816 mg, 5.0 equivalents). The mixture was stirred at 90°C for 36 hours. The reaction mixture was purified by reverse-phase flash [C18, 0.1% formic acid] to give the title compound (301 mg, 46% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 625.8.

[0266] Step C. 5-(6-chloro-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 5-(7-bromo-6-chloro-8-fluoro-2-fluoro-2-fluoro-2-fluoro-3-hydroxynaphthalen-1-yl)-2-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide in dioxane (3 mL) and HO (1 mL). Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (300 mg, 1.0 equiv.), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (273 mg, 1.8 equiv.), RuPhos A mixture of PdG3 (40.2 mg, 0.1 equiv.), RuPhos (67.21 mg, 0.3 equiv.), and Cs2CO3 (469 mg, 3.0 equiv.) was degassed and purged with N2 three times, after which the mixture was stirred at 80 °C for 6 h under a N2 atmosphere. The reaction mixture was extracted with ethyl acetate (3 × 10 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative HPLC [Unisil 150 × 50 mm × 3 μm; A: water (FA), B: ACN; B%: 15%–45% over 10 min] to afford the title compound (100 mg, 27% yield, 0.7% FA) as a white solid. 1H NMR (400 MHz, methanol-d4) δ = 8.09 (s, 1H), 7.70-6.65 (m, 1H), 7.31-7.21 (m, 2H), 6.89 (d, J = 2.4 Hz, 1H), 6.74 (s, 1H), 5.48-5.30 (m, 1H), 5.21-5.06 (m, 2H), 4.57-4.50 (m, 2H), 4.43-4.27 (m, 4H), 3.60-3.41 (m ,3H),3.35(s,3H),3.19-3.13(m,1H),3.08(s,3H),2.67-2.57(m,1H),2.51-2.31(m,4H),2.29-2.21( LCMS (ESI, M+1): m / z=734.2.

[0267] Example 26

[0268] [ka] (R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol

[0269] [ka]

[0270] Step A. (R)-1-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-3-methylpiperidin-3-ol: To a mixture of 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (100 mg, 1.0 equiv.), (3R)-3-methylpiperidin-3-ol (41.0 mg, 2.0 equiv.) and 4 Å molecular sieves (10 mg) in DMF (1 mL) was added DIEA (69.0 mg, 3.0 equiv.). The mixture was stirred at 60° C. for 24 hours. The mixture was filtered and washed with DMF (1 mL). The residue was purified by preparative HPLC [Phenomenex C18 75 × 30 mm × 3 μm; A: water (FA), B: ACN, B%: 18% to 48% over 7 min] to give the title compound (58.4 mg, 56% yield) as a yellow solid; SFC: Rt = 0.992 min, 1.715 min; (Column: Chiralpak IC-3 50 × 4.6 mm ID, 3 μm; Mobile phase: Phase A for CO2, Phase B for MeOH (0.05% DEA); Gradient elution: 40% MeOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35 ° C; Back pressure: 100 bar). 1H NMR (400MHz, methanol-d4) δ=7.97(d,J=8.6Hz,1H),7.65(dd,J=6.0,9.2Hz,1H),7.31(dd, J=7.2,8.4Hz,1H),7.27-7.18(m,2H),6.95(d,J=1.6Hz,1H),4.48-4.35(m,2H),4.28(br d,J=12.0Hz,1H),4.12(br d,J=13.2Hz,1H),3.63-3.40(m,2H),3.15-2.98(m,2H),2.78(s,6H),2.45(dt,J=3.2,7.2Hz,2H),2.23-2.06(m,1 H),1.89-1.71(m,3H),1.27(d,J=12.8Hz,3H),0.94-0.85(m,2H),0.82-0.72(m,5H);LCMS(ESI,M+1):m / z=577.3.

[0271] Example 27

[0272] [ka] 4-(4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0273] [ka]

[0274] Step A. 7-Bromo-2-chloro-8-fluoro-6-iodo-N,N-dimethylquinazolin-4-amine: To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-iodo-quinazoline (9.20 g, 1.0 equiv.) and DIEA (8.46 g, 3.0 equiv.) in THF (80 mL) was added N-methylmethanamine (2 M, 21.8 mL, 2.0 equiv.) dropwise. The mixture was stirred at −40° C. for 0.5 h. The reaction mixture was dissolved in DCM (700 mL). The mixture was diluted with water (10 mL) and extracted with DCM (30 mL×3). The organic layer was dried over anhydrous sodium sulfate, concentrated, and triturated with MTBE (100 mL) at 20° C. for 20 min to give the title compound (8.00 g, 85% yield) as a yellow solid.

[0275] Step B. 7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-6-iodo-N,N-dimethylquinazolin-4-amine: To a solution of 7-bromo-2-chloro-8-fluoro-6-iodo-N,N-dimethyl-quinazolin-4-amine (8.00 g, 1.0 equiv.), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (8.88 g, 3.0 equiv.) in dioxane (40 mL) was added DIEA (7.21 g, 3.0 equiv.). The mixture was stirred at 100° C. for 96 hours. The reaction mixture was poured into water (200 mL) and a solid formed. The solid was filtered and the filter cake was triturated with PE (200 mL) at 20° C. for 1 hour to give the title compound (7.70 g, 66% yield) as a yellow solid; LCMS (ESI, M+3): m / z=554.9.

[0276] Step C. 7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N,N-dimethyl-6-vinylquinazolin-4-amine: 7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-6-vinylquinazolin-4-amine in dioxane (10 mL) and HO (1 mL). To a solution of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (334 mg, 1.2 equiv.), K2CO3 (749 mg, 3.0 equiv.), and Pd(dppf)Cl2 (13.2 mg, 0.01 equiv.) were added. After degassing and purging with N2 three times, the mixture was stirred under N2 atmosphere at 40 °C for 16 h. The mixture was poured into water (20 mL) and filtered. The filtrate was extracted with ethyl acetate (2 × 20 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude was purified by reverse phase flash [C18, 0.1% formic acid] to give the title compound (300 mg, 35% yield) as a yellow solid; LCMS (ESI, M+3): m / z=455.0.

[0277] Step D. 4-(4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: 7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a( To a solution of (5H)-yl)methoxy)-N,N-dimethyl-6-vinylquinazolin-4-amine (1.80 g, 1.0 equiv.) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (1.37 g, 1.2 equiv.), Ad2nBuP-Pd-G3 (393 mg, 0.15 equiv.) and Cs2CO3 (326 mg, 3 equiv.) were added. The mixture was stirred at 90 °C for 12 h. The mixture was poured into water (20 mL) and filtered. The filtrate was extracted with ethyl acetate (2 × 20 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude was purified by preparative HPLC [Phenomenex luna C18 150 × 40 mm × 5 μm; A: water (FA), B: ACN; B%: 20% to 50% over 10 min] to give the title compound (475 mg, 21% yield) as a yellow solid; 1 H NMR (400 MHz, methanol-d4) δ = 8.58-8.46 (m, 1H), 8.26 (s, 1H), 7.77-7.60 (m, 1H), 7.32-7.16 (m, 2H), 6.93-6.80 (m, 1H), 6.37-6.17 (m, 1H), 5.78-5.60 (m, 1H), 5.53-5.27 (m, 1H), 5.19-5.05 (m, 1H), 4.86 (s, 9H), 4.0 ... .53-4.34(m,2H),3.73-3.56(m,1H),3.55(s,6H),3.44(s,2H),3.24-3.16(m,1H),2.59-2.34(m,3H),2 .31-2.20(m,2H),2.19-2.09(m,2H),2.05-1.95(m,1H),0.81-0.67(m,3H);LCMS(ESI,M+1):m / z=563.2.

[0278] Example 28

[0279] [ka] 4-(Dimethylamino)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-ol

[0280] [ka]

[0281] Step A. 7-Bromo-2,6-dichloro-8-fluoro-N,N-dimethyl-quinazolin-4-amine: To a solution of 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (5.1 g, 1.0 equiv.) in THF (50 mL) was added DIEA (5.99 g, 8.07 mL, 3.0 equiv.) and N-methylmethanamine (2 M, 23.16 mL, 3.0 equiv.). The mixture was stirred at −40° C. for 0.5 h. The mixture was poured into water (20 mL) and filtered. The filtrate was extracted with ethyl acetate (2×50 mL). The organic phase was dried over NaSO and concentrated in vacuo. The crude material was purified by slurrying with acetonitrile (20 mL) at 25° C. for 0.5 h to give the title compound (6.2 g, 88% yield) as a white solid. LCMS (ESI, M+1): m / z = 339.8.

[0282] Step B. 7-Bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N,N-dimethylquinazolin-4-amine: To a mixture of 7-bromo-2,6-dichloro-8-fluoro-N,N-dimethyl-quinazolin-4-amine (6.2 g, 1.0 equivalent), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (14.6 g, 5.0 equivalent) was added. The mixture was stirred at 90° C. for 24 hours. The mixture was filtered. The crude was purified by recrystallization from acetonitrile to give the title compound (4.1 g, 48% yield) as a white solid; LCMS (ESI, M+1): m / z=462.9.

[0283] Step C. 6-Chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N,N-dimethylquinazolin-4-amine: 7-Bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N,N-dimethylquinazolin-4-amine in dioxane (32 mL) and HO (8 mL). A mixture of methylquinazolin-4-amine (4.3 g, 1.0 equiv.), 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.03 g, 1.5 equiv.), RuPhos-Pd-G3 (778.89 mg, 0.1 equiv.), RuPhos (1.30 g, 0.3 equiv.), and Cs2CO3 (9.10 g, 3.0 equiv.) was degassed and purged with N2 three times. The mixture was then stirred at 90 °C under a N2 atmosphere for 3 h. The mixture was poured into water (10 mL) and filtered. The filtrate was extracted with ethyl acetate (4 × 30 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude was purified by reverse phase flash [C18, 0.1% formic acid] to give the title compound (1.6 g, 28% yield) as a yellow solid; LCMS (ESI, M+1): m / z=615.3.

[0284] Step D. 4-(Dimethylamino)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-ol: 6-chloro-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N,N-dimethylquinazolin-4-amine (640 mg, 1.0 equiv.), Pd(dba) (95.3 mg, 0.1 equiv.), t-Bu in dioxane (5 mL) and HO (1 mL). A mixture of Xphos (88.4 mg, 0.2 equiv.) and KOH (175 mg, 3.0 equiv.) was degassed and purged with N2 three times, after which the mixture was stirred under N2 atmosphere at 90 °C for 12 h. The mixture was poured into water (2 mL) and filtered. The filtrate was extracted with ethyl acetate (4 × 5 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude was purified by reverse-phase flash [C18, 0.1% formic acid] to give the title compound (120 mg, 19% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 597.3.

[0285] Step E. 4-(Dimethylamino)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-ol: To a solution of 4-(dimethylamino)-7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-6-ol (35 mg, 1.0 equiv.) in ACN (1 mL) was added HCl·dioxane (4 M, 1 mL) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative HPLC [Phenomenex luna C18 150×25mm×10um; A: water (FA); B: ACN; B%: 14%-34% over 2 min] to give the title compound (120 mg, 19% yield) as a pale yellow solid; 1 H NMR (400 MHz, methanol-d4) δ = 7.65-7.61 (m, 1H), 7.47 (d, J = 1.2 Hz, 1H), 7.28-7.16 (m, 2H), 6.92 (d, J = 2.4 Hz, 1H), 5.34 (s, 1H), 4.52-4.37 (m, 2H), 3.73-3.53 (m, 3H), 3.5 3-3.41(m,6H),3.24(d,J=5.6Hz,1H),2.60-2.37(m,4H),2.35-2.25(m,1H),2.21- 2.10(m,2H),2.01(d,J=4.4Hz,1H),0.85-0.77(m,3H);LCMS(ESI,M+1):m / z=553.4.

[0286] Example 29

[0287] [ka] 4-(6-cyclopropyl-4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0288] [ka]

[0289] Step A. 7-Bromo-6-cyclopropyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N,N-dimethylquinazolin-4-amine: 7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl) in dioxane (5 mL) A mixture of (methoxy)-6-iodo-N,N-dimethylquinazolin-4-amine (500 mg, 1.0 equiv.), cyclopropylboronic acid (233 mg, 3.0 equiv.), Pd(dppf)Cl (66.1 mg, 0.1 equiv.), and KPO (1.5 M, 1.8 mL, 3.0 equiv.) was degassed and purged with N three times. The mixture was then stirred at 80 °C under a N atmosphere for 12 h. The mixture was poured into water (2 mL) and filtered. The filtrate was extracted with ethyl acetate (3 × 40 mL). The organic phase was dried over NaSO and concentrated in vacuo. The crude material was purified by preparative HPLC [YMC Triart C18 150 x 25 mm x 5 μm; A: water (FA); B: ACN; B%: 18% to 48% over 10 min] to give the title compound (92 mg, 22% yield) as a white solid. LCMS (ESI, M+1): m / z = 467.1.

[0290] Step B. 4-(6-Cyclopropyl-4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: 7-Bromo-6-cyclopropyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N, in dioxane (5 mL) and HO (1.0 mL). A mixture of N-dimethylquinazolin-4-amine (82 mg, 1.0 equiv.), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (83.2 mg, 1.50 equiv.), RuPhos-Pd-G3 (14.7 mg, 0.1 equiv.), RuPhos (24.6 mg, 0.3 equiv.), and Cs2CO3 (171 mg, 3.0 equiv.) was degassed and purged with N2 three times. The mixture was then stirred at 90 °C under a N2 atmosphere for 12 h. The mixture was poured into water (1.0 mL) and filtered. The filtrate was extracted with ethyl acetate (3 × 2 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude was purified by preparative HPLC [Phenomenex luna C18 150×25mm×10um; A; water (FA); B: ACN; B%: 22%-52% over 10 min] to give the title compound (14.6 mg, 14% yield) as a white solid; 1 H NMR (400 MHz, methanol-d4) δ = 7.66-7.62 (m, 1H), 7.49 (s, 1H), 7.32-7.17 (m, 2H), 6.94 (d, J = 2.6 Hz, 1H), 5.46-5.25 (m, 1H), 4.43-4.25 (m, 2H), 3.62-3.49 (m, 1H), 3.46 (s, 6H), 3.40 -3.33(m,2H),3.15-3.06(m,1H),2.65-2.53(m,1H),2.48-2.17(m,4H),2.11-2.01(m,2H ),1.99-1.86(m,1H),1.51-1.39(m,1H),0.80-0.56(m,7H);LCMS(ESI,M+1):m / z=577.5.

[0291] Example 30

[0292] [ka] 4-(4-(dimethylamino)-6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0293] [ka]

[0294] Step A. 4-(4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: 7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol in methoxycyclopentane (18 mL) To a solution of (H)-yl)methoxy)-N,N-dimethyl-6-vinylquinazolin-4-amine (1.80 g, 1.0 equiv.) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (1.37 g, 1.2 equiv.), Ad2nBuP-Pd-G3 (393 mg, 0.15 equiv.) and Cs2CO3 (326 mg, 3.0 equiv.) were added. The mixture was stirred at 90 °C for 12 h. The mixture was poured into water (20 mL) and filtered. The filtrate was extracted with ethyl acetate (2 × 20 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography [SiO2, petroleum ether / ethyl acetate=10 / 1 to 1 / 1] to give the title compound (475 mg, yield 21%) as a yellow solid; 1H NMR (400 MHz, methanol-d4) δ = 8.58-8.46 (m, 1H), 8.26 (s, 1H), 7.77-7.60 (m, 1H), 7.32-7.16 (m, 2H), 6.93-6.80 (m, 1H), 6.37-6.17 (m, 1H), 5.78-5.60 (m, 1H), 5.53-5.27 (m, 1H), 5.19-5.05 (m, 1H), 4.86 (s, 9H), 4.06 (s, 9H). 53-4.34(m,2H),3.73-3.56(m,1H),3.55(s,6H),3.44(brs,2H),3.24-3.16(m,1H),2.59-2.34(m,3H),2 .31-2.20(m,2H),2.19-2.09(m,2H),2.05-1.95(m,1H),0.81-0.67(m,3H);LCMS(ESI,M+1):m / z=563.2.

[0295] Step B. 4-(4-(Dimethylamino)-6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To Pd / C (20.0 mg, 10% purity) in MeOH (4 mL) was added 4-(4-(Dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-vinylquinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (200 mg, 1.0 equiv.) with N. The mixture was degassed and purged with H three times, after which the mixture was stirred under an H atmosphere at 25 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC [Phenomenex Synergi C18 150×25mm×10μm; A: water (FA), B: ACN; B%: 19%-49% over 10 min] to give the title compound (31 mg, 15% yield) as a pale yellow solid; 1H NMR (400 MHz, methanol-d4) δ = 8.58-8.48 (m, 1H), 7.97-7.88 (m, 1H), 7.72-7.62 (m, 1H), 7.33-7.17 (m, 2H), 6.94-6.86 (m, 1H), 5.51-5.31 (m, 1H), 4.55-4.36 (m, 2H), 3.71-3.54 (m, 2H), 3.52 (s ,6H),3.50-3.44(m,1H),3.26-3.17(m,1H),2.62-2.45(m,2H),2.45-2.25(m,4H),2.22-2.10 (m,3H),2.06-1.94(m,1H),1.11-0.98(m,3H),0.79-0.70(m,3H);LCMS(ESI,M+1):m / z=565.2.

[0296] Example 31

[0297] [ka] 4-(4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-methylquinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0298] [ka]

[0299] Step A. 7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N,N,6-trimethylquinazolin-4-amine: A mixture of 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-6-iodo-N,N-dimethylquinazolin-4-amine (500 mg, 1 equiv.), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (516 μL, 2 equiv.), and KPO (1.5 M, 1.8 mL, 3 equiv.), Pd(dppf)Cl (66 mg, 0.1 equiv.) in dioxane (5 mL) was degassed and purged with N three times. The mixture was stirred at 50° C. under a N atmosphere for 12 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (4×10 mL). The organic phase was dried over NaSO and concentrated in vacuo. The crude product was purified by reverse-phase flash [C18, 0.1% formic acid] and preparative TLC (dichloromethane / methanol=5 / 1) to give the title compound (50 mg, 12% yield) as a white solid; LCMS (ESI, M+1): m / z=441.1.

[0300] Step B. 4-(4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-methylquinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: 7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N,N,6-trimethylquinazoline-4-ol in dioxane (1 mL) A mixture of CsCO (110 mg, 3 equiv.), RuPhos (15.8 mg, 0.3 equiv.), and RuPhos-Pd-G (9.5 mg, 0.1 equiv.) in HO (0.2 mL) was degassed and purged with N three times, and then the mixture was stirred at 90 °C under N atmosphere for 12 h.

[0301] The mixture was diluted with water (5 mL) and extracted with ethyl acetate (4 × 5 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 μm; A: water (FA), B: ACN; B%: 14% to 44%, 2 min] and lyophilized to give the title compound (19.2 mg, 30% yield) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ = 7.89 (s, 1H), 7.68-7.64 (m, 1H), 7.31-7.14 (m, 2H), 6.87 (d, J = 2.4 Hz, 1H), 5.47-5.20 (m, 1H), 4.40-4.34 (m, 1H), 4.32-4.25 (m, 1H), 3.48-3.45 (s, 6H), 3 .44-3.34(m3H),3.14-3.04(m,1H),2.66-2.53(m,1H),2.48-2.25(m,2H),2.24-2.15(m,2 H),2.11-1.99(m,5H),1.99-1.88(m,1H),0.77-0.73(m,3H);LCMS(ESI,M+1):m / z=551.3.

[0302] Example 32

[0303] [ka] (5R)-7-(6-chloro-7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

[0304] [ka]

[0305] Step A. 7-Bromo-6-chloro-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline: To a mixture of 7-bromo-2,6-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)quinazoline (500 mg, 1.0 equiv.) in dioxane (5 mL) was added 1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethanol (161 mg, 0.9 equiv.), DIEA (656 mg, 4.0 equiv.), and 4 Å molecular sieves (50 mg). The mixture was stirred at 40° C. for 16 hours. The reaction mixture was diluted with EtOAc (20 mL) and water (30 mL). The mixture was extracted with EtOAc (20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by reverse-phase flash [water (0.1% FA) / acetonitrile]. The desired fractions were collected, neutralized with solid NaHCO3, and concentrated under vacuum to remove acetonitrile. The aqueous layer was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound (210 mg, 33% yield) as a yellow solid; 1 H NMR(400MHz,DMSO-d6)δ=8.02(d,J=1.8Hz,1H),5.35-5.23(m,2H),4.14(s,2H),3.00-2.90(m,2H) ), 2.58 (brs, 2H), 1.92-1.73 (m, 6H), 1.65-1.54 (m, 2H); LCMS (ESI, M+1, M+3): m / z=498.0, 500.0.

[0306] Step B. 6-Chloro-7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline: 7-Bromo-6-chloro-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (240 mg, 1.0 equiv.), 5,6-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (223 mg, 1.3 equiv.), RuPhos in dioxane (5 mL) and HO (1 mL). A mixture of PdG3 (40.6 mg, 0.1 equiv.), RuPhos (22.5 mg, 0.1 equiv.), and Cs2CO3 (470 mg, 3.0 equiv.) was degassed and purged with N2 three times, after which the mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with water (20 mL). The mixture was then extracted with EA (20 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by reverse-phase flash [water (0.1% FA) / acetonitrile]. The desired fractions were collected, neutralized with solid NaHCO3, and concentrated in vacuo to remove acetonitrile. The aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (130 mg, 35% yield) as a yellow solid; LCMS (ESI, M+1): m / z=648.3.

[0307] Step C. (5R)-7-(6-chloro-7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: 6-chloro-7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl) in DMF (1 mL) and ACN (1 mL). To a solution of (trihydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (130 mg, 1.0 equiv.) was added (5R)-1,3,9-triazaspiro[4.5]decane-2,4-dione (102 mg, 3.0 equiv.) and KPO (128 mg, 3.0 equiv.). The reaction mixture was stirred at 40 °C for 16 h. The mixture was filtered, and the filtrate was purified by reverse-phase flash [water (0.1% FA) / acetonitrile]. The desired fractions were collected, neutralized with solid NaHCO, and concentrated in vacuo to remove acetonitrile. The aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (60 mg, 39% yield) as a yellow solid; LCMS (ESI, M+1): m / z=717.4.

[0308] Step D. (5R)-7-(6-chloro-7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: (5R)-7-(6-chloro-7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione in DCM (1 mL) To a solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (50.0 mg, 1.0 equiv.) was added TFA (2 mL, 387 equiv.). The reaction mixture was stirred at 0 °C for 1 h. The mixture was then stirred at 20 °C for 16 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC [Column: Unisil 3-100 C18 Ultra 150 × 50 mm × 3 μm; A: water (FA), B: ACN, B%: 10% to 40% over 7 min]. The desired fractions were collected, concentrated under vacuum to remove acetonitrile, and lyophilized to give the title compound (60 mg, 39% yield) as a yellow solid; 1 H NMR (400MHz, methanol-d4) δ=8.13(s,1H),7.62-7.49(m,1H),7.49-7.34(m,1H),4.77-4.60(m,2H),4.49(br d,J=13.2Hz,1H),4.39(br d,J=13.2Hz,1H),3.86-3.51(m,5H),3.29-3.25(m,1H),2.51(s,3H),2.33(br dd,J=6.8,11.8Hz,3H),2.28-2.15(m,6H),2.14-2.06(m,5H),2.01(brs,1H);LCMS(ESI,M+1):m / z=633.4.

[0309] Example 33

[0310] [ka] (5R)-7-(6-chloro-7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

[0311] [ka]

[0312] Step A. 7-Bromo-2,6-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)quinazoline: To a solution of 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (4.8 g, 1.0 equiv.) in THF (40 mL) was added t-BuONa (2 M, 7.99 mL, 1.1 equiv.) and 2,2,2-trifluoroethanol (1.45 g, 1.0 equiv.) at −40° C. The mixture was stirred at −40° C. for 1.5 hours. The mixture was poured into water (20 mL) and filtered. The filtrate was extracted with ethyl acetate (3×40 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude was purified by column chromatography to give the title compound (5.4 g, 94% yield) as a yellow solid; LCMS (ESI, M+1): m / z=394.8.

[0313] Step B. 7-Bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline: To a solution of 7-bromo-2,6-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)quinazoline (1 g, 1.0 equiv.) in DMF (10 mL) was added DIEA (984 mg, 1.33 mL, 3.0 equiv.), 4 Å molecular sieves (100 mg), and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (485 mg, 1.2 equiv.). The mixture was stirred at 60° C. for 12 hours. The mixture was poured into water (20 mL) and filtered. The filtrate was extracted with ethyl acetate (3 x 20 mL). The organic phase was dried over NaSO and concentrated in vacuo. The crude was purified by reverse-phase flash (C18, 0.1% formic acid) to give the title compound (310 mg, 24% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 518.0.

[0314] Step C. 6-chloro-7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline: 7-bromo-6-chloro-8-fluoro-2-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2R,7aS-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline in dioxane (2.5 mL) and HO (0.5 mL) To a solution of 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (250 mg, 1.0 equiv.), 5,6-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (310 mg, 1.8 equiv.), RuPhos Pd G3 (40.5 mg, 48.4 µmol, 0.1 equiv.), Cs2CO3 (473 mg, 3 equiv.), and RuPhos (67.7 mg, 0.3 equiv.) were added. The mixture was stirred at 80 °C for 6 h. The reaction mixture was filtered. The crude was purified by column chromatography to give the title compound (239 mg, 74% yield) as a white solid; LCMS (ESI, M+1): m / z=666.3.

[0315] Step D. (5R)-7-(6-chloro-7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: 6-chloro-7-(5,6-dimethyl-1-(tetrahydro) To a solution of (2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (100 mg, 1.0 equiv.) was added DIEA (58.21 mg, 3.0 equiv.) and (5R)-1,3,9-triazaspiro[4.5]decane-2,4-dione (76.2 mg, 3.0 equiv.). The mixture was stirred at 60° C. for 12 hours. The mixture was poured into water (3 mL) and filtered. The filtrate was extracted with ethyl acetate (2×4 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude was purified by reverse phase flash (C18, 0.1% formic acid) to give the title compound (50 mg, 45% yield) as a white solid; LCMS (ESI, M+1): m / z=735.4.

[0316] Step E. (5R)-7-(6-chloro-7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: (5R)-7-(6-chloro-7-(5,6 To a solution of 8-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (30 mg, 1.0 equiv.) was added TFA (0.5 mL). The mixture was stirred at 25° C. for 12 hours. The reaction mixture was quenched by adding 4 mL of saturated NaHCO3 solution at 0° C. The reaction mixture was extracted with ethyl acetate (3×5 mL). The combined organic layers were concentrated and purified by preparative HPLC [Waters Xbridge 150 × 25 mm × 5 um; mobile phase: A: water (ammonia hydroxide) B: ACN; B%: 24% to 54% over 9 min] to give the title compound (8.78 mg, 27% yield) as a white solid; 1 H NMR (400MHz, methanol-d4) δ=8.08(d,J=1.3Hz,1H),7.48(s,1H),7.43(s,1H),5 .38-5.22(m,1H),4.38(s,2H),4.24(s,2H),3.64-3.61(m,1H),3.55-3.47(m, 1H),3.26-3.15(m,3H),3.03-2.94(m,1H),2.50(s,3H),2.38-2.19(m,3H),2. 12(s,3H),2.09-2.03(m,2H),2.01-1.88(m,5H);LCMS(ESI,M+1):m / z=651.2.

[0317] Example 34

[0318] [ka] 4-(6-chloro-4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0319] [ka]

[0320] Step A. 4-(6-chloro-4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: 7-Bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine-7a-yl)methoxy)quinazolin-7-yl) in dioxane (1.5 mL) and HO (0.3 mL). To a mixture of (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methoxy)-N,N-dimethylquinazolin-4-amine (200 mg, 1.0 equiv.), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (205 mg, 1.5 equiv.), CsCO (423 mg, 3.0 equiv.), and RuPhos (60.6 mg, 0.3 equiv.), RuPhos-Pd-G (36.2 mg, 0.1 equiv.) was added. The mixture was stirred at 90 °C for 3 h. The mixture was diluted with water (3 mL) and extracted with EtOAc (3 × 10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse-phase flash chromatography [C18, 0.1% formic acid]. The crude product was purified by preparative HPLC [Phenomenex C18 75×30 mm×3 μm; A: water (FA), B: ACN; B%: 18%-48% over 7 min] and [Waters Xbridge 150×25 mm×5 μm; A: water (NH4HCO3), B: ACN; B%: 54%-84% over 7 min] and lyophilized to give the title compound (21.6 mg, 8.7% yield) as a yellow solid; 1H NMR (400MHz, methanol-d4) δ=8.13(brs,1H),7.73-7.57(m,1H),7.34-7.12(m,2H ),6.90(brs,1H),5.43-5.15(m,1H),4.37-4.14(m,2H),3.53-3.39(m,6H),3. 28-3.11(m,3H),3.08-2.93(m,1H),2.67-2.51(m,1H),2.40-2.17(m,3H),2.1 6-2.08(m,1H),2.02-1.82(m,3H),0.80(brs,3H);LCMS(ESI,M+1):m / z=571.4.

[0321] Example 35

[0322] [ka] (5R)-7-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

[0323] [ka]

[0324] Step A. 7-(5,6-Dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline: 7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline in methoxycyclopentane (10 mL) A mixture of (-trifluoroethoxy)quinazoline (350 mg, 1.0 equiv.), 5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (310 mg, 1.2 equiv.), and CsCO (1 M, 2.18 mL, 3.0 equiv.) was degassed and purged with N three times. Ad2nBuP-Pd-G3 (52.9 mg, 0.1 equiv.) was added, and the mixture was stirred at 80 °C under N2 for 6 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 reverse-phase flash (0.1% FA condition) to give the title compound (350 mg, 71% yield) as a white solid; LCMS (ESI, M+1): m / z=632.3.

[0325] Step B. (5R)-7-(7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: 7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H in DMF (0.5 mL) To a solution of (2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)indazol-4-yl-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (100 mg, 1.0 equiv.), (R)-1,3,7-triazaspiro[4.5]decane-2,4-dione (40.2 mg, 1.5 equiv.), and DIEA (61.4 mg, 82.7 μL, 3.0 equiv.) was added 4 Å MS (25.0 mg). The mixture was stirred at 40 °C for 144 h. The reaction mixture was filtered, washed with DMF (2 mL), and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Column: Waters Xbridge 150 × 25 mm × 5 μm; Mobile phase: [water (NH4HCO3)-ACN]; B%: 43% to 73%, 10 min] and lyophilized to give the title compound (50.0 mg, 45% yield) as a white solid; LCMS (ESI, M+1): m / z = 701.4.

[0326] Step C. (5R)-7-(7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: (5R)-7-(7-(5,6-dimethyl-1- To a solution of (tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (50.0 mg, 1.0 equiv.) was added TsOH (122 mg, 10 equiv.). The mixture was stirred at 0° C. for 0.5 h. The mixture was quenched with water (1 mL) and extracted with ethyl acetate (2×2 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, purified by preparative HPLC [Column: Waters Xbridge 150 × 25 mm × 5 μm; Mobile phase: [water (NH4HCO3)-ACN]; B%: 30% to 60%, 9 min], and lyophilized to give the title compound (5.38 mg, 9.0% yield, 1.9 FA) as a white solid; SFC: Chiralpak IG-3 50 × 4.6 mm ID, 3 μm in CO2 [40% EtOH (0.05% DEA)], flow rate: 3 mL / min, detector: 220 nm, t R1 =0.737 min, t R2 =1.437 minutes; 1 H NMR (400MHz, methanol-d4) δ=7.95(d,J=8.4Hz,1H),7.55-7.43(m,2H),7.31(dd,J=6.8 ,8.4Hz,1H),5.41(brs,1H),5.28(brs,1H),4.60-4.37(m,2H),4.31(s,2H),3.73-3 .64(m,1H),3.62-3.51(m,1H),3.49-3.38(m,1H),3.14-2.99(m,1H),2.50(s,3H),2 .45-2.25(m,2H),2.25-2.14(m,6H),2.10-1.86(m,7H);LCMS(ESI,M+1):m / z=617.3.

[0327] Example 36

[0328] [ka] 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one

[0329] [ka]

[0330] Step A. 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one: 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4-(2,2, A mixture of 2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (50.0 mg, 1.0 equiv.), 1,3,9-triazaspiro[4.5]decan-2-one (50.0 mg, 3.6 equiv.), KPO (37.8 mg, 2.0 equiv.), and 4 Å molecular sieves (25 mg) was degassed and purged with N three times. The mixture was then stirred at 60 °C under a N atmosphere for 16 h. The reaction mixture was cooled to room temperature. Ethyl acetate (40 mL) and water (40 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined extracts were washed with brine (40 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase column (column: Phenomenex Synergi C18 150 × 25 mm × 10 um; mobile phase: [water (FA)-ACN]; B%: 18% to 38%, 10 min) and lyophilized to obtain the title compound (29.0 mg, yield 53%, 0.51 FA) as a white solid;1 H NMR (400 MHz, methanol-d4) δ = 7.93-7.84 (m, 1H), 7.70-7.60 (m, 1H), 7.37-7.29 (m, 1H), 7.27-7.19 (m, 2H), 6.95 (d, J = 2.0 Hz, 1H), 4.43-4.34 (m, 2H), 4.00-3.74 (m, 4H), 3.46-3.35 ( m,1H),3.30-3.27(m,1H),2.82(brs,2H),2.72-2.52(m,6H),2.49-2.35(m,2H),2.05-1 .82(m,4H),0.84(s,2H),0.77(q,J=7.2Hz,3H),0.66(s,2H);LCMS(ESI,M+1):m / z=617.3

[0331] Example 37

[0332] [ka] 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide

[0333] [ka]

[0334] Step A. 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide: 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8- To a mixture of fluoro-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (10.0 mg, 1.0 equiv.), 2λ6-thia-1,3,9-triazaspiro[4.5]decane 2,2-dioxide (10.2 mg, 3.0 equiv.), and 4Å molecular sieves (10.0 mg, 1.0 equiv.) was added K3PO4 (11.34 mg, 3.0 equiv.). The mixture was stirred at 60 °C for 12 hours. The reaction mixture was filtered and purified by reverse-phase flash [C18, 0.1% formic acid] to give the title compound (77.8 mg, 67% yield, 0.95 FA) as a yellow solid. 1 H NMR (400 MHz, methanol-d4) δ = 7.96 (br d, J = 8.4 Hz, 1H), 7.73-7.60 (m, 1H), 7.38-7.32 (m, 1H), 7.27-7.20 (m, 2H), 6.96-6.93 (m, 1H), 4.53-4.33 (m, 3H), 4.23 (br t,J=14.4Hz,1H),3.81-3.58(m,2H),3.42(d,J=11.6Hz,1H),3.27-3.12(m,3H),2.89(s,6H),2.56-2.37( m,2H),2.14-1.98(m,2H),1.97-1.81(m,2H),0.95(s,2H),0.85-0.72(m,5H);LCMS(ESI,M+1):m / z=653.3

[0335] Example 38

[0336] [ka] 6-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one

[0337] [ka]

[0338] Step A. 8-[2-[[1-[(dimethylamino)methyl]cyclopropyl]methoxy]-7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-quinazolin-4-yl]-1,8-diazaspiro[3.5]nonan-2-one: To a solution of 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (50.0 mg, 1 equiv.) and 1,6-diazaspiro[3.5]nonan-2-one (37.4 mg, 3.0 equiv.) in DMF (0.1 mL) and MeCN (0.1 mL) was added KPO (56.7 mg, 3.0 equiv.). The mixture was stirred at 40 °C for 12 hours. The mixture was quenched with water (3 mL) and extracted with ethyl acetate (3 × 2 mL). The combined organic layers were washed with brine (3 × 2 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Column: Waters Xbridge 150 × 25 mm × 5 μm; Mobile phase: [water (NH4HCO3)-ACN]; B%: 36% to 66%, 9 min] and lyophilized to give the title compound (25.3 mg, 46% yield) as a yellow solid. SFC: Chiralcel OD-3 50 × 4.6 mm ID, 3 μm in CO2 [5% to 40% MeOH (0.05% DEA) in CO2], flow rate: 3 mL / min, detector: 220 nm, t R1 :2.029 minutes, t R2 :2.124 minutes, t R3 :2.254 minutes; 1H NMR (400 MHz, methanol-d4) δ = 7.84 (d, J = 8.4 Hz, 1H), 7.65 (dd, J = 6.4, 9.2 Hz, 1H), 7.36-7.16 (m, 3H), 6.95 (d, J = 2.8 Hz, 1H), 4.36 (t, J = 3.6 Hz, 2H), 4.22-4.02 (m, 2H), 3.96-3. .82(m,1H),3.76-3.56(m,1H),2.92-2.72(m,2H),2.56-2.36(m,4H),2.32(s,6H),2 .12-1.92(m,4H),0.86-0.66(m,5H),0.56-0.46(m,2H);LCMS(ESI,M+1):m / z=602.3.

[0339] Example 39

[0340] [ka] 5-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

[0341] [ka]

[0342] Step A. 5-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione: 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy) in DMF (0.5 mL) To a solution of 50.0 mg (1.0 equiv.) of 8-fluoro-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol was added 25.0 mg (2.0 equiv.), ACN (0.5 mL), and KPO (56.7 mg, 3.0 equiv.). The mixture was stirred at 60 °C for 24 hours. The reaction mixture was filtered and purified by preparative HPLC (Phenomenex Luna C18 150 × 25 mm × 10 μm column; mobile phase: [water (FA)-ACN]; B%: 12% to 42%, 10 min) to give the title compound (36.5 mg, 30.8% yield) as a white solid. 1 H NMR (400MHz, methanol-d4) δ=8.07(br d,J=8.8Hz,1H),7.65(t,J=6.8Hz,1H),7.36(br t,J=8.0Hz,1H),7.28-7.20(m,2H),6.96(s,1H),4.76-4.61(m,2H),4.38(s,2H),4.25-4.12(m,2H),3.68(br d,J=7.2Hz,2H),2.99(s,2H),2.84-2.68(m,6H),2.49-2.36(m,2H),0.89(s,2H),0.82-0.71(m,5H);LCMS(ESI,M+1):m / z=602.4.

[0343] Example 40

[0344] [ka] 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

[0345] [ka]

[0346] Step A. 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: To a mixture of 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoro-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (100 mg, 1.0 equiv.), 1,3,9-triazaspiro[4.5]decane-2,4-dione (60.3 mg, 2.0 equiv.) and 4 Å molecular sieves (10 mg) in DMF (0.5 mL) was added DIEA (69.0 mg, 3.0 equiv.). The mixture was stirred at 60° C. for 24 hours. The residue was filtered, washed with DMF (1 mL), purified by preparative HPLC [Phenomenex C18 75×30 mm×3 μm; A: water (FA), B: ACN; B%: 15% to 45% over 7 minutes], and lyophilized to give the title compound (54.6 mg, 47% yield) as a yellow solid; 1H NMR (400MHz, methanol-d4) δ=7.88(d,J=8.8Hz,1H),7.65(dd,J=6.0,9.2Hz,1H),7.37-7.29(m ,1H),7.28-7.17(m,2H),6.96(d,J=2.4Hz,1H),4.51-4.22(m,4H),3.71(dd,J=13.6,15.2H z,1H),3.65-3.47(m,1H),3.10-2.90(m,2H),2.85-2.63(m,6H),2.53-2.33(m,2H),2.28-2 .13(m,1H),2.11-1.86(m,3H),0.89(s,2H),0.81-0.67(m,5H);LCMS(ESI,M+1):m / z=631.3.

[0347] Example 41

[0348] [ka] 5-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0349] [ka]

[0350] Step A. 5-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide) in DMF (0.05 mL) To a mixture of (methoxy)-8-fluoro-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (150 mg, 1.0 equiv.), N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (167 mg, 3.0 equiv.), and 4 Å molecular sieves (50 mg), DIEA (103 mg, 3.0 equiv.) was added. The mixture was stirred at 100 °C for 24 h. The residue was filtered, washed with DMF (1 mL), and purified by preparative HPLC [Phenomenex C18 75 × 30 mm × 3 μm; A: water (FA), B: ACN; B%: 18% to 48% in 7 min] to obtain the crude product. The crude was purified by preparative HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3), B: ACN; B%: 35% to 65% over 9 min] and lyophilized to give the title compound (23.2 mg, 13% yield) as a white solid; 1 H NMR (400MHz, methanol-d4) δ=7.91(d,J=8.8Hz,1H),7.64(dd,J=6.0,9.2Hz,1H),7.30(dd,J=6.8,8 .8Hz,1H),7.26-7.16(m,2H),6.94(d,J=2.4Hz,1H),6.67(s,1H),5.27-5.03(m,2H),4.60-4.48( m,2H),4.40-4.24(m,4H),3.34(s,3H),3.08(s,3H),2.52-2.43(m,3H),2.42-2.35(m,3H),2.31( s,6H),0.76(t,J=7.2Hz,3H),0.73-0.66(m,2H),0.58-0.46(m,2H);LCMS(ESI,M+1):m / z=670.4.

[0351] Example 42

[0352] [ka] 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0353] [ka]

[0354] Step A. 4-(7-Bromo-2-chloro-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: To a solution of 7-bromo-2,4-dichloro-8-fluoroquinazoline (500 mg, 1.0 equiv.) and 6-methyl-1,4-oxazepan-6-ol (199 mg, 0.9 equiv.) in dichloromethane (5 mL) was added DIEA (655 mg, 3 equiv.). The mixture was stirred at 0-20 °C for 16 h. The reaction mixture was quenched by adding water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with saturated brine (3 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude was purified by reverse phase flash (0.1% FA conditions) to give the title compound (150 mg, 41% yield) as a yellow solid; Column: Chiralcel OD-3 50 x 4.6 mm ID, 3 μm in CO2 [5% to 40% MeOH (0.05% DEA) in CO2], Flow rate: 3 mL / min, Detector: 220 nm, t R1 :2.029 minutes, t R2 :2.124 minutes, t R3 :2.254 minutes; 1H NMR(400MHz,DMSO-d6)δ=8.24-8.14(m,1H),7.78-7.63(m,1H),5.09(s,1H),4.25-4.10(m,2H),4.07-3.8 8(m,3H),3.78(ddd,J=3.2,6.8,14.4Hz,1H),3.57-3.48(m,2H),1.11(s,3H);LCMS(ESI,M+1):m / z=391.9.

[0355] Step B. 4-(7-Bromo-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: To a solution of 4-(7-bromo-2-chloro-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (270 mg, 1.0 equiv.) in DMSO (3 mL) was added (1-((dimethylamino)methyl)cyclopropyl)methanol (179 mg, 2.0 equiv.), DIEA (268 mg, 3 equiv.), and 4 Å molecular sieves (80.0 mg), and the reaction mixture was stirred at 80° C. for 36 hours. The reaction mixture was quenched by adding water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with saturated brine (3×10 mL), dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure. The crude was purified by reverse-phase flash (0.1% FA condition) to give the title compound (8.33 mg, 20% yield) as a white solid; 1 H NMR (400 MHz, methanol-d4) δ = 9.13 (s, 1H), 7.67 (dd, J = 6.0, 9.2 Hz, 1H), 7.30 (d, J = 2.8 Hz, 1H), 7.24 (t, J = 9.6 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 5.42-5.22 (m, 1H), 4.41-4.24 (m, 2H), 4.02-3.90(m,2H),3.27-3.13(m,3H),3.05-2.98(m,1H),2.71(t,J=6.4Hz,2H),2.50(b rs,1H),2.39-2.19(m,2H),2.18-2.10(m,2H),2.04-1.90(m,3H),0.78(t,J=7.2Hz,3H).

[0356] Step C. 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: 4-[7-bromo-2-[[1-[(dimethylamino)methyl]cyclopropyl]methoxy]-8-fluoro-quinazolin-4-yl]-6-methyl-1,4 in CPME (1 mL) A mixture of 5-oxazepan-6-ol (130 mg, 1.0 equiv.), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (128 mg, 1.5 equiv.), Ad2nBuP-Pd-G3 (39.2 mg, 0.2 equiv.), and Cs2CO3 (1 M, 807 μL, 3.0 equiv.) was degassed and purged with N2 three times. The mixture was then stirred at 90 °C under a N2 atmosphere for 2 h. The reaction mixture was quenched by adding water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with saturated brine (3 × 10 mL), dried over Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 * 25mm * 10 μm; mobile phase: [water (FA)-ACN]; B%: 16%-46%, 10 min) to give the title compound (150 mg, 41% yield) as a yellow solid; 1 H NMR (400 MHz, methanol-d4) δ = 8.60-8.49 (m, 1H), 8.25-8.13 (m, 1H), 7.72-7.61 (m, 1H), 7.39-7.30 (m, 1H), 7.28-7.19 (m, 2H), 7.00-6.93 (m, 1H), 4.53-4.31 (m, 4H), 4.18-3. .88(m,4H),3.75-3.60(m,2H),3.18-2.97(m,2H),2.82(s,6H),2.56-2.37(m,2H),1 .30-1.21(m,3H),0.95-0.88(m,2H),0.83-0.73(m,5H);LCMS(ESI,M+1):m / z=593.4.

[0357] Example 43

[0358] [ka] 4-(4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0359] [ka]

[0360] Step A. 7-Bromo-2-chloro-8-fluoro-N,N-dimethylquinazolin-4-amine: To a solution of 7-bromo-2,4-dichloro-8-fluoro-quinazoline (600 mg, 1.0 equiv.) and DIEA (786 mg, 3.0 equiv.) in DCM (5 mL), N-methylmethanamine (2 M in THF, 979 mg, 10 equiv.) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (20 mL) and extracted with DCM (4 × 10 mL). The organic phase was dried over Na SO , concentrated, and purified by reverse-phase flash [C18, 0.1% FA] to give the title compound (320 mg, 47% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 305.9.

[0361] Step B. 7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-N,N-dimethylquinazolin-4-amine: To a solution of 7-bromo-2-chloro-8-fluoro-N,N-dimethyl-quinazolin-4-amine (250 mg, 1.0 equiv.) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (196 mg, 1.5 equiv.) in dioxane (2 mL), DIEA (265 mg, 2.5 equiv.) and 4 Å molecular sieves (25 mg) were added. The mixture was stirred at 100° C. for 120 hours. The reaction mixture was filtered and purified by reverse phase flash [C18, 0.1% FA] to give the title compound (180 mg, 49% yield) as a yellow solid; LCMS (ESI, M+1): m / z=427.1.

[0362] Step C. 4-(4-(dimethylamino)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)) in methoxycyclopentane (1.5 mL) To a mixture of (methoxy)-N,N-dimethylquinazolin-4-amine (150 mg, 1.0 equiv.), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (166 mg, 1.5 equiv.), and KPO (1.5 M in HO, 3.0 equiv.) was added AdBuP-Pd-G (50 mg, 0.1 equiv.) under a N atmosphere. The mixture was stirred at 90 °C under a N atmosphere for 1 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The organic phase was dried over NaSO and concentrated. The crude was purified by reverse-phase flash [C18, 0.1% FA] and preparative HPLC Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: water (FA)-CAN; B%: 15% to 45%, 10 min) to give the title compound (91.21 mg, yield 45.51%, 0.61 FA) as a white solid; 1H NMR (400MHz, methanol-d4) δ=8.06(br d,J=8.6Hz,1H),7.64(br dd,J=6.0,8.8Hz,1H),7.29-7.22(m,1H),7.41-7.10(m,2H),6.95(s,1H),5.58-5.34(m,1H),4. 66-4.37(m,2H),3.84-3.60(m,3H),3.50(s,6H),3.31-3.12(m,1H),2.63-2.02(m,8H),0.77(br t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=537.2.

[0363] Example 44

[0364] [ka] 4-(4-(7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepin-5(6H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0365] [ka]

[0366] Step A. 4-(4-(7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepin-5(6H)-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: 5-Ethyl-6-fluoro-4-(8-fluoro)naphthalen-2-ol in DMF (0.1 mL) and ACN (0.1 mL). To a solution of 1-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)naphthalen-2-ol (100 mg, 1.0 equiv.) and 5,6,7,8-tetrahydro-4H-triazolo[1,5-a][1,4]diazepine (59.0 mg, 2.0 equiv., HCl) was added KPO (215 mg, 6.0 equiv.). The mixture was stirred at 40 °C for 72 h. The mixture was poured into water (2 mL) and filtered. The filtrate was extracted with ethyl acetate (3 × 10 mL). The organic phase was dried over NaSO and concentrated in vacuo. The crude product was purified by preparative HPLC [Phenomenex Gemini-NX C18 150 × 25 mm × 10 μm; A: (water (FA)), B: ACN]; B%: 15% to 45% over 10 min to give the title compound (10 mg, 9.1% yield) as a yellow solid; 1 H NMR (400 MHz, methanol-d4) δ = 8.51 (s, 1H), 8.02-7.90 (m, 1H), 7.72-7.58 (m, 1H), 7.44-7.29 (m, 1H), 7.29-7.19 (m, 2H), 7.19-7.18 (m, 1H), 6.93 (dd, J = 2.4, 7.2 Hz, 1H), 5 .54-5.14(m,2H),4.83-4.72(m,1H),4.49-4.29(m,3H),3.66-3.32(m,5H),3.27-3 .09(m,1H),2.71-1.83(m,10H),0.77(q,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=630.2.

[0367] Example 45

[0368] [ka] 7-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide

[0369] [ka]

[0370] Step A. 7-(8-chloro-7-fluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline: 7-Bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline in toluene (3 mL) A mixture of (2,2,2-trifluoroethoxy)quinazoline (350 mg, 1.0 equiv.), (5-chloro-6-fluoro-4-trimethylstannyl-2-naphthyl)oxy-triisopropylsilane (433 mg, 1.2 equiv.), CuI (40.0 mg, 0.3 equiv.), and BINAP (87.1 mg, 0.2 equiv.) was degassed and purged with N2 three times. Pd(dppf)Cl2 (51.2 mg, 0.1 equiv.) was added, and the mixture was stirred at 90 °C under a N2 atmosphere for 12 h. The mixture was filtered. The filtrate was diluted with water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The organic phase was dried over Na2SO4, concentrated and purified by reverse phase flash [C18, 0.1% FA] to give the title compound (130 mg, 16% yield) as a yellow solid; LCMS (ESI, M+1, M+3): m / z = 772.1, 774.1.

[0371] Step B. 7-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide: 7-(8-chloro-7-fluoro-3-((triisopropylsilyl)oxy)naphthalene- in DMF (0.8 mL) To a solution of (1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (70.0 mg, 1.0 equiv.) and 2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide (32.6 mg, 1.5 equiv.) was added KPO (72.4 mg, 3.0 equiv.) and 4 Å molecular sieves (20 mg). The mixture was stirred at 60 °C for 12 h. The mixture was filtered and purified by preparative HPLC [Phenomenex Synergi C18 150 × 25 mm × 10 μm; mobile phase: water (FA)-ACN; B%: 20% to 40%, 10 min] to give the title compound (19.6 mg, 23% yield, 0.42 FA) as a yellow solid; 1 H NMR (400MHz, methanol-d4)δ=7.87-7.75(m,1H),7.66(br dd,J=2.8,9.6Hz,1H),7.44-7.32(m,2H),7.15-7.11(m,1H),5.55-5.31(m,1H),4. 57-4.41(m,2H),4.40-4.27(m,1H),4.27-4.10(m,1H),3.77-3.46(m,6H),3.42(br d,J=11.2Hz,1H),3.22(br d,J=11.2Hz,2H),2.65-2.24(m,4H),2.16(brs,2H),2.05(br d,J=9.2Hz,3H),1.95-1.78(m,2H);LCMS(ESI,M+1):m / z=707.0

[0372] Example 46

[0373] [ka] (5R)-7-(7-(5,6-dimethyl-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

[0374] [ka]

[0375] Step A. 7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline: 7-Bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline in methoxycyclopentane (3.5 mL) To a mixture of tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (350 mg, 1 equiv.), 5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (374 mg, 1.5 equiv.), CsCO (1.5 M, 1.40 mL, 3 equiv.) was added at 25 °C. The mixture was degassed and purged with N three times, followed by the addition of Ad2nBuP-Pd-G3 (51.0 mg, 70.0 µmol, 0.1 equiv.). The reaction was degassed and purged with N three times and stirred at 90 °C under N atmosphere for 2 h. The reaction mixture was diluted with HO (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dried over anhydrous NaSO, concentrated, and purified by reverse-phase HPLC [0.1% FA condition] to give the title compound (357 mg, 78% yield) as a white solid; LCMS (ESI, M+1): m / z = 650.4.

[0376] Step B. 5R)-7-(7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: 7-(5,6-dimethyl-1-(tetrahydro-2H)-pyran-2-yl)-1H-indazol-4-yl) in DMF (1.4 mL) and ACN (1.4 mL) To a mixture of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (280 mg, 1 equiv.), (R)-1,3,7-triazaspiro[4.5]decane-2,4-dione (146 mg, 2 equiv.), KPO (274 mg, 3 equiv.) and 4 Å molecular sieves (250 mg) were added. The mixture was degassed and purged with N three times and stirred at 60 °C under N atmosphere for 12 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC [0.1% NH3·H2O] to give the title compound (140 mg, 45% yield) as a yellow solid; 1 H NMR (400 MHz, methanol-d4) δ = 7.71 (d, J = 9.6 Hz, 1H), 7.65 (s, 1H), 7.52 (s, 1H), 5.82 (br d, J = 8.4 Hz, 1H), 5.43-5.18 (m, 1H), 4.41-4.29 (m, 2H), 4.25 (s, 2H), 4.03 (br d,J=11.6Hz,1H),3.84(dt,J=2.4,11.2Hz,1H),3.61(d,J=13.2Hz,1H),3.52-3.41(m,1H),3.28-3.16(m,2H),3.07-2.95(m ,1H),2.53(s,3H),2.52-2.44(m,1H),2.41-2.09(m,8H),2.08-1.83(m,9H),1.81-1.59(m,2H);LCMS(ESI,M+1):m / z=719.5.

[0377] Step C. (5R)-7-(7-(5,6-dimethyl-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: (5R-7-(7-(5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazoline)-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione) in MeOH (0.4 mL) To a solution of (2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (40.0 mg, 1 equiv.), HCl·MeOH (4 M, 28.7 equiv.) was added and stirred at 20°C for 6 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC [column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 20% to 50%, 9 min] to give the title compound (14.3 mg, 39% yield) as a white solid. 1 H NMR (400MHz, methanol-d4)δ=7.72(br d,J=10.0Hz,1H),7.51(d,J=10.0Hz,2H),5.44-5.15(m,1H),4.42-4.29(m,2H),4.29-4.19(m,2H),3.58(dd,J=4.4,13.2Hz,1H),3.4 7-3.37(m,1H),3.24-3.14(m,2H),3.07-2.94(m,1H),2.50(s,3H),2.41-2.07(m,8H),2.07-1.74(m,6H);LCMS(ESI,M+1):m / z=635.5.

[0378] Example 47

[0379] [ka] 5-(6,8-Difluoro-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0380] [ka]

[0381] Step A. 6,8-Difluoro-7-(3-(methoxymethoxy)naphthalen-1-yl)quinazoline-2,4-diol: A mixture of 2-[3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (425 mg, 1.5 equiv.), 7-bromo-6,8-difluoro-quinazoline-2,4-diol (250 mg, 1.0 equiv.), CsCO (882 mg, 3.0 equiv.), and AdBuP-Pd-G (65.7 mg, 0.1 equiv.) in ethyl alcohol (20 mL) and water (4 mL) was degassed and purged with nitrogen three times, after which the mixture was stirred under a nitrogen atmosphere at 80° C. for 1.5 hours. The mixture was concentrated under reduced pressure to provide a residue. The residue was purified by preparative TLC (PE / EA=3 / 1) to give the title compound (120 mg, yield 14.1%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ = 7.89-7.75 (m, 2H), 7.62-7.36 (m, 5H), 5.42-5.27 (m, 2H), 3.61-3.52 (m, 3H); LCMS (ESI, M+1): m / z = 385.0

[0382] Step B. 4-(2,4-Dichloro-6,8-difluoroquinazolin-7-yl)naphthalen-2-ol: A mixture of 6,8-difluoro-7-[3-(methoxymethoxy)-1-naphthyl]quinazoline-2,4-diol (30.0 mg, 1.0 equiv.), POCl (144 mg, 12 equiv.), and DIEA (40.3 mg, 4.0 equiv.) was stirred under a N atmosphere at 130° C. for 0.2 h. The mixture was concentrated under reduced pressure to afford the title compound (30 mg, crude) as a yellow oil, which was used in the next step without further purification.

[0383] Process C 5-(2-chloro-6,8-difluoro-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: A mixture of 4-(2,4-dichloro-6,8-difluoroquinazolin-7-yl)naphthalen-2-ol (50.0 mg, 1.0 equiv.), N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (37.1 mg, 1.5 equiv.) and DIEA (46.0 mg, 3.0 equiv.) in DCM (2 mL) was degassed and purged with N three times, after which the mixture was stirred under N at −40° C. for 1 h. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; B%: 39% to 69%, 10 min) to give the title compound (10 mg, 15% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 549.4

[0384] Step D. 5-(6,8-Difluoro-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: A mixture of 5-[2-chloro-6,8-difluoro-7-(3-hydroxy-1-naphthyl)quinazolin-4-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (10 mg, 1 equiv.) and Pd / C (5 mg, 10% purity, 0.1 equiv.) in MeOH (2 mL) was degassed and purged with H three times, after which the mixture was stirred under an H atmosphere at 25° C. for 1 h. The mixture was filtered and concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Unisil 3-100 C18 Ultra 150 × 50 mm × 3 um; mobile phase: [water (FA)-ACN]; B%: 28% to 58%, 7 min) to give the title compound (1.08 mg, 11% yield) as an off-white solid; 1 H NMR (400MHz, methanol-d4) δ=8.64(s,1H),7.83-7.75(m,2H),7.47-7.40(m,1H),7.35(br d,J=8.8Hz,1H),7.30(d,J=2.0Hz,1H),7.27-7.20(m,1H),7.15(d,J=2.4Hz,1H),6.70(s,1H) ,5.18(s,2H),4.59(s,4H),3.35(s,2H),3.34(s,3H),3.08(s,3H);LCMS(ESI,M+1):m / z=515.3

[0385] Example 48

[0386] [ka] (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

[0387] [ka]

[0388] Step A. (R)-1-(7-Bromo-6,8-difluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol: To a solution of (R)-1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (200 mg, 1.0 equiv.) in DMSO (0.3 mL) was added (hexahydro-1H-pyrrolidin-7a-yl)methanol (719 mg, 10 equiv.). The mixture was stirred at 90° C. for 12 hours. 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 reverse-phase flash (0.1% FA) to give the title compound (130 mg, 42% yield) as a white solid. LCMS (ESI, M+1, M+3): m / z = 497.1, 499.1

[0389] Step B. (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol: (R)-1-(7-bromo-6,8-difluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol in CPME (3 mL) A mixture of ethylpiperidin-3-ol (100 mg, 1.0 equiv.), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (95.4 mg, 1.5 equiv.), Ad2nBuP-Pd-G3 (14.6 mg, 0.1 equiv.), and K3PO4 (2 M, 301 μL, 3.0 equiv.) was degassed and purged with N2 three times. The mixture was then stirred at 90 °C under a N2 atmosphere for 3 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 reverse-phase flash chromatography (0.1% FA) to give the title compound (130 mg, 42% yield) as a white solid. SFC:Chiralpak IG-3 50×4.6mm ID, 3μm [40%EtOH(0.05%DEA)] in CO2, flow rate: 3mL / min, detector: 220nm, t R1 =1.106 min, t R2 =1.615 minutes; 1 H NMR (400MHz, methanol-d4)δ=7.82(br d,J=10.4Hz,1H),7.68(dd,J=5.6,8.4Hz,1H),7.34-7.18(m,2H),6.98(d,J=2.8Hz,1H),4.47(brs,2H),4.31(brs,1H),4.11(br d,J=13.2Hz,1H),3.60 3.46(m,1H),3.44-3.36(m,3H),3.10-2.90(m,2H),2.66-2.36(m,2H),2.32-2.16(m,3H),2.02(brs,4H),1.96-1.92 (m,2H),1.86-1.82(m,1H),1.82-1.72(m,2H),1.36-1.22(m,3H),0.81(q,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=607.2.

[0390] Example 49

[0391] [ka] 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one

[0392] [ka]

[0393] Step A. 1-(1-(((7-Bromo-6,8-difluoro-4-(2,2,2-trifluoroethoxy)quinazolin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine: To a solution of 7-bromo-2-chloro-6,8-difluoro-4-(2,2,2-trifluoroethoxy)quinazoline (3.0 g, 1.0 equiv.) and (1-((dimethylamino)methyl)cyclopropyl)methanol (1.03 g, 1.0 equiv.) in DMF (15 mL) was added DIPEA (2.05 g, 2.0 equiv.) and 4 Å molecular sieves (200 mg). The mixture was stirred at 40° C. under a N atmosphere for 14 hours. The reaction mixture was filtered. The filtrate was purified by reverse phase flash [water (FA, 0.1%) / acetonitrile=3 / 1] to give the title compound (0.93 g, 22% yield) as a pale yellow solid; LCMS (ESI, M+1, M+3): m / z=470.1, 472.1.

[0394] Step B. 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: 1-(1-(((7-bromo-6,8-difluoro-4-(2,2,2-trifluoroethoxy)quinazolin-2-yl)oxy)) in methoxycyclopentane (20 mL) To a mixture of (methyl)cyclopropyl)-N,N-dimethylmethanamine (1 g, 1 equiv.) and 5-ethyl-6-fluoro-4-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (1 g, 1.5 equiv.) under a N atmosphere, CsCO (1.5 M in HO, 4.25 mL, 3.0 equiv.) and AdBuP-Pd-G (155 mg, 0.1 equiv.) were added. The mixture was stirred at 70 °C for 12 h. The mixture was diluted with HO (30 mL) and extracted with ethyl acetate (4 × 20 mL). The combined organic layers were dried over anhydrous NaSO, concentrated, and purified by reverse-phase flash [water (FA, 0.1%) / acetonitrile = 3 / 2] to give the title compound (0.87 g, 68% yield) as a pale yellow solid. LCMS (ESI, M+1): m / z = 580.2.

[0395] Step C. 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one: To a solution of 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (170 mg, 1 equiv.) and 1,3,7-triazaspiro[4.5]decan-2-one (91 mg, 2.0 equiv.) in DMF (1 mL) was added 4 Å molecular sieves (20 mg) and KPO (124 mg, 2.0 equiv.). The mixture was stirred at 60°C for 13 hours under a N2 atmosphere. The mixture was filtered. The filtrate was purified by preparative HPLC [column: Phenomenex Synergi C18 150 x 25 mm x 10 μm; mobile phase: water (FA)-ACN; B%: 17% to 47%, 10 min] to give the title compound (17.3 mg, 9% yield, 0.27 FA) as a white solid. 1 H NMR (400MHz, methanol-d4)δ=7.70-7.65(m,2H),7.29(d,J=2.4Hz,1H),7.25(t,J= 9.2Hz,1H),6.98(d,J=2.8Hz,1H),4.40-4.37(m,2H),3.87-3.82(m,4H),3.42(d ,J=9.2Hz,1H),3.30-3.28(m,1H),2.70-2.66(m,2H),2.59-2.41(m,8H),2.03- 1.93(m,4H),0.84-0.78(m,5H),0.62-0.59(m,2H);LCMS(ESI,M+1):m / z=635.3.

[0396] Example 50

[0397] [ka] 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide

[0398] [ka]

[0399] Step A. 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide: 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide in DMF (0.9 mL) To a solution of (methoxy)-6,8-difluoro-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (130 mg, 1 equivalent) and 2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide (80 mg, 1.9 equivalents) was added 4 Å molecular sieves (20 mg) and KPO (95 mg, 2.0 equivalents). The mixture was stirred at 60 °C under a N atmosphere for 16 hours. The mixture was filtered. The filtrate was purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: water (FA)-ACN; B%: 20% to 50%, 10 min] to obtain the title compound (82.4 mg, yield 49%, 0.83 FA) as a white solid; 1H NMR (400MHz, methanol-d4)δ=7.73-7.67(m,2H),7.30(d,J=2.8Hz,1H),7.28-7.22(m, 1H),6.99(dd,J=2.8,6.8Hz,1H),4.47-4.31(m,3H),4.25-4.15(brs,1H),3.69(br t,J=13.2Hz,1H),3.63-3.53(m,1H),3.40(dd,J=3.2,11.8Hz,1H),3.21(d,J=12.0Hz,1H),3.15(br d,J=3.2Hz,2H),2.87(s,6H),2.65-2.51(m,1H),2.43(ddd,J=3.6,7.2,10.4Hz,1H),2.04(br d,J=11.2Hz,2H),1.93-1.87(m,2H),0.95-0.91(m,2H),0.81-0.79(m,5H);LCMS(ESI,M+1):m / z=671.3.

[0400] Example 51

[0401] [ka] 6-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one

[0402] [ka]

[0403] Step A. 6-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one: To a solution of 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (120 mg, 1 equiv.) and 1,6-diazaspiro[3.5]nonan-2-one (60 mg, 2.1 equiv.) in DMF (0.9 mL) was added 4 Å molecular sieves (20 mg) and KPO (88 mg, 2.0 equiv.). The mixture was stirred at 60°C for 11 hours under a N2 atmosphere. The mixture was filtered. The filtrate was purified by preparative HPLC [column: Phenomenex Synergi C18 150 x 25 mm x 10 µm; mobile phase: water (FA)-ACN; B%: 17% to 47%, 10 min] to give the title compound (70.0 mg, 50% yield, 0.67 FA) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ = 7.70-7.65 (m, 2H), 7.30 (d, J = 2.8 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 4.41-4.39 (m, 2H), 4.14-4.11 (m, 2H), 3.87-3.84 (m, 1H), 3.66 (ddd, J = 4.0, 8.4, 12.4 Hz, 1H), 3.34-2.98 (m ,2H),2.89-2.83(m,1H),2.77(s,6H),2.75-2.73(m,1H),2.62-2.49(m,1H),2.42(ddd,J=2.8,7.2,14.4Hz,1H ),2.05-1.95(m,4H),0.91-0.88(m,2H),0.80(t,J=7.3Hz,3H),0.77-0.72(m,2H);LCMS(ESI,M+1):m / z=620.3.

[0404] Example 52

[0405] [ka] 5-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

[0406] [ka]

[0407] Step A. 5-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione: 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione in DMF (0.9 mL) To a solution of (methoxy)-6,8-difluoro-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (130 mg, 1 equivalent) and tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (65 mg, 2.1 equivalents) was added 4 Å molecular sieves (20 mg) and KPO (95 mg, 2.0 equivalents). The mixture was stirred at 60 °C under a N atmosphere for 13 hours. The mixture was filtered. The filtrate was purified by preparative HPLC [column: Phenomenex Synergi C18 150 × 25 mm × 10 μm; mobile phase: water (FA)-ACN; B%: 18% to 48%, 10 min] to obtain the title compound (51.5 mg, yield 35%, 0.73 FA) as a white solid; 1H NMR (400MHz, methanol-d4)δ=7.87(br d,J=10.0Hz,1H),7.68(dd,J=6.0,8.8Hz,1H),7.30(d,J=2.4Hz,1H),7.25(t,J=9.2Hz,1H),7.00(d,J=2.4Hz,1H),4.65(br dd,J=5.2,13.2Hz,2H),4.41-4.38(m,2H),4.18(br dd,J=8.8,12.0Hz,2H),3.69(br d,J=7.6Hz,2H),3.10-3.02(m,2H),2.81-2.78(m,6H),2.55-2.49(m,1H),2.47- 2.42(m,1H),0.91-0.88(m,2H),0.81-0.76(m,5H);LCMS(ESI,M+1):m / z=620.3.

[0408] Example 53

[0409] [ka] 6-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-azaspiro[3.5]nonan-2-ol

[0410] [ka]

[0411] Step E. 6-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-azaspiro[3.5]nonan-2-ol: To a solution of 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (130 mg, 1 equiv.) and 6-azaspiro[3.5]nonan-2-ol (80 mg, 2.5 equiv.) in DMF (0.9 mL) was added 4 Å molecular sieves (20 mg) and KPO (95 mg, 2.0 equiv.). The mixture was stirred at 60°C under a N2 atmosphere for 16 hours. The mixture was filtered. The filtrate was purified by preparative HPLC [column: Phenomenex Synergi C18 150 x 25 mm x 10 µm; mobile phase: water (FA)-ACN; B%: 18% to 48%, 10 min] to give the title compound (54.6 mg, 36% yield, 0.5 FA) as a white solid. 1 H NMR (400MHz, methanol-d4) δ=7.67(dd,J=6.0,9.2Hz,1H),7.65-7.62(m,1H),7.30(d,J=2.8Hz,1H),7.24(t,J=9.2Hz, 1H),7.00(d,J=2.4Hz,1H),4.39(d,J=3.2Hz,2H),4.30-4.26(m,1H),3.91-3.83(m,2H),3.80-3.77(m,2H),2.93(br d,J=4.8Hz,2H),2.68(br d,J=3.6Hz,6H),2.56(brs,1H),2.44(dt,J=2.8,7.2Hz,1H),2.35-2.18(m,2H),1. 82-1.70(m,6H),0.86-0.78(m,5H),0.74-0.71(m,2H);LCMS(ESI,M+1):m / z=621.3.

[0412] Example 54

[0413] [ka] 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

[0414] [ka]

[0415] Step A. 7-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione: 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione in MeCN (0.2 mL) and DMF (0.2 mL) To a mixture of (methoxy)-6,8-difluoro-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (60.0 mg, 1.0 equiv.), 1,3,7-triazaspiro[4.5]decane-2,4-dione (35.0 mg, 2.0 equiv.), and 4 Å molecular sieves (10.0 mg, 1.0 equiv.) was added KPO (65.9 mg, 3.0 equiv.). The mixture was stirred at 40 °C for 12 h. The reaction mixture was filtered and purified by preparative HPLC [column: Phenomenex Synergi C18 150 × 25 mm × 10 um; mobile phase: [water (FA)-ACN]; B%: 18% to 40%, 11 min] and lyophilized to give the title compound (19.8 mg, yield 29%) as a white solid; 1H NMR (400MHz, methanol-d4) δ=7.73-7.66(m,2H),7.32-7.30(m,1H),7.26(t,J=9.2 Hz,1H),7.01-6.96(m,1H),4.45-4.36(m,3H),4.35-4.34(m,1H),4.35(brs,1H) ),3.73-3.64(m,1H),3.64-3.55(m,1H),3.19-3.10(m,2H),2.85(s,6H),2.62- 2.51(m,1H),2.49-2.36(m,1H),2.27-2.17(m,1H),2.10-2.01(m,2H),1.96(br d,J=13.6Hz,1H),0.93(m,2H),0.83-0.76(m,5H);LCMS(ESI,M+1):m / z=649.4.

[0416] Example 55

[0417] [ka] 5-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0418] [ka]

[0419] Step A. 5-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a mixture of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (1.00 g, 1.0 equiv.), N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (597 mg, 0.9 equiv.) and 4 Å molecular sieves (100 mg, 1.0 equiv.) in DCM (10 mL) was added DIEA (1.24 g, 3 equiv.) at 0° C. and the mixture was then stirred at 20° C. for 2 h. The reaction mixture was filtered and purified by reverse phase flash [C18, 0.1% formic acid conditions] to give the title compound (1.50 g, 89% yield) as a white solid; LCMS (ESI, M+1, M+3): m / z = 485.0, 487.0.

[0420] Step B. 5-(7-Bromo-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-N,N-di in DMF (5 mL) To a mixture of methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (500 mg, 1.0 equiv.), (1-((dimethylamino)methyl)cyclopropyl)methanol (399 mg, 3.0 equiv.), and 4 Å molecular sieves (100 mg, 1.0 equiv.), DIEA (399 mg, 3.0 equiv.) was added, and the mixture was stirred at 110° C. for 36 hours. The reaction mixture was filtered and purified by reverse-phase flash [C18, 0.1% formic acid] to give the title compound (200 mg, 28% yield) as a white solid; LCMS (ESI, M+1, M+3): m / z = 578.1, 580.1.

[0421] Step C. 5-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 5-(7-bromo-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1 A mixture of [1,5-a][1,4]diazepine-2-carboxamide (180 mg, 1.0 equiv.), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (197 mg, 2.0 equiv.), CsCO (304 mg, 1.5 M in water, 3 equiv.), and [2-(2-aminophenyl)phenyl]palladium(1+); bis(1-adamantyl)-butyl-phosphane; methanesulfonate (22.7 mg, 0.1 equiv.) was degassed and purged with N three times. The mixture was stirred under N at 60 °C for 12 h. The mixture was diluted with water (10 mL), filtered, and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash [C18, 0.1% formic acid condition] to give the title compound (115 mg, 51% yield) as a yellow solid; 1 H NMR (400MHz, methanol-d4)δ=7.73-7.65(m,2H),7.30-7.28(m,1H),7.27-7.21(m,1H),7.00-6.96(m,1H),6.69-6.65(m,1H) ),5.20-5.05(m,2H),4.57-4.52(m,2H),4.36-4.24(m,4H),3.35(m,3H),3.09-3.06(m,3H),2.61-2.53(m,1H),2.46(br d,J=6.4Hz,2H),2.43-2.36(m,3H),2.33-2.30(m,6H),0.82-0.77(m,3H),0.73-0.69(m,2H),0.54-0.49(m,2H);LCMS(ESI,M+1):m / z=688.4.

[0422] Example 56

[0423] [ka] 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0424] [ka]

[0425] Step A. 4-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: To a solution of 7-bromo-2,4-dichloro-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (198 mg, 0.95 equiv.) in DCM (5 mL) was added dropwise at 0° C. The mixture was stirred at 15° C. for 1 hour. The mixture was diluted with HO (20 mL) at 0° C. and extracted with DCM (3×10 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by column chromatography [SiO2, petroleum ether / ethyl acetate = 2 / 1 to 1 / 1] to give the title compound (0.5 g, 76% yield) as a pale yellow solid; LCMS (ESI, M+1, M+3): m / z = 408.0, 410.0.

[0426] Step B. 4-(7-Bromo-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: To a mixture of 4-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (0.5 g, 1.0 equiv.) and (1-((dimethylamino)methyl)cyclopropyl)methanol (316 mg, 2.0 equiv.) in DMSO (2.5 mL) was added DIPEA (319 mg, 2.0 equiv.) and 4 Å molecular sieves (30 mg). The mixture was stirred at 90° C. for 13 hours. The reaction mixture was filtered. The filtrate was purified by reverse phase flash [water (FA, 0.1%) / acetonitrile=3 / 2] to give the title compound (0.35 g, 50% yield) as a pale yellow solid; LCMS (ESI, M+1, M+3): m / z=501.1, 503.1.

[0427] Step C. 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: 4-(7-bromo-2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol in methoxycyclopentane (6.25 mL) To a solution of (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-methyl-1,4-oxazepan-6-ol (0.35 g, 1.0 equiv.) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (255 mg, 1.3 equiv.) under a N2 atmosphere, K3PO4 (1.5 M in HO, 1.23 mL, 3.0 equiv.) and Ad2nBuP-Pd-G3 (45 mg, 0.1 equiv.) were added. The mixture was stirred at 80 °C for 3 h. The mixture was diluted with HO (2 mL) and extracted with ethyl acetate (4 × 3 mL). The combined organic phase was dried over Na2SO4 and concentrated. The residue was purified by reverse-phase flash [water (FA, 0.1%) / acetonitrile = 13 / 7] and preparative HPLC [column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: water (NH4HCO3)-ACN; B%: 59%~89%, 10 min] to give the title compound (156 mg, yield 40%, 0.26 FA) as a white solid; 1 H NMR (400 MHz, methanol-d4) δ = 8.16-8.09 (m, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.30 (d, J = 2.8 Hz, 1H), 7.25 (t, J = 9.2 Hz, 1H), 7.01-6.96 (m, 1H), 4.46-4.42 (m, 1H), 4.41-4.35 (m, 3H), 4.04-3.35 (m, 3H). 97(m,2H),3.93-3.84(m,2H),3.38-3.64(m,2H),2.69-2.54(m,3H),2.49(s,6H),2.45-2.36( m,1H),1.27-1.25(m,3H),0.85-0.77(m,5H),0.63-0.58(s,2H);LCMS(ESI,M+1):m / z=611.4.

[0428] Example 57

[0429] [ka] (1R,5R,6R)-3-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol

[0430] [ka]

[0431] Step A. (1R,5R,6R)-3-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: 4-[2-[[1-[(dimethylamino)methyl] To a mixture of [1R,5R,6R]-3-azabicyclo[3.2.1]octan-6-ol (51.35 mg, 2.0 equiv.) and [1R,5R,6R]-3-azabicyclo[3.2.1]octan-6-ol (117 mg, 1.0 equiv.), KPO (128 mg, 3.0 equiv.) was added. The mixture was stirred at 40 °C for 12 hours. The mixture was filtered and purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; B%: 36%-56%, 2 min) to obtain the title compound (27 mg, 22% yield) as a white solid. 1H NMR(400MHz,chloroform-d)δ=7.59-7.52(m,1H),7.43(br d,J=10.0Hz,1H),7.27-7.24(m,1H),7.21-7.13(m,1H),7.10-6.94(m,1H),4.91(br d,J=11.6Hz,1H),4.75-4.71(m,1H),4.53-4.37(m,1H),4.33(brs,2H),4.21-3.95(m,1 H),3.76-3.54(m,1H),3.37-3.28(m,1H),2.99-2.90(m,1H),2.89-2.72(m,1H),2.70-2 .59(m,6H),2.58-2.33(m,2H),2.33-2.23(m,2H),2.21-2.04(m,1H),1.83-1.70(m,2H) ,1.35-1.01(m,1H),0.87-0.75(m,4H),0.71-0.62(m,2H);LCMS(ESI,M+1):m / z=607.3.

[0432] Example 58

[0433] [ka] (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(pyrrolidin-1-yl)methanone

[0434] [ka]

[0435] Step A. (5-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(pyrrolidin-1-yl)methanone: To a solution of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (500 mg, 1.0 equiv.) in DCM (4 mL) was added DIEA (1.65 g, 8.0 equiv.) and pyrrolidin-1-yl(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone (560 mg, 1.5 equiv.). The mixture was stirred at 0° C. for 0.5 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent and purified by column chromatography (SiO, petroleum ether:ethyl acetate=5 / 1 to dichloromethane:methanol=10:1) to give the title compound (460 mg, 56% yield) as a yellow solid; LCMS (ESI, M+1, M+3): m / z=510.8, 512.8.

[0436] Step B. (5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(pyrrolidin-1-yl)methanone: (5-(7-bromo-2-chloro-6,8-di To a solution of (fluoroquinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(pyrrolidin-1-yl)methanone (240 mg, 1.0 equiv.) was added CsF (712 mg, 10 equiv.) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (373 mg, 5.0 equiv.). The mixture was stirred at 60° C. for 12 hours. The reaction mixture was filtered and purified by preparative HPLC [Column: YMC Triart C18 250 × 50 mm × 7 μm; Mobile phase: (water (NH3·H2O)-ACN); B%: 47% to 77% over 20 min] to give the title compound (70 mg, 23% yield) as a white solid; LCMS (ESI, M+1, M+3): m / z = 634.3, 636.3.

[0437] Step C. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(pyrrolidin-1-yl)methanone: (5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- To a solution of (pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(pyrrolidin-1-yl)methanone (60 mg, 1.0 equiv.) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (89.7 mg, 3.0 equiv.) was added KPO (60.2 mg, 3 equiv.) and Ad2nBuP-Pd-G3 (6.89 mg, 0.1 equiv.). The mixture was degassed and purged with N2 three times and stirred under N2 at 90 °C for 1.5 h. The reaction mixture was filtered and purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 μm; A: water (10 mM HCOOH), B: ACN, B%: 24% to 54% over 10 min] to give the title compound (4.17 mg, yield 5.9%) as a white solid; 1H NMR (400MHz, methanol-d4) δ=7.80-7.64(m,2H),7.33-7.20(m,2H),6.98(d,J=2.4Hz,1H),6.79(s, 1H),5.46-5.26(m,1H),5.21-5.06(m,2H),4.58-4.51(m,2H),4.38-4.24(m,4H),3.93(t,J=6.4 Hz,2H),3.59(t,J=6.8Hz,2H),3.43-3.36(m,2H),3.19-3.06(m,2H),2.64-2.52(m,1H),2.48-2 .35(m,4H),2.34-2.26(m,1H),2.24-2.16(m,1H),2.12-2.03(m,2H),2.00-1.90(m,5H),0.80(br t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=744.4

[0438] Example 59

[0439] [ka] 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-N-isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0440] [ka]

[0441] Step A. 5-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-N-isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (300 mg, 1.0 equiv.), 4 Å molecular sieves (10 mg) in DCM (0.5 mL) was added DIEA (370 mg, 3.0 equiv.) and N-isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (297 mg, 1.2 equiv., HCl). The mixture was stirred at 0° C. for 1 hour. The mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase flash [C18, 0.1% formic acid] to give the title compound (201 mg, 38% yield) as a yellow solid. LCMS (ESI, M+1, M+3): m / z = 498.8, 500.8.

[0442] Step B. 5-(7-Bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N-isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 5-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-N-isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide in dioxane (1 mL) To a solution of (180 mg, 1.0 equiv.) and 4 Å molecular sieves (10 mg) was added DIEA (186 mg, 4.0 equiv.) and (((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (287 mg, 5.0 equiv.). The mixture was stirred at 90° C. for 5 hours. The mixture was filtered to obtain a residue. The residue was purified by reverse-phase flash [C18, 0.1% formic acid condition] to obtain the title compound (60 mg, 26% yield) as a yellow solid. LCMS (ESI, M+1, M+3): m / z = 621.8, 623.8.

[0443] Step C. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N-isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N-isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide in methoxycyclopentane (0.5 mL). To a mixture of (roridin-7a-yl)methoxy)quinazolin-4-yl)-N-isopropyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (45.0 mg, 1.0 equiv.), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (68.6 mg, 3.0 equiv.), and KPO (46.0 mg, 3.0 equiv.) was added Ad2nBuP-Pd-G3 (5.30 mg, 0.1 equiv.). The mixture was degassed and purged with N2 three times. The mixture was stirred at 90 °C under a N2 atmosphere for 1.5 hours. The mixture was filtered to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; B%: 20% to 50%, 10 min) to give the title compound (9.4 mg, 17% yield, FA) as a white solid. 1H NMR (400 MHz, methanol-d₄) δ = 7.77 (d, J = 10.0 Hz, 1H), 7.68 (dd, J = 6.0, 9.2 Hz, 1H), 7.30-7.23 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 6.77 (s, 1H), 5.48-5.34 (m, 1H), 5.20-5.04 (m, 2H), 4.52-4.49 (m, 1H), 4.40-4.36 (m, 2H). ,4.34-4.28(m,2H),4.16(td,J=6.8,13.2Hz,1H),3.52-3.46(m,2H),3.22-3.13(m,2H),2.61-2.50(m,1H) ),2.47-2.30(m,5H),2.29-2.10(m,4H),2.02-1.94(m,1H),1.23(d,J=6.8Hz,6H),0.80(t,J=7.6Hz,3H). LCMS (ESI, M+1): m / z=732.5.

[0444] Example 60

[0445] [ka] 4-(4-(dimethylamino)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0446] [ka]

[0447] Step A: 4-(4-(dimethylamino)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: A mixture of 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol in N-methylmethanamine (1 M, 1.64 mL, 5.0 equiv.) was stirred at 60° C. for 12 hours. The mixture was concentrated and purified by reverse-phase HPLC (Column: Waters Xbridge 150 × 25 mm × 5 μm; Mobile phase: [water (NH4HCO3)-ACN]; B%: 55% to 85% over 8 min) to give the title compound (41.9 mg, 23% yield) as a yellow solid; SFC: Column: Chiralpak IC-3 50 × 4.6 mm ID, 3 μm Mobile phase: Phase A for CO2 and Phase B for IPA (0.05% DEA); Gradient elution: 40% IPA (0.05% DEA) in CO2 Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35°C; Back pressure: 100 bar. 1 H NMR(400MHz,DMSO-d6)δ=9.97(s,1H),7.91(d,J=10.4Hz,1H),7.78(dd,J=6.0,8.4Hz,1H), 7.42-7.32(m,2H),7.05-6.98(m,1H),5.44-5.11(m,1H),4.10(dd,J=4.0,10.4Hz,1H),4.0 4-3.96(m,1H),3.45-3.35(m,6H),3.15-2.98(m,3H),2.83-2.80(m,1H),2.47-2.28(m,2H) ,2.19-1.95(m,3H),1.88-1.69(m,3H),0.75(t,J=7.2Hz,3H),LCMS(ESI,M+1):m / z=555.3.

[0448] Example 61

[0449] [ka] 4-(4-(7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0450] [ka]

[0451] Step A. 4-(4-(7,8-dihydro-4H-[1,2,3]triazolo[1,5-a][1,4]diazepin-5(6H)-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: 4-(6,8-difluoro-2-(((2R,7 To a solution of aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (200 mg, 1.0 equiv.) and 5,6,7,8-tetrahydro-4H-triazolo[1,5-a][1,4]diazepine (90.7 mg, 2.0 equiv.) was added DIEA (127 mg, 3.0 equiv.). The mixture was stirred at 90°C for 12 hours. The mixture was poured into water (2 mL) and filtered. The filtrate was extracted with ethyl acetate (3 x 10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude was purified by reverse phase flash [Waters Xbridge 150 x 25 mm x 5 um; mobile phase: A: water (NH4HCO3); B: ACN; B%: 40% to 70% over 8.5 min] to give the title compound (7.74 mg, 3.4% yield) as a white solid; 1H NMR (400 MHz, methanol-d4) δ = 7.83-7.76 (m, 1H), 7.72-7.63 (m, 2H), 7.31-7.20 (m, 2H), 7.00-6.95 (m, 1H), 5.39-5.09 (m, 3H), 4.79-4.71 (m, 2H), 4.44-4.27 (m, 2H), 4.23-4.1 2(m,2H),3.29-3.15(m,3H),3.07-2.96(m,1H),2.63-2.50(m,1H),2.46-2.34(m,3H) ,2.31-2.07(m,3H),2.04-1.86(m,3H),0.84-0.75(m,3H);LCMS(ESI,M+1):m / z=648.4

[0452] Example 62

[0453] [ka] 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[4.5]decane-1,3-dione

[0454] [ka]

[0455] Step A. 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[4.5]decane-1,3-dione: 4-(6,8-difluoro-2-(((2R,7aS)-2- To a mixture of (fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (200 mg, 1.0 equiv.), 2,7-diazaspiro[4.5]decane-1,3-dione (66.2 mg, 1.2 equiv.), and 4 Å molecular sieves (50.0 mg, 1.0 equiv.) was added KPO (209 mg, 3.0 equiv.). The mixture was stirred at 40 °C for 12 h. The reaction mixture was filtered and purified by preparative HPLC [column: Waters Xbridge 150 × 25 mm × 5 um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 44%~74%, 9 min] and lyophilized to give the title compound (16.8 mg, yield 7%) as a yellow solid; 1 H NMR (400 MHz, methanol-d4) δ = 7.67 (dd, J = 6.0, 8.8 Hz, 1H), 7.63-7.58 (m, 1H), 7.31-7.28 (m, 1H), 7.27-7.21 (m, 1H), 7.00-6.97 (m, 1H), 5.40-5.21 (m, 1H), 4.42 (br t,J=12.0Hz,1H),4.34-4.13(m,3H),3.67-3.53(m,2H),3.27-3.11(m,3H),3.04-2.91(m,2H),2.72-2.64(m,1H),2.61-2.52(m ,1H),2.47-2.37(m,1H),2.24(brs,1H),2.22-2.07(m,3H),2.06-1.83(m,6H),0.86-0.73(m,3H);LCMS(ESI,M+1):m / z=678.5.

[0456] Example 63

[0457] [ka] 5-((R)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0458] Example 64

[0459] [ka] 5-((S)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0460] [ka]

[0461] Step A: 5-((R)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide and 5-((S)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidine 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide was purified by SFC (column: DAICEL Separation by CHIRALPAK IC (250 mm × 30 mm, 10 μm); mobile phase: [IPA-ACN]; B%: 40% to 40% over 7.0 min followed by purification by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm; phase A: water (NH4HCO3); phase B: ACN, B%: 48% to 78% over 10 min) gave two peaks.

[0462] Example 63 as a white solid (124 mg, 13% yield); Column: Chiralpak IC-3 50 x 4.6 mm ID, 3 μm, Mobile phase: [40% IPA + ACN (0.05% DEA)] in CO2, Flow rate: 3 mL / min, Detector: 220 nm, tR: 1.289 min; 11H NMR (400 MHz, DMSO-d6) δ 7.78 - 7.63 (m, 2H), 7.34 - 7.19 (m, 2H), 6.98 (d, J = 2.8 Hz, 1H), 6.70 (s, 1H), 5.40 - 5.21 (m, 1H), 5.20 - 5.04 (m, 2H), 4.58 - 4.49 (m, 2H), 4.41 - 4.08 (m, 4H), 3.37 - 3.33 (m, 3H), 3.27 - 3.13 (m, 3H), 3.12 - 3.05 (m, 3H), 3.04 - 2.96 (m, 1H), 2.67 - 2.51 (m, 1H), 2.45 - 2.31 (m, 3H), 2.27 - 2.06 (m, 3H), 2.05 - 1.82 (m, 3H), 0.86 - 0.73 (m, 3H); LCMS (ESI, M+1): m / z = 718.5。

[0463] Example 64 as a white solid (148 mg, yield 16%); Column: Chiralpak IC-3 50×4.6 mm I.D., 3 μm, Mobile phase: Phase A: 40% IPA, Phase B: ACN in CO2 (0.05% DEA), Flow rate: 3 mL / min, Detector: 220 nm, tR: 1.979 min; 1 1H NMR (400 MHz, DMSO-d6) δ 7.77 - 7.64 (m, 2H), 7.33 - 7.20 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 6.70 (s, 1H), 5.40 - 5.22 (m, 1H), 5.21 - 5.06 (m, 2H), 4.64 - 4.43 (m, 2H), 4.40 - 4.15 (m, 4H), 3.35 (s, 3H), 3.27 - 3.13 (m, 3H), 3.08 (s, 3H), 3.04 - 2.97 (m, 1H), 2.63 - 2.51 (m, 1H), 2.45 - 2.33 (m, 3H), 2.25 - 2.05 (m, 3H), 2.04 - 1.84 (m, 3H), 0.80 (t, J = 7.6 Hz, 3H); LCMS [ESI, M+1]: m / z = 718.5。

[0464] Example 65

[0465]

Chemical Structure

[0466] Example 66

[0467] [ka] (S)-4-((R)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0468] [ka]

[0469] Step A. (S)-4-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: To a solution of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (12.0 g, 1.0 equiv.), 4 Å molecular sieves (2 g), and DIEA (19.8 g, 4.0 equiv.) in DCM (100 mL) was added a solution of (S)-6-methyl-1,4-oxazepan-6-ol (5.77 g, 0.9 equiv., HCl) in DCM (20 mL) at 0 °C. The solution was diluted with water (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo, and purified with petroleum ether:ethyl acetate = 5:1 for 15 min. ℃ Trituration at rt for 15 min afforded the title compound (9.6 g, 56% yield) as a yellow solid. LCMS (ESI, M+1, M+3): m / z = 408.0, 410.0.

[0470] Step B. (S)-4-(7-Bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: A mixture of (S)-4-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (3.20 g, 1.0 equiv.) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (16 mL) was stirred at 90° C. for 36 hours. The solution was diluted with MeOH (50 mL) and purified by reverse-phase flash (C18, 0.1% formic acid condition) to give the title compound (7.8 g, 3 batches, 57% yield) as a yellow solid; LCMS (ESI, M+1, M+3): m / z = 531.0, 533.2.

[0471] Step C. (6S)-4-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: (S)-4-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl) in methoxycyclopentane (90 mL) A mixture of 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (7.50 g, 1.0 equiv.), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (5.80 g, 1.3 equiv.), Ad2nBuP-Pd-G3 (1.03 g, 0.1 equiv.), and K3PO4 (1.5 M in water, 28.2 mL, 3.0 equiv.) was degassed and purged with N2 three times. The mixture was then stirred at 90 °C under a N2 atmosphere for 2 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by reverse-phase flash [C18, 0.1% formic acid conditions] to give the title compound (6.3 g, 48% yield) as a yellow solid; SFC conditions: Chiralcel OJ-3 50 x 4.6 mm ID, 3 um; mobile phase: Phase A: CO2, Phase B: MeOH (0.05% DEA); gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; flow rate: 3 mL / min; detector: PDA; column temperature: 35 C; back pressure: 100 bar; LCMS (ESI, M+1): m / z = 641.3.

[0472] Step D. (S)-4-((S)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol and (S)-4-((R)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: The title compounds were prepared by HPLC using SFC (DAICEL CHIRALCEL OJ (250 mm)). 50 mm, 10 μm); mobile phase A: water, B: (0.1% NH3·H2O in MeOH), B%: 30%-30% over 2.5 min to separate two peaks.

[0473] Example 65 (723 mg, 10% yield). SFC conditions: Chiralcel OJ-3 50 x 4.6 mm ID, 3 um; Mobile phase: Phase A: CO2, Phase B: MeOH (0.05% DEA); Gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35°C; Back pressure: 100 bar; 1 H NMR (400 MHz, methanol-d4) δ = 8.08 (dd, J = 1.6, 10.4 Hz, 1H), 7.67 (dd, J = 6.0, 9.2 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.24 (t, J = 9.2 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 5.42-5.19 (m, 1H), 4.47-4.40 (m, 1H), 4.37-4.18 (m, 3H), 4.10-3.96 (m, 2H), 3.9 1-3.80(m,2H),3.71-3.59(m,2H),3.29-3.13(m,3H),3.05-2.97(m,1H),2.64-2.53(m,1H),2.49-2.40(m,1H),2.38 -2.24(m,1H),2.23-2.08(m,2H),2.03-1.82(m,3H),1.24(s,3H),0.82(t,J=7.2Hz,3H);LCMS(ESI,M+3):m / z=641.3.

[0474] Example 66 (744 mg, 10% yield). SFC conditions: Chiralcel OJ-3 50 x 4.6 mm ID, 3 um; Mobile phase: Phase A: CO2, Phase B: MeOH (0.05% DEA); Gradient elution: 5% to 40% MeOH (0.05% DEA) in CO2; Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35°C; Back pressure: 100 bar; 1 H NMR (400MHz, methanol-d4) δ=8.11(dd,J=1.2,10.4Hz,1H),7.67(dd,J=6.0,9.2Hz,1H),7.28(d,J=2.8Hz,1H),7.24(t ,J=9.2Hz,1H),6.98(d,J=2.4Hz,1H),5.41-5.17(m,1H),5.52-4.44(m,1H),4.37-4.19(m,3H),4.06-3.95(m,2H),3 .88-3.78(m,2H),3.73-3.57(m,2H),3.28-3.13(m,3H),3.05-2.96(m,1H),2.61-2.48(m,1H),2.45-2.35(m,1H),2. 35-2.16(m,2H),2.16-2.07(m,1H),2.03-1.82(m,3H),1.26(s,3H),0.78(t,J=7.2Hz,3H));LCMS[ESI,M+1]:641.3.

[0475] Example 67

[0476] [ka] (1R,5R,6R)-3-((R)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol

[0477] Example 68

[0478] [ka] (1R,5R,6R)-3-((S)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol

[0479] [ka]

[0480] Step A: (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro)quinazolin-4-yl) in DMF (2 mL) To a mixture of 1H-pyrrolidin-7a((5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol (1.0 g, 1.0 equiv.), (1R,5R,6R)-3-azabicyclo[3.2.1]octan-6-ol (625.97 mg, 3.0 equiv.), DIEA (636 mg, 3.0 equiv.) and 4 Å molecular sieves (0.5 g) were added. The mixture was heated at 60°C for 12 hours. Water (10 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by reverse phase flash [C18, 0.1% formic acid conditions] to give the title compound (0.82 g, 70% yield) as a yellow solid; LCMS (ESI, M+1): m / z=637.5.

[0481] Step B: (1R,5R,6R)-3-((R)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol and (1R,5R,6R)-3-((S)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: The title compounds were purified by SFC (column: Waters Xbridge 150×25 mm×5 μm; Mobile phase: [water (NH4HCO3)-ACN]; B%: 57%-87% over 8 minutes. Two peaks were separated.

[0482] Example 67 as a yellow solid (179 mg, 21% yield). SFC: 100% ee, "Column: Chiralpak IC-3 50 x 4.6 mm ID, 3 μm Mobile phase: Phase A for CO2 and Phase B for EtOH (0.05% DEA); Gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2 Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35°C; Back pressure: 100 bar." 1 H NMR (400 MHz, methanol-d4) δ = 8.05-7.92 (m, 1H), 7.67 (dd, J = 6.0, 8.4 Hz, 1H), 7.36-7.19 (m, 2H), 6.97 (d, J = 2.0 Hz, 1H), 5.39-5.21 (m, 1H), 4.70 (d, J = 12.0 Hz, 1H), 4.69-4.62 (m, 1H), 4.37-4.16 (m, 3H), 3.55-3.52 (m ,1H),3.48-3.42(m,1H),3.23-3.19(m,3H),3.04-2.98(m,1H),2.62-2.55(m,1H),2.47-2.31(m,3H),2.3 1-2.10(m,5H),1.98-1.75(m,4H),1.55-1.42(m,1H),0.80(t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=637.3.

[0483] Example 68 as a yellow solid (179 mg, 21% yield). SFC: 98.9% ee, Column: Chiralpak IC-3 50 x 4.6 mm ID, 3 μm. Mobile phase: Phase A for CO2 and Phase B for EtOH (0.05% DEA); Gradient elution: 5% to 40% EtOH (0.05% DEA) in CO2. Flow rate: 3 mL / min; Detector: PDA; Column temperature: 35°C; Back pressure: 100 bar. 1 H NMR (400 MHz, methanol-d4) δ = 8.08-7.93 (m, 1H), 7.67 (dd, J = 6.0, 9.2 Hz, 1H), 7.37-7.16 (m, 2H), 6.97 (d, J = 2.4 Hz, 1H), 5.40-5.20 (m, 1H), 4.76-4.54 (m, 2H), 4.40-4.15 (m, 3H), 3.57 (d, J = 12.0 Hz, 1H), 3.49-3.41 ( m,2H),3.25-3.16(m,2H),3.08-2.95(m,1H),2.62-2.51(m,1H),2.50-2.29(m,3H),2.28-2.11(m,4H),1 .99-1.77(m,4H),1.66-1.58(m,1H),1.57-1.43(m,1H),0.80(t,J=8Hz,3H);LCMS(ESI,M+1):m / z=637.4.

[0484] Example 69

[0485] [ka] (R)-1-((R)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

[0486] Example 70

[0487] [ka] (R)-1-((S)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

[0488] [ka]

[0489] Step A. (R)-1-((R)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol and R)-1-((S)-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol: The title compounds were purified by SFC [Conditions: Column: DAICEL CHIRALPAK Two peaks were separated by AD (250 mm x 50 mm, 10 μm); mobile phase: [0.1% NH 3 H 2 O / IPA]; B%: 55%-55%, 4.1 min].

[0490] Example 69 as a yellow solid (6.85 g, 20% yield); 1H NMR(400MHz,メタノール-d4)δ=7.80(d,J=9.6Hz,1H),7.67(dd,J=6.0,9.2Hz,1H),7.29(d,J=2.4Hz, 1H),7.24(t,J=9.2Hz,1H),6.98(d,J=2.8Hz,1H),5.44-5.15(m,1H),4.34-4.18(m,3H),4.05(br d,J=13.2Hz,1H),3.46-3.35(m,2H),3.28-3.13(m,3H),3.06-2.95(m,1H),2.63-2.51(m,1H),2.4 7-2.11(m,5H),2.03-1.71(m,6H),1.29(s,3H),0.81(t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=625.5.

[0491] Example 70: yellow solid として (6.02g, yield 18%); 1 H NMR(400MHz,メタノール-d4)δ=7.76(br d,J=8.8Hz,1H),7.67(dd,J=6.0,9.2Hz,1H),7.29(d,J=2.4Hz,1H),7.24(t,J=9 .2Hz,1H),6.98(d,J=2.4Hz,1H),5.45-5.16(m,1H),4.33-4.15(m,3H),4.05(br d,J=13.2Hz,1H),3.50(d,J=13.2Hz,1H),3.42-3.34(m,1H),3.29-3.12(m,3H),2.97-3.03(m,1H),2.63-2.50 (m,1H),2.45-2.10(m,5H),2.02-1.70(m,6H),1.25(s,3H),0.80(t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=625.3.

[0492] Example 71

[0493]

change

[0494] [ka]

[0495] Step A. 6-(7-Bromo-2-chloro-8-fluoroquinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane: To a mixture of 7-bromo-2,4-dichloro-8-fluoroquinazoline (300 mg, 1.0 equiv.) and 1-oxa-8-azaspiro[3.5]nonane in DCM (10 mL); oxalic acid (349 mg, 1.0 equiv.) was added DIEA (393 mg, 3.0 equiv.). The reaction mixture was stirred at −40° C. under a nitrogen atmosphere for 2 hours. The mixture was concentrated and purified by flash silica gel chromatography [SiO, petroleum ether / ethyl acetate=3 / 1] to give the title compound (300 mg, 69% yield) as a yellow solid. 1 H NMR (400MHz, chloroform-d) δ=7.76(d,J=9.2Hz,1H),7.55(dd,J=6.4,8.8Hz,1H),4.57(t ,J=8.0Hz,2H),4.25(d,J=13.2Hz,1H),4.03(td,J=4.4,13.2Hz,1H),3.66(d,J=13.2H) z,1H),3.41(ddd,J=2.8,9.6,13.2Hz,1H),2.43(t,J=8.0Hz,2H),2.32-2.18(m,1H), 2.10-1.97(m,1H),1.93-1.84(m,1H),1.83-1.73(m,1H);LCMS(ESI,M+1):m / z=388.0.

[0496] Step B. 6-(7-Bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane: A mixture of 8-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-1-oxa-8-azaspiro[3.5]nonane (110 mg, 1.0 equiv.) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol (453 mg, 10 equiv.) in DMSO (0.05 mL) was stirred at 90° C. under a N atmosphere for 12 hours. The mixture was concentrated and purified by preparative HPLC [FA conditions; column: Phenomenex Synergi C18 150 × 25 mm × 10 μm; mobile phase: [water (FA)-ACN]; B%: 9% to 39%, 10 min] to give the title compound (75.0 mg, 50% yield) as a yellow solid. 1 H NMR(400MHz,chloroform-d)δ=8.32(s,1H),7.68(dd,J=1.2,8.8Hz,1H),5.47-5.29(m,1H),4.57(t,J=7.6Hz,2H),4.47(t,J=2.8Hz,2H),4.14(br dd,J=4.4,13.2Hz,2H),4.09-3.97(m,3H),3.76-3.58(m,4H),3.42-3.29(m,2H ),3.13-3.05(m,1H),2.41(brs,2H),2.34(brs,1H),2.23-2.17(m,1H),2.09(br d,J=5.6Hz,2H),1.91-1.83(m,1H),1.81-1.73(m,1H);LCMS[ESI,M+1]:m / z=511.0

[0497] Step C. 5-Ethyl-6-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)naphthalen-2-ol: 5-Ethyl-6-fluoro-4-(4,4,5,5)-2-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)naphthalen-2-ol in methoxycyclopentane (3.0 mL) and HO (0.6 mL) To a mixture of 1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (37.2 mg, 1.2 equiv.) and 6-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (50.0 mg, 1.0 equiv.) was added Ad2nBuPd G3 (cataCXium® A Pd G3) (7.10 mg, 0.1 equiv.) and Cs2CO3 (96.0 mg, 3.0 equiv.). The reaction mixture was degassed and purged with nitrogen three times and stirred under a N2 atmosphere at 80 °C for 2 h. The mixture was concentrated and purified by preparative HPLC [column: Waters Xbridge 150 × 25 mm × 5 um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 37%–67%, 9 min] to give the title compound (13.5 mg, 25% yield, HCOOH salt) as a white solid. 1 H NMR (400MHz, methanol-d4) δ = 8.54 (s, 1H), 8.02-7.92 (m, 1H), 7.70-7.60 (m, 1H), 7.40-7.28 (m, 1H), 7.27-7.18 (m, 2H), 6.96 (d, J = 2.0Hz, 1H), 5.50-5.24 (m, 1H), 4.58 (brs, 2H), 4.43-4.31 (m, 2H), 4.25-4.07(m,1H),3.89-3.68(m,1H),3.57-3.33(m,4H),3.18-3.05(m,1H),2.54-2.27(m,6H), 2.26-2.16(m,2H),2.08(brs,3H),2.01-1.88(m,2H),1.80(ddd,J=2.4,4.0,8.4Hz,1H),0.78(br t,J=7.2Hz,3H);LCMS[ESI,M+1]:619.1.

[0498] Example 72

[0499] [ka] 7-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide

[0500] [ka]

[0501] Step A. 7-(8-chloro-7-fluoro-3-((triisopropylsilyl)oxy)naphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline: To a solution of 7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (480 mg, 1.0 equiv.) and (5-chloro-6-fluoro-4-trimethylstannyl-2-naphthyl)oxy-triisopropyl-silane (513 mg, 1.0 equiv.) in DMAc (5 mL) was added CataCXium A Pd G3 (72.5 mg, 0.1 equiv.) was added under N. The reaction mixture was stirred at 90° C. under N for 5 h. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (2×40 mL). The combined layers were washed with brine (40 mL), dried over sodium sulfate, concentrated, and purified by reverse-phase flash (C18, 0.1% FA) to give the title compound (140 mg, 30% yield) as a colorless oil.

[0502] Step B. 7-(7-(8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide: 7-(8-chloro-7-fluoro-3-((triisopropylsilyl)oxy)naphthalene) in DMF (0.6 mL) To a solution of (2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (60 mg, 1.0 equiv.) and 2-thia-1,3,7-triazaspiro[4.5]decane 2,2-dioxide (53.2 mg, 3.5 equiv.) was added 4 Å molecular sieves (7 g) and potassium phosphate (33.8 mg, 2.0 equiv.). The reaction mixture was stirred at 60° C. under a N atmosphere for 12 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, concentrated, and purified by preparative HPLC (Column: Phenomenex luna C18 150 x 25 mm x 10 μm; A: water (FA); B: ACN, B%: 12% to 42% over 2 min) to give the title compound (36.0 mg) as a yellow solid (FA salt). NMR (400MHz, methanol-d4) δ = 8.51 (brs, 1H), 8.01-7.90 (m, 1H), 7.78 (ddd, J = 2.0, 5.6, 9.2Hz, 1H), 7.37 (dt, J = 1.6, 8.8Hz, 1H), 7.34-7.29 (m, 2H), 7.09 (s, 1H), 5.60-5.31 (m, 1H), 4.64-4.47 (m, 2H), 4.47-4.32 (m, 1H),4.30-4.16(m,1H),3.82-3.50(m,5H),3.43(d,J=11.9Hz,1H),3.29-3.19(m,2H),2.64-2.36(m,2H), 2.36-2.27(m,1H),2.25-2.13(m,2H),2.12-1.96(m,3H),1.95-1.81(m,2H);LCMS[ESI,M+1]:m / z=689.1.

[0503] Example 73

[0504] [ka] (3-chloro-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-((((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone

[0505] [ka]

[0506] Step A. (5-(7-Bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone: To a solution of 7-bromo-2,4-dichloro-8-fluoroquinazoline (1.00 g, 1.0 equiv.) and (3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone (1.15 g, 1.2 equiv.) in dichloromethane (10 mL) was added DIEA (1.31 g, 3.0 equiv.). The reaction mixture was stirred at −40° C. for 0.5 h. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (4×15 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and slurried with acetonitrile (30 mL) at 20° C. for 20 minutes to give the title compound (1.20 g, 64% yield) as a white solid; LCMS (ESI, M+1): m / z=545.0.

[0507] Step B. (5-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone: (5-(7-bromo-2-chloro-8-fluoro A mixture of (quinazolin-4-yl)-3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone (1.10 g, 1.0 equiv.) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (965 mg, 3.0 equiv.) was stirred at 110° C. for 12 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (4×15 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid] to give the title compound (100 mg, 7.1% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 668.0.

[0508] Step C. (3-chloro-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone: (5-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)- To a mixture of (roridin-7a-yl)methoxy)quinazolin-4-yl)-3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone (100 mg, 1.0 equiv.), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (71.1 mg, 1.5 equiv.), and KPO (95.5 mg, 3.0 equiv.) under a nitrogen atmosphere was added Ad2nBup-Pd-G3 (10.9 mg, 0.10 equiv.). The reaction mixture was stirred at 90°C for 2 hours. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (4 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3), B: ACN, B%: 51% to 81% over 10 min] and preparative HPLC [Phenomenex C18 75 × 30 mm × 3 μm; A: water (FA), B: ACN, B%: 18% to 48% over 7 min] to give the title compound (54.2 mg, 46% yield, HCOOH salt) as a white solid; 1H NMR (400 MHz, methanol-d4) δ = 7.92 (d, J = 8.8 Hz, 1H), 7.68-7.64 (m, 1H), 7.38-7.34 (m, 1H), 7.28-7.19 (m, 2H), 6.94 (d, J = 2.4 Hz, 1H), 5.53-5.33 (m, 1H), 5.21-5.03 (m, 2H), 4.47-4.30 (m, 6H) ),3.75(s,4H),3.67(s,4H),3.65-3.40(m,3H),3.26-3.15(m,1H),2.61-2.31(m,6H),2.30- 2.22(m,1H),2.19-2.08(m,2H),2.03(s,1H),0.79-0.75(m,3H);LCMS(ESI,M+1):m / z=776.3.

[0509] Example 74

[0510] [ka] 3-chloro-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0511] [ka]

[0512] Step A. 5-(7-Bromo-2-chloro-8-fluoroquinazolin-4-yl)-3-chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 7-bromo-2,4-dichloro-8-fluoroquinazoline (950 mg, 1.0 equiv.) and 3-chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (779 mg, 1.0 equiv.) in dichloromethane (9 mL) was added DIEA (2.07 g, 5.0 equiv.) at −40° C. The reaction mixture was stirred at −40° C. for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, triturated with acetonitrile (10 mL) at 20 °C for 20 min, filtered, and concentrated to give the title compound (1.13 g, 69% yield) as a white solid; LCMS (ESI, M+1): m / z = 503.1.

[0513] Step B. 5-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 5-(7-bromo-2-chloro-8-fluoroxyl)quinazolin-4-yl A mixture of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (792 mg, 5.0 equiv.) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (500 mg, 1.0 equiv.) was stirred at 110° C. for 12 hours. The reaction mixture was cooled to 20° C. and diluted with water (5 mL). The crude material was slurried with HO (6 mL) at 20° C. for 20 minutes and triturated with acetonitrile (4 mL) at 20° C. for 20 minutes to give the title compound (420 mg, 61% yield) as a white solid; LCMS (ESI, M+1): m / z=626.1.

[0514] Step C. 3-chloro-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 5-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- To a mixture of 1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (150 mg, 1.0 equiv.), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (114 mg, 1.5 equiv.), and KPO (153 mg, 3.0 equiv.) was added Ad2nBuP-Pd-G3 (17.5 mg, 0.10 equiv.). The reaction mixture was stirred at 90 °C under a N2 atmosphere for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash chromatography [C18, 0.1% formic acid condition] and preparative HPLC [Waters Xbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3), B: ACN, B%: 46% to 76% over 8 min] to give the title compound (30.3 mg, 17% yield) as a white solid; 1H NMR (400MHz, methanol-d4) δ=7.88(d,J=8.8Hz,1H),7.65(dd,J=6.0,9.2Hz,1H),7.32(dd,J=6.8,8.4Hz,1H),7 .28-7.17(m,2H),6.94(d,J=2.4Hz,1H),5.44-5.24(m,1H),5.22-5.03(m,2H),4.52-4.40(m,2H),4.40-4.29 (m,2H),4.25(s,2H),3.49-3.34(m,1H),3.29-3.17(m,2H),3.11(d,J=12.4Hz,6H),3.08-2.99(m,1H),2.56- 2.28(m,5H),2.27-2.10(m,2H),2.05-1.89(m,3H),0.77(dt,J=3.2,7.2Hz,3H);LCMS(ESI,M+1):m / z=734.2.

[0515] Example 75

[0516] [ka] 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0517] [ka]

[0518] Step A. 5-(7-Bromo-2-chloro-8-fluoroquinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 7-bromo-2,4-dichloro-8-fluoroquinazoline (840 mg, 1.0 equiv.) and DIEA (1.10 g, 3.0 equiv.) in dichloromethane (1.0 mL) was added N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (214 mg, 2.0 equiv.) at −40° C. The reaction mixture was stirred at −40° C. for 0.5 h. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (3 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and triturated with acetonitrile (15 mL) to give the title compound (1.10 g, 80% yield) as a white solid; LCMS (ESI, M+1): m / z = 483.1.

[0519] Step B. 5-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 5-(7-bromo-2-chloro-8-fluoro A mixture of (quinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (400 mg, 1.0 equivalent) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (1.18 g, 10 equivalents) was stirred at 90° C. for 12 hours. The reaction mixture was slurried with water (15 mL) to give the title compound (300 mg, 54% yield) as a brown solid.

[0520] Step C. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 5-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide in methoxycyclopentane (2 mL) and water (0.5 mL). To a mixture of (di-(2 ...3-(2-(2-(2-(2-(2-(2-(2-(2-(2-(3-(2-(2-(2-(2-(2-(2-(2-(3-(2-(2-(2-(2-(2-(2-(3-(2-(2-(2-(2-(3-(2-(2-(2-(2-(2-(2-(3-(2-(2-(2-(2-(3-(2-(2-(2-(2-(3-(2-(2-(2-(2-(3-(2-(2-(2-(2-(3-(2-(2-(2-(3-(2-(2-(2-(3-(2-(2-(2-(2-(3-(2-(2-(2-(3-(2-(2-(2-(3-(2-(2-(2-(3-(2-(2-(2-(3-(2-(2-(2-(3-(2-(2-(2-(3-(2-(2-(2-(3- The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Phenomenex luna C18 150 × 25 mm × 10 μm; A: water (FA), B: ACN, B%: 21% to 51% over 8 min] to give the title compound (100 mg, 98% yield, HCOOH salt) as a yellow solid; 1H NMR (400 MHz, methanol-d4) δ = 8.56-8.50 (m, 1H), 7.92-7.82 (m, 1H), 7.70-7.58 (m, 1H), 7.38-7.28 (m, 1H), 7.27-7.17 (m, 2H), 6.98-6.88 (m, 1H), 5.49-5.27 (m, 1H), 5.21-5.01 (m, 2H), 4.51-4.42 (m, 2H), 4 .41-4.23(m,4H),3.60-3.36(m,3H),3.22-3.15(m,1H),3.15-3.11(m,3H),3.11-3.05(m,3H),2.52 -2.27(m,6H),2.25-2.05(m,6H),2.03-1.87(m,1H),0.84-0.67(m,3H);LCMS(ESI,M+1):m / z=714.2.

[0521] Example 76

[0522] [ka] (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(4-methylpiperazin-1-yl)methanone

[0523] [ka]

[0524] Step A. (5-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(4-methylpiperazin-1-yl)methanone: To a solution of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (880 mg, 1.0 equiv.) and DIEA (1.10 g, 3.0 equiv.) in dichloromethane (1 mL) was added (4-methylpiperazin-1-yl)(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanone (775 mg, 1.1 equiv.). The reaction mixture was stirred at −40° C. for 0.5 hours. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (3 × 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and slurried with acetonitrile (15 mL) to give the title compound (800 mg, 52% yield) as a white solid; LCMS (ESI, M+1): m / z = 542.2.

[0525] Step B. (5-(7-Bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(4-methylpiperazin-1-yl)methanone: (5-(7-Bromo-2-chloro-6,8-di A mixture of (fluoroquinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(4-methylpiperazin-1-yl)methanone (400 mg, 1.0 equivalent) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (1.18 g, 10 equivalents) was stirred at 90° C. for 12 hours. The reaction mixture was concentrated and slurried with water (15 mL) to give the title compound (300 mg, 54% yield) as a brown solid; LCMS (ESI, M+1): m / z=665.1.

[0526] Step C. (5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(4-methylpiperazin-1-yl)methanone: (5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H- To a mixture of (pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(4-methylpiperazin-1-yl)methanone (250 mg, 1.0 equiv.) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (143 mg, 1.2 equiv.) under a N atmosphere was added Ad2nBup-Pd-G3 (41.1 mg, 0.15 equiv.) and Cs2CO3 (368 mg, 3.0 equiv.). The reaction mixture was stirred at 90 °C for 12 h. The reaction mixture was quenched with HO (5 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Phenomenex luna C18 150 × 25 mm × 10 μm; A: water (FA), B: ACN, B%: 10% to 40% over 8 min] to give the title compound (90.0 mg, 96% yield, HCOOH salt) as a yellow solid; 1H NMR (400 MHz, methanol-d4) δ = 8.46-8.43 (m, 1H), 7.84-7.76 (m, 1H), 7.72-7.65 (m, 1H), 7.34-7.29 (m, 1H), 7.29-7.22 (m, 1H), 7.28-7.21 (m, 1H), 7.01-6.96 (m, 1H), 6.76-6.70 (m, 1H), 5.65-5.41 (m, 1H), 5.25-5.06 (m,2H),4.59-4.31(m,6H),4.22-4.00(m,2H),3.92-3.64(m,5H),3.40-3.33(m,1H),2.70-2.45(m,7H), 2.45-2.31(m,7H),2.30-2.20(m,2H),2.18-2.05(m,1H),0.91-0.72(m,3H);LCMS(ESI,M+1):m / z=773.2.

[0527] Example 77

[0528] [ka] 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0529] [ka]

[0530] Step A. 6-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane: To a mixture of 7-bromo-2,4-dichloro-6,8-difluoroquinazolin-4-yl (1.50 g, 1.0 equiv.) and 1-oxa-6-azaspiro[3.5]nonane (905 mg, 1.1 equiv., 0.5% oxalic acid) in DCM (15 mL) was added DIEA (2.47 g, 4.0 equiv.) and 4 Å molecular sieves (1.5 g). The reaction mixture was stirred at 0° C. for 15 hours. The mixture was filtered. The filtrate was concentrated and triturated with petroleum ether:ethyl acetate = 3:1 (10 V) at 25° C. for 30 minutes to give the title compound (1.50 g, 77.6% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=8.01(dd,J=1.6,9.8Hz,1H),4.39(t,J=7.8Hz,2H),4.29(br d,J=13.6Hz,1H),4.12-4.02(m,1H),3.67(d,J=13.6Hz,1H),3.32(s,1H),2.42-2.28 (m,2H),2.15-2.05(m,1H),1.88-1.75(m,2H),1.73-1.61(m,1H),1.32-1.20(m,1H).

[0531] Step B. 6-(7-Bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane: A mixture of 6-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (500 mg, 1.0 equiv.) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (197 mg, 1.0 equiv.) was heated to 110° C. for 2 hours. The reaction mixture was concentrated and triturated with petroleum ether:ethyl acetate=1:5 (3 mL) at 25° C. for 10 min to give the title compound (230 mg, 35% yield) as a brown solid; LCMS (ESI, M+1): m / z=527.1.

[0532] Step C. 6-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane: 6-(7-bromo-6,8-difluoro-2-(((2R, To a mixture of 7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (80.0 mg, 1.0 equiv.), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (60.1 mg, 1.1 equiv.), Ad2nBuPPd G3 (cataCXium® A Pd G3) (11.1 mg, 0.1 equiv.) and K3PO4 (96.6 mg, 3.0 equiv.) were added. The reaction mixture was stirred at 100 °C under a N2 atmosphere for 12 hours. The mixture was diluted with HO (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL × 3), dried over sodium sulfate, filtered, concentrated, and purified by column chromatography [SiO2, DCM:MeOH = 10 / 1] to give the title compound (55 mg, crude) as a yellow solid; LCMS (ESI, M+1): m / z = 681.3.

[0533] Step D. 4-(6,8-Difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a mixture of 6-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (20.0 mg, 1.0 equiv.) in DCM (0.5 mL) was added TFA (770 mg, 229.8 equiv.). The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was quenched by adding saturated aqueous NaHCO3 (20 mL) at 0° C., followed by extraction with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by preparative HPLC [column: Phenomenex C18 75 * 30mm * 3 μm; mobile phase: (water (FA)-CAN); B%: 20% to 50%, 7 min] to give the title compound (6.40 mg, 30.8% yield, HCOOH salt) as a yellow solid. 1H NMR (400MHz, methanol-d4)δ=8.54(s,1H),7.84(t,J=9.8Hz,1H),7.68(dd,J=6.0,9.0Hz,1H),7.29(d,J=2.4Hz,1H),7.25(t,J=9.4Hz,1H),7.00(d,J= 2.4Hz,1H),5.41-5.21(m,1H),4.66-4.52(m,2H),4.48-4.36(m,1H),4.3 5-4.21(m,2H),4.21-4.09(m,1H),3.65(dd,J=13.8,19.6Hz,1H),3.36(br d,J=2.3Hz,1H),3.29-3.15(m,3H),3.08-2.97(m,1H),2.65-2.52(m,1H),2.48(t,J=7.9Hz,2H),2.44-2.33(m,1H),2.32-2.21(m ,2H),2.20-2.11(m,1H),2.09-1.96(m,3H),1.95-1.85(m,2H),1.85-1.74(m,1H),0.86-0.76(m,3H);LCMS(ESI,M+1):m / z=637.1.

[0534] Example 78

[0535] [ka] 3-chloro-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0536] [ka]

[0537] Step A. 5-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (1.20 g, 1.0 equiv.) in dichloromethane (10 mL) was added N-ethyl-N-propan-2-ylpropan-2-amine (4.78 mL, 5.0 equiv.) and 3-chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide hydrochloride (1.28 g, 1.2 equiv.). The reaction mixture was stirred at −40° C. for 1 hour. The mixture was quenched with water (50 mL) and extracted with dichloromethane (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (2.00 g, crude) as a yellow solid.

[0538] Step B. 5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 5-(7-bromo-2-chloro) in DMSO (0.5 mL) To a solution of (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl)methanol (6.12 g, 10.0 equiv.) was added [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol (6.12 g, 10.0 equiv.). The mixture was stirred at 90° C. for 48 hours. The mixture was diluted with water (5 mL) and extracted with dichloromethane (2×20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash (0.1% FA condition) to give the title compound (292 mg, 9% yield) as a yellow solid; LCMS (ESI, M+3): m / z=644.3.

[0539] Step C. 3-Chloro-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro- To a mixture of 1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (100 mg, 1.0 equiv.), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (73.8 mg, 1.5 equiv.), and tripotassium phosphate (1.5 M in water, 0.25 mL, 3.0 equiv.) was added CataCXium A Pd G3 (11.3 mg, 0.1 equiv.). The reaction mixture was degassed and purged with N2 three times and stirred under N2 atmosphere at 90 °C for 16 h. The mixture was diluted with water (10 mL) and extracted with dichloromethane (2 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash (0.1% FA condition) followed by preparative HPLC [Column: Waters Xbridge 150 × 25 mm × 5 μm; A: water (NH4HCO3), B: ACN; B%: 49% to 79% over 9 min] to give the title compound (7.99 mg, 7% yield) as a yellow solid. 1H NMR (400MHz, methanol-d4)δ=7.70-7.63(m,2H),7.30(d,J=2.4Hz,1H),7.21(s,1H),6.98-6.95(m,1H),5.35(b rs,1H),5.12-5.06(m,2H),4.50-4.45(m,2H),4.35-4.26(m,2H),4.24-4.19(m,2H),3.22(brs,1H),3.18(br d,J=2.8Hz,1H),3.13(s,3H),3.10(s,3H),3.05-2.98(m,2H),2.63-2.51(m,1H),2.48-2.37( LCMS (ESI, M+1): m / z=752.3.

[0540] Example 79

[0541] [ka] (3-chloro-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone

[0542] [ka]

[0543] Step A. (5-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone: To a solution of (3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone hydrochloride (1.23 g, 1.2 equiv.) in DCM (10 mL) was added DIEA (2.06 g, 5.0 equiv.) and 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (1.00 g, 1.0 equiv.). The reaction mixture was stirred at −40° C. for 1 hour. The mixture was quenched with HO (50 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (2.00 g, crude) as a yellow oil; LCMS (ESI, M+1): m / z = 563.1.

[0544] Step B. (5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone: [5-(7-bromo-2- To a solution of chloro-6,8-difluoro-quinazolin-4-yl)-3-chloro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-2-yl]-morpholino-methanone (2.00 g, 1.0 equiv.) was added ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (5.66 g, 10 equiv.). The reaction mixture was stirred at 90° C. for 2 days. The mixture was diluted with water (20 mL) and extracted with DCM (2×100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash (0.1% FA condition) to give the title compound (843 mg, 32% yield) as a yellow solid. LCMS (ESI, M+1): m / z=686.2.

[0545] Step C. (3-chloro-5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone: (5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro To a mixture of 1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)(morpholino)methanone (100 mg, 1.0 equiv.), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (69.2 mg, 1.5 equiv.), and KPO (1.5 M in water, 292 μL, 3.0 equiv.) was added CataCXium A Pd G (10.6 mg, 0.1 equiv.). The reaction was degassed, purged with nitrogen three times, and stirred under a N atmosphere at 90 °C for 5 h. The mixture was extracted with DCM (30 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reverse-phase flash (0.1% FA conditions). The desired fractions were collected, neutralized with solid NaHCO3, and concentrated in vacuo to remove acetonitrile. The aqueous layer was extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC (Column: Waters Xbridge 150 × 25 mm × 5 μm; A: [water (ammonia hydroxide)]; B: ACN, B%: 46%–76% over 9 min) to give the title compound (8.35 mg, 7% yield, HOOH salt) as a white solid. 1H NMR (400MHz, methanol-d4)δ=7.71-7.62(m,2H),7.29(d,J=2.4Hz,1H),7.25(t,J=9.2Hz,1H),6.99-6.95(m,1H),5.38 -5.25(m,1H),5.14-5.07(m,2H),4.54-4.40(m,2H),4.36-4.27(m,2H),4.25-4.18(m,2H),3.74(s,4H),3.67(s,4H) ,3.63-3.63(m,1H),3.25-3.14(m,2H),3.07-2.98(m,1H),2.64-2.52(m,1H),2.48-2.39(m,3H),2.34-2.20(m,1H) ,2.18-2.08(m,2H),2.02-1.95(m,2H),1.94-1.85(m,1H),0.80(dt,J=2.8,7.3Hz,3H);LCMS(ESI,M+1):m / z=794.5.

[0546] Example 80

[0547] [ka] 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0548] [ka]

[0549] Step A. 5-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (1.0 g, 1.0 equiv.) and DIEA (617 mg, 1.5 equiv.) in DCM (10 mL) was added a solution of N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (602 mg, 0.85 equiv.) and DIEA (823 mg, 2.0 equiv.) in DMF (3 mL) at 0° C. The reaction mixture was stirred at 25° C. for 12 hours. 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), dried over Na2SO4, concentrated, and purified by reverse-phase flash [C18, 0.1% formic acid] to give the title compound (1.2 g, 53% yield, 71% purity) as a yellow solid; LCMS (ESI, M+1, M+3, M+5): m / z = 499.1, 501.1, 503.1.

[0550] Step B. 5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 5-(7-bromo-2-chloro)-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide in DMSO (2 mL) To a solution of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (1.27 g, 14 equiv.) was added ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (1.27 g, 14 equiv.). The mixture was stirred at 90° C. for 24 hours. 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), dried over Na2SO4, concentrated, and purified by reverse-phase flash [C18, 0.1% formic acid] to give the title compound (200 mg, 54% yield) as a yellow solid; LCMS (ESI, M+1, M+3): m / z = 622.2, 624.2.

[0551] Step C. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide) in methoxycyclopentane (2 mL) To a solution of (1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (200 mg, 1.0 equiv.) and 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (203 mg, 2.0 equiv.) was added KPO (1.5 M in HO, 642 μL, 3.0 equiv.) and CataCXium A Pd G (23.4 mg, 0.1 equiv.). The mixture was stirred at 90° C. for 5 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 10 mL). The organic layer was dried over Na2SO4, concentrated, and purified by preparative HPLC [column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: water (FA)-ACN; B%: 18% to 48% over 10 min] to give the title compound (101 mg, 42% yield, HCOOH salt) as a white solid; 1H NMR (400MHz, methanol-d4)δ=7.70-7.63(m,2H),7.29(d,J=2.6Hz,1H),7.25(t,J=9.4Hz,1H),6.97(d,J=2.6Hz,1H),5.50-5.28(m,1H),5.05(br dd,J=2.8,8.1Hz,2H),4.47(br d,J=6.7Hz,2H),4.35(br d,J=2.6Hz,1H),4.32(br d,J=11.1Hz,3H),3.57-3.39(m,3H),3.20-3.12(m,4H),3.08(s,3H),2.62-2.44(m,2H),2.43-2.31(m,4H),2.21 (brs,1H),2.18(s,3H),2.15-2.05(m,2H),2.03-1.91(m,1H),0.80(t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=732.4.

[0552] Example 81

[0553] [ka] 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,3-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0554] [ka]

[0555] Step A. 5-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-N,3-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: To a solution of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (300 mg, 1.0 equiv.) and DIEA (247 mg, 2.0 equiv.) in dichloromethane (4.5 mL) was added a solution of N,3-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (298 mg, 1.5 equiv.) in dichloromethane (3 mL) at −40° C. The reaction mixture was stirred at 40° C. for 0.5 h. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (30 mL). The organic layer was dried over sodium sulfate and concentrated to give the title compound (447 mg, crude) as a yellow solid; LCMS (ESI, M+1, M+3): m / z = 485.0, 487.0.

[0556] Step B. 5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,3-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 5-(7-bromo-2- To a solution of chloro-6,8-difluoroquinazolin-4-yl)-N,3-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (250 mg, 1.0 equiv.) was added ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (410 mg, 5.0 equiv.). The reaction mixture was stirred at 90° C. for 8 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate, concentrated, and purified by reverse-phase flash [C18, 0.1% formic acid] to give the title compound (37.0 mg, 11% yield) as a yellow solid; LCMS (ESI, M+1, M+3): m / z = 608.0, 610.1.

[0557] Step C. 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,3-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide: 5-(7-bromo-6,8-difluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,3-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide in methoxycyclopentane (1 mL) To a mixture of (hydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-N,3-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (37.0 mg, 1.0 equiv.), 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (28.8 mg, 1.5 equiv.), and KPO (1.5 M in water, 122 μL, 3.0 equiv.) was added cataCXium A Pd G (4.43 mg, 0.1 equiv.). The reaction mixture was degassed, purged with N three times, and stirred at 90 °C under N for 2 h. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL). The organic layer was dried over sodium sulfate, concentrated, and purified by preparative HPLC [Phenomenex luna C18 150×25mm×10um; A, water (FA); B, ACN; B%: 17%-47% over 10 min] to give the title compound (14.4 mg, 33% yield, HCOOH salt) as a white solid; 1H NMR (400 MHz, methanol-d4) δ = 7.72-7.62 (m, 2H), 7.32-7.22 (m, 2H), 6.97 (d, J = 2.4 Hz, 1H), 5.46-5.25 (m, 1H), 5.11-4.96 (m, 3H), 4.52-4.42 (m, 2H), 4.35-4.22 (m, 4H), 3.51-3.38 (m, 1H) ),3.15-3.07(m,1H),2.86(s,3H),2.63-2.48(m,1H),2.46-2.19(m,9H),2.18-2.10(m,1H) ,2.09-2.01(m,2H),1.98-1.86(m,1H),0.80(t,J=7.2Hz,3H);LCMS(ESI,M+1):m / z=718.5.

[0558] Example 82

[0559] [ka] 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0560] [ka]

[0561] Step A. 1-(1-(((7-Bromo-6,8-difluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine: A mixture of 6-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-1-oxa-6-azaspiro[3.5]nonane (300 mg, 1.0 equiv.) and (1-((dimethylamino)methyl)cyclopropyl)methanol (95.8 mg, 1.0 equiv.) was heated to 110° C. for 1 h. The mixture was diluted with HO (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL × 3), dried over sodium sulfate, filtered, concentrated, and purified by reverse-phase MPLC [C18, 0.1% formic acid] to give the title compound (350 mg, 90.2% yield) as a yellow liquid; LCMS (ESI, M+1): m / z = 499.0.

[0562] Step B. 1-(1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine: Preparation of 1-(1-(((7-bromo-6,8-difluoro-4- To a mixture of (1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine (300 mg, 1.0 equiv.) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (239 mg, 1.1 equiv.) was added Ad2nBuPd G3 (cataCXium® A Pd G3) (43.9 mg, 0.1 equiv.) and K3PO4 (384 mg, 3.0 equiv.). The reaction was degassed and purged with nitrogen three times, then stirred at 100 °C for 12 h. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL x 3), dried over sodium sulfate, filtered, concentrated, and purified by reverse-phase MPLC [C18, 0.1% formic acid] to give the title compound (160 mg, crude) as a yellow liquid; LCMS (ESI, M+1): m / z = 651.5.

[0563] Step C. 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol: To a mixture of 1-(1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-6,8-difluoro-4-(1-oxa-6-azaspiro[3.5]nonan-6-yl)quinazolin-2-yl)oxy)methyl)cyclopropyl)-N,N-dimethylmethanamine (100 mg, 1.0 equiv.) in DCM (3 mL) was added TFA (770 mg, 43.9 equiv.). The reaction was stirred at 0° C. for 1 hour. The reaction mixture was quenched with saturated aqueous NaHCO3 (20 mL) at 0 °C and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over sodium sulfate, filtered, concentrated, and purified by preparative HPLC (column: Phenomenex C18 75 * 30mm * 3 um; mobile phase: [water (FA)-ACN]; B%: 18% to 48%, 7 min) to give the title compound (24.7 mg, 23.8% yield, HCOOH salt) as a yellow solid. 1 H NMR (400MHz, methanol-d4) δ=8.55(s,1H),7.91-7.79(m,1H),7.67(dd,J=6.0,8.8Hz,1H),7.29(d,J=2 .4Hz,1H),7.24(t,J=9.4Hz,1H),7.04-6.88(m,1H),4.62-4.51(m,1H),4.49-4.32(m,3H),4.14(br t,J=12.8Hz,1H),4.07-3.92(m,1H),3.76-3.60(m,1H),3.37(br d,J=11.8Hz,1H),2.70(br d,J=2.4Hz,2H),2.61-2.41(m,8H),2.38-2.20(m,2H),2.16-1.97(m,1H),1.96-1.85(m,1H) ,1.80(td,J=4.3,8.8Hz,1H),0.88-0.75(m,5H),0.61(brs,2H);LCMS(ESI,M+1):m / z=607.2.

[0564] Example 83

[0565] [ka] (3R)-1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6,8-difluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol

[0566] [ka]

[0567] Step A. tert-Butyl (4-(6,8-difluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-yl)carbamate: (R)-1-(7-bromo-6,8-difluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazoline in cyclopentyl methyl ether (6 mL) To a solution of (2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)boronic acid (423 mg, 1.5 equiv.), [2-(2-aminophenyl)phenyl]palladium bis(1-adamantyl)butylphosphane methanesulfonate (65.9 mg, 0.1 equiv.), potassium phosphate tripotassium (576.14 mg), and water (1.36 mL) were added. The reaction mixture was degassed and purged with N2 three times and stirred at 90 °C for 3 h. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate (500 mg), concentrated, and purified by reverse-phase flash (0.1% FA) to give the title compound (450 mg, 70% yield). LCMS (ESI, M+1): m / z = 685.2.

[0568] Step B. (3R)-1-(7-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-6,8-difluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol: To a solution of tert-butyl (4-(6,8-difluoro-2-((hexahydro-1H-pyrrolidin-7a-yl)methoxy)-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)quinazolin-7-yl)-7-fluorobenzo[d]thiazol-2-yl)carbamate (100 mg, 1.0 equiv.) in acetonitrile (1 mL) was added HCl / dioxane (4 M, 2 mL). The mixture was stirred at 0° C. for 1 hour. The reaction mixture was slowly added dropwise to iced sodium bicarbonate solution at 0°C and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate (500 mg), concentrated, purified by preparative HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 μm; A: water (FA); B: ACN; B%: 14% to 44%, 10 min), and lyophilized to give the title compound (17.8 mg, 20% yield, HCOOH salt) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ = 7.73 (ddd, J = 1.6, 10.4, 18.4 Hz, 1H), 7.30 (ddd, J = 3.6, 5.2, 8.8 Hz, 1H), 6.99 (t, J = 8.8 Hz, 1H), 4.42-4.32 (m, 2H), 4.30-4.18 (m, 1H), 4.06 (br d,J=13.0Hz,1H),3.47(dd,J=5.6,13.2Hz,1H),3.42-3.34(m,1H),3.29-3.21(m,2H),2.95-2.82(m,2H),2.15(td,J=6.4, 12.4Hz,3H),2.07-1.92(m,4H),1.90-1.80(m,3H),1.79-1.70(m,2H),1.26(d,J=2.0Hz,3H);LCMS(ESI,M+1):m / z=585.4.

[0569] Example 84

[0570] [ka] 4-(4-(dimethylamino)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalen-2-ol

[0571] [ka]

[0572] Step A. Methyl 8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthoate: To a mixture of 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl trifluoromethanesulfonate (20 g, 52.3 mmol, 1.00 equiv.), TEA (15.9 g, 157 mmol, 21.8 mL, 3.00 equiv.) in MeOH (100 mL) and DMSO (100 mL) was added Pd(dppf)Cl (3.83 g, 5.23 mmol, 0.1 equiv.) in one portion at 20 °C under CO, then heated to 80 °C and stirred for 3 h. The residue was poured into ice water (500 mL) and stirred for 30 min. The aqueous phase was extracted with dichloromethane (200 mL × 2), and the combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography column (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 10 / 1) to give the title compound (12.0 g, 41.1 mmol, 78.5% yield) as a pale yellow solid. 1 H NMR:(400MHz,CDCl3)δ7.53-7.51(m,1H),7.39-7.38(d,J=4.0Hz,1H),7.26-7.25(d,J=4.0Hz,1H),7. 20-7.15(m,1H),5.19(s,2H),3.90(s,3H),3.43(s,3H),2.81-2.78(q,2H),1.18-1.14(t,J=8.0Hz,3H)

[0573] Step B. (8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)methanol: To a mixture of methyl 8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthoate (12.0 g, 41.1 mmol, 1.00 equiv.) in THF (120 mL) under N was added LiAlH (1.25 g, 32.8 mmol, 0.80 equiv.) at 0° C. under N. The mixture was stirred at 20° C. for 2 hours. Water (1.25 mL) was added to the reaction solution and stirred for 10 minutes, 15% NaOH (1.25 mL) was added and stirred for 10 minutes, then water (4.00 mL) was added to the reaction solution and stirred for 10 minutes. The mixture was filtered and concentrated in vacuo to provide the title compound (9.66 g, crude) as a yellow solid.

[0574] Step C. 8-Ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthaldehyde: To a mixture of (8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)methanol (9.66 g, 36.6 mmol, 1.00 equiv) and MnO (63.6 g, 731 mmol, 20.0 equiv) in dichloromethane (100 mL) was added in one portion under N at 20 °C. The mixture was stirred at 20 °C for 16 h. The mixture was filtered and concentrated in vacuo to give the title compound (9.00 g, crude) as a brown-black solid. 1 H NMR: (400MHz, CDCl3). δ10.6(s,1H),7.65-7.64(d,J=4.0Hz,1H),7.63-7.59(m,1H),7.51-7.50(d,J=4.0Hz,1H), 7.24-7.18(m,1H),5.22(s,2H),3.44(s,3H),2.97-2.95(q,2H),1.33-1.29(t,J=8.0Hz,3H)

[0575] Step D. Methyl 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-5-hydroxy-3-oxopentanoate: To a mixture of NaH (4.12 g, 103 mmol, 60% purity, 3.00 equiv) in THF (50.0 mL) at 20 °C under N was added methyl 3-oxobutanoate (12.0 g, 103 mmol, 11.1 mL, 3.00 equiv) at 20 °C. After stirring the mixture at 20°C for 30 minutes, n-BuLi (2.5 M, 41.2 mL, 3.00 equiv.) was added dropwise at -10°C. The mixture was stirred at -10°C for 30 minutes, and then a solution of 8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthaldehyde in THF (50.0 mL) was added dropwise at -10°C. The mixture was stirred at -10°C for 2 hours. The residue was poured into NH4Cl (200 mL) and stirred for 30 minutes. The aqueous phase was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give the title compound (10.0 g, 26.4 mmol, 77.0% yield) as a yellow solid. 1 H NMR: EW34545-10-P1A (400MHz, CDCl3). δ7.72-7.71(d,J=4.0Hz,1H),7.63-7.59(m,1H),7.33-7.34(d,J=4.0Hz,1H),7.24-7.19(m,1H),6.15-6.12(m,1H),5.31-5.27(m ,2H),3.75(s,3H),3.54(s,2H),3.55(s,3H),3.37-3.31(m,1H),3.08-2.95(m,3H),2.80-2.73(m,1H),1.34-1.30(t,J=8.0Hz,3H)

[0576] Step E. Methyl 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-oxo-3,4-dihydro-2H-pyran-5-carboxylate: To a mixture of methyl 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-5-hydroxy-3-oxopentanoate (5.00 g, 13.2 mmol, 1.00 equiv) in dichloromethane (50.0 mL) was added DMF-DMA (1.89 g, 15.7 mmol, 2.11 mL, 1.20 equiv) in one portion at 20 °C under N. The mixture was stirred at 20 °C for 1 h. Then, BF.EtO (2.44 g, 17.2 mmol, 2.12 mL, 1.30 equiv) was added at 20 °C, and the mixture was stirred at 20 °C for 2 h. The residue was poured into ice water (50.0 mL) and stirred for 30 minutes. The aqueous phase was extracted with dichloromethane (20.0 mL × 2), and the combined organic phases were washed with brine (20.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give the title compound (4.30 g, 11.1 mmol, 83.8% yield) as a yellow oil. LCMS: RT = 0.935 min, Hz = 389.2 [M+H] + .

[0577] Step F. Methyl 6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-oxotetrahydro-2H-pyran-3-carboxylate: To a mixture of methyl 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-oxo-3,4-dihydro-2H-pyran-5-carboxylate (3.00 g, 7.72 mmol, 1.00 equiv.) in THF (30.0 mL) at 20 °C under N was added L-selectride (1 M, 11.6 mL, 1.50 equiv.) dropwise at −70 °C. The mixture was stirred at −70 °C for 2 h. The residue was poured into NH Cl (100 mL) and stirred for 30 min. The aqueous phase was extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with brine (30.0 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate=10 / 1) to give the title compound (1.00 g, 2.56 mmol, 33.1% yield) as a white solid. 1 H NMR:(400MHz,CDCl3),δ7.56-7.54(m,2H),7.30-7.29(d,J=4.0Hz,1H),7.14-7.11(m,1H),5.59-5.53(m,1H),5.21(s,2H),5.46-5.45(m,1H) ,4.42-4.37(m,1H),3.75(s,3H),3.44(s,3H),3.17-3.24(m,1H),2.78 -2.71(m,1H),2.64-2.60(m,2H),2.56-2.32(m,2H),1.27-1.25(m,3H).

[0578] Step G. 7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(methylthio)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-ol: To a mixture of methyl 6-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-oxotetrahydro-2H-pyran-3-carboxylate (1.10 g, 2.82 mmol, 1.00 equiv.) in MeOH (10.0 mL) was added CHONa (5 M, 2.82 mL, 5.00 equiv.) and methyl carbamimidothioate sulfate (784 mg, 2.82 mmol, 1.00 equiv.) at 0° C. under N. The mixture was stirred at 20° C. for 16 h. The residue was poured into ice water (20.0 mL) and stirred for 30 min. The pH was adjusted to approximately 3 by slow addition of 1M HCl, and the aqueous phase was extracted with dichloromethane (20 mL × 2). The combined organic phases were washed with brine (10.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give the title compound (500 mg, 1.16 mmol, 31.7% yield) as a white solid. LCMS: EW34545-18-P1A, RT = 0.965 min, [M+H] + =431.2.

[0579] Step H. 7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(methylthio)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate: To a mixture of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(methylthio)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-ol (500 mg, 1.16 mmol, 1.00 equiv) and TEA (353 mg, 3.48 mmol, 3.00 equiv) in dichloromethane (5.00 mL) was added TfO (492 mg, 1.74 mmol, 1.50 equiv) at −40° C. under N. The mixture was stirred at 20° C. for 1 hour. The residue was poured into ice water (20.0 mL) and stirred for 30 minutes. The aqueous phase was extracted with dichloromethane (20.0 mL x 2), and the combined organic phase was washed with brine (10.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, methyl tert-butyl ether) to give the title compound (650 mg, 924 umol) as a yellow solid. LCMS: RT = 1.166 min, [M+H] + =563.2

[0580] Step I. 7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-N,N-dimethyl-2-(methylthio)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine: To a mixture of MeNH (113 mg, 1.39 mmol, 1.20 equiv., HCl) and DIEA (448 mg, 3.47 mmol, 3.00 equiv.) in THF (6.50 mL) was added 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(methylthio)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (650 mg, 1.16 mmol, 1.00 equiv.) in one portion under N at 20° C. The mixture was stirred at 20° C. for 16 hours. The residue was poured into ice water (20.0 mL) and stirred for 30 minutes. The aqueous phase was extracted with dichloromethane (5.00 mL × 2), and the combined organic phases were washed with brine (5.00 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give compound 16 (350 mg, 765 μmol, 66.2% yield) as a yellow oil. LCMS: RT = 0.876 min, [M+H] + =458.2.

[0581] Step J. 7-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-N,N-dimethyl-2-(methylsulfonyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine: To a mixture of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-N,N-dimethyl-2-(methylthio)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (350 mg, 765 μmol, 1 equiv.) and ethyl acetate (5.00 mL) was added m-CPBA (388 mg, 1.91 mmol, 85% purity, 2.50 equiv.) in one portion at 20° C. under N. The mixture was stirred at 20° C. for 1 hour. The residue was poured into NaSO (20.0 mL) and stirred for 30 min. The aqueous phase was extracted with dichloromethane (5.00 mL × 2). The combined organic phases were washed with brine (5.00 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give the title compound (330 mg, 674 μmol, 88.1% yield) as a white solid.

[0582] Step K. 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N,N-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine: ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (52.0 m) in THF (1.00 mL). To a mixture of 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-N,N-dimethyl-2-(methylsulfonyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (100 mg, 204 μmol, 1.00 equiv.) in THF (1.00 mL) was added dropwise under N at 0°C. The mixture was stirred at 20°C for 1 hour. The residue was poured into water (20.0 mL) and stirred for 30 minutes. The aqueous phase was extracted with dichloromethane (5.00 mL × 2), and the combined organic phase was washed with brine (5.00 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (SiO2, DCM:MeOH=8:1) to give the title compound (70.0 mg, 123 umol, 60.2% yield) as a white solid. LCMS: RT=0.824 min, [M+H] + =569.4.

[0583] Step L. 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-N,N-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine: 7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene) in dioxane (500 uL) To a mixture of N,N-dimethyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (70.0 mg, 123 μmol, 1.00 equiv.) and HCl / dioxane (4 M, 500 μL, 16.3 equiv.) was added under N2 at 20 °C, and the mixture was stirred at 20 °C for 1 h. The residue was poured into water (20.0 mL) and stirred for 30 min. The pH was adjusted to approximately 9 with aqueous NaHCO3, and the mixture was extracted with dichloromethane (5.00 mL × 2). The combined organic phase was washed with brine (5.00 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the title compound (15.0 mg, 28.6 umol, 23.2% yield) as a white solid. 1 H NMR: (400MHz, DMSO-d6). δ9.82(s,1H),7.44-7.43(d,J=4.0Hz,1H),7.30-7.26(t,J=8.0Hz,1H),7.16-7.15(d,J=4.0Hz,1H), 5.49-5.46(m,1H),5.31-5.17(m,1H),5.01-4.98(d,J=12.0Hz,1H),4.84-4.81(d,J=12.0Hz,1H),3. 98-3.94(m,1H),3.86-3.83(m,1H),3.10-3.04(m,3H),3.02(s,6H),2.98(s,1H),2.83-2.76(m,3H), 2.08-1.93(m,3H),1.82-1.71(m,3H),1.27-1.23(t,J=8.0Hz,3H);LCMS:RT=0.791min, m / z=525.3(M+H) + .

[0584] Example 85

[0585] [ka] (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0586] Synthesized according to Example 84. The title compound was obtained as a white solid. 1 H NMR: (400MHz, MeDH-d6). δ7.63-7.59(m,1H),7.52-7.51(d,J=4.0Hz,1H),7.24-7.19(t,J=8.0Hz,1H),7.14(s,1H),5.74-5.64 (m,1H),5.36-5.22(m,1H),4.61(s,3H),4.22-4.06(m,2H),3.60-3.51(m,1H),3.48-3.41(m,2H),3.4 2-3.15(m,6H),3.03-2.99(m,1H),2.98-2.83(m,2H),2.43-2.21(m,2H),2.01-1.95(m,4H),1.94-1.6 0(m,5H),1.35-1.32(t,J=8.0Hz,3H),1.25-1.23(d,J=8.0Hz,3H);LCMS:RT=0.799 min, m / z=595.3(M+H).

[0587] Example 86

[0588] [ka] (1R,5R,6R)-3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol

[0589] Synthesized according to Example 84. The title compound was obtained as a white solid. 1 H NMR: (400MHz,MeOD). δ7.51-7.48(m,1H),7.39-7.42(dd,J=4.0Hz,1H),7.12-7.07(t,J=8.0Hz,1H),7.03-7.03(d,J=4.0Hz, 1H),5.57-5.54(m,1H),5.26-5.12(m,1H),5.05-4.93(m,2H),4.49(s,3H),4.36-4.17(m,2H),4.10-3.8 9(m,3H),3.16-3.02(m,4H),2.98-2.88(m,2H),2.81-2.74(m,2H),2.23-2.00(m,6H),1.98-1.76(m,4H) ),1.66-1.59(m,2H),1.23-1.20(t,J=6.0Hz,3H);LCMS:EW35153-25-P1H, RT=0.790 min, m / z=607.4(M+H).

[0590] Example 87

[0591] [ka] 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione

[0592] Synthesized according to Example 84. The title compound was obtained as a white solid. 1H NMR:(400MHz,MeOD):δ7.52-7.48(m,1H),7.42-7.39(dd,J=4.0Hz,1H),7.12-7.08(t,J=8.0Hz,1H),7 .03-7.02(t,J=4.0Hz,1H),5.61-5.57(m,1H),5.27-5.14(m,1H),4.90-4.86(m,2H),4.49(s,4H),4.1 5-3.96(m,3H),3.69-3.65(m,1H),3.34-3.30(m,1H),3.18-2.92(m,5H),2.85-2.75(m,2H),2.24-2.0 9(m,2H), 2.04-1.97(m,2H), 1.90-1.71(m,6H), 1.24-1.19(m,3H); LCMS: RT=0.804 min, m / z=649.4(M+H).

[0593] Example 88

[0594] [ka] 5-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0595] Synthesized according to Example 84. The title compound was obtained as a white solid. 1H NMR: (400MHz,MeOD). δ7.50-7.46(m,1H),7.36-7.35(dd,J=4.0Hz,1H),7.11-7.06(t,J=8.0Hz,1H),7.02-7.01(d,J=4.0Hz,1H),6.48(s,1H),5.58-5.55 (m,1H),5.24-5.10(m,1H),4.94-4.91(d,J=12.0Hz,1H),4.68-4.66(m,3H),4.40-3.37(m,2H),3.69-3.65(m,1H),4.04-3.89(m,3H) ,3.81-3.79(m,1H),3.21(s,6H),3.17-3.14(m,2H),3.08-3.02(m,2H),2.97(s,2H),2.91-2.87(m,1H),2.85-2.75(m,2H),2.17-2. 05(m,3H),2.01-1.94(m,2H),1.88-1.84(m,2H),1.79-1.74(m,2H),1.23-1.19(t,J=8.0Hz,3H);LCMS:RT=0.825 min, m / z=688.4(M+H).

[0596] Example 89

[0597] [ka] 6-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one

[0598] [ka]

[0599] Step A. 7-Bromo-6,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline: To a solution of 7-bromo-2-chloro-6,8-difluoro-4-(2,2,2-trifluoroethoxy)quinazoline (3.50 g, 1.0 equiv.) in ACN (50 mL) was added CsCO (9.10 g, 3.0 equiv.) and 1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethanol (1.3 g, 1.0 equiv.). The reaction was stirred at 60 °C for 3 h. The mixture was diluted with water (40 mL) and extracted with EtOAc (2 x 30 mL). The combined layers were purified by column chromatography [SiO2, PE / EtOAc = 10 / 1 to 1 / 1] to give the title compound (2.9 g, 58% yield) as a white solid; LCMS (ESI, M+1, M+3): m / z = 482.0, 484.0.

[0600] Step B. 7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline: 7-Bromo-6,8-difluoro-2-((tetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline in THF (30 mL) and HO (6.0 mL) To a mixture of 2-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (983 mg, 1.0 equiv.), 2-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (983 mg, 1.0 equiv.), and KPO (1.85 g, 3.0 equiv.) was added CataCXium A Pd G (211 mg, 0.1 equiv.). The reaction was degassed and purged with nitrogen three times. The reaction was stirred at 60 °C for 2 h. The mixture was diluted with water (40 mL) and extracted with EtOAc (2 × 30 mL). The combined layers were washed with brine (40 mL), dried over sodium sulfate, concentrated, and purified by column chromatography [SiO2, PE / EtOAc = 1 / 1 to 0 / 1] to give the title compound (1.10 g, 48% yield) as a yellow solid; LCMS (ESI, M+1): m / z = 614.1.

[0601] Step C. 3-Chloro-4-cyclopropyl-5-(6,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)phenol: To a solution of 7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (50.0 mg, 1.0 equiv.) in ACN (2.0 mL) was added HCl·dioxane (2 M, 2.0 mL). The reaction was stirred at 0° C. for 1 hour. The mixture was concentrated in vacuo. The residue was diluted with water (0.1 mL). The mixture was adjusted to pH=7 with saturated NaHCO3 (2 mL) and extracted with EtOAc (2 x 2 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the title compound (43.0 mg, 92% yield) as a yellow solid; LCMS (ESI, M+1): m / z=570.1.

[0602] Step D. 6-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one: To a solution of 3-chloro-4-cyclopropyl-5-(6,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazolin-7-yl)phenol (33.0 mg, 1.0 equiv.) in DMF (2.0 mL) was added KPO (24.5 mg, 2.0 equiv.) and 1,8-diazaspiro[3.5]nonan-2-one (20.2 mg, 2.5 equiv.). The reaction was stirred for 12 hours at 100° C. The mixture was filtered and purified by preparative HPLC [Waters Xbridge 150×25 mm×5 um; mobile phase: water (ammonia hydroxide v / v)-ACN; B%: 22%-52%, 9 min] to give the title compound (8.0 mg, 22% yield) as a white solid; 1H NMR(400MHz,DMSO-d6)δ=7.60(d,J=9.2Hz,1H),6.95(d,J=2.4Hz,1H),6.63(d,J=2.4Hz,1H),4.14(d,J=12.4Hz,1H),3.99(d,J=12.0 Hz,1H),3.84-3.68(m,1H),2.70-2.53(m,2H),2.44-2.24(m,6H),2.06-1.90(m,3H),1.75-1.41(m,11H),0.71-0.51(m,2H),0.11(br d,J=4.4Hz,2H);LCMS(ESI,M+1):m / z=610.1.

[0603] Example 90

[0604] [ka] 4-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol

[0605] [ka]

[0606] Step A. 4-(7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: 7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-6,8 in DMF (1.0 mL) To a mixture of 1H-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (60.0 mg, 1.0 equiv.) and 6-methyl-1,4-oxazepan-6-ol (25.6 mg, 2.0 equiv.) were added 4 Å molecular sieves (10.0 mg, 1.0 equiv.) and KPO (31.1 mg, 1.5 equiv.). The reaction was stirred at 60 °C for 12 h. The mixture was filtered and purified by preparative TLC [SiO, DCM / MeOH = 10 / 1] to give the title compound (35.4 mg, 55% yield) as a yellow solid. LCMS (ESI, M+1): m / z = 645.2.

[0607] Step B. 4-(7-(3-Chloro-2-cyclopropyl-5-hydroxyphenyl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol: To a solution of 4-(7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (35.4 mg, 1.0 equiv.) in MeCN (1.0 mL) was added HCl·dioxane (4 M, 1.0 mL). The reaction was stirred at 0° C. for 0.5 h. The mixture was concentrated in vacuo. The residue was diluted with water (0.5 mL). The mixture was adjusted to pH 7 with saturated NaHCO3 (1 mL) and extracted with EtOAc (2 × 2 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: water (ammonia hydroxide v / v)-ACN; B%: 43% to 73%, 9 min] to give the title compound (2.80 mg, 9.0% yield) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ = 7.63 (br d,J=9.2Hz,1H),6.94(d,J=2.4Hz,1H),6.63(dd,J=2.4,6.0Hz,1H),4.68-4 .54(m,2H),4.24-4.09(m,2H),3.93-3.77(m,2H),3.70-3.56(m,2H),3.50(d ,J=12.4Hz,1H),3.47-3.39(m,1H),2.87-2.77(m,1H),2.72-2.56(m,5H),2. 19-2.06(m,3H),1.82-1.67(m,4H),1.66-1.55(m,2H),1.10(s,3H),0.62(br t,J=6.8Hz,2H),0.17(brs,2H);LCMS(ESI,M+1):m / z=601.3.

[0608] Example 91

[0609] [ka] 5-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione

[0610] [ka]

[0611] Step A. 5-(7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione: 7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)- in DMF (1.0 mL) To a mixture of 6,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-4-(2,2,2-trifluoroethoxy)quinazoline (60.0 mg, 1.0 equiv.) and tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (50.0 mg, 3.2 equiv.), 4 Å molecular sieves (10.0 mg) and KPO (31.1 mg, 1.5 equiv.) were added. The reaction was stirred at 60 °C for 12 h. The mixture was filtered and purified by preparative TLC [SiO, DCM / MeOH = 10 / 1] to give the title compound (30.2 mg, 43% yield) as a yellow solid. LCMS (ESI, M+1): m / z = 654.2.

[0612] Step B. 5-(7-(3-Chloro-2-cyclopropyl-5-hydroxyphenyl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione: To a solution of 5-(7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (30.2 mg, 1.0 equiv.) in MeCN (1.0 mL) was added HCl·dioxane (4 M, 1.0 mL). The reaction was stirred at 0 °C for 0.5 h. The mixture was concentrated under vacuum. The mixture was diluted with NaHCO3 (2 mL) and extracted with EtOAc (2 x 2 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC [Phenomenex C18 75 x 30 mm x 3 um; mobile phase: water (FA)-ACN; B%: 18% to 48%, 7 min; B%: 43% to 73%, 9 min] to give the title compound (5.0 mg, 15.2% yield, 0.2HCOOH) as a white solid. 1 H NMR (400MHz, methanol-d4) δ=7.62(dd,J=1.2,8.8Hz,1H),6.94(d,J=2.4Hz,1H),6.67-6.59(m,1H),4.19-4.06(m,2H),3.85(qd,J=7.6,11.2Hz,1H),3.54(br t,J=6.4Hz,2H),3.51-3.45(m,4H),3.21(br dd,J=7.2,11.2Hz,2H),2.22-2.01(m,3H),1.84-1.63(m,6H),1.37-1.26(m,1H),0.61(br t,J=6.8Hz,2H),0.16(br d,J=4.4Hz,2H);LCMS(ESI,M+1):m / z=610.3.

[0613] Example 92

[0614] [ka] 3-(7-(3-chloro-2-cyclopropyl-5-hydroxyphenyl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol

[0615] [ka]

[0616] Step A. 3-(7-Bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a mixture of 7-bromo-2,4-dichloro-6,8-difluoroquinazoline (800 mg, 1.2 equiv.) and 4 Å molecular sieves (1.50 g) in DCM (15 mL) was added DIEA (1.54 g, 3.0 equiv.) and 3-azabicyclo[3.2.1]octan-6-ol (320 mg, 1.0 equiv.). The reaction was stirred at 0 °C for 0.5 h. The mixture was diluted with ice water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by recrystallization from EtOAc (20 mL) at 25° C. to give the title compound (600 mg, 68% yield) as a yellow solid; LCMS (ESI, M+1, M+3): m / z=404.1, 406.1.

[0617] Step B. 3-(7-Bromo-2,6,8-trifluoroquinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a solution of 3-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol (600 mg, 1.0 equiv.) in DMSO (5.0 mL) was added KF (1.77 g, 21 equiv.). The reaction was stirred at 120° C. for 12 hours. The mixture was filtered. The filtrate was diluted with EtOAc (50 mL). The mixture was washed with brine (2×30 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound (570 mg, crude) as a yellow solid; LCMS (ESI, M+1, M+3): m / z = 387.9, 389.9

[0618] Step C. 3-(7-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-2,6,8-trifluoroquinazolin-4-yl)-3-azabicyclo[3.2.1]octan-6-ol: To a mixture of 3-(7-bromo-2,6,8-...

Claims

1. Formula (I): 【Chemistry 1】 [In the formula: A is aryl or heteroaryl, and said aryl or heteroaryl is selected from 1 to 4 R １ optionally substituted with; B is, 【Chemistry 2】 and Y １ is hydrogen, hydroxy, halogen, C1-C4 alkyl, 1 to 4 R ９ L-C3-C6 cycloalkyl optionally substituted with 1 to 4 R ８ L-heteroaryl optionally substituted with 1 to 4 R ８ L-aryl optionally substituted with L-C(O)-NH ２ or optionally substituted with 1-2 oxo (=O) or oxo-containing substituents, and further 1-2 R ８ an L-heterocycle optionally substituted with Y ２ is hydrogen or C1-C4 alkyl; Or Y １ and Y ２ are combined 【Transformation 3】 (wherein X is a bond, —S—, —O—, —N<, —CH ２ -N<, -CH ２ -CH ２ -N<, -CH-, -CH ２ -CH ２ -, -CH ２ -CH ２ -CH ２ --, --O-CH ２ - and -S-CH ２ - selected from; 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, —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)haloC1-C3 alkyl-, or C3-C6 cycloalkyl, wherein said C3-C6 cycloalkyl is optionally substituted with halogen or C1-C3 alkyl; Each R ２ are independently hydrogen, deuterium, hydroxy, halogen, C1-C3 alkyl, ═CH ２ , ═CH(halogen), ═C(halogen) ２ , C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, -OC(O)N(R ５ ) ２ , -CO ２ R ５ , or -CO ２ N (R ５ ) ２ and Each R ３ are independently hydrogen, deuterium, hydroxy, halogen, C1-C3 alkyl, ═CH ２ , ═CH(halogen), ═C(halogen) ２ , C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(=O)-, -COC(O)N(R ５ ) ２ , -CO ２ R ５ , or -CO ２ N (R ５ ) ２ and R ４ is hydrogen, halogen, or C1-C3 alkyl; Each R ５ are independently hydrogen or C1-C3 alkyl; Each R ６ are independently hydrogen, hydroxy, C1-C4 hydroxyalkyl, or heteroaryl; Each R ７ are independently hydrogen, C1-C3 alkyl, hydroxy, halogen, C1-C3 haloalkyl, —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), -C(O)NH ２ , —C(O)NH(C1-C3 alkyl), —C(O)N(C1-C3 alkyl) ２ , —CN, aryl, —CH ２ -S(O) ２ NH ２ or 1 to 2 C1-C3 alkyl, —CN or C(O)NH ２ is heteroaryl optionally substituted independently by Two R on the same atom ７ are optionally joined to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, said spirocyclic ring being optionally substituted with 1 to 4 substituents independently selected from oxo (=O), halogen, hydroxy, C1-C3 alkyl, and -O-(C1-C3 alkyl); Two R on adjacent atoms ７ is optionally linked 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 are optionally joined to form (i) hydroxy, cyano, halogen, C1-C4 alkyl, and NH ２ -CH optionally substituted with 1 to 2 substituents selected from ２ (ii) at most one —O—, (iii) at most one —S—, (iv) at most one —NH—; Each R ８ are independently C1-C3 alkyl, hydroxy, halogen, -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), -C(O)NH ２ , —C(O)NH(C1-C3 alkyl), —C(O)N(C1-C3 alkyl) ２ , —C(O)-pyrrolidine or —CN; Each R ９ are independently C1-C3 alkyl, hydroxy, halogen, oxo (=O), -O-(C1-C3 alkyl), -(C1-C3 alkyl)-OH, -C(O)OH, -C(O)O(C1-C3 alkyl), -C(O)NH ２ , —C(O)NH(C1-C3 alkyl), —C(O)N(C1-C3 alkyl) ２ or -CN; R １０ is absent, hydrogen, deuterium, hydroxy, halogen, C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C3 alkenyl, deuterated C2-C3 alkenyl or C3-C6 cycloalkyl; L is a bond, —C1-C4 alkyl-, —NH—, —N(C1-C3 alkyl)-, or cyclopropyl-CH ２ - and; Z is C or O, and when Z is C, the six-membered ring containing Z is aromatic, and when Z is O, the six-membered ring containing Z is oxane; each n is 0 to 3; o is 1 to 6; and p is 1 to 8. or a pharmaceutically acceptable salt thereof.

2. A is aryl optionally substituted with 1-4 R 1 ; Y １ and Y ２ are combined 【Chemistry 4】 (wherein X is a bond, —S—, —O—, —N<, —CH ２ -N<, -CH ２ -CH ２ -N<, -CH-, -CH ２ -CH ２ -, -CH ２ -CH ２ -CH ２ --, --O-CH ２ - and -S-CH ２ - selected from 2. The compound of claim 1, wherein the compound forms:

3. A is 1 to 4 R １ is heteroaryl optionally substituted with Y １ and Y ２ are combined 【Transformation 5】 (wherein X is a bond, —S—, —O—, —N<, —CH ２ -N<, -CH ２ -CH ２ -N<, -CH-, -CH ２ -CH ２ -, -CH ２ -CH ２ -CH ２ --, --O-CH ２ - and -S-CH ２ - selected from 2. The compound of claim 1, wherein the compound forms:

4. B, 【Transformation 6】 2. The compound of claim 1, wherein:

5. -L-B is, 【Transformation 7】 2. The compound of claim 1, wherein:

6. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is naphthyl.

7. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is indazolyl or benzothiophenyl.

8. At least one R １ is C1-C4 alkyl, or a pharmaceutically acceptable salt thereof.

9. At least one R １ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is fluorine.

10. At least one R １ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydroxy.

11. At least one R ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is fluorine.

12. At least one R ３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is halogen.

13. 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein said halogen is fluorine.

14. R ２ and R ３ At least one of the following is independently: =CH ２ , =CHF, =CF ２ 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

15. R ４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is halogen.

16. 16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein said halogen is fluorine.

17. R ６ or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein one or both of the following is C1-C4 alkyl:

18. R ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein one or both of: is hydrogen.

19. Two R on the same atom ７ are joined to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, said spirocyclic ring being optionally substituted with one or more substituents selected from oxo (=O), halogen, hydroxy, C1-C3 alkyl, and -O-(C1-C3 alkyl), or a pharmaceutically acceptable salt thereof.

20. Two R on adjacent atoms ７ are 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 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound forms a fused ring selected from heterocycles optionally substituted with:

21. Two R on non-adjacent atoms ７ optionally attached to (i) hydroxy, cyano, halogen, C1-C4 alkyl, and NH ２ -CH optionally substituted with 1 to 2 substituents selected from ２ 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound forms a bridge containing 1 to 3 members selected from: (i) at most one -O-; (ii) at most one -S-; (iii) at most one -NH-;

22. At least one R ８ is C1-C4 alkyl, or a pharmaceutically acceptable salt thereof.

23. At least one R ８ is hydroxy or C1-C3 alkyl-hydroxy, or a pharmaceutically acceptable salt thereof.

24. 1 or 2 R ８ 21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein is oxo (=O).

25. Y １ and Y ２ or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1, wherein: 【Request Item 26】 【Chemistry 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】 and pharmaceutically acceptable salts thereof.

27. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

28. The pharmaceutical composition of claim 27 for inhibiting wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H activity.

29. A pharmaceutical composition for treating cancer, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof.

30. 30. The pharmaceutical composition of claim 29, wherein the therapeutically effective amount of the compound is about 0.01 to 100 mg / kg per day.

31. 31. The pharmaceutical composition of claim 30, wherein the therapeutically effective amount of the compound is about 0.1 to 50 mg / kg per day.

32. The cancer is Cardiac: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrohamartoma, 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 tract: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, breast fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: 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 (osteochondroma), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma) tumor, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas); gynecology: uterus (endometrial cancer (serous cystic carcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa- 30. The pharmaceutical composition of claim 29, wherein the tumor is selected from the group consisting of: 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, botulism sarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer); hematologic system: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorder, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentigo dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma.

33. 33. The pharmaceutical composition of claim 32, wherein the cancer is a KRas G12A-associated cancer.

34. 33. The pharmaceutical composition of claim 32, wherein the cancer is a KRas G12C-associated cancer.

35. 33. The pharmaceutical composition of claim 32, wherein the cancer is a KRas G12D-associated cancer.

36. 33. The pharmaceutical composition of claim 32, wherein the cancer is a KRas G12R-associated cancer.

37. 33. The pharmaceutical composition of claim 32, wherein the cancer is a KRas G12S-associated cancer.

38. 33. The pharmaceutical composition of claim 32, wherein the cancer is a KRas G12V-associated cancer.

39. 33. The pharmaceutical composition of claim 32, wherein the cancer is a KRas G13D-associated cancer.

40. 33. The pharmaceutical composition of claim 32, wherein the cancer is a KRas Q61H-associated cancer.

41. 33. The pharmaceutical composition of claim 32, wherein the cancer is a KRas G12A-associated cancer.

42. 33. The pharmaceutical composition of claim 32, wherein the cancer is associated with at least one of wild-type KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H.

43. 33. The pharmaceutical composition of claim 32, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colon cancer, rectal cancer, or pancreatic cancer.

44. The pharmaceutical composition of claim 29, wherein the cancer is associated with wild-type KRas or a KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, or KRas Q61H mutation.

45. The pharmaceutical composition of claim 29, for administration via a route selected from the group consisting of parenteral, intraperitoneal, intradermal, intracardiac, intraventricular, intracranial, intracerebrospinal, intrasynovial, intrathecal, intramuscular, intravitreal, intravenous, intraarterial, oral, buccal, sublingual, transdermal, topical, intratracheal, rectal, subcutaneous, and local administration.

46. The pharmaceutical composition described in claim 45, wherein the route of administration is oral.

47. 46. ​​The pharmaceutical composition of claim 45, wherein the route of administration is intravenous injection.

48. 46. ​​The pharmaceutical composition of claim 45, wherein the route of administration is intramuscular injection.

49. 46. ​​The pharmaceutical composition of claim 45, wherein the administration utilizes a delivery device.

50. 46. ​​The pharmaceutical composition of claim 45, wherein the administration occurs in a hospital setting.

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