Compounds for degrading and inhibiting krass (g12d) protein

Abstract

The present application provides a compound of Formula (I), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof. The compound can be used as a KRAS (G12D) protein degrader and / or inhibitor.

Description

Cross-references to related applications

[0001] This application claims priority to International Application No. PCT / CN2023 / 084077, filed March 27, 2023; U.S. Application No. 63 / 494,607, filed April 6, 2023; U.S. Application No. 63 / 602,537, filed November 24, 2023; and International Application No. PCT / CN2023 / 135267, filed November 30, 2023, the entire contents of which are incorporated herein by reference. Background of the Invention

[0002] Rat sarcoma virus (RAS) protein is a known pathogenic factor for human cancer. Although targeting RAS protein has significant clinical implications, the development of highly effective inhibitors is extremely difficult, hence this target is often referred to as "untreatable".

[0003] In human cells, three closely related RAS genes (HRAS, KRAS, and NRAS) encode four highly homologous protein isoforms (H-Ras, N-Ras, K-Ras4A, and K-Ras4B). RAS proteins belong to the guanosine triphosphatases (GTPases) class and regulate many key molecular and cellular activities, including cell proliferation, differentiation, and death (see Front. Oncol., October 18, 2019). They cycle between inactive (bound to GDP) and active (bound to GTP) states in response to extracellular stimuli and to transmit cellular signals. This switching process is regulated by guanine nucleotide exchange factor (GEF) and GTPase activator protein (GAP), the former catalyzing nucleotide exchange and the latter promoting GTP hydrolysis. Upon activation, RAS further activates downstream effector pathways, such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways. However, mutations in RAS disrupt the guanine exchange cycle. In this case, the mutant typically no longer requires the action of the GAP protein, causing RAS to be abnormally "locked" in the on state (i.e., continuously bound to GTP), thereby activating downstream signaling pathways and leading to tumor cell proliferation. See, for example, PNAS, March 4, 2014, 111(9):3401-3406; Nat Rev. Drug Discov., August 2020, 19(8):533–552.

[0004] Approximately one-quarter of human cancers are associated with RAS gene mutations, resulting in millions of deaths globally each year. Among these mutations, KRAS accounts for the largest proportion (approximately 85%), while NRAS and HRAS are relatively less common (12% and 3%, respectively) (see J. Internal Med., 2020, 288; 183–191). KRAS mutations show extremely high detection rates in several high-mortality cancers, such as pancreatic cancer (90%), colorectal cancer (45%), and lung cancer (30%) (see Curr. Topics in Med. Chem., 2019, 19(23), 2079). Therefore, KRAS has become a compelling and promising cancer target.

[0005] KRAS mutations are primarily concentrated at codon 12 (also known as residue 12). This position is normally occupied by a glycine (G) residue. A mutation at residue 12 of glycine to any amino acid other than proline creates steric hindrance, preventing GAP proteins from binding to KRAS, weakening the hydrolysis efficiency of GTP, and causing the KRAS protein to remain in a GTP-bound activated state (see Curr. Topics in Med. Chem., ibid.). The most common KRAS mutation type in human cancers is G12D (glycine 12 mutated to aspartic acid), accounting for 33% of all cases, especially in pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) (see Mol. Oncol., Dec 2022 16(22):3911–3915). In contrast, G12C (glycine 12 mutated to cysteine) accounts for approximately 13% of all KRAS-mutated tumor cases, while mutation types such as G12V and G12F are even rarer.

[0006] Although some targeted drugs have made progress in recent years (such as AMG510 (sotorasib) and MRTX849 (adagrasib)), there is still a lack of effective new drugs and therapies for cancers caused by KRAS (G12D) mutations. Summary of the Invention

[0007] This invention provides compounds of formula (I), their tautomers, stereoisomers, or pharmaceutically acceptable salts. These compounds are capable of reducing intracellular KRAS protein levels and / or inhibiting KRAS activity, and therefore can be used as KRAS(G12D) protein degraders and / or inhibitors.

[0008] Compound (I) is a PROTAC (proteolytic targeting chimeric) compound. It links a ligand targeting the KRAS (G12D) protein to a ligand of the E3 ubiquitin ligase via a linker chain. The KRAS (G12D) ligand binds to the KRAS (G12D) protein, while the E3 ligand binds to / recruits the ubiquitin ligase. This bifunctional compound promotes the formation of a complex between the target protein KRAS (G12D) and the E3 ligase within the cell, thereby inducing the degradation of the target protein using the ubiquitin-proteasome system. Specifically, the E3 ligase recognizes the protein to be degraded and ubiquitinates it, thus promoting its degradation in the proteasome.

[0009] In one aspect, the present invention provides compounds of formula (I). in: X is N or CR 3 ; G is CR 14 R 15 Or O; J is CR 5a R 5b Or O, provided that G and J are not both O at the same time; Or, when G is CR 14 R 15 And J is CR 5a R 5b At that time, the carbon atoms of G and J (i.e., respectively bonded to R) 14 R 15 and R 5a R 5b (atoms) optionally with R 14 Or R 15 , and / or R 5a Or R 5b [i.e. R] 14 Or R 15 ;R 5a Or R 5b ; or R 14 Or R 15 , and R 5a Or R 5b Together they form C3-C6 cycloalkyl or cycloolefin groups; The dashed line between G and J indicates that there is a single or double bond between them. L is an alkynyl, arylene, heteroarylene, C3-C8 monocyclic or bicyclic alkylene, or C3-C8 heterocyclic alkylene, and optionally is influenced by one or more R. 9 replace; Q is an alkynyl, aryl, heteroaryl, monocyclic or bicyclic cycloalkyl or heterocyclic alkyl, and optionally substituted with one or more halogens, alkyl, haloalkyl, alkoxyalkyl, hydroxy, hydroxyalkyl, -O-alkyl or cycloalkyl; R 1 It is a C1-C6 alkyl, alkoxyalkyl, haloalkyl, monocyclic or bicyclic cycloalkyl or heterocyclic group, each optionally marked with one or more R groups. 10 replace; R 2 It can be a saturated or unsaturated heterocyclic group, a fused bicyclic heterocyclic group, a bridged bicyclic heterocyclic group, a spirocyclic heterocyclic group, or -NR. 16 R 16′ ; wherein the heterocyclic group is optionally surrounded by one or more R 11 The heterocyclic group is substituted, and the heterocyclic group contains 1 to 3 cyclic skeleton heteroatoms, each heteroatom being independently oxygen, sulfur or nitrogen; R 3 H, halogen, C1-C6 alkyl or haloalkyl, or C3-C8 cycloalkyl or heterocyclic group; wherein the C1-C6 alkyl or haloalkyl, or C3-C8 cycloalkyl or heterocyclic group is optionally surrounded by one or more R 13 replace; R 4 It is H, aryl, heteroaryl, fused aryl, fused heteroaryl, aryl fused spiroheterocyclic, or heteroaryl fused spiroheterocyclic, each optionally bonded by one or more R 12 Substitution; wherein the heteroaryl or heterocyclic group contains 1 to 4 cyclic skeleton heteroatoms, each heteroatom being independently oxygen, sulfur or nitrogen; wherein the -CH2- group in the fused aryl, fused heteroaryl, aryl fused spirocyclic or heteroaryl fused spirocyclic group is optionally replaced by -C(=O)-. R 5a and R 5b Each of the following can be independently H, alkyl, halogen, haloalkyl, hydroxyl, hydroxyalkyl, -O-alkyl, alkoxyalkyl, -NR 14 R 15 -alkylamino, or -alkylaminoalkyl; or R 5a and R 5b Together with the atoms they are connected to, they form cycloalkyl groups; R 6 It is a C1-C6 alkyl, C3-C8 cycloalkyl, or C4-C8 heterocyclic group; wherein the cycloalkyl or heterocyclic alkyl is optionally substituted with an alkyl, halogen, or haloalkyl group; R 7a and R 7b Each of the following can be independently H, C1-C6 alkyl, halogen, haloalkyl, hydroxyl, hydroxyalkyl, -O-alkyl, alkoxyalkyl, -NR 14 R 15-alkylamino, -alkylaminoalkyl, -alkyl-C(=O)-NR 14 R 15 C3-C8 cycloalkyl or C4-C8 heterocycloalkyl; or, R 7a and R 7b Together with the atoms they are connected to, they form a cycloalkylene group; R 8 The aryl or heteroaryl group is H, halogen, alkyl, monocyclic or bicyclic aryl or heteroaryl; wherein the aryl or heteroaryl group is optionally substituted by one or more substituents, each substituent being independently halogen, alkyl, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, -O-alkyl, -SF5, -NR. 14 R 15 or alkoxyalkyl; R 9 R 10 R 11 and R 12 Each of the following can be independently H, halogen, -CN, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, -O-alkyl, -NR 14 R 15 -NH-C(O)-R 16 -SO2-R 15 C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, haloalkoxy, cycloalkyl, alkyl-cycloalkyl, heterocyclic, alkyl-heterocyclic, aryl or heteroaryl; or, R 9 R 10 R 11 and R 12 Any two atoms connected to them together form a cycloalkyl or heterocyclic group; each of the aryl, heteroaryl, cycloalkyl, or heterocyclic group is optionally further substituted by an alkyl, halogen, or haloalkyl group; R 13 H, halogen, alkyl, haloalkyl, haloalkoxy, -CN, oxo, -NR 14 R 15 , hydroxyl, hydroxyalkyl, -O-alkyl, alkoxyalkyl, cycloalkyl or heterocyclic groups; R 14 and R 15 Each is independently H or alkyl; R 16 and R 16′ Each is independently an H, alkyl, cycloalkyl, or heterocyclic group, each optionally bound by one or more R groups. 11 replace; Or its pharmaceutically acceptable salt, or its tautomer or stereoisomer.

[0010] In some implementations, R 2 Selected from the following structures: Where Y is NH, -CH(CN)-, CH2, or O; and R 2 Optionally by one or more R 11 The groups are further substituted.

[0011] In some embodiments, L is a bridged bicyclic cycloalkylene, aryl fused cycloalkylene, or arylene.

[0012] In some other implementations, L is

[0013] In some implementations, K is

[0014] In some implementations, Q is Q may optionally be substituted with one or more alkyl, halogen or haloalkyl groups.

[0015] In some implementations, X is CR 3 .

[0016] R 3 Examples include, but are not limited to: H, F, trifluoromethyl, C1-C6 alkyl or C3-C5 cycloalkyl.

[0017] In some implementations, R 4 It is H, or selected from the following groups: Where R 4a R 4b R 4c and R 4d Each can be independently H, alkyl, halogen, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, -O-alkyl, alkoxyalkyl, -CN, alkynyl, cycloalkyl, heterocyclic or hydroxyalkynyl.

[0018] In some implementations, R 6 It can be C1-C6 alkyl, C3-C6 cycloalkyl, oxetane alkyl, or azirne alkyl.

[0019] In some implementations, R 8 Selected from the following groups: Among them, each R 8 Optionally substituted with one or more substituents, each substituent being independently selected from halogens, alkyl groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, -O-alkyl groups, -SF5 groups, amino groups, or alkoxyalkyl groups.

[0020] In some implementations, R 13 For H.

[0021] In some implementations, R 14 and R 15 Each can be either H or methyl.

[0022] In some embodiments, the compound is of formula (II): Where L is And optionally by one or more R 9 Substitute; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0023] In some embodiments, the compound is of formula (III): Where L is And optionally by one or more R 9 Substitute; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0024] In some implementations, R 4 for And R 4a R 4b R 4c and R 4d Each can be independently H, alkyl, halogen, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, -O-alkyl, alkoxyalkyl, -CN, alkynyl, cycloalkyl, heterocyclic or hydroxyalkynyl.

[0025] In some embodiments, the compound is of formula (IV): Where L is And optionally by one or more R 9 Replace; R 4a R 4b R 4c and R 4d Each is independently H, alkyl, halogen or haloalkyl; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0026] In some embodiments, the halogen is -F or -CL.

[0027] In some implementations, R 6 It is a C1-C6 alkyl group.

[0028] In some embodiments, the compound is of formula (V): Where L is And optionally by one or more R 9 replace; Where R 4b R 4c and R 4d Each is independently H, alkyl, halogen or haloalkyl; or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0029] Without limiting the scope of the invention, exemplary compounds of the present invention are listed below:

[0030] In some embodiments, the compounds of the present invention target the KRAS protein having a G12D mutation.

[0031] Another aspect of the invention relates to pharmaceutical compositions comprising the compounds described above and pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions may also comprise a second therapeutic agent.

[0032] Another aspect of the present invention provides a method for treating cancer in a subject, wherein the cancer is characterized by the presence of a KRAS (G12D) mutation. The method includes administering a therapeutically effective amount of the compound or pharmaceutical composition as described above to the subject. Cancers treatable (including those with reduced recurrence potential) by the method of the present invention include pancreatic cancer, colorectal cancer, or lung cancer. Detailed Implementation

[0033] Preferred embodiments of the invention will now be described in detail, with further examples thereof. Although the invention will be described in conjunction with preferred embodiments, it should be understood that these preferred embodiments are not intended to limit the invention to these embodiments. Rather, the invention is intended to cover alternatives, modifications, and equivalents that may be included within the spirit and scope of the invention as defined in the claims. Furthermore, in the detailed description, numerous specific details are set forth to provide a thorough understanding of the invention. However, it will be apparent to those skilled in the art that the invention may be practiced without these specific details. In other instances, well-known methods, procedures, components, and other features have not been described in detail so as not to unnecessarily obscure aspects of the invention. definition

[0034] Unless the context otherwise indicates, all references to compound formulas (including the uses, methods and other aspects of the invention) in all parts of this document include references to all other subforms, subgroups, preferred embodiments, implementations and examples as defined herein.

[0035] Unless otherwise stated, the following terms used in this specification and claims shall have the meanings described below:

[0036] As used herein, the term “or” is intended to include both “and” and “or”. In other words, the term “or” can also be replaced with “and / or”.

[0037] As used herein, the term “unsaturated” or “partially unsaturated” refers to a portion that contains at least one double or triple bond.

[0038] As used herein, the term "saturation" refers to a portion that does not include double or triple bonds, i.e., the portion contains only single bonds.

[0039] As used herein, the term "alkyl" refers to a saturated straight-chain (i.e., unbranched) or branched hydrocarbon chain group consisting of carbon and hydrogen atoms, which is unsaturated and has the stated number of carbon atoms (e.g., C1-C1). 10Alkyl). Whenever it appears in this document, a numerical range (e.g., "1 to 10") refers to the integers within the given range. For example, "1 to 10 carbon atoms" means that an alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and 4 carbon atoms, up to a maximum of 10 carbon atoms, although this definition also covers the occurrence of the term "alkyl" without a specified numerical range. Examples include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, and hexyl. Representative saturated straight-chain alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl; while saturated branched alkyl groups include isopropyl, sec-butyl, isobutyl, tert-butyl, and isopentyl.

[0040] As used herein, the term "substituted alkyl" refers to an alkyl group substituted with one or more substituents. Examples of substituents include, but are not limited to, halogens, hydroxyl groups, cyano groups, amino groups, alkoxy groups, alkoxyalkyl groups, haloalkyl groups, alkoxy groups, amino groups, methylamino groups, dimethylamino groups, sulfones, sulfonamides, aryl groups, heteroaryl groups, heterocyclic groups, trifluoroethyl groups, hydroxyethyl groups, cyanoethyl groups, methoxyethyl groups, and trifluoropropyl groups.

[0041] As used herein, the term "alkylene" itself, or as part of other molecules, refers to a divalent group derived from an alkane, which can be straight-chain or branched. In this context, the prefix (e.g., C...) 1-6 (or C1-C6) indicates the number of carbon atoms or a range of carbon atoms. For example, the term "C" used in this article... 1-4 "Alkylene" or "C1-C4 alkylene" refers to an alkylene group having 1 to 4 carbon atoms.

[0042] As used herein, the term "alkoxy" or "alkoxy group" refers to a saturated straight-chain or branched hydrocarbon bonded to an oxygen atom. Alkoxy groups may have the general formula -O-alkyl. Representative saturated straight-chain alkoxy groups include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexoxy, etc.; while saturated branched alkoxy groups include isopropoxy, sec-butoxy, isobutoxy, tert-butoxy, isopentoxy, etc. Cyclic alkoxy groups are referred to herein as "cycloalkoxy". 1-4 "Alkoxy group" refers to an alkoxy group that has 1, 2, 3 or 4 carbon atoms.

[0043] As used herein, the term "alkoxyalkyl" refers to an alkyl group substituted with one, two, or three alkoxy groups.

[0044] As used herein, the term "alkenyl" itself, or as part of other substituents, refers to an unsaturated branched or straight chain having at least one carbon-carbon double bond, obtained by removing a hydrogen atom from a single carbon atom of a parent alkene. The group can be in either the cis or trans conformation of the double bond. Typical alkenyl groups include, but are not limited to, vinyl, propenyl, etc.

[0045] As used herein, the term "alkynyl" itself, or as part of other substituents, refers to a carbon chain containing at least one carbon-carbon triple bond, which may be straight-chain, branched, or a combination thereof. Examples of alkynyl groups include ethynyl, propynyl, 3-methyl-1-pentynyl, 2-heptyynyl, etc.

[0046] As used herein, the term "ethynyl" refers to a divalent group derived from an ethynyl group, which can be a straight-chain or branched group containing at least one carbon-carbon triple bond. For example, "C2-C 10 "Imyynyl" indicates that the ynylyl chain contains two to ten carbon atoms.

[0047] As used in this article, the term "carbonyl" refers to -C(=O)-.

[0048] As used herein, the term "cycloalkyl" itself, or as part of other substituents, refers to a non-aromatic carbonyl ring consisting of at least three carbon atoms. The term cycloalkyl includes monocyclic cycloalkyl, bicyclic cycloalkyl, polycyclic cycloalkyl, bridged cycloalkyl, fused cycloalkyl, and spirocyclic cycloalkyl. In bridged cycloalkyl, the rings share at least two common non-adjacent atoms. In fused bicyclic cycloalkyl, the two rings share a covalent bond. In spirocyclic cycloalkyl, one atom is shared by two different rings.

[0049] As used herein, the term "heterocyclic alkyl" is a type of cycloalkyl as defined above and is included within the meaning of "cycloalkyl," wherein at least one carbon atom of the ring is substituted with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl and heterocyclic alkyl groups may be substituted or unsubstituted.

[0050] As used herein, the term "heterocyclic" or "heterocyclic group" refers to a group derived from a monocyclic, bridged bicyclic, fused bicyclic, spirocyclic, or polycyclic moiety comprising at least one non-aromatic ring containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents if defined). The heterocyclic group may be saturated or partially unsaturated. In some embodiments, the heterocyclic group may comprise 1 to 4 heteroatoms as ring members. The heterocyclic groups of this disclosure may be linked to a parent molecule moiety via carbon atoms or heteroatoms in the group. Therefore, the term includes, but is not limited to, "heterocyclic alkyl," "heteroaryl," "bicyclic heterocyclic," "aryl-fused heterocyclic alkyl," and "polycyclic heterocyclic."

[0051] As used herein, the terms “halogenated” or “halogen” refer to fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), or iodine (iodinated, -I). “Halogenated alkyl” refers to an alkyl group as defined above, wherein one or more hydrogen atoms have been substituted with a halogen independently selected from fluorine, chlorine, bromine, and iodine. “Fluorinated alkyl” refers to an alkyl group as defined above, wherein one or more hydrogen atoms have been substituted with a fluorine atom. Unless otherwise specified in quantity, a halogenated alkyl group may include the maximum chemically possible number of halogen atoms on the alkyl group as substituents. For example, a fluoroethyl group may be -CH2CF3, -CHF-CH3, or -CH2CH2F.

[0052] As used herein, the term "hydrogen" (or H) includes its isotope deuterium (D or H). 2 H) and tritium ( 3 H) means that any or all hydrogen atoms in the compound of this invention can be replaced by deuterium (D or 2 H) and tritium ( 3 H) substitution.

[0053] As used herein, the term "hydroxyl group" or "hydroxyl group" refers to the -OH group.

[0054] As used herein, the term "hydroxyalkyl" itself, or as part of other parts, refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl substituent. Therefore, the term "hydroxyalkyl" includes monohydroxyalkyl, dihydroxyalkyl, trihydroxyalkyl, and the like.

[0055] As used herein, the terms “cyano” or “-CN” refer to a -C≡N group. The term “cyanoalkyl” as used herein refers to an alkyl group having at least one -CN substituent.

[0056] As used in this article, the term "carbonyl" refers to the —C(═O)— group.

[0057] As used herein, the term "amino" or "amine" refers to -NH2. The term "alkylamino" refers to a group with the general formula -NHR, and "dialkylamino" refers to a group with the general formula -NRR', where R and R' are each independently alkyl.

[0058] As used herein, the term "alkylamino" refers to an amino group attached to an alkylene group. Typically, alkylamino groups are linked to the parent compound via their alkylene moiety.

[0059] As used herein, the term "alkylaminoalkyl" refers to an alkyl group bonded to a nitrogen atom, which is also bonded to another alkyl group.

[0060] As used in this article, the term "nitro" refers to -NO2.

[0061] Dashed lines represent single or double bonds to satisfy the valence requirements of the atoms connected by the bond. It should be understood that, in some cases, the bond may be aromatic.

[0062] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having 6 to 12 carbon atoms with a fully conjugated π-electron system. Non-limiting examples of aryl groups include phenyl, naphthyl, and anthracene. The "aryl" group may be substituted or unsubstituted.

[0063] As used herein, the term "aryl" refers to a divalent group derived from an aryl group as defined above, obtained by removing a hydrogen atom from the ring carbon atom of the aryl group.

[0064] As used herein, the term "heteroaryl" refers to a monocyclic or fused ring (i.e., a ring sharing adjacent atom pairs) of 5 to 12 ring atoms, containing one, two, three, or four cyclic heteroatoms selected from N, O, or S, with the remaining ring atoms being C, and having a fully conjugated π-electron system. Non-limiting examples of unsubstituted heteroaryls include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, triazole, tetraazole, triazine, carbazole, benzimidazole, benzoxazole, benzothiazole, indazole, and quinazoline. The heteroaryl group may be substituted or unsubstituted.

[0065] As used herein, the term "heteroaryl" refers to a divalent group derived from a heteroaryl group as defined above, obtained by removing a hydrogen atom from a cyclic carbon atom or a cyclic heteroatom of the heteroaryl group.

[0066] The groups defined above may include prefixes and / or suffixes commonly used in the art to produce other recognized substituents. For example, the term "haloalkoxy" or "haloalkyloxy" refers to a haloalkyl group connected to a parent molecule moiety via an oxygen atom. The term "(haloalkyl)oxyalkyl" refers to an alkyl group substituted with one, two, or three (haloalkyl)oxy groups. As another example, the term "hydroxyalkylamino" refers to an amino group substituted with one or two hydroxyalkyl groups.

[0067] As used in this article, the term -SO2- has the following general formula:

[0068] As used herein, the term "-alk-" (used alone or in combination with other terms) represents an alkylene group, such as -alk-C(O)-R. 8 .

[0069] As used in this article, the term "oxo" (alone or in combination with other terms) refers to =O.

[0070] As used herein, the term "stereoisomer" refers to isomers that have the same molecular formula but differ in the spatial arrangement of atoms, not in the order of atomic bonding. When the stereochemistry of a disclosed compound is not specified in its name or structural description, it should be understood that the name or structure encompasses all possible stereoisomers, including substantially pure stereoisomers and mixtures thereof. Enantiomers and diastereomers are both stereoisomers. The term "enantiomer" refers to one of a pair of mirror-image molecular entities that are not superimposed. The term "diastereomer" refers to stereoisomers that are not mirror images of each other. The term "racemic mixture" or "racemic mixture" refers to a mixture of two enantiomers in equimolar amounts, wherein the mixture is optically inactive.

[0071] As used in this article, the term "chirality" refers to the property of a molecule that, due to its structural characteristics, cannot be perfectly superimposed on its mirror image.

[0072] As used in this article, the term “rt” or “RT” refers to room temperature; the term “h” after a number (e.g., 2h) refers to an hour; and the term “min” after a number [e.g., 30min(s)] refers to a minute.

[0073] As used herein, the term "tautomer" refers to two or more isomers of a compound that coexist in equilibrium and rapidly interconvert through the migration of atoms or groups within the molecule. Therefore, this disclosure is intended to cover all possible tautomers, even if the structural formula depicts only one of them.

[0074] As used herein, the terms “optional” or “optionally” mean that the event or situation described below may, but does not necessarily, occur, including both the possibility that the event or situation occurs and the possibility that it does not. For example, “optionally substituted alkyl” means that the “alkyl” may or may not be substituted.

[0075] As used herein, the term "KRAS(G12D)" refers to the KRAS protein that has undergone the G12D mutation. Specifically, this means that the 12th amino acid of the wild-type KRAS protein is changed from glycine to aspartic acid.

[0076] PROTAC, short for Proteolytic Targeting Chip, is a heterobifunctional small molecule compound composed of three parts: a ligand for the E3 ubiquitin ligase, a ligand for the target protein (POI), and a linker strand connecting the two parts. Therefore, PROTAC acts as a bridge, bringing the POI closer to the E3 ubiquitin ligase, enabling the E3 ligase complex to catalyze the ubiquitination of the target protein. The resulting polyubiquitin chain labels the target protein, which is then degraded by the proteasome.

[0077] As used herein, the term "pharmaceutically acceptable salt" refers to a non-toxic anionic salt of an acid formed by an acid addition reaction, such as hydrochloride, hydrobromide, sulfate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, and gluconate. It should be understood that references to compounds of formula (I) herein also include their pharmaceutically acceptable salts.

[0078] When the compounds of the present invention contain a carboxyl group, the compounds can be reacted with the corresponding alcohol (e.g., C40, C60 ... 1-6 The alcohol reacts to produce a pharmaceutically acceptable ester.

[0079] As used herein, the term "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or their pharmaceutically acceptable salts or prodrugs, with other chemical components (e.g., pharmaceutically acceptable excipients). Pharmaceutical compositions are designed to facilitate the administration of compounds to a living organism.

[0080] As used herein, the term "pharmaceuticalally acceptable excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0081] As used herein, the term “therapeutic effective dose” refers to a dose of a compound that provides relief to one or more symptoms of the disease being treated. In cancer treatment, a therapeutic effective dose is a dose that produces the following effects: (1) shrinking tumor volume; (2) inhibiting tumor metastasis; (3) inhibiting tumor growth; and / or (4) relieving one or more symptoms associated with cancer.

[0082] As used herein, the terms “object” and “patient” are used interchangeably and, as used herein, refer to any mammal, including but not limited to humans, including human patients or objects to whom the compositions of the present invention may be administered. The term “mammal” includes human patients and non-human primates, as well as laboratory animals such as rabbits, rats, mice, and other animals.

[0083] Those skilled in the art will understand that the compounds described herein can be administered to patients via a variety of routes, depending on the chosen route of administration. For example, they can be administered orally, parenterally, orally, sublingually, nasally, rectally, via patch, pump, or transdermally, with corresponding pharmaceutical compositions formulated accordingly. Parenterical administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and local administration modalities. Parenterical administration can be performed via continuous infusion over a selected time period. Isomer form

[0084] The present invention provides compounds of formula (I), their tautomers, stereoisomers or pharmaceutically acceptable salts, esters or prodrugs, which can be used as KRAS(G12D) protein degraders and / or inhibitors, and relates to methods of using them.

[0085] The compounds of the present invention may exist in one or more stereoisomers, including enantiomers, diastereomers, transisomers, and geometric isomers. Those skilled in the art will understand that when a stereoisomer is enriched relative to other stereoisomers or isolated from other stereoisomers, it may exhibit higher activity or beneficial efficacy. Furthermore, those skilled in the art understand how to isolate, enrich, or selectively prepare said stereoisomers. Therefore, the present invention includes compounds of formula (I), their stereoisomers, and pharmaceutically acceptable salts thereof. The compounds of the present invention may exist in mixtures of stereoisomers, single stereoisomers, or optically active forms.

[0086] Furthermore, compounds of formula (I) (or their salts, prodrugs, or conjugates) may exhibit polymorphism or may form solvents with water or organic solvents. This invention also covers any such polymorphs, any solvates, or any mixtures thereof.

[0087] The following examples illustrate selected implementations of the present invention and do not imply limitation of the scope of the invention. Example 1A refers to isomer A of Example 1, and Example 1B refers to isomer B of Example 1; the two are stereoisomers of each other. Examples 1A and 1B: (2S,4R)-1-((S)-2-(4-(4-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-((R)-6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide Examples 2A and 2B: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide Examples 3A and 3B: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide Examples 4A and 4B: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide Examples 5A and 5B: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide Examples 6A and 6B: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(3,5-dimethylisooxazol-4-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide Examples 7A and 7B: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-(4-(1-ethyl-1H-pyrazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide Example 8 (mixture): (2S,4R)-1-((2S)-2-(4-(4-(((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide Example 9 (mixture): (2S,4R)-1-((2S)-2-(4-(4-(((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide Example 10 (mixture): (2S,4R)-1-((2S)-2-(4-(4-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide Examples 11A and 11B: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide Examples 12A and 12B: (2S,4R)-1-((2S)-2-(4-(4-(((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide Examples 13A and 13B: (2S,4R)-1-((2S)-2-(4-(4-(((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide Examples 14A and 14B: (2S,4R)-1-((2S)-2-(4-(3-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)bicyclo[1.1.1]pentane-1-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide Examples 15A and 15B: (2S,4R)-1-((2S)-2-(4-(3-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)bicyclo[1.1.1]pentane-1-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide Examples 16A and 16B: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide The experimental steps are as follows:

[0088] The abbreviations used are explained as follows: TEA: Triethylamine; DIPEA: N,N-Diisopropylethylamine; HBTU: O-(benzotriazol-1-yl)-N,N,N',N'-Tetramethylurea hexafluorophosphate; DMF: N,N-Dimethylformamide; NMR: Proton nuclear magnetic resonance; MS: Mass spectrometry, where (+) indicates positive ion mode, usually given as M +1 (or M+H) absorption peak, where M is the molecular weight. All compounds were analyzed by MS and / or 1 Characterized by H NMR.

[0089] Preparation of RB1: (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide Step 1: tert-butyl N-[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]carbamate

[0090] A mixture of tert-butyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (3.0 g, 9.5 mmol, 1.0 equivalent), 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrazole (4.0 g, 19.0 mmol, 2.0 equivalent), Pd(dppf)Cl2 (0.7 g, 948.8 μmol, 0.1 equivalent), and Na2CO3 (2.0 g, 19.0 mmol, 2.0 equivalent) in dioxane (45 mL) and water (4.5 mL) was degassed and purged three times with N2. The mixture was then stirred at 100 °C for 12 hours under N2 atmosphere. The reaction mixture was quenched with water at 25 °C and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was then subjected to rapid silica gel chromatography (SPCC). 80g Purification was performed using a silica gel rapid column with an eluent of 0–25% ethyl acetate / petroleum ether gradient at a flow rate of 40 mL / min to obtain tert-butyl N-[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]carbamate (2.9 g, 8.6 mmol, yield 90.6%) as a black solid. MS (ES-API positive): 332.3 (M+1) + . Step 2: (2R)-2-amino-2-[4-(2-ethylpyrazol-3-yl)phenyl]ethanol

[0091] At 0 °C, HCl / dioxane (10 mL, 4 M) was added to a solution of tert-butyl N-[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]carbamate (2.8 g, 8.4 mmol, 1.0 equivalent) in DCM (6 mL). The mixture was stirred at 0 °C for 0.5 h. The reaction was monitored by LCMS. After the reaction was complete, the mixture was concentrated under vacuum to give crude (2R)-2-amino-2-[4-(2-ethylpyrazol-3-yl)phenyl]ethanol (2.6 g, 8.35 mmol, 98.8% yield) as a white solid, which could be used in the next step without further purification. MS (ES-API positive): 232.1 (M+1) + . Step 3: tert-butyl N-[(1S)-1-[(2S,4R)-2-[[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]carbamoyl]-4-hydroxypyrrolidine-1-carbonyl]-2-methylpropyl]carbamate

[0092] A mixture of (2S,4R)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-methylbutyryl]-4-hydroxypyrrolidine-2-carboxylic acid (2.8 g, 8.4 mmol, 1.0 equivalent), (2R)-2-amino-2-[4-(2-ethylpyrazol-3-yl)phenyl]ethanol (2.3 g, 8.4 mmol, 1.0 equivalent), EDCI (2.0 g, 12.7 mmol, 1.5 equivalent), HOBt (1.4 g, 10.1 mmol, 1.2 equivalent), and DIEA (4.4 mL, 25.3 mmol, 3.0 equivalent) in DMF (16 mL) was degassed and purged three times with N2. The mixture was then stirred at 0 °C for 2 hours under N2 atmosphere. The reaction mixture was quenched with brine at 25 °C and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was then subjected to rapid silica gel chromatography (…). 80g Purification was performed using a silica gel rapid column chromatography with 0–25% ethyl acetate as eluent at a flow rate of 40 mL / min to give tert-butyl N-[(1S)-1-[(2S,4R)-2-[[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]carbamoyl]-4-hydroxypyrrolidine-1-carbonyl]-2-methylpropyl]carbamate (4.4 g, 7.8 mmol, yield 93.0%) as a white solid. MS (ES-API positive): 544.3 (M+1) + . Step 4: (2S,4R)-1-[(2S)-2-amino-3-methylbutyryl]-N-[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]-4-hydroxypyrrolidine-2-carboxamide

[0093] HCl / dioxane (4M, 5 mL, 5.4 equivalents) was added to a solution of tert-butyl N-[(1S)-1-[(2S,4R)-2-[[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]carbamoyl]-4-hydroxypyrrolidine-1-carbonyl]-2-methylpropyl]carbamate (2.0 g, 3.7 mmol, 1.0 equivalent) in DCM (5 mL). The mixture was stirred at 0 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give compound (2S,4R)-1-[(2S)-2-amino-3-methylbutyryl]-N-[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]-4-hydroxypyrrolidine-2-carboxamide (1.8 g, 3.5 mmol, yield 96.4%) as an orange-red solid. MS (ES-API positive): 444.2 (M+1) + . Step 5: (2S,4R)-1-[(2S)-2-azido-3-methylbutyryl]-N-[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]-4-hydroxypyrrolidine-2-carboxamide

[0094] Add FSO₂N₃ (0.4 M, 984 μL, 1.0 equivalence) and KHCO₃ (3.0 M, 500 μL, 4.0 equivalence) to a solution of (2 S, 4 R)-1-[(2 S)-2-amino-3-methylbutyryl]-N-[(1 R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]-4-hydroxypyrrolidine-2-carboxamide (167 mg, 375.0 μmol, 1.0 equivalence) in DMSO (2 mL) and KHCO₃ (3.0 M, 500 μL, 4.0 equivalence). Stir the mixture at 25 °C for 1 hour. Filter the reaction mixture, wash the filter cake with ethyl acetate, dilute the filtrate with water (20 mL), and extract with ethyl acetate (10 mL x 3). Wash the combined organic layers with brine (15 mL x 2), dry to Na₂SO₄, filter, and concentrate under reduced pressure. Separately analyze the residue by rapid silica gel chromatography (…). 4g Purification was performed using a silica gel fast column (eluting with 5% ethyl acetate / methanol at a flow rate of 30 mL / min) to give (2S,4R)-1-[(2S)-2-azido-3-methylbutyryl]-N-[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]-4-hydroxypyrrolidine-2-carboxamide (160 mg, yield 90.5%) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.56-7.26(m, 5H), 6.21(br s, 1H), 5.09(br s, 1H), 4.76-4.61(m, 1H), 4.54(br s, 1H), 4.22-3.97 (m, 2H), 3.94-3.73 (m, 2H), 3.65 (m, 2H), 3.49-3.33 (m, 1H), 2.21 (br s, 2H), 2.05-1.92 (m, 1H), 1.41-1.32 (m, 3H), 1.08-0.89 (m, 6H). MS (ES-API positive): 470.1 (M+1) + . Preparation of RB2: (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazo-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0095] RB2 was synthesized using the same route as RB1, and it was a white solid. 1 H NMR (500MHz, CDCl3) δ8.74 (s, 1H), 7.48-7.38 (m, 4H), 5.15 (dt, J=3.9, 7.2Hz, 1H), 4. 13 (d, J=7.2Hz, 1H), 4.01-3.92 (m, 1H), 3.85 (dd, J=6.6, 11.8Hz, 1H), 3.79-3.73 (m, 1H) ), 3.69-3.63 (m, 1H), 3.42 (d, J=9.0Hz, 1H), 2.55 (s, 3H), 2.43 (ddd, J=4.7, 8.0, 13.2 Hz, 1H), 2.05 (s, 1H), 1.30-1.24 (m, 2H), 1.11 (d, J=6.6Hz, 3H), 1.02 (d, J=6.7Hz, 3H). MS (ES-API positive): 473.2 (M+1) + . Preparation of RB3: (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0096] RB3 was synthesized using the same route as RB1, and it was a yellow solid. MS (ES-API positive): 454.3 (M+1) + . Preparation of RB4: (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazo-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0097] RB4 was synthesized using the same route as RB1, and it was a yellow solid. 1 H NMR (400MHz, (DMSO-D6) δ9.00-8.96 (m, 1H), 7.55-7.50 (m, 1H), 7.46-7.41 (m, 2H) ,7.39-7.34(m,2H),4.94-4.86(m,1H),4.54-4.46(m,1H),4.32-4.24(m,1H),3.7 2 (d, J=8.2Hz, 1H), 3.57-3.49 (m, 2H), 2.46 (s, 3H), 2.14-2.01 (m, 2H), 1.39 (d, J=7.1Hz, 3H), 1.29-1.26 (m, 3H), 0.97 (d, J=16.5Hz, 5H). MS (ES-API positive): 457.0 (M+1) + . Preparation of RB5: (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-N-(4-(1-ethyl-1H-pyrazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide

[0098] RB5 was synthesized using the same route as RB1, and it was a white solid. 1H NMR (400MHz, (CD3)2SO) δ8.60 (t, J=5.9Hz, 1H), 7.51-7.47 (m, 1H), 7.43-7.38 (m, 4H), 6.32 (d, J=1.8Hz, 1H), 4.53-4.45 (m, 1H), 4.42-4.28 (m, 3H), 4.11 (q, J=7.3Hz , 2H), 3.78 (d, J=8.1Hz, 1H), 3.58 (d, J=2.6Hz, 2H), 3.31 (s, 1H), 2.15-2.06 (m, 2H) , 1.90 (ddd, J=4.5, 8.5, 12.9Hz, 1H), 1.29 (t, J=7.2Hz, 3H), 0.98 (t, J=6.8Hz, 6H). MS (ES-API positive): 440.2 (M+1) + . Preparation of RB6: (2S,4R)-1-((S)-2-azido-3-methylbutyryl)-4-hydroxy-N-(4-(4-methylthiazo-5-yl)benzyl)pyrrolidine-2-carboxamide

[0099] RB6 was synthesized using the same route as RB1, and it was a yellow oily substance. 1 H NMR (400MHz, (CD3)2SO) δ9.01-8.97 (m, 1H), 8.61 (t, J=5.9Hz, 1H), 7.46-7.35 (m, 4H), 4.49 (t, J=8.1Hz, 1H), 4.40-4.26 (m, 3H), 4.13-4.09 (m, 1H), 3.65-3.55 (m, 3H), 2.45 (s, 3H), 2.15-2.06 (m, 2H), 1.90 (ddd, J=4.5, 8.5, 12.9Hz, 1H), 0.97 (t, J=6.7Hz, 6H). MS (ES-API positive): 443.1 (M+1) + . Preparation of LB1: tert-butyl 3-(6-cyclopropyl-8-((4-ethynylbenzyl)oxy)-7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Step 1: tert-butyl 3-(7-bromo-2-chloro-8-fluoro-6-iodo-quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0100] TEA (2.8 g, 28.4 mmol, 3.9 mL, 3.0 equivalent) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.0 g, 9.4 mmol, 1.0 equivalent) were added to a solution of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazolin (4.0 g, 9.4 mmol, 1.0 equivalent) in DCM (40 mL). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with water and then extracted with DCM (40 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was subjected to rapid silica gel chromatography (…). 80g Purification was performed using a silica gel fast column with an eluent of 0–15% ethyl acetate / petroleum ether gradient at a flow rate of 30 mL / min to give tert-butyl 3-(7-bromo-2-chloro-8-fluoro-6-iodo-quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (6.0 g, 9.0 mmol, yield 95.2%). MS (ES-API positive): 598.9 (M+1) + . Step 2: tert-butyl 3-[7-bromo-8-fluoro-6-iodo-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0101] KF (778 mg, 13.3 mmol, 8.0 equivalent) and (2S)-2-methoxyprop-1-ol (452 ​​mg, 5.0 mmol, 482.2 μL, 3.0 equivalent) were added to a solution of tert-butyl-3-(7-bromo-2-chloro-8-fluoro-6-iodo-quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.0 g, 1.6 mmol, 1.0 equivalent) in DMSO (10 mL). The mixture was stirred at 120 °C for 16 hours. After removing most of the solvent, water was added and the mixture was extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was analyzed by rapid silica gel chromatography (…). 80g Purification was performed using a silica gel rapid column with an eluent of 0–15% ethyl acetate / petroleum ether gradient at a flow rate of 30 mL / min to obtain tert-butyl 3-[7-bromo-8-fluoro-6-iodo-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, a yellow solid. MS (ES-API positive): 651.0 (M+1) + . Step 3: tert-butyl-3-[8-benzyloxy-7-bromo-6-cyclopropyl-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0102] Pd(dppf)Cl2 (138 mg, 189.3 μmol, 0.1 equivalent) and K2CO3 (785 mg, 5.6 mmol, 3.0 equivalent) were added to a solution of tert-butyl-3-[8-benzyloxy-7-bromo-6-iodo-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.4 g, 1.8 mmol, 1.0 equivalent) and potassium cyclopropyltrifluoroborate (336 mg, 2.2 mmol, 1.2 equivalent) in toluene (12 mL) and water (1.2 mL). The reaction mixture was stirred at 80 °C for 36 hours. After the reaction was complete, the mixture was cooled to room temperature, and the salts were removed by filtration. The filtrate was diluted with water and then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Uni C18 40×150×5μm; mobile phase: [water (HCl)-ACN]; B%: 53%-83%, 10 min) to give tert-butyl 3-[8-benzyloxy-7-bromo-6-cyclopropyl-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, as a white solid. MS (ES-API positive): 655.2 (M+1) + . Step 4: tert-butyl 3-[8-benzyloxy-6-cyclopropyl-7-(6-fluoro-5-methyl-2-triphenyl-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0103] To a solution of tert-butyl-3-[8-benzyloxy-7-bromo-6-cyclopropyl-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (520 mg, 795.5 μmol, 1.0 equivalent) in THF (5 mL), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2-triphenyl-indazole (536 mg, 1.0 mmol, 1.3 equivalent), CataCXium A Pd G3 (58 mg, 79.5 μmol, 0.1 equivalent) and K3PO4 (507 mg, 2.3 mmol, 3.0 equivalent) were added, followed by water (0.5 mL). The mixture was then stirred at 65 °C for 3 hours under a N2 atmosphere. The reactants were cooled to room temperature, and the salts were removed by filtration. The filtrate was diluted with water and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was subjected to rapid silica gel chromatography (…). 20g Purification was performed using a silica gel fast column with an eluent gradient of 0–25% ethyl acetate / petroleum ether at a flow rate of 30 mL / min to obtain tert-butyl 3-[8-benzyloxy-6-cyclopropyl-7-(6-fluoro-5-methyl-2-triphenyl-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, a white solid. MS (ES-API positive): 965.5 (M+1) + . Step 5: tert-butyl 3-(6-cyclopropyl-7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-8-hydroxy-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0104] Under a nitrogen atmosphere, Pd / C (120 mg, 10% purity) was added to a solution of tert-butyl-3-[8-benzyloxy-6-cyclopropyl-7-(6-fluoro-5-methyl-2-triphenyl-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (530 mg, 0.4 mol, 1.0 equivalent) in methanol (10 mL). The suspension was degassed and purged three times with H2. The mixture was stirred at room temperature for 16 hours under a H2 (30 Psi) atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 3-(6-cyclopropyl-7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-8-hydroxy-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, a white solid that can be used in the next step without further purification. MS (ES-API positive): 875.4 (M+1) + . Step 6: tert-butyl-3-(6-cyclopropyl-8-((4-ethynylbenzyl)oxy)-7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0105] Cs₂CO₃ (330 mg, 1.0 mmol, 3.0 equivalence) and 1-(bromomethyl)-4-ethynylbenzene (132 mg, 676.5 μmol, 2.0 equivalence) were added to a solution of tert-butyl-3-(6-cyclopropyl-7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-8-hydroxy-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (370 mg, 338.3 μmol, 1.0 equivalence) in DMF (4 mL). The mixture was stirred at 40 °C for 2 h. The reaction mixture was quenched with brine at 25 °C and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was analyzed by rapid silica gel chromatography (…). 12g Purification was performed using a silica gel fast column with an eluent gradient of 0–40% ethyl acetate / petroleum ether at a flow rate of 40 mL / min to obtain tert-butyl 3-(6-cyclopropyl-8-((4-ethynylbenzyl)oxy)-7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate, a white solid. MS (ES-API positive): 989.4 (M+1) + . Preparation of LB2: tert-butyl(1R,4R)-5-(6-cyclopropyl-8-((4-ethynylbenzyl)oxy)-7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0106] LB2 was synthesized using a method similar to that used for LB1, and it was a white solid. MS (ES-API positive): 975.4 (M+1) + . Preparation of LB3: tert-butyl(1R,4R)-5-[6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-2-triphenyl-indazol-4-yl)-2-(tetrahydropyran-4-yl)oxy-quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0107] LB3 was synthesized using a similar method and was a yellow solid. MS (ES-API positive): 987.5 (M+1) + . Preparation of LB4: (1R,4R)-tert-butyl5-(6-cyclopropyl-8-((3-ethynylbicyclo[1.1.1]pentan-1-yl)methoxy)-7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0108] LB4 was synthesized using a similar method and was a white solid. MS (ES-API positive): 965.6 (M+1) + . Preparation of intermediate 11: 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2-triphenyl-2H-indazole Step 1: 4-Bromo-6-fluoro-2-triphenyl-indazole

[0109] TrtCl (15.6 g, 55.8 mmol, 1.2 equivalence) and TEA (16.2 mL, 116.3 mmol, 2.5 equivalence) were added to a solution of 4-bromo-6-fluoro-2H-indazole (10.0 g, 46.5 mmol, 1.0 equivalence) in DCM (130 mL). The mixture was stirred at 25 °C for 16 h and then concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1) to give 4-bromo-6-fluoro-2-triphenyl-indazole (16.0 g, 33.4 mmol, yield 72.2%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.92 (d, J=0.7Hz, 1H), 7.40-7.30 (m, 10H), 7.22-7.17 (m, 6H), 7.10 (dd, J=2.0, 8.8Hz, 1H). Step 2: 4-Bromo-6-fluoro-5-methyl-2-triphenyl-indazole

[0110] Under a nitrogen atmosphere at -78°C, n-butyllithium (6.8 mL, 2.5 M, 2.0 equivalent) was added dropwise to a solution of diisopropylamine (2.4 mL, 17.1 mmol, 2.0 equivalent) in 20 mL of THF. After the addition was complete, the mixture was stirred at the same temperature for 30 minutes, and then a solution of 4-bromo-6-fluoro-2-triphenyl-indazole (4.5 g, 8.6 mmol, 1.0 equivalent) in 20 mL of THF was added dropwise at -78°C. The resulting mixture was stirred at -78°C under a nitrogen atmosphere for 30 minutes, and then a solution of iodomethane (1.1 mL, 17.1 mmol, 2.0 equivalent) in 5 mL of THF was added dropwise at -78°C. The mixture was then heated to 25°C and stirred at that temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was quenched with saturated NH4Cl at -78°C and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0 to 20 / 1) to give 4-bromo-6-fluoro-5-methyl-2-triphenyl-indazole (2.3 g, 4.8 mmol, yield 55.8%) as a pale yellow solid. 1H NMR (400MHz, CDCl3) δ7.84 (s, 1H), 7.39-7.29 (m, 10H), 7.23-7.14 (m, 6H), 2.40 (d, J = 2.6Hz, 3H). Step 3: 6-Fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2-triphenyl-indazole

[0111] To a solution of 4-bromo-6-fluoro-5-methyl-2-triphenyl-indazole (5.8 g, 12.3 mmol, 1.0 equivalent) in dioxane (15 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentane (6.2 g, 24.6 mmol, 2.0 equivalent), Pd(dppf)Cl2 (0.9 g, 1.2 mmol, 0.1 equivalent), and KOAc (2.4 g, 24.6 mmol, 2.0 equivalent) were added. The mixture was refluxed and stirred for 16 hours under a nitrogen atmosphere. The reaction mixture was quenched with water at 25 °C and then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1) to give 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2-triphenyl-indazole, a light green solid. 1 H NMR (400MHz, CDCl3) δ 8.07 (s, 1H), 7.35-7.30 (m, 10H), 7.23-7.17 (m, 6H), 2.52 (d, J = 2.9Hz, 3H), 1.26 (s, 12H). Examples 1A and 1B: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide Step 1: tert-butyl(1R,4R)-5-(6-cyclopropyl-8-((4-(1-((S)-1-((2S,4R)-2-(((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobutane-2- (2.2.1)-1H-1,2,3-triazol-4-yl)benzyl)oxy)-7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0112] tert-butyl(1R,4R)-5-[6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-2-triphenyl-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (145 mg, 148.7 μmol, 1.0 equivalent), (2S,4R)-1-[(2S)-2-azido-3-methylbutyryl]-N-[(1R) A mixture of 1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]-4-hydroxypyrrolidine-2-carboxamide (83 mg, 176.8 μmol, 1.2 equivalents), CuSO4 (1.0 M, 149 μL, 1.0 equivalents), and sodium ascorbate (44 mg, 223.0 μmol, 1.5 equivalents) in DMSO (0.5 mL) and water (0.5 mL) was degassed and purged three times with N2. The mixture was then stirred at 50 °C for 3 hours under N2 atmosphere. The reaction mixture was diluted with brine at 25 °C and then extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, ethyl acetate / methanol = 10 / 1) to give tert-butyl(1R,4R)-5-[6-cyclopropyl-8-[[4-[1-[(1S)-1-[(2S,4R)-2-[[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]carbamoyl]-4-hydroxypyrrolidine-1-carbonyl]-2-methylpropyl]triazol-4-yl]phenyl]methoxy]-7-(6-fluoro-5-methyl-2-triphenyl-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (crude product), which is a white solid. MS (ES-API positive): 1445.6 (M+1) + . Step 2: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0113] Add HCl / dioxane (4M, 3mL) to a solution of tert-butyl(1R,4R)-5-[6-cyclopropyl-8-[[4-[1-[(1S)-1-[(2S,4R)-2-[[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]carbamoyl]-4-hydroxypyrrolidine-1-carbonyl]-2-methylpropyl]triazol-4-yl]phenyl]methoxy]-7-(6-fluoro-5-methyl-2-triphenyl-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (250mg, 173.0μmol, 1.0 equivalent) in DCM (4mL). The mixture was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA conditions, column: Boston Green ODS150 x 30 mm x 5 μm; mobile phase: [water (HCl) - acetonitrile]; B%: 22%-37%, 10 min), and then lyophilized to give two isomers: Example 1A and Example 1B, both white solids.

[0114] The retention time for Example 1A is 2.22 minutes. 1H NMR (400MHz, CD3OD) δ8.49 (br s, 1H), 8.21 (br d, J=2.3Hz, 1H), 7.76 (br s, 1H), 7.51 (s, 7H), 7.28-7.14 (m, 1H), 6.83-6.58 (m, 3H), 5.66 (br s, 1H), 5.33 (br d, J=10.1Hz, 1H), 4.99 (br t, J=5.7Hz, 1H), 4.68 (br s, 3H), 4.56 (br d, J=7.7Hz, 5H), 4.41 (br s, 1H), 4.34 (br d, J=7.0Hz, 2H), 3.92-3.81(m, 2H), 3.77(br d, J=6.0Hz, 2H), 3.73-3.43 (m, 3H), 3.31 (s, 3H), 2.58 (br s, 1H), 2.45 (br d, J=4.4Hz, 1H), 2.19 (br dd, J=7.8, 12.7Hz, 2H), 2.06 (br s, 3H), 1.96-1.82 (m, 1H), 1.45 (br s, 1H), 1.38 (br t, J=7.0Hz, 3H), 1.19 (br s, 3H), 1.08 (br d, J=6.0Hz, 3H), 0.75 (br d, J=6.1Hz, 4H), 0.69 (br s, 3H). MS (ES-API positive): 1102.4 (M+1) + .

[0115] The retention time for Example 1B was 2.33 minutes. 1H NMR (400MHz, CD3OD) δ8.72-8.59(m, 1H), 8.39-8.31(m, 1H), 8.11(br s, 1H), 7.72-7.54(m, 7H), 7.44-7.35(m, 1H), 6.93-6.78(m, 3H), 5.73(br s, 1H), 5.46 (d, J = 10.3Hz, 1H), 5.12 (t, J = 5.9Hz, 1H), 4.86-4.77 (m, 3H), 4.76-4.57 (m, 5H), 4.54 (br d, J = 1.9Hz, 1H), 4.50-4.44 (m, 2H), 3.96 (br s, 2H), 3.89 (d, J=6.1Hz, 2H), 3.84-3.65 (m, 3H), 3.46-3.38 (m, 3H), 2.76-2.65 (m, 1H), 2.58 (br d, J=11.0Hz, 1H), 2.43-2.27 (m, 2H), 2.19 (d, J=1.8Hz, 3H), 2.02-1.96 (m, 1H), 1.56-1. 48(m, 4H), 1.35-1.27(m, 3H), 1.25-1.15(m, 3H), 0.91-0.81(m, 4H), 0.80-0.69(m, 3H). MS (ES-API positive): 1102.5 (M+1) + . Examples 2A and 2B: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0116] Example 2A is a white solid. The retention time of Example 2A is 1.35 minutes. 1H NMR (400MHz, CD3OD) δ10.07-10.00 (m, 1H), 8.54 (br s, 1H), 7.75 (br s, 1H), 7.59 (s, 6H), 7.35-7.25 (m, 1H), 6.78 (br d, J=7.63Hz, 2H), 5.75 (br s, 1H), 5.45-5.18 (m, 1H), 5.16-5.05 (m, 1H), 4.78 (br s, 3H), 4.72-4.55 (m, 5H), 4.55-4.37 (m, 1H), 4.10-3.52 (m, 7H), 3.44-3.38 (m, 3H), 2.69-2.65 (m, 1H) ), 2.64-2.60(m, 3H), 2.59-2.43(m, 1H), 2.37-2.19(m, 2H), 2.15(s, 3H), 2.07-1.93(m, 1H), 1.57(br s, 1H), 1.29 (br d, J=6.08Hz, 3H), 1.18 (br d, J=6.44Hz, 3H), 0.93-0.66 (m, 1H), 0.93-0.66 (m, 6H). MS (ES-API positive): 1105.5 (M+1) + .

[0117] Example 2B is a white solid. The retention time of Example 2B is 1.44 minutes. 1 H NMR (400MHz, CD3OD) δ10.04-9.96(m, 1H), 8.67-8.43(m, 1H), 7.84(br s, 1H), 7.66-7.52(m, 7H), 7.39-7.28(m, 1H), 6.79(br d, J=7.99Hz, 2H), 5.71(br s, 1H), 5.40 (d, J=10.25Hz, 1H), 5.17-5.03 (m, 1H), 4.85-4.55 (m, 8H), 4.54-4.41 (m, 1H) ), 4.08-3.54(m, 7H), 3.45-3.38(m, 3H), 2.71-2.64(m, 1H), 2.64-2.60(m, 3H), 2.54(br d, J=11.80Hz, 1H), 2.40-2.22(m, 2H), 2.15(d, J=1.79Hz, 3H), 2.10-1.93(m, 1H), 1.61-1.48(m, 1H), 1.32-1.23(m, 3H), 1.18(br d, J=6.56Hz, 3H), 0.90-0.70 (m, 7H). MS (ES-API positive): 1105.5 (M+1) + . Examples 3A and 3B: (2S,4R)-1-[(2S)-2-[4-[4-[[6-cyclopropyl-4-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl]oxymethyl]phenyl]triazol-1-yl]-3-methylbutyryl]-4-hydroxy-N-[(1S)-1-[4-(4-methylthiazolyl-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0118] Example 3A is a white solid. The retention time of Example 3A is 1.83 minutes. 1 H NMR (400MHz, CD3OD) δ10.01 (s, 1H), 8.48 (s, 1H), 7.75 (br s, 1H), 7.66-7.42 (m, 7H), 7.28 (br d, J=9.7Hz, 1H), 6.76 (br d, J=8.0Hz, 2H), 5.76 (br s, 1H), 5.39 (d, J=10.1Hz, 1H), 5.08 (q, J=7.1Hz, 1H), 4.96 (br s, 1H), 4.84-4.37 (m, 10H), 4.01-3.49 (m, 5H), 3.42 (s, 3H), 2.68-2.57 (m, 4H), 2.53 (br d, J=11.6Hz, 1H), 2.35-2.19 (m, 2H), 2.14 (s, 3H), 2.04-1.89 (m, 1H), 1.55 (d, J=7.0Hz, 4H), 1.30 (d, J=6.3Hz, 3H), 1.18 (br d, J=6.4Hz, 3H), 0.84 (br d, J=6.6Hz, 3H), 0.83-0.65 (m, 4H). LCMS m / z: 1089.5(M+1) + .

[0119] Example 3B is a white solid. The retention time of Example 3B is 1.89 minutes. 1H NMR (400MHz, CD3OD) δ10.05-9.91 (m, 1H), 8.59-8.40 (m, 1H), 7.78 (br s, 1H), 7.56 (q, J=8.5Hz, 7H), 7.30 (d, J=9.5Hz, 1H), 6.77 (br d, J=8.0Hz, 2H), 5.74 (br s, 1H), 5.39 (d, J=10.3Hz, 1H), 5.08 (br d, J=6.9Hz, 1H), 4.96 (br s, 1H), 4.85-4.47 (m, 10H), 3.96-3.51 (m, 5H), 3.42 (s, 3H), 2.69-2.59 (m, 4H), 2.54 (br d, J=12.3Hz, 1H), 2.36-2.20 (m, 2H), 2.14 (s, 3H), 2.04-1.89 (m, 1H), 1.71-1.52 (m, 4H), 1.30 (d, J=6.3Hz, 3H), 1.18 (brd, J=6.6Hz, 3H), 0.85 (br d, J=6.6Hz, 3H), 0.75 (br d, J=7.3Hz, 4H). LCMS m / z: 1089.5(M+1) + . Examples 4A and 4B: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0120] Example 4A is a yellow solid. The retention time of Example 4A is 1.83 minutes. 1H NMR (400MHz, CD3OD) δ 8.56-8.50 (m, 1H), 8.31 (d, J=2.7Hz, 1H), 7.63-7.55 (m, 6H), 7.29 (br d, J=9.2Hz, 1H), 6.86-6.75 (m, 3H), 5.76 (br s, 1H), 5.47-5.36 (m, 1H), 5.16-5.06 (m, 1H), 4.83-4.75 (m, 3H), 4.73-4.61 (m, 4H), 4.57 (t, J=8.3Hz, 1H), 4.51-4.41 (m, 3H), 3.91 (br s, 4H), 3.65-3.52 (m, 1H), 3.42 (s, 3H), 2.71-2.43 (m, 3H), 2.29 (br d, J=11.7Hz, 2H), 2.14 (s, 3H), 2.06-1.92 (m, 1H), 1.70 (d, J=7.0Hz, 1H), 1.61-1.42 (m , 7H), 1.30 (d, J=6.3Hz, 3H), 1.21-1.15 (m, 3H), 0.87-0.81 (m, 4H), 0.79-0.66 (m, 3H). MS (ES-API positive): 1087.0 (M+1) + .

[0121] The retention time for Example 4B was 1.89 minutes. 1H NMR (400MHz, CD3OD) δ8.59 (s, 1H), 8.35 (d, J=2.7Hz, 1H), 7.61-7.51 (m, 7H), 7.36 (d, J=9.3Hz, 1H), 6.86 (d, J=2.9Hz, 1H), 6.81 (br d, J=7.9Hz, 2H), 5.72(br s, 1H), 5.45 (d, J=10.1Hz, 1H), 5.19-5.06 (m, 1H), 4.82-4.75 (m, 2H), 4.74-4.63 (m, 4H), 4.60 (brt, J=8.4Hz, 1H), 4.52-4.42 (m, 3H), 3.95-3.77 (m, 4H), 3.62 (br d, J=11.0Hz, 1H), 3.42 (s, 3H), 2.79-2.40 (m, 3H), 2.36-2.23 (m, 2H), 2.17 (s, 3H), 1.99 (td, J=4.3, 8.9Hz, 1H), 1.70 (d , J=7.0Hz, 1H), 1.59-1.42 (m, 7H), 1.30 (d, J=6.4Hz, 3H), 1.19 (d, J=6.6Hz, 3H), 0.89-0.83 (m, 3H), 0.80-0.68 (m, 4H). MS (ES-API positive): 1086.9 (M+1) + . Examples 5A and 5B: (2S,4R)-1-[(2S)-2-[4-[4-[[6-cyclopropyl-4-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-(tetrahydropyran-4-yl)oxy-quinazolin-8-yl]oxymethyl]phenyl]triazol-1-yl]-3-methylbutyryl]-4-hydroxy-N-[(1R)-2-hydroxy-1-[4-(4-methylthiazolyl-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide

[0122] Example 5A is a white solid. The retention time of Example 5A is 1.71 minutes. 1H NMR (400MHz, CD3OD) δ10.04-9.94(m, 1H), 8.62-8.49(m, 1H), 7.68(br s, 1H), 7.64-7.56 (m, 7H), 7.35-7.26 (m, 1H), 6.84-6.77 (m, 2H), 5.74-5.63 (m, 1H), 5.56-5.47(m, 1H), 5.43-5.36(m, 1H), 5.22-4.93(m, 2H), 4.80-4.71(m, 3H), 4.70-4 .57(m, 3H), 4.50(brs, 1H), 4.02-3.90(m, 4H), 3.86(d, J=6.1Hz, 2H), 3.74-3.60(m, 4H), 2.71-2.64(m, 1H), 2.62(s, 3H), 2.57-2.49(m, 1H), 2.34-2.23(m, 2H), 2.17(br s, 3H), 2.15-2.05 (m, 2H), 2.04-1.96 (m, 1H), 1.94-1.81 (m, 2H), 1.64-1.54 (m, 1H), 1.18 (br d, J=6.4Hz, 3H), 0.84 (br d, J=6.3Hz, 4H), 0.81-0.66 (m, 3H). MS (ES-API positive): 1117.5 (M+1) + .

[0123] Example 5B is a white solid with a retention time of 1.78 minutes. 1H NMR (400MHz, CD3OD) δ9.92-9.89 (m, 1H), 8.62-8.49 (m, 1H), 7.81-7.70 (m, 1H), 7.66-7.53 (m, 7H), 7.32 (br d, J=9.7Hz, 1H), 6.81 (br d, J=7.7Hz, 2H), 5.71-5.61 (m, 1H), 5.56-5.44 (m, 1H), 5.39 (d, J=10.3H z, 1H), 5.22-4.93 (m, 2H), 4.81-4.74 (m, 2H), 4.74-4.56 (m, 4H), 4.50 (br d, J=0.8Hz, 1H), 4.02-3.89 (m, 4H), 3.86 (d, J=6.2Hz, 2H), 3.77-3.57 (m, 4H), 2.7 2-2.63(m, 1H), 2.62-2.58(m, 3H), 2.57-2.47(m, 1H), 2.37-2.22(m, 2H), 2.15(br d, J=1.8Hz, 4H), 2.08-1.94(m, 2H), 1.93-1.76(m, 2H), 1.63-1.50(m, 1H), 1.18(br d, J=6.4Hz, 3H), 0.90-0.80 (m, 4H), 0.79-0.66 (m, 3H). MS (ES-API positive): 1117.5 (M+1) + . Examples 6A and 6B (2S,4R)-1-((S)-2-(4-(4-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0124] Example 6A is a white solid. The retention time of Example 6A is 1.77 minutes. 1H NMR (400MHz, CD3OD) δ8.55 (br s, 1H), 7.77 (br s, 1H), 7.61 (br d, J=5.0Hz, 3H), 7.49 (br d, J=7.9Hz, 2H), 7.37-7.30 (m, 3H), 6.91-6.72 (m, 2H), 5.77 (br s, 1H), 5.42 (br d, J=10.0Hz, 1H), 5.08 (br t, J=6.0Hz, 1H), 4.80 (br s, 3H), 4.74-4.61 (m, 5H), 4.53 (br s, 1H), 3.99-3.91 (m, 2H), 3.86 (br d, J=6.1Hz, 3H), 3.78-3.58(m, 2H), 3.43(s, 3H), 2.67(br s, 1H), 2.57(br s, 1H), 2.41-2.39(m, 3H), 2.31(br s, 1H), 2.28(br d, J=5.0Hz, 1H), 2.26-2.23(m, 3H), 2.17(br s, 3H), 2.11-2.00(m, 1H), 1.58(br s, 1H), 1.31(br s, 3H), 1.19(br d, J=6.2Hz, 3H), 0.90-0.70 (m, 7H); MS (ES-API positive): 1104.2 (M+1) + .

[0125] Example 6B is a white solid. The retention time of Example 6B is 1.84 minutes. 1H NMR (500MHz, CD3OD) δ 8.62-8.49 (m, 1H), 7.79 (br s, 1H), 7.68-7.55 (m, 3H), 7.53-7.46 (m, 2H), 7.38-7.29 (m, 3H), 6.80 (br d, J=7.6Hz, 2H), 5.74 (br s, 1H), 5.41 (d, J=10.2Hz, 1H), 5.08 (br t, J=6.1Hz, 1H), 4.79 (br s, 3H), 4.70-4.57 (m, 5H), 4.53 (br s, 1H), 4.00-3.90 (m, 2H), 3.89-3.79 (m, 3H), 3.77-3.56 (m, 2H), 3.47-3.38 (m, 3H), 2.68-2.63 (m, 1H) 2.56 (br d, J=11.0Hz, 1H), 2.44-2.39(m, 3H), 2.34(br d, J=11.4Hz, 1H), 2.31-2.28(m, 1H), 2.28-2.23(m, 3H), 2.16(br s, 3H), 2.04-2.01 (m, 1H), 1.57 (br s, 1H), 1.33-1.26 (m, 3H), 1.20 (br d, J=6.4Hz, 3H), 0.86 (br d, J=6.6Hz, 3H), 0.83-0.67 (m, 4H). MS (ES-API positive): 1104.2 (M+1) + . Examples 7A and 7B (2S,4R)-1-[(2S)-2-[4-[4-[[6-cyclopropyl-4-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl]oxymethyl]phenyl]triazol-1-yl]-3-methylbutyryl]-N-[[4-(2-ethylpyrazol-3-yl)phenyl]methyl]-4-hydroxy-pyrrolidine-2-carboxamide]

[0126] Example 7A is a yellow solid. The retention time of Example 7A is 2.31 minutes. 1H NMR (400MHz, CD3OD) δ 8.49-8.37 (m, 1H), 8.02 (br s, 1H), 7.70-7.63 (m, 1H), 7.62-7.49 (m, 7H), 7.27 (d, J=9.8Hz, 1H), 6.75 (br d, J=8.0Hz, 2H), 6.66 (s, 1H), 5.80-5.71 (m, 1H), 5.43-5.36 (m, 1H), 4.80-4.72 (m, 3H), 4.71-4.62 (m, 3H), 4. 61-4.45(m, 5H), 4.35(q, J=7.3Hz, 2H), 4.04-3.96(m, 1H), 3.94-3.88(m, 1H), 3.87-3.80(m, 1H), 3.78-3.68(m , 1H), 3.67-3.57(m, 1H), 3.45-3.40(m, 3H), 2.69-2.62(m, 1H), 2.56-2.50(m, 1H), 2.34-2.23(m, 2H), 2.19-2. 06 (m, 4H), 1.62-1.52 (m, 1H), 1.49-1.39 (m, 3H), 1.30 (d, J = 6.3Hz, 3H), 1.21-1.10 (m, 3H), 0.87-0.69 (m, 7H). MS (ES-API positive): 1072.5 (M+1) + .

[0127] Example 7B is a yellow solid. The retention time of Example 7B is 2.40 minutes. 1H NMR (400MHz, CD3OD) δ 8.53-8.44 (m, 1H), 8.26-8.16 (m, 1H), 8.01-7.70 (m, 1H), 7.64-7.50 (m, 7H), 7.39-7. 16(m, 1H), 6.84-6.65(m, 3H), 5.80-5.65(m, 1H), 5.49-5.33(m, 1H), 4.82-4.75(m, 3H), 4.67-4.49(m, 8H), 4.45-4.34(m, 2H), 4.04-3.71(m, 4H), 3.67-3.55(m, 1H), 3.41(s, 3H), 2.75-2.60(m, 1H), 2.59-2.45(m, 1H ), 2.36-2.24(m, 2H), 2.17-2.05(m, 4H), 1.59-1.37(m, 4H), 1.32-1.26(m, 3H), 1.19-1.12(m, 3H), 0.81(br d, J=6.7Hz, 3H), 0.79-0.65 (m, 4H). MS (ES-API positive): 1072.5 (M+1) + . Examples 11A and 11B: (2S,4R)-1-[(2S)-2-[4-[4-[[6-cyclopropyl-4-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl]oxymethyl]phenyl]triazol-1-yl]-3-methylbutyryl]-4-hydroxy-N-[[4-(4-methylthiazolyl-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

[0128] Example 11A is a white solid. The retention time of Example 11A is 1.44 minutes. 1H NMR (400MHz, DMSO-d6) δ9.01 (s, 1H), 9.00-8.97 (m, 1H), 8.67-8.64 (m, 1H), 7.71-7.34 (m, 11H), 5.34 (br d, J=10.1Hz, 2H), 4.59-4.53(m, 2H), 3.77-3.71(m, 4H), 3.30(s, 4H), 2.71-2.62(m, 3H), 2.46(s, 3H), 2.33(br d, J=1.7Hz, 2H), 2.00 (d, J=1.9Hz, 6H), 1.48-1.32 (m, 2H), 1.27-1.01 (m, 9H), 0.78-0.67 (m, 6H). MS (ES-API positive): 1075.5 (M+1) + .

[0129] Example 11B is a white solid. The retention time of Example 11B is 1.51 minutes. 1 H NMR (400MHz, DMSO-d6) δ9.02-9.00 (m, 1H), 8.99 (s, 1H), 8.65 (s, 1H), 7.65 (d, J=8.1Hz, 2H), 7.48-7.36 (m, 9H), 5.76 (s, 1H), 5.34 (br d, J=10.1Hz, 2H), 4.69-4.49 (m, 4H), 4.45-4.26 (m, 9H), 3.76-3.69 (m, 6H), 3.62-3.53 (m, 2H), 3.43 (ddd, J=2.4, 4.5, 11.3Hz, 2H), 3.30 (s, 4H), 2.69-2.65 (m, 2H), 2.36-2.30 (m, 3H), 2.30-2.24 (m, 2H), 2.02-1.97 (m, 4H), 1.16 (d, J=6.2Hz, 3H), 1.07 (br d, J=6.7Hz, 3H). MS (ES-API positive): 1075.5 (M+1) + . Examples 12A and 12B (2S,4R)-1-[(2S)-2-[4-[4-[[6-cyclopropyl-4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl]oxymethyl]phenyl]triazol-1-yl]-3-methylbutyryl]-4-hydroxy-N-[(1R)-2-hydroxy-1-[4-(4-methylthiazolyl-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide]

[0130] The obtained Example 12A was a light yellow solid with a retention time of 4.41 minutes. 1 H NMR (400MHz, CD3OD) δ10.06-10.02 (m, 1H), 8.52 (s, 1H), 7.91 (s, 1H), 7.60-7.54 (m, 6H), 7.51 (s, 1H), 7.34 (d, J=9.5Hz, 1H), 6.81 (br d, J=8.1Hz, 2H), 5.42 (d, J=10.1Hz, 1H), 5.08 (br t, J=6.0Hz, 2H), 4.81 (br d, J=11.9Hz, 1H), 4.72-4.63 (m, 4H), 4.54-4.49 (m, 1H), 4.40-4.30 (m, 3H), 4.24-4.10 (m, 1H), 3.9 7-3.89(m, 2H), 3.88-3.81(m, 3H), 3.43-3.1(m, 3H), 2.70-2.64(m, 1H), 2.63-2.62(m, 3H), 2.28(br dd, J=7.9, 13.2Hz, 1H), 2.16(br d, J=2.1Hz, 6H), 2.07-1.96(m, 3H), 1.52(quin, J=6.8Hz, 1H), 1.32-1.29(m, 3H), 1.18(br d, J=6.6Hz, 3H), 0.86 (d, J=6.7Hz, 3H), 0.82-0.69 (m, 4H). MS (ES-API positive): 1119.5 (M+1) + .

[0131] The obtained Example 12B was a light yellow solid with a retention time of 6.25 minutes. 1H NMR (400MHz, CD3OD) δ10.01 (s, 1H), 8.50-8.47 (m, 1H), 7.79-7.72 (m, 1H), 7.60-7.55 (m, 6H), 7.50 (s, 1H), 7.33-7.28 (m, 1H), 6.78 (br d, J=8.1Hz, 2H), 5.40 (d, J=10.3Hz, 1H), 5.10-5.01 (m, 2H), 4.83-4.79 (m, 1H), 4.69-4.61 (m, 4H), 4.54-4.48 (m, 1H), 4.35 (br s, 3H), 4.27-4.20 (m, 1H), 3.97-3.88 (m, 2H), 3.88-3.81 (m, 3H), 3.43-3.41 (m, 3H), 2.70-2.63 (m, 1H), 2.63-2.61 (m, 3H), 2.27 (br dd, J=8.4, 13.2Hz, 1H), 2.16 (br d, J=2.0Hz, 6H), 2.06-1.96 (m, 3H), 1.54 (br t, J=6.6Hz, 1H), 1.31 (d, J=6.3Hz, 3H), 1.18 (d, J=6.6Hz, 3H), 0.85 (d, J=6.7Hz, 3H), 0.81-0.71 (m, 4H). MS (ES-API positive): 1119.5 (M+1) + . Examples 13A and 13B: (2S,4R)-1-((2S)-2-(4-(4-(((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0132] Example 13A is a white solid. The retention time of Example 13A is 3.77 minutes. 1H NMR (400MHz, CD3OD) δ = 8.51 (s, 1H), 8.31-8.24 (s, 1H), 7.86 (s, 1H), 7.64-7.49 (m, 7H), 7.33 (d, J = 9.5Hz, 1H), 6 .86-6.76 (m, 3H), 5.42 (d, J = 10.1Hz, 1H), 5.15-5.03 (m, 2H), 4.80 (d, J = 11.6Hz, 1H), 4.72-4.32 (m, 10H), 4.25-4 .09 (m, 1H), 3.99-3.76 (m, 5H), 3.41 (s, 3H), 2.67 (s, 2H), 2.28 (m, J=7.9, 12.8Hz, 1H), 2.16 (d, J=2.1Hz, 5H), 2. 02 (m, J=4.3, 8.9Hz, 3H), 1.54-1.44 (m, 4H), 1.30 (d, J=6.4Hz, 3H), 1.19 (d, J=6.6Hz, 3H), 0.85 (d, J=6.7Hz, 7H). MS (ES-API positive): 1116.5 (M+1) + .

[0133] Example 13B is a white solid. The retention time of Example 13B is 5.17 minutes. 1 H NMR (400MHz, CD3OD) δ8.54 (s, 1H), 8.39-8.29 (s, 1H), 7.99 (s, 1H), 7.65-7.47 (m, 7H), 7.34 (d, J=9.4H z, 1H), 6.89-6.77 (m, 3H), 5.44 (d, J = 10.3Hz, 1H), 5.09 (t, J = 6.0Hz, 2H), 4.87 (d, J = 12.3Hz, 1H), 4.74- 4.18(m, 11H), 4.02-3.75(m, 5H), 3.42(s, 3H), 2.68(s, 2H), 2.36-2.25(m, 1H), 2.17(d, J=2.1Hz, 5H), 2.11-1.96 (m, 3H), 1.54-1.45 (m, 4H), 1.31 (d, J=6.3Hz, 3H), 1.19 (d, J=6.6Hz, 3H), 0.90-0.68 (m, 7H). MS (ES-API positive): 1116.6 (M+1) + . Examples 14A and 14B: (2S,4R)-1-[(2S)-2-[4-[3-[[6-cyclopropyl-4-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl]oxymethyl]-1-bicyclo[1.1.1]pentyl]triazol-1-yl]-3-methylbutyryl]-N-[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]-4-hydroxy-pyrrolidine-2-carboxamide]

[0134] Example 14A is a yellow solid. The retention time of Example 14A is 2.21 minutes. 1 ¹H NMR (400MHz, CD3OD) shift δ = 8.16–8.11 (m, 1H), 7.96–7.91 (m, 1H), 7.60–7.54 (m, 6H), 7.47–7.39 (m, 1H), 6.78–6.66 (m, 1H), 5.77–5.72 (m, 1H), 5.34–5.29 (m, 1H), 5.10–5.02 (m, 2H), 4.78–4.74 (m, 2H), 4.69–4.66 (m, 2H), 4.60–4.54 (m, 2H), 4.43–4.33 (m, 3H), 3.90–3.82 (m, 5H). H), 3.67-3.62(m, 2H), 3.43-3.41(m, 3H), 2.67-2.62(m, 1H), 2.56-2.48(m, 2H), 2.33-2.25(m, 2H), 2.16-2.12(m, 3H), 2.05-1.91(m, 1H) ), 1.61-1.51(m, 5H), 1.52-1.50(m, 1H), 1.47-1.40(m, 4H), 1.32-1.27(m, 3H), 1.25-1.24(m, 1H), 1.12-1.06(m, 3H), 0.76-0.63(m, 7H). MS (ES-API positive): 1092.5 (M+1) + .

[0135] Example 14B is a yellow solid with a retention time of 2.22 minutes. 1H NMR (400MHz, CD3OD) displacement δ = 8.34-8.23 (m, 2H), 7.97-7.84 (m, 1H), 7.64-7.56 (m, 5H), 7.54-7.42 (m, 1H), 6.85-6.76 (m, 1H), 5.73 (br s, 1H), 5.54-5.34 (m, 1H), 5.10-5.01 (m, 2H), 4.77 (br s, 2H), 4.68 (br s, 2H), 4.63-4.56 (m, 1H), 4.53-4.31 (m, 4H), 3.85 (br d, J=5.4Hz, 5H), 3.68-3.55(m, 2H), 3.46-3.37(m, 3H), 2.70-2.63(m, 1H), 2.62-2.48(m, 2H), 2.36-2.21(m, 2H), 2.16(br s, 3H), 2.02-1.89 (m, 1H), 1.77-1.60 (m, 6H), 1.52-1.40 (m, 4H), 1.35-1.27 (m, 3H), 1.16-1.05 (m, 3H), 0.85-0.67 (m, 7H). MS (ES-API positive): 1092.5 (M+1) + . Examples 15A and 15B: (2S,4R)-1-((2S)-2-(4-(3-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)bicyclo[1.1.1]pentane-1-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0136] Example 15A is a white solid with a retention time of 1.38 minutes. 1H NMR (500MHz, CD3OD) δ10.01 (br s, 1H), 7.98 (br s, 1H), 7.66-7.54 (m, 6H), 7.45 (d, J=9.46Hz, 1H), 5.78 (br s, 1H), 5.34 (br d, J=10.38Hz, 1H), 5.17-4.97(m, 2H), 4.82-4.76(m, 2H), 4.74-4.69(m, 2H), 4.59(br t, J=8.39Hz, 2H), 4.50(br s, 1H), 3.85-3.92(m, 4H), 3.84-3.75(m, 2H), 3.70-3.62(m, 2H), 3.48-3.42(m , 3H), 2.68(s, 1H), 2.64(s, 3H), 2.58-2.49(m, 2H), 2.34-2.26(m, 1H), 2.25(br d, J=7.48Hz, 1H), 2.18(s, 3H), 2.09-1.95(m, 1H), 1.66(br d, J=9.16Hz, 3H), 1.60-1.53 ​​(m, 4H), 1.34 (d, J=6.41Hz, 3H), 1.14 (d, J=6.56Hz, 3H), 0.90-0.82 (m, 1H), 0.82-0.68 (m, 6H). MS (ES-API positive): 1095.5 (M+1) + .

[0137] Example 15B is a white solid with a retention time of 1.44 minutes. 1H NMR (500MHz, CD3OD) δ10.04 (s, 1H), 8.16 (br s, 1H), 7.82 (br s, 1H), 7.62-7.55 (m, 5H), 7.47 (br d, J=8.54Hz, 1H), 5.73 (br s, 1H), 5.41 (br s, 1H), 5.24-5.22 (m, 2H), 5.09-4.97 (m, 2H), 4.82-4.74 (m, 2H), 4.72-4.65 (m, 2H), 4.58 (t, J=8.39Hz, 1H), 4.48 (brs, 1H), 3.98-3.78 (m , 6H), 3.75-3.69(m, 1H), 3.77-3.65(m, 1H), 3.65-3.55(m, 2H), 3.46-3.38(m, 3H), 3.32-3.31(m, 6H), 2.67(s, 1H), 2.62(s, 3H), 2.55(br d, J=12.36Hz, 1H), 2.58-2.43 (m, 1H), 2.38-2.23 (m, 2H), 2.15 (d, J=1.83Hz, 3H), 1.94 (s, 1H), 2.05-1.91 (m, 1H), 1.83-1.81 (m, 1H), 1.70 (br d, J=9.61Hz, 2H), 1.66-1.60(m, 3H), 1.51(br d, J=5.49Hz, 1H), 1.32 (d, J=6.41Hz, 3H), 1.16-1.09 (m, 3H), 1.06-0.98 (m, 1H), 0.82-0.69 (m, 6H). MS (ES-API positive): 1095.5 (M+1) + . Examples 16A and 16B (2S,4R)-1-[(2S)-2-[4-[4-[[6-cyclopropyl-4-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-(tetrahydropyran-4-yl)oxy-quinazolin-8-yl]oxymethyl]phenyl]triazol-1-yl]-3-methylbutyryl]-N-[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]-4-hydroxy-pyrrolidine-2-carboxamide]

[0138] Example 16A is a light yellow solid with a retention time of 1.66 minutes. 1H NMR (400MHz, CD3OD) 8.69-8.58 (m, 1H), 8.36-8.28 (m, 1H), 7.89 (s, 1H), 7.66-7.58 (m, 7H), 7.35 (d, J=9.5Hz, 1H), 6.90-6.77 (m, 3H), 5.69 (br s, 1H), 5.52 (td, J=4.2, 8.0Hz, 1H), 5.43 (d, J=10.3Hz, 1H), 5.10 (t, J=6.0Hz, 1H), 4.82-4.63 (m, 5H), 4.53-4.41 (m, 3H), 4.02-3.82 (m, 6H), 3.75-3.60 (m, 4H), 2.75-2.62 (m, 1H), 2.54 (br d, J=11.0Hz, 1H), 2.40-2.24(m, 2H), 2.23-1.77(m, 9H), 1.56(br d, J=4.8Hz, 1H), 1.51-1.45 (m, 3H), 1.22-1.16 (m, 3H), 0.85 (d, J=6.7Hz, 4H), 0.82-0.67 (m, 3H). MS (ES-API positive): 1114.6 (M+1) + .

[0139] Example 16B is a light yellow solid. The retention time of Example 29 is 2.32 minutes. 1 H NMR (400MHz, CD3OD) δ = 8.73 (s, 1H), 8.44-8.31 (m, 1H), 8.21 (br s, 1H), 7.73-7.56 (m, 7H), 7.43 (br d, J = 9.3Hz, 1H), 6.95-6.82 (m, 3H), 5.66 (br s, 1H), 5.60-5.42 (m, 2H), 5.13 (br t, J=6.1Hz, 1H), 4.82-4.68 (m, 5H), 4.57-4.44 (m, 3H), 4.05-3.86 (m, 6H), 3.79-3.60 (m, 4H), 2.70 (td, J=6.6, 10.2Hz, 1H), 2.58 (br d, J=10.5Hz, 1H), 2.46-2.28(m, 2H), 2.24-2.11(m, 5H), 2.08-1.73(m, 4H), 1.57-1.45(m, 4H), 1.25-1.17(m, 3H), 0.88(br d, J=6.6Hz, 4H), 0.76 (br d, J=7.4Hz, 3H). MS (ES-API positive): 1114.6 (M+1) + . Example 30: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide Step 1: tert-butyl(1S,4S)-5-(8-(benzyloxy)-7-bromo-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0140] Under a nitrogen atmosphere, CuI (55.1 mg, 289.5 μmol, 0.3 equivalent) and methyl-2,2-difluoro-2-(fluorosulfonyl)acetate (370 mg, 1.9 mmol, 2.0 equivalent) were added to a solution of tert-butyl(1S,4S)-5-[8-benzyloxy-7-bromo-6-iodo-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (700 mg, 965.0 μmol, 1.0 equivalent) in DMF (15 mL). The mixture was stirred at 80 °C for 4 hours. The reaction was monitored by LCMS. After the reaction was complete, it was quenched with brine at room temperature and then extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was analyzed by rapid silica gel chromatography (…). 12g Purification was performed using a silica gel fast column with an eluent gradient of 0–40% ethyl acetate / petroleum ether at a flow rate of 40 mL / min to obtain tert-butyl(1S,4S)-5-(8-(benzyloxy)-7-bromo-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (550 mg, 634.4 μmol, yield 65.8%) as a white solid. MS (ES-API positive): 667.2 (M+1) + . Step 2: tert-butyl(1S,4S)-5-(8-(benzyloxy)-7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0141] tert-butyl(1S,4S)-5-(8-(benzyloxy)-7-bromo-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (550 mg, 824.0 μmol, 1.0 equivalent), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2-triphenyl-indazole (491 mg, 947.6 μmol, 1.1 equivalents), Pd2(dba)3 (75 mg, 82.4 μmol, 0.1 equivalents), SPhos (67.6 mg, 164.8 μmol, 0.2 equivalents), and K3PO4 (612.14 mg, 2.88 mmol, 3.5 equivalents) were degassed in a mixture of dioxane (2 mL) and water (0.2 mL) and purged three times with N2. The mixture was then stirred at 120 °C for 8 hours under N2 atmosphere. The reaction mixture was quenched with brine at room temperature and then extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was analyzed by rapid silica gel chromatography (…). 20g The compound was purified by a silica gel fast column with a gradient of 0–40% ethyl acetate / petroleum ether as eluent at a flow rate of 40 mL / min, and further purified by preparative HPLC (neutral conditions: column: Phenomenex Gemini NX 150 × 30 mm, 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 80%–100%, 11 min) to give tert-butyl(1S,4S)-5-(8-(benzyloxy)-7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, as a white solid. MS (ES-API positive): 979.4 (M+1) + . Step 3: tert-butyl(1S,4S)-5-(7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-hydroxy-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0142] Pd / C (20 mg, 10% purity) was added to a solution of tert-butyl(1S,4S)-5-(8-(benzyloxy)-7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (80 mg, 81.7 μmol, 1.0 equivalent) in methanol (3 mL) and THF (1 mL). The suspension was degassed and purged three times with H2. The mixture was stirred at 30 °C for 18 hours under an H2 (30 Psi) atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl(1S,4S)-5-(7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-hydroxy-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (crude product), a white solid. MS (ES-API positive): 647.3 (M+1) + . Step 4: tert-butyl(1S,4S)-5-(7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-8-hydroxy-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0143] TEA (42 μL, 309.1 μmol, 5.0 equivalents) and triphenylchloromethane (42 mg, 215 μmol, 1.76 equivalents) were added to a solution of tert-butyl(1S,4S)-5-(7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-hydroxy-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (80 mg, 122.8 μmol, 2.0 equivalents) in DCM (3 mL) and THF (1 mL). The mixture was heated and stirred at 40 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1:1) to give tert-butyl(1S,4S)-5-(7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-8-hydroxy-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, a white solid. MS (ES-API positive): 889.3 (M+1) + . Step 5: tert-butyl(1S,4S)-5-(8-((4-ethynylbenzyl)oxy)-7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0144] Cs₂CO₃ (49 mg, 151.8 μmol, 3.0 equivalent) and 1-(bromomethyl)-4-ethynylbenzene (20 mg, 101.2 μmol, 2.0 equivalent) were added to a solution of tert-butyl(1S,4S)-5-(7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-8-hydroxy-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (45 mg, 50.6 μmol, 1.0 equivalent) in DMF (1 mL). The mixture was stirred at 40 °C for 1 hour. The reaction mixture was quenched with brine at room temperature and then extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1:1) to give tert-butyl(1S,4S)-5-(8-((4-ethynylbenzyl)oxy)-7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (40 mg, 37.1 μmol, yield 73.3%), as a white solid. MS (ES-API positive): 1003.3 (M+1) + . Step 6: tert-butyl(1S,4S)-5-(8-((4-(1-((S)-1-((2S,4R)-2-(((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobutane-2-yl)-1H-1,2,3-triazol-4-yl)benzyl)oxy)-7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0145] tert-butyl(1S,4S)-5-(8-((4-ethynylbenzyl)oxy)-7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (40 mg, 39.88 μmol, 1 equivalent), (2S,4R)-1-[(2S)-2-azido- A mixture of 3-methylbutyryl]-N-[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]-4-hydroxypyrrolidine-2-carboxamide (21 mg, 43.8 μmol, 1.1 equivalents), CuSO4 (1.0 M, 12.0 μL, 0.3 equivalents), and sodium ascorbate (7 mg, 31.9 μmol, 0.8 equivalents) in DMSO (1 mL) was stirred at 50 °C for 3 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. After the reaction was completed, it was quenched with brine at room temperature and then extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the compound tert-butyl(1S,4S)-5-(8-((4-(1-((S)-1-((2S,4R)-2-(((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobutane- 2-yl)-1H-1,2,3-triazol-4-yl)benzyl)oxy)-7-(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, is a white solid (55 mg, crude) and can be used in the next step without further purification. MS (ES-API positive): 1472.7 (M+1) + . Step 7: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0146] tert-butyl(1S,4S)-5-(8-((4-(1-((S)-1-((2S,4R)-2-(((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)carbamoyl)-4-hydroxypyrrolidine-1-yl)-3-methyl-1-oxobutane-2-yl)-1H-1,2,3-triazol-4-yl)benzyl)oxy)-7 -(6-fluoro-5-methyl-2-triphenyl-2H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (55 mg, 37.35 μmol, 1 equivalent) was added to a solution of HCl / dioxane (4 M, 2 mL) in dichloromethane (3 mL). The mixture was stirred at room temperature for 0.5 h. The reaction was monitored by LCMS, and the solvent was removed under vacuum after the reaction was complete. The residue was purified by preparative HPLC (HCl conditions, column: Boston Green ODS 150×30mm×5μm; mobile phase: [water (HCl)-ACN]; B%: 20%-40%, 11 min) to give compound 30 (18.65 mg, 16.0 μmol, yield 42.9%) as a white solid with a retention time of 2.522 min. 1H NMR (400MHz, CD3OD) δ8.56-8.52(m, 1H), 8.46(br s, 1H), 8.25-8.22(m, 1H), 7.86(br s, 1H), 7.64-7.56 (m, 6H), 7.31-7.24 (m, 1H), 6.81-6.78 (m, 1H), 6.71 (br d, J=8.0Hz, 2H), 5.83 (br s, 1H), 5.43 (d, J = 10.3Hz, 1H), 5.14-5.09 (m, 1H), 5.06 (br d, J = 11.7Hz, 1H), 4.84 (br s, 1H), 4.77 (br d, J=11.4Hz, 2H), 4.69-4.61 (m, 3H), 4.53 (br s, 1H), 4.43 (q, J=7.1Hz, 2H), 3.95 (br d, J=6.1Hz, 2H), 3.93-3.84 (m, 4H), 3.70 (br d, J=9.9Hz, 1H), 3.46 (s, 3H), 2.73-2.65 (m, 1H), 2.61 (br d, J=11.3Hz, 1H), 2.37 (br d, J=11.3Hz, 1H), 2.30 (br dd, J=8.3, 13.2Hz, 1H), 2.17-1.98 (m, 5H), 1.49 (t, J=7.2Hz, 3H), 1.33 (d, J=6.2Hz, 3H), 1.20 (br d, J=6.6Hz, 3H), 0.88 (br d, J=6.6Hz, 3H). MS (ES-API positive): 1130.4 (M+1) + . Example 31: (2S,4R)-1-((2S)-2-(4-(5-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)bicyclo[4.2.0]oct-1,3,5-trien-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide Step 1: 5-Bromobicyclo[4.2.0]oct-1,3,5-triene-2-carboxaldehyde

[0147] At -78 °C, n-butyllithium (2.5 M, 840 μL, 1.1 equivalent) was added to a solution of 2,5-dibromobicyclo[4.2.0]octyl-1,3,5-triene (500 mg, 1.91 mmol, 1.0 equivalent) in THF (5 mL). The mixture was stirred at the same temperature for 0.5 h, and then DMF (419 mg, 5.73 mmol, 441 μL, 3 equivalent) was added at -78 °C. After the addition was complete, the mixture was gradually heated to room temperature and stirred at room temperature for 1 h. The reaction was monitored by TLC (petroleum ether / ethyl acetate = 20 / 1). After the reaction was complete, the reaction mixture was quenched with water at 0 °C, diluted with water, and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was analyzed by rapid silica gel chromatography (…). 4g Purification was performed using a silica gel fast column with a 0–3% petroleum ether / ethyl acetate gradient as eluent at a flow rate of 100 mL / min to obtain compound 5-bromobicyclo[4.2.0]oct-1,3,5-triene-2-carboxaldehyde, which was a white solid. 1 H NMR (400MHz, CDCl3) δ10.02 (s, 1H), 7.54-7.45 (m, 2H), 3.45-3.39 (m, 2H), 3.29-3.24 (m, 2H). Step 2: 5-(2-triisopropylsilylethynyl)bicyclo[4.2.0]oct-1,3,5-triene-2-carboxaldehyde

[0148] A mixture of 5-bromobicyclo[4.2.0]oct-1,3,5-trien-2-carboxaldehyde (388 mg, 1.84 mmol, 1.0 equivalent), ethynyltriisopropylsilane (406 mg, 2.23 mmol, 0.5 mL, 1.2 equivalent), CuI (35 mg, 183.78 μmol, 0.1 equivalent), Pd(PPh3)2Cl2 (130 mg, 185.21 μmol, 0.1 equivalent), PPh3 (10 mg, 38.13 μmol, 0.02 equivalent), and TEA (8.72 g, 86.21 mmol, 12 mL, 46.9 equivalent) in THF (3 mL) was degassed and purged three times with N2. The mixture was then stirred at 65 °C for 2 hours under N2 atmosphere. The reaction mixture was partitioned with water and EtOAc. The organic phase was separated, washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was then subjected to rapid silica gel chromatography (HPLC). 12g Purification was performed using a silica gel rapid column with petroleum ether / EtOAc as the eluent, wherein the EtOAc gradient was 0–5%, the flow rate was 100 mL / min, and the wavelength was 254 nm. The compound 5-(2-triisopropylsilylethynyl)bicyclo[4.2.0]oct-1,3,5-triene-2-carboxaldehyde was obtained as a yellow oil. 1 H NMR (400MHz, CDCl3) δ10.02 (s, 1H), 7.59 (d, J=8.2Hz, 1H), 7.41 (d, J=8.1Hz, 1H), 3.45-3.38 (m, 2H), 3.36-3.29 (m, 2H), 1.14 (s, 21H). MS (ES-API positive): 313.3 (M+1) + . Step 3: [5-(2-triisopropylsilylethynyl)-2-bicyclo[4.2.0]oct-1,3,5-trienyl]methanol

[0149] At 0 °C, NaBH4 (80 mg, 2.11 mmol, 1.1 equivalent) was added to a solution of 5-(2-triisopropylsilylethynyl)bicyclo[4.2.0]oct-1,3,5-trien-2-carboxaldehyde (621 mg, 1.99 mmol, 1.0 equivalent) in methanol (8 mL). The mixture was then stirred at room temperature for 0.5 h. The reaction mixture was quenched with water at room temperature and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was analyzed by rapid silica gel chromatography (…). 12g Purification was performed using a silica gel rapid column with petroleum ether / EtOAc as the eluent (EtOAc gradient ranging from 0% to 26%) at a flow rate of 50 mL / min and a wavelength of 254 nm. The resulting compound, [5-(2-triisopropylsilylethynyl)-2-bicyclo[4.2.0]oct-1,3,5-trienyl]methanol, was a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.31-7.27 (m, 1H), 7.11 (d, J = 8.1Hz, 1H), 4.66 (s, 2H), 3.26-3.20 (m, 2H), 3.20-3.14 (m, 2H), 1.13 (s, 21H). Step 4: 2-[5-(bromomethyl)-2-bicyclo[4.2.0]oct-1,3,5-trienyl]ethynyl-triisopropylsilane

[0150] CBr4 (185 mg, 557.86 μmol, 1.1 equivalent) and PPh3 (160 mg, 610.02 μmol, 1.2 equivalent) were added to a solution of [5-(2-triisopropylsilylethynyl)-2-bicyclo[4.2.0]oct-1,3,5-trienyl]methanol (158 mg, 502.33 μmol, 1.0 equivalent) in DCM (5 mL). The mixture was then stirred at room temperature for 12 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was analyzed by rapid silica gel chromatography (…). 4g Purification was performed using a silica gel fast column with 100% petroleum ether as eluent at a flow rate of 20 mL / min and a wavelength of 254 nm to obtain compound 2-[5-(bromomethyl)-2-bicyclo[4.2.0]oct-1,3,5-trienyl]ethynyl-triisopropylsilane, which was a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.31-7.28 (m, 1H), 7.13 (d, J = 8.1Hz, 1H), 4.42 (s, 2H), 3.26-3.23 (m, 2H), 3.22-3.19 (m, 2H), 1.16 (s, 21H). Step 5: tert-butyl(1S,4S)-5-[6-cyclopropyl-7-(6-fluoro-5-methyl-2-triphenyl-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-8-[[5-(2-triisopropylsilylethynyl)-2-bicyclo[4.2.0]oct-1,3,5-trienyl]methoxy]quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0151] To a solution of tert-butyl(1S,4S)-5-[6-cyclopropyl-7-(6-fluoro-5-methyl-2-triphenyl-indazol-4-yl)-8-hydroxy-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (100 mg, 116.14 μmol, 1.0 equivalent) in DMF (5 mL), 2-[5-(bromomethyl)-2-bicyclo[4.2.0]oct-1,3,5-trienyl]ethynyl-triisopropylsilane (90 mg, 238.45 μmol, 2.05 equivalent) and Cs₂CO₃ (120 mg, 368.30 μmol, 3.17 equivalent) were added. The mixture was stirred at 40 °C for 1 hour. The reaction mixture was partitioned with water and EtOAc. The organic phase was separated, washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was then subjected to rapid silica gel chromatography (HPLC). 4g Purification was performed using a silica gel rapid column with petroleum ether / EtOAc as the eluent (EtOAc gradient 0–30%) at a flow rate of 20 mL / min and a wavelength of 254 nm. The compound tert-butyl(1S,4S)-5-[6-cyclopropyl-7-(6-fluoro-5-methyl-2-triphenyl-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-8-[[5-(2-triisopropylsilylethynyl)-2-bicyclo[4.2.0]oct-1,3,5-trienyl]methoxy]quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (150 mg, crude product) was obtained as a yellow solid. MS (ES-API positive): 1158.1 (M+1) + .

[0152] The subsequent synthesis steps are similar to those in Example 30. 1 H NMR (400MHz, CD3OD) δ8.48-8.39(m, 1H), 8.39-8.31(m, 1H), 8.18(br s, 1H), 7.77-7.48(m, 5H), 7.32(br d, J=9.3Hz, 2H), 6.88 (d, J=2.9Hz, 1H), 6.72-6.60 (m, 1H), 5.86-5.65 (m, 1H), 5.50 (d, J=10.0Hz, 1H), 5.30-5.07 (m, 2H), 4.87-4.77 (m, 2H), 4.77-4 .57(m, 5H), 4.56-4.40(m, 3H), 4.13-3.76(m, 6H), 3.69-3.53(m, 1H), 3.44 (s, 3H), 3.24-3.09 (m, 2H), 2.80-2.66 (m, 3H), 2.62-2.52 (m, 1H), 2.33 (br d, J=11.9Hz, 2H), 2.24-1.94 (m, 4H), 1.58-1.46 (m, 3H), 1.44-1.26 (m, 4H), 1.25-1.16 (m, 3H), 0.88 (br d, J=6.6Hz, 3H), 0.93-0.64 (m, 4H). MS (ES-API positive): 1128.5 (M+1) + . Example 32: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)-2-chlorophenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide Step 1: [3-chloro-4-(2-triisopropylsilylethynyl)phenyl]methanol

[0153] CuI (86 mg, 451.51 μmol, 0.02 equivalents), Pd(PPh3)2Cl2 (634 mg, 903.02 μmol, 0.04 equivalents), and ethynyltriisopropylsilane (5.2 g, 28.22 mmol, 6.33 mL, 1.25 equivalents) were added to a solution of (4-bromo-3-chloro-phenyl)methanol (5 g, 22.58 mmol, 1 equivalent) in 50 mL of triethylamine. The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was quenched with water and then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was analyzed by rapid silica gel chromatography (…). 80g Purification was performed using a silica gel rapid column with an eluent gradient of 0–25% ethyl acetate / petroleum ether at a flow rate of 100 mL / min.

[0154] The compound [3-chloro-4-(2-triisopropylsilylethynyl)phenyl]methanol was obtained as a colorless oil. MS (ES-API positive): 323.2 (M+1) + . Step 2: (3-chloro-4-ethynyl-phenyl)methanol

[0155] CsF (8.47 g, 55.74 mmol, 2.06 mL, 5 equivalents) was added to a solution of [3-chloro-4-(2-triisopropylsilylethynyl)phenyl]methanol (3.6 g, 11.15 mmol, 1 equivalent) in DMF (35 mL). The mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC. After the reaction was complete, the reaction mixture was quenched with water and then extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was analyzed by rapid silica gel chromatography (…). 80g Purification was performed using a silica gel fast column with an eluent gradient of 0–30% ethyl acetate / petroleum ether at a flow rate of 100 mL / min to give (1 g, 6.00 mmol, yield 53.8%) of the compound (3-chloro-4-ethynyl-phenyl)methanol, as a colorless oil. MS (ES-API positive): 167.0 (M+1) + . Step 3: 4-(bromomethyl)-2-chloro-1-ethynylbenzene

[0156] CBr4 (757 mg, 2.28 mmol, 1.9 equivalents), PPh3 (630 mg, 2.40 mmol, 2 equivalents), and 2,6-rutidine (644 mg, 6.00 mmol, 699.08 μL, 5 equivalents) were added to a solution of (3-chloro-4-ethynyl-phenyl)methanol (200 mg, 1.20 mmol, 1 equivalent) in DCM (3 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water and then extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was analyzed by rapid silica gel chromatography (…). 4g Purification was performed using a silica gel fast column with an eluent gradient of 0–30% ethyl acetate / petroleum ether at a flow rate of 60 mL / min to obtain the compound 4-(bromomethyl)-2-chloro-1-ethynylbenzene, which is a brown solid. MS (ES-API positive): 228.9 (M+1) + .

[0157] The subsequent synthesis steps are similar to those in Example 30. Example 32: 1H NMR (400MHz, CD3OD) 8.70-8.55 (m, 1H), 8.37-8.25 (m, 1H), 8.01-7.90 (m, 1H), 7.71-7.66 (m, 1H), 7.65-7.57 (m, 5H), 7.32-7.25 (m, 1H), 6. 86-6.82 (m, 1H), 6.81-6.76 (m, 1H), 6.73-6.69 (m, 1H), 5.81-5.73 (m, 1H), 5.51-5.43 (m, 1H), 5.15-5.05 (m, 1H), 4.84-4.59 (m, 8H), 4.55- 4.48 (m, 1H), 4.48-4.40 (m, 2H), 4.03-3.75 (m, 6H), 3.69-3.58 (m, 1H), 3.48-3.41 (m, 3H), 2.71-2.61 (m, 1H), 2.59-2.50 (m, 1H), 2.38-2.2 5(m, 2H), 2.18(s, 3H), 2.06-1.98(m, 1H), 1.55-1.42(m, 4H), 1.37-1.29(m, 3H), 1.24-1.15(m, 3H), 0.93-0.84(m, 3H), 0.82-0.66(m, 4H); MS (ES-API positive): 1136.5 (M+1) + . Example 33: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(3,6-difluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0158] This compound was prepared using a method similar to that used in Example 32. 1H NMR (500MHz, CD3OD) δ=8.46 (s, 1H), 7.90 (d, J=2.4Hz, 1H), 7.61-7.49 (m, 7H), 7.17-7.13 (m, 1H), 6.82 (d, J=8.2Hz, 2H), 6.56 (d, J=2.4Hz, 1H), 5.76 (br s, 1H), 5.39 (d, J = 10.2Hz, 1H), 5.08 (t, J = 6.0Hz, 1H), 4.92-4.87 (m, 3H), 4.76 (br s, 1H), 4.72-4.65 (m, 2H), 4.65-4.57 (m, 2H), 4.51 (br s, 1H), 4.33-4.24 (m, 2H), 3.95-3.91 (m, 1H), 3.88-3.82 (m, 3H), 3.72-3.54 (m, 2H), 3.43-3.42 (m, 3H), 2.71-2.61 (m, 1H), 2.52 (br d, J=11.7Hz, 1H), 2.33-2.22(m, 2H), 2.11(d, J=2.3Hz, 3H), 2.06-1.98(m, 1H), 1.62-1.52(m, 1H), 1.44-1.39 (m, 3H), 1.34-1.27 (m, 4H), 1.18 (d, J=6.7Hz, 3H), 0.88-0.82 (m, 3H), 0.81-0.71 (m, 4H). MS (ES-API positive): 1120.4 (M+1) + . Example 34: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-4-(1-ethyl-1H-pyrazol-5-yl)-1-hydroxybut-3-yn-2-yl)-4-hydroxypyrrolidine-2-carboxamide Step 1: tert-butyl(4R)-4-ethynyl-2,2-dimethyl-oxazolidine-3-carboxylate

[0159] K₂CO₃ (2.41 g, 17.45 mmol, 2 equivalences) was added to a solution of tert-butyl(4S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylate (2.00 g, 8.72 mmol, 1 equivalence) and 1-diazo-1-dimethoxyphosphorylprop-2-one (2.51 g, 13.08 mmol, 1.5 eq) in methanol (40 mL). The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, filtered through diatomaceous earth, and concentrated. The residue was analyzed by rapid silica gel chromatography (…). 20g Purification was performed using a silica gel fast column with an eluent gradient of 0–13% ethyl acetate / petroleum ether at a flow rate of 40 mL / min to obtain tert-butyl(4R)-4-ethynyl-2,2-dimethyl-oxazolidine-3-carboxylate, which is a brown oily substance. 1 H NMR (400MHz, CDCl3) δ4.72-4.40 (m, 1H), 4.08-3.98 (m, 2H), 2.27 (s, 1H), 1.64 (s, 3H), 1.50 (s, 12H). Step 2: tert-butyl(4R)-4-[2-(2-ethylpyrazol-3-yl)ethynyl]-2,2-dimethyl-oxazolidine-3-carboxylate

[0160] Pd(dppf)Cl2 (470 mg, 642.33 μmol, 0.1 equivalent) was added to a solution of tert-butyl(4R)-4-ethynyl-2,2-dimethyl-oxazolidine-3-carboxylate (1.45 g, 6.42 mmol, 1 equivalent), 1-ethyl-5-iodopyrazole (1.42 g, 6.42 mmol, 1 equivalent), CuI (123 mg, 645.84 μmol, 0.1 equivalent), and TEA (1.95 g, 19.25 mmol, 2.68 mL, 3 equivalent) in DMSO (20 mL). The mixture was stirred at 70 °C for 20 hours under a nitrogen atmosphere. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (60 mL × 2), dried over Na2SO4, and analyzed by rapid silica gel chromatography (…). 40g Purification was performed using a silica gel fast column with an eluent gradient of 0–10% ethyl acetate / petroleum ether at a flow rate of 18 mL / min to obtain tert-butyl(4R)-4-[2-(2-ethylpyrazol-3-yl)ethynyl]-2,2-dimethyl-oxazolidine-3-carboxylate, which was a light yellow oil. 1H NMR (400MHz, CDCl3) δ7.43 (s, 1H), 6.37 (s, 1H), 4.97-4.69 (d, 1H), 4.19-4.04 (m, 3H), 1.58 (s, 3H), 1.55-1.49 (m, 12H), 1.44 (t, J=7.2Hz, 3H). LCMS(ES-API positive): 320.1(M+1) + . Step 3: (2R)-2-amino-4-(2-ethylpyrazol-3-yl)but-3-yn-1-ol

[0161] HCl / dioxane (4M, 15 mL, 14.63 equivalents) was added to a solution of tert-butyl(4R)-4-[2-(2-ethylpyrazol-3-yl)ethynyl]-2,2-dimethyl-oxazolidine-3-carboxylate (1.31 g, 4.10 mmol, 1 equivalent) in DCM (15 mL). The mixture was stirred at room temperature for 6 hours. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was concentrated to give (2R)-2-amino-4-(2-ethylpyrazol-3-yl)but-3-yn-1-ol as a white solid. LCMS (ES-API positive): 216.0 (M+1) + . Step 4: tert-butyl(2S,4R)-2-[[(1R)-3-(2-ethylpyrazol-3-yl)-1-(hydroxymethyl)prop-2-ynyl]carbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate

[0162] A solution mixture of (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid (896 mg, 3.87 mmol, 1 equivalent), DIEA (1.50 g, 11.57 mmol, 2.02 mL, 3 equivalent), HOBt (626 mg, 4.63 mmol, 1.2 equivalent), and EDCI (888 mg, 4.63 mmol, 1.2 equivalent) in DCM (20 mL) was stirred at 0 °C for 10 min. Then, (2R)-2-amino-4-(2-ethylpyrazol-3-yl)but-3-yn-1-ol (1.28 g, 3.86 mmol, 1 equivalent, HCl salt) was added, and the mixture was stirred at room temperature for 4 h. The mixture was concentrated and analyzed by rapid silica gel chromatography (…). 20g Purification was performed using a silica gel rapid column with a 0–5% methanol / dichloromethane gradient as eluent at a flow rate of 30 mL / min to obtain tert-butyl(2S,4R)-2-[[(1R)-3-(2-ethylpyrazol-3-yl)-1-(hydroxymethyl)prop-2-ynyl]carbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate, which was a colorless oil. 1 H NMR (400MHz, CDCl3) δ9.05 (d, J=7.7Hz, 1H), 7.54-7.50 (d, 1H), 6.48 (d, J= 2.0Hz, 1H), 5.50 (s, 2H), 4.61 (s, 1H), 4.53-4.44 (m, 1H), 4.34-4.26 (m, 2H ), 3.79 (m, J=6.0, 12.8Hz, 2H), 3.42 (m, J=3.3, 12.0Hz, 1H), 2.50 (m, J=7.6 , 13.5Hz, 1H), 2.35-2.20 (m, 1H), 2.13-2.02 (m, 1H), 1.41 (t, J=7.2Hz, 3H). LCMS (ES-API positive): 337.2 (M+1) + . Step 5: (2S,4R)-N-[(1R)-3-(2-ethylpyrazol-3-yl)-1-(hydroxymethyl)prop-2-ynyl]-4-hydroxy-pyrrolidine-2-carboxamide

[0163] To a solution of tert-butyl(2S,4R)-2-[[(1R)-3-(2-ethylpyrazol-3-yl)-1-(hydroxymethyl)prop-2-ynyl]carbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate (1.13 g, 1.93 mmol, 1 equivalent) in DCM (10 mL), HCl / dioxane (4 M, 10 mL, 20.73 equivalents) was added. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated to give (2S,4R)-N-[(1R)-3-(2-ethylpyrazol-3-yl)-1-(hydroxymethyl)prop-2-ynyl]-4-hydroxy-pyrrolidine-2-carboxamide. LCMS (ES-API positive): 293.1 (M+1) + . Step 6: (2S,4R)-1-[(2S)-2-azido-3-methyl-butyryl]-N-[(1R)-3-(2-ethylpyrazol-3-yl)-1-(hydroxymethyl)prop-2-ynyl]-4-hydroxy-pyrrolidine-2-carboxamide

[0164] A solution mixture of (2S)-2-amino-3-methyl-butyric acid (281 mg, 2.39 mmol, 1 equivalent), DIEA (941 mg, 7.28 mmol, 1.27 mL, 3.04 equivalent), HOBt (386 mg, 2.85 mmol, 1.19 equivalent), and EDCI (547 mg, 2.85 mmol, 1.19 equivalent) in DCM (20 mL) was stirred at 0 °C for 10 min. Then, (2S,4R)-N-[(1R)-3-(2-ethylpyrazol-3-yl)-1-(hydroxymethyl)prop-2-ynyl]-4-hydroxy-pyrrolidine-2-carboxamide (700 mg, 2.39 mmol, 1 equivalent) was added. The mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure, then subjected to rapid silica gel chromatography (…). 20g Purification was performed using a silica gel rapid column with petroleum ether:EE (ethyl acetate / ethanol = 3 / 1) = 1:1 as the eluent, where the EE gradient was 0–40% and the flow rate was 40 mL / min. The result was (2S,4R)-1-[(2S)-2-azido-3-methyl-butyryl]-N-[(1R)-3-(2-ethylpyrazol-3-yl)-1-(hydroxymethyl)prop-2-ynyl]-4-hydroxy-pyrrolidine-2-carboxamide, which was a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.43 (d, J=1.8Hz, 1H), 6.95 (d, J=8.7Hz, 1H), 6.40 (d, J=1.8Hz, 1H), 5 .14-5.06 (m, 1H), 4.66 (s, 1H), 4.57 (t, J=7.9Hz, 1H), 4.25 (q, J=7.2Hz, 2H), 3.93 (m, J=3.5, 7.5Hz, 1H), 3.73 (m, J=3.8Hz, 2H), 3.65 (md, J=11.0Hz, 2H), 3.36 (d, J=8.9Hz, 1H), 2.40 (m, 1H), 2.26-2.18 (m, 2H), 1.45 (t, J=7.2Hz, 3H), 1.07 (d, J=6.6Hz, 3H), 0.97 (d, J=6.6Hz, 3H). LCMS(ES-API positive): 418.2(M+1) + .

[0165] The subsequent synthesis steps are similar to those in Example 30. 1H NMR (400MHz, CD3OD) δ8.39 (s, 1H), 7.55-7.47 (d, 3H), 7.45 (d, J = 1.9Hz, 1H), 7.40 (s, 1H), 7.27 (d, J = 9.7Hz, 1H), 6.78 (d, J = 8.0Hz, 2H), 6.44 (d, J = 1.9Hz, 1H), 5.35 (d, J=10.3Hz, 1H), 5.27 (d, J=11.4Hz, 1H), 5.21 (s, 1H), 5.00 (t, J=5.7Hz, 1H), 4.80 (d, J=11.6Hz, 1H), 4.70-4.43 (m, 3H), 4.39 (d, J=5.2Hz, 2H), 4.29(m, J=7.4, 14.3Hz, 3H), 4.05-3.73(m, 8H), 3.42(s, 3H ), 3.13 (d, J=9.8Hz, 1H), 2.70-2.56 (m, 1H), 2.24 (m, J=8.0, 12.2Hz, 1H), 2.08 (s, 5H), 1.91 (d, J=10.4Hz, 1H), 1.41 (t, J=7.2Hz, 4H), 1.24 (d, J=6. 3Hz, 3H), 1.16 (d, J=6.6Hz, 3H), 0.85-0.78 (d, 3H), 0.62 (m, J=5.0Hz, 4H). LCMS (ES-API positive): 1050.8 (M+1) + . Example 35: (2S,4R)-1-((2S)-2-(4-(4-(((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0166] This compound was prepared using a method similar to that used in Example 32. 1H NMR (500MHz, CD3OD) δ8.52 (br d, J=3.1Hz, 1H), 8.25 (s, 1H), 7.86 (br s, 1H), 7.64-7.52 (m, 6H), 7.51-7.47 (m, 1H), 7.34-7.28 (m, 1H), 6.81 (dd, J=2.0, 5.8Hz, 3H), 5.59-5.51 ( m, 1H), 5.43-5.38 (m, 1H), 5.23-4.93 (m, 3H), 4.77 (s, 3H), 4.52-4.48 (m, 1H), 4.44-4.39 (m, 2H), 4.34 (br s, 4H), 4.02-3.88 (m, 4H), 3.86 (d, J=6.1Hz, 2H), 3.72-3.66 (m, 2H), 2.68-2.58 (m, 1H), 2.31-2.22 (m, 1H), 2.15 (br d, J=2.0Hz, 7H), 2.03-1.85 (m, 5H), 1.55-1.48 (m, 1H), 1.48-1.42 (m, 3H), 1.20 -1.14 (m, 3H), 0.86-0.81 (m, 3H), 0.81-0.65 (m, 4H); MS (ES-API positive): 1128.4 (M+1) + . Example 36: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((5-(1-ethyl-1H-pyrazol-5-yl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)methyl)-4-hydroxypyrrolidine-2-carboxamide

[0167] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.47 (s, 1H), 8.22-8.17 (m, 1H), 7.90-7.77 (m, 1H), 7.62-7.54 (m, 7H), 7.33 (d, J=9.5Hz, 1H), 6.82 (br d, J=8.1Hz, 2H), 6.79-6.74(m, 1H), 5.50-5.02(m, 4H), 4.78-4.73(m, 1H), 4.70-4.62(m, 4H), 4.52(s , 1H), 4.41 (q, J=7.1Hz, 3H), 4.15 (d, J=16.7Hz, 5H), 3.96-3.75 (m, 7H), 3.43-3.38 (m, 3H), 2.69-2.65 (m, 1H), 2.28 (s, 1H), 2.19 (s, 3H), 2.06-1.96 (m, 1H), 1.54 (d, J=7.2Hz, 1H), 1.49-1.44 (m, 3H), 1.31- 1.28 (m, 3H), 1.19 (d, J=6.6Hz, 3H), 0.88-0.77 (m, 6H), 0.75-0.69 (m, 1H); MS (ES-API positive): 1098.4 (M+1) + . Example 37: (2S,4R)-1-((2S)-2-(4-(4-(((4-(3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0168] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.74-8.08(m, 1H), 7.95-7.78(m, 1H), 7.77-7.39(m, 4H), 7.37-7.19(m, 3H), 6.75(br d, J=7.9Hz, 2H), 6.62-6.43(m, 1H), 5.75(br s, 1H), 5.38(d, J=10.4Hz, 1H), 4.84-4.75(m, 5H), 4.68(br dd, J=3.2, 11.2Hz, 2H), 4.64-4.58(m, 2H), 4.57-4.52(m, 2H), 4.46-4.37(m, 2H), 4.37-4.21(m, 2H), 4 .02-3.94(m, 1H), 3.93-3.82(m, 2H), 3.81-3.72(m, 1H), 3.69-3.54(m, 1H), 3.46-3.37(m, 3H), 3.25(br d, J=4.6Hz, 2H), 2.75-2.58(m, 1H), 2.58-2.48(m, 1H), 2.36-2.19(m, 2H), 2.18-1.97( m, 4H), 1.54 (td, J=6.4, 13.1Hz, 1H), 1.48-1.34 (m, 3H), 1.30 (d, J=6.4Hz, 3H), 1.17 (br d, J=6.6Hz, 3H), 0.91-0.59 (m, 7H); MS (ES-API positive): 1132.5 (M+1) + . Example 38: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((1-(methylsulfonyl)piperidin-4-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0169] This compound was prepared using a method similar to that used in Example 32. 1H NMR (500MHz, CD3OD) δ=8.50 (s, 1H), 7.95 (d, J=2.3Hz, 1H), 7.74-7.51 (m, 8H), 7.32 (d, J=9.5Hz, 1H), 6.82 (br d, J=6.9Hz, 2H), 6.60 (d, J=2.3Hz, 1H), 5.74 (br s, 1H), 5.56 (br s, 1H), 5.41 (d, J=10.2Hz, 1H), 5.10 (t, J=6.0Hz, 1H), 4.80 (br s, 3H), 4.73-4.57 (m, 3H), 4.53 (br s, 1H), 4.37-4.29 (m, 2H), 3.97-3.93 (m, 1H), 3.89 (d, J=6.1Hz, 2H), 3.84-3.62 (m, 2H), 3.56-3.35 (m, 4H), 3.01-2. 86(m, 3H), 2.75-2.51(m, 2H), 2.37-2.13(m, 7H), 2.10-2.01(m, 4H), 1.63-1.54(m, 1H), 1.47-1.41(m, 3H), 1.19(br d, J=6.6Hz, 3H), 0.89-0.72 (m, 7H), MS (ES-API positive): 1191.5 (M+1) + . Example 39: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-4-((S)-3-hydroxy-3-methylpiperidin-1-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide)

[0170] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.46 (s, 1H), 7.89 (d, J=2.1Hz, 1H), 7.66 (s, 1H), 7.58-7.49 (m, 6H), 7.31-7.25 (m, 1H), 6.75 (d, J=8.1Hz, 2H), 6.56 (d, J=2. 1Hz, 1H), 5.39 (d, J = 10.3Hz, 1H), 5.24-5.00 (m, 2H), 4.77 (d, J = 11.4Hz, 1H), 4.65-4.49 (m, 6H), 4.29 (q, J=7.4Hz, 2H), 4.01-3.89 (m, 2H), 3.88-3 .78(m, 3H), 3.65-3.57(m, 1H), 3.42(s, 3H), 2.69-2.61(m, 1H), 2.31-2. 16(m, 2H), 2.14(s, 3H), 2.05-1.99(m, 1H), 1.96-1.82(m, 3H), 1.50(dd, J =5.2, 11.7Hz, 1H), 1.44-1.36(m, 6H), 1.35-1.32(m, 1H), 1.29(d, J=6.3 Hz, 4H), 1.18 (d, J=6.7Hz, 3H), 0.84 (d, J=6.3Hz, 3H), 0.83-0.70 (m, 4H). MS (ES-API positive): 1120.7 (M+1) + . Example 40: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-4-(2,4-difluorophenyl)-1-hydroxybut-3-yn-2-yl)-4-hydroxypyrrolidine-2-carboxamide

[0171] This compound was prepared using a method similar to that used in Example 34. 1H NMR (400MHz, CD3OD) 8.54-8.40 (m, 1H), 7.83-7.70 (m, 1H), 7.64-7.44 (m, 4H), 7.40-7.24 (m, 1H), 7.09-6.90 (m, 2H), 6.86-6.62 (m , 2H), 5.81-5.71(m, 1H), 5.44-5.35(m, 1H), 5.11-5.07(m, 1H), 5.01-4.97(m, 2H), 4.81-4.76(m, 2H), 4.71-4.66(m, 1H), 4.63-4. 54 (m, 3H), 4.53-4.48 (m, 1H), 4.02-3.94 (m, 1H), 3.94-3.82 (m, 3H), 3.81-3.76 (m, 2H), 3.68-3.56 (m, 1H), 3.45-3.38 (m, 3H), 2.7 1-2.61 (m, 1H), 2.59-2.50 (m, 1H), 2.33-2.07 (m, 6H), 1.58-1.48 (m, 1H), 1.32-1.28 (m, 3H), 1.21-1.12 (m, 3H), 0.89-0.70 (m, 7H). MS (ES-API positive): 1068.4 (M+1) + . Example 41: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-1-hydroxy-4-(4-methylthiazolyl-5-yl)but-3-yn-2-yl)pyrrolidine-2-carboxamide

[0172] This compound was prepared using a method similar to that used in Example 34. 1H NMR (400MHz, CD3OD) δ8.82 (s, 1H), 8.38 (s, 1H), 7.54-7.49 (m, 3H), 7.40 (s, 1H), 7.27 (d, J=9.6Hz, 1H), 6.78 (d, J=8.1Hz, 2H), 5.34 (d, J=10.4Hz, 1H), 5 .27(d, J=11.4Hz, 1H), 5.22(s, 1H), 5.01(t, J=5.7Hz, 1H), 4.81(d, J=11.4H z, 1H), 4.54 (s, 1H), 4.49 (t, J=8.3Hz, 1H), 4.41-4.39 (m, 2H), 4.31 (d, J=9.5 Hz, 1H), 3.99-3.78 (m, 8H), 3.43-3.41 (m, 3H), 3.13 (d, J=10.5Hz, 1H), 2.66 -2.60(m, 1H), 2.49(s, 3H), 2.24(m, J=7.8, 13.1Hz, 1H), 2.10(s, 1H), 2.08(d , J=2.0Hz, 4H), 1.90 (d, J=10.4Hz, 1H), 1.48-1.41 (m, 1H), 1.26-1.23 (m, 3H ), 1.18-1.14 (m, 3H), 0.83 (d, J=6.7Hz, 3H), 0.67 (s, 1H), 0.64-0.58 (m, 3H). MS (ES-API positive): 1053.5 (M+1) + . Example 42: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-4-(2,6-difluorophenyl)-1-hydroxybut-3-yn-2-yl)-4-hydroxypyrrolidine-2-carboxamide

[0173] This compound was prepared using a method similar to that used in Example 34. 1H NMR (400MHz, CD3OD) δ 8.43-8.37 (m, 1H), 7.55-7.47 (m, 3H), 7.45-7.34 (m, 2H), 7.27 (d, J=9.8Hz, 1H), 7.06-6.92 (m, 2H), 6.83-6.74 (m, 2H), 5.34 ( d, J=10.2Hz, 1H), 5.27 (d, J=11.4Hz, 1H), 5.22 (s, 1H), 5.05 (t, J=5.9Hz, 1H), 4.81 (d, J=11.4Hz, 1H), 4.54 (s, 1H), 4.50 (t, J=8.4Hz, 1H), 4.43-4. 38(m, 2H), 4.32(d, J=9.2Hz, 1H), 4.13-3.66(m, 8H), 3.44-3.41(m, 3H), 3 .14 ​​(d, J=10.1Hz, 1H), 2.63 (d, J=6.6, 10.3Hz, 1H), 2.25 (m, J=7.6, 13.2H z, 1H), 2.17-2.06 (m, 5H), 1.91 (d, J=10.1Hz, 1H), 1.48-1.42 (m, 1H), 1.2 6-1.22(m, 3H), 1.18-1.12(m, 3H), 0.84-0.79(m, 3H), 0.69-0.58(m, 4H). MS (ES-API positive): 1068.5 (M+1) + . Example 43: (2S,4R)-1-((2S)-2-(4-(4-(((2-((2-oxaspiro[3.5]nonane-7-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0174] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.45-8.39 (m, 1H), 7.56 (d, J=8.2Hz, 2H), 7.53-7.47 (m, 4H), 7.45-7.41 (m, 3H), 7.31-7.25 (m, 1H), 6.88-6.81 (m, 2H) , 6.33-6.26 (m, 1H), 5.39-5.32 (m, 1H), 5.25-5.21 (m, 1H), 5.17 (s, 1H), 4.50 (s, 1H), 4.45 (s, 2H), 4.33-4.27 (m, 3H), 4.17 (q, J=7.1Hz, 2H) , 3.85 (d, J=6.1Hz, 2H), 3.28 (s, 1H), 3.12 (d, J=9.7Hz, 1H), 2.67-2.60 (m, 1H), 2.26-2.19 (m, 1H), 2.09 (d, J=2.0Hz, 5H), 2.04-1.96 (m, 3H) , 1.92-1.88 (m, 1H), 1.63-1.53 ​​(m, 4H), 1.46-1.41 (m, 1H), 1.37-1.29 (m, 4H), 1.16 (d, J=6.6Hz, 3H), 0.85-0.80 (m, 3H), 0.69-0.58 (m, 4H). MS (ES-API positive): 1154.5 (M+1) + . Example 44: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)-2-methylphenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0175] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD)8.38-8.20 (m, 1H), 8.13-7.88 (m, 1H), 7.81-7.43 (m, 6H), 7.3 9-7.24(m, 2H), 6.72-6.40(m, 3H), 5.82-5.62(m, 1H), 5.49-5.37(m, 1H), 5.08(br t, J=6.0Hz, 1H), 4.86-4.77(m, 3H), 4.75-4.57(m, 5H), 4.55-4.46(m, 1H), 4.39-4.28(m, 2H), 4.10-3.92(m, 2H), 3.92-3.83(m, 3H), 3.80(br d, J=12.8Hz, 1H), 3.68-3.56(m, 1H), 3.44(s, 3H), 2.67(s, 1H), 2.55(br d, J=11.1Hz, 1H), 2.38-2.19 (m, 5H), 2.13 (s, 3H), 2.07-1.96 (m, 1H), 1.59-1.38 (m, 4H), 1.31 (br d, J=6.3Hz, 3H), 1.19 (br d, J=6.4Hz, 3H), 0.92-0.59 (m, 7H). MS (ES-API positive): 1116.5 (M+1) + . Example 45: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)-2-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0176] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.61-8.32 (m, 1H), 7.91-7.83 (m, 1H), 7.80 (d, J=7.9Hz, 1H), 7.73-7.57 (m, 2H ), 7.57-7.37(m, 4H), 7.29-7.17(m, 1H), 6.58-6.50(m, 1H), 6.48(s, 1H), 6.44-6.29(m, 1H), 5.76(br s, 1H), 5.51-5.17 (m, 1H), 5.15-5.02 (m, 1H), 4.84-4.73 (m, 4H), 4.72-4.56 (m, 5H), 4.51 (br s, 1H), 4.35-4.24 (m, 2H), 3.99-3.92 (m, 1H), 3.91-3.84 (m, 3H), 3.81 (s, 3H), 3.76-3 .68 (m, 1H), 3.68-3.57 (m, 1H), 3.45-3.41 (m, 3H), 2.63 (td, J=7.4, 10.5Hz, 1H), 2.57 -2.46(m, 1H), 2.36-2.22(m, 2H), 2.18-2.09(m, 3H), 2.07-1.95(m, 1H), 1.60-1.48(m , 1H), 1.47-1.34 (m, 3H), 1.30 (d, J=6.3Hz, 3H), 1.22-1.05 (m, 3H), 0.97-0.55 (m, 7H). MS (ES-API positive): 1132.4 (M+1) + . Example 46: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-4-(2-ethylpyridin-3-yl)-1-hydroxybut-3-yn-2-yl)-4-hydroxypyrrolidine-2-carboxamide

[0177] This compound was prepared using a method similar to that used in Example 34. 1H NMR (400MHz, CD3OD) δ8.73-8.67(m, 1H), 8.63-8.58(m, 1H), 8.44(s, 1H), 7. 93 (dd, J=5.8, 8.0Hz, 1H), 7.59-7.47 (m, 4H), 7.29-7.25 (m, 1H), 6.75 (d, J=8 .1Hz, 2H), 5.75 (s, 1H), 5.39 (d, J=10.3Hz, 1H), 5.06-5.02 (m, 1H), 4.77 (s, 2H), 4.71-4.65(m, 2H), 4.61(d, J=6.6Hz, 2H), 4.58-4.54(m, 2H), 4.51(d, J= 7.7Hz, 1H), 3.99 (dd, J=3.0, 10.3Hz, 1H), 3.91 (d, J=11.0Hz, 1H), 3.87-3.8 3(m, 3H), 3.44-3.42(m, 4H), 3.29-3.23(m, 2H), 2.66(s, 1H), 2.53(d, J=12.2 Hz, 1H), 2.32-2.26 (m, 2H), 2.13 (d, J=1.9Hz, 4H), 1.57-1.53 ​​(m, 1H), 1.44 (t , J=7.6Hz, 3H), 1.30 (d, J=6.4Hz, 3H), 1.20-1.16 (m, 3H), 0.86-0.74 (m, 8H). MS (ES-API positive): 1061.5 (M+1) + . Example 47: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-2-(2,2-difluoro-3-methoxypropoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0178] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ 8.48-8.44 (m, 1H), 8.04 (d, J = 2.6Hz, 1H), 7.70 (s, 1H), 7.62-7.52 (m, 7H), 7.28 (d, J = 9.6Hz, 1H), 6.75 (d, J = 8.2Hz, 2H) , 6.68-6.62(m, 1H), 5.78(s, 1H), 5.39(d, J=10.2Hz, 1H), 5.10-4.91(m , 4H), 4.78(s, 2H), 4.68-4.57(m, 3H), 4.53-4.48(m, 1H), 4.38-4.31(m , 2H), 4.08-3.90 (m, 2H), 3.88-3.72 (m, 5H), 3.63 (d, J=15.3Hz, 1H), 3.48 (s, 3H), 2.70-2.60 (m, 1H), 2.54 (d, J=11.4Hz, 1H), 2.34-2.21 (m, 2 H), 2.15-2.11(m, 3H), 2.05-1.97(m, 1H), 1.59-1.51(m, 1H), 1.46-1.4 0 (m, 3H), 1.18 (d, J=6.6Hz, 3H), 0.86-0.82 (m, 3H), 0.81-0.72 (m, 4H). MS (ES-API positive): 1138.5 (M+1) + . Example 48: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-(3,3,3-trifluoro-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0179] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.51-8.42(m, 1H), 8.04-7.94(m, 1H), 7.67(br s, 1H), 7.61-7.51 (m, 7H), 7.32-7.24 (m, 1H), 6.75 (d, J=8.3Hz, 2H), 6.66-6.59 (m, 1H ), 5.74 (brd, J=4.6Hz, 1H), 5.39 (d, J=10.4Hz, 1H), 5.12-5.06 (m, 1H), 4.83-4.74 (m, 4 H), 4.67-4.56(m, 3H), 4.53-4.48(m, 1H), 4.38-4.29(m, 3H), 3.94-3.91(m, 1H), 3.86( d, J=6.1Hz, 2H), 3.83-3.74 (m, 1H), 3.66 (d, J=7.6Hz, 4H), 2.74-2.59 (m, 1H), 2.54 (br d, J=11.4Hz, 1H), 2.36-2.20 (m, 2H), 2.13 (d, J=1.9Hz, 3H), 2.05-1.98 (m, 1H), 1.64-1.27 (m, 5H), 1.18 (d, J=6.7Hz, 3H), 0.91-0.64 (m, 8H). MS (ES-API positive): 1156.3 (M+1) + . Example 49: (2S,4R)-1-((2S)-2-(4-(4-(((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0180] This compound was prepared using a method similar to that used in Example 34. 1H NMR (400MHz, CD3OD) δ8.93-8.83 (m, 1H), 8.43 (d, J=1.9Hz, 1H), 7.59-7.53 (m, 2H), 7.51-7.43 (m, 5H), 7.36 (s, 1H), 7.31-7.25 (m, 1H), 6.82 (d, J=8.1H z, 2H), 5.39-5.28 (m, 2H), 5.24 (d, J=11.6Hz, 1H), 5.10-5.03 (m, 1H), 4.61 (d, J=8.2Hz, 2H), 4.54-4.46(m, 1H), 4.40-4.33(m, 1H), 4.31-4.24(m, 1H), 4.05-3.89(m, 4H), 3.88-3.80(m, 2H), 3.65(s, 2H), 3.53(s, 4H), 2.67(s, 1 H), 2.51-2.45(m, 3H), 2.29-2.20(m, 1H), 2.17-2.10(m, 2H), 2.07-2.04(m, 3H), 2.02-1.96 (m, 1H), 1.96-1.78 (m, 6H), 1.50-1.41 (m, 1H), 1.17 (d, J=6 .6Hz, 3H), 0.83 (d, J=6.6Hz, 3H), 0.75-0.67 (m, 1H), 0.62 (d, J=5.2Hz, 3H). MS (ES-API positive): 1131.4 (M+1) + . Example 51: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((hexahydrofurano[2,3-b]furan-3-yl)methoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0181] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ 8.53-8.46 (m, 1H), 8.20-8.13 (m, 1H), 7.76 (br s, 1H), 7.65-7.52 (m, 7H), 7.34-7.25 (m, 1H), 6.83-6.71 (m, 3H), 5.75 (br d, J=4.6Hz, 2H), 5.40 (d, J=10.1Hz, 1H), 5.09 (t, J=6.0Hz, 1H), 4.84-4.76 (m, 3H), 4.71-4.47 (m, 6H), 4. 39(q, J=7.3Hz, 2H), 4.11-4.03(m, 1H), 4.02-3.73(m, 8H), 3.70-3.56(m, 1H), 3.70-3.56(m, 1H), 2.84(br s, 1H), 2.70-2.62 (m, 2H), 2.54 (br d, J=11.7Hz, 1H), 2.39-2.18 (m, 3H), 2.14 (d, J=2.3Hz, 3H), 2.09-1.90 (m, 2H), 1.60-1.50(m, 1H), 1.49-1.41(m, 3H), 1.18(d, J=6.6Hz, 3H), 0.85(br d, J=6.7Hz, 3H), 0.81-0.68 (m, 4H). MS (ES-API positive): 1156.4 (M+1) + . Example 52: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-(2,2-difluorocyclopropyl)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide Step 1: tert-butyl(1S,4S)-5-[7-bromo-2-[(2S)-2-methoxypropoxy]-8-[[4-(2-triisopropylsilylethynyl)phenyl]methoxy]-6-vinyl-quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0182] To a solution of tert-butyl(1S,4S)-5-[7-bromo-6-iodo-2-[(2S)-2-methoxypropoxy]-8-[[4-(2-triisopropylsilylethynyl)phenyl]methoxy]quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.0 g, 3.3 mmol, 1.0 equivalent) in toluene (30 mL), K₂CO₃ (1.4 g, 9.9 mmol, 3.0 equivalent), potassium vinyltrifluoroborate (576.7 mg, 4.3 mmol, 1.3 equivalent), and Pd(dppf)Cl₂·CH₂Cl₂ (270.5 mg, 331.2 μmol, 0.1 equivalent) were added. Water (3.0 mL) was then added. The mixture was stirred at 70 °C for 16 hours. The reactants were cooled to room temperature, quenched with water, and then extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was analyzed by rapid silica gel chromatography (…). 40g Purification was performed using a silica gel fast column with an eluent of 0–15% ethyl acetate / petroleum ether gradient at a flow rate of 30 mL / min to obtain tert-butyl(1S,4S)-5-[7-bromo-2-[(2S)-2-methoxypropoxy]-8-[[4-(2-triisopropylsilylethynyl)phenyl]methoxy]-6-vinyl-quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, a white solid.

[0183] MS (ES-API positive): 805.3 (M+1) + . Step 2: tert-butyl(1S,4S)-5-[7-bromo-6-(2,2-difluorocyclopropyl)-2-[(2S)-2-methoxypropoxy]-8-[[4-(2-triisopropylsilylethynyl)phenyl]methoxy]quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0184] To a solution of tert-butyl(1S,4S)-5-[7-bromo-2-[(2S)-2-methoxypropoxy]-8-[[4-(2-triisopropylsilylethynyl)phenyl]methoxy]-6-vinyl-quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (670.0 mg, 831.3 μmol, 1.0 equivalent) in toluene (14 mL), TBAB (536.0 mg, 1.7 mmol, 2.0 equivalent) and [bromo(difluoro)methyl]-trimethylsilane (422.1 mg, 2.1 mmol, 2.5 equivalent) were added. The mixture was stirred at 110 °C for 1 hour, cooled to room temperature, and [bromo(difluoro)methyl]-trimethylsilane (422.1 mg, 2.1 mmol, 2.5 equivalent) was added. The mixture was then stirred at 110 °C for 2 hours. After the reaction was complete, the residue was quenched with water and then extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 80%-100%, 11 min) to give tert-butyl(1S,4S)-5-[7-bromo-6-(2,2-difluorocyclopropyl)-2-[(2S)-2-methoxypropoxy]-8-[[4-(2-triisopropylsilylethynyl)phenyl]methoxy]quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, as a white solid. MS (ES-API positive): 857.3 (M+1) + . Step 3: tert-butyl(1S,4S)-5-[6-(2,2-difluorocyclopropyl)-7-(6-fluoro-5-methyl-2-triphenylmethyl-indazole-4-] 2-[(2S)-2-methoxypropoxy]-8-[[4-(2-triisopropylsilylethynyl)phenyl]methoxy]quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0185] Pd2 (d ba)3 (8.6 mg, 9.3 μmol, 0.1 equivalent), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-2-triphenylmethyl-indazole (58.2 mg, 112.2 μmol, 1.2 equivalent), K3PO4 (59.5 mg, 280.4 μmol, 3.0 equivalent), and SPhOS (7.7 mg, 18.7 μmol, 0.2 equivalent). Water (0.2 mL) was then added. The mixture was stirred at 120 °C for 3 hours. The residue was quenched with water and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was analyzed by rapid silica gel chromatography (…). 12g Purification was performed using a silica gel fast column with a 0–20% ethyl acetate / petroleum ether gradient as eluent at a flow rate of 30 mL / min to obtain tert-butyl(1S,4S)-5-[6-(2,2-difluorocyclopropyl)-7-(6-fluoro-5-methyl-2-triphenylmethyl-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]-8-[[4-(2-triisopropylsilylethynyl)phenyl]methoxy]quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, a white solid. MS (ES-API positive): 1167.6 (M+1) + .

[0186] The desired product was obtained by using a method similar to step 5 of Example 30.

[0187] The desired product was obtained using a method similar to that used in Example 32.

[0188] The subsequent synthesis steps are similar to those in Example 32. 1H NMR (400MHz, CD3OD) δ8.47-8.45 (m, 1H), 7.85-7.82 (m, 1H), 7.79 (d, J=2.1 Hz, 1H), 7.57-7.52 (m, 5H), 7.48 (s, 2H), 7.32-7.30 (m, 1H), 6.78-6.74 (m, 2 H), 6.49 (d, J = 2.3Hz, 1H), 5.78-5.75 (m, 1H), 5.39 (d, J = 10.1Hz, 1H), 5.08 ( t, J=6.2Hz, 1H), 4.78 (s, 3H), 4.72-4.67 (m, 3H), 4.65-4.57 (m, 5H), 4.29-4 .24 (m, 3H), 3.95-3.90 (m, 2H), 3.86 (d, J = 6.2Hz, 3H), 3.70 (d, J = 3.7Hz, 1H) , 3.43 (s, 3H), 2.63 (d, J = 6.4Hz, 1H), 2.55 (d, J = 11.0Hz, 2H), 2.31 (d, J = 11. 3Hz, 2H), 2.13 (d, J=2.5Hz, 3H), 2.02-1.97 (m, 1H), 1.85-1.78 (m, 1H), 1.75 -1.69 (m, 1H), 1.41-1.37 (m, 4H), 1.32-1.30 (m, 3H), 1.18 (d, J=6.6Hz, 3H). MS (ES-API positive): 1138.4 (M+1) + . Example 53: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-2-((1-(difluoromethyl)cyclopropyl)methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0189] This compound was prepared using a method similar to that used in Example 32. 1H NMR (500MHz, CD3OD) δ8.46-8.26 (m, 1H), 7.57-7.46 (m, 6H), 7.46-7.40 (m, 3H), 7.33-7.20 (m, 1H), 6.80 (d, J=8.2Hz, 2H), 6.36-5.92 (m, 2H), 5.3 7(d, J=10.2Hz, 1H), 5.28-5.23(m, 2H), 5.14-5.06(m, 1H), 5.06-5.06(m , 1H), 4.84-4.79(m, 1H), 4.66-4.57(m, 2H), 4.56-4.50(m, 3H), 4.33(br d, J=9.0Hz, 1H), 4.26-4.14(m, 2H), 4.01-3.78(m, 6H), 3.16(br d, J=9.9Hz, 1H), 2.71-2.64(m, 1H), 2.26(br dd, J=7.9, 13.0Hz, 1H), 2.14-2.08 (m, 4H), 2.07-1.81 (m, 2H), 1.54-1.44 (m, 1H), 1.39-1.32 (m, 3H), 1.19 (d, J=6.6Hz, 3H), 0.94 (br d, J=1.5Hz, 2H), 0.87-0.77(m, 5H), 0.73-0.53(m, 4H). MS (ES-API positive): 1134.4 (M+1) + . Example 54: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-4-(benzo[d]thiazolyl-6-yl)-1-hydroxybut-3-yn-2-yl)-4-hydroxypyrrolidine-2-carboxamide

[0190] This compound was prepared using a method similar to that used in Example 34. 1H NMR (400MHz, CD3OD) δ9.53-9.44 (m, 1H), 8.51 (s, 1H), 8.28-8.13 (m, 1H), 8.07-7.93 (m, 1H), 7.91-7.7 5 (m, 1H), 7.70-7.58 (m, 2H), 7.55 (d, J = 8.2Hz, 2H), 7.38-7.30 (m, 1H), 6.78 (d, J = 8.2Hz, 2H), 5.74 (br s, 1H), 5.46-5.38 (m, 1H), 5.00 (t, J=5.8Hz, 1H), 4.87 (br d, J=12.3Hz, 2H), 4.81-4.76(m, 2H), 4.72-4.65(m, 2H), 4.65-4.61(m, 2H), 4.58(br d, J=3.7Hz, 1H), 4.55-4.49 (m, 1H), 4.03-3.97 (m, 1H), 3.95-3.91 (m, 1H), 3.86 (td, J=3.2, 6.3Hz, 1H), 3.81 (br d, J=5.8Hz, 2H), 3.65-3.58(m, 1H), 3.43(s, 3H), 2.70-2.61(m, 1H), 2.57-2.52(m, 1H), 2.33-2.26(m, 2H), 2.18-2.13(m, 4H), 1.55-1.47 (m, 1H), 1.31 (d, J=6.4Hz, 3H), 1.21-1.15 (m, 3H), 0.88-0.83 (m, 3H), 0.80-0.72 (m, 4H); MS (ES-API positive): 1089.2 (M+1) + . Example 55: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-3-(methylamino)-3-oxopropyl)-4-hydroxypyrrolidine-2-carboxamide Step 1: tert-butyl N-[(1S)-1-(4-bromophenyl)-3-(methylamino)-3-oxopropyl]carbamate

[0191] To a solution of (3S)-3-(4-bromophenyl)-3-(tert-butoxycarbonylamino)propionic acid (1 g, 2.91 mmol, 1 equivalent) in DCM (10 mL), HATU (1.33 g, 3.50 mmol, 1.2 equivalent) and DIEA (1.13 g, 8.73 mmol, 1.52 mL, 3 equivalent) were added. The mixture was stirred at 0 °C for 15 min. Then, methylamine hydrochloride (300 mg, 4.44 mmol, 1.53 equivalent) was added. The mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. After the reaction was complete, the resulting mixture was diluted with water (100 mL), extracted with DCM (50 mL × 2), washed with saturated NH4Cl aqueous solution (50 mL × 2) and brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM (20 mL), and then petroleum ether (70 mL) was added. The solid was collected by filtration and dried under vacuum to give tert-butyl N-[(1S)-1-(4-bromophenyl)-3-(methylamino)-3-oxopropyl]carbamate, which was a white solid (1 g, 2.74 mmol, yield 94.3%). 1 H NMR (400MHz, CD3OD) δ7.46 (d, J=8.5Hz, 2H), 7.23 (d, J=8.5Hz, 2H), 4.96 (d, J=6.4Hz, 1H), 2.64 (s, 3H), 2.56 (s, 2H), 1.46-1.37 (m, 9H). MS (ES-API positive): 356.9 (M+1) + . Step 2: tert-butyl N-[(1S)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-3-(methylamino)-3-oxopropyl]carbamate

[0192] Pd(dppf)Cl2 (103 mg, 140.77 μmol, 0.101 equivalent) was added to a solution of tert-butyl N-[(1S)-1-(4-bromophenyl)-3-(methylamino)-3-oxopropyl]carbamate (500 mg, 1.40 mmol, 1 equivalent), 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazole (465 mg, 2.09 mmol, 1.5 equivalent) and Na2CO3 (300 mg, 2.83 mmol, 2.02 equivalent) in dioxane (20 mL) and water (2 mL). The mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. After the reaction was complete, the salt was removed by filtration, the filtrate was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated NH4Cl aqueous solution (100 mL × 2) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was analyzed by rapid chromatography (PCR). 12g Purification was performed using a silica gel fast column, petroleum ether / ethyl acetate gradient (0–70%), flow rate 50 mL / min, 254 nm, to obtain tert-butyl N-[(1S)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-3-(methylamino)-3-oxopropyl]carbamate, a white solid. 1 H NMR (400MHz, CD3OD) δ7.51 (d, J=1.9Hz, 1H), 7.46-7.39 (m, 4H), 6.31 (d, J=1.8Hz, 1H), 5.07 (s, 1H), 4 .16 (q, J=7.2Hz, 2H), 2.66 (s, 3H), 2.64-2.60 (m, 2H), 1.44-1.30 (m, 12H); mS (ES-API positive): 373.2 (M+1) + . Step 3: (3S)-3-amino-3-[4-(2-ethylpyrazol-3-yl)phenyl]-N-methylpropionamide

[0193] To a solution of tert-butyl N-[(1S)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-3-(methylamino)-3-oxopropyl]carbamate (455 mg, 1.22 mmol, 1 equivalent) in DCM (5 mL) and methanol (1 mL), HCl / dioxane (4 M, 5 mL, 16.37 equivalents) was added. The mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to give compound (3S)-3-amino-3-[4-(2-ethylpyrazol-3-yl)phenyl]-N-methylpropionamide (475 mg, crude), a pale yellow foam, which was ready for use in the next step without further purification. MS (ES-API positive): 273.1 (M+1) + . Step 4: tert-butyl(2S,4R)-2-[[(1S)-1-[4-(ethylpyrazol-3-yl)phenyl]-3-(methylamino)-3-oxopropyl]carbamoyl]-4-hydroxypyrrolidine-1-carboxylate

[0194] T4P (1.52 g, 2.11 mmol, 50% wt EtOAc, 1.52 equivalence) and DIEA (949 mg, 7.34 mmol, 1.28 mL, 5.31 equivalence) were added to a solution of (2S,4R)-1-tert-butoxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid (320 mg, 1.38 mmol, 1.28 mL, 5.31 equivalence) in DCM (10 mL), and the mixture was stirred at 0 °C for 5 min. Then (3S)-3-amino-3-[4-(2-ethylpyrazol-3-yl)phenyl]-N-methylpropionamide (384 mg, 1.41 mmol, 1.02 equivalence) was added. The mixture was stirred at room temperature for 1 h. The reaction mixture was partitioned with water and DCM (10 mL × 3). The organic phases were separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was analyzed by rapid silica gel chromatography (…). 12g Purification was performed using a silica gel fast column with petroleum ether / EE (ethyl acetate: ethanol = 1:1) as the eluent, where the EE gradient was 0–100%, the flow rate was 50 mL / min, and the wavelength was 254 nm. The compound tert-butyl(2S,4R)-2-[[(1S)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-3-(methylamino)-3-oxopropyl]carbamoyl]-4-hydroxypyrrolidine-1-carboxylate was obtained as a white solid. MS (ES-API positive): 486.3 (M+1) + .

[0195] Using a method similar to that in Example 32, the final compound was obtained as a yellow solid. 1H NMR (400MHz, CD3OD) δ8.50-8.41(m, 1H), 7.97-7.81(m, 1H), 7.68-7.58(m, 2H), 7. 58-7.48(m, 6H), 7.33-7.24(m, 1H), 6.79-6.70(m, 2H), 6.61-6.49(m, 1H), 5.75(br s, 1H), 5.40-5.37 (m, 1H), 4.84-4.75 (m, 4H), 4.70-4.66 (m, 1H), 4.63-4.56 (m, 3H), 4.54 (s, 2H), 4.34-4.24 (m, 2H), 3.99-3.91(m, 1H), 3.90-3.81(m, 2H), 3.79-3.69(m, 1H), 3.68-3.57(m, 1H), 3.44-3.41(m, 3H), 2.92-2.81(m, 1H), 2. 1 .61-1.51 (m, 1H), 1.43-1.35 (m, 3H), 1.30 (d, J=6.4Hz, 4H), 1.19-1.09 (m, 3H), 0.88-0.81 (m, 3H), 0.81-0.71 (m, 4H). MS (ES-API positive): 1143.3 (M+1) + . Example 56: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-(((3R,3aS,6aR)-hexahydrofurano[2,3-b]furan-3-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0196] Example 56 was prepared using a method similar to that of Example 32. 1H NMR (400MHz, CD3OD) δ = 8.46-8.37 (m, 1H), 7.57-7.38 (m, 10H), 7.28 (d, J = 9.9Hz, 1H), 6.79 (d, J = 8.5Hz, 2H ), 6.31 (d, J = 2.0Hz, 1H), 5.68 (d, J = 5.1Hz, 1H), 5.59-5.49 (m, 1H), 5.36 (d, J = 10.0Hz, 1H), 5.23 (s, 3H), 5. 13-5.03 (m, 2H), 4.60 (s, 1H), 4.53-4.45 (m, 1H), 4.37-4.30 (m, 1H), 4.25 (s, 1H), 4.05-3.80 (m, 10H), 3.51 -3.45(m, 1H), 3.20-3.10(m, 1H), 2.66(s, 1H), 2.30-2.17(m, 2H), 2.14-2.11(m, 1H), 2.04(s, 1H), 1.92(br d, J=9.3Hz, 2H), 1.51-1.40 (m, 1H), 1.17 (d, J=6.7Hz, 4H), 0.84 (d, J=6.6Hz, 3H), 0.71-0.59 (m, 4H). MS (ES-API positive): 1142.4 (M+1) + . Example 57: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6,7-difluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0197] Example 57 was prepared using a method similar to that of Example 32. 1H NMR (400MHz, CD3OD) δ = 8.42 (s, 1H), 7.54-7.41 (m, 9H), 6.81 (d, J = 8.2Hz, 2H), 6.31 (d, J = 1.9Hz, 1H), 5.39-5.19 (m, 3H), 5.08 (br t, J=6.1Hz, 1H), 4.83 (br s, 2H), 4.50 (br s, 1H), 4.42-4.37 (m, 2H), 4.31 (br d, J=8.6Hz, 1H), 4.17 (q, J=7.3Hz, 2H), 3.95-3.81 (m, 6H), 3.42 (s, 3H), 3.30-3.28 (m, 1H), 3.14 (br d, J=9.2Hz, 1H), 2.70-2.61(m, 1H), 2.28-2.20(m, 1H), 2.13-2.08(m, 4H), 2.06-1.98(m, 1H), 1.91(br d, J=9.8Hz, 1H), 1.45-1.38 (m, 1H), 1.37-1.31 (m, 3H), 1.30-1.22 (m, 4H), 1.17 (d, J=6.6Hz, 3H), 0.87-0.80 (m, 3H), 0.69-0.56 (m, 4H). MS (ES-API positive): 1120.5 (M+1) + . Example 58: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((1,1,1-trifluoro-3-methoxypropyl-2-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0198] Example 58 was prepared using a method similar to that of Example 32. 1H NMR (400MHz, CD3OD) δ 8.51-8.44 (m, 1H), 8.12-8.05 (m, 1H), 7.73 (s, 1H), 7.61-7.53 (m, 7H), 7.30 (d, J=9.5Hz, 1H), 6.77 (d , J=8.1Hz, 2H), 6.73-6.63 (m, 1H), 6.40-6.23 (m, 1H), 5.80 (s, 1H), 5.40 (d, J=10.3Hz, 1H), 5.09 (t, J=6.0Hz, 1H), 4.83 (br d, J=11.8Hz, 1H), 4.78 (s, 2H), 4.69-4.57 (m, 3H), 4.51 (s, 1H), 4.36 (q, J=7.4Hz, 2H), 4.03-3.91 (m, 4H), 3.87 (d, J = 6.1Hz, 2H), 3.83-3.74 (m, 1H), 3.62 (d, J = 5.2Hz, 1H), 3.45-3.42 (m, 3H), 2.70 -2.62(m, 1H), 2.57-2.52(m, 1H), 2.34-2.23(m, 2H), 2.14(d, J=2.3Hz, 3H), 2.07-1.96(m, 1H), 1. 60-1.51 (m, 1H), 1.48-1.40 (m, 3H), 1.18 (d, J=6.6Hz, 3H), 0.87-0.83 (m, 3H), 0.82-0.72 (m, 4H). MS (ES-API positive): 1156.4 (M+H) + . Example 59: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-1-hydroxy-4-(4-methylthiazolyl-5-yl)but-3-yn-2-yl)pyrrolidine-2-carboxamide

[0199] Example 59 was prepared using a method similar to that of Example 34. 1H NMR (400MHz, CD3OD) δ9.08-9.01 (m, 1H), 8.48-8.43 (m, 1H), 7.70-7.65 (m, 1H), 7.61-7.54 (m, 3H), 7.29 (d, J=9.5 Hz, 1H), 6.80-6.74(m, 2H), 5.72-5.67(m, 1H), 5.58-5.50(m, 1H), 5.41-5.36(m, 1H), 5.03-4.99(m, 1H), 4.79(br s, 3H), 4.62-4.53 (m, 3H), 4.52-4.46 (m, 1H), 4.03-3.95 (m, 3H), 3.94-3.89 (m, 1H), 3.77 (br s, 2H), 3.74-3.62(m, 4H), 2.68-2.64(m, 1H), 2.55(br s, 4H), 2.31-2.22 (m, 2H), 2.17-2.10 (m, 6H), 1.96-1.85 (m, 2H), 1.61- 1.50 (m, 1H), 1.21-1.15 (m, 3H), 0.86-0.81 (m, 3H), 0.80-0.72 (m, 4H). MS (ES-API positive): 1065.4 (M+1) + . Example 60: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-4-(2,3-difluorophenyl)-1-hydroxybut-3-yn-2-yl)-4-hydroxypyrrolidine-2-carboxamide

[0200] Example 60 was prepared using a method similar to that of Example 34. 1H NMR (400MHz, CD3OD) δ8.47 (s, 1H), 7.58-7.47 (m, 3H), 7.41 (s, 1H), 7.34-7.07 (m, 4H), 6.86-6.76 (m, 2H), 5.41-5.17 (m, 3H), 5.06-5. 00 (m, 1H), 4.85-4.78 (m, 1H), 4.60-4.48 (m, 2H), 4.45-4.32 (m, 3H), 4.06-3.95 (m, 2H), 3.94-3.78 (m, 5H), 3.46-3.41 (m, 3H), 3.37 (br s, 1H), 3.18(br d, J=9.9Hz, 1H), 2.71-2.59 (m, 1H), 2.32-2.23 (m, 1H), 2.06-2.02 (m, 1H), 2.18-2.00 (m, 5H), 1 .98-1.91 (m, 1H), 1.52-1.42 (m, 1H), 1.31-1.14 (m, 6H), 0.88-0.80 (m, 3H), 0.73-0.59 (m, 4H). MS (ES-API positive): 1068.4 (M+1) + . Example 61: (2S,4R)-1-((2S)-2-(4-(4-(((4-(3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0201] Example 61 was prepared using a method similar to that of Example 32. 1H NMR (400MHz, CD3OD): δ8.53-8.49(m, 1H), 8.31-8.21(m, 1H), 7.77(ms, 1H), 7.60-7.52(m, 6H), 7.35-7.26(m, 2H), 6.77(m, 3H), 5.42 (d, J=10.3Hz, 1H), 5.22 (m, 2H), 5.09 (m, 1H), 4.86 (m, 1H), 4.70-4.59 (m, 4H), 4.51 (m, 1H), 4.44-4.38 (m, 4H), 4.3 3-4.25(m, 2H), 3.95-3.82(m, 9H), 3.43(s, 3H), 2.68-2.65(m, 1H), 2.33-2.24(m, 1H), 2.15(s, 3H), 2.04-1.97(m, 1H), 1.53 (d, J=7.0Hz, 1H), 1.47 (t, J=7.2Hz, 3H), 1.31 (J=6.4Hz, 3H), 1.19 (J=6.7Hz, 3H), 0.86 (d, J=6.6Hz, 3H), 0.79-0.68 (m, 4H). MS (ES-API positive): 1132.4 (M+1) + . Example 62: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-2-((1-(2,2-difluoroethyl)cyclopropyl)methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0202] Example 62 was prepared using a method similar to that of Example 32. 1H NMR (400MHz, CD3OD) δ 8.43-8.29 (m, 1H), 7.53-7.42 (m, 6H), 7.42-7.36 (m, 3H), 7.29-7.18 (m, 1H), 6.76 (d, J=8.2Hz, 2H), 6.31-6.25 (m , 1H), 6.18-5.96 (m, 1H), 5.33 (d, J=10.4Hz, 1H), 5.25-5.12 (m, 2H), 5.09-5.01 (m, 1H), 4.78-4.72 (m, 1H), 4.61-4.54 (m, 1H), 4.47 (br s, 1H), 4.26 (q, J=11.3Hz, 3H), 4.14 (q, J=7.2Hz, 2H), 3.96-3.76 (m, 6H), 3.12 (br d, J=9.9Hz, 1H), 2.67-2.56(m, 1H), 2.24-2.17(m, 1H), 2.11-1.86(m, 9H), 1.48-1.36(m, 1H), 1.34-1.23 (m, 4H), 1.14 (d, J=6.6Hz, 3H), 0.80 (d, J=6.6Hz, 3H), 0.70-0.53 (m, 8H). MS (ES-API positive): 1148.5 (M+1) + . Example 63: (2S,4R)-1-((2S)-2-(4-(4-(((2-((2-oxaspiro[3.5]nonane-7-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0203] Example 63 was prepared using a method similar to that of Example 32. 1H NMR (400MHz, CD3OD) δ8.88 (s, 1H), 8.41 (s, 1H), 7.62-7.49 (m, 3H), 7.49-7.39 (m, 5H), 7.29-7.24 (m, 1H), 6.85 (d, J=8.3Hz, 2H), 5.39 -5.31(m, 1H), 5.27(s, 1H), 5.19-5.16(m, 1H), 5.10-5.00(m, 2H), 4.79-4.74(m, 1H), 4.63-4.56(m, 1H), 4.52-4.47(m, 1H), 4.44(s, 2 H), 4.35-4.24(m, 3H), 3.99-3.76(m, 6H), 3.28(s, 1H), 3.15-3.08(m, 1H), 2.65(s, 1H), 2.50-2.45(m, 3H), 2.26-2.19(m, 1H), 2.15-1 .95 (m, 9H), 1.92-1.87 (m, 1H), 1.70-1.49 (m, 4H), 1.48-1.40 (m, 1H), 1.16 (d, J = 6.6Hz, 3H), 0.83 (d, J = 6.6Hz, 3H), 0.72-0.53 (m, 4H). MS (ES-API positive): 1157.4 (M+1) + . Example 64: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-4-(2-chlorophenyl)-1-hydroxybut-3-yn-2-yl)-4-hydroxypyrrolidine-2-carboxamide 1H NMR (500MHz, CD3OD) δ8.50-8.40(m, 1H), 7.69-7.64(m, 1H), 7.63-7.57(m, 1H), 7.57-7.49( m, 3H), 7.46-7.39 (m, 1H), 7.37-7.31 (m, 1H), 7.31-7.20 (m, 2H), 6.79-6.72 (m, 2H), 5.75 (br s, 1H), 5.39 (d, J=10.1Hz, 1H), 5.06-4.98 (m, 1H), 4.85-4.81 (m, 2H), 4.80-4.76 (m, 2H), 4.69-4.65 (m, 1H), 4.61-4.58 (m, 2H), 4.56 (br s, 1H), 4.51 (t, J=8.4Hz, 1H), 4.01-3.95 (m, 1H), 3.95-3.88 (m, 1H), 3.88-3.83 (m, 1H), 3.83 -3.78(m, 2H), 3.78-3.69(m, 1H), 3.67-3.58(m, 1H), 3.42(s, 3H), 2.69-2.58(m, 1H), 2.53(br d, J=11.1Hz, 1H), 2.33-2.22(m, 2H), 2.13(d, J=2.3Hz, 4H), 1.59-1.51(m, 1H), 1.30 (d, J=6.4Hz, 3H), 1.21-1.13 (m, 3H), 0.86-0.80 (m, 3H), 0.80-0.71 (m, 4H). MS (ES-API positive): 1066.3 (M+1) + . Example 65: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-2-((4-(difluoromethyl)tetrahydro-2H-pyran-4-yl)methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0204] Example 65 was prepared using a method similar to that of Example 32. 1H NMR (500MHz, CD3OD) δ8.47 (br s, 1H), 8.52-8.44 (m, 1H), 7.76-7.68 (m, 1H), 7.60 (br s, 4H), 7.53-7.48 (m, 4H), 7.30 (br d, J=9.6Hz, 1H), 6.85-6.76 (m, 2H), 6.44 (d, J=1.7Hz, 1H), 6.15-5.81 (m, 2H), 5.40 (br d, J=9.8Hz, 1H), 5.11-5.08 (m, 1H), 4.63 (br t, J=8.1Hz, 2H), 4.52(br s, 1H), 4.54-4.50 (m, 1H), 4.54-4.50 (m, 1H), 4.26-4.22 (m, 2H), 4.02-3.92 (m, 2H), 3.88 (br d, J=6.0Hz, 3H), 3.82-3.70 (m, 4H), 2.68 (br s, 4H), 2.36-2.24 (m, 2H), 2.16 (br s, 3H), 2.08-1.95 (m, 2H), 1.90 (br s, 2H), 1.76 (br s, 2H), 1.60 (brs, 1H), 1.39 (t, J=7.2Hz, 4H), 1.18-1.18 (m, 1H), 1.19 (br d, J=6.3Hz, 1H), 1.20-1.18 (m, 1H), 1.11-1.02 (m, 1H), 1.09-1.02 (m, 1H), 0.91-0.81 (m, 5H), 0.79 (br s, 4H). MS (ES-API positive): 1178.4 (M+1) + . Example 66: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5,7-dimethyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0205] Example 66 was prepared using a method similar to that of Example 32. 1H NMR (400MHz, CD3OD) δ = 8.57-8.49 (m, 1H), 8.23-8.18 (m, 1H), 7.96-7.79 (m, 1H), 7.63-7.49 (m, 7H), 6.80-6.70 (m, 3H), 5.75 (br s, 1H), 5.46-5.39 (m, 1H), 5.09 (t, J=6.0Hz, 1H), 4.82-4.74 (m, 2H), 4.74-4.57 (m, 5H), 4.52 (br s, 1H), 4.41 (q, J=7.2Hz, 2H), 4.10-3.52 (m, 8H), 3.47-3.40 (m, 3H), 2.72-2.62 (m, 1H), 2.54 (br d, J=12.2Hz, 1H), 2.40-2.24(m, 5H), 2.13(d, J=2.4Hz, 3H), 2.06-1.97(m, 1H), 1.52(br d, J=6.1Hz, 1H), 1.49-1.43 (m, 3H), 1.34-1.25 (m, 3H), 1.19 (br d, J=6.6Hz, 3H), 0.89-0.83 (m, 3H), 0.76 (br d, J=4.1Hz, 4H). MS (ES-API positive): 1117.7 (M+1) + . Example 67: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-1-hydroxy-4-(thieno[2,3-d]thiazolyl-5-yl)but-3-yn-2-yl)pyrrolidine-2-carboxamide

[0206] Example 67 was prepared using a method similar to that of Example 34. 1H NMR (400MHz, CD3OD) δ9.18-9.10 (m, 1H), 8.48 (s, 1H), 7.87-7.78 (m, 1H), 7.60 (br s, 1H), 7.56-7.53 (m, 2H), 7.49-7.32 (m, 1H), 7.30 (d, J=9.8Hz, 1H), 6.79-6.74 (m, 2H), 5.74 (br s, 1H), 5.41 (d, J = 10.3Hz, 1H), 5.12-4.99 (m, 1H), 4.77 (s, 2H), 4.72-4.66 (m, 2H), 4.62 (br d, J = 3.0Hz, 1H), 4.60 (br s, 1H), 4.58-4.55 (m, 1H), 4.52-4.48 (m, 1H), 4.02-3.96 (m, 1H), 3.94-3.90 (m, 1H), 3.85 (tt, J=3.3, 6.4Hz, 2H), 3.79 (br dd, J=1.1, 5.8Hz, 2H), 3.64-3.60 (m, 1H), 3.43 (s, 3H), 2.65 (td, J=6.6, 10.2Hz, 1H), 2.54 (br d, J=10.8Hz, 1H), 2.29 (br d, J=13.1Hz, 2H), 2.16-2.10 (m, 5H), 1.56-1.50 (m, 1H), 1.30 (d, J=6.4Hz, 3H), 1.19-1.14 (m, 3H), 0.86-0.82 (m, 3H), 0.76 (br dd, J=3.9, 11.8Hz, 4H); mS (ES-API positive): 1095.4 (M+1) + . Example 68: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclobutyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0207] Example 68 was prepared using a method similar to that of Example 32. 1H NMR (500MHz, CD3OD) δ8.54-8.48 (m, 1H), 8.28-8.22 (m, 1H), 7.99 (s, 1H), 7.83-7.68 (m, 1H), 7.62-7.41 (m, 6H) , 7.36-7.26(m, 1H), 6.82-6.70(m, 3H), 5.82-5.76(m, 1H), 5.48-5.38(m, 1H), 5.23-4.96(m, 2H), 4.81-4.59(m, 5H), 4.57-4.48(m, 2H), 4.42(q, J=7.3Hz, 2H), 4.08-3.78(m, 6H), 3.67-3.56(m, 1H), 3.44(s, 4H), 2.71-2.49( m, 3H), 2.35-2.22 (m, 2H), 2.17-2.08 (m, 4H), 2.04-1.87 (m, 3H), 1.77-1.58 (m, 3H), 1.49-1.37 (m, 3H), 1.31 (br d, J=6.4Hz, 3H), 1.18 (br d, J=6.6Hz, 3H), 0.87-0.83 (m, 3H). MS (ES-API positive): 1116.4 (M+1) + . Example 69: (2S,4R)-1-((2S)-2-(4-(4-(((2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0208] Example 69 was prepared using a method similar to that of Example 32. 1H NMR (400MHz, CD3OD) δ8.43-8.41 (m, 1H), 7.56-7.48 (m, 6H), 7.44-7.40 (m, 3H), 7.2 7 (d, J=9.4Hz, 1H), 6.82 (d, J=8.2Hz, 2H), 6.32-6.29 (m, 1H), 5.38-5.33 (m, 1H), 5. 28-5.23 (m, 1H), 5.20-5.18 (m, 1H), 5.15-5.11 (m, 1H), 5.07 (t, J=6.1Hz, 1H), 4.79 -4.76 (m, 1H), 4.71-4.65 (m, 5H), 4.60 (t, J=8.2Hz, 2H), 4.50 (s, 1H), 4.31 (d, J=8.3 Hz, 1H), 4.17 (d, J=7.2Hz, 2H), 3.96-3.92 (m, 2H), 3.90-3.82 (m, 4H), 3.27 (s, 1H), 3.16-3.12(m, 1H), 2.80(d, J=7.3, 11.6Hz, 2H), 2.66-2.59(m, 1H), 2.42-2.36(m, 2H ), 2.26-2.21(m, 1H), 2.08(d, J=2.1Hz, 4H), 2.06-1.98(m, 2H), 1.93-1.89(m, 1H), 1.46-1.42 (m, 1H), 1.37-1.31 (m, 4H), 1.17 (d, J=6.6Hz, 3H), 0.83 (d, J=6.6Hz, 3H). MS (ES-API positive): 1126.4 (M+1) + . Example 70: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((4-methoxycyclohexyl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0209] Example 70 was prepared using a method similar to that of Example 32. 1H NMR (400MHz, CD3OD) δ = 8.44-8.40 (m, 1H), 7.54 (s, 1H), 7.53-7.50 (m, 4H), 7.48 (s, 1H), 7.43 (br d, J=8.3Hz, 4H), 7.26 (s, 1H), 6.82-6.75 (m, 2H), 6.31 (d, J=1.9Hz, 1H), 5.38-5.33 (m, 1H), 5.27 (d, J=11.1Hz, 1H), 5.20 (br d, J=1.8Hz, 2H), 5.07 (s, 1H), 4.79 (dd, J=3.3, 11.0Hz, 1H), 4.60 (t, J=8.5Hz, 1H), 4.50 (br d, J=1.5Hz, 1H), 4.32 (br d, J=7.0Hz, 1H), 3.97-3.91 (m, 3H), 3.90 (s, 1H), 3.88-3.79 (m, 4H), 3.34 (d, J=2.3Hz, 6H), 3.18-3.11 (m, 1H), 2.68-2.61 (m, 1H), 2.28-2.18 (m, 2H), 2.14-2.07 (m, 6H), 1.94-1.85 (m, 4H), 1.72-1.59 (m, 3H), 1.35 (s, 5H), 1.19-1.13 (m, 4H), 0.84 (d, J=6.7Hz, 4H), 0.66-0.57 (m, 4H). MS (ES-API positive): 1142.6 (M+1) + . Example 71: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-1-hydroxy-4-(1-methyl-1H-indazol-3-yl)but-3-yn-2-yl)pyrrolidine-2-carboxamide

[0210] Example 71 was prepared using a method similar to that of Example 34. 1H NMR (400MHz, CD3OD) δ8.47-8.33(m, 1H), 7.84-7.64(m, 1H), 7.59-7.54(m, 1H), 7.53-7.42(m, 4H), 7.41-7.37(m, 1H), 7.31-7.21(m, 2H), 6.87-6.64(m , 2H), 5.35 (d, J=10.3Hz, 1H), 5.30-5.24 (m, 1H), 5.21 (s, 1H), 5.11-5.04 (m , 1H), 4.83-4.77(m, 1H), 4.57-4.48(m, 2H), 4.39(d, J=5.0Hz, 2H), 4.32(br d, J=9.4Hz, 1H), 4.06 (s, 3H), 4.00-3.90 (m, 3H), 3.88-3.83 (m, 3H), 3.82-3.77 (m, 1H), 3.42 (s, 3H), 3.13 (br d, J=9.3Hz, 1H), 2.68-2.58(m, 1H), 2.30-2.22(m, 1H), 2.21-1.95(m, 6H), 1.91(br d, J=9.5Hz, 1H), 1.47-1.42 (m, 1H), 1.24 (d, J=6.4Hz, 3H), 1.20-1.12 (m, 3H), 0.86-0.77 (m, 3H), 0.69-0.58 (m, 4H). MS (ES-API positive): 1086.3 (M+1) + . Example 72: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide

[0211] This compound was prepared using a method similar to that described in Example 73 below. 1H NMR (400MHz, CD3OD) δ8.95-8.79 (m, 1H), 8.50-8.36 (m, 1H), 7.68-7.35 (m, 8H), 7. 32-7.24(m, 1H), 6.88-6.73(m, 2H), 5.38-5.28(m, 2H), 5.27-5.19(m, 2H), 4.85(br s, 1H), 4.79-4.75 (m, 1H), 4.50-4.45 (m, 1H), 4.35-4.27 (m, 1H), 4.14-4.07 (m, 1H) , 4.02-3.78(m, 6H), 3.58-3.48(m, 2H), 3.31-3.28(m, 1H), 3.19-3.08(m, 1H), 2.70- 2.60(m, 1H), 2.56-2.42(m, 3H), 2.22-2.01(m, 7H), 1.98-1.74(m, 4H), 1.49-1.40( m, 1H), 1.32-1.23 (m, 3H), 1.22-1.09 (m, 3H), 0.93-0.78 (m, 3H), 0.76-0.51 (m, 4H). MS (ES-API positive): 1131.5 (M+1) + . Example 73: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide Step 1: tert-butyl N-[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]carbamate

[0212] A mixture of tert-butyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (10 g, 31.6 mmol, 1 equivalent), 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazole (14.1 g, 63.5 mmol, 2 equivalent), Pd(dppf)Cl2 (2.4 g, 3.3 mmol, 0.1 equivalent), and Na2CO3 (7.1 g, 66.7 mmol, 2.1 equivalent) in dioxane (200 mL) and water (20 mL) was degassed and purged three times with N2. The mixture was then stirred at 100 °C for 16 hours under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to remove dioxane. The residue was diluted with water and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was analyzed by rapid chromatography (…). 220g Purification was performed using a silica gel fast column chromatography with an eluent gradient of 0–50% ethyl acetate / petroleum ether at a flow rate of 100 mL / min, yielding tert-butyl N-[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]carbamate as a white solid. MS (ES-API positive): 332.0 (M+1) + . Step 2: tert-butyl N-[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-oxoethyl]carbamate

[0213] Under a nitrogen atmosphere, a solution of tert-butyl N-[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxyethyl]carbamate (1.1 g, 3.3 mmol, 1 equivalent) in anhydrous DCM (20 mL) was treated with DMP (1.8 g, 4.2 mmol, 1.3 mL, 1.3 equivalent) at 0 °C. The reaction mixture was then slowly heated to room temperature and stirred for 1 hour. The reaction mixture was diluted with DCM (50 mL) and quenched with saturated NaHCO3 (20 mL) and saturated Na2S2O3 aqueous solution (20 mL), and stirred until a clear separation of the two layers was observed. The layers were separated, and the aqueous phase was extracted with DCM (20 mL × 2). The combined organic phases were washed with saturated NaHCO3 aqueous solution (20 mL) and brine (20 mL), dried (via Na2SO4), and concentrated under vacuum. The residual compound (1.1 g, crude) was used directly for the next step without further purification. Step 3: tert-butyl N-[1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxypropyl]carbamate

[0214] Under a nitrogen atmosphere, a solution of MeMgBr (3 M, 3.2 mL, 3 equivalents) was added to a solution of tert-butyl N-[(1R)-1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-oxoethyl]carbamate (1.1 g, 3.2 mmol, 1 equivalent) in anhydrous THF (12 mL) at 0 °C. The mixture was heated to room temperature and stirred at room temperature for 2 hours. The reaction mixture was carefully quenched with a saturated aqueous solution of ammonium chloride (20 mL) and then extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with a saturated aqueous solution of NaCl (15 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (neutral conditions) (column: Phenomenex Gemini NX 150×30 mm, 5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 32%-62%, 11 min) to give compound P1 (tert-butyl N-[1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxypropyl]carbamate): minor product, retention time 0.963 min; compound P2 (tert-butyl N-[1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxypropyl]carbamate): major product, retention time 0.988 min. Both were pale yellow oils. MS (ES-API positive): 346.2 (M+1) + . Step 4: 1-Amino-1-[4-(2-ethylpyrazol-3-yl)phenyl]prop-2-ol (P2)

[0215] HCl / dioxane (2M, 2mL, 4.9 equivalents) was added to a stirred solution of tert-butyl N-[1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxypropyl]carbamate (280 mg, 810.6 μmol, 1 equivalent) in DCM (1 mL). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by preparative HPLC (HCl conditions) (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (HCl)-ACN]; B%: 13%–33%, 11 min). MS (ES-API positive): 246.2 (M+1) + .

[0216] Step 5: tert-butyl(2S,4R)-2-[[1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxypropyl]carbamoyl]-4-hydroxypyrrolidine-1-carboxylate

[0217] A solution of 1-amino-1-[4-(2-ethylpyrazol-3-yl)phenyl]prop-2-ol (110 mg, 448.4 μmol, 1 equivalent), (2S,4R)-1-tert-butoxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid (103.7 mg, 448.4 μmol, 1 equivalent), and DIEA (463.6 mg, 3.6 mmol, 624.8 μL, 8 equivalents) in DCM (3 mL) was stirred at 0 °C for 3 min, and then T4P (484.6 mg, 672.6 μmol, 50% purity, 1.5 equivalents) was added at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, quenched with saturated NaHCO3 aqueous solution (20 mL), and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated NaCl aqueous solution (30 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. Residues were obtained by rapid chromatography (PCR). 4g Purification was performed using a silica gel fast column with an eluent gradient of 0–35% EE (ethyl acetate:ethanol = 3:1) / petroleum ether at a flow rate of 18 mL / min, yielding tert-butyl(2S,4R)-2-[[1-[4-(2-ethylpyrazol-3-yl)phenyl]-2-hydroxypropyl]carbamoyl]-4-hydroxypyrrolidine-1-carboxylate, as a white solid. MS (ES-API positive): 459.3 (M+1). + .

[0218] The subsequent steps are similar to those in Example 32. Example 73: 1H NMR (400MHz, CD3OD) δ8.48 (s, 1H), 8.00 (d, J = 2.4Hz, 1H), 7.67-7.51 (m, 8H), 7.29 (d, J = 9.4Hz, 1H), 6.76 (d, J=8.2Hz, 2H), 6.64 (d, J=2.4Hz, 1H), 5.75 (s, 1H), 5.39 (d, J=10.3Hz, 1H), 4.91 (br s, 1H), 4.84-4.76 (m, 3H), 4.71-4.65 (m, 2H), 4.64-4.57 (m, 3H), 4.51 (br d, J=1.8Hz, 1H), 4.33 (q, J=7.4Hz, 2H), 4.13-4.08 (m, 1H), 3.98-3.81 (m, 3H), 3.44-3.42 (m, 3H), 2.65 (br d, J=10.1Hz, 1H), 2.53 (br d, J=12.4Hz, 1H), 2.28(br d, J=13.1Hz, 2H), 2.17-2.08 (m, 4H), 2.05-1.96 (m, 1H), 1.60-1.52 (m, 1H), 1.43 (t, J=7.3Hz, 3H), 1.3 6-1.28 (m, 4H), 1.23 (d, J=6.4Hz, 3H), 1.17 (d, J=6.7Hz, 3H), 0.85 (s, 3H), 0.77 (m, J=3.6, 8.3Hz, 4H). LCMS(ES-API positive): 1116.4(M) + . Example 74: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((1r,3S)-3-methoxycyclobutoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0219] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.41 (s, 1H), 7.50 (s, 6H), 7.43 (s, 3H), 7.30-7.24 (m, 1H), 6.7 9-6.71 (m, 2H), 6.30 (d, J=1.8Hz, 1H), 5.47-5.40 (m, 1H), 5.38-5.33 (m, 1H), 5.31-5 .24(m, 1H), 5.21-5.17(m, 1H), 5.09-5.04(m, 1H), 4.81-4.74(m, 1H), 4.63-4.56(m, 1H), 4.52-4.41(m, 1H), 4.35-4.28(m, 1H), 4.21-4.12(m, 3H), 3.98-3.87(m, 3H), 3.8 5(d, J=6.2Hz, 3H), 3.29-3.26(m, 1H), 3.25(s, 3H), 3.15-3.10(m, 1H), 2.67-2.62(m , 1H), 2.48 (s, 4H), 2.27-2.19 (m, 1H), 2.13-2.09 (m, 1H), 2.07 (d, J=2.1Hz, 3H), 2.0 4-1.98(m, 1H), 1.93-1.86(m, 1H), 1.48-1.41(m, 1H), 1.34(t, J=7.2Hz, 3H), 1.16(d , J=6.7Hz, 3H), 0.83 (d, J=6.7Hz, 3H), 0.69-0.56 (m, 4H); mS (ES-API positive): 1114.4 (M+1) + . Example 75: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0220] This compound was prepared using a method similar to that of Example 73. After SFC separation, Example 75 was obtained. 1HNMR (400MHz, CD3OD) δ 8.59-8.52 (m, 1H), 8.35-8.28 (m, 1H), 8.05-7.91 (m, 1H), 7.65-7.52 (m, 7H), 7.34 (d, J=9.4Hz, 1H), 6.87-6.82 (m, 1H), 6.79 (br d, J=8.1Hz, 2H), 5.75(br s, 1H), 5.43 (d, J=10.3Hz, 1H), 4.92-4.86 (m, 2H), 4.83-4.76 (m, 2H), 4.74-4.58 (m, 5H), 4.53-4.42 (m, 3H), 4.13(t, J=6.4Hz, 1H), 3.95-3.76(m, 4H), 3.69-3.58(m, 1H), 3.46-3.41(m, 3H), 2.75-2.60(m, 1H), 2.56(br d, J=11.4Hz, 1H), 2.32(br d, J=11.7Hz, 1H), 2.23(br dd, J=8.8, 12.8Hz, 1H), 2.16 (d, J=2.1Hz, 3H), 1.99-1.88 (m, 1H), 1.53-1.46 (m, 4H ), 1.33-1.25 (m, 6H), 1.22-1.15 (m, 3H), 0.86 (d, J=6.6Hz, 3H), 0.81-0.69 (m, 4H). MS (ES-API positive): 1116.4 (M+1) + . Example 76: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6,7-difluoro-5-methyl-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0221] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.91-8.85 (m, 1H), 8.46-8.42 (m, 1H), 7.57-7.53 (m, 2H), 7.5 1 (s, 1H), 7.48-7.44 (m, 5H), 6.82 (d, J = 8.2Hz, 2H), 5.36 (d, J = 10.3Hz, 1H), 5.31 (t d, J=4.6, 8.7Hz, 1H), 5.28-5.22 (m, 1H), 5.20 (s, 1H), 5.09-5.01 (m, 1H), 4.80 (d, J =11.6Hz, 1H), 4.60 (t, J = 8.3Hz, 1H), 4.50 (s, 1H), 4.31 (d, J = 8.8Hz, 1H), 4.00-3.9 0(m, 5H), 3.88-3.82(m, 3H), 3.56-3.48(m, 2H), 3.28(s, 1H), 3.15-3.11(m, 1H), 2. 67-2.61 (m, 1H), 2.49-2.47 (m, 3H), 2.24 (d, J=7.8, 13.2Hz, 1H), 2.16-2.08 (m, 6H) , 2.06-2.02 (m, 1H), 1.90 (d, J=9.1Hz, 1H), 1.87-1.80 (m, 2H), 1.44-1.38 (m, 1H), 1 .17 (d, J=6.6Hz, 3H), 0.84 (d, J=6.7Hz, 3H), 0.70-0.64 (m, 1H), 0.64-0.58 (m, 3H). MS (ES-API positive): 1136.2 (M+1) + . Example 77: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-4-(3-fluorophenyl)-1-hydroxybut-3-yn-2-yl)-4-hydroxypyrrolidine-2-carboxamide

[0222] This compound was prepared using a method similar to that used in Example 34. 1H NMR (400MHz, CD3OD) δ8.50-8.31 (m, 1H), 7.51 (d, J=6.9Hz, 3H), 7.40 (s, 1H), 7.38-7.3 2(m, 1H), 7.30-7.24(m, 2H), 7.19(td, J=1.9, 9.6Hz, 1H), 7.10(d, J=2.5Hz, 1H), 6.78( d, J=8.2Hz, 2H), 5.35 (d, J=10.4Hz, 1H), 5.31-5.25 (m, 1H), 5.22 (s, 1H), 4.95 (t, J=5. 8Hz, 1H), 4.81 (d, J=11.3Hz, 1H), 4.54 (s, 1H), 4.48 (t, J=8.3Hz, 1H), 4.44-4.36 (m, 2H ), 4.36-4.27(m, 1H), 3.96(d, J=3.6Hz, 1H), 3.95-3.89(m, 2H), 3.86(s, 1H), 3.83(s, 1 H), 3.80 (d, J=6.2Hz, 1H), 3.77 (d, J=6.0Hz, 2H), 3.42 (s, 3H), 3.19-3.09 (m, 1H), 2.69 -2.56 (m, 1H), 2.29-2.21 (m, 1H), 2.15-1.98 (m, 5H), 1.91 (d, J=10.1Hz, 1H), 1.50-1.4 0 (m, 1H), 1.27-1.21 (m, 3H), 1.20-1.11 (m, 3H), 0.87-0.77 (m, 3H), 0.71-0.54 (m, 4H). MS (ES-API positive): 1050.5 (M+1) + . Example 78: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-4-(3-chloro-2-fluorophenyl)-1-hydroxybut-3-yn-2-yl)-4-hydroxypyrrolidine-2-carboxamide

[0223] This compound was prepared using a method similar to that used in Example 34. 1H NMR (400MHz, CD3OD) δ8.50 (s, 1H), 7.96-7.77 (m, 1H), 7.63-7.29 (m, 6H), 7.19-7.06 (m, 1H), 6.77 (br d, J=7.7Hz, 2H), 5.75 (br s, 1H), 5.42 (d, J = 10.1Hz, 1H), 5.02 (brt, J = 5.8Hz, 1H), 4.89-4.60 (m, 7H), 4.54 (br dd, J=8.4, 17.2Hz, 2H), 4.03-3.97(m, 1H), 3.97-3.91(m, 1H), 3.90-3.71(m, 4H), 3.67-3.59(m, 1H), 3.43(s, 3H), 2.69-2.61(m, 1H), 2.56(br d, J=10.5Hz, 1H), 2.38-2.23(m, 2H), 2.20-2.06(m, 4H), 1.51(br d, J=6.4Hz, 1H), 1.30(br d, J=6.0Hz, 3H), 1.22-1.13(m, 3H), 0.89-0.81(m, 3H), 0.75(br d, J=7.3Hz, 4H). MS (ES-API positive): 1084.3 (M+1) + . Example 79: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-2-((1-(difluoromethyl)cyclopropyl)methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0224] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ = 8.89 (s, 1H), 8.43-8.40 (m, 1H), 7.47 (s, 9H), 7.31-7.24 (m , 1H), 6.81-6.75 (m, 2H), 6.23-5.86 (m, 1H), 5.36 (d, J=10.1Hz, 1H), 5.23 (s, 2H), 5 .06(s, 1H), 4.65-4.56(m, 3H), 4.49(s, 3H), 4.36-4.28(m, 1H), 3.98-3.91(m, 2H), 3.85(d, J=6.3Hz, 3H), 3.18-3.11(m, 1H), 2.66(s, 1H), 2.51-2.46(m, 3H), 2.23(br d, J=15.7Hz, 1H), 2.15-2.06 (m, 4H), 2.06-1.98 (m, 2H), 1.95-1.87 (m, 1H), 1.50-1.39 (m, 1H), 1.3 5-1.26 (m, 2H), 1.17 (d, J=6.7Hz, 3H), 0.93 (d, J=2.1Hz, 2H), 0.87-0.78 (m, 6H), 0.72-0.56 (m, 4H). MS (ES-API positive): 1137.6 (M+1) + . Example 80: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-4-(benzo[d]thiazolyl-4-yl)-1-hydroxybut-3-yn-2-yl)-4-hydroxypyrrolidine-2-carboxamide

[0225] This compound was prepared using a method similar to that used in Example 34. 1H NMR (400MHz, CD3OD) δ9.42-9.22 (m, 1H), 8.47-8.34 (m, 1H), 8.11 (d, J=8.1Hz, 1H) ,7.81-7.65(m,1H),7.60-7.46(m,4H),7.43-7.33(m,1H),7.31-7.26(m,1H),6.91 -6.45(m, 2H), 5.37(d, J=10.3Hz, 1H), 5.32-5.26(m, 1H), 5.24(s, 1H), 5.12-5.02 (m, 1H), 4.83 (d, J = 11.4Hz, 1H), 4.70-4.47 (m, 3H), 4.42 (d, J = 5.1Hz, 2H), 4.34 (br d, J=7.5Hz, 1H), 4.03-3.79 (m, 7H), 3.44 (s, 3H), 3.16 (br d, J=10.3Hz, 1H), 2.67-2.51 (m, 1H), 2.36-2.24 (m, 1H), 2.21-2.07 (m, 5H), 1.93 (br d, J=10.6Hz, 1H), 1.52-1.41 (m, 1H), 1.26 (d, J=6.3Hz, 3H), 1.20-1.11 (m, 3H), 0.86-0.76 (m, 3H), 0.72-0.58 (m, 4H). MS (ES-API positive): 1089.3 (M+1) + Example 81: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((3-(1-ethyl-1H-pyrazol-5-yl)bicyclo[1.1.1]pent-1-yl)methyl)-4-hydroxypyrrolidine-2-carboxamide

[0226] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.75-8.37(m, 1H), 8.20(d, J=2.9Hz, 1H), 7.96(br s, 1H), 7.68-7.47(m, 3H), 7.33(br d, J=9.4Hz, 1H), 6.80 (d, J=8.2Hz, 2H), 6.66-6.57 (m, 1H), 5.76 (br s, 1H), 5.42 (d, J=10.1Hz, 1H), 4.92-4.78 (m, 3H), 4.75-4.60 (m, 4H), 4.58-4.48 (m, 4H), 4.03-3.97 (m, 1H ), 3.95-3.78(m, 3H), 3.69-3.60(m, 1H), 3.51-3.43(m, 4H), 3.40-3.35(m, 1H), 2.71-2.65(m, 1H), 2.57(br d, J=11.2Hz, 1H), 2.39-2.24(m, 7H), 2.17(d, J=2.1Hz, 3H), 2.13-2.04(m, 1H), 1.59-1.46(m , 4H), 1.32 (d, J=6.3Hz, 3H), 1.21 (d, J=6.6Hz, 3H), 0.87 (d, J=6.6Hz, 3H), 0.82-0.72 (m, 4H). MS (ES-API positive): 1062.4 (M+1) + . Example 82: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide

[0227] This compound was prepared using a method similar to that used in Example 73. 1H NMR (400MHz, CD3OD) δ 8.91-8.86 (m, 1H), 8.44-8.38 (m, 1H), 7.55-7.50 (m, 3H), 7.48-7.44 (m, 4H), 7.43-7.38 (m, 1H), 7.32-7.24 (m, 1H), 6.83-6. 76 (m, 2H), 5.38-5.32 (m, 1H), 5.31-5.25 (m, 1H), 5.24-5.20 (m, 1H), 4.85 (d, J=6.32Hz, 1H), 4.83-4.79 (m, 1H), 4.63-4.55 (m, 1H), 4.50-4.45 (m, 1 H), 4.43-4.37(m, 2H), 4.36-4.30(m, 1H), 4.15-4.07(m, 1H), 3.97-3.78 (m, 5H), 3.45-3.40 (m, 3H), 3.18-3.11 (m, 1H), 2.70-2.59 (m, 1H), 2.53-2 .47(m, 3H), 2.23-2.06(m, 5H), 2.04-1.89(m, 2H), 1.50-1.40(m, 1H), 1.3 1-1.21 (m, 7H), 1.21-1.13 (m, 3H), 0.88-0.80 (m, 3H), 0.73-0.56 (m, 4H). MS (ES-API positive): 1119.5 (M+1) + . Example 83: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-2-((1,1-difluoro-3-methoxypropyl-2-yl)oxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0228] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ 8.58-8.39 (m, 1H), 8.02 (d, J = 2.4Hz, 1H), 7.73-7.50 (m, 8H), 7.31 (d, J = 9.8Hz, 1H), 6.78 (d, J = 8.1Hz, 2H), 6.65 (d, J = 2.4Hz, 1 H), 6.48-6.12(m, 1H), 6.01-5.88(m, 1H), 5.78(s, 1H), 5.41(d, J=10.1Hz, 1H), 5.11(t, J=6.1Hz, 1H), 4.84-4.75(m, 3H), 4.74-4.61(m, 3H), 4.53(br s, 1H), 4.35 (q, J=7.4Hz, 2H), 4.03-3.84 (m, 6H), 3.78 (br d, J=14.3Hz, 1H), 3.69-3.58 (m, 1H), 3.44 (s, 3H), 2.68-2.61 (m, 1H), 2.55 (br d, J=11.7Hz, 1H), 2.36-2.24 (m, 2H), 2.15 (d, J=2.3Hz, 3H), 2.08-1.99 (m, 1H), 1.65-1.56 (m, 1H), 1.50-1.41 (m, 3H), 1.20 (d, J=6.7Hz, 3H), 0.91-0.71 (m, 7H); mS (ES-API positive): 1138.4 (M+1) + . Example 84: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(5-(1-ethyl-1H-pyrazol-5-yl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide Step 1: (NZ,S)-N-[[5-(2-ethylpyrazol-3-yl)-2-bicyclo[4.2.0]oct-1,3,5-trien-2-yl]methylene]-2-methylpropane-2-sulfinamide

[0229] To a solution of 5-(2-ethylpyrazol-3-yl)bicyclo[4.2.0]octyl-1,3,5-trien-2-carboxaldehyde (1 g, 4.4 mmol, 1 equivalent) in DCM (10 mL), (S)-2-methylpropane-2-sulfinamide (540 mg, 4.5 mmol, 1 equivalent) and Cs₂CO₃ (1.5 g, 4.6 mmol, 1 equivalent) were added. The mixture was stirred at 40 °C for 16 hours. The reaction mixture was filtered, and the filter cake was washed with DCM. The combined filtrates were concentrated under reduced pressure. The residue was analyzed by rapid chromatography (PCR). 20g Purification was performed using a silica gel rapid column with petroleum ether / EtOAc as the eluent (EtOAc gradient ranging from 0% to 20%) at a flow rate of 80 mL / min and a wavelength of 254 nm. The compound (NZ,S)-N-[[5-(2-ethylpyrazol-3-yl)-2-bicyclo[4.2.0]oct-1,3,5-trien-2-yl]methylene]-2-methylpropane-2-sulfinamide was obtained as a yellow oil. MS (ES-API positive): 330.1 (M+1) + . Step 2: (S)-N-[(1R,2S)-1-[5-(2-ethylpyrazol-3-yl)-2-bicyclo[4.2.0]oct-1,3,5-trien-2-yl]-2-hydroxypropyl]-2-methylpropane-2-sulfinamide

[0230] A samarium diiodide (0.1 M, 54.6 mL, 3 equivalents) solution was cooled to -78 °C. Then, a solution of (NZ,S)-N-[[5-(2-ethylpyrazol-3-yl)-2-bicyclo[4.2.0]oct-1,3,5-trien-2-yl]methylene]-2-methylpropane-2-sulfinamide (600 mg, 1.8 mmol, 1 equivalent), acetaldehyde (5 M, 546.4 μL, 1.5 equivalents), and THF (40 mL) in dry t-BuOH (270 mg, 3.6 mmol, 348.4 μL, 2 equivalents) was added in portions over 0.5 hours at -78 °C, followed by stirring at -78 °C for 2 hours. The reaction mixture was quenched with saturated Na₂S₂O₃ (12 mL) and DCM (100 mL) was added, forming a white precipitate, which was filtered through diatomaceous earth. The mixture was separated, the organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. It was then purified by column chromatography (SiO2, petroleum ether / EtOAc = 1:0–0:1) to give compound (S)-N-[(1R,2S)-1-[5-(2-ethylpyrazol-3-yl)-2-bicyclo[4.2.0]oct-1,3,5-trien-2-yl]-2-hydroxypropyl]-2-methylpropane-2-sulfinamide, as a yellow oil. MS (ES-API positive): 376.2 (M+1) + . Step 3: (1R,2S)-1-amino-1-[5-(2-ethylpyrazol-3-yl)-2-bicyclo[4.2.0]oct-1,3,5-trien-2-yl]prop-2-ol

[0231] To a solution of (S)-N-[(1R,2S)-1-[5-(2-ethylpyrazol-3-yl)-2-bicyclo[4.2.0]oct-1,3,5-trien-2-yl]-2-hydroxypropyl]-2-methylpropane-2-sulfinamide (220 mg, 585.8 mmol, 1 equivalent) in dry DCM (3 mL), HCl / dioxane (2 M, 3 mL, 10.2 equivalent) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was concentrated under vacuum and purified by preparative HPLC (HCl conditions) (column: Boston Green ODS 150×30mm×5μm; mobile phase: [water (HCl)-ACN]; B%: 10%-30%, 11 min) to give the compound (1R,2S)-1-amino-1-[5-(2-ethylpyrazol-3-yl)-2-bicyclo[4.2.0]oct-1,3,5-trien-2-yl]prop-2-ol, as a yellow oil. MS (ES-API positive): 272.1 (M+1) + . Step 4: tert-butyl(2S,4R)-2-[[(1R,2S)-1-[5-(2-ethylpyrazol-3-yl)-2-bicyclo[4.2.0]oct-1,3,5-trien-2-yl]-2-hydroxypropyl]carbamoyl]-4-hydroxypyrrolidine-1-carboxylate

[0232] At 0 °C, T4P (474.0 mg, 657.9 μmol, 50% purity, 1.5 equivalents) was added to a solution of (2S,4R)-1-tert-butoxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid (121.7 mg, 526.3 μmol, 1.2 equivalents), (1R,2S)-1-amino-1-[5-(2-ethylpyrazol-3-yl)-2-bicyclo[4.2.0]oct-1,3,5-trien-2-yl]prop-2-ol (135 mg, 438.6 μmol, 1 equivalent, HCl), and DIPEA (283.4 mg, 2.2 mmol, 382 μl, 5 equivalents) in DCM (3 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, quenched with saturated aqueous NaHCO3 solution (8 mL), and extracted with ethyl acetate (15 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was then subjected to rapid chromatography (LCC). 4g Purification was performed using a silica gel fast column with a 0–50% EE (ethyl acetate / ethanol = 3 / 1) / petroleum ether gradient as the eluent at a flow rate of 25 mL / min, yielding tert-butyl(2S,4R)-2-[[(1R,2S)-1-[5-(2-ethylpyrazol-3-yl)-2-bicyclo[4.2.0]oct-1,3,5-trien-2-yl]-2-hydroxypropyl]carbamoyl]-4-hydroxypyrrolidine-1-carboxylate, as a pale yellow oil. MS (ES-API positive): 485.3 (M+1) + .

[0233] The subsequent synthesis steps were similar to those in Example 32, resulting in Example 84, which was an off-white solid. 1H NMR (400MHz, CD3OD) δ8.48 (s, 1H), 7.96 (d, J=2.4Hz, 1H), 7.71-7.64 (m, 1H), 7.58 (br d, J=8.1Hz, 3H), 7.38-7.26 (m, 3H), 6.77 (d, J=8.2Hz, 2H), 6.60 (d, J=2.4Hz, 1H), 5.69 (br s, 1H), 5.58-5.53 (m, 1H), 5.38 (br d, J=10.3Hz, 1H), 4.81(br s, 1H), 4.77(br s, 2H), 4.64-4.58(m, 3H), 4.50(br s, 1H), 4.39-4.32 (m, 3H), 4.18-4.13 (m, 1H), 4.05-3.88 (m, 5H), 3.70 (br d, J=8.7Hz, 4H), 3.24 (br t, J=3.8Hz, 2H), 2.69-2.61 (m, 1H), 2.54 (br d, J=11.0Hz, 1H), 2.29(br d, J=12.0Hz, 1H), 2.22-2.11(m, 6H), 2.05-1.86(m, 4H), 1.54(br d, J=6.7Hz, 1H), 1.47-1.40 (m, 3H), 1.28 (d, J=6.3Hz, 3H), 1.19 (s, 3H), 0.84 (brd, J=6.6Hz, 3H), 0.76 (br dd, J=3.7, 8.1Hz, 4H). MS (ES-API positive): 1154.5 (M+1) + . Example 85: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(5-(1-ethyl-1H-pyrazol-5-yl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0234] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ8.46 (s, 1H), 7.88-7.83 (m, 1H), 7.67-7.50 (m, 4H), 7.38-7.24 (m, 3H), 6.75 (d, J=8.1Hz , 2H), 6.55-6.50 (m, 1H), 5.75 (s, 1H), 5.38 (d, J=10.3Hz, 2H), 4.83 (s, 1H), 4.80 (s, 1H), 4.77 (s, 2H), 4.67 (br d, J=3.2Hz, 2H), 4.64-4.56(m, 4H), 4.50(s, 1H), 4.31(q, J=7.4Hz, 2H), 4.18-4.13( t, 1H), 3.92 (m, J=6.6Hz, 3H), 3.79-3.72 (m, 1H), 3.65 (m, 1H), 3.43 (s, 3H), 3.23 (br t, J=3.6Hz, 2H), 2.68-2.61 (m, 1H), 2.53 (d, J=12.4Hz, 1H), 2.29 (d, J=11.4Hz, 1H), 2.24-2.11 (m, 4H), 2.04-1.95 (m, 1H), 1.58-1.53 ​​(m, 1H), 1.42 (t, J=7.3Hz, 3H), 1.29 (dd, J=6.5, 9.1Hz, 6H), 1.18 (d, J=6.6Hz, 3H), 0.89-0.70 (m, 7H). MS (ES-API positive): 1142.4 (M+1) + . Example 86: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((3-methoxycyclopentyl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0235] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.43-8.39(m, 1H), 7.53-7.47(m, 6H), 7.45-7.40(m, 3H ), 7.30-7.24(m, 1H), 6.80-6.73(m, 2H), 6.33-6.27(m, 1H), 5.62-5.55(m, 1H ), 5.35 (d, J = 10.4Hz, 1H), 5.32-5.25 (m, 1H), 5.20 (s, 1H), 5.11-5.04 (m, 1H) , 4.85-4.76 (m, 2H), 4.60 (s, 1H), 4.50 (s, 1H), 4.31 (d, J=8.7Hz, 1H), 4.17 (q , J=7.1Hz, 2H), 4.04(d, J=4.1Hz, 1H), 3.98(s, 3H), 3.87-3.82(m, 3H), 3.28( d, J=1.8Hz, 3H), 3.15-3.10(m, 1H), 2.66-2.59(m, 1H), 2.27-2.12(m, 4H), 2. 10-2.01(m, 6H), 1.94-1.88(m, 2H), 1.81-1.73(m, 1H), 1.48-1.40(m, 1H), 1. 37-1.32 (m, 3H), 1.17 (d, J=6.6Hz, 3H), 0.85-0.81 (m, 3H), 0.69-0.57 (m, 4H). MS (ES-API positive): 1129.1 (M+1) + . Example 87: (2S,4R)-1-((2S)-2-(4-(4-(((2-((2-oxaspiro[3.5]nonane-7-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0236] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.49-8.33 (m, 1H), 7.59-7.46 (m, 6H), 7.45-7.38 (m, 3H), 7.31-7.24 (m, 1H), 6.90 -6.80 (m, 2H), 6.34-6.28 (m, 1H), 5.35 (d, J=10.4Hz, 1H), 5.27-5.15 (m, 2H), 5.09-5.02 (m, 1H), 4.77 (br d, J=11.7Hz, 1H), 4.62-4.56 (m, 3H), 4.49-4.44 (m, 3H), 4.34-4.27 (m, 3H), 4.17 (q, J=7. 2Hz, 2H), 4.11 (t, J=6.3Hz, 1H), 3.96-3.81 (m, 4H), 3.41 (dt, J=4.1, 6.6Hz, 1H), 3.28 (br d, J=10.6Hz, 1H), 3.11(br d, J=8.8Hz, 1H), 2.69-2.62(m, 1H), 2.14-2.05(m, 6H), 2.00-1.96(m, 2H), 1.89(br d, J=9.7Hz, 1H), 1.64-1.52 (m, 4H), 1.47-1.41 (m, 1H), 1.35 (t, J=7.2Hz, 3H), 1. 25 (d, J=6.4Hz, 3H), 1.17 (d, J=6.6Hz, 3H), 0.87-0.80 (m, 3H), 0.71-0.57 (m, 4H). MS (ES-API positive): 1168.5 (M+1) + . Example 88: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclobutyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0237] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.45-8.38(m, 1H), 7.93-7.85(m, 1H), 7.57-7.47(m, 5H), 7.44-7.40(m, 2H), 7.33-7.26(m, 2H) , 6.82-6.74 (m, 2H), 6.31 (d, J=1.7Hz, 1H), 5.37-5.24 (m, 3H), 4.80-4.72 (m, 2H), 4.62-4.57 (m, 2H), 4.48 (s, 1H), 4. 43-4.36(m, 3H), 4.22-4.09(m, 3H), 3.95-3.77(m, 5H), 3.43(s, 3H), 3.25-3.13(m, 2H), 2.69-2.59(m, 1H), 2.21-2.0 9(m, 2H), 2.07-2.00(m, 4H), 1.99-1.91(m, 3H), 1.78-1.62(m, 4H), 1.38-1.32(m, 3H), 1.25(d, J=6.3Hz, 6H), 1.17(br d, J=6.6Hz, 3H), 0.83 (br d, J=6.6Hz, 3H). MS (ES-API positive): 1130.4 (M+1) + . Example 89: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6,7-difluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0238] This compound was prepared using a method similar to that used in Example 32. 1H NMR (500MHz, CD3OD) δ8.52-8.44(m, 1H), 8.03-7.97(m, 1H), 7.67(br d, J=2.4Hz, 1H), 7.61-7.54 (m, 5H), 7.53-7.50 (m, 2H), 6.75 (d, J=8.2Hz, 2H), 6.68-6.61 (m, 1H), 5.75 (br s, 1H), 5.39 (d, J=10.2Hz, 1H), 4.89 (br s, 2H), 4.82-4.73 (m, 2H), 4.71-4.56 (m, 5H), 4.49 (br s, 1H), 4.35 (q, J=7.3Hz, 2H), 4.12 (quin, J=6.3Hz, 1H), 3.97-3.92 (m, 1H), 3.92-3.88 (m, 1H), 3.86 (dt, J=3.4 , 6.3Hz, 1H), 3.81-3.72(m, 1H), 3.68-3.54(m, 1H), 3.43(s, 3H), 2.72-2.58(m, 1H), 2.57-2.48(m, 1H), 2.29(br d, J=11.0Hz, 1H), 2.23-2.12(m, 4H), 2.05-1.92(m, 1H), 1.53(quin, J=6.8Hz, 1H), 1.46-1.41(m, 3H), 1.30 (d, J=6.3Hz, 3H), 1.28-1.23 (m, 3H), 1.19 (d, J=6.6Hz, 3H), 0.88-0.82 (m, 3H), 0.81-0.71 (m, 4H). MS (ES-API positive): 1134.4 (M+1) + . Example 90: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6,7-difluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide

[0239] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ9.68-9.65 (m, 1H), 8.48-8.45 (m, 1H), 7.66 (d, J=3.1Hz, 1H), 7.57 (br d, J=8.3Hz, 2H), 7.55-7.53(m, 5H), 6.74(d, J=8.2Hz, 2H), 5.77(br s, 1H), 5.39 (d, J = 10.3Hz, 1H), 4.81-4.76 (m, 3H), 4.70 (s, 1H), 4.67 (d, J = 3.2Hz, 1H), 4.64-4.58 (m, 3H), 4.50- 4.47(m, 1H), 4.14-4.09(m, 1H), 3.97-3.82(m, 4H), 3.47-3.42(m, 4H), 2.69-2.62(m, 1H), 2.59(s, 3H), 2.52(br d, J=11.8Hz, 1H), 2.29(br d, J=11.8Hz, 1H), 2.22-2.18(m, 1H), 2.14(d, J=2.7Hz, 3H), 1.97-1.91(m, 1H), 1.59-1.53(m, 1H), 1.30( d, J=6.4Hz, 4H), 1.26 (d, J=6.3Hz, 3H), 1.19 (d, J=6.6Hz, 3H), 0.85 (d, J=6.6Hz, 4H), 0.78-0.71 (m, 3H). MS (ES-API positive): 1137.4 (M+1) + . Example 92: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-4-(benzo[d]thiazolyl-7-yl)-1-hydroxybut-3-yn-2-yl)-4-hydroxypyrrolidine-2-carboxamide

[0240] This compound was prepared using a method similar to that used in Example 34. 1H NMR (400MHz, CD3OD) δ0.69-0.79 (m, 4H) 0.81-0.87 (m, 3H) 1.14-1.20 (m, 3H) 1.28-1.31 (m, 4H) 1.48-1.57 (m, 1H) 2.11-2.15 (m, 3H) 2.26-2. 33 (m, 2H) 2.54 (d, J = 11.68Hz, 1H) 2.59-2.70 (m, 1H) 3.41-3.44 (m, 3H) 3.58-3.67 (m, 1H) 3.74-3.81 (m, 1H) 3.82-3.89 (m, 3H) 3.89-3.95 (m, 1 H)3.96-4.04(m,1H)4.48-4.64(m,5H)4.65(s,2H)4.80-4.86(m,2H)5.03-5.10(m,1H)5.32-5.45(m,1H)5.71-5.78(m,1H)6.69-6.80(m,2 H) 7.23-7.34 (m, 1H) 7.47-7.64 (m, 5H) 7.74-7.84 (m, 1H) 7.97-8.11 (m, 1H) 8.42-8.52 (m, 1H) 9.30-9.40 (m, 1H); mS (ES-API positive): 1089.3 (M+1) + . Example 93: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((hexahydro-1H-cyclopenta[c]furan-5-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0241] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.93-8.85 (m, 1H), 8.43 (s, 1H), 7.56 (d, J=1.5Hz, 1H), 7.53 (s, 1H), 7.49 (s, 4H), 7.47 (s, 1H), 7.42 (s, 1H), 7.34-7.24(m, 2H), 6.82(dd, J=1.7, 8.2Hz, 2H), 5.87(s, 1H), 5.43(s, 1H), 5.32-5.22(m, 2H), 5.19-5.05(m, 2H), 5.03(br d, J=2.9Hz, 2H), 4.76 (s, 1H), 4.65-4.62 (m, 1H), 4.56-4.47 (m, 1H), 4.36-4.31 (m, 1H), 4.01-3.89 (m, 5H) ), 3.43-3.38(m, 1H), 3.31-3.25(m, 1H), 3.19-3.12(m, 1H), 2.71-2.62(m, 1H), 2.49-2.48(m, 1H), 2.54- 2.48(m, 3H), 2.48-2.47(m, 1H), 2.30-2.22(m, 1H), 2.15-2.02(m, 7H), 1.95-1.90(m, 1H), 1.87-1.79(m, 1H), 1.65-1.55 (m, 1H), 1.50-1.43 (m, 1H), 1.19 (d, J=6.7Hz, 3H), 0.88-0.83 (m, 3H), 0.72-0.60 (m, 4H). MS (ES-API positive): 1143.4 (M+1) + . Example 94: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclobutyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0242] This compound was prepared using a method similar to that used in Example 32. 1H NMR (500MHz, CD3OD) δ8.88-8.85 (m, 1H), 8.41 (s, 1H), 7.89 (s, 1H), 7.53 (d, J=8.2 Hz, 2H), 7.48-7.44 (m, 4H), 7.34 (s, 1H), 7.28 (d, J=9.6Hz, 1H), 6.78 (d, J=8.2Hz, 2H), 5.37-5.30 (m, 2H), 5.28-5.22 (m, 2H), 5.06 (t, J=6.1Hz, 1H), 4.73 (d, J=11.3 Hz, 1H), 4.62-4.58 (m, 4H), 4.50 (s, 1H), 4.37 (d, J=8.7Hz, 1H), 4.01-3.96 (m, 2H), 3.95-3.92(m, 2H), 3.89(s, 1H), 3.87-3.84(m, 2H), 3.57-3.50(m, 2H), 3.27-3.20 (m, 1H), 3.15 (d, J=10.4Hz, 1H), 2.67-2.61 (m, 1H), 2.49-2.46 (m, 3H), 2.24 (dd, J =8.0, 13.4Hz, 1H), 2.16-2.10 (m, 3H), 2.04 (d, J = 2.0Hz, 3H), 2.02-1.91 (m, 4H), 1 .88-1.81 (m, 2H), 1.74-1.65 (m, 3H), 1.16 (d, J=6.7Hz, 3H), 0.83 (d, J=6.7Hz, 3H). MS (ES-API positive): 1131.3 (M+1) + . Example 95: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxy-3-methylbutyl)-4-hydroxypyrrolidine-2-carboxamide

[0243] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ8.46 (s, 1H), 7.94-7.89 (m, 1H), 7.64-7.54 (m, 6H), 7.49 (d, J = 8.2Hz, 2H), 7.28 (d, J = 9.5Hz, 1H), 6.75 (d, J = 8.2Hz, 2H), 6.58 ( d, J=2.4Hz, 1H), 5.77-5.74 (m, 1H), 5.37 (d, J=10.1Hz, 1H), 5.05 (d, J=7.2 Hz, 1H), 4.84-4.76 (m, 4H), 4.71-4.66 (m, 1H), 4.63-4.53 (m, 4H), 4.47 (br s, 1H), 4.31 (q, J=7.3Hz, 2H), 3.96-3.83 (m, 3H), 3.79-3.70 (m, 1H), 3.67 (dd, J=5.5, 7.0Hz, 1H), 3.43 (s, 3H), 2.72-2.61 (m, 1H), 2.53 (br d, J=13.4Hz, 1H), 2.32-2.26 (m, 1H), 2.13 (d, J=2.3Hz, 4H), 1.95-1.85 (m, 2H), 1.59-1.52 (m, 1H), 1.45-1.40 (m, 3H), 1.30 ( d, J=6.4Hz, 3H), 1.18 (d, J=6.6Hz, 3H), 1.07 (d, J=6.8Hz, 3H), 0.99 (d, J=6.7Hz, 3H), 0.87-0.82 (m, 3H), 0.80-0.72 (m, 4H). MS (ES-API positive): 1145.2 (M+1) + . Example 96: (2S,4R)-1-((2S)-2-(4-(4-(((2-((2-oxaspiro[3.5]nonane-7-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide

[0244] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ8.88 (s, 1H), 8.43-8.41 (m, 1H), 7.56 (d, J=8.2Hz, 2H), 7.51 (s, 1H) , 7.47-7.43 (m, 5H), 7.30-7.25 (m, 1H), 6.89-6.83 (m, 2H), 5.35 (d, J=10.1Hz, 1H), 5.27- 5.20(m, 1H), 5.18(s, 1H), 5.08-5.03(m, 1H), 4.77(d, J=11.6Hz, 1H), 4.61-4.58(m, 1H), 4.49-4.45(m, 3H), 4.34-4.28(m, 3H), 4.11(t, J=6.3Hz, 1H), 3.94-3.80(m, 4H), 3.13(br d, J=1.5Hz, 1H), 2.69-2.60(m, 1H), 2.50(s, 3H), 2.20-2.05(m, 8H), 2.03-1.95(m, 3H), 1.92-1.88(m, 1H), 1.65-1.55(m, 4H), 1.49-1.43 (m, 1H), 1.33-1.27 (m, 1H), 1.25 (d, J=6.3Hz, 3H), 1.17 (d, J=6.7Hz, 3H), 0.83 (d, J=6.7Hz, 3H), 0.69-0.59 (m, 4H). MS (ES-API positive): 1171.6 (M+1) + . Example 97: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-7-(7-chloro-6-fluoro-5-methyl-1H-indazol-4-yl)-6-cyclopropyl-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0245] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ = 9.77-9.66 (m, 1H), 8.46 (s, 1H), 7.65 (s, 1H), 7.58-7.51 (m, 7H), 6 .70 (d, J=8.2Hz, 2H), 5.76 (s, 1H), 5.41 (d, J=10.3Hz, 1H), 5.08 (t, J=6.0Hz, 1H), 4.77 (br s, 2H), 4.73-4.66 (m, 2H), 4.65-4.58 (m, 3H), 4.51 (br s, 1H), 3.96-3.83 (m, 5H), 3.44 (s, 3H), 2.66 (br d, J=10.1Hz, 1H), 2.59 (s, 3H), 2.57-2.44 (m, 2H), 2.32-2.22 (m, 2H), 2.14 (d, J=2.7Hz, 3H), 2.05-1.97 (m, 1H), 1.54 (br s, 1H), 1.31 (d, J=6.3Hz, 4H), 1.19 (d, J=6.4Hz, 3H), 1.04 (dd, J=6.7, 10.4Hz, 1H), 0.88-0.73 (m, 7H), MS (ES-API positive): 1139.9 (M+1)+. Example 98: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-4-(2-chloro-3-fluorophenyl)-1-hydroxybut-3-yn-2-yl)-4-hydroxypyrrolidine-2-carboxamide

[0246] This compound was prepared using a method similar to that used in Example 34. 1H NMR (400MHz, CD3OD) δ 8.44-8.34 (m, 1H), 7.51 (d, J=7.7Hz, 3H), 7.40 (s, 1H), 7.38-7.34 (m, 1H), 7.32-7.21 (m, 3H), 6.82-6.72 (m, 2H), 5.35 (d, J=10.3Hz, 1H), 5.27 (d, J=11.6Hz, 1H), 5.22 (s, 1H), 5.03 (t, J=5.8Hz, 1H), 4.59 (s, 3H), 4.52 (d, J=7.5, 16.6Hz, 2H), 4.40 (d, J=5.1Hz, 2 H), 4.31 (d, J=7.9Hz, 1H), 3.98-3.85 (m, 3H), 3.84-3.78 (m, 3H), 3.43-3.40 (m, 3H), 3.17-3.09 (m, 1H), 2.68-2.57 (m, 1H), 2.29-2.21 (m, 1H) , 2.17-2.06 (m, 5H), 1.91 (d, J=10.4Hz, 1H), 1.49-1.40 (m, 1H), 1.27- 1.22 (m, 3H), 1.19-1.12 (m, 3H), 0.86-0.77 (m, 3H), 0.70-0.55 (m, 4H). MS (ES-API positive): 1084.3 (M+1) + . Example 99: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6,7-difluoro-5-methyl-1H-indazol-4-yl)-2-(((1r,4S)-4-methoxycyclohexyl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0247] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ0.57-0.68 (m, 4H) 0.84 (d, J = 6.44Hz, 3H) 1.15-1.19 (m, 3H) 1.36-1.45 (m, 3H) 1.58-1.68 (m, 2H) 1.92 (d, J = 10.01Hz, 1 H) 2.02 (s, 1H) 2.11 (d, J = 1.55Hz, 6H) 2.17-2.28 (m, 3H) 2.46-2.50 (m, 3H) 2.61-2.69 (m, 1H) 3.15 (d, J = 9.78Hz, 1H) 3.33 (s, 3H) 3.85 (q, J = 6. 20Hz, 3H) 3.89-3.98 (m, 3H) 4.29-4.35 (m, 1H) 4.47-4.53 (m, 1H) 4.56-4.67 (m, 4H) 5.06 (t, J = 6.14Hz, 1H) 5.09-5.14 (m, 1H) 5.18-5.20 (m, 1H ) 5.22-5.31 (m, 1H) 5.36 (d, J = 10.25Hz, 1H) 6.79 (d, J = 7.99Hz, 2H) 7.43-7.48 (m, 5H) 7.49-7.55 (m, 3H) 8.41-8.45 (m, 1H) 8.85-8.90 (m, 1H). MS (ES-API positive): 1160.4 (M+1) + . Example 100: (2S,4R)-1-((2S)-2-(4-(4-(((2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0248] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ 8.48-8.38 (m, 1H), 7.57-7.47 (m, 6H), 7.42 (d, J = 6.6Hz, 3H), 7.28 (d, J = 9.8Hz, 1H), 6.86-6.78 (m, 2H), 6.34-6.2 7 (m, 1H), 5.35 (d, J = 10.4Hz, 1H), 5.25 (d, J = 11.4Hz, 1H), 5.18 (s, 1H), 5.12 (t, J = 7.0Hz, 1H), 4.67 (s, 4H), 4.62-4.57 (m, 4H), 4.48 (br s, 1H), 4.31(br d, J=9.1Hz, 1H), 4.18 (q, J=7.2Hz, 2H), 4.14-4.07 (m, 1H), 3.93-3.88 (m, 2H), 3.83 (br d, J=10.0Hz, 1H), 3.27 (s, 1H), 3.13 (br d, J=9.3Hz, 1H), 2.81 (br dd, J=7.2, 11.7Hz, 2H), 2.67-2.61 (m, 1H), 2.39 (br dd, J=7.0, 12.3Hz, 2H), 2.17 (br dd, J=8.0, 13.2Hz, 1H), 2.13-2.04(m, 4H), 2.00-1.92(m, 1H), 1.92-1.87(m, 1H), 1.47-1.40(m, 1H), 1. 38-1.33 (m, 3H), 1.25 (d, J=6.3Hz, 3H), 1.17 (d, J=6.6Hz, 3H), 0.83 (d, J=6.7Hz, 3H), 0.71-0.57 (m, 4H). MS (ES-API positive): 1140.4 (M+1) + . Example 101: (2S,4R)-1-((2S)-2-(4-(4-(((2-((6-oxaspiro[3.4]octan-2-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0249] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.50-8.39 (m, 1H), 7.61-7.48 (m, 6H), 7.47-7.41 (m, 3H), 7. 33-7.25(m, 1H), 6.90-6.78(m, 2H), 6.34-6.29(m, 1H), 5.40-5.24(m, 3H), 5.21(br s, 1H), 5.09 (t, J=6.0Hz, 1H), 4.83-4.76 (m, 2H), 4.52 (br s, 1H), 4.33 (br d, J=9.6Hz, 1H), 4.19 (q, J=7.2Hz, 2H), 4.00-3.83 (m, 6H), 3.82-3.74 (m, 2H), 3.7 4-3.69(m, 2H), 3.19-3.12(m, 1H), 2.72-2.44(m, 4H), 2.37-2.22(m, 3H), 2.10(br d, J=1.6Hz, 4H), 2.08-2.02(m, 2H), 1.97-1.89(m, 2H), 1.51-1.43(m, 1H), 1.40 -1.33 (m, 3H), 1.19 (d, J=6.4Hz, 3H), 0.85 (d, J=6.4Hz, 3H), 0.75-0.58 (m, 4H). MS (ES-API positive): 1140.3 (M+1) + . Example 102: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((1S,3R)-3-methoxycyclobutoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0250] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.90-8.85 (m, 1H), 8.41 (s, 1H), 7.54-7.49 (m, 3H), 7.47- 7.44(m, 4H), 7.40(s, 1H), 7.31-7.25(m, 1H), 6.76(d, J=8.2Hz, 2H), 5.48-5.41 (m, 1H), 5.35 (d, J=10.3Hz, 1H), 5.31-5.24 (m, 1H), 5.20 (s, 1H), 5.06 (t, J=6.1 Hz, 1H), 4.79 (d, J=11.2Hz, 1H), 4.61 (d, J=8.2Hz, 2H), 4.50 (s, 1H), 4.33 (d, J= 9.8Hz, 1H), 4.20-4.14(m, 1H), 4.00-3.88(m, 3H), 3.85(d, J=6.3Hz, 3H), 3.25( s, 3H), 3.15 (d, J=9.5Hz, 1H), 2.69-2.62 (m, 1H), 2.51-2.46 (m, 7H), 2.28-2.20 (m, 1H), 2.12 (d, J = 10.4Hz, 1H), 2.09-2.00 (m, 4H), 1.92 (d, J = 10.5Hz, 1H), 1.4 8-1.41 (m, 1H), 1.17 (d, J=6.6Hz, 3H), 0.83 (d, J=6.6Hz, 3H), 0.69-0.58 (m, 4H). MS (ES-API positive): 1118.1 (M+1) + . Example 103: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6,7-difluoro-5-methyl-1H-indazol-4-yl)-2-(((1S,4R)-4-methoxycyclohexyl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0251] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.89 (s, 1H), 8.43 (s, 1H), 7.60-7.50 (m, 3H), 7.47 (s, 5H), 6.86-6.78 (m, 2H), 5.41-5.33 (m, 1H), 5.29 (s, 1H), 5.22-5 .16(m, 2H), 5.10-5.03(m, 1H), 4.85-4.79(m, 2H), 4.64-4.58(m, 2H), 4.54-4.47(m, 1H), 4.35-4.27(m, 1H), 3.94-3.90(m, 2H), 3.85(d, J=6 .2Hz, 3H), 3.39-3.35(m, 1H), 3.34(s, 3H), 3.17-3.11(m, 1H), 2.71-2.61(m, 1H), 2.49(s, 3H), 2.28-2.20(m, 1H), 2.11(d, J=2.4Hz, 3H), 2. 10-2.06 (m, 1H), 2.06-1.80 (m, 8H), 1.71-1.60 (m, 2H), 1.45-1.37 (m, 1H), 1.17 (d, J=6.6Hz, 3H), 0.84 (d, J=6.6Hz, 3H), 0.72-0.54 (m, 4H). MS (ES-API positive): 1163.4 (M+1) + . Example 104: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((hexahydro-1H-cyclopenta[c]furan-5-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0252] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ 8.50-8.34 (m, 1H), 7.58-7.48 (m, 6H), 7.47-7.40 (m, 3H), 7.29 (d, J = 9.6Hz, 1H), 6.86-6.78 (m, 2H), 6.35-6.30 (m , 1H), 5.98-5.89 (m, 1H), 5.38 (d, J=10.3Hz, 1H), 5.33-5.22 (m, 2H), 5.21-5.06 (m, 2H), 4.86-4.76 (m, 2H), 4.72-4.59 (m, 3H), 4.52 (br s, 1H), 4.34(br d, J=9.2Hz, 1H), 4.23-4.14(m, 2H), 4.01-3.84(m, 8H), 3.45-3.36(m, 2H), 3.31-3.27(m, 1H), 3.19-3.12(m, 1H), 2.71-2.42(m, 3H), 2.26(br dd, J=8.0, 13.1Hz, 1H), 2.17-2.02(m, 3H), 1.93(br d, J=10.8Hz, 1H), 1.87-1.77(m, 1H), 1.65-1.54(m, 1H), 1.51-1.42(m, 1H), 1.4 0-1.32 (m, 3H), 1.19 (d, J=6.4Hz, 3H), 0.85 (d, J=6.4Hz, 3H), 0.74-0.58 (m, 4H). MS (ES-API positive): 1140.5 (M+1) + . Example 105: (2S,4R)-1-((2S)-2-(4-(4-(((2-((7-oxaspiro[3.5]nonane-2-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0253] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ=8.41 (s, 1H), 7.59-7.39 (m, 9H), 7.30-7.24 (m, 1H), 6.86 (d, J=8.0Hz, 2H), 6.30 (d, J=1.9Hz, 1H), 5.40-5.23 (m, 3H), 5.18 (br s, 1H), 5.07 (s, 1H), 4.80-4.73 (m, 1H), 4.63-4.55 (m, 1H), 4.52-4.46 (m, 1H), 4.35-4.27 (m, 1H), 4.16 (d, J=7.2Hz, 2H), 3 .97-3.79(m, 6H), 3.62-3.42(m, 5H), 3.17-3.06(m, 1H), 2.70-2.58(m, 1H), 2.49-2.39(m, 2H), 2.28-2.17(m, 1H), 2.09(br d, J=2.3Hz, 4H), 2.03-1.94(m, 1H), 1.99(br d, J=6.6Hz, 2H), 1.92-1.86(m, 1H), 1.66-1.51(m, 4H), 1.49-1.39(m, 1H), 1.33( t, J=7.2Hz, 3H), 1.16 (d, J=6.6Hz, 3H), 0.82 (d, J=6.7Hz, 3H), 0.70-0.51 (m, 4H). MS (ES-API positive): 1154.3 (M+1) + . Example 106: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclobutyl-7-(6,7-difluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0254] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.43-8.39(m, 1H), 7.87(s, 1H), 7.53-7.50(m, 2H), 7.49(br d, J=6.2Hz, 3H), 7.45-7.42 (m, 2H), 7.34 (d, J=2.9Hz, 1H), 6.78 (d, J=8.2Hz, 2H), 6.32- 6.29 (m, 1H), 5.36 (d, J=10.1Hz, 1H), 5.30-5.25 (m, 2H), 5.07 (t, J=6.0Hz, 1H), 4.80 (br d, J=11.7Hz, 1H), 4.50(br s, 1H), 4.42-4.37 (m, 3H), 4.17 (q, J=7.0Hz, 2H), 4.00-3.89 (m, 4H), 3.87-3.80 (m, 3H), 3.42 (s, 3H), 3.36 (br d, J=10.1Hz, 1H), 3.24-3.16(m, 2H), 2.68-2.61(m, 1H), 2.30-2.20(m, 1H), 2.14(br d, J=10.7Hz, 1H), 2.06 (d, J=2.4Hz, 3H), 2.04-1.98 (m, 2H), 1.94 (br d, J=9.9Hz, 2H), 1.79-1.64 (m, 4H), 1.36-1.32 (m, 3H), 1.28 (s, 1H), 1.25 (d, J=6.3Hz, 3H), 1.17 (br d, J=6.7Hz, 3H), 0.84 (d, J=6.6Hz, 3H). MS (ES-API positive): 1134.4 (M+1) + . Example 107: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-4-(1,4-diazacycloheptane-1-yl)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide)

[0255] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ = 8.50-8.44 (m, 1H), 7.96-7.90 (m, 1H), 7.68-7.59 (m, 2H), 7.51 (br s, 6H), 7.32-7.27 (m, 1H), 6.80-6.73 (m, 2H), 6.61-6.56 (m, 1H), 5.40 (d, J=9.8Hz, 1H), 5.08 (br t, J=6.0Hz, 1H), 4.82-4.77(m, 1H), 4.71-4.57(m, 5H), 4.51(br s, 2H), 4.44(br s, 2H), 4.34-4.27(m, 2H), 3.99-3.90(m, 2H), 3.89-3.82(m, 3H), 3.78-3.68(m, 2H), 3.47-3.40(m, 5H), 2.68-2.61(m, 1H), 2.51(br s, 2H), 2.27(br dd, J=8.3, 13.5Hz, 1H), 2.16-2.11(m, 3H), 2.05-1.96(m, 1H), 1.58-1.51(m, 1H), 1.45-1.39( m, 3H), 1.30 (dd, J=1.5, 6.3Hz, 3H), 1.21-1.15 (m, 3H), 0.87-0.82 (m, 3H), 0.81-0.70 (m, 4H). MS (ES-API positive): 1104.4 (M+1) + . Example 108: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-4-(4-chloropyridin-3-yl)-1-hydroxybut-3-yn-2-yl)-4-hydroxypyrrolidine-2-carboxamide

[0256] This compound was prepared using a method similar to that used in Example 34. 1H NMR (500MHz, CD3OD) δ 8.67-8.57 (m, 1H), 8.45-8.38 (m, 2H), 7.59-7.50 (m, 3H), 7.46 (s, 1H), 7.34 (s, 1H), 7.29 (d, J=9.8Hz, 1H), 6.82-6.77 (m, 2H ), 5.37-5.32(m, 2H), 5.29-5.25(m, 1H), 5.06-5.02(m, 1H), 4.55-4.48( m, 4H), 4.44-4.38 (m, 2H), 4.05-4.01 (m, 1H), 4.00-3.96 (m, 1H), 3.89 (br d, J=11.0Hz, 1H), 3.84-3.79(m, 3H), 3.72-3.68(m, 1H), 3.42-3.41(m, 3H) ,2.66-2.59(m,1H),2.44-2.38(m,1H),2.29-2.22(m,1H),2.14-2.10(m,2 H), 2.08 (d, J=2.3Hz, 3H), 1.50-1.45 (m, 1H), 1.32-1.28 (m, 2H), 1.25-1.2 3 (m, 3H), 1.17 (d, J=6.7Hz, 3H), 0.83 (d, J=6.6Hz, 3H), 0.69-0.61 (m, 4H). MS (ES-API positive): 1067.5 (M+1) + . Example 109: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((1r,3S)-3-methoxycyclobutoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0257] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ8.42 (s, 1H), 7.52 (s, 6H), 7.44-7.39 (m, 3H), 7.31-7 .25(m, 1H), 6.79-6.74(m, 2H), 6.34-6.29(m, 1H), 5.49-5.41(m, 1H), 5.38- 5.32(m, 1H), 5.30-5.25(m, 1H), 5.22-5.16(m, 1H), 4.95-4.91(m, 1H), 4.81 -4.77(m, 1H), 4.64-4.59(m, 1H), 4.50-4.45(m, 1H), 4.34-4.29(m, 1H), 4.2 2-4.10(m, 4H), 3.97-3.81(m, 4H), 3.30-3.27(m, 1H), 3.26(s, 3H), 3.16-3 .11(m, 1H), 2.70-2.61(m, 1H), 2.54-2.46(m, 4H), 2.22-2.14(m, 1H), 2.08( d, J=2.1Hz, 4H), 2.00-1.89 (m, 2H), 1.49-1.42 (m, 1H), 1.38-1.33 (m, 3H), 1 .28-1.23 (m, 3H), 1.20-1.15 (m, 3H), 0.86-0.82 (m, 3H), 0.71-0.58 (m, 4H). MS (ES-API positive): 1128.5 (M+1) + . Example 110: (2S,4R)-1-((2S)-2-(4-(4-(((2-((2-oxaspiro[3.5]nonane-7-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6,7-difluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0258] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.47-8.40 (m, 1H), 7.56 (d, J=8.1Hz, 2H), 7.54-7.49 (m, 3H), 7.49-7.46 (m, 2H), 7.45- 7.40 (m, 2H), 6.93-6.82 (m, 2H), 6.35-6.25 (m, 1H), 5.36 (d, J = 10.3Hz, 1H), 5.24 (d, J = 11.9Hz, 1H), 5.17 (br s, 1H), 5.10-5.04 (m, 2H), 4.80 (br d, J=11.8Hz, 1H), 4.65-4.55 (m, 3H), 4.50 (br s, 1H), 4.45 (s, 2H), 4.35-4.27 (m, 3H), 4.17 (q, J=7.2Hz, 2H), 3.94-3.90 (m, 2H), 3.88-3.80 (m, 3H), 3.28 (br d, J=10.7Hz, 1H), 3.12 (brd, J=10.4Hz, 1H), 2.69-2.60 (m, 1H), 2.28-2.20 (m, 1H), 2.13-2.05 (m, 6H), 2.02-1.97 (m, 2H), 1.89 (br d, J=10.0Hz, 1H), 1.64-1.51 (m, 4H), 1.45-1.38 (m, 1H), 1.37-1.32 (m, 3H), 1.17 (d, J=6.7Hz, 3H), 0.88-0.80 (m, 3H), 0.69-0.56 (m, 4H). MS (ES-API positive): 1172.6 (M+1) + . Example 111: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-4-(2-aminobenzo[d]thiazolyl-6-yl)-1-hydroxybut-3-yn-2-yl)-4-hydroxypyrrolidine-2-carboxamide

[0259] This compound was prepared using a method similar to that used in Example 34. 1H NMR (400MHz, CD3OD) δ = 8.39 (s, 1H), 7.68 (d, J = 1.2Hz, 1H), 7.54-7.49 (m, 3H), 7.39 (s, 1H), 7.36-7.23 (m, 3H), 6. 78 (d, J=8.3Hz, 2H), 5.34 (d, J=10.5Hz, 1H), 5.27 (d, J=11.3Hz, 1H), 5.22 (s, 1H), 4.56-4.45 (m, 3H), 4.40 (d, J=5 .0Hz, 2H), 4.35-4.29(m, 1H), 3.98-3.74(m, 7H), 3.44-3.40(m, 3H), 3.19-3.11(m, 1H), 2.66(s, 1H), 2.16-2.01( m, 6H), 1.95-1.88 (m, 1H), 1.34-1.27 (m, 2H), 1.24 (d, J=6.4Hz, 3H), 1.16 (d, J=6.7Hz, 3H), 0.83 (d, J=6.8Hz, 3H). MS (ES-API positive): 1104.3 (M+1) + . Example 112: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-(3-methoxypyrrolidine-1-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0260] This compound was prepared using a method similar to that used in Example 32. 11H NMR (400 MHz, CD3OD) δ 8.40 (s, 1H), 7.54 - 7.46 (m, 5H), 7.44 - 7.38 (m, 4H), 7.25 (s, 1H), 6.79 (br d, J = 7.9 Hz, 2H), 6.30 (d, J = 1.8 Hz, 1H), 5.35 (d, J = 10.4 Hz, 1H), 5.17 (s, 1H), 5.06 (s, 1H), 4.66 - 4.55 (m, 5H), 4.52 - 4.46 (m, 1H), 4.30 - 4.24 (m, 1H), 4.16 (d, J = 7.2 Hz, 3H), 3.97 - 3.88 (m, 1H), 3.98 - 3.87 (m, 1H), 3.96 - 3.87 (m, 1H), 3.86 - 3.83 (m, 1H), 3.86 - 3.82 (m, 1H), 3.87 - 3.82 (m, 1H), 3.87 - 3.80 (m, 1H), 3.86 - 3.78 (m, 1H), 3.86 - 3.77 (m, 1H), 3.86 - 3.77 (m, 1H), 3.87 - 3.77 (m, 1H), 3.87 - 3.76 (m, 1H), 3.87 - 3.76 (m, 1H), 3.86 - 3.75 (m, 1H), 3.86 - 3.75 (m, 1H), 3.75 - 3.75 (m, 1H), 3.75 - 3.75 (m, 1H), 3.75 - 3.72 (m, 1H), 3.69 - 3.68 (m, 1H), 3.80 - 3.67 (m, 1H), 3.81 - 3.65 (m, 1H), 3.75 - 3.64 (m, 1H), 3.75 - 3.63 (m, 1H), 3.75 - 3.62 (m, 1H), 3.75 - 3.60 (m, 1H), 3.69 - 3.55 (m, 1H), 3.51 - 3.40 (m, 1H), 3.39 - 3.35 (m, 1H), 3.37 (d, J = 1.3 Hz, 3H), 3.16 - 3.09 (m, 1H), 2.65 (s, 1H), 2.27 - 2.19 (m, 1H), 2.28 - 2.16 (m, 1H), 2.09 - 2.09 (m, 1H), 2.08 (br s, 3H), 2.11 - 2.06 (m, 1H), 2.03 (s, 1H), 1.91 - 1.85 (m, 1H), 1.34 (t, J = 7.2 Hz, 3H), 1.16 (d, J = 6.6 Hz, 3H), 0.82 - 0.82 (m, 1H), 0.82 (d, J = 6.7 Hz, 3H), 0.55 (br d, J = 7.6 Hz, 3H). MS (ES-API positive): 1113.5 (M+1) + . Example 113: (2S,4R)-1-((2S)-2-(4-(4-(((2-((7-oxaspiro[3.5]nonane-2-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0261] This compound was prepared using a method similar to that used in Example 84. 1 H NMR (400MHz, CD3OD) δ = 8.43 (s, 1H), 7.57 (d, J = 8.2Hz, 2H), 7.54-7.47 (m, 4H), 7.45-7.39 (m, 3H), 7.28 ( d, J=9.4Hz, 1H), 6.87 (d, J=8.2Hz, 2H), 6.31 (d, J=1.9Hz, 1H), 5.38-5.25 (m, 3H), 5.19 (s, 1H), 4.77 (br d, J=11.6Hz, 1H), 4.60(br d, J=2.6Hz, 7H), 4.50-4.44(m, 1H), 4.32(br d, J=9.3Hz, 1H), 4.18 (d, J=7.2Hz, 3H), 3.95 (s, 1H), 3.93-3.81 (m, 3H), 3.60-3.46 (m, 5H), 3.15 (br d, J=9.8Hz, 1H), 2.66 (s, 1H), 2.45 (qd, J=3.9, 11.8Hz, 2H), 2.10 (d, J=2.3Hz, 5H), 2.07-1.88 (m, 5H), 1.66-1.60 (m, 2H), 1.56 (br dd, J=4.2, 6.0Hz, 2H), 1.44(br d, J=7.0Hz, 1H), 1.39-1.28 (m, 4H), 1.25 (d, J=6.3Hz, 3H), 1.17 (d, J=6.7Hz, 3H), 0.83 (d, J=6.7Hz, 3H). MS (ES-API positive): 1168.4 (M+1) + . Example 114: (2S,4R)-1-((2S)-2-(4-(4-(((2-((6-oxaspiro[3.4]octan-2-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0262] This compound was prepared using a method similar to that used in Example 84. 1 H NMR (400MHz, CD3OD) δ = 8.50-8.39 (m, 1H), 7.65-7.49 (m, 6H), 7.47-7.40 (m, 3H), 7.34-7.22 (m, 1H), 6.88 (d, J = 8.1Hz, 1H), 6.81 (d, J = 8 .4Hz, 1H), 6.37-6.29(m, 1H), 5.39-5.34(m, 1H), 5.33-5.25(m, 2H), 5.24-5.18(m, 1H), 4.82-4.76(m, 1H), 4.66-4.58(m, 1H), 4.50(br s, 1H), 4.37-4.29 (m, 1H), 4.24-4.09 (m, 3H), 3.99-3.92 (m, 2H), 3.92-3.83 (m, 2H), 3.82-3.74 (m, 2H), 3.73-3.69 (m, 2H), 3.29 (br s, 1H), 3.18-3.11(m, 1H), 2.72-2.57(m, 3H), 2.56-2.48(m, 1H), 2.37-2.16(m, 3H), 2.11(br dd, J=2.4, 5.1Hz, 4H), 2.07-1.92 (m, 4H), 1.54-1.43 (m, 1H), 1.40-1.34 (m, 3H), 1.31-1.25 (m, 3H), 1.19 (d, J=6.8Hz, 3H), 0.85 (d, J=6.8Hz, 3H), 0.76-0.58 (m, 3H), 0.59-0.58 (m, 1H). MS (ES-API positive): 1154.5 (M+1) + . Example 115: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((hexahydro-1H-cyclopenta[c]furan-5-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0263] This compound was prepared using a method similar to that used in Example 84. 1 H NMR (400MHz, CDCl3) δ7.99 (d, J=2.0Hz, 1H), 7.78 (br d, J=8.4Hz, 1H), 7.57-7.47 (m, 3H), 7.42-7.32 (m, 4H), 7.27-7.21 (m, 3H), 7.10-7.01 (m, 1H), 6.68 (dd, J=2.4, 7.9Hz, 2 H), 6.22 (d, J = 1.6Hz, 1H), 5.94 (quin, J = 6.8Hz, 1H), 5.35-5.25 (m, 2H), 5.24-5.14 (m, 2H), 5.10-4.99 (m, 2H), 4.67 (br t, J=8.4Hz, 1H), 4.53(br s, 1H), 4.38-4.31(m, 1H), 4.25(br d, J=9.2Hz, 1H), 4.12 (q, J=7.2Hz, 2H), 4.03-3.96 (m, 2H), 3.93-3.75 (m, 5H), 3.49-3.35 (m, 2H), 3.3 2-3.22(m, 2H), 2.68-2.43(m, 4H), 2.19-2.10(m, 7H), 1.81-1.60(m, 4H), 1.44-1.35(m, 5H), 1.17(br d, J=6.4Hz, 3H), 1.11 (d, J=6.4Hz, 3H), 0.83 (br d, J=6.4Hz, 3H), 0.59-0.40 (m, 4H). MS (ES-API positive): 1154.5 (M+1) + . Example 116: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-1-hydroxy-4-(2-methyl-2H-indazol-4-yl)but-3-yn-2-yl)pyrrolidine-2-carboxamide

[0264] This compound was prepared using a method similar to that used in Example 34. 1 H NMR (400MHz, CD3OD) δ8.43-8.35 (m, 1H), 7.95-7.89 (m, 1H), 7.60-7.46 (m, 4H), 7.42-7.33 (m, 2H), 7.31-7.25 (m, 1H), 6.69 (s, 2H), 5.41-5 .33 (m, 1H), 5.30-5.20 (m, 2H), 5.10-5.03 (m, 1H), 4.80 (d, J=11.6Hz, 1H), 4.68-4.60 (m, 1H), 4.52 (dd, J=7.5, 16.2Hz, 2H), 4.43-4.37 (m, 2 H), 4.32 (d, J = 8.9Hz, 1H), 4.03-3.97 (m, 1H), 3.94 (s, 1H), 3.89-3.77 (m, 5H), 3.44-3.40 (m, 3H), 3.14 (d, J = 9.8Hz, 1H), 2.89-2.80 (m, 3H) , 2.33-2.01 (m, 7H), 1.94-1.88 (m, 1H), 1.48-1.42 (m, 1H), 1.24 (d, J=6.3Hz, 3H), 1.18-1.13 (m, 3H), 0.84-0.75 (m, 3H), 0.69-0.58 (m, 4H). MS (ES-API positive): 1087.0 (M+1) + . Example 117: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-1-hydroxy-4-(2-methylbenzo[d]thiazolyl)but-3-yne-2-yl)pyrrolidine-2-carboxamide

[0265] This compound was prepared using a method similar to that used in Example 34. 1 H NMR (400MHz, CD3OD) δ8.43-8.37(m, 1H), 8.34-8.27(m, 1H), 7.63-7.56(m, 1H), 7 .55(d, J=8.2Hz, 3H), 7.44-7.38(m, 1H), 7.30-7.13(m, 3H), 6.73(s, 2H), 5.38-5 .32(m,1H),5.30-5.25(m,1H),5.23-5.20(m,1H),5.05-5.01(m,1H),4.93-4.89 (m, 1H), 4.83-4.77 (m, 1H), 4.61-4.57 (m, 1H), 4.56-4.45 (m, 2H), 4.39 (d, J=5.0H z, 2H), 4.34-4.29 (m, 1H), 4.22 (s, 3H), 4.01-3.96 (m, 1H), 3.95-3.91 (m, 1H), 3. 91-3.75(m, 5H), 3.41(s, 3H), 3.17-3.11(m, 1H), 2.67-2.58(m, 1H), 2.20(s, 1H), 2.16-2.11(m, 1H), 2.08(d, J=2.3Hz, 3H), 1.93(s, 1H), 1.48-1.40(m, 1H), 1.24( d, J=6.4Hz, 3H), 1.16 (d, J=6.7Hz, 3H), 0.82 (d, J=6.6Hz, 3H), 0.72-0.56 (m, 4H). MS (ES-API positive): 1103.4 (M+1) + . Example 118: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-1-hydroxy-4-(thiazo[4,5-c]pyridin-7-yl)but-3-yn-2-yl)pyrrolidine-2-carboxamide

[0266] This compound was prepared using a method similar to that used in Example 34. 1 H NMR (400MHz, CD3OD) δ = 9.37-9.21 (m, 1H), 9.04 (s, 1H), 8.57-8.41 (m, 1H), 8.37-8.14 (m, 1H), 7.41 (br d, J=6.1Hz, 3H), 7.56-7.38 (m, 1H), 7.31-7.28 (m, 1H), 7.18 (d, J=9.9Hz, 1H), 6.76-6.50 (m, 2H), 5.25 (br d, J=10.4Hz, 2H), 4.30 (br d, J=4.6Hz, 2H), 4.22(br d, J=9.5Hz, 1H), 3.93-3.80(m, 4H), 3.78-3.66(m, 5H), 3.34-3.30(m, 3H), 3.08-3.01(m, 1H), 2.60-2.48(m, 2H), 2.18(br dd, J=7.1, 13.4Hz, 1H), 2.03 (br d, J=8.9Hz, 2H), 1.98 (br d, J=2.0Hz, 3H), 1.81 (br d, J=10.7Hz, 1H), 1.38-1.32 (m, 1H), 1.18 (br s, 2H), 1.16-1.13 (m, 3H), 1.10-1.03 (m, 3H), 0.76-0.68 (m, 3H), 0.57-0.46 (m, 4H). MS (ES-API positive): 1090.3 (M+1) + . Example 119: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-2-(3,3-difluoro-2-methoxypropoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0267] This compound was prepared using a method similar to that used in Example 84. 1 H NMR (400MHz, CD3OD) δ8.50-8.46(m, 1H), 8.16-8.12(m, 1H), 7.72(br s, 1H), 7.63-7.50 (m, 8H), 7.29 (d, J=9.4Hz, 1H), 6.78-6.71 (m, 3H), 6. 10 (d, J=4.3Hz, 1H), 5.74 (s, 1H), 5.39 (d, J=10.1Hz, 1H), 5.06 (s, 1H), 5 .01-4.94(m, 2H), 4.88-4.72(m, 6H), 4.67-4.56(m, 3H), 4.48(s, 1H), 4. 45-4.33(m, 3H), 4.16-4.07(m, 1H), 4.00-3.86(m, 3H), 3.84-3.72(m, 1H ), 3.64-3.60 (m, 1H), 3.59 (s, 4H), 2.67 (s, 1H), 2.54 (d, J = 10.8Hz, 1H), 2.30 (brd, J = 12.0Hz, 1H), 2.20 (dd, J = 8.0, 13.1Hz, 1H), 2.14 (d, J = 2.3 Hz, 3H), 1.93 (ddd, J=4.4, 9.0, 13.1Hz, 1H), 1.57-1.51 (m, 1H), 1.48-1. 44 (m, 3H), 1.29-1.25 (m, 3H), 1.18 (d, J=6.7Hz, 3H), 0.89-0.71 (m, 8H). MS (ES-API positive): 1152.5 (M+1) + . Example 120: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclobutyl-7-(6,7-difluoro-5-methyl-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0268] This compound was prepared using a method similar to that used in Example 32. 1 H NMR (400MHz, CD3OD) δ 8.90-8.85 (m, 1H), 8.44-8.41 (m, 1H), 7.89-7.84 (m, 1H), 7.59-7.51 (m, 2H), 7.48-7.44 (m, 4H), 7.37 (d, J=3.0Hz, 1H), 6.80 (d, J = 8.2Hz, 2H), 5.38-5.23 (m, 4H), 5.06 (t, J = 6.1Hz, 1H), 4.76 (d, J = 11.6Hz, 1H), 4.64-4.58 (m, 2H), 4.50 (brs, 1H), 4.37 (br d, J=8.7Hz, 1H), 4.01-3.96 (m, 3H), 3.92 (br dd, J=4.0, 8.3Hz, 2H), 3.85 (d, J=6.1Hz, 2H), 3.58-3.50 (m, 2H), 3.34 (br s, 1H), 3.25-3.13 (m, 2H), 2.66 (s, 1H), 2.49-2.47 (m, 3H), 2.28-2.19 (m, 1H), 2.16-2.10(m, 3H), 2.06(d, J=2.6Hz, 3H), 2.04-1.99(m, 2H), 1.93(br d, J=10.5Hz, 2H), 1.88-1.80 (m, 2H), 1.76-1.62 (m, 4H), 1.17 (d, J=6.7Hz, 3H), 0.86-0.81 (m, 3H). MS (ES-API positive): 1149.5 (M+1) + . Example 121: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-(((1r,4S)-4-methoxycyclohexyl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0269] This compound was prepared using a method similar to that used in Example 84. 1 H NMR (400MHz, CD3OD) δ0.56-0.69 (m, 4H) 0.83 (d, J=6.68Hz, 3H) 1.17 (d, J=6.56 Hz, 3H) 1.25 (d, J = 6.32Hz, 3H) 1.29 (d, J = 4.29Hz, 1H) 1.32-1.37 (m, 4H) 1.39-1. 46(m,2H)1.60-1.68(m,2H)1.88-1.98(m,2H)2.07-2.11(m,5H)2.16-2.27(m,3 H)2.60(s,1H)3.10-3.16(m,1H)3.28-3.30(m,1H)3.32-3.34(m,3H)3.80-3.89 (m, 2H) 3.90-3.96 (m, 2H) 4.07-4.13 (m, 1H) 4.14-4.20 (m, 2H) 4.31 (d, J = 8.82H z, 1H) 4.45-4.51 (m, 1H) 4.56-4.63 (m, 2H) 4.76-4.80 (m, 1H) 4.86 (s, 1H) 5.13 (J =8.29, 4.23Hz, 2H) 5.30 (s, 1H) 5.32-5.36 (m, 1H) 6.28-6.33 (m, 1H) 6.74-6.80 ( m, 2H) 7.26-7.30 (m, 1H) 7.38-7.43 (m, 3H) 7.47-7.56 (m, 6H) 8.39-8.44 (m, 1H). MS (ES-API positive): 1156.5 (M+1) + . Example 122: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-2-(3,3-difluoro-2-methoxypropoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0270] This compound was prepared using a method similar to that used in Example 84. 1 H NMR (400MHz, CD3OD) δ = 8.55-8.52 (m, 1H), 8.32-8.29 (m, 1H), 7.93 (s, 1H), 7.63- 7.59(m, 4H), 7.57-7.54(m, 2H), 7.32(d, J=9.4Hz, 1H), 6.86-6.83(m, 1H), 6.78( d, J=8.1Hz, 2H), 6.25-5.95 (m, 1H), 5.75 (s, 1H), 5.42 (d, J=10.3Hz, 1H), 5.09-4 .96 (m, 2H), 4.88 (d, J=6.2Hz, 2H), 4.78 (s, 2H), 4.73 (dd, J=5.4, 11.8Hz, 2H), 4. 66-4.59(m, 2H), 4.50-4.42(m, 3H), 4.12(t, J=6.3Hz, 1H), 4.00-3.91(m, 3H), 3. 82(s, 1H), 3.62-3.59(m, 4H), 2.70-2.64(m, 1H), 2.55(d, J=11.7Hz, 1H), 2.31(d , J=11.2Hz, 1H), 2.24-2.14(m, 4H), 1.98-1.89(m, 1H), 1.52-1.46(m, 4H), 1.30- 1.26 (m, 3H), 1.19 (d, J=6.6Hz, 3H), 0.86 (d, J=6.6Hz, 3H), 0.76 (d, J=7.7Hz, 4H). MS (ES-API positive): 1152.5 (M+1) + . Example 123: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-1-hydroxy-4-phenylbut-3-yn-2-yl)pyrrolidine-2-carboxamide

[0271] This compound was prepared using a method similar to that used in Example 34. 1 H NMR (400MHz, CD3OD) δ8.44 (s, 1H), 7.63 (s, 1H), 7.61-7.58 (m, 1H), 7.56 (d, J=8.2Hz, 2H) , 7.46-7.39 (m, 2H), 7.35-7.32 (m, 2H), 7.32-7.24 (m, 2H), 6.75 (d, J=8.2Hz, 2H), 5.75 (br s, 1H), 5.38 (d, J = 10.3Hz, 1H), 4.96 (br t, J = 5.8Hz, 2H), 4.83-4.76 (m, 3H), 4.68 (br dd, J=3.3, 11.3Hz, 1H), 4.63-4.54 (m, 4H), 4.52-4.47 (m, 1H), 4.02-3.96 (m, 1H), 3.93-3.88 (m, 1H), 3.85 (dt, J=3.3, 6.3Hz, 1H), 3.77 (d, J=5.8Hz, 2H), 3.66-3.59 (m, 1H), 3.42 (s, 3H), 2.67-2.58 (m, 1H), 2.53 (br d, J=11.4Hz, 1H), 2.32-2.22(m, 2H), 2.13(br d, J=2.5Hz, 4H), 1.56(br t, J=6.7Hz, 1H), 1.30 (d, J=6.4Hz, 3H), 1.19-1.14 (m, 3H), 0.84 (d, J=6.6Hz, 3H), 0.79-0.71 (m, 4H). MS (ES-API positive): 1032.9 (M+1) + . Example 124: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-(4-methoxypiperidin-1-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0272] This compound was prepared using a method similar to that used in Example 32. 1 H NMR (400MHz, CD3OD) δ = 8.51 (s, 1H), 7.75-7.68 (m, 3H), 7.63 (s, 1H), 7.53-7.46 (m , 5H), 7.38 (d, J=9.5Hz, 1H), 7.03 (d, J=8.3Hz, 2H), 6.44 (d, J=2.3Hz, 1H), 5.56 (br s, 1H), 5.40 (d, J=10.4Hz, 1H), 5.09-5.04 (m, 1H), 4.71 (s, 1H), 4.61-4.54 (m, 3H), 4.50 (brs, 1H), 4.23 (q, J=7.4Hz, 2H), 3.94-3.76 (m, 6H), 3.61-3.46 (m, 5H), 3.33 (s, 3H), 2.64 (brd, J=11.0Hz, 1H), 2.46 (br d, J=11.3Hz, 1H), 2.21 (d, J=2.4Hz, 5H), 2.01 (s, 2H), 1.88 (br s, 2H), 1.59 (br s, 3H), 1.38 (t, J=7.2Hz, 3H), 1.33-1.22 (m, 1H), 1.17 (d, J=6.7Hz, 3H), 0.83 (br d, J=6.7Hz, 4H), 0.79-0.69 (m, 3H). MS (ES-API positive): 1128.2 (M+1) + . Example 125: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-(3-(methoxymethyl)pyrrolidine-1-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0273] This compound was prepared using a method similar to that used in Example 32. 1 H NMR (400MHz, CD3OD) δ = 8.56-8.52 (m, 1H), 8.09 (d, J = 2.6Hz, 1H), 7.73 (br s, 3H), 7.61-7.55 (m, 4H), 7.50 (br s, 1H), 7.40 (d, J = 10.0Hz, 1H), 7.06 (br s, 2H), 6.70 (d, J=2.5Hz, 1H), 5.56 (br s, 1H), 5.42 (d, J=10.0Hz, 1H), 5.10 (t, J=6.0Hz, 1H), 4.72 (br s, 1H), 4.66-4.58 (m, 3H), 4.52 (br s, 1H), 4.37 (q, J=7.4Hz, 2H), 3.97-3.84 (m, 5H), 3.79 (brs, 2H), 3.58 (br s, 2H), 3.48 (br d, J=18.5Hz, 2H), 3.35 (br s, 3H), 2.65 (br s, 2H), 2.48 (br d, J=12.4Hz, 1H), 2.35-1.73 (m, 10H), 1.59 (br s, 1H), 1.46 (t, J=7.3Hz, 3H), 1.31 (br s, 1H), 1.19 (d, J=6.6Hz, 3H), 0.88-0.81 (m, 4H), 0.75 (br s, 3H). MS (ES-API positive): 1128.2 (M+1) + . Example 126: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-(3-methoxyazacyclobutane-1-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0274] This compound was prepared using a method similar to that used in Example 32. 1 H NMR (400MHz, CD3OD) δ = 8.52 (s, 1H), 8.25 (d, J = 2.6Hz, 1H), 7.82 (br s, 1H), 7.61 (s, 6H), 7.51 (br s, 1H), 7.33 (br d, J=9.3Hz, 1H), 6.87-6.80 (m, 3H), 5.67 (br s, 1H), 5.43 (d, J=10.3Hz, 1H), 5.10 (t, J=6.0Hz, 1H), 4.75 (br s, 1H), 4.67-4.58 (m, 3H), 4.53 (br s, 2H), 4.43 (q, J=7.2Hz, 3H), 3.94 (br s, 2H), 3.88 (d, J=5.8Hz, 2H), 3.83-3.68 (m, 5H), 3.58 (br d, J=5.8Hz, 4H), 3.41 (s, 3H), 2.67 (br s, 1H), 2.52 (br d, J=11.0Hz, 1H), 2.27 (br d, J=12.8Hz, 2H), 2.17 (s, 3H), 2.07-2.00 (m, 1H), 1.51-1.47 (m, 4H), 1.20 (br d, J=6.7Hz, 3H), 0.87 (br d, J=6.4Hz, 4H), 0.74 (br s, 3H); mS (ES-API positive): 1099.3 (M+1) + . Example 127: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((4-methoxycyclohexyl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0275] This compound was prepared using a method similar to that used in Example 84. 1 H NMR (500MHz, CD3OD) δ0.58-0.69 (m, 4H) 0.83 (d, J = 6.56Hz, 3H) 1.14-1.18 (m, 3H) 1. 21(d, J=6.26Hz, 3H) 1.27-1.30 (m, 1H) 1.34 (t, J=7.25Hz, 4H) 1.39 (s, 2H) 1.59-1.66 (m, 2H) 1.88-1.93 (m, 1H) 2.01-2.04 (m, 1H) 2.06-2.12 (m, 6H) 2.18-2.24 (m, 3H) 2.6 6(s,1H)3.11-3.16(m,1H)3.32-3.34(m,3H)3.80-3.90(m,2H)3.91-3.96(m,2H)4.0 5-4.13(m,1H)4.14-4.20(m,2H)4.27-4.35(m,1H)4.47-4.52(m,1H)4.55-4.67(m, 2H)4.76-4.82(m,1H)4.89-4.91(m,1H)5.11-5.15(m,1H)5.18-5.21(m,1H)5.24-5. 31(m,1H)5.32-5.38(m,1H)6.28-6.33(m,1H)6.74-6.81(m,2H)7.25-7.31(m,1H)7 .40-7.45(m,3H)7.45-7.50(m,2H)7.50-7.53(m,3H)7.56(s,1H)8.38-8.45(m,1H). MS (ES-API positive): 1156.4 (M+1) + . Example 128: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclobutyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0276] This compound was prepared using a method similar to that used in Example 84. 1 H NMR (400MHz, CD3OD) δ8.45-8.41 (m, 1H), 7.89 (s, 1H), 7.53-7.47 (m, 5H), 7.44-7.41 (m, 2H), 7.32-7.2 7 (m, 2H), 6.77 (d, J=8.1Hz, 2H), 6.33-6.30 (m, 1H), 5.35 (d, J=10.3Hz, 1H), 5.30-5.25 (m, 2H), 4.76 (br d, J=11.6Hz, 2H), 4.66-4.60(m, 4H), 4.50(br s, 1H), 4.43-4.37 (m, 3H), 4.17 (q, J=7.0Hz, 2H), 4.13-4.08 (m, 1H), 3.96-3.90 ( m, 3H), 3.84-3.79 (m, 1H), 3.43 (s, 3H), 3.35 (s, 1H), 3.27-3.20 (m, 1H), 3.16 (br d, J=9.3Hz, 1H), 2.68-2.63(m, 1H), 2.24-2.18(m, 1H), 2.12(br d, J=9.8Hz, 1H), 2.04 (s, 3H), 2.01-1.96 (m, 2H), 1.94-1.91 (m, 1H), 1.76 (br d, J=7.9Hz, 1H), 1.73-1.64 (m, 3H), 1.35 (t, J=7.2Hz, 3H), 1.25 (d, J=6.3H z, 3H), 1.21 (d, J=6.3Hz, 2H), 1.16 (d, J=6.4Hz, 3H), 0.83 (d, J=6.6Hz, 3H). MS (ES-API positive): 1130.5 (M+1) + . Example 129: (2S,4R)-1-((2S)-2-(4-(4-(((2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0277] This compound was prepared using a method similar to that used in Example 32. 1 H NMR (400MHz, CD3OD) δ8.90-8.85 (m, 1H), 8.44-8.41 (m, 1H), 7.58-7.53 (m, 2H), 7.52-7. 50(m, 1H), 7.47-7.47(m, 1H), 7.48-7.45(m, 3H), 7.42-7.38(m, 1H), 7.31-7.25(m, 1H), 6 .84-6.79(m, 2H), 5.38-5.33(m, 1H), 5.28-5.23(m, 1H), 5.20(s, 1H), 5.15-5.10(m, 1H), 5.06 (t, J=6.0Hz, 1H), 4.81-4.76 (m, 1H), 4.67 (s, 4H), 4.61 (d, J=6.8Hz, 3H), 4.52-4.47 (m, 1H), 4.35-4.30 (m, 1H), 3.98 (s, 1H), 3.96-3.91 (m, 1H), 3.87-3.83 (m, 3H), 3.19-3.1 3(m, 1H), 2.84-2.77(m, 2H), 2.66-2.62(m, 1H), 2.49-2.47(m, 3H), 2.42-2.36(m, 2H), 2. 27-2.20 (m, 1H), 2.12 (d, J = 9.7Hz, 1H), 2.08 (d, J = 2.4Hz, 3H), 2.05-2.01 (m, 1H), 1.95-1 .90 (m, 1H), 1.47-1.41 (m, 1H), 1.18-1.15 (m, 3H), 0.85-0.81 (m, 3H), 0.68-0.58 (m, 4H). MS (ES-API positive): 1129.4 (M+1) + . Example 130: (2S,4R)-1-((2S)-2-(4-(4-(((2-((2-oxaspiro[3.5]nonane-7-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0278] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ8.43 (s, 1H), 7.56 (br d, J=8.1Hz, 2H), 7.53-7.50 (m, 2H), 7.50-7.46 (m, 2H), 7.46-7.40 (m, 3H), 7.28 (br d, J=9.6Hz, 1H), 6.86 (br d, J=7.9Hz, 2H), 6.31 (d, J=1.5Hz, 1H), 5.35 (br d, J=10.2Hz, 1H), 5.24 (br d, J=12.1Hz, 1H), 5.18 (br s, 1H), 5.10-5.01 (m, 2H), 4.78 (br d, J=11.4Hz, 1H), 4.64-4.60 (m, 1H), 4.50 (br s, 1H), 4.46 (s, 2H), 4.35-4.26 (m, 3H), 4.17 (q, J=7.2Hz, 2H), 4.10 (br t, J=6.1Hz, 1H), 3.94 (br s, 2H), 3.89 (br s, 1H), 3.83 (br d, J=8.9Hz, 1H), 3.13 (br d, J=10.5Hz, 1H), 2.68-2.61 (m, 1H), 2.24-2.17 (m, 1H), 2.10 (br d, J=1.2Hz, 6H), 2.03-1.96 (m, 3H), 1.90 (br d, J=9.8Hz, 1H), 1.64-1.54 (m, 4H), 1.48-1.42 (m, 1H), 1.35 (br t, J=7.2Hz, 4H), 1.21 (d, J=6.3Hz, 3H), 1.16 (br d, J=6.4Hz, 3H), 0.83 (br d, J=6.6Hz, 3H), 0.71-0.58 (m, 4H). MS (ES-API positive): 1168.6 (M+1) + . Example 131: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((1r,3S)-3-methoxycyclobutoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0279] This compound was prepared using a method similar to that used in Example 84. 1 H NMR (400MHz, CD3OD) δ8.43 (s, 1H), 7.56-7.46 (m, 6H), 7.45-7.39 (m, 3H), 7.31-7.26(m, 1H), 6.79(s, 2H), 6.34-6.28(m, 1H), 5.48-5.41(m, 1H), 5.3 8-5.33(m, 1H), 5.31(s, 1H), 5.21-5.17(m, 1H), 4.82-4.76(m, 2H), 4.68- 4.58(m, 2H), 4.52-4.47(m, 1H), 4.35-4.29(m, 1H), 4.20-4.08(m, 4H), 3.9 6-3.81(m, 4H), 3.30-3.27(m, 1H), 3.25(s, 3H), 3.16-3.11(m, 1H), 2.68- 2.60 (m, 1H), 2.53-2.45 (m, 4H), 2.26-2.18 (m, 1H), 2.08 (s, 4H), 2.03-1.9 9(m, 1H), 1.94-1.88(m, 1H), 1.48-1.42(m, 1H), 1.37-1.32(m, 3H), 1.21( d, J=6.3Hz, 2H), 1.19-1.14 (m, 3H), 0.87-0.80 (m, 3H), 0.69-0.57 (m, 4H). MS (ES-API positive): 1129.2 (M+1) + . Example 132: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((hexahydro-1H-cyclopenta[c]furan-5-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide

[0280] This compound was prepared using a method similar to that used in Example 84. 1H NMR (500MHz, CD3OD) δ8.89 (s, 1H), 8.42 (s, 1H), 7.54 (d, J=1.8Hz, 1H), 7.54-7.52 (m, 2H), 7.49-7.47 (m, 1H), 7 .48-7.45 (m, 2H), 7.46-7.45 (m, 1H), 7.41 (s, 1H), 7.28 (d, J=9.6Hz, 1H), 6.81 (dd, J=2.2, 8.3Hz, 2H), 5.92 (br d, J=5.3Hz, 1H), 5.35 (d, J=10.2Hz, 1H), 5.31-5.21 (m, 2H), 5.01-4.92 (m, 2H), 4.91 (br d, J=1.8Hz, 2H), 4.79 (br t, J=3.1Hz, 1H), 4.49 (br d, J=1.2Hz, 1H), 4.33 (br d, J=9.8Hz, 1H), 4.12 (t, J=6.3Hz, 1H), 3.97-3.83 (m, 7H), 3.39 (dd, J=6.9, 10.7Hz, 1H), 3.41-3.36 (m, 1H), 3.29-3.26 (m, 1H), 3.15 (br d, J=10.5Hz, 1H), 2.67(s, 1H), 2.56-2.46(m, 5H), 2.18(br s, 1H), 2.12 (brs, 1H), 2.10 (s, 3H), 2.14-2.08 (m, 1H), 2.07-2.02 (m, 2H), 2.00-1.91 (m, 2H), 1.81 (br s, 1H), 1.63-1.55 (m, 1H), 1.45 (s, 1H), 1.32-1.29 (m, 1H), 1.25 (d, J=6.3Hz, 3H), 1.18 (d, J=6.6Hz, 3H), 0.86-0.82 (m, 3H), 0.68 (br s, 1H), 0.71-0.59 (m, 3H), 0.64-0.59 (m, 1H). MS (ES-API positive): 1157.4 (M+1) + . Example 133: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-1-hydroxy-4-(1H-indazol-4-yl)but-3-yn-2-yl)pyrrolidine-2-carboxamide

[0281] This compound was prepared using a method similar to that used in Example 34. 1 H NMR (400MHz, CD3OD) δ8.43 (s, 1H), 7.56 (br d, J=8.1Hz, 2H), 7.53-7.50 (m, 2H), 7.50-7.46 (m, 2H), 7.46-7.40 (m, 3H), 7.28 (br d, J=9.6Hz, 1H), 6.86 (br d, J=7.9Hz, 2H), 6.31 (d, J=1.5Hz, 1H), 5.35 (br d, J=10.2Hz, 1H), 5.24 (br d, J=12.1Hz, 1H), 5.18 (br s, 1H), 5.10-5.01 (m, 2H), 4.78 (br d, J=11.4Hz, 1H), 4.64-4.60 (m, 1H), 4.50 (br s, 1H), 4.46 (s, 2H), 4.35-4.26 (m, 3H), 4.17 (q, J=7.2Hz, 2H), 4.10 (br t, J=6.1Hz, 1H), 3.94 (br s, 2H), 3.89 (br s, 1H), 3.83 (br d, J=8.9Hz, 1H), 3.13 (br d, J=10.5Hz, 1H), 2.68-2.61 (m, 1H), 2.24-2.17 (m, 1H), 2.10 (br d, J=1.2Hz, 6H), 2.03-1.96 (m, 3H), 1.90 (br d, J=9.8Hz, 1H), 1.64-1.54 (m, 4H), 1.48-1.42 (m, 1H), 1.35 (br t, J=7.2Hz, 4H), 1.21 (d, J=6.3Hz, 3H), 1.16 (br d, J=6.4Hz, 3H), 0.83 (br d, J=6.6Hz, 3H), 0.71-0.58 (m, 4H). MS (ES-API positive): 1072.5 (M+1) + . Example 134: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-1-hydroxy-4-(1-methyl-1H-indazol-4-yl)but-3-yn-2-yl)pyrrolidine-2-carboxamide

[0282] This compound was prepared using a method similar to that used in Example 34. 1 H NMR (400MHz, CD3OD) δ8.40 (s, 1H), 8.12 (s, 1H), 7.56 (br d, J=8.5Hz, 4H), 7.35 (br s, 2H), 7.31-7.24 (m, 2H), 6.71 (s, 2H), 5.40-5.32 (m, 1H), 5.31-5.23 (m, 1H), 5.23-5.18 (m, 1H), 5.08 (s, 1H), 4.82- 4.77(m, 1H), 4.59-4.47(m, 2H), 4.43-4.36(m, 2H), 4.33-4.28(m, 1H), 4.08-3.95(m, 4H), 3.94-3.88(m, 2H), 3.78(br s, 4H), 3.41 (s, 3H), 3.30-3.26 (m, 1H), 3.15-3.10 (m, 1H), 2.69-2.59 (m, 1H), 2.31-2.23 (m, 1H), 2.19-2.12 (m, 1H), 2.08 (br d, J=2.3Hz, 4H), 1.92-1.87 (m, 1H), 1.47-1.41 (m, 1H), 1.24 (d, J=6.3Hz, 3H), 1.16 (d, J=6.7Hz, 3H), 0.87-0.76 (m, 3H), 0.61 (br d, J=5.2Hz, 4H). MS (ES-API positive): 1087.1 (M+1) + . Example 135: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((1S,3R)-3-methoxycyclobutoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide

[0283] This compound was prepared using a method similar to that used in Example 84. 1 H NMR (400MHz, CD3OD) δ8.88 (s, 1H), 8.41 (s, 1H), 7.57-7.50 (m, 3H), 7.49-7.43 (m, 4H), 7.40 (s, 1H), 7.28 (d, J=9.9Hz, 1H), 6.76 (d, J=8.1Hz, 2H), 5.48-5.40 (m, 1H), 5.38-5.31(m, 1H), 5.30-5.24(m, 1H), 5.22-5.17(m, 1H), 4.88-4.82(m, 3H), 4.81- 4.76(m, 1H), 4.62-4.57(m, 1H), 4.51-4.45(m, 1H), 4.34-4.29(m, 1H), 4.20-4.14( m, 1H), 4.14-4.06 (m, 1H), 3.98-3.91 (m, 2H), 3.90-3.78 (m, 2H), 3.25 (s, 3H), 3.17 -3.09(m, 1H), 2.69-2.61(m, 1H), 2.52-2.47(m, 6H), 2.22-2.13(m, 1H), 2.08(d, J= 2.3Hz, 4H), 2.01-1.87 (m, 2H), 1.49-1.41 (m, 1H), 1.25 (d, J=6.4Hz, 3H), 1.17 (d, J =6.6Hz, 3H), 0.83 (d, J = 6.7Hz, 3H), 0.73-0.54 (m, 4H); mS (ES-API positive): 1131.4 (M+1) + . Example 136: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclobutyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((1r,3S)-3-methoxycyclobutoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0284] This compound was prepared using a method similar to that used in Example 84. 1 H NMR (500MHz, CD3OD) δ8.42-8.40 (m, 1H), 7.88 (s, 1H), 7.53-7.49 (m, 5H), 7.42 (d, J=8.2Hz, 2H), 7.32-7.27 (m, 2H) , 6.75 (d, J = 8.1Hz, 2H), 6.32-6.30 (m, 1H), 5.47-5.42 (m, 1H), 5.34 (d, J = 10.2Hz, 1H), 5.30-5.24 (m, 2H), 4.58 (br s, 3H), 4.48(br s, 1H), 4.39(br d, J=7.5Hz, 1H), 4.20-4.15(m, 3H), 4.14-4.10(m, 1H), 3.99(br s, 1H), 3.95-3.91 (m, 2H), 3.89-3.85 (m, 1H), 3.46-3.33 (m, 2H), 3.26-3.25 (m, 3H ), 3.24-3.17(m, 2H), 2.68-2.63(m, 1H), 2.51-2.48(m, 3H), 2.20-2.13(m, 2H), 2. 03(d, J=2.4Hz, 3H), 1.98-1.93(m, 3H), 1.76-1.62(m, 4H), 1.35(t, J=7.2Hz, 3H), 1.29 (s, 1H), 1.25 (d, J=6.4Hz, 3H), 1.17 (d, J=6.6Hz, 3H), 0.84 (d, J=6.7Hz, 3H). MS (ES-API positive): 1142.5 (M+1) + . Example 137: (2S,4R)-1-((2S)-2-(4-(4-(((2-((2-oxaspiro[3.5]nonane-7-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclobutyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0285] This compound was prepared using a method similar to that used in Example 32. 1H NMR (500MHz, CD3OD) δ8.43-8.40 (m, 1H), 7.88 (s, 1H), 7.56-7.51 (m, 3H), 7. 50-7.46(m, 2H), 7.44-7.42(m, 2H), 7.36-7.33(m, 1H), 7.28(d, J=10.1Hz, 1H ), 6.84 (d, J=8.2Hz, 2H), 6.31-6.28 (m, 1H), 5.35 (d, J=10.2Hz, 1H), 5.26-5. 21(m, 2H), 5.10-5.05(m, 2H), 4.76-4.71(m, 1H), 4.61-4.57(m, 3H), 4.50(br s, 1H), 4.46 (s, 2H), 4.39-4.27 (m, 3H), 4.17 (q, J=7.3Hz, 2H), 3.97-3.94 (m, 1H), 3.94-3.91 (m, 1H), 3.89 (br s, 1H), 3.86 (d, J=6.3Hz, 1H), 3.62-3.51 (m, 1H), 3.62-3.51 (m, 1H), 3.28-3.21 (m, 1H), 3.15 (br d, J=9.6Hz, 1H), 2.68-2.63 (m, 1H), 2.23 (br dd, J=8.1, 13.1Hz, 1H), 2.16-2.09(m, 3H), 2.05-2.03(m, 3H), 2.02-2.01(m, 1H), 2.00-1.97(m, 2H), 1.92(br d, J=10.1Hz, 1H), 1.74-1.70 (m, 2H), 1.69-1.65 (m, 1H), 1.60-1.56 (m, 2H), 1.36-1. 32 (m, 4H), 1.28 (s, 2H), 1.26-1.22 (m, 1H), 1.16 (d, J=6.6Hz, 3H), 0.91-0.81 (m, 4H). MS (ES-API positive): 1168.5 (M+1) + . Example 138: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-2-cyclopropyl-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide

[0286] This compound was prepared using a method similar to that used in Example 84. 1 H NMR (400MHz, CD3OD) δ = 8.94-8.86 (m, 1H), 8.43 (s, 1H), 7.55 (br t, J = 8.6Hz, 5H), 7.50-7.40 (m, 3H), 7.33-7.26 (m, 1H), 6.82 (br d, J=7.9Hz, 2H), 5.40-5.30 (m, 2H), 5.29-5.22 (m, 2H), 5.07 (br d, J=3.8Hz, 1H), 4.83-4.77 (m, 2H), 4.68-4.61 (m, 2H), 4.49 (br s, 1H), 4.37 (br d, J=9.9Hz, 1H), 4.05-3.86 (m, 6H), 3.61-3.49 (m, 3H), 3.23-3.19 (m, 1H), 2.68-2.63 (m, 1H), 2.54-2.47 (m, 3H), 2.23-2.13 (m, 4H), 2.11 (br s, 3H), 2.05(br s, 1H), 2.00-1.92 (m, 2H), 1.89-1.79 (m, 2H), 1.50-1.42 (m, 1H), 1.34-1.29 (m, 1H), 1.19 (brd, J=6.1Hz, 3H), 0.87-0.80 (m, 3H), 0.65 (br d, J=5.5Hz, 3H), 0.55-0.47 (m, 1H), 0.43-0.32 (m, 2H). MS (ES-API positive): 1157.5 (M+1) + . Example 139: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)butyl)pyrrolidine-2-carboxamide

[0287] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ 8.89-8.85 (m, 1H), 8.42 (s, 1H), 7.56-7.52 (m, 3H), 7.50-7.44 (m, 4H), 7.44-7.42 (m, 1H), 7.28 (d, J=9.5Hz, 1H), 6.80 (d, J=8.2Hz, 2H), 5.37-5.29 (m, 2H), 5.25 (d, J=11.3Hz, 1H), 5.20 (s, 1H), 4 .91-4.89(m, 2H), 4.61-4.56(m, 1H), 4.50-4.44(m, 1H), 4.34-4.29(m, 1 H), 4.01-3.82 (m, 7H), 3.56-3.49 (m, 2H), 3.16-3.11 (m, 1H), 2.70-2.61 (m, 1H), 2.50-2.48 (m, 3H), 2.22-2.04 (m, 8H), 1.98-1.89 (m, 2H), 1.87- 1.80(m,2H),1.76-1.65(m,1H),1.48-1.42(m,1H),1.40-1.30(m,1H),1 .18(d, J=6.6Hz, 3H), 1.06-1.01(m, 3H), 0.84(d, J=6.6Hz, 3H), 0.67(br s, 1H), 0.65-0.58 (m, 3H). MS (ES-API positive): 1145.7 (M+1) + . Example 140: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-1-hydroxy-4-(1-methyl-1H-benzi[d]imidazol-4-yl)but-3-yn-2-yl)pyrrolidine-2-carboxamide

[0288] This compound was prepared using a method similar to that used in Example 34. 1H NMR (500MHz, CD3OD) δ0.58-0.71 (m, 4H) 0.75-0.85 (m, 3H) 1.13-1.19 (m, 3H) 1.23 (s, 3H) 1.40-1.49 (m, 1H) 1.88-1.95 (m, 1H) 2.00-2.04 (m, 1H) 2.05-2.10 (m, 3H) 2.15 (J = 8.81, 4.37Hz, 1H) 2.24-2.31 (m, 1H) 2.59-2.66 (m, 1H) 3.12-3.18 (m, 1H) 3.42 (s, 3H) 3.78-3.87 (m, 4H) 3.88- 3.93 (m, 3H) 3.96-4.04 (m, 1H) 4.25-4.34 (m, 1H) 4.35-4.44 (m, 2H) 4.54-4.63 (m, 4H) 4.79-4.82 (m, 1H) 5.00 (s, 2H) 5.22 (s, 1H) 5.25-5.31 ( m, 1H) 5.32-5.39 (m, 1H) 6.65-6.87 (m, 2H) 7.25-7.33 (m, 2H) 7.38-7.46 (m, 2H) 7.46-7.56 (m, 3H) 7.56-7.62 (m, 1H) 8.21 (s, 1H) 8.37 (s, 1H). MS (ES-API positive): 1086.4 (M+1) + . Example 141: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-4-(3,5-difluorophenyl)-1-hydroxybut-3-yn-2-yl)-4-hydroxypyrrolidine-2-carboxamide

[0289] This compound was prepared using a method similar to that used in Example 34. 1H NMR (400MHz, CD3OD) δ8.50-8.44(m, 1H), 7.77-7.65(m, 1H), 7.62-7.49(m, 3H), 7.31(br s, 1H), 7.11-6.93 (m, 3H), 6.75 (d, J=8.1Hz, 2H), 5.78-5.72 (m, 1H), 5. 39(d, J=10.3Hz, 1H), 4.97-4.95(m, 1H), 4.85-4.76(m, 3H), 4.71-4.55( m, 5H), 4.53-4.46 (m, 1H), 4.01-3.96 (m, 1H), 3.95-3.89 (m, 1H), 3.88-3 .73(m, 4H), 3.68-3.59(m, 1H), 3.43(s, 3H), 2.69-2.60(m, 1H), 2.54(br d, J=11.3Hz, 1H), 2.35-2.23(m, 2H), 2.16-2.08(m, 4H), 1.59-1.49(m, 1H), 1. 30 (d, J=6.3Hz, 3H), 1.20-1.14 (m, 3H), 0.87-0.81 (m, 3H), 0.80-0.70 (m, 4H). MS (ES-API positive): 1068.5 (M+1) + . Example 142: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclobutyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((1R,2R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide

[0290] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ8.90-8.84 (m, 1H), 8.46-8.41 (m, 1H), 7.87-7.82 (m, 1H), 7.56-7.5 1(m, 2H), 7.48-7.44(m, 4H), 7.40(s, 1H), 7.32-7.26(m, 1H), 6.83-6.77(m, 2H), 5.39-5.3 2(m, 1H), 5.30-5.24(m, 1H), 5.07-5.00(m, 1H), 4.84(d, J=5.2Hz, 1H), 4.65-4.60(m, 1H) , 4.52-4.47(m, 1H), 4.45-4.39(m, 2H), 4.13-4.06(m, 1H), 3.98-3.92(m, 1H), 3.91-3.86( m, 1H), 3.84-3.79 (m, 1H), 3.42 (d, J=8.7Hz, 7H), 3.28-3.24 (m, 1H), 3.23-3.16 (m, 1H), 3 .14-3.06(m, 1H), 2.66-2.60(m, 1H), 2.50-2.47(m, 3H), 2.41-2.32(m, 1H), 2.25-2.16(m, 2H), 2.11-1.92(m, 7H), 1.77-1.63(m, 4H), 1.32-1.28(m, 1H), 1.25(d, J=2.0, 6.2Hz, 3H) , 1.21 (d, J=6.2Hz, 3H), 1.18-1.14 (m, 3H), 0.85-0.80 (m, 3H); mS (ES-API positive): 1135.4 (M+1) + . Example 143: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide

[0291] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ0.61-0.75 (m, 4H) 0.83 (d, J = 6.56Hz, 3H) 1.16 (d, J = 6.68Hz, 3H) 1.21 (d, J=6.32Hz, 3H) 1.25 (J=6.26, 1.73Hz, 4H) 1.27-1.36 (m, 3H) 1.44-1.51 (m, 1H) 1.96-2.04 (m, 2H) 2.06 (s, 3H) 2.14-2.26 (m, 2H) 2.27-2.39 (m, 1H) 2.47-2. 50(m,3H)2.59-2.66(m,1H)3.01-3.10(m,1H)3.11-3.19(m,1H)3.35(s,3H)3.39-3 .44 (m, 4H) 3.78-3.84 (m, 1H) 3.86-3.97 (m, 2H) 4.09 (t, J = 6.14Hz, 1H) 4.37-4.44 ( m, 2H) 4.49 (s, 1H) 4.63 (J = 8.29Hz, 2H) 4.84 (d, J = 4.89Hz, 1H) 4.95-5.02 (m, 2H) 5.2 7 (J=11.50, 6.97Hz, 1H) 5.33-5.38 (m, 1H) 6.82 (d, J=7.87Hz, 2H) 7.29 (d, J=9.18H z, 1H) 7.44-7.49 (m, 6H) 7.55 (d, J=7.15Hz, 2H) 8.43 (d, J=2.38Hz, 1H) 8.89 (s, 1H). MS (ES-API positive): 1121.4 (M+1) + . Example 144: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide

[0292] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ8.92-8.86 (m, 1H), 8.41-8.34 (m, 1H), 7.47 (s, 8H), 7 .29-7.23(m, 1H), 6.83-6.70(m, 2H), 5.35-5.21(m, 2H), 5.05-4.93(m, 2H) , 4.87-4.81(m, 2H), 4.75-4.69(m, 1H), 4.60-4.53(m, 1H), 4.46-4.39(m, 2 H), 4.16-4.09(m, 1H), 3.98-3.92(m, 1H), 3.91-3.85(m, 1H), 3.84-3.78(m, 1H), 3.42(d, J=1.3Hz, 3H), 3.35(s, 3H), 3.17-3.11(m, 1H), 3.09-3.03(m, 1H), 2.62-2.54 (m, 1H), 2.51 (d, J=2.1Hz, 3H), 2.37-2.26 (m, 2H), 2.23-2. 13(m, 2H), 2.12-2.08(m, 1H), 2.06(s, 3H), 1.50-1.41(m, 1H), 1.29-1.23( m, 3H), 1.18 (d, J=6.2Hz, 3H), 1.10-0.95 (m, 3H), 0.74 (s, 3H), 0.72 (s, 4H). MS (ES-API positive): 1121.4 (M+1) + . Example 145: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6,7-difluoro-5-methyl-1H-indazole-4- )-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((1R,2R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide

[0293] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ10.13-9.93(m, 1H), 8.62-8.44(m, 1H), 7.74-7.65(m, 2H), 7.62-7.53(m, 6H), 6.76(br d, J=8.0Hz, 2H), 5.87-5.67 (m, 1H), 5.42 (d, J=10.1Hz, 1H), 4.88-4.77 (m, 1H), 4.75-4.58 (m, 4H), 4.51 (br s, 1H), 4.23-4.05 (m, 1H), 4.02-3.82 (m, 4H), 3.75-3.64 (m, 4H), 3.56-3.47 (m, 2H ), 3.43(s, 3H), 2.69-2.58(m, 5H), 2.55-2.41(m, 1H), 2.33-2.19(m, 1H), 2.16(br d, J=2.5Hz, 3H), 2.07-1.90(m, 1H), 1.61-1.45(m, 1H), 1.41-1.28(m, 4H), 1.28-1.20(m, 3H), 1.18(br d, J=6.7Hz, 3H), 0.86 (d, J=6.4Hz, 3H), 0.83-0.66 (m, 4H). MS (ES-API positive): 1139.4 (M+1) + . Example 146: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6,7-difluoro-5-methyl-1H-indazole-4- )-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0294] This compound was prepared using a method similar to that used in Example 84. 1H NMR (500MHz, CD3OD) δ8.49-8.42(m, 1H), 7.93-7.59(m, 3H), 7.59-7.50(m, 4H) , 7.50-7.41(m, 2H), 6.81-6.69(m, 2H), 6.54-6.29(m, 1H), 5.86-5.64(m, 1H), 5.39(d, J=10.2Hz, 1H), 4.84-4.77(m, 2H), 4.71-4.58(m, 4H), 4.54-4.36(m, 1 H), 4.32-4.19 (m, 2H), 4.12 (quin, J=6.3Hz, 1H), 3.99-3.76 (m, 4H), 3.74-3.64 (m, 4H), 3.55-3.46 (m, 2H), 3.43 (s, 3H), 2.69-2.59 (m, 2H), 2.53-2.37 (m, 1H) , 2.25-2.08 (m, 4H), 1.96 (ddd, J=4.6, 8.8, 13.0Hz, 1H), 1.59-1.49 (m, 1H), 1. 43-1.35 (m, 3H), 1.32 (dd, J=1.8, 6.3Hz, 3H), 1.26 (d, J=6.3Hz, 3H), 1.19 (d, J =6.6Hz, 3H), 0.88-0.83 (m, 3H), 0.82-0.67 (m, 4H); mS (ES-API positive): 1136.6 (M+1) + . Example 147: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((1r,3S)-3-methoxycyclobutoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(5-(1-ethyl-1H-pyrazol-5-yl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0295] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ 8.54-8.30 (m, 1H), 7.65-7.44 (m, 5H), 7.35-7.25 (m, 2H), 7.25-7.18 (m, 1H), 6.79 (d, J=8.1Hz, 2H), 6.34-6. 23 (m, 1H), 5.44 (quin, J=5.9Hz, 1H), 5.35 (d, J=10.3Hz, 1H), 5.25-5.15 (m, 2H), 4.88-4.83 (m, 2H), 4.60 (t, J=8.2Hz, 1H), 4.49 (br s, 1H), 4.31(br d, J=8.8Hz, 1H), 4.24-4.10(m, 4H), 4.00-3.74(m, 4H), 3.37-3.32(m, 1H), 3.30-3.08(m, 8H), 2.73-2.57(m, 1H), 2.55-2.43(m, 4H), 2.18(br dd, J=7.3, 12.9Hz, 1H), 2.13-2.05(m, 1H), 2.05-1.94(m, 4H), 1.90(br d, J=9.9Hz, 1H), 1.51-1.41 (m, 1H), 1.39-1.32 (m, 3H), 1.27 (d, J=6.4Hz, 3H), 1.17 (d, J=6.6Hz, 3H), 0.88-0.79 (m, 3H), 0.76-0.54 (m, 4H). MS (ES-API positive): 1154.6 (M+1) + . Example 148: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(pentafluoro-16-thioalkyl)phenyl)propyl)pyrrolidine-2-carboxamide

[0296] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ=8.47 (s, 1H), 7.81 (d, J=8.6Hz, 2H), 7.60 (d, J=5.0Hz, 3H), 7.62-7.52 (m, 3H), 7.30 (d, J=9.5Hz, 1H) , 6.80-6.73 (m, 2H), 5.78 (s, 1H), 5.39 (d, J=10.4Hz, 1H), 5.04-5.01 (m, 1H), 5.01-4.95 (m, 1H), 4.87-4.83 (m, 2H), 4.79 (br d, J=6.6Hz, 2H), 4.71-4.66(m, 1H), 4.65-4.57(m, 3H), 4.49(br d, J=2.1Hz, 1H), 4.15-4.05(m, 1H), 3.97-3.84(m, 3H), 3.79-3.63(m, 2H), 3.44(s, 3H), 2.70-2.63(m, 1H), 2.54(br d, J=12.2Hz, 1H), 2.34-2.25(m, 1H), 2.15(d, J=2.3Hz, 4H), 2.02-1.88(m, 1H), 1.63-1.52( m, 1H), 1.34-1.23 (m, 4H), 1.18 (d, J=6.6Hz, 3H), 0.85 (d, J=6.4Hz, 3H), 0.83-0.75 (m, 4H). MS (ES-API positive): 1148.4 (M+1) + . Example 149: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(5-(1-ethyl-1H-pyrazole-5-yl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0297] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ0.58-0.74 (m, 4H) 0.79-0.86 (m, 3H) 1.17 (d, J = 6.56H z, 3H) 1.23-1.30 (m, 7H) 1.31-1.43 (m, 4H) 1.43-1.50 (m, 1H) 1.95-2.08 (m, 4 H)2.11-2.23(m,2H)2.27-2.37(m,1H)2.59-2.68(m,1H)3.00-3.14(m,2H) 3.16-3.24(m,3H)3.33-3.40(m,5H)3.43(s,3H)3.78-3.84(m,1H)3.85-3.9 7 (m, 2H) 4.12-4.24 (m, 3H) 4.41 (d, J = 5.13Hz, 2H) 4.49 (s, 1H) 4.56-4.63 (m , 1H) 4.91 (s, 1H) 4.96-5.02 (m, 1H) 5.26 (J = 11.38, 7.09Hz, 1H) 5.35 (d, J = 9. 66Hz, 1H) 6.31 (d, J = 1.79Hz, 1H) 6.82 (d, J = 7.99Hz, 2H) 7.22 (d, J = 8.23Hz, 1H) 7.25-7.32 (m, 2H) 7.48 (s, 2H) 7.51-7.58 (m, 3H) 8.42 (d, J=2.38Hz, 1H). MS (ES-API positive): 1144.5 (M+1) + . Example 150: (2S,4R)-1-((2S)-2-(4-(4-(((2-((2-oxaspiro[3.3]heptane-6-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((1R,2R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide

[0298] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ8.90-8.85 (m, 1H), 8.46-8.41 (m, 1H), 7.59-7.53 (m, 2H), 7.51-7.4 5(m, 5H), 7.41-7.37(m, 1H), 7.30-7.25(m, 1H), 6.86-6.79(m, 2H), 5.38-5.33(m, 1H), 5. 29-5.20(m, 2H), 5.16-5.11(m, 1H), 4.82-4.77(m, 1H), 4.70-4.65(m, 4H), 4.64-4.59(m, 1H), 4.53-4.47 (m, 1H), 4.36 (d, J=8.6Hz, 1H), 4.12-4.06 (m, 2H), 3.97-3.92 (m, 1H), 3.91 -3.85(m, 2H), 3.39(d, J=10.3Hz, 1H), 3.26-3.18(m, 1H), 2.86-2.76(m, 2H), 2.67-2.60( m, 1H), 2.50-2.47 (m, 3H), 2.39 (dd, J=6.6, 12.3Hz, 2H), 2.24-2.15 (m, 2H), 2.09 (d, J=2. 3Hz, 3H), 2.02(d, J=3.5, 5.1Hz, 1H), 1.98-1.94(m, 1H), 1.49-1.42(m, 1H), 1.35-1.27(m , 1H), 1.21 (d, J=6.3Hz, 3H), 1.16 (d, J=6.6Hz, 3H), 0.85-0.81 (m, 3H), 0.71-0.59 (m, 4H). MS (ES-API positive): 1143.4 (M+1) + . Example 151: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-(((1S,3S)-3-methoxycyclopentyl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0299] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ = 8.42-8.40 (m, 1H), 7.51 (br s, 5H), 7.49 (s, 1H), 7.44-7.42 (m, 1H), 7.42-7.39 (m, 2H), 7.30-7.25 (m, 1H), 6.78-6.76 (m, 1H), 6.75 (s, 1H), 6.31 (d, J=1.9Hz, 1H), 5.59 (br s, 1H), 5.33 (s, 1H), 5.29 (d, J=11.7Hz, 1H), 5.21 (s, 1H), 4.84-4.77 (m, 2H), 4.60 (s, 1H), 4.51-4 .44(m, 1H), 4.35-4.28(m, 1H), 4.22-4.01(m, 5H), 3.97-3.80(m, 4H), 3.17-3.10(m, 2H), 2.66(s, 1H), 2.26-2.13(m, 4H), 2.08(d, J=2.1Hz, 6H), 2.00-1.86(m, 3H), 1.83-1.70(m, 1H), 1.51-1.40( m, 1H), 1.35 (s, 3H), 1.25 (d, J=6.4Hz, 3H), 1.17 (d, J=6.6Hz, 3H), 0.84 (d, J=6.6Hz, 3H), 0.62 (br d, J=5.1Hz, 5H). MS (ES-API positive): 1142.4 (M+1) + . Example 152: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(5-(1-ethyl-1H-pyrazol-5-yl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0300] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.29-8.25(m, 1H), 7.45-7.37(m, 4H), 7.33-7.29(m, 2H), 7.18-7.12(m, 2H), 6.71-6.63(m, 2 H), 6.22 (d, J=1.9Hz, 1H), 5.26-5.10 (m, 3H), 4.96-4.89 (m, 1H), 4.71-4.60 (m, 2H), 4.54 (t, J=8.1Hz, 1H), 4.45 (br s, 1H), 4.33-4.27(m, 2H), 4.21(br d, J=8.9Hz, 1H), 4.10 (q, J=7.2Hz, 2H), 3.88-3.81 (m, 2H), 3.81-3.66 (m, 2H), 3.74-3.65 (m, 3H), 3.32-3 .31(m, 3H), 3.28-3.24(m, 1H), 3.11(t, J=3.9Hz, 2H), 3.06-3.00(m, 1H), 2.56-2.46(m, 1H), 2.22-2.13( m, 1H), 2.12-2.03 (m, 1H), 2.02-1.95 (m, 4H), 1.84-1.77 (m, 1H), 1.38-1.31 (m, 1H), 1.26 (t, J=7.2Hz, 3H ), 1.15-1.11 (m, 3H), 1.07-1.01 (m, 1H), 0.98 (d, J=6.6Hz, 2H), 0.69 (d, J=6.6Hz, 3H), 0.57-0.47 (m, 4H). MS (ES-API positive): 1128.5 (M+1) + . Example 153: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-4-((S)-7-methyl-1,4-diazacycloheptane-1-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide)

[0301] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.45-8.40(m, 1H), 7.59-7.53(m, 2H), 7.53-7.47(m, 5H), 7.45-7.41(m, 2H), 7.30-7.25( m, 1H), 6.83-6.78 (m, 2H), 6.33-6.27 (m, 1H), 5.40-5.31 (m, 1H), 5.18-5.13 (m, 1H), 5.10-5.04 (m, 1H), 4.91 (br d, J=11.6Hz, 1H), 4.82-4.80 (m, 1H), 4.63-4.58 (m, 1H), 4.53-4.47 (m, 1H), 4. 44-4.38(m, 3H), 4.20-4.13(m, 2H), 4.03-3.88(m, 2H), 3.86(d, J=6.1Hz, 2H), 3.83-3.78(m, 1H), 3.60-3.53(m, 1H), 3.42(s, 3H), 3.39-3.33(m, 1H), 3.24-3 .19(m, 1H), 3.15-3.09(m, 1H), 2.67-2.61(m, 2H), 2.42-2.33(m, 1H), 2.24(br dd, J=7.7, 12.9Hz, 1H), 2.05-1.99 (m, 4H), 1.93-1.84 (m, 1H), 1.53 (d, J=6.2Hz, 3H), 1.50-1.46 (m, 1H), 1.37-1. 32 (m, 3H), 1.24 (d, J=6.3Hz, 3H), 1.17 (d, J=6.7Hz, 3H), 0.85-0.80 (m, 3H), 0.75-0.69 (m, 1H), 0.65-0.57 (m, 3H). MS (ES-API positive): 1118.5 (M+1) + . Example 154: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-4-((R)-7-methyl-1,4-diazacycloheptane-1-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide)

[0302] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.43-8.39 (m, 1H), 7.54-7.46 (m, 7H), 7.45-7.41 (m, 2H), 7.29-7.23 (m, 1H) , 6.77 (d, J=8.2Hz, 2H), 6.33-6.26 (m, 1H), 5.39-5.32 (m, 1H), 5.30 (d, J=11.6Hz, 1H), 5.12-5.05 (m, 1H), 4.83-4.80 (m, 1H), 4.76 (d, J=11.6Hz, 1H), 4.64-4.56 (m, 1H), 4.50 (rs, 1H), 4.45-4.37 ( m, 3H), 4.16 (q, J=7.2Hz, 2H), 4.05-3.88 (m, 2H), 3.86 (d, J=6.2Hz, 2H), 3.82-3.77 (m, 1H), 3.55 (r dd, J=9.4, 14.8Hz, 1H), 3.43 (s, 3H), 3.40-3.32 (m, 1H), 3.21 (r dd, J=1.5, 13.9Hz, 1H), 3.10 (r dd, J=6.8, 13.9Hz, 1H), 2.67-2.58(m, 2H), 2.43-2.33(m, 1H), 2.28-2.19(m , 1H), 2.09 (d, J=2.3Hz, 3H), 2.05-1.99 (m, 1H), 1.88 (td, J=10.2, 15.4Hz, 1 H), 1.53 (d, J=6.2Hz, 3H), 1.49-1.44 (m, 1H), 1.34 (t, J=7.2Hz, 3H), 1.25 (d , J=6.4Hz, 3H), 1.17 (d, J=6.7Hz, 3H), 0.86-0.80 (m, 3H), 0.70-0.55 (m, 4H). MS (ES-API positive): 1118.6 (M+1) + . Example 155: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-4-(6-hydroxy-6-methyl-1,4-diazacycloheptane-1-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide)

[0303] This compound was prepared using a method similar to that used in Example 32. 1 H NMR (400MHz, CD3OD) δ8.45-8.41(m, 1H), 7.79-7.72(m, 1H), 7.56-7.40(m, 8H), 7.32-7.25(m, 1H), 6.87-6.76( m, 2H), 6.33-6.28 (m, 1H), 5.40-5.23 (m, 2H), 5.10-5.04 (m, 1H), 4.88-4.83 (m, 2H), 4.63-4.57 (m, 1H), 4.50 (br s, 1H), 4.46-4.37 (m, 3H), 4.37-4.28 (m, 1H), 4.21-4.13 (m, 2H), 4.03-3.83 (m, 4H), 3.83-3.70 (m, 3H), 3.44-3.40(m, 3H), 3.17-3.09(m, 1H), 3.01-2.89(m, 1H), 2.87-2.76(m, 1H), 2.67-2.63(m, 1H), 2.30-2. 19 (m, 1H), 2.08 (d, J=2.3Hz, 3H), 2.05-1.99 (m, 1H), 1.48-1.42 (m, 1H), 1.37-1.33 (m, 3H), 1.29 (s, 3H), 1.25-1.21 (m, 3H), 1.20-1.14 (m, 3H), 0.87-0.81 (m, 3H), 0.73-0.57 (m, 4H); MS (ES-API positive): 1134.5 (M+1) + . Example 156: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-4-(1,4-diazacycloheptane-1-yl)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((1r,3r)-3-methoxycyclobutoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide)

[0304] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ0.57-0.72 (m, 4H) 0.83 (d, J=6.56Hz, 3H) 1.17 (d, J=6. 08Hz, 3H) 1.25 (d, J = 6.32Hz, 3H) 1.33-1.38 (m, 3H) 1.41-1.50 (m, 1H) 1.95 (d, J=13.26, 8.91, 4.41Hz, 1H) 2.05 (d, J=2.26Hz, 3H) 2.11-2.21 (m, 3H) 2.49 (d, J=4.29Hz, 4H) 2.61-2.70 (m, 1H) 2.94-3.04 (m, 2H) 3.18-3.24 (m, 2H) 3.25 (s, 3H)3.84-3.98(m,2H)4.02-4.10(m,4H)4.10-4.13(m,1H)4.14-4.20(m,3H) 4.48 (s, 1H) 4.60 (t, J = 8.23Hz, 1H) 4.83 (s, 2H) 5.24 (d, J = 11.32Hz, 1H) 5.35 ( d, J=10.25Hz, 1H) 5.44 (t, J=6.02Hz, 1H) 6.27-6.36 (m, 1H) 6.77 (d, J=8.11Hz , 2H) 7.24-7.30 (m, 1H) 7.41 (d, J = 8.23Hz, 2H) 7.45-7.58 (m, 7H) 8.42 (s, 1H). MS (ES-API positive): 1130.6 (M+1) + . Example 157: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-4-(1,4-diazacycloheptane-1-yl)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide

[0305] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ8.88 (s, 1H), 8.41 (s, 1H), 7.54 (s, 1H), 7.52-7.51 (m, 1H), 7.50-7.48 (m, 1H), 7.45 (s, 5H), 7.27 (d, J=9.8Hz, 1H), 6.83-6.7 6(m, 2H), 5.38-5.31(m, 1H), 5.28-5.22(m, 1H), 4.85-4.81(m, 2H), 4.64 -4.56(m, 1H), 4.51-4.45(m, 1H), 4.42-4.38(m, 2H), 4.15-4.00(m, 5H), 3 .97-3.76(m, 3H), 3.42(s, 3H), 3.25-3.21(m, 2H), 3.04-2.95(m, 2H), 2. 66(s, 1H), 2.49(s, 3H), 2.21-2.11(m, 3H), 2.06(d, J=2.3Hz, 3H), 1.99(s , 1H), 1.50-1.42 (m, 1H), 1.25 (d, J=6.3Hz, 6H), 1.17 (d, J=6.7Hz, 3H), 0 .83 (d, J=6.6Hz, 3H), 0.72-0.65 (m, 1H), 0.58 (s, 2H), 0.65-0.57 (m, 1H). MS (ES-API positive): 1121.5 (M+1) + . Example 158: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-4-(2,3,6,7-tetrahydro-1H-azacycloheptene-1-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide)

[0306] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ0.58-0.64(m, 3H), 0.66-0.73(m, 1H), 0.81-0.85(m, 3H), 1.17(d , J=6.68Hz, 3H), 1.25(d, J=6.44Hz, 3H), 1.28-1.38(m, 4H), 1.41-1.50(m, 1H), 2.04(br s, 1H), 2.06 (d, J=2.38Hz, 3H), 2.17-2.30 (m, 1H), 2.61-2.69 (m, 5H), 3.43 (s, 3H), 3.75-3.98 (m, 5H), 4.10 (br t, J=5.42Hz, 4H), 4.17 (q, J=7.19Hz, 2H), 4.38-4.42 (m, 2H), 4.47-4.52 (m, 1H), 4.6 0 (t, J=8.34Hz, 1H), 5.07 (t, J=6.14Hz, 1H), 5.22-5.29 (m, 1H), 5.36 (d, J=10.37Hz, 1 H), 5.84 (t, J=2.98Hz, 2H), 6.28-6.32 (m, 1H), 6.77-6.82 (m, 2H), 7.24-7.30 (m, 1H), 7.42-7.45 (m, 2H), 7.47-7.56 (m, 7H), 8.39-8.45 (m, 1H); mS (ES-API positive): 1101.5 (M+1) + . Example 159: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclobutyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide

[0307] This compound was prepared using a method similar to that used in Example 84. 1H NMR (500MHz, CD3OD) δ8.89-8.85 (m, 1H), 8.43-8.40 (m, 1H), 7.86-7.83 (m, 1H), 7 .55-7.50(m, 2H), 7.48-7.44(m, 4H), 7.40(s, 1H), 7.32-7.26(m, 1H), 6.82-6.77 (m, 2H), 6.68-6.67 (m, 1H), 5.37-5.32 (m, 1H), 5.30-5.23 (m, 1H), 5.10-5.03 (m, 1H), 4.60(t, J=8.2Hz, 1H), 4.50-4.45(m, 1H), 4.44-4.40(m, 2H), 4.15-4.07(m, 1H), 3.96-3.91(m, 1H), 3.90-3.85(m, 1H), 3.84-3.79(m, 1H), 3.47-3.41(m, 4H) , 3.41-3.36(m, 4H), 3.28-3.23(m, 1H), 3.18-3.11(m, 1H), 3.02(s, 1H), 2.68-2. 63(m, 2H), 2.49(s, 3H), 2.39-2.30(m, 1H), 2.23-2.14(m, 2H), 2.04-1.95(m, 6H) , 1.77-1.65 (m, 4H), 1.29-1.22 (m, 7H), 1.17 (d, J=6.6Hz, 3H), 0.85-0.81 (m, 3H). MS (ES-API positive): 1135.5 (M+1) + . Example 160: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((1r,3S)-3-methoxycyclobutoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(5-(1-ethyl-1H-pyrazol-5-yl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0308] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ8.48-8.31 (m, 1H), 7.57-7.46 (m, 4H), 7.40 (s, 1H), 7.33-7.17 (m, 3H), 6.76 (d, J =8.2Hz, 2H), 6.36-6.20 (m, 1H), 5.52-5.39 (m, 1H), 5.35 (d, J = 10.3Hz, 1H), 5.32-5.23 (m, 1H), 5.23-5 .15(m, 1H), 5.13-5.01(m, 1H), 4.63-4.55(m, 1H), 4.54-4.43(m, 1H), 4.38-4.25(m, 1H), 4.23-4.11(m , 3H), 4.05-3.70 (m, 6H), 3.30-3.09 (m, 9H), 2.65 (qd, J=6.5, 16.9Hz, 1H), 2.54-2.43 (m, 4H), 2.24 (br dd, J=7.8, 12.9Hz, 1H), 2.14-2.00(m, 5H), 1.91(br d, J=10.1Hz, 1H), 1.50-1.40 (m, 1H), 1.40-1.21 (m, 4H), 1.17 (d, J=6.6Hz, 3H), 0.89-0.79 (m, 3H), 0.73-0.52 (m, 4H). MS (ES-API positive): 1140.5 (M+1) + . Example 161: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-4-(6-hydroxy-6-methyl-1,4-oxazacycloheptane-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide)

[0309] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.38-8.30(m, 1H), 8.00-7.55(m, 1H), 7.48-7.37(m, 6H), 7.35-7.31(m, 2H), 7. 21-7.13(m, 1H), 6.74-6.65(m, 2H), 6.24-6.17(m, 1H), 5.31-5.14(m, 1H), 5.13-5.04(m, 1H), 4.98(br d, J=5.1Hz, 1H), 4.53-4.44 (m, 2H), 4.43-4.16 (m, 5H), 4.11-4.04 (m, 2H), 3.97-3.90 (m, 2H), 3 .86-3.75(m, 5H), 3.75-3.60(m, 3H), 3.58-3.52(m, 1H), 3.34-3.30(m, 3H), 2.61-2.49(m, 1H), 2 .18-2.09(m, 1H), 2.02-1.98(m, 3H), 1.97-1.90(m, 1H), 1.41-1.34(m, 1H), 1.28-1.20(m, 4H), 1.19-1.14(m, 5H), 1.10-1.10(m, 1H), 1.09-1.05(m, 3H), 0.76-0.72(m, 3H), 0.67-0.55(m, 4H). MS (ES-API positive): 1135.5 (M+1) + . Example 162: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-4-(2-ethyl-2H-indazol-4-yl)-1-hydroxybut-3-yn-2-yl)-4-hydroxypyrrolidine-2-carboxamide

[0310] This compound was prepared using a method similar to that used in Example 34. 1H NMR (400MHz, CD3OD) δ8.42-8.38 (m, 1H), 8.37-8.25 (m, 1H), 7.61 (d, J=8.6H z, 1H), 7.55-7.49 (m, 3H), 7.40 (s, 1H), 7.30-7.23 (m, 2H), 7.23-7.17 (m, 1H ), 6.81-6.73 (m, 2H), 5.34 (s, 1H), 5.30-5.21 (m, 2H), 5.04 (t, J=5.8Hz, 1H) , 4.81 (d, J = 11.6Hz, 1H), 4.57-4.47 (m, 4H), 4.40 (d, J = 5.1Hz, 2H), 4.32 (br d, J=8.6Hz, 1H), 3.99 (dd, J=3.7, 10.6Hz, 1H), 3.94 (s, 1H), 3.89 (br d, J=11.1Hz, 1H), 3.84 (br d, J=5.8Hz, 3H), 3.82-3.76 (m, 1H), 3.42 (s, 3H), 3.34-3.32 (m, 1H), 3.16-3. 12(m, 1H), 2.68-2.59(m, 1H), 2.30-2.23(m, 1H), 2.17-2.07(m, 5H), 1.91(br d, J=10.4Hz, 1H), 1.63-1.57(m, 3H), 1.48-1.42(m, 1H), 1.24(d, J=6.4Hz, 3H), 1.17( d, J=6.7Hz, 3H), 0.83 (d, J=6.6Hz, 3H), 0.70-0.59 (m, 4H); mS (ES-API positive): 1100.5 (M+1) + . Example 163: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-2-((1r,3R)-3-methoxycyclobutoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-4-(1-ethyl-1H-indazol-4-yl)-1-hydroxybut-3-yn-2-yl)-4-hydroxypyrrolidine-2-carboxamide

[0311] This compound was prepared using a method similar to that used in Example 34. 1H NMR (400MHz, CD3OD) δ8.43 (s, 1H), 8.16 (d, J=0.7Hz, 1H), 7.63-7.58 (m, 1H), 7.57 (br s, 3H), 7.47-7.37 (m, 2H), 7.34-7.26 (m, 2H), 6.78 (d, J=8.2Hz, 2H), 5.46 (t, J=6 .0Hz, 1H), 5.37 (d, J=10.3Hz, 1H), 5.29 (d, J=11.4Hz, 1H), 5.21 (s, 1H), 5.07 (t, J=5.8Hz, 1H), 4.81 (d, J=11.3Hz, 1H), 4.59-4.51 (m, 2H), 4.49-4.46 (m, 1H), 4.4 3-4.31(m, 1H), 4.22-4.15(m, 1H), 4.03-3.98(m, 1H), 3.98-3.79(m, 5H), 3.30(br s, 1H), 3.27 (s, 3H), 3.19-3.12 (m, 1H), 2.68 (s, 3H), 2.48-2.47 (m, 1H), 2.56-2. 47(m, 3H), 2.33-2.25(m, 1H), 2.18-2.12(m, 1H), 2.09(d, J=2.4Hz, 3H), 1.93(br d, J=9.9Hz, 1H), 1.51-1.42 (m, 4H), 1.22-1.14 (m, 3H), 0.89-0.80 (m, 3H), 0.72-0.57 (m, 4H). MS (ES-API positive): 1112.6 (M+1) + . Example 164: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(5-(1-ethyl-1H-pyrazole-5-yl)bicyclo[4.2.0]oct-1(6),2,4-trien-2-yl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0312] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ8.41 (s, 1H), 7.58-7.41 (m, 5H), 7.33-7.18 (m, 3H), 6.86-6.73 (m, 2H), 6.30 (d, J=1.9Hz, 1H), 5.40-5.13 (m, 2H), 5.05-4.89 (m, 2H), 4.60 (t, J=8.1Hz, 1H), 4.49 (br s, 1H), 4.41 (dd, J=3.2, 5.2Hz, 2H), 4.26-4.09 (m, 3H), 3.98-3.74 (m, 3H), 3.47-3.37 (m, 4H) , 3.37-3.32(m, 4H), 3.30-3.18(m, 5H), 3.15-2.99(m, 2H), 2.71-2.57(m, 1H), 2.37-2.24(m, 1 H), 2.17 (dt, J=8.0, 13.0Hz, 2H), 2.09-1.94 (m, 4H), 1.53-1.40 (m, 1H), 1.39-1.33 (m, 3H), 1 .26 (dd, J=6.4, 10.9Hz, 6H), 1.17 (d, J=6.6Hz, 3H), 0.83 (d, J=6.6Hz, 3H), 0.75-0.56 (m, 4H). MS (ES-API positive): 1144.6 (M+1) + . Example 165: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4- (1r,3S)-2-((1r,3S)-3-methoxycyclobutoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0313] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.42 (s, 1H), 7.57-7.41 (m, 9H), 7.29 (d, J=9.5Hz, 1H), 6.79 (d, J=8.2Hz, 2H), 6.38-6.24 (m, 1H), 5.55-5.40 (m, 1H), 5. 36 (d, J=10.4Hz, 1H), 5.27 (d, J=11.3Hz, 1H), 5.12-5.05 (m, 1H), 5.04-4.96 (m, 1H), 4.60 (t, J=8.3Hz, 1H), 4.53-4.40 (m, 1H), 4.23-4.10 (m, 3H), 4.00-3.76(m, 4H), 3.62-3.34(m, 2H), 3.28-3.16(m, 5H), 3.14-2 .99(m,2H),2.72-2.59(m,1H),2.58-2.36(m,5H),2.36-2.20(m,2H),2 .19-2.08 (m, 1H), 2.08-1.98 (m, 4H), 1.52-1.41 (m, 1H), 1.39-1.23 (m, 4H), 1.17 (d, J = 6.6Hz, 3H), 0.83 (d, J = 6.7Hz, 3H), 0.74-0.57 (m, 4H). MS (ES-API positive): 1116.6 (M+1) + . Example 166: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4- )-2-((1r,3S)-3-methoxycyclobutoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0314] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.88 (s, 1H), 8.42 (s, 1H), 7.54 (br d, J=8.1Hz, 2H), 7.49-7.39 (m, 6H), 7.29 (br d, J=9.4Hz, 1H), 6.79 (d, J=8.2Hz, 2H), 5.51-5.41 (m, 1H), 5.36 (d, J=10.3H z, 1H), 5.31-5.23 (m, 1H), 5.19-4.93 (m, 3H), 4.60 (t, J=8.3Hz, 1H), 4.50 (br s, 1H), 4.22-4.09 (m, 1H), 4.00-3.76 (m, 4H), 3.55-3.33 (m, 2H), 3.28-3.12 (m, 5H), 3.11-2.97 (m, 2H), 2.73-2.58 (m, 1H), 2.54-2 .43 (m, 7H), 2.40-2.07 (m, 4H), 2.07-1.97 (m, 4H), 1.53-1.39 (m, 1H), 1.17 (d, J = 6.4Hz, 3H), 0.87-0.78 (m, 3H), 0.74-0.57 (m, 4H). MS (ES-API positive): 1119.6 (M+1) + . Example 167: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide

[0315] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ8.89-8.85 (m, 1H), 8.43-8.40 (m, 1H), 7.54 (d, J=8.2Hz, 2H), 7 .49-7.44(m, 6H), 7.28(d, J=9.5Hz, 1H), 6.84-6.79(m, 2H), 5.38-5.32(m, 1H), 5.30- 5.24 (m, 1H), 5.03-4.97 (m, 1H), 4.90 (s, 1H), 4.60 (t, J=8.2Hz, 1H), 4.48 (s, 1H), 4. 43-4.39 (m, 2H), 4.11 (J=6.2Hz, 1H), 3.96-3.91 (m, 1H), 3.90-3.85 (m, 1H), 3.84-3.7 8(m, 1H), 3.42(s, 3H), 3.41-3.37(m, 1H), 3.34(s, 3H), 3.24-3.16(m, 1H), 3.14-3.0 7(m, 1H), 3.05-2.99(m, 1H), 2.66-2.62(m, 1H), 2.50-2.48(m, 3H), 2.34-2.26(m, 1H) , 2.21-2.12(m, 2H), 2.06(d, J=2.1Hz, 3H), 2.00-1.92(m, 1H), 1.50-1.43(m, 1H), 1. 25 (d, J=6.3Hz, 7H), 1.17 (d, J=6.7Hz, 3H), 0.83 (d, J=6.6Hz, 3H), 0.72-0.61 (m, 4H). MS (ES-API positive): 1121.5 (M+1) + . Example 168: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((1r,3S)-3-methoxycyclobutoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-4-(2-ethyl-2H-indazol-7-yl)-1-hydroxybut-3-yn-2-yl)-4-hydroxypyrrolidine-2-carboxamide

[0316] This compound was prepared using a method similar to that used in Example 34. 1H NMR (400MHz, CD3OD) δ8.41-8.37 (m, 1H), 8.31 (s, 1H), 7.77-7.66 (m, 1H), 7.54-7.50 (m, 3H ), 7.44 (d, J=6.8Hz, 1H), 7.40 (s, 1H), 7.29-7.25 (m, 1H), 7.05 (d, J=7.1, 8.3Hz, 1H), 6.76 (d, J=8.2Hz, 2H), 5.47-5.41(m, 1H), 5.39-5.31(m, 1H), 5.31-5.24(m, 1H), 5.22-5.18(m, 1H), 5.08-5.02(m, 1H), 4.80-4.77(m, 1H), 4.56-4.53(m, 2H), 4.53-4.49(m, 2H), 4.33-4. 28(m, 1H), 4.19-4.14(m, 1H), 4.02-3.97(m, 1H), 3.95-3.89(m, 2H), 3.87-3.82(m, 3H), 3. 28(s, 1H), 3.25(s, 3H), 3.16-3.11(m, 1H), 2.66-2.63(m, 1H), 2.55-2.43(m, 5H), 2.31-2. 24(m, 1H), 2.10-2.06(m, 4H), 1.91(d, J=10.0Hz, 1H), 1.61(t, J=7.4Hz, 3H), 1.47-1.42(m , 1H), 1.16 (d, J=6.7Hz, 3H), 0.84-0.79 (m, 3H), 0.68 (d, J=7.4Hz, 1H), 0.63-0.58 (m, 3H). MS (ES-API positive): 1112.5 (M+1) + . Example 169: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(5-(1-ethyl-1H-pyrazole-5-yl)bicyclo[4.2.0]octyl-1(6),2,4-trien-2-yl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0317] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ8.43 (s, 1H), 7.61-7.52 (m, 4H), 7.50-7.47 (m, 2H), 7.33-7.22 (m, 3H), 6.84 (d, J=8.2Hz, 1H), 6.3 7-6.30(m, 1H), 5.51-5.35(m, 1H), 5.33-5.26(m, 1H), 5.13-5.07(m, 1H), 5.04-4.98(m, 1H), 4.65-4.57(m, 1H), 4.53(br s, 1H), 4.48-4.41 (m, 2H), 4.23-4.17 (m, 2H), 3.99-3.89 (m, 3H), 3.87-3.79 (m, 1H), 3.44 (s, 3H), 3.38-3.36 (m, 4H), 3.32-3.26 (m, 3H), 3.23 (t, J=3.9Hz, 2H), 3 .19-3.12(m, 1H), 3.10-3.02(m, 1H), 2.73-2.67(m, 1H), 2.38-2.28(m, 1H), 2.27 -2.13(m, 2H), 2.13-2.02(m, 4H), 1.54-1.44(m, 1H), 1.41-1.34(m, 4H), 1.34(br s, 1H), 1.26 (d, J=6.4Hz, 3H), 1.19 (br d, J=6.6Hz, 3H), 0.89-0.79 (m, 3H), 0.76-0.70 (m, 1H), 0.70-0.60 (m, 3H). MS (ES-API positive): 1130.6 (M+1) + . Example 170: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4- (1R,2S)-2-((1r,3S)-3-methoxycyclobutoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0318] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ 8.45-8.40 (m, 1H), 7.56-7.49 (m, 5H), 7.47 (d, J = 2.4Hz, 2H), 7.43-7.40 (m, 2H), 7.29 (d, J = 9.8Hz, 1H), 6.79 (d, J = 8.2Hz, 2 H), 6.31 (d, J=1.9Hz, 1H), 5.49-5.43 (m, 1H), 5.35 (d, J=10.4Hz, 1H), 5.27 (d, J=11.3Hz, 1H), 5.06-4.92 (m, 2H), 4.60 (t, J=8.2Hz, 1H), 4.48 (br s, 1H), 4.18 (q, J=7.2Hz, 3H), 4.14-4.09 (m, 1H), 3.97-3.83 (m, 2H), 3.41 (br dd, J=7.6, 12.0Hz, 1H), 3.33 (s, 3H), 3.28-3.17 (m, 5H), 3.12-3.01 (m, 2H), 2.69-2. 60 (m, 1H), 2.53-2.46 (m, 4H), 2.33-2.26 (m, 1H), 2.21-2.11 (m, 2H), 2.05 (d, J=2.3H z, 3H), 1.95 (ddd, J=4.4, 8.9, 13.3Hz, 1H), 1.49-1.43 (m, 1H), 1.37-1.33 (m, 3H), 1. 25 (d, J=6.4Hz, 3H), 1.17 (d, J=6.6Hz, 3H), 0.83 (d, J=6.6Hz, 3H), 0.73-0.61 (m, 4H). MS (ES-API positive): 1130.6 (M+1) + . Example 171: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4- (1R,2S)-2-((1r,3S)-3-methoxycyclobutoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide

[0319] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ 8.89-8.84 (m, 1H), 8.42 (s, 1H), 7.56-7.52 (m, 2H), 7.48-7.44 (m, 6H), 7.29 (d, J=9.4Hz, 1H), 6.79 (d, J =8.1Hz, 2H), 5.49-5.42 (m, 1H), 5.35 (d, J = 10.3Hz, 1H), 5.30-5.25 (m, 1H), 5.03-4.98 (m, 1H), 4.60 (t, J = 8.3Hz, 1H), 4.48 (br s, 1H), 4.19-4.09 (m, 2H), 3.96-3.84 (m, 2H), 3.44-3.37 (m, 1H), 3.32 (br s, 3H), 3.26-3.16 (m, 5H), 3.11-3.01 (m, 2H), 2.65 (td, J=6.6, 10.4Hz, 1H), 2.54-2.44(m, 8H), 2.32-2.25(m, 1H), 2.16(td, J=7.3, 14.3Hz, 2H), 2.05(d, J=2.3Hz, 3H), 1.95 (ddd, J=4.5, 8.8, 13.2Hz, 1H), 1.49-1.43 (m, 1H), 1.27-1 .23 (m, 3H), 1.17 (d, J=6.6Hz, 3H), 0.83 (d, J=6.6Hz, 3H), 0.72-0.61 (m, 4H). MS (ES-API positive): 1133.5 (M+1) + . Example 172: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((1r,3S)-3-methoxycyclobutoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-4-(1-ethyl-1H-indazol-7-yl)-1-hydroxybut-3-yn-2-yl)-4-hydroxypyrrolidine-2-carboxamide

[0320] This compound was prepared using a method similar to that used in Example 34. 1H NMR (500MHz, CD3OD) δ8.39 (s, 1H), 8.05 (s, 1H), 7.76 (s, 1H), 7.57-7.49 (m, 4H), 7.40 (s, 2H), 7.27 (d, J=9.8Hz, 2H), 7.15-7.08 (m, 1H), 6.76 ( d, J=8.2Hz, 2H), 5.47-5.40 (m, 1H), 5.38-5.33 (m, 1H), 5.28 (d, J=11.3Hz, 1H), 5.20 (s, 1H), 5.07 (t, J=5.8Hz, 1H), 4.61-4.45 (m, 3H), 4.31 (br d, J=9.3Hz, 1H), 4.17 (s, 1H), 4.04-3.95 (m, 1H), 3.95-3.89 (m, 2H), 3.89-3.83 (m, 3H), 3.29-3.21 (m, 4H) , 3.19-3.10(m, 2H), 2.69-2.60(m, 1H), 2.54-2.44(m, 5H), 2.30-2.22(m, 1H), 2.18-2.00(m, 6H), 1.91(br d, J=10.4Hz, 1H), 1.51-1.44 (m, 4H), 1.20-1.14 (m, 3H), 0.85-0.81 (m, 3H). MS (ES-API positive): 1112.5 (M+1) + . Example 173: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4- 2-((1r,3S)-3-methoxycyclobutoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(5-(1-ethyl-1H-pyrazole-5-yl)bicyclo[4.2.0]octyl-1(6),2,4-trien-2-yl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0321] This compound was prepared using a method similar to that used in Example 84. 1H NMR (500MHz, CD3OD) δ8.41 (s, 1H), 7.56-7.50 (m, 3H), 7.50-7.45 (m, 2H), 7.32-7.2 6 (m, 2H), 7.25-7.19 (m, 1H), 6.79 (d, J=8.2Hz, 2H), 6.30 (d, J=2.0Hz, 1H), 5.50-5. 42 (m, 1H), 5.35 (d, J = 10.4Hz, 1H), 5.31-5.22 (m, 1H), 5.18-4.95 (m, 2H), 4.93-4.8 8(m, 2H), 4.60(t, J=8.2Hz, 1H), 4.53-4.31(m, 1H), 4.25-4.10(m, 4H), 4.00-3.77(m , 2H), 3.49-3.33(m, 2H), 3.29-3.23(m, 4H), 3.23-3.12(m, 4H), 3.12-2.96(m, 2H), 2.73-2.57(m, 1H), 2.55-2.44(m, 4H), 2.34-2.23(m, 1H), 2.22-2.08(m, 2H), 2.07-2 .03 (m, 3H), 1.99 (ddd, J=4.6, 8.8, 13.2Hz, 1H), 1.52-1.41 (m, 1H), 1.38-1.33 (m, 3 H), 1.32-1.22 (m, 4H), 1.17 (d, J=6.6Hz, 3H), 0.86-0.78 (m, 3H), 0.74-0.59 (m, 4H). MS (ES-API positive): 1156.6 (M+1) + . Example 174: (2S,4R)-1-((2S)-2-(4-(4-(((4-(4-cyanopiperidin-1-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0322] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.43-8.39 (m, 1H), 8.51-8.31 (m, 1H), 7.57-7.46 (m, 6H), 7.45-7.40 (m, 2 H), 7.33-7.25 (m, 2H), 6.82 (d, J=8.1Hz, 2H), 6.30 (d, J=1.8Hz, 1H), 5.39-5.24 (m, 2H), 5.07 (br t, J=5.8Hz, 1H), 4.63-4.56 (m, 1H), 4.49 (br s, 1H), 4.44-4.39 (m, 2H), 4.16 (q, J=7.2Hz, 2H), 4.03 (br dd, J=3.8, 9.8Hz, 2H), 3.97-3.77(m, 5H), 3.72-3.61(m, 2H), 3.41(s, 3H), 3.18(br s, 1H), 2.65 (s, 1H), 2.29-2.14 (m, 3H), 2.11-2.00 (m, 6H), 1.46 (br s, 1H), 1.37-1.31 (m, 1H), 1.38-1.30 (m, 1H), 1.34 (t, J=7.2Hz, 1H), 1.24 (d, J=6.3Hz, 4H), 1.16 (d, J=6.6Hz, 3H), 0.83 (d, J=6.7Hz, 3H), 0.74-0.58 (m, 4H); mS (ES-API positive): 1114.5 (M+1) + . Example 175: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclobutyl-7-(6,7-difluoro-5-methyl-1H-indazole-4- )-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((1R,2R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide

[0323] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ 8.88 (s, 1H), 8.42 (s, 1H), 7.83 (s, 1H), 7.54 (d, J = 8.2Hz, 2H), 7.50-7.41 (m, 5H), 6.82 (d, J = 8.2Hz, 2H), 5.39-5.32 (m, 1 H), 5.29-5.21(m, 1H), 5.09-5.01(m, 1H), 4.92-4.90(m, 1H), 4.86(s, 1 H), 4.86-4.84(m, 1H), 4.64-4.55(m, 1H), 4.45(s, 1H), 4.38(s, 2H), 4.1 5-4.06 (m, 1H), 3.97-3.74 (m, 3H), 3.43 (s, 3H), 3.39 (s, 3H), 3.28-3.2 0 (m, 2H), 3.18-3.10 (m, 1H), 3.01 (s, 1H), 2.66-2.58 (m, 1H), 2.53-2.46 (m, 3H), 2.39-2.31 (m, 1H), 2.23-2.10 (m, 2H), 2.05-1.91 (m, 6H), 1.78 -1.61(m, 4H), 1.29-1.22(m, 6H), 1.21-1.14(m, 3H), 0.90-0.79(m, 3H). MS (ES-API positive): 1153.5 (M+1) + . Example 176: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-1-hydroxy-4-(2-(methylamino)benzo[d]thiazolyl-6-yl)but-3-yne-2-yl)pyrrolidine-2-carboxamide

[0324] This compound was prepared using a method similar to that used in Example 34. 1H NMR (400MHz, CD3OD) δ 8.44-8.39 (m, 1H), 7.70 (s, 1H), 7.57-7.51 (m, 3H), 7.48-7.35 (m, 3H), 7.29 (d, J=9.9Hz, 1H), 6.80 (d, J= 8.1Hz, 2H), 5.37 (d, J=10.0Hz, 1H), 5.29 (d, J=11.1Hz, 1H), 5.25-5.17 (m, 1H), 4.99-4.95 (m, 1H), 4.85-4.83 (m, 1H), 4.56 (br s, 1H), 4.51 (br t, J=8.2Hz, 1H), 4.42 (br d, J=5.0Hz, 2H), 4.37-4.30 (m, 1H), 3.94 (br dd, J=3.1, 10.8Hz, 2H), 3.90-3.83 (m, 2H), 3.82-3.78 (m, 2H), 3.44 (s, 3H), 3.14 (br dd, J=1.3, 5.7Hz, 1H), 3.06-3.03 (m, 3H), 2.69-2.65 (m, 1H), 2.31-2.24 (m, 1H), 2.17-2.12 (m, 1H), 2.10 (d, J=2.3Hz, 3H), 2.04 (br d, J=8.6Hz, 1H), 1.96-1.88(m, 1H), 1.51-1.42(m, 1H), 1.38-1.30(m, 1H), 1.28-1.24(m, 3H), 1.20-1.15 (m, 3H), 0.87-0.81 (m, 3H), 0.70-0.60 (m, 4H); mS (ES-API positive): 1118.6 (M+1) + . Example 177: (2S,4R)-1-((2S)-2-(4-(4-(((4-(azacycloheptane-1-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0325] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.42 (s, 1H), 7.55-7.46 (m, 7H), 7.45-7.41 (m, 2H), 7.27 (d, J=9.7Hz, 1H), 6.79 (d, J=8.2 Hz, 2H), 6.33-6.27 (m, 1H), 5.36 (d, J=10.4Hz, 1H), 5.27-5.19 (m, 1H), 5.11 (s, 1H), 4.61-4.58 (m, 1H), 4.50 (br s, 1H), 4.42-4.37 (m, 2H), 4.17 (q, J=7.2Hz, 2H), 4.03-3.97 (m, 4H), 3.97-3.88 (m, 2H), 3.88-3.83 (m, 2H), 3.83-3.78(m, 1H), 3.43(s, 3H), 2.69-2.60(m, 1H), 2.28-2.18(m, 1H), 2.09-2.01(m, 8H), 1.75(br d, J=3.3Hz, 4H), 1.48-1.41(m, 1H), 1.38-1.28(m, 4H), 1.27-1.22(m, 3H), 1.19-1.14(m, 3H), 0.86-0.80 (m, 3H), 0.72-0.66 (m, 1H), 0.63-0.57 (m, 3H); mS (ES-API positive): 1103.6 (M+1) + . Example 178: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-4-((R)-7-methyl-1,4-diazacycloheptane-1-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide)

[0326] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.43-8.39 (m, 1H), 7.54-7.46 (m, 7H), 7.45-7.41 (m, 2H), 7.29-7.23 (m, 1H) , 6.77 (d, J=8.2Hz, 2H), 6.33-6.26 (m, 1H), 5.39-5.32 (m, 1H), 5.30 (d, J=11.6Hz, 1H), 5.12-5.05 (m, 1H), 4.83-4.80 (m, 1H), 4.76 (d, J=11.6Hz, 1H), 4.64-4.56 (m, 1H), 4.50 (rs, 1H), 4.45-4.37 ( m, 3H), 4.16 (q, J=7.2Hz, 2H), 4.05-3.88 (m, 2H), 3.86 (d, J=6.2Hz, 2H), 3.82-3.77 (m, 1H), 3.55 (r dd, J=9.4, 14.8Hz, 1H), 3.43 (s, 3H), 3.40-3.32 (m, 1H), 3.21 (r dd, J=1.5, 13.9Hz, 1H), 3.10 (r dd, J=6.8, 13.9Hz, 1H), 2.67-2.58(m, 2H), 2.43-2.33(m, 1H), 2.28-2.19(m , 1H), 2.09 (d, J=2.3Hz, 3H), 2.05-1.99 (m, 1H), 1.88 (td, J=10.2, 15.4Hz, 1 H), 1.53 (d, J=6.2Hz, 3H), 1.49-1.44 (m, 1H), 1.34 (t, J=7.2Hz, 3H), 1.25 (d , J=6.4Hz, 3H), 1.17 (d, J=6.7Hz, 3H), 0.86-0.80 (m, 3H), 0.70-0.55 (m, 4H). MS (ES-API positive): 1118.6 (M+1) + . Example 179: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-4-(1,4-diazacycloheptane-1-yl)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0327] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.90-8.83 (m, 1H), 8.41 (s, 1H), 7.57-7.40 (m, 8H), 7.32-7.23 (m, 1H), 6.79 (d, J=8.2Hz, 2H), 5.41-5.31 (m, 1H), 5.29- 5.18(m, 1H), 5.10(s, 1H), 4.85-4.83(m, 1H), 4.64-4.55(m, 1H), 4.53- 4.46(m, 1H), 4.43-4.37(m, 2H), 4.13-4.01(m, 4H), 3.99-3.73(m, 5H), 3.42(s, 3H), 3.26-3.21(m, 2H), 3.05-2.94(m, 2H), 2.66(s, 1H), 2.49( s, 3H), 2.29-2.20 (m, 1H), 2.19-2.12 (m, 2H), 2.06 (d, J=2.4Hz, 4H), 1. 50-1.42 (m, 1H), 1.24 (d, J=6.3Hz, 3H), 1.17 (d, J=6.6Hz, 3H), 0.87-0.79 (m, 3H), 0.73-0.65 (m, 1H), 0.62 (s, 3H); mS (ES-API positive): 1107.5 (M+1) + . Example 180: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-4-(1,4-oxazacycloheptane-4-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide)

[0328] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ 8.44-8.39 (m, 1H), 7.56-7.40 (m, 9H), 7.27 (d, J = 9.8Hz, 1H), 6.80 (d, J = 8.2Hz, 2H), 6.34-6.27 (m, 1H), 5.36 (d, J = 10.4Hz, 1H), 5.31-5.23 (m, 1H), 5.07 (t, J=6.0Hz, 1H), 4.65-4.56 (m, 2H), 4.53- 4.46(m, 1H), 4.45-4.38(m, 2H), 4.22-4.08(m, 6H), 4.07-4.00(m, 2H), 3. 99-3.91(m, 1H), 3.91-3.74(m, 6H), 3.43(s, 3H), 2.72-2.58(m, 1H), 2.2 9-2.17(m, 3H), 2.06(d, J=2.4Hz, 3H), 2.04(s, 1H), 1.51-1.41(m, 1H), 1 .39-1.28(m, 4H), 1.27-1.21(m, 3H), 1.17(d, J=6.7Hz, 3H), 0.87-0.80( m, 3H), 0.74-0.66 (m, 1H), 0.66-0.53 (m, 3H); mS (ES-API positive): 1105.5 (M+1) + . Example 181: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-4-(2,3,6,7-tetrahydro-1H-azacycloheptene-1-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide)

[0329] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.45-8.39(m, 1H), 7.56-7.47(m, 7H), 7.45-7.42(m, 2H), 7.30-7.24(m, 1H), 6.82-6.77(m, 2H), 6.32-6.28(m, 1H), 5.84(t, J=3.0Hz, 2H) , 5.36 (d, J=10.4Hz, 1H), 5.29-5.22 (m, 1H), 5.07 (t, J=6.1Hz, 1H), 4.60 (t, J=8 .3Hz, 1H), 4.52-4.47(m, 1H), 4.42-4.38(m, 2H), 4.17(q, J=7.2Hz, 2H), 4.10(br t, J=5.4Hz, 4H), 3.98-3.75 (m, 5H), 3.43 (s, 3H), 2.69-2.61 (m, 5H), 2.30-2.17 (m, 1H), 2.06 (d, J=2.4Hz, 3H), 2.04 (br s, 1H), 1.50-1.41 (m, 1H), 1.38-1.28 (m, 4H), 1.25 (d, J=6.4Hz, 3H), 1.17 ( d, J=6.7Hz, 3H), 0.85-0.81 (m, 3H), 0.73-0.66 (m, 1H), 0.64-0.58 (m, 3H). MS (ES-API positive): 1101.5 (M+1) + . Example 182: (2S,4R)-1-((2S)-2-(4-(4-(((4-(4-cyanoazacycloheptane-1-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0330] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.41 (d, J=1.9Hz, 1H), 7.57-7.38 (m, 10H), 7.27 (br d, J=8.8Hz, 1H), 6.80 (br d, J=6.4Hz, 2H), 6.34-6.27 (m, 1H), 5.35 (d, J=10.3Hz, 1H), 5.24 (dd, J=4.5, 11.4Hz, 1H), 5.11-5.03 (m, 1H), 4.64-4.56 (m, 2H), 4.50 (br d, J=2.0Hz, 1H), 4.41(br d, J=5.1Hz, 2H), 4.13-3.94(m, 5H), 3.94-3.88(m, 1H), 3.88-3.83(m, 2H), 3.83-3.76(m, 1H), 3.43(s, 3H), 3.18(br s, 1H), 2.71-2.56 (m, 1H), 2.42-2.19 (m, 4H), 2.13-1.98 (m, 7H), 1.52-1.41 (m, 1H), 1.34 (t, J=7.2Hz, 4H), 1.28-1.22 (m, 3H), 1.20-1.13 (m, 3H), 0.83 (d, J=6.7Hz, 3H), 0.75-0.54 (m, 5H); mS (ES-API positive): 1128.6 (M+1) + . Example 183: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-4-((S)-7-methyl-1,4-diazacycloheptane-1-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide)

[0331] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ8.45-8.40(m, 1H), 7.59-7.53(m, 2H), 7.53-7.47(m, 5H), 7.45-7.41(m, 2H), 7.30-7.25( m, 1H), 6.83-6.78 (m, 2H), 6.33-6.27 (m, 1H), 5.40-5.31 (m, 1H), 5.18-5.13 (m, 1H), 5.10-5.04 (m, 1H), 4.91 (br d, J=11.6Hz, 1H), 4.82-4.80 (m, 1H), 4.63-4.58 (m, 1H), 4.53-4.47 (m, 1H), 4. 44-4.38(m, 3H), 4.20-4.13(m, 2H), 4.03-3.88(m, 2H), 3.86(d, J=6.1Hz, 2H), 3.83-3.78(m, 1H), 3.60-3.53(m, 1H), 3.42(s, 3H), 3.39-3.33(m, 1H), 3.24-3 .19(m, 1H), 3.15-3.09(m, 1H), 2.67-2.61(m, 2H), 2.42-2.33(m, 1H), 2.24(br dd, J=7.7, 12.9Hz, 1H), 2.05-1.99 (m, 4H), 1.93-1.84 (m, 1H), 1.53 (d, J=6.2Hz, 3H), 1.50-1.46 (m, 1H), 1.37-1. 32 (m, 3H), 1.24 (d, J=6.3Hz, 3H), 1.17 (d, J=6.7Hz, 3H), 0.85-0.80 (m, 3H), 0.75-0.69 (m, 1H), 0.65-0.57 (m, 3H). MS (ES-API positive): 1118.5 (M+1) + . Example 184: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-4-(1,4-diazacycloheptane-1-yl)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide)

[0332] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ = 8.46-8.37 (m, 1H), 7.55-7.45 (m, 7H), 7.44-7.39 (m, 2H), 7.30-7.24 (m, 1 H), 6.79 (d, J=8.1Hz, 2H), 6.31 (d, J=1.9Hz, 1H), 5.40-5.17 (m, 2H), 4.87-4.86 (m, 1H), 4.84 (br s, 1H), 4.63-4.57 (m, 1H), 4.52-4.44 (m, 1H), 4.42-4.37 (m, 2H), 4.21-4.04 (m, 7H), 3.96-3.77 (m, 3 H), 3.42 (s, 3H), 3.27-3.22 (m, 2H), 3.05-2.95 (m, 2H), 2.66 (s, 1H), 2.22-2.11 (m, 3H), 2.06 (d, J=2. 1Hz, 3H), 2.00-1.91 (m, 1H), 1.50-1.42 (m, 1H), 1.35 (s, 3H), 1.25 (dd, J=2.8, 6.3Hz, 6H), 1.17 (d, J= 6.6Hz, 3H), 0.83 (d, J=6.7Hz, 3H), 0.73-0.65 (m, 1H), 0.65-0.56 (m, 3H); mS (ES-API positive): 1118.5 (M+1) + . Example 185: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-1-hydroxy-4-(2-methyl-2H-pyrazolo[3,4-c]pyridin-4-yl)but-3-yn-2-yl)pyrrolidine-2-carboxamide

[0333] This compound was prepared using a method similar to that used in Example 34. 1H NMR (400MHz, CD3OD) δ9.05 (s, 1H), 8.48 (s, 1H), 8.39 (s, 1H), 8.17 (s, 1H), 7.54-7.49 (m, 4H), 7.40 (s, 1H), 7.27 ( d, J=10.5Hz, 1H), 6.79 (d, J=7.7Hz, 2H), 5.35 (d, J=10.1Hz, 1H), 5.29 (s, 1H), 5.26 (s, 1H), 5.22 (s, 1H), 5.05 (br t, J=5.8Hz, 2H), 4.57-4.53(m, 2H), 4.51(s, 1H), 4.42-4.38(m, 3H), 4.33(s, 4H), 4.32-4.29(m, 1H), 4.27(s, 1H), 3.97(br d, J=3.6Hz, 1H), 3.93(br s, 1H), 3.90(s, 1H), 3.85(br d, J=6.1Hz, 3H), 3.16-3.11 (m, 4H), 2.08 (d, J=2.4Hz, 4H), 1.93-1.88 (m, 1H) , 1.24 (d, J=6.3Hz, 4H), 1.17 (d, J=6.6Hz, 4H), 0.83 (d, J=6.7Hz, 3H), 0.62 (br d, J=3.9Hz, 3H). MS (ES-API positive): 1087.6 (M+1) + . Example 186: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((R)-pyrrolidine-3-yl)amino)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-N-((1R,2S)-1-(5-(1-ethyl-1H-pyrazole-5-yl)bicyclo[4.2.0]octyl-1(6),2,4-trien-2-yl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide

[0334] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ8.41 (s, 1H), 7.51 (d, J=2.0Hz, 3H), 7.50-7.42 (m, 2H), 7.24 (s , 2H), 7.19 (s, 1H), 6.85-6.76 (m, 2H), 6.28 (d, J=1.8Hz, 1H), 5.38-5.31 (m, 1H), 5.27 (d, J=11.6Hz, 1H), 4.96 (s, 1H), 4.93 (s, 2H), 4.86-4.86 (m, 1H), 4.64-4.56 (m, 1H), 4 .49(s, 1H), 4.45-4.37(m, 2H), 4.24-4.10(m, 3H), 3.97-3.83(m, 2H), 3.83-3.75(m, 1 H), 3.42 (s, 3H), 3.39-3.33 (m, 4H), 3.25 (d, J=4.2Hz, 2H), 3.22 (s, 3H), 3.09 (s, 1H), 3.06 (s, 1H), 2.66-2.60 (m, 1H), 2.38-2.27 (m, 1H), 2.24-2.10 (m, 2H), 2.06 (d, J=2.3 Hz, 3H), 2.02 (s, 1H), 1.50-1.41 (m, 1H), 1.39-1.32 (m, 3H), 1.26 (dd, J=6.4, 11.4Hz, 6H), 1.20-1.12 (m, 3H), 0.87-0.76 (m, 3H), 0.76-0.68 (m, 1H), 0.59 (d, J=4.8Hz, 3H). MS (ES-API positive): 1144.6 (M+1) + . Example 187: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((R)-pyrrolidine-3-yl)amino)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide

[0335] This compound was prepared using a method similar to that used in Example 84. 1H NMR (400MHz, CD3OD) δ8.88 (s, 1H) 8.42 (s, 1H) 7.51-7.57 (m, 2H) 7.43-7.50 (m, 6H) 7.28 (d, J=10.01Hz, 1H) 6.82 (d, J =8.23Hz, 2H) 5.21-5.40 (m, 2H) 4.93-5.03 (m, 1H) 4.89-4.92 (m, 1H) 4.84-4.85 (m, 1H) 4.59 (t, J = 8.29Hz, 1H) 4.48 (br s, 1H) 4.37-4.44 (m, 2H) 4.11 (quin, J = 6.32Hz, 1H) 3.75-3.96 (m, 3H) 3.42 (s, 3H) 3.34 ( s, 3H) 2.98-3.26 (m, 4H) 2.62-2.67 (m, 1H) 2.44-2.52 (m, 3H) 2.29-2.38 (m, 1H) 2.10-2. 20 (m, 2H) 2.01-2.08 (m, 3H) 1.89-2.00 (m, 1H) 1.41-1.51 (m, 1H) 1.25 (d, J = 6.32Hz, 6H) 1.17 (d, J=6.68Hz, 3H) 0.79-0.86 (m, 3H) 0.58-0.73 (m, 4H); mS (ES-API positive): 1121.5 (M+1) + . Example 188: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-1-hydroxy-4-(6-methyl-1H-indazol-4-yl)but-3-yn-2-yl)pyrrolidine-2-carboxamide

[0336] This compound was prepared using a method similar to that used in Example 34. 1H NMR (400MHz, CD3OD) δ8.40 (s, 1H), 8.12-7.99 (m, 1H), 7.51 (d, J=3.6Hz, 3H ), 7.43-7.37(m, 1H), 7.34-7.26(m, 2H), 7.14-7.04(m, 1H), 6.82-6.71(m, 2 H), 5.40-5.31(m, 1H), 5.30-5.25(m, 1H), 5.22(s, 1H), 5.06-5.01(m, 1H), 4 .83-4.82(m, 1H), 4.81-4.79(m, 1H), 4.56-4.48(m, 2H), 4.41-4.37(m, 2H), 4.35-4.30 (m, 1H), 4.01-3.80 (m, 7H), 3.42 (s, 3H), 3.16-3.13 (m, 1H), 2.67 -2.63(m, 1H), 2.45(s, 3H), 2.31-2.23(m, 1H), 2.12(s, 1H), 2.08(s, 3H), 2. 07-1.99(m, 1H), 1.94-1.88(m, 1H), 1.49-1.41(m, 1H), 1.27-1.23(m, 3H), 1 .20-1.15 (m, 3H), 0.85-0.80 (m, 3H), 0.70-0.65 (m, 1H), 0.64-0.59 (m, 3H). MS (ES-API positive): 1086.5 (M+1) + . Example 189: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-((S)-2-methoxypropoxy)-4-((R)-7-methyl-1,4-diazacycloheptane-1-yl)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutyryl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0337] This compound was prepared using a method similar to that used in Example 32. 1H NMR (400MHz, CD3OD) δ0.53-0.74 (m, 4H) 0.77-0.91 (m, 3H) 1.17 (d, J = 6.56H z, 3H) 1.22-1.30 (m, 3H) 1.40-1.49 (m, 1H) 1.49-1.69 (m, 3H) 1.81-1.95 (m, 1 H)1.97-2.05(m,1H)2.05-2.16(m,3H)2.17-2.32(m,1H)2.39(t,J=14.90,7 .21Hz, 1H) 2.44-2.57 (m, 3H) 2.59-2.68 (m, 2H) 3.07-3.15 (m, 1H) 3.20-3.24 (m, 1H) 3.34-3.40 (m, 1H) 3.43 (s, 3H) 3.52-3.60 (m, 1H) 3.72-4.06 (m, 5H) 4 .35-4.46 (m, 3H) 4.49 (s, 1H) 4.60 (t, J = 8.34Hz, 1H) 4.71-4.81 (m, 2H) 5.06 ( t, J=6.08Hz, 1H) 5.17-5.51 (m, 2H) 6.77...

Claims

1. A compound of formula (I): in: X is N or CR 3 ; G is CR 14 R 15 Or O; J is CR 5a R 5b Or O, provided that G and J are not both O at the same time; When G is CR 14 R 15 And J is CR 5a R 5b At that time, the carbon atoms of G and J (i.e., respectively bonded to R) 14 R 15 and R 5a R 5b (atoms) optionally with R 14 Or R 15 、or / and R 5a Or R 5b Together they form C3-C6 cycloalkyl or cycloalkenyl groups; Between G and J This indicates that there is a single or double bond between G and J; L is an alkynyl, arylene, heteroarylene, C3-C8 monocyclic or bicyclic alkylene, or C3-C8 heterocyclic alkylene, and optionally is influenced by one or more R. 9 replace; K is Q is an alkynyl, arylene, heteroarylene, monocyclic or bicyclic cycloalkyl or heterocyclic alkyl, and is optionally substituted with one or more halogens, alkyl, haloalkyl, alkoxyalkyl, hydroxy, hydroxyalkyl, -O-alkyl or cycloalkyl; R 1 It is a C1-C6 alkyl, alkoxyalkyl, haloalkyl, monocyclic or bicyclic cycloalkyl or heterocyclic group, each optionally marked with one or more R groups. 10 replace; R 2 It can be a saturated or unsaturated heterocyclic group, a bridged bicyclic heterocyclic group, a fused bicyclic heterocyclic group, a spirocyclic heterocyclic group, or -NR. 16 R 16 ′; wherein the heterocyclic group is optionally surrounded by one or more R 11 The heterocyclic group is substituted, and the heterocyclic group contains 1 to 3 cyclic skeleton heteroatoms, each heteroatom being independently oxygen, sulfur or nitrogen; R 3 H, halogen, C1-C6 alkyl or haloalkyl, or C3-C8 cycloalkyl or heterocyclic group; wherein the C1-C6 alkyl or haloalkyl, or C3-C8 cycloalkyl or heterocyclic group is optionally surrounded by one or more R 13 replace; R 4 It is H, aryl, heteroaryl, fused aryl, fused heteroaryl, aryl fused spiroheterocyclic, or heteroaryl fused spiroheterocyclic, each optionally bonded by one or more R 12 Substitution; wherein the heteroaryl or heterocyclic group contains 1 to 4 cyclic skeleton heteroatoms, each heteroatom being independently oxygen, sulfur or nitrogen; wherein the -CH2- group in the fused aryl, fused heteroaryl, aryl fused spirocyclic or heteroaryl fused spirocyclic group is optionally replaced by -C(=O)-. R 5a and R 5b Each of the following can be independently H, alkyl, halogen, haloalkyl, hydroxyl, hydroxyalkyl, -O-alkyl, alkoxyalkyl, -NR 14 R 15 -alkylamino, or -alkylaminoalkyl; or R 5a and R 5b Together with the atoms they are connected to, they form cycloalkyl groups; R 6 It is a C1-C6 alkyl, C3-C8 cycloalkyl, or C4-C8 heterocyclic group; wherein the cycloalkyl or heterocyclic alkyl is optionally substituted with an alkyl, halogen, or haloalkyl group; R 7a and R 7b Each of the following can be independently H, C1-C6 alkyl, halogen, haloalkyl, hydroxyl, hydroxyalkyl, -O-alkyl, alkoxyalkyl, -NR 14 R 15 -alkylamino, -alkylaminoalkyl, -alkyl-C(=O)-NR 14 R 15 C3-C8 cycloalkyl or C4-C8 heterocycloalkyl; or, R 7a and R 7b Together with the atoms they are connected to, they form cycloalkyl groups; R 8 It is H, halogen, alkyl, monocyclic or bicyclic aryl or heteroaryl; wherein the aryl or heteroaryl group is optionally substituted by one or more substituents, each substituent being independently selected from halogen, alkyl, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, -O-alkyl, -SF5, -NR 14 R 15 or alkoxyalkyl; R 9 R 10 R 11 and R 12 Each of the following can be independently H, halogen, -CN, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, -NR 14 R 15 -NH-C(O)-R 16 -O-alkyl, -SO2-R 15 C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, haloalkoxy, cycloalkyl, alkyl-cycloalkyl, heterocyclic, alkyl-heterocyclic, aryl or heteroaryl; or, R 9 R 10 R 11 and R 12 Any two atoms connected together in the aryl group form a cycloalkyl or heterocyclic group; each of the aryl, heteroaryl, cycloalkyl or heterocyclic group is optionally further substituted by an alkyl, halogen or haloalkyl group; R 13 H, halogen, alkyl, haloalkyl, haloalkoxy, -CN, oxo, -NR 14 R 15 , hydroxyl, hydroxyalkyl, -O-alkyl, alkoxyalkyl, cycloalkyl or heterocyclic groups; R 14 and R 15 Each is independently H or alkyl; R 16 and R 16 Each of the following groups is independently H, alkyl, cycloalkyl, or heterocyclic, and each is optionally bounded by one or more R groups. 11 replace; Or its pharmaceutically acceptable salt, tautomer or stereoisomer.

2. The compound of claim 1, wherein R 2 for Y is NH, -CH(CN)-, CH2, or O; and each R... 2 Optional by one or more R 11 replace.

3. The compound of claim 1 or 2, wherein L is a bridged bicyclic cycloalkylene, aryl fused cycloalkylene, or arylene.

4. The compound according to any one of claims 1 to 3, wherein L is 5. The compound according to any one of claims 1 to 4, wherein K is 6. The compound according to any one of claims 1 to 5, wherein Q is Q may optionally be substituted with one or more alkyl, halogen or haloalkyl groups.

7. The compound according to any one of claims 1 to 6, wherein R 4 For H, And R 4a R 4b R 4c and R 4d Each can be independently H, alkyl, halogen, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, -O-alkyl, alkoxyalkyl, -CN, alkynyl, cycloalkyl, heterocyclic or hydroxyalkynyl.

8. The compound according to any one of claims 1 to 7, wherein R 6 It can be C1-C6 alkyl, C3-C6 cycloalkyl, oxetane alkyl, or azirne alkyl.

9. The compound according to any one of claims 1 to 8, wherein R 8 for: And R 8 Optionally substituted with one or more substituents, each substituent being independently selected from halogens, alkyl groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, -O-alkyl groups, -SF5 groups, amino groups, or alkoxyalkyl groups.

10. The compound according to any one of claims 1 to 9, wherein R 13 For H.

11. The compound of claim 1, wherein G is O.

12. The compound of claim 1, wherein J is CH2.

13. The compound of claim 1, wherein the compound is of formula (II): Where L is And L is optionally controlled by one or more R 9 replace.

14. The compound according to any one of claims 1-13, wherein X is CR 3 .

15. The compound of claim 14, wherein R 3 H, F, trifluoromethyl, C 1-6 Alkyl or C 3-5 Cycloalkyl.

16. The compound of claim 1, wherein the compound is of formula (III): Where L is And L is optionally controlled by one or more R 9 replace.

17. The compound of claim 1 or 16, wherein R 4 for And R 4a R 4b R 4c and R 4d Each can be independently H, alkyl, halogen, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, -O-alkyl, alkoxyalkyl, -CN, alkynyl, cycloalkyl, heterocyclic or hydroxyalkynyl.

18. The compound of claim 1, wherein the compound is of formula (IV): Where L is And L is optionally controlled by one or more R 9 Replace; and R 4a R 4b R 4c and R 4d Each is independently H, alkyl, halogen, or haloalkyl.

19. The compound of claim 18, wherein the halogen is -F or -Cl.

20. The compound of claim 1 or 18, wherein R 6 It is a C1-C6 alkyl group.

21. The compound of claim 1, wherein the compound is of formula (V): Where L is And L is optionally controlled by one or more R 9 replace; Where R 4b R 4c and R 4d Each is independently H, alkyl, halogen, or haloalkyl.

22. The compound according to any one of claims 1 to 21, wherein the compound is selected from the group consisting of:

23. The compound of any one of claims 1-22, wherein the compound is capable of degrading or inhibiting KRAS protein with G12D mutation.

24. A pharmaceutical composition comprising the compound of any one of claims 1-23, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

25. The pharmaceutical composition of claim 24 further comprises a second therapeutic agent.

26. A method of treating a disease caused by a KRAS (G12D) mutation, comprising administering to a subject in need a therapeutically effective amount of the compound of any one of claims 1 to 23 or the pharmaceutical composition of claim 24 or 25.

27. The method of claim 26, wherein the disease caused by the KRAS(G12D) mutation is cancer, characterized in that... The KRAS(G12D) mutation is present.

28. The method of claim 27, wherein the cancer is pancreatic cancer, colorectal cancer, or lung cancer.

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