Compounds for the degradation and inhibition of Kras(G12D) protein

Abstract

Provided herein are compounds of formula (I), or their tautomers, stereoisomers, or pharmaceutically acceptable salts. These compounds are useful as KRAS(G12D) proteolytic agents and / or inhibitors. [Case 1] TIFF2026511222000314.tif64165

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to PCT application PCT / CN2023 / 084077 filed on 27 March 2023, U.S. application 63 / 494,607 filed on 6 April 2023, U.S. application 63 / 602,537 filed on 24 November 2023, and PCT application PCT / CN2023 / 135267 filed on 30 November 2023, all of which are incorporated herein by reference in their entirety. [Background technology]

[0002] The RAS (rat sarcoma virus) protein plays a causal role in human cancers. However, despite the clinical significance of targeting RAS, the discovery of potent inhibitors of RAS has been difficult. For many years, the RAS protein has earned a reputation for being "untreatable."

[0003] In human cells, three closely related RAS genes (HRAS, KRAS, and NRAS) encode four highly related protein isoforms (H-Ras, N-Ras, K-Ras4A, and K-Ras4B). These RAS proteins are guanosine triphosphate (GTPases) and are involved in a broad spectrum of major molecular and cellular activities, particularly proliferation, differentiation, and cell death (Front. Oncol., 18 October 2019). RAS proteins constantly cycle between an inactive guanosine diphosphate (GDP)-bound state and an active guanosine triphosphate (GTP)-bound state, relaying intracellular signals in response to extracellular stimuli. RAS protein activation is also regulated by guanine nucleotide exchange factors (GEFs), which catalyze nucleotide exchange, and GTPase-activating proteins (GAPs), which assist in GTP hydrolysis. When activated, RAS directly interacts with and activates several downstream effector pathways, including the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K) pathway. However, mutations in RAS typically become GAP-independent and disrupt the guanine exchange cycle by "fixing" RAS to an activated GTP-bound state, 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., 2020 Aug;19(8):533-552.

[0004] Mutations in the RAS gene are found in approximately one-quarter of human cancers and are a major cause of up to one million deaths worldwide annually. The majority of these mutations occur in KRAS (85%), with less frequency in NRAS (12%) and HRAS (3%) (J. Internal Med., 2020, 288; 183-191). KRAS mutations appear frequently in a range of highly fatal cancers, including pancreatic cancer (90%), colorectal cancer (45%), and lung cancer (30%) (Curr. Topics in Med. Chem., 2019, 19(23), 2079). Therefore, KRAS is an interesting and promising cancer target.

[0005] KRAS typically mutates at codon / residue 12, which is occupied by a glycine (G) residue. When glycine at residue 12 is mutated to something other than proline, steric hindrance occurs, which inhibits the binding of GAP proteins to RAS, reduces GTP hydrolysis, and thereby increases the level of GTP-binding activity (Curr. Topics in Med. Chem., above). The most common KRAS mutation in human cancer is KRAS(G12D) (glycine 12 to aspartic acid), which is present in 33% of all cases and is particularly frequent in pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) (Mol. Oncol., 2022 Dec. 16(22):3911-3915). KRAS(G12C) (glycine 12 to cysteine) mutations are found in approximately 13% of all KRAS-mutated tumors. Other mutations such as G12C and G12F occur at a lower frequency.

[0006] Despite some recent advances [e.g., AMG510 (Sotorasib) and MRTX849 (Adagrasib)], there remains a significant need for the development of new drugs and therapies to treat cancers mediated by KRAS (G12D) mutations. [Overview of the Initiative]

[0007] Provided herein are compounds of formula (I), their tautomers, stereoisomers, or pharmaceutically acceptable salts, which reduce the cellular level of the KRAS protein and / or inhibit the activity of KRAS. Thus, this compound may be useful as a KRAS(G12D) proteolytic agent and / or inhibitor.

[0008] The compound of formula (I) is a PROTAC (proteolysis targeting chimera molecule) compound, in which a ligand targeting the KRAS(G12D) protein and a ligand of an E3 ubiquitin ligase are linked by a linker, wherein the KRAS(G12D) ligand is capable of binding to the KRAS(G12D) protein, and the E3 ligand is capable of binding / mobilizing the ubiquitin ligase. Such bifunctional compounds promote the formation of an intracellular complex of the target protein KRAS(G12D) and the E3 ligase, and utilize the ubiquitin-proteasome system to induce the degradation of the target protein. A protein called an E3 ligase recognizes and ubiquitinates the protein to be degraded, and promotes its degradation by the proteasome.

[0009] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a tautomer or stereoisomer thereof. [Chemical Formula] (In the formula, 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 then optionally, the carbon atoms of G and J (each of R 14 and R 15 , as well as R 5aand R 5b However, those that are bound to them are R 14 Or R 15 , or / and R 5a Or R 5b [that is, R 14 Or R 15 ;R 5a Or R 5b ; or R 14 Or R 15 , and R 5a or R 5b Together with ], they form C3-C6 cycloalkylenes or cycloalkenylenes; Between G and J [ka] (Dashed line) indicates a single or double bond between G and J; L is an alkylylene, arylene, heteroarylene, a C3-C8 monocyclic or bicyclic cycloalkylene, or a C3-C8 heterocycloalkylene, and one or more R 9 It is arbitrarily replaced by; K is [ka] is; Q is an alkylylene, arylene, heteroarylene, monocyclic or bicyclic cycloalkylene or heterocycloalkylene, optionally substituted with one or more halo, alkyl, haloalkyl, alkoxyalkyl, hydroxy, hydroxyalkyl, -O-alkyl, or cycloalkyl groups; R 1 These are C1-C6 alkyl, alkoxyalkyl, haloalkyl, monocyclic or bicyclic cycloalkyl or heterocyclyl, each of which contains one or more R 10 It is arbitrarily replaced by; R 2 This includes saturated or unsaturated heterocyclyls, condensed bicyclic heterocyclyls, bridged bicyclic heterocyclyls, or spirocyclic heterocyclyls, or -NR. 16 R16’ Here, a heterocyclyl is one or more R 11 The heterocyclyl is optionally substituted, where each of the heteroatoms is independently oxygen, sulfur, or nitrogen; R 3 is H, halo, C1-C6 alkyl or haloalkyl, or C3-C8 cycloalkyl or heterocyclyl, where C1-C6 alkyl or haloalkyl, or C3-C8 cycloalkyl or heterocyclyl is one or more R 13 It is arbitrarily replaced by; R 4 is H, aryl, heteroaryl, condensed aryl, condensed heteroaryl, aryl-condensed spiroheterocyclyl, or heteroaryl-condensed spiroheterocyclyl, each of which is one or more R 12 The -CH2- group in the condensed aryl, condensed heteroaryl, aryl-condensed spiroheterocyclyl, or heteroaryl-condensed spiroheterocyclyl is optionally substituted with -C(=O)-; where the heteroaryl or heterocyclyl each independently contains 1 to 4 ring-forming heteroatoms which are oxygen, sulfur, or nitrogen; where the -CH2- group in the condensed aryl, condensed heteroaryl, aryl-condensed spiroheterocyclyl, or heteroaryl-condensed spiroheterocyclyl is optionally substituted with -C(=O)-; R 5a and R 5b These are, independently, H, alkyl, halo, haloalkyl, hydroxyl, hydroxyalkyl, -O-alkyl, alkoxyalkyl, and -NR. 14 R 15 , -alkamino or -alkaminoalkyl; or, R 5a and R 5b They, together with the atoms to which they are bonded, form a cycloalkyl group; R 6 is a C1-C6 alkyl, C3-C8 cycloalkyl, or C4-C8 heterocyclyl; where the cycloalkyl or heterocycloalkyl is optionally substituted with alkyl, halo, or haloalkyl; R 7a and R 7bThese are, independently, H, C1-C6 alkyl, halo, haloalkyl, hydroxyl, hydroxyalkyl, -O-alkyl, alkoxyalkyl, and -NR. 14 R 15 -Alkamino, -Alkaminoalkyl, -Alkylene-C(=O)-NR 14 R 15 , C3-C8 cycloalkyl, or C4-C8 heterocycloalkyl; or, R 7a and R 7b These, together with the atoms to which they are bonded, form cycloalkylenes; R 8 Here, H, halo, alkyl, monocyclic or bicyclic aryl or heteroaryl are, respectively, halo, alkyl, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, -O-alkyl, -SF5, -NR 14 R 15 , or optionally substituted with one or more substituents that are alkoxyalkyl groups; R 9 , R 10 , R 11 and R 12 These are, independently, H, halo, -CN, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxyalkyl, -O-alkyl, and -NR. 14 R 15 -NH-C(O)-R 16 , -SO 2- R 15 , C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, haloalkoxy, cycloalkyl, -alkylene-cycloalkyl, heterocyclyl, -alkylene-heterocyclyl, aryl, or heteroaryl; or R9, R 10 , R 11 and R 12 Two of these, together with the atom to which they are bonded, form a cycloalkyl or heterocycline; each of the aryl, heteroaryl, cycloalkyl, or heterocycline is further optionally substituted with alkyl, halo, or haloalkyl; R13 H, halo, alkyl, haloalkyl, haloalkoxy, -CN, oxo, -NR 14 R 15 , hydroxy, hydroxyalkyl, -O-alkyl, alkoxyalkyl, cycloalkyl or heterocyclyl; R 14 and R 15 Each of these is independently either H or alkyl; R 16 and R 16’ Each of these is independently H, alkyl, cycloalkyl, or heterocyclyl, and each of these is one or more R 11 (It is arbitrarily replaced.)

[0010] In some embodiments, R 2 The following structures are selected. [ka] (wherein Y is NH, -CH(CN)-, CH2, or O; and R 2 This can optionally include one or more R 11 (Further substitution is performed using the base.)

[0011] In some embodiments, L is a crosslinked bicyclic cycloalkylene, an aryl condensed cycloalkylene, or an arylene.

[0012] In some other embodiments, L is [ka] That is the case.

[0013] In some embodiments, K is [ka] That is the case.

[0014] In some embodiments, Q is [ka] Furthermore, Q is optionally substituted with one or more alkyl, halo, or haloalkyl groups.

[0015] In some embodiments, X is CR 3 That is the case.

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

[0017] In some embodiments, R 4 is H, or a group selected from the following: [ka] (In the formula, R 4a , R 4b , R 4c , and R 4d These are, independently, H, alkyl, halo, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, -O-alkyl, alkoxyalkyl, -CN, alkynyl, cycloalkyl, heterocyclyl, or hydroxyalkalkynyl.

[0018] In some embodiments, R 6 These are C1-C6 alkyl, C3-C6 cycloalkyl, oxetanyl, or azetidinyl.

[0019] In some embodiments, R 8 The following can be selected: [ka] (In the formula, each R 8 (It is optionally substituted with one or more substituents independently selected from halo, alkyl, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, -O-alkyl, -SF5, amino, or alkoxyalkyl.)

[0020] In some embodiments, R 13 is H.

[0021] In some embodiments, R 14 and R 15 are each independently H or methyl.

[0022] In some embodiments, the compound is of formula (II), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

Chemical formula

Chemical formula

[0023] In some embodiments, the compound is of formula (III), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

Chemical formula

Chemical formula

[0024] In some embodiments, R 4 is

Chemical formula

[0025] In some embodiments, the compound is of formula (IV), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. [ka] (In the formula, L is, [ka] And, arbitrarily one or more R 9 It is replaced with;R 4a , R 4b , R 4c and R 4d These are, independently, H, alkyl, halo, and haloalkyl.

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

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

[0028] In some embodiments, the compound is of formula (V), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. [ka] (In the formula, L is, [ka] and one or more R 9 It is arbitrarily replaced with;R 4b , R 4c and R 4d Each of these is independently H, alkyl, halo, or haloalkyl.

[0029] While not limiting, exemplary compounds of the present invention are listed below:

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

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

[0031] Another aspect of the present invention includes pharmaceutical compositions comprising the compounds described herein and pharmaceutically acceptable carriers or excipients, respectively. Such compositions may include a second therapeutic agent.

[0032] Yet another aspect of the present invention provides a method for treating cancer in a subject that needs it, wherein the cancer is characterized by the presence of a KRAS (G12D) mutation. The method comprises administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition as described above. Cancers that can be treated (including reducing the likelihood of recurrence) by the methods of the present teachings include pancreatic cancer, colorectal cancer, or lung cancer.

Embodiments of the Invention

[0033] Hereinafter, preferred embodiments of the present invention will be described in detail, and examples thereof will be further illustrated. Although the present invention will be described in conjunction with preferred embodiments, it will be understood that these embodiments are not intended to limit the present invention to these embodiments. On the contrary, the present invention is intended to cover alternatives, modifications, and equivalents that may be included within the spirit and scope of the present invention as defined by the claims. Further, in the detailed description of the present invention, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be apparent to those skilled in the art that the present 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 in order not to unnecessarily obscure aspects of the present invention.

[0034] Definitions Unless the context indicates otherwise, all references to compound formulas in all parts of this specification (including uses, methods, and other aspects of the present invention) include references to all other dependent formulas, dependent groups, priorities, embodiments, and examples defined herein.

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

[0036] As used herein, the term "or" means to include both "and" and "or". In other words, the term "or" may be replaced with "and / or".

[0037] As used herein, the terms “unsaturated” or “partially unsaturated” refer to a part containing at least one double or triple bond.

[0038] As used herein, the term “saturated” refers to a portion that does not contain double or triple bonds, i.e., a portion that contains only single bonds.

[0039] As used herein, the term "alkyl" refers to a saturated, linear (i.e., unbranched) or branched hydrocarbon chain radical composed of carbon and hydrogen atoms, without unsaturation, and having the number of carbon atoms described herein (e.g., C1- 10 Alkyl). Wherever it appears herein, a numerical range such as "1-10" refers to each integer within a given range; for example, the term "1 to 10 carbon atoms" means that an alkyl group can consist of a number of carbon atoms including 1, 2, 3, 4, etc., up to 10 and 10. However, this definition also covers instances of the term "alkyl" where no numerical range is specified. Examples include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. Representative saturated linear 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, cyano, amino, alkoxyl, alkoxyalkyl, haloalkyl, alkoxy, amino, methylamino, dimethylamino, sulfone, sulfonamide, aryl, heteroaryl, heterocyclyl, trifluoroethyl, hydroxyethyl, cyanoethyl, methoxyethyl, and trifluoropropyl.

[0041] As used herein, the term "alkylene," both by itself and as part of another molecule, means a divalent radical derived from an alkane, which may be linear or branched. In this context, the prefix (e.g., C) is used. 1-6 (or C1-C6) represents the number of carbon atoms, or the range of carbon atoms. For example, as used herein, "C 1-4 The terms "alkylene" or "C1-C4 alkylene" refer to an alkylene group having 1 to 4 carbon atoms.

[0042] As used herein, the terms “alkoxy” or “alkoxyl” refer to saturated linear or branched hydrocarbons linked to an oxygen atom. Alkoxy groups may have the general formula -O-alkyl. Representative saturated linear alkoxy groups include methoxy, ethoxyl, n-propoxy, n-butoxy, n-pentoxy, and n-hexoxy, while saturated branched alkoxys include isopropoxy, sec-butoxy, isobutoxy, tert-butoxy, and isopentoxy. Cyclic alkoxys are referred to herein as “cycloalkoxy.” 1-4 "Alkoxy" refers to an alkoxyl that has one, two, three, or four 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” refers to an unsaturated branched or linear group having at least one carbon-carbon double bond, derived by removing a hydrogen atom from a single carbon atom of a parent alkene, either by itself or as part of another substituent. The group may be in either a cis or trans conformation with respect to the double bond. Typical alkenyl groups include, but are not limited to, ethenyl and propenyl.

[0045] As used herein, the term "alkynyl" refers to a carbon chain that contains at least one carbon-carbon triple bond, either by itself or as part of another substituent, and may be linear, branched, or a combination thereof. Examples of alkynyls include ethynyl, propargyl, 3-methyl-1-pentynyl, and 2-heptynyl.

[0046] As used herein, the term "alkynylene" refers to a divalent radical derived from an alkynyl, which may be linear or branched and contain at least one carbon-carbon triple bond. For example, "C2-C 10 The term "alkynylene" indicates the presence of 2 to 10 carbon atoms in the alkynylene chain.

[0047] As used herein, the term "carbonyl group" refers to -C(=O)-.

[0048] As used herein, the term "cycloalkyl" refers to a ring of non-aromatic carbon atoms containing at least three carbon atoms, either by itself or as part of another substituent. The term cycloalkyl includes monocyclic cycloalkyls, bicyclic cycloalkyls, polycyclic cycloalkyls, cross-linked cycloalkyls, condensed cycloalkyls, and spirocycloalkyls. In cross-linked cycloalkyls, the rings share at least two common non-adjacent atoms. In condensed bicyclic cycloalkyls, the two rings share a covalent bond. In spirocyclic cycloalkyls, one atom is common to two different rings.

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

[0050] As used herein, the terms “heterocyclic” or “heterocyclyl” refer to a group derived from a monocyclic, bridging bicyclic, fused bicyclic, spirocyclic, or polycyclic moiety, comprising at least one non-aromatic ring containing one or more ring-forming 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 another substituent, if defined). Heterocyclyls may be saturated or partially unsaturated. In certain embodiments, heterocyclyls may contain 1 to 4 heteroatoms as ring members. Heterocyclyl groups of this disclosure may be bonded to the parent molecule moiety via carbon atoms or heteroatoms in the group. Thus, the terms encompass, but are not limited to, “heterocycloalkyl,” “heteroaryl,” “bicyclic heterocyclic,” “aryl-fused heterocycloalkyl,” and “polycyclic heterocyclic.”

[0051] As used herein, the terms "halo" or "halogen" refer to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iod, -I). "Haloalkyl" refers to the alkyl group as defined above, in which one or more hydrogen atoms are substituted with a halogen independently selected from fluoro, chloro, bromo, and iod. "Fluoroalkyl" means the alkyl group as defined above, in which one or more hydrogen atoms are substituted with a fluoro atom. Unless otherwise specified, a haloalkyl group may contain as many halo atoms as chemically possible as substituents on the alkyl group. For example, fluoroethyl may be -CH2CF3, -CHF-CH3, or -CH2CH2F.

[0052] As used herein, the term "hydrogen" (or H) refers to its isotope deuterium (D or H). 2 H), and tritium ( 3 The compound of the present invention contains H, and one or any hydrogen atom in the compound is deuterium (D or 2 H) and tritium ( 3 This means that it can be replaced with any of H).

[0053] As used herein, the terms "hydroxyl" or "hydroxy" refer to the -OH group.

[0054] As used herein, the term “hydroxyalkyl” refers to an alkyl group in which one or more hydrogen atoms are substituted with a hydroxyl substituent, either by itself or as part of a part thereof. Thus, the term “hydroxyalkyl” includes monohydroxyalkyl, dihydroxyalkyl, trihydroxyalkyl, and so on.

[0055] As used herein, the terms "cyano" or "-CN" mean a -C≡N group. As used herein, the term "cyanoalkyl" means an alkyl group having at least one -CN substituent.

[0056] As used herein, the term "carbonyl" refers to a -C(=O)- group.

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

[0058] As used herein, the term "alcamino" refers to an amino group bonded to an alkylene group. Generally, when a compound is bonded to an alcamino group, the alkylene portion of the alcamino is bonded to the compound.

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

[0060] As used herein, the term "nitro" refers to -NO2.

[0061] The dashed lines represent single or double bonds necessary to complete the valence(s) of the atoms connected by the bond. In some cases, the bond may be aromatic.

[0062] As used herein, the term “aryl” refers to a 6-12 carbon atom monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a fully conjugated π-electron system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. The “aryl” group may be substituted or unsubstituted.

[0063] As used herein, the term "arylene" refers to a divalent group derived from the aryl radical as defined above 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 a pair of adjacent atoms) of 5 to 12 ring atoms, comprising one, two, three, or four ring heteroatoms selected from N, O, or S, with the remaining ring atom being C, and further having a fully conjugated π-electron system. Examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, triazole, tetrazole, triazine, carbazole, benzimidazole, benzoxazole, benzothiazole, indazole, and quinazoline. Heteroaryl groups may be substituted or unsubstituted.

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

[0066] The groups defined above may include prefixes and / or suffixes commonly used in the art to create additional well-known substituents. For example, the terms “haloalkoxy” or “haloalkyloxy” refer to a haloalkyl group bonded to the parent molecule via an oxygen atom. The term “(haloalkyl)oxyalkyl” refers to an alkyl group substituted with one, two, or three (haloalkyl)oxy groups. Another example is the term “hydroxyalcamino” refer to an amino group substituted with one or two hydroxyalkyl groups.

[0067] As used herein, the term -SO2- means [ka] This refers to the formula.

[0068] As used herein, the term "-alk-" (alone or in combination with other terms) refers to an alkylene group, e.g., -alk-C(O)-R 8 It refers to.

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

[0070] As used herein, the term “stereoisomer” refers to isomers of the same structure that differ only in the spatial arrangement of atoms, and not in the order of atomic linkage. Where a disclosed compound is named or described by structure without indicating stereochemistry, the naming or structure is understood to encompass all possible stereoisomers, including essentially pure stereoisomers and combinations thereof. Enantiomers and diastereomers are examples of stereoisomers. The term “enantiomer” refers to one of a pair of molecular species that are mirror images of each other and cannot be superimposed. The term “diastereomer” refers to a stereoisomer that is not a mirror image of each other. The term “racemic mixture” refers to a composition containing equimolar amounts of two enantiomer species, which are not optically active.

[0071] As used herein, the term "chiral" refers to a structural characteristic of a molecule that makes it impossible to superimpose it onto its enantiomer.

[0072] As used herein, the terms "rt" or "RT" mean room temperature; the term "h" following a number (e.g., 2h) means hour(s); and the term "min" following a number (e.g., 30min(s)) means minute(s).

[0073] As used herein, the term “tautomer” refers to each of two or more isomers of a compound that coexist in equilibrium and are readily exchanged by the movement of atoms or groups within the molecule. Thus, this disclosure is intended to cover all possible tautomers, even if the structure depicts only one of them.

[0074] As used herein, the terms “optional” or “optionally” mean that the event or situation described thereafter may or may not occur. This includes examples of when the event or situation occurs and when it does not occur. For example, “optionally substituted alkyl” means that the alkyl may be substituted or unsubstituted.

[0075] As used herein, the term "KRAS(G12D)" refers to the KRAS protein having the G12D mutation. Specifically, the 12th amino acid of the KRAS protein is aspartic acid (Asp or D) instead of glycine (Gly or G) as in the wild type.

[0076] PROTAC, known as a proteolysis-targeting chimera, is a heterobifunctional small molecule compound containing three components: an E3 ubiquitin ligase ligand, a ligand that targets the target protein (POI), and a linker that connects the two parts. Therefore, PROTAC acts as a bridge, bringing the POI closer to the E3 ubiquitin ligase. This allows the E3 ligase complex to catalyze the ubiquitination of the target. The resulting polyubiquitin chain labels the target protein for degradation by the proteasome.

[0077] As used herein, the term “pharmaceutically acceptable salt” prepared by acid addition refers to salts formed from acids that form non-toxic acid anions, such as hydrochlorides, hydrobroms, sulfates, phosphates, or acid phosphates, acetates, maleates, fumarates, lactates, tartrates, citrates, and glucons. As used herein, references to compounds of formula (I) will be understood to include pharmaceutically acceptable salts.

[0078] If the compound of the present invention has a carboxyl group, the compound may be used with the corresponding alcohol (e.g., C 1-6 By reacting with an alcohol, it can be converted into a pharmaceutically acceptable ester by conventional methods (e.g., condensation reaction of a carboxylic acid with an alcohol).

[0079] As used herein, the term “pharmaceutical composition” refers to a mixture of one or more compounds described herein, or a pharmaceutically acceptable salt or prodrug thereof, with other chemical components such as pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to a living organism.

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

[0081] As used herein, the term “therapeutic dose” means the amount of a compound administered that alleviates, to some extent, one or more symptoms of the disorder being treated. In the context of cancer treatment, a therapeutic dose means an amount that has the following effects: (1) reducing the size of a tumor; (2) inhibiting tumor metastasis; (3) inhibiting tumor growth; and / or (4) alleviating one or more symptoms associated with cancer.

[0082] As used herein, the terms “subject” and “patient” are interchangeable and, as used herein, mean any mammal, including but not limited to humans, including a human patient or subject 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, and mice, and other animals.

[0083] The compounds taught herein may be administered to a patient in various forms, depending on the chosen route of administration, as will be understood by those skilled in the art. The compounds taught herein may be administered, for example, orally, parenterally, buccally, sublingually, nasally, rectally, in patches, in pumps, or transdermally, and in appropriately formulated pharmaceutical compositions. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transdermal, nasal, intrapulmonary, intrathecal, rectally, and topically. Parenteral administration may be carried out by continuous infusion over a selected period.

[0084] isomeric form The present invention provides compounds of formula (I), or tautomers, stereoisomers, or pharmaceutically acceptable salts, esters, or prodrugs thereof, which are useful as KRAS(G12D) proteolytic agents and / or inhibitors, and methods for using them. [ka]

[0085] The compounds of the present invention may exist as one or more stereoisomers. These stereoisomers include enantiomers, diastereomers, atropisomers, and geometric isomers. Those skilled in the art will understand that one stereoisomer may be more active or exhibit beneficial effects when concentrated relative to other stereoisomers or when separated from other stereoisomers. Furthermore, those skilled in the art will know how to separate, concentrate, or selectively prepare such stereoisomers. Therefore, the present invention comprises the compound of formula (I), its stereoisomers, and its pharmaceutically acceptable salts. The compounds of the present invention may exist as mixtures of stereoisomers, individual stereoisomers, or optically active compounds.

[0086] Furthermore, the compound of formula (I) (or its salts, prodrugs, or conjugates) may exhibit polymorphism or form solvents with water or organic solvents. The present invention also encompasses any such polymorphs, any solvates, or any mixtures thereof.

[0087] The following examples illustrate selected embodiments of the present invention and do not limit the scope of the invention. Example 1A refers to isomer A of Example 1, and Example 1B refers to isomer B of Example 1. These are stereoisomers. Examples 1A and 1B: (2S,4R)-1-((S)-2-(4-(((4-(((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-((R)-6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide Examples 2A and 2B: (2S,4R)-1-((2S)-2-(4-(((4-(((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide Examples 3A and 3B: (2S,4R)-1-((2S)-2-(4-(((4-(((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide Examples 4A and 4B: (2S,4R)-1-((2S)-2-(4-(((4-(((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide Examples 5A and 5B: (2S,4R)-1-((2S)-2-(4-(((4-(((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide Examples 6A and 6B: (2S,4R)-1-((2S)-2-(4-(((4-(((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(3,5-dimethylisoxazole-4-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide Examples 7A and 7B: (2S,4R)-1-((2S)-2-(4-(((4-(((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-(4-(1-ethyl-1H-pyrazole-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide Example 8 (Mixture): (2S,4R)-1-((2S)-2-(4-(4-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-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]octan-3-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide Example 10 (Mixture): (2S,4R)-1-((2S)-2-(4-(((4-(((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide Examples 11A and 11B: (2S,4R)-1-((2S)-2-(4-(((4-(((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide Examples 12A and 12B: (2S,4R)-1-((2S)-2-(4-(4-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-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]octan-3-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-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]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-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]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-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]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

[0088] The experimental procedure is as follows: Abbreviations are used. TEA: Triethylamine, DIPEA is N,N-diisopropylethylamine. HBTU: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate. DMF: N,N-dimethylformamide. NMR: Proton nuclear magnetic resonance. MS: Mass spectrometry. (+) generally indicates M +1 (or M+H) refers to the positive mode that gives absorption, where M is the molecular weight. All compounds are MS and / or 1 Characterized by 1H NMR.

[0089] Preparation of RB1: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka]

[0090] Step 1: tert-butyl N-[(1R)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxy-ethyl]carbamate A solution of tert-butyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (3.0 g, 9.5 mmol, 1.0 eq), 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (4.0 g, 19.0 mmol, 2.0 eq), Pd(dppf)Cl2 (0.7 g, 948.8 μmol, 0.1 eq), and Na2CO3 (2.0 g, 19.0 mmol, 2.0 eq) in dioxane (45 mL) / H2O (4.5 mL) was degassed, purged three times with N2, and the mixture was stirred at 100°C for 12 hours under an N2 atmosphere. The reaction mixture was rapidly cooled by adding water at 25°C and extracted with SiO2 (100 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80g SepaFlash® silica flash column, eluent 0-25% ethyl acetate / petroleum ether gradient, 40 mL / min). The compound tert-butyl N-[(1R)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxy-ethyl]carbamate (2.9 g, 8.6 mmol, 90.6% yield) was obtained as a black solid. MS (ES-API positive): 332.3 (M+1) + .

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

[0092] Step 3: tert-butyl N-[(1S)-1-[(2S,4R)-2-[[(1R)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxy-ethyl]carbamoyl]-4-hydroxy-pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate A 16 mL solution of DMF containing a mixture of (2S,4R)-1-[(2S)-2-(tert-butoxycarbonylamino)-3-methylbutanoyl]-4-hydroxypyrrolidine-2-carboxylic acid (2.8 g, 8.4 mmol, 1.0 eq), (2R)-2-amino-2-[4-(2-ethylpyrazole-3-yl)phenyl]ethanol (2.3 g, 8.4 mmol, 1.0 eq), EDCI (2.0 g, 12.7 mmol, 1.5 eq), HOBt (1.4 g, 10.1 mmol, 1.2 eq), and DIEA (4.4 mL, 25.3 mmol, 3.0 eq) was degassed, purged three times with N2, and the mixture was stirred at 0°C for 2 hours under an N2 atmosphere. The reaction was rapidly cooled by adding brine at 25°C and extracted with SiO2 (20 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent 0-25% ethyl acetate, 40 mL / min). The compound tert-butyl N-[(1S)-1-[(2S,4R)-2-[[(1R)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxy-ethyl]carbamoyl]-4-hydroxy-pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate (4.4 g, 7.8 mmol, yield 93.0%) was obtained as a white solid. MS (ES-API positive): 544.3 (M+1) + .

[0093] Step 4: (2S,4R)-1-[(2S)-2-amino-3-methyl-butanoyl]-N-[(1R)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxy-ethyl]-4-hydroxy-pyrrolidine-2-carboxamide To a solution of tert-butyl N-[(1S)-1-[(2S,4R)-2-[[(1R)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxy-ethyl]carbamoyl]-4-hydroxy-pyrrolidine-1-carbonyl]-2-methyl-propyl]carbamate (2.0 g, 3.7 mmol, 1.0 eq) in DCM (5 mL), HCl / dioxane (4 M, 5 mL, 5.4 eq) was added. The mixture was stirred at 0°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure. The compound (2S,4R)-1-[(2S)-2-amino-3-methyl-butanoyl]-N-[(1R)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxy-ethyl]-4-hydroxy-pyrrolidine-2-carboxamide (1.8 g, 3.5 mmol, yield 96.4%) was obtained as an orange-red solid. MS (ES-API positive): 444.2 (M+1) + .

[0094] Step 5: (2S,4R)-1-[(2S)-2-azido-3-methylbutanoyl]-N-[(1R)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxy-ethyl]-4-hydroxypyrrolidine-2-carboxamide (2S,4R)-1-[(2S)-2-amino-3-methyl-butanoyl]-N-[(1R)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxy-ethyl]-4-hydroxy-pyrrolidine-2-carboxamide (167 mg, 375.0 μmol, 1.0 eq) in DMSO (2 mL) was mixed with FSO2N3 (0.4 M, 984 μL, 1.0 eq) and KHCO3 (3.0 M, 500 μL, 4.0 eq). The mixture was stirred at 25°C for 1 hour. The reaction product was filtered, the filter cake was washed with ethyl acetate, the filtrate was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (15 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® silica flash column, eluent 5% ethyl acetate / methanol, 30 mL / min). The compound (2S,4R)-1-[(2S)-2-azido-3-methyl-butanoyl]-N-[(1R)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxy-ethyl]-4-hydroxy-pyrrolidine-2-carboxamide (160 mg, yield 90.5%) was obtained 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) + .

[0095] Preparation of RB2: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka] RB2 was synthesized as a white solid using the same pathway as RB1. 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, 13.2Hz, 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) + .

[0096] Preparation of RB3: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-N-((S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] RB3 was synthesized as a yellow solid using the same pathway as RB1. MS (ES-API positive): 454.3 (M+1) + .

[0097] Preparation of RB4: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka] RB4 was synthesized as a yellow solid using the same pathway as RB1. 1H 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),3.72( 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=7.1 Hz,3H),1.29-1.26(m,3H),0.97(d,J=16.5Hz,5H) MS(ES-API positive):457.0(M+1). + .

[0098] Preparation of RB5: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-N-(4-(1-ethyl-1H-pyrazole-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide [ka] RB5 was synthesized as a white solid using the same pathway as RB1. 1 H 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), 3.3Hz,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) + .

[0099] Preparation of RB6: (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazole-5-yl)benzyl)pyrrolidine-2-carboxamide [ka] RB6 was synthesized as a yellow oily substance using the same pathway as RB1. 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) + .

[0100] Preparation of LB1: tert-butyl 3-(6-cyclopropyl-8-((4-ethynylbenzyl)oxy)-7-(6-fluoro-5-methyl-2-trityl-2H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] Step 1: tert-butyl 3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a 40 mL solution of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (4.0 g, 9.4 mmol, 1.0 eq) in DCM, TEA (2.8 g, 28.4 mmol, 3.9 mL, 3.0 eq) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.0 g, 9.4 mmol, 1.0 eq) were added. The mixture was stirred at 25°C for 16 hours. Water was added to rapidly cool the reaction product, and it was extracted using DCM (40 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent 0-15% ethyl acetate / petroleum ether gradient, 30 mL / min). The compound tert-butyl 3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was obtained as a white solid (6.0 g, 9.0 mmol, 95.2% yield). MS (ES-API positive): 598.9 (M+1) + .

[0101] 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 To a 10 mL solution of tert-butyl 3-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.0 g, 1.6 mmol, 1.0 eq) in DMSO (10 mL), KF (778 mg, 13.3 mmol, 8.0 eq) and (2S)-2-methoxypropan-1-ol (452 ​​mg, 5.0 mmol, 482.2 μL, 3.0 eq) were added. The mixture was stirred at 120 °C for 16 hours. Most of the solvent was removed, water was added, and the mixture was extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 80g SepaFlash® silica flash column, eluent 0-15% ethyl acetate / petroleum ether gradient, 30 mL / min). The compound 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 was obtained as a yellow solid. MS (ES-API positive): 651.0 (M+1) + .

[0102] Step 3: tert-butyl 3-[8-benzyloxy-7-bromo-6-cyclopropyl-2-[(2S)-2-methoxypropoxy]quinazoline-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 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 eq) and potassium cyclopropyl (trifluoro)boranoid (336 mg, 2.2 mmol, 1.2 eq) in toluene (12 mL) / H2O (1.2 mL), Pd(dppf)Cl2 (138 mg, 189.3 μmol, 0.1 eq) and K2CO3 (785 mg, 5.6 mmol, 3.0 eq) were added. The reaction mixture was then stirred at 80 °C for 36 hours. After the reaction was complete, the mixture was cooled to rt, the salt was removed by filtration, the filtrate was diluted with water, and extracted with ethyl acetate (15 mL x 3). The combined organic phases 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]; gradient: 53%~83% B 10 min). The compound 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 was obtained as a white solid. MS (ES-API positive): 655.2 (M+1) + .

[0103] Step 4: tert-butyl 3-[8-benzyloxy-6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 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 eq) in THF (5 mL), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-trityl-indazole (536 mg, 1.0 mmol, 1.3 eq), cataCXiumAPdG3 (58 mg, 79.5 μmol, 0.1 eq), and K3PO4 (507 mg, 2.3 mmol, 3.0 eq) were added, followed by the addition of H2O (0.5 mL), and the mixture was stirred at 65°C for 3 hours under an N2 atmosphere. The reaction mixture was cooled to rt, the salt was removed by filtration, the filtrate was diluted with water, and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 0-25% ethyl acetate / petroleum ether gradient, 30 mL / min). The compound tert-butyl 3-[8-benzyloxy-6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was obtained as a white solid. MS (ES-API positive): 965.5 (M+1) + .

[0104] Step 5: tert-butyl 3-(6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-2H-indazole-4-yl)-8-hydroxy-2-((S)-2-methoxypropoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a solution of tert-butyl 3-[8-benzyloxy-6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-indazole-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 eq) in MeOH (10 mL), Pd / C (120 mg, purity 10%) was added under an N2 atmosphere. The suspension was degassed and purged three times with H2. The mixture was stirred at RT for 16 hours under H2 (30 psi). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The compound tert-butyl 3-(6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-2H-indazole-4-yl)-8-hydroxy-2-((S)-2-methoxypropoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was obtained as a white solid and used in the next step without further purification. MS (ES-API positive): 875.4 (M+1) + .

[0105] Step 6: tert-butyl 3-(6-cyclopropyl-8-((4-ethynylbenzyl)oxy)-7-(6-fluoro-5-methyl-2-trityl-2H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a solution of tert-butyl 3-(6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-2H-indazole-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 eq) in DMF (4 mL), Cs2CO3 (330 mg, 1.0 mmol, 3.0 eq) and 1-(bromomethyl)-4-ethynylbenzene (132 mg, 676.5 μmol, 2.0 eq) were added. The mixture was stirred at 40°C for 2 hours. The reaction was rapidly cooled by adding brine at 25°C and extracted with ELISA (20 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® silica flash column, eluent 0-40% ethyl acetate / petroleum ether gradient, 40 mL / min). The compound tert-butyl 3-(6-cyclopropyl-8-((4-ethynylbenzyl)oxy)-7-(6-fluoro-5-methyl-2-trityl-2H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was obtained as a white solid. MS (ES-API positive): 989.4 (M+1) + .

[0106] Preparation of LB2: tert-butyl (1R,4R)-5-(6-cyclopropyl-8-((4-ethynylbenzyl)oxy)-7-(6-fluoro-5-methyl-2-trityl-2H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate LB2 was synthesized using the same method as LB1 and obtained as a white solid. MS (ES-API positive): 975.4 (M+1) + . [ka]

[0107] Preparation of LB3: tert-butyl (1R,4R)-5-[6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-2-trityl-indazole-4-yl)-2-tetrahydropyran-4-yloxy-quinazoline-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate LB3 was synthesized similarly and obtained as a yellow solid. MS (ES-API positive): 987.5 (M+1) + .

[0108] Preparation of LB4: (1R,4R)-tert-butyl 5-(6-cyclopropyl-8-((3-ethynylbicyclo[1.1.1]pentan-1-yl)methoxy)-7-(6-fluoro-5-methyl-2-trityl-2H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate LB4 was similarly obtained as a white solid. MS (ES-API positive): 965.6 (M+1) + .

[0109] Preparation of intermediate 11: 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-trityl-2H-indazole [ka] Step 1: 4-bromo-6-fluoro-2-trityl-indazole To a solution of 4-bromo-6-fluoro-2H-indazole (10.0 g, 46.5 mmol, 1.0 eq) in DCM (130 mL), TrtCl (15.6 g, 55.8 mmol, 1.2 eq) and TEA (16.2 mL, 116.3 mmol, 2.5 eq) were added. The mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1). 4-bromo-6-fluoro-2-trityl-indazole (16.0 g, 33.4 mmol, yield 72.2%) was obtained 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).

[0110] Step 2: 4-bromo-6-fluoro-5-methyl-2-trityl-indazole To a 20 mL solution of diisopropylamine (2.4 mL, 17.1 mmol, 2.0 eq) in THF, n-BuLi (6.8 mL, 2.5 M, 2.0 eq) was added dropwise at -78°C under N2 conditions. After addition, the mixture was stirred at this temperature for 30 min, and a 20 mL solution of 4-bromo-6-fluoro-2-trityl-indazole (4.5 g, 8.6 mmol, 1.0 eq) in THF was added dropwise at -78°C. The resulting mixture was stirred at -78°C under N2 conditions for 30 min, and then a 5 mL solution of MeI (1.1 mL, 17.1 mmol, 2.0 eq) in THF was added dropwise at -78°C. The mixture was then warmed to 25°C and stirred at this temperature for a further 2 hours under N2 conditions. The reaction mixture was rapidly cooled by adding saturated NH4Cl at -78°C and extracted with siRNA (30 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 0~20 / 1). 4-bromo-6-fluoro-5-methyl-2-trityl-indazole (2.3 g, 4.8 mmol, yield 55.8%) was obtained 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).

[0111] Step 3: 6-Fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-trityl-indazole To a solution of 4-bromo-6-fluoro-5-methyl-2-trityl-indazole (5.8 g, 12.3 mmol, 1.0 eq) in dioxane (15 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (6.2 g, 24.6 mmol, 2.0 eq), Pd(dppf)Cl2 (0.9 g, 1.2 mmol, 0.1 eq), and KOAc (2.4 g, 24.6 mmol, 2.0 eq) were added. The mixture was stirred under reflux and N2 for 16 hours. The reaction was rapidly cooled by adding water at 25°C, and the mixture was extracted with ELISA (30 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1). 6-Fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-trityl-indazole was obtained as a pale green solid. 1 H NMR (400MHz, CDCl3) δ8.07(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).

[0112] Examples 1A and 1B: (2S,4R)-1-((2S)-2-(4-((((4-(((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Step 1: tert-butyl (1R,4R)-5-(6-cyclopropyl-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-oxobutan-2-yl)-1H-1,2,3-triazole-4-yl)benzyl)oxy)-7-(6-fluoro-5-methyl-2-trityl-2H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (1R,4R)-5-[6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-2-trityl-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (145 mg, 148.7 μmol, 1.0 eq), (2S,4R)-1-[(2S)-2-azido-3-methylbutanoyl]-N-[(1R)-1 A mixture of -[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxy-ethyl]-4-hydroxy-pyrrolidine-2-carboxamide (83 mg, 176.8 μmol, 1.2 eq), CuSO4 (1.0 M, 149 μL, 1.0 eq), and sodium ascorbate (44 mg, 223.0 μmol, 1.5 eq) was degassed in a DMSO (0.5 mL) / H2O (0.5 mL) solution, purged three times with N2, and then stirred under an N2 atmosphere at 50°C for 3 hours. The reaction mixture was diluted with brine at 25°C and extracted with ELISA (10 mL x 2). The combined organic phase was 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). The compound tert-butyl (1R,4R)-5-[6-cyclopropyl-8-[[4-[1-[(1S)-1-[(2S,4R)-2-[[(1R)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxy-ethyl]carbamoyl]-4-hydroxy-pyrrolidine-1-carbonyl]-2-methyl-propyl]triazole-4-yl]phenyl]methoxy]-7-(6-fluoro-5-methyl-2-trityl-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (crude) was obtained as a white solid. MS (ES-API positive): 1445.6 (M+1) + .

[0113] Step 2: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide To a solution of tert-butyl (1R,4R)-5-[6-cyclopropyl-8-[[4-[1-[(1S)-1-[(2S,4R)-2-[[(1R)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxy-ethyl]carbamoyl]-4-hydroxy-pyrrolidine-1-carbonyl]-2-methyl-propyl]triazole-4-yl]phenyl]methoxy]-7-(6-fluoro-5-methyl-2-trityl-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (250 mg, 173.0 μmol, 1.0 eq) in DCM (4 mL), HCl / dioxane (4 M, 3 mL) was added. 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 ODS 150 × 30 mm × 5 μm; mobile phase: [water (HCl)-ACN]; gradient: 22%~37% B 10 min), and then purified by lyophilization to obtain two isomers. Both Example 1A and Example 1B were obtained as white solids.

[0114] The holding time for Example 1A was 2.22 min. 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ポジティブ):1102.4(M+1) + .

[0115] The holding time of Example 1B is 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) + .

[0116] Examples 2A and 2B: (2S,4R)-1-((2S)-2-(4-(((4-(((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka] Example 2A is a white solid. The holding time for Example 2A was 1.35 min. 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 holding time for Example 2B was 1.44 min. 1H 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 = 6.56 Hz, 3H), 0.90-0.70 (m, 7H). MS (ES-API positive): 1105.5 (M+1) + .

[0118] Examples 3A and 3B: (2S,4R)-1-[(2S)-2-[4-[4-[[6-Cyclopropyl-4-[(1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl]-7-(6-Fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-Methoxypropoxy]Quinazolin-8-yl]oxymethyl]Phenyl]Triazole-1-yl]-3-Methylbutanoyl]-4-Hydroxy-N-[(1S)-1-[4-(4-Methylthiazole-5-yl)phenyl]ethyl]Pyrrolidine-2-Carboxamide [ka] Example 3A was a white solid. The holding time for Example 3A was 1.83 min. 1H 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 holding time of Example 3B was 1.89 min. 1 H 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(br d,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)+.

[0120] Examples 4A and 4B: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Example 4A is a yellow solid. The retention time for Example 4A was 1.83 min. 1 H NMR(400MHz,CD3OD)δ8.56-8.50(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 holding time for Example 4B was 1.89 min. 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(br t,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) + .

[0122] Examples 5A and 5B: (2S,4R)-1-[(2S)-2-[4-[4-[[6-Cyclopropyl-4-[(1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl]-7-(6-Fluoro-5-methyl-1H-indazole-4-yl)-2-Tetrahydropyran-4-yloxyquinazoline-8-yl]oxymethyl]phenyl]triazole-1-yl]-3-methylbutanoyl]-4-Hydroxy-N-[(1R)-2-Hydroxy-1-[4-(4-methylthiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ka] Example 5A is a white solid. The holding time for Example 5A was 1.71 min. 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),5.56-5.4 7(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(br s,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 was a white solid, and its retention time was 1.78 min. 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) + .

[0124] Examples 6A and 6B: (2S,4R)-1-((S)-2-(4-((((4-(((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-2H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(3,5-dimethylisoxazole-4-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Example 6A is a white solid. The holding time for Example 6A was 1.77 min. 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 holding time for Example 6B was 1.84 min. 1H NMR(500MHz,CD3OD)δ8.62-8.49(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) + .

[0126] Examples 7A and 7B: (2S,4R)-1-[(2S)-2-[4-[4-[[6-Cyclopropyl-4-[(1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl]-7-(6-Fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-Methoxypropoxy]Quinazolin-8-yl]oxymethyl]Phenylen]triazole-1-yl]-3-Methylbutanoyl]-N-[[4-(2-Ethylpyrazole-3-yl)phenyl]methyl]-4-Hydroxypyrrolidine-2-carboxamide [ka] Example 7A is a yellow solid. The retention time for Example 7A was 2.31 min. 1H NMR(400MHz,CD3OD)δ8.49-8.37(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 for Example 7B was 2.40 min. 1H NMR(400MHz,CD3OD)δ8.53-8.44(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) + .

[0128] Examples 11A and 11B: (2S,4R)-1-[(2S)-2-[4-[4-[[6-Cyclopropyl-4-[(1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl]-7-(6-Fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-Methoxypropoxy]Quinazolin-8-yl]oxymethyl]Phenyl]Triazole-1-yl]-3-Methylbutanoyl]-4-Hydroxy-N-[[4-(4-Methylthiazole-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide [ka] Example 11A was obtained as a white solid. The retention time of Example 11A was 1.44 min. 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ポジティブ):1075.5(M+1) + .

[0129] Example 11B is a white solid. The holding time of Example 11B is 1.51 min. 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ポジティブ):1075.5(M+1) + .

[0130] Example 12A and Example 12B: (2S,4R)-1-[(2S)-2-[4-[4-[[6-Cyclopropyl-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]quinazoline-8-yl]oxymethyl]phenyl]triazole-1-yl]-3-methyl-butanoyl]-4-hydroxy-N-[(1R)-2-hydroxy-1-[4-(4-methylthiazole-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide [ka] The compound of Example 12A was obtained as a pale yellow solid, and its retention time was 4.41 min. 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),5.1Hz,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 compound of Example 12B was obtained as a pale yellow solid, and its retention time was 6.25 min. 1 H 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),5.1Hz,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) + .

[0132] Examples 13A and 13B: (2S,4R)-1-((2S)-2-(4-(4-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Example 13A was a white solid. The holding time for Example 13A was 3.77 min. 1 H 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 holding time for Example 13B was 5.17 min. 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=9.4Hz,1 H),6.4Hz,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) + .

[0134] Examples 14A and 14B: (2S,4R)-1-[(2S)-2-[4-[3-[[6-Cyclopropyl-4-[(1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl]-7-(6-Fluoro-5-methyl-1H-indazole-4-yl)-2-[(2S)-2-Methoxypropoxy]Quinazolin-8-yl]oxymethyl]-1-Bicyclo[1.1.1]Pentanyl]Triazole-1-yl]-3-Methylbutanoyl]-N-[(1R)-1-[4-(2-Ethylpyrazole-3-yl)phenyl]-2-Hydroxyethyl]-4-Hydroxypyrrolidine-2-Carboxamide [ka] Example 14A is a yellow solid. The retention time for Example 14A was 2.21 min. 1 H 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,5 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 was a yellow solid, and its retention time was 2.22 min. 1 H NMR (400MHz, CD3OD) shift 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) + .

[0136] Examples 15A and 15B: (2S,4R)-1-((2S)-2-(4-(3-(((4-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka] Example 15A was a white solid, and its retention time was 1.38 min. 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ポジティブ):1095.5(M+1) + .

[0137] Example 15B contains a white solid and a holding time of 1.44 min. 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(br s,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) + .

[0138] Examples 16A and 16B: (2S,4R)-1-[(2S)-2-[4-[4-[[6-Cyclopropyl-4-[(1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl]-7-(6-Fluoro-5-methyl-1H-indazole-4-yl)-2-Tetrahydropyran-4-yloxyquinazoline-8-yl]oxymethyl]phenyl]triazole-1-yl]-3-methylbutanoyl]-N-[(1R)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxyethyl]-4-hydroxypyrrolidine-2-carboxamide [ka] Example 16A was a pale yellow solid, and its retention time was 1.66 min. 1 H 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 pale yellow solid. The retention time for Example 16B was 2.32 min. 1H 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) + .

[0140] Example 30: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] 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 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 eq) in DMF (15 mL), CuI (55.1 mg, 289.5 μmol, 0.3 eq) and 2,2-difluoro-2-fluorosulfonylmethyl acetate (370 mg, 1.9 mmol, 2.0 eq) were added under N2. The mixture was stirred at 80°C for 4 hours. The reaction was monitored by LC-MS, and after the reaction was complete, the reaction mixture was rapidly cooled by adding brine of RT and extracted with ELISA (30 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® silica flash column, eluent 0-40% ethyl acetate / petroleum ether gradient, 40 mL / min). The compound tert-butyl (1S,4S)-5-(8-(benzyloxy)-7-bromo-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate (550 mg, 634.4 μmol, yield 65.8%) was obtained as a white solid. MS (ES-API positive): 667.2 (M+1) + .

[0141] Step 2: tert-butyl (1S,4S)-5-(8-(benzyloxy)-7-(6-fluoro-5-methyl-2-trityl-2H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazoline-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate 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 eq), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-trityl-yl A mixture of dazole (491 mg, 947.6 μmol, 1.1 eq), Pd2(dba)3 (75 mg, 82.4 μmol, 0.1 eq), SPhos (67.6 mg, 164.8 μmol, 0.2 eq), and K3PO4 (612.14 mg, 2.88 mmol, 3.5 eq) was degassed in a dioxane (2 mL) / H2O (0.2 mL) solution, purged three times with N2, and then stirred at 120°C for 8 hours under an N2 atmosphere. The reaction mixture was rapidly cooled by adding RT brine and extracted with SiO2 (20 mL x 2). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluent 0-40% ethyl acetate / petroleum ether gradient, 40 mL / min), and further purified by preparative HPLC (neutral conditions: column: Phenomenexgemini NX 150×30 mm, 5 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 80%-100% B 11 min). The compound tert-butyl (1S,4S)-5-(8-(benzyloxy)-7-(6-fluoro-5-methyl-2-trityl-2H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate was obtained as a white solid. MS (ES-API positive): 979.4 (M+1) + .

[0142] Step 3: tert-butyl (1S,4S)-5-(7-(6-fluoro-5-methyl-1H-indazole-4-yl)-8-hydroxy-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazoline-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(8-(benzyloxy)-7-(6-fluoro-5-methyl-2-trityl-2H-indazole-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 eq) in MeOH (3 mL) / THF (1 mL), Pd / C (20 mg, purity 10%) was added. The suspension was degassed and purged three times with H2. The mixture was stirred at 30°C for 18 hours under H2 (30 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The compound tert-butyl (1S,4S)-5-(7-(6-fluoro-5-methyl-1H-indazole-4-yl)-8-hydroxy-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (crude) was obtained as a white solid. MS (ES-API positive): 647.3 (M+1) + .

[0143] Step 4: tert-butyl (1S,4S)-5-(7-(6-fluoro-5-methyl-2-trityl-2H-indazole-4-yl)-8-hydroxy-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazoline-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(7-(6-fluoro-5-methyl-1H-indazole-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 eq) in DCM (3 mL) / THF (1 mL), TEA (42 μL, 309.1 μmol, 5.0 eq) and trityl chloride (42 mg, 215 μmol, 1.76 eq) were added. 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). The compound tert-butyl (1S,4S)-5-(7-(6-fluoro-5-methyl-2-trityl-2H-indazole-4-yl)-8-hydroxy-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazoline-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was obtained as a white solid. MS (ES-API positive): 889.3 (M+1) + .

[0144] Step 5: tert-butyl (1S,4S)-5-(8-((4-ethynylbenzyl)oxy)-7-(6-fluoro-5-methyl-2-trityl-2H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazoline-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-(7-(6-fluoro-5-methyl-2-trityl-2H-indazole-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 eq) in DMF (1 mL), Cs2CO3 (49 mg, 151.8 μmol, 3.0 eq) and 1-(bromomethyl)-4-ethynylbenzene (20 mg, 101.2 μmol, 2.0 eq) were added. The mixture was stirred at 40°C for 1 hour. The reaction mixture was rapidly cooled by adding brine of RT and extracted with ELISA (15 mL x 3). The combined organic phases 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). The compound tert-butyl (1S,4S)-5-(8-((4-ethynylbenzyl)oxy)-7-(6-fluoro-5-methyl-2-trityl-2H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazoline-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate (40 mg, 37.1 μmol, yield 73.3%) was obtained as a white solid. MS (ES-API positive): 1003.3 (M+1) + .

[0145] Step 6: 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-oxobutan-2-yl)-1H-1,2,3-triazole-4-yl)benzyl)oxy)-7-(6-fluoro-5-methyl-2-trityl-2H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazoline-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate tert-butyl (1S,4S)-5-(8-((4-ethynylbenzyl)oxy)-7-(6-fluoro-5-methyl-2-trityl-2H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazoline-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate (40 mg, 39.88 μmol, 1 eq), (2S,4R)-1-[(2S)-2-azido-3-methyl A DMSO (1 mL) solution of a mixture of ru-butanoyl]-N-[(1R)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxy-ethyl]-4-hydroxypyrrolidine-2-carboxamide (21 mg, 43.8 μmol, 1.1 eq), CuSO4 (1.0 M, 12.0 μL, 0.3 eq), and sodium ascorbate (7 mg, 31.9 μmol, 0.8 eq) was stirred at 50°C for 3 hours under an N2 atmosphere. The reaction was monitored by LC-MS, and after the reaction was complete, the reaction mixture was rapidly cooled by adding brine of RT and extracted with SiO4 (15 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The compound 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-oxobutan-2-yl)-1H-1,2,3-triazole-4-yl)benzyl)oxy)-7-(6-fluoro-5-methyl-2-trityl-2H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazoline-4-yl)-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate was obtained as a white solid (55 mg, crude), which was used in the next step without further purification. MS (ES-API positive): 1472.7 (M+1) + .

[0146] Step 7: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide 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-oxobutan-2-yl)-1H-1,2,3-triazole-4-yl)benzyl)oxy)-7-( 6-Fluoro-5-methyl-2-trityl-2H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-6-(trifluoromethyl)quinazoline-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (55 mg, 37.35 μmol, 1 eq) was dissolved in DCM (3 mL) and HCl / dioxane (4 M, 2 mL) was added. The mixture was stirred at RT for 0.5 hours. The reaction was monitored by LC-MS, and after the reaction was complete, the solvent was removed under vacuum. The residue was purified by preparative HPLC (HCl preparation column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (HCl)-ACN]; gradient: 20%~40% B 11 min). Compound 30 (18.65 mg, 16.0 μmol, yield 42.9%) was obtained as a white solid. Retention time: 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) + .

[0147] Example 31: (2S,4R)-1-((2S)-2-(4-(5-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)bicyclo[4.2.0]octa-1,3,5-trien-2-yl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Step 1: 5-bromovicyclo[4.2.0]octa-1,3,5-triene-2-carbaldehyde To a solution of 2,5-dibromovicyclo[4.2.0]octa-1,3,5-triene (500 mg, 1.91 mmol, 1.0 eq) in THF (5 mL), n-BuLi (2.5 M, 840 μL, 1.1 eq) was added at -78 °C, and the mixture was stirred at the same temperature for 0.5 hours. Then, DMF (419 mg, 5.73 mmol, 441 μL, 3 eq) was added at -78 °C. After the addition was complete, the mixture was gradually warmed to rt and stirred at RT for 1 hour. The reaction was monitored by TLC (petroleum ether / siRNA = 20 / 1), and after the reaction was complete, the reaction mixture was rapidly cooled by adding H2O at 0 °C, diluted with H2O, and extracted with siRNA (5 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® silica flash column, eluent 0-3% petroleum ether / ethyl acetate gradient, 100 mL / min). Compound 5-bromovicyclo[4.2.0]octa-1,3,5-triene-2-carbaldehyde was obtained as 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).

[0148] Step 2: 5-(2-triisopropylsilylethynyl)bicyclo[4.2.0]octa-1,3,5-triene-2-carbaldehyde A solution of 5-bromovicyclo[4.2.0]octa-1,3,5-triene-2-carbaldehyde (388 mg, 1.84 mmol, 1.0 eq), ethinyl(triisopropyl)silane (406 mg, 2.23 mmol, 0.5 mL, 1.2 eq), CuI (35 mg, 183.78 μmol, 0.1 eq), Pd(PPh3)2Cl2 (130 mg, 185.21 μmol, 0.1 eq), PPh3 (10 mg, 38.13 μmol, 0.02 eq), and TEA (8.72 g, 86.21 mmol, 12 mL, 46.9 eq) in THF (3 mL) was degassed, purged three times with N2, and the mixture was stirred at 65°C for 2 hours under an N2 atmosphere. The reaction mixture was partitioned between H2O and RINKAN. The organic phase was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® silica flash column, petroleum ether / Â1, Â1 0-5%, flow rate 100 mL / min, 254 nm). Compound 5-(2-triisopropylsilylethynyl)bicyclo[4.2.0]octa-1,3,5-triene-2-carbaldehyde 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) + .

[0149] Step 3: [5-(2-triisopropylsilylethynyl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]methanol 5-(2-triisopropylsilylethynyl)bicyclo[4.2.0]octa-1,3,5-triene-2-carbaldehyde (621 mg, 1.99 mmol, 1.0 eq) was dissolved in MeOH (8 mL), to which NaBH4 (80 mg, 2.11 mmol, 1.1 eq) was added at 0°C. The mixture was then stirred at RT for 0.5 hours. The reaction mixture was rapidly cooled by adding H2O from RT, diluted with H2O, and extracted with siRNA (10 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® silica flash column, petroleum ether / siRNA, siRNA 0-26%, flow rate: 50 mL / min, 254 nm). The compound [5-(2-triisopropylsilylethynyl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]methanol was obtained as 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).

[0150] Step 4: 2-[5-(bromomethyl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]ethynyl-triisopropylsilane To a 5 mL solution of DCM containing [5-(2-triisopropylsilylethynyl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]methanol (158 mg, 502.33 μmol, 1.0 eq), CBr4 (185 mg, 557.86 μmol, 1.1 eq) and PPh3 (160 mg, 610.02 μmol, 1.2 eq) were added. The mixture was stirred under N2 at RT for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, 100% petroleum ether, flow rate: 20 mL / min, 254 nm). Compound 2-[5-(bromomethyl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]ethynyl-triisopropylsilane was obtained as 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).

[0151] Step 5: tert-butyl (1S,4S)-5-[6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]-8-[[5-(2-triisopropylsilylethynyl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]methoxy]quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate To a solution of tert-butyl (1S,4S)-5-[6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-indazole-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 eq) in DMF (5 mL), 2-[5-(bromomethyl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]ethynyl-triisopropylsilane (90 mg, 238.45 μmol, 2.05 eq) and Cs2CO3 (120 mg, 368.30 μmol, 3.17 eq) were added. The mixture was stirred at 40°C for 1 hour. The reaction mixture was partitioned between H2O and ELISA. The organic phase was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4g SepaFlash® silica flash column, petroleum ether / siRNA, siRNA 0-30%, flow rate: 20 mL / min, 254 nm). The compound tert-butyl (1S,4S)-5-[6-cyclopropyl-7-(6-fluoro-5-methyl-2-trityl-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]-8-[[5-(2-triisopropylsilylethynyl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]methoxy]quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptan-2-carboxylate (150 mg, crude) was obtained as a yellow solid. MS (ES-API positive): 1158.1 (M+1) + .

[0152] The remaining synthesis was the same as in Example 30. 1H 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) + .

[0153] Example 32: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)-2-chlorophenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Step 1: [3-Chloro-4-(2-triisopropylsilylethynyl)phenyl]methanol To a solution of (4-bromo-3-chlorophenyl)methanol (5 g, 22.58 mmol, 1 eq) in TEA (50 mL), CuI (86 mg, 451.51 μmol, 0.02 eq), Pd(PPh3)2Cl2 (634 mg, 903.02 μmol, 0.04 eq), and ethinyl(triisopropyl)silane (5.2 g, 28.22 mmol, 6.33 mL, 1.25 eq) were added. The mixture was stirred under N2 at RT for 2 hours. After the reaction was complete, the reaction mixture was rapidly cooled by adding H2O and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 80g SepaFlash® silica flash column, eluent 0-25% ethyl acetate / petroleum ether gradient, 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) + .

[0155] Step 2: (3-chloro-4-ethynylphenyl)methanol To a solution of [3-chloro-4-(2-triisopropylsilylethynyl)phenyl]methanol (3.6 g, 11.15 mmol, 1 eq) in DMF (35 mL), CsF (8.47 g, 55.74 mmol, 2.06 mL, 5 eq) was added. The mixture was stirred at RT for 1 hour. The reaction was monitored by TLC, and after the reaction was complete, the reaction mixture was rapidly cooled by adding H2O and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® silica flash column, eluent: 0-30% ethyl acetate / petroleum ether gradient, 100 mL / min). The compound (3-chloro-4-ethynyl-phenyl)methanol (1 g, 6.00 mmol, yield 53.8%) was obtained as a colorless oil. MS (ES-API positive): 167.0 (M+1) + .

[0156] Step 3: 4-(bromomethyl)-2-chloro-1-ethynylbenzene To a solution of (3-chloro-4-ethynylphenyl)methanol (200 mg, 1.20 mmol, 1 eq) in DCM (3 mL), CBr4 (757 mg, 2.28 mmol, 1.9 eq), TPP (630 mg, 2.40 mmol, 2 eq), and 2,6-lutidine (644 mg, 6.00 mmol, 699.08 μL, 5 eq) were added. The mixture was stirred at RT for 16 hours. The reaction mixture was rapidly cooled by adding H2O and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent: 0-30% ethyl acetate / petroleum ether gradient, 60 mL / min). The compound 4-(bromomethyl)-2-chloro-1-ethynylbenzene was obtained as a brown solid. MS (ES-API positive): 228.9 (M+1) + .

[0157] The remaining synthesis was the same as in Example 30. Example 32: 1 H 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) + .

[0158] Example 33: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(3,6-difluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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) + .

[0159] Example 34: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-4-(1-ethyl-1H-pyrazole-5-yl)-1-hydroxybuta-3-in-2-yl)-4-hydroxypyrrolidine-2-carboxamide [ka] Step 1: tert-butyl (4R)-4-ethynyl-2,2-dimethyl-oxazolidine-3-carboxylate To a solution of tert-butyl (4S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylate (2.00 g, 8.72 mmol, 1 eq) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one (2.51 g, 13.08 mmol, 1.5 eq) in MeOH (40 mL), K2CO3 (2.41 g, 17.45 mmol, 2 eq) was added. The mixture was stirred at RT for 3 hours. The reaction mixture was diluted with ethyl acetate, filtered through diatomaceous earth, and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent: 0-13% ethyl acetate / petroleum ether gradient, 40 mL / min) to obtain tert-butyl (4R)-4-ethynyl-2,2-dimethyl-oxazolidine-3-carboxylate as 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).

[0160] Step 2: tert-butyl (4R)-4-[2-(2-ethylpyrazole-3-yl)ethynyl]-2,2-dimethyl-oxazolidine-3-carboxylate To a DMSO (20 mL) solution of tert-butyl (4R)-4-ethynyl-2,2-dimethyl-oxazolidine-3-carboxylate (1.45 g, 6.42 mmol, 1 eq), 1-ethyl-5-iodopyrazole (1.42 g, 6.42 mmol, 1 eq), CuI (123 mg, 645.84 μmol, 1.01 e-1 eq), and TEA (1.95 g, 19.25 mmol, 2.68 mL, 3 eq), Pd(dppf)Cl2 (470 mg, 642.33 μmol, 0.1 eq) was added. The mixture was stirred at 70°C under N2 for 20 hours. The reaction product was rapidly cooled with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (60 mL x 2), dried on Na2SO4, and purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0-10% ethyl acetate / petroleum ether gradient, 18 mL / min) to obtain tert-butyl (4R)-4-[2-(2-ethylpyrazole-3-yl)ethynyl]-2,2-dimethyl-oxazolidine-3-carboxylate as a pale yellow oil. 1 ¹H NMR (400MHz, CDCl3): δ 7.43 (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). MS (ES-API positive): 320.1 (M+1) + .

[0161] Step 3: (2R)-2-amino-4-(2-ethylpyrazole-3-yl)buta-3-in-1-ol To a solution of tert-butyl (4R)-4-[2-(2-ethylpyrazole-3-yl)ethynyl]-2,2-dimethyl-oxazolidine-3-carboxylate (1.31 g, 4.10 mmol, 1 eq) in DCM (15 mL), HCl / dioxane (4 M, 15 mL, 14.63 eq) was added. The mixture was stirred at RT for 6 hours. The reaction was monitored by LC-MS. After the reaction was complete, the reaction mixture was concentrated to obtain (2R)-2-amino-4-(2-ethylpyrazole-3-yl)buta-3-in-1-ol as a white solid. MS (ES-API positive): 216.0 (M+1) + .

[0162] Step 4: tert-butyl (2S,4R)-2-[[(1R)-3-(2-ethylpyrazole-3-yl)-1-(hydroxymethyl)prop-2-inyl]carbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate A mixture of (2S,4R)-1-tert-butoxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid (896 mg, 3.87 mmol, 1 eq), DIEA (1.50 g, 11.57 mmol, 2.02 mL, 3 eq), HOBt (626 mg, 4.63 mmol, 1.2 eq), and EDCI (888 mg, 4.63 mmol, 1.2 eq) in 20 mL of DCM was stirred at 0°C for 10 min. Next, (2R)-2-amino-4-(2-ethylpyrazole-3-yl)buta-3-in-1-ol (1.28 g, 3.86 mmol, 1 eq, HCl salt) was added, and the mixture was stirred at RT for 4 hours. The mixture was concentrated and purified by flash silica gel chromatography (ISCO®; 20g SepaFlash® silica flash column, eluent: 0-5% methanol / dichloromethangular radiant, 30 mL / min) to obtain tert-butyl (2S,4R)-2-[[(1R)-3-(2-ethylpyrazole-3-yl)-1-(hydroxymethyl)prop-2-inyl]carbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate as a colorless oil. 1H 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). MS(ES-API positive):337.2(M+1) + .

[0163] Step 5: (2S,4R)-N-[(1R)-3-(2-ethylpyrazole-3-yl)-1-(hydroxymethyl)prop-2-inyl]-4-hydroxy-pyrrolidine-2-carboxamide To a solution of tert-butyl (2S,4R)-2-[[(1R)-3-(2-ethylpyrazole-3-yl)-1-(hydroxymethyl)propa-2-inyl]carbamoyl]-4-hydroxypyrrolidine-1-carboxylate (1.13 g, 1.93 mmol, 1 eq) in DCM (10 mL), HCl / dioxane (4 M, 10 mL, 20.73 eq) was added. The mixture was stirred at RT for 0.5 hours. The reaction mixture was concentrated to obtain (2S,4R)-N-[(1R)-3-(2-ethylpyrazole-3-yl)-1-(hydroxymethyl)propa-2-inyl]-4-hydroxypyrrolidine-2-carboxamide. MS (ES-API positive): 293.1 (M+1) + .

[0164] Step 6: (2S,4R)-1-[(2S)-2-azido-3-methylbutanoyl]-N-[(1R)-3-(2-ethylpyrazole-3-yl)-1-(hydroxymethyl)propa-2-inyl]-4-hydroxypyrrolidine-2-carboxamide A mixture of (2S)-2-amino-3-methylbutanoic acid (281 mg, 2.39 mmol, 1 eq), DIEA (941 mg, 7.28 mmol, 1.27 mL, 3.04 eq), HOBt (386 mg, 2.85 mmol, 1.19 eq), and EDCI (547 mg, 2.85 mmol, 1.19 eq) in DCM (20 mL) was stirred at 0°C for 10 minutes. Next, (2S,4R)-N-[(1R)-3-(2-ethylpyrazole-3-yl)-1-(hydroxymethyl)prop-2-inyl]-4-hydroxypyrrolidine-2-carboxamide (700 mg, 2.39 mmol, 1 eq) was added. The mixture was stirred at RT for 4 hours. The reaction mixture was quenched with water (40 mL) and extracted with ELISA (20 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried on Na2SO4, filtered, concentrated under reduced pressure, and purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, EE:EE (ethyl acetate / EtOH=3 / 1)=1:1, 40 mL / min) of 0-40% petroleum ether to obtain (2S,4R)-1-[(2S)-2-azido-3-methyl-butanoyl]-N-[(1R)-3-(2-ethylpyrazole-3-yl)-1-(hydroxymethyl)prop-2-inyl]-4-hydroxy-pyrrolidine-2-carboxamide as 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),5.8H z,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). MS(ES-API positive):418.2(M+1) + .

[0165] The remaining synthesis was the same as in Example 30. 1 H 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). MS(ES-API positive):1050.8(M+1) + .

[0166] Example 35: (2S,4R)-1-((2S)-2-(4-(4-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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) + .

[0167] Example 36: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-(5-(1-ethyl-1H-pyrazole-5-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)methyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0168] Example 37: (2S,4R)-1-((2S)-2-(4-(4-(((4-(3-Oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0169] Example 38: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1-(methylsulfonyl)piperidine-4-yl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0170] Example 39: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-4-((S)-3-hydroxy-3-methylpiperidine-1-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1HNMR(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) + .

[0171] Example 40: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-4-(2,4-difluorophenyl)-1-hydroxybuta-3-in-2-yl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0172] Example 41: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-1-hydroxy-4-(4-methylthiazole-5-yl)buta-3-in-2-yl)pyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0173] Example 42: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-4-(2,6-difluorophenyl)-1-hydroxybuta-3-in-2-yl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 34. 1H NMR(400MHz,CD3OD)δ8.43-8.37(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) + .

[0174] Example 43: (2S,4R)-1-((2S)-2-(4-(((2-((2-Oxaspiro[3.5]nonane-7-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0175] Example 44: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)-2-methylphenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0176] Example 45: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)-2-methoxyphenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0177] Example 46: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-4-(2-ethylpyridine-3-yl)-1-hydroxybuta-3-in-2-yl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0178] Example 47: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-2-(2,2-difluoro-3-methoxypropoxy)-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1H NMR(400MHz,CD3OD)δ8.48-8.44(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) + .

[0179] Example 48: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-(3,3,3-trifluoro-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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(br d,J=4.6Hz,1H),5.39(d,J=10.4Hz,1H),5.12-5.06(m,1H),4.83-4.74(m,4H),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) + .

[0180] Example 49: (2S,4R)-1-((2S)-2-(4-(4-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0181] Example 51: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((hexahydrofluoro[2,3-b]furan-3-yl)methoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1H NMR(400MHz,CD3OD)δ8.53-8.46(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) + .

[0182] Example 52: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-(2,2-difluorocyclopropyl)-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Step 1: tert-butyl (1S,4S)-5-[7-bromo-2-[(2S)-2-methoxypropoxy]-8-[[4-(2-triisopropylsilylethynyl)phenyl]methoxy]-6-vinyl-quinazoline-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate 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 eq) in toluene (30 mL), K2CO3 (1.4 g, 9.9 mmol, 3.0 eq), potassium vinyltrifluoroborate (576.7 mg, 4.3 mmol, 1.3 eq), and Pd(dppf)Cl2.CH2Cl2 (270.5 mg, 331.2 μmol, 0.1 eq) were added. Then H2O (3.0 mL) was added. The mixture was stirred at 70°C for 16 hours. The reaction was cooled to rt, water was added and the mixture was rapidly cooled, and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® silica flash column, eluent: 0-15% ethyl acetate / petroleum ether gradient, 30 mL / min). The compound 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]heptan-2-carboxylate was obtained as a white solid.

[0183] MS (ES-API positive): 805.3 (M+1) + .

[0184] Step 2: tert-butyl (1S,4S)-5-[7-bromo-6-(2,2-difluorocyclopropyl)-2-[(2S)-2-methoxypropoxy]-8-[[4-(2-triisopropylsilylethynyl)phenyl]methoxy]quinazoline-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate 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 eq) in toluene (14 mL), TBAB (536.0 mg, 1.7 mmol, 2.0 eq) and [bromo(difluoro)methyl]-trimethylsilane (422.1 mg, 2.1 mmol, 2.5 eq) were added. The mixture was stirred at 110°C for 1 hour, then cooled to RT. [Bromo(difluoro)methyl]-trimethylsilane (422.1 mg, 2.1 mmol, 2.5 eq) was added, and the mixture was stirred at 110°C for 2 hours. After the reaction was complete, water was added to the residue and it was rapidly cooled. The residue was then extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150: Welch Xtimate C18 150 × 25 mm × 5 μm; mobile phase: [water (0.1% TFA)-CH3CN]; gradient: 80%~100% B 11 min). The compound tert-butyl (1S,4S)-5-[7-bromo-6-(2,2-difluorocyclopropyl)-2-[(2S)-2-methoxypropoxy]-8-[[4-(2-triisopropylsilylethynyl)phenyl]methoxy]quinazoline-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was obtained as a white solid. MS (ES-API positive): 857.3 (M+1) + .

[0185] Step 3: tert-butyl (1S,4S)-5-[6-(2,2-difluorocyclopropyl)-7-(6-fluoro-5-methyl-2-trityl-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]-8-[[4-(2-triisopropylsilylethynyl)phenyl]methoxy]quinazoline-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Pd2 (dba)3 (8.6 mg, 9.3 μmol, 0.1 eq), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-trityl-indazole (58.2 mg, 112.2 μmol, 1.2 eq), K3PO4 (59.5 mg, 280.4 μmol, 3.0 eq), and SPhOS (7.7 mg, 18.7 μmol, 0.2 eq) were added. Next, H2O (0.2 mL) was added. The mixture was stirred at 120 °C for 3 hours. The residue was rapidly cooled with water and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® silica flash column, eluent: 0-20% ethyl acetate / petroleum ether gradient, 30 mL / min). The compound tert-butyl (1S,4S)-5-[6-(2,2-difluorocyclopropyl)-7-(6-fluoro-5-methyl-2-trityl-indazole-4-yl)-2-[(2S)-2-methoxypropoxy]-8-[[4-(2-triisopropylsilylethynyl)phenyl]methoxy]quinazoline-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was obtained as a white solid. MS (ES-API positive): 1167.6 (M+1) + .

[0186] In Example 30, the desired product was obtained by the same method as in Step 5.

[0187] The desired product was obtained by the same method as in Example 32.

[0188] The rest of the synthesis was the same as in Example 32. 1 H 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) + .

[0189] Example 53: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-2-((1-(difluoromethyl)cyclopropyl)methoxy)-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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) + .

[0190] Example 54: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-4-(benzo[d]thiazole-6-yl)-1-hydroxybuta-3-in-2-yl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 34. 1 H 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) + .

[0191] Example 55: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-3-(methylamino)-3-oxopropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Step 1: tert-butyl N-[(1S)-1-(4-bromophenyl)-3-(methylamino)-3-oxopropyl]carbamate To a 10 mL solution of (3S)-3-(4-bromophenyl)-3-(tert-butoxycarbonylamino)propanoic acid (1 g, 2.91 mmol, 1 eq) in DCM (10 mL), HATU (1.33 g, 3.50 mmol, 1.2 eq) and DIEA (1.13 g, 8.73 mmol, 1.52 mL, 3 eq) were added. The mixture was stirred at 0°C for 15 min. Next, methylamine hydrochloride (300 mg, 4.44 mmol, 1.53 eq) was added. The mixture was stirred at RT for 2 hours. The reaction was monitored by LC-MS. After the reaction was complete, the resulting mixture was diluted with water (100 mL), extracted with DCM (50 mL x 2), washed with saturated NH4 aqueous solution (50 mL x 2) and brine (50 mL x 2), dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM (20 mL), then petroleum ether (70 mL) was added, the solid was collected by filtration, and then dried under vacuum to obtain tert-butyl N-[(1S)-1-(4-bromophenyl)-3-(methylamino)-3-oxopropyl]carbamate as a white solid (1 g, 2.74 mmol, 94.3% yield). 1H 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) + .

[0192] Step 2: tert-butyl N-[(1S)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-3-(methylamino)-3-oxopropyl]carbamate To a solution of tert-butyl N-[(1S)-1-(4-bromophenyl)-3-(methylamino)-3-oxopropyl]carbamate (500 mg, 1.40 mmol, 1 eq), 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (465 mg, 2.09 mmol, 1.5 eq), and Na2CO3 (300 mg, 2.83 mmol, 2.02 eq) in dioxane (20 mL) / H2O (2 mL), Pd(dppf)Cl2 (103 mg, 140.77 μmol, 1.01 e-1 eq) was added. The mixture was stirred at 100 °C under N2 for 16 hours. The reaction was monitored by LC-MS. 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 x 3). The combined organic phase was washed with saturated NH4Cl aqueous solution (100 mL x 2) and brine (100 mL), dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 12 g AgelaFlash® silica flash column, petroleum ether / ethyl acetate, ethyl acetate 0-70%, flow rate = 50 mL / min, 254 nm). The compound tert-butyl N-[(1S)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-3-(methylamino)-3-oxopropyl]carbamate was obtained as a white solid. 1H 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),4.1 6(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) + .

[0193] Step 3: (3S)-3-amino-3-[4-(2-ethylpyrazole-3-yl)phenyl]-N-methyl-propanamide To a solution of tert-butyl N-[(1S)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-3-(methylamino)-3-oxopropyl]carbamate (455 mg, 1.22 mmol, 1 eq) in DCM (5 mL) / MeOH (1 mL), HCl / dioxane (4 M, 5 mL, 16.37 eq) was added. The mixture was stirred at RT for 1 hour. The resulting mixture was concentrated under reduced pressure. Compound (3S)-3-amino-3-[4-(2-ethylpyrazole-3-yl)phenyl]-N-methyl-propanamide (475 mg, crude) was obtained as a pale yellow foam, which was used directly in the next step without further purification. MS (ES-API positive): 273.1 (M+1) + .

[0194] Step 4: tert-butyl (2S,4R)-2-[[(1S)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-3-(methylamino)-3-oxopropyl]carbamoyl]-4-hydroxypyrrolidine-1-carboxylate To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid (320 mg, 1.38 mmol, 1 eq) in DCM (10 mL), T4P (1.52 g, 2.11 mmol, 50% wt siRNA solution, 1.52 eqs) and DIEA (949 mg, 7.34 mmol, 1.28 mL, 5.31 eqs) were added, and the mixture was stirred at 0°C for 5 min. Next, (3S)-3-amino-3-[4-(2-ethylpyrazole-3-yl)phenyl]-N-methyl-propanamide (384 mg, 1.41 mmol, 1.02 eqs) was added. The mixture was stirred at RT for 1 hour. The reaction mixture was partitioned between H2O and DCM (10 mL x 3). The organic phase was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® silica flash column, petroleum ether / EE (ethyl acetate:ethanol = 1:1), EE 0-100%, flow rate: 50 mL / min, 254 nm). The compound tert-butyl (2S,4R)-2-[[(1S)-1-[4-(2-ethylpyrazole-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] The final compound was obtained as a yellow solid by the same method as in Example 32. 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. 81-2.72(m,1H),2.69-2.65(m,3H),2.59-2.48(m,1H),2.32-2.17(m,2H),2.13(d,J=2.3Hz,3H),2.04-1.95(m,1H),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) + .

[0196] Example 56: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-(((3R,3aS,6aR)-hexahydrofluoro[2,3-b]furan-3-yl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Example 56 was prepared in the same manner as in Example 32. 1 H 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) + .

[0197] Example 57: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6,7-difluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Example 57 was prepared in the same manner as in 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) + .

[0198] Example 58: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1,1,1-trifluoro-3-methoxypropane-2-yl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Example 58 was prepared in the same manner as in Example 32. 1H NMR(400MHz,CD3OD)δ8.51-8.44(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) + .

[0199] Example 59: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-1-hydroxy-4-(4-methylthiazole-5-yl)buta-3-in-2-yl)pyrrolidine-2-carboxamide [ka] Example 59 was prepared in the same manner as 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) + .

[0200] Example 60: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-4-(2,3-difluorophenyl)-1-hydroxybuta-3-in-2-yl)-4-hydroxypyrrolidine-2-carboxamide [ka] Example 60 was prepared in the same manner as 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) + .

[0201] Example 61: (2S,4R)-1-((2S)-2-(4-(4-(((4-(3-Oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Example 61 was prepared in the same manner as in 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) + .

[0202] Example 62: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-2-((1-(2,2-difluoroethyl)cyclopropyl)methoxy)-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Example 62 was prepared in the same manner as Example 32. 1H NMR(400MHz,CD3OD)δ8.43-8.29(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) + .

[0203] Example 63: (2S,4R)-1-((2S)-2-(4-(((2-((2-Oxaspiro[3.5]nonane-7-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka] Example 63 was prepared in the same manner as in 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]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-4-(2-chlorophenyl)-1-hydroxybuta-3-in-2-yl)-4-hydroxypyrrolidine-2-carboxamide [ka] 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) + .

[0204] Example 65: (2S,4R)-1-((2S)-2-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-2-((4-(difluoromethyl)tetrahydro-2H-pyran-4-yl)methoxy)-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Example 65 was prepared in the same manner as in Example 32. 1 H 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(br s,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) + .

[0205] Example 66: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5,7-dimethyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Example 66 was prepared in the same manner as in Example 32. 1 H 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) + .

[0206] Example 67: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-1-hydroxy-4-(thieno[2,3-d]thiazole-5-yl)buta-3-in-2-yl)pyrrolidine-2-carboxamide [ka] Example 67 was prepared in the same manner as Example 34. 1 H 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) + .

[0207] Example 68: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclobutyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Example 68 was prepared in the same manner as in Example 32. 1 H 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) + .

[0208] Example 69: (2S,4R)-1-((2S)-2-(4-(((2-((2-Oxaspiro[3.3]heptan-6-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-(((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Example 69 was prepared in the same manner as in 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) + .

[0209] Example 70: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((4-methoxycyclohexyl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Example 70 was prepared in the same manner as in Example 32. 1 H 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) + .

[0210] Example 71: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-1-hydroxy-4-(1-methyl-1H-indazole-3-yl)buta-3-in-2-yl)pyrrolidine-2-carboxamide [ka] Example 71 was prepared in the same manner as Example 34. 1 H 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) + .

[0211] Example 72: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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) + .

[0212] Example 73: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Step 1: tert-butyl N-[(1R)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxy-ethyl]carbamate A mixture of tert-butyl N-[(1R)-1-(4-bromophenyl)-2-hydroxyethyl]carbamate (10 g, 31.6 mmol, 1 eq), 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (14.1 g, 63.5 mmol, 2 eq), Pd(dppf)Cl2 (2.4 g, 3.3 mmol, 0.1 eq), and Na2CO3 (7.1 g, 66.7 mmol, 2.1 eq) was degassed in a dioxane (200 mL) / H2O (20 mL) solution, purged three times with N2, and then stirred at 100°C for 16 hours under an N2 atmosphere. The reaction mixture was filtered, concentrated under reduced pressure to remove dioxane, and the residue was diluted with aqueous H2O and extracted with SiO2 (50 mL x 3). The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 220g SepaFlash® silica flash column, eluent: 0-50% ethyl acetate / petroleum ether gradient, 100 mL / min). The compound tert-butyl N-[(1R)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxyethyl]carbamate was obtained as a white solid. MS (ES-API positive): 332.0 (M+1) + .

[0213] Step 2: tert-butyl N-[(1R)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-oxo-ethyl]carbamate A solution of tert-butyl N-[(1R)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxy-ethyl]carbamate (1.1 g, 3.3 mmol, 1 eq) in anhydrous DCM (20 mL) was treated with DMP (1.8 g, 4.2 mmol, 1.3 mL, 1.3 eq) under N2 at 0°C. 3 eq) was added, and the reaction mixture was allowed to stand slowly until it warmed to rt, then stirred for 1 hour. The reaction mixture was diluted with DCM (50 mL), saturated NaHCO3 (20 mL) and saturated Na2S2O3 aqueous solution (20 mL) were added, and the mixture was rapidly cooled and stirred until two clearly distinguishable phases were observed. The phases were separated, and the aqueous phase was extracted with DCM (20 mL x 2). The combined organic phase was washed with saturated NaHCO3 (20 mL) aqueous solution and brine (20 mL), dried to (Na2SO4), and the solvent was concentrated under vacuum. The compound residue (1.1 g, crude) was used in the next step without further purification.

[0214] Step 3: tert-butyl N-[1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxypropyl]carbamate A solution of MeMgBr (3M, 3.2 mL, 3 eq) was added to a solution of tert-butyl N-[(1R)-1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-oxo-ethyl]carbamate (1.1 g, 3.2 mmol, 1 eq) in anhydrous THF (12 mL) at 0°C under an N2 atmosphere. The mixture was heated to rt and stirred at RT for 2 hours. The reaction mixture was carefully quenched with saturated ammonium chloride aqueous solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated NaCl aqueous solution (15 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (neutral conditions) (column: Phenomenexgemini NX 150×30mm, 5μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 32%~62% B 11min). Compound P1 (tert-butyl N-[1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxypropyl]carbamate): small amount of product, retention time 0.963 min; Compound P2 (tert-butyl N-[1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxypropyl]carbamate): main product, retention time 0.988 min. Both were obtained as pale yellow oily substances. MS (ES-API positive): 346.2 (M+1) + .

[0215] Step 4: 1-Amino-1-[4-(2-ethylpyrazole-3-yl)phenyl]propan-2-ol (P2) [ka] To a solution of tert-butyl N-[1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxypropyl]carbamate (280 mg, 810.6 μmol, 1 eq) in DCM (1 mL), HCl / dioxane (2 M, 2 mL, 4.9 eq) was added under stirring. The mixture was stirred at RT for 1 hour. After the reaction was complete, the mixture was concentrated under vacuum. The residue was purified by preparative HPLC (HCl) (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (HCl)-ACN]; gradient: 13%~33% B, 11 min). MS (ES-API positive): 246.2 (M+1) + .

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

[0217] A mixture of 1-amino-1-[4-(2-ethylpyrazole-3-yl)phenyl]propan-2-ol (110 mg, 448.4 μmol, 1 eq), (2S,4R)-1-tert-butoxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid (103.7 mg, 448.4 μmol, 1 eq), and DIEA (463.6 mg, 3.6 mmol, 624.8 μL, 8 eq) in DCM (3 mL) was stirred at 0°C for 3 minutes, and then T4P (484.6 mg, 672.6 μmol, 50% purity, 1.5 eq) was added at 0°C. The mixture was stirred at RT for 1 hour. The reaction mixture was concentrated under reduced pressure, quenched with saturated NaHCO3 aqueous solution (20 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated NaCl aqueous solution (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 4g SepaFlash® silica flash column, eluent: 0-35% EE (ethyl acetate:ethyl alcohol = 3:1) / petroleum ether gradient, 18 mL / min). The compound tert-butyl (2S,4R)-2-[[1-[4-(2-ethylpyrazole-3-yl)phenyl]-2-hydroxy-propyl]carbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate was obtained as a white solid. MS (ES-API positive): 459.3 (M+1) + .

[0218] The remaining steps were the same as 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) + .

[0219] Example 74: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3S)-3-methoxycyclobutoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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),3.85( 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,1 H),2.48(s,4H),2.27-2.19(m,1H),2.13-2.09(m,1H),2.07(d,J=2.1Hz,3H),2.04-1 0.98(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) + .

[0220] Example 75: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 73. After SFC separation, Example 75 was obtained. 1 H NMR(400MHz,CD3OD)δ8.59-8.52(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=6.4.13(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) + .

[0221] Example 76: (2S,4R)-1-((2S)-2-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6,7-difluoro-5-methyl-1H-indazole-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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) + .

[0222] Example 77: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-4-(3-fluorophenyl)-1-hydroxybuta-3-in-2-yl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 34. 1 H 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), 1.50-1.40 (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) + .

[0223] Example 78: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-4-(3-chloro-2-fluorophenyl)-1-hydroxybuta-3-in-2-yl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 34. 1 H 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(br t,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 dd,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) + .

[0224] Example 79: (2S,4R)-1-((2S)-2-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-2-((1-(difluoromethyl)cyclopropyl)methoxy)-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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) + .

[0225] Example 80: 2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-4-(benzo[d]thiazole-4-yl)-1-hydroxybuta-3-in-2-yl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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) + .

[0226] Example 81: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-(((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((3-(1-ethyl-1H-pyrazole-5-yl)bicyclo[1.1.1]pentan-1-yl)methyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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),2.17(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) + .

[0227] Example 82: (2S,4R)-1-((2S)-2-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 73. 1H NMR(400MHz,CD3OD)δ8.91-8.86(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) + .

[0228] Example 83: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-2-((1,1-difluoro-3-methoxypropane-2-yl)oxy)-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1H NMR(400MHz,CD3OD)δ8.58-8.39(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) + .

[0229] Example 84: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(5-(1-ethyl-1H-pyrazole-5-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] Step 1: (NZ,S)-N-[[5-(2-ethylpyrazole-3-yl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]methylene]-2-methyl-propane-2-sulfinamide [ka] To a 10 mL solution of 5-(2-ethylpyrazole-3-yl)bicyclo[4.2.0]octa-1,3,5-triene-2-carbaldehyde (1 g, 4.4 mmol, 1 eq) in DCM, (S)-2-methylpropan-2-sulfinamide (540 mg, 4.5 mmol, 1 eq) and Cs2CO3 (1.5 g, 4.6 mmol, 1 eq) 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 filtrate was concentrated under reduced pressure. The residue was flash-chromatographed (ISCO®; 20 g SepaFlash® silica flash column, petroleum ether / Âi, Âi 0-20%, flow rate: 80 mL / min, 254 nm). The compound (NZ,S)-N-[[5-(2-ethylpyrazole-3-yl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]methylene]-2-methyl-propane-2-sulfinamide was obtained as a yellow oil. MS (ES-API positive): 330.1 (M+1) + .

[0230] Step 2: (S)-N-[(1R,2S)-1-[5-(2-ethylpyrazole-3-yl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]-2-hydroxypropyl]-2-methylpropane-2-sulfinamide [ka] A solution of samarium diiodide (0.1 M, 54.6 mL, 3 eq) was cooled to -78°C. (NZ,S)-N-[[5-(2-ethylpyrazole-3-yl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]methylene]-2-methyl-propane-2-sulfinamide (600 mg, 1.8 mmol, 1 eq), a solution of dried t-BuOH (270 mg, 3.6 mmol, 348.4 μL, 2 eq) of acetaldehyde (5 M, 546.4 μL, 1.5 eq), and THF (40 mL) were gradually added over 0.5 hours at -78°C, and the mixture was stirred at -78°C for 2 hours. The reaction mixture was rapidly cooled with saturated Na2S2O3 (12 mL), and DCM (100 mL) was added. A white precipitate formed, which was filtered on Celite. The mixture was separated, the organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. It was then purified by column chromatography (SiO2, petroleum ether / siRNA = 1:0-0:1). Compound (S)-N-[(1R,2S)-1-[5-(2-ethylpyrazole-3-yl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]-2-hydroxypropyl]-2-methyl-propane-2-sulfinamide was obtained as a yellow oil. MS (ES-API positive): 376.2 (M+1) + .

[0231] Step 3: (1R,2S)-1-amino-1-[5-(2-ethylpyrazole-3-yl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]propan-2-ol (S)-N-[(1R,2S)-1-[5-(2-ethylpyrazole-3-yl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]-2-hydroxypropyl]-2-methyl-propane-2-sulfinamide (220 mg, 585.8 mmol, 1 eq) in 3 mL of dried DCM was mixed with HCl / dioxane (2 M, 3 mL, 10.2 eq). The reaction mixture was stirred at RT for 1 hour. The reaction was monitored by LC-MS, and after the reaction was complete, the reaction mixture was concentrated under vacuum and purified by preparative HPLC (HCl) (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (HCl)-ACN]; gradient: 10%~30% B 11 min). The compound (1R,2S)-1-amino-1-[5-(2-ethylpyrazole-3-yl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]propan-2-ol was obtained as a yellow oil. MS (ES-API positive): 272.1(M+1)+.

[0232] Step 4: tert-butyl (2S,4R)-2-[[(1R,2S)-1-[5-(2-ethylpyrazole-3-yl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]-2-hydroxy-propyl]carbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate (2S,4R)-1-tert-butoxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid (121.7 mg, 526.3 μmol, 1.2 eq), (1R,2S)-1-amino-1-[5-(2-ethylpyrazole-3-yl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]propan-2-ol (135 mg, 438.6 μmol, 1 eq, HCl), and DIPEA (283.4 mg, 2.2 mmol, 382 μl, 5 eq) were mixed in a DCM (3 mL) solution, to which T4P (474.0 mg, 657.9 μmol, 50% purity, 1.5 eq) was added at 0°C. The mixture was stirred at RT for 1 hour. The reaction mixture was concentrated under reduced pressure, quenched with saturated NaHCO3 aqueous solution (8 mL), and extracted with ethyl acetate (15 mL x 3). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO®; 4g SepaFlash® silica flash column, eluent: 0-50% EE (ethyl acetate / ethyl alcohol = 3 / 1) / petroleum ether gradient, 25 mL / min). The compound tert-butyl (2S,4R)-2-[[(1R,2S)-1-[5-(2-ethylpyrazole-3-yl)-2-bicyclo[4.2.0]octa-1,3,5-trienyl]-2-hydroxy-propyl]carbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate was obtained as a pale yellow oil. MS (ES-API positive): 485.3 (M+1) + .

[0233] The remaining synthesis was the same as in Example 32. Example 84 was obtained as a grayish-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),5.4Hz,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(br d, J=6.6Hz, 3H), 0.76 (br dd, J=3.7, 8.1Hz, 4H). MS (ES-API positive): 1154.5 (M+1) + .

[0234] Example 85: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(5-(1-ethyl-1H-pyrazole-5-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H 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) + .

[0235] Example 86: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((3-methoxycyclopentyl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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) + .

[0236] Example 87: (2S,4R)-1-((2S)-2-(4-(((2-((2-Oxaspiro[3.5]nonane-7-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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) + .

[0237] Example 88: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclobutyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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) + .

[0238] Example 89: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6,7-difluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0239] Example 90: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6,7-difluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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),1.7Hz,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) + .

[0240] Example 92: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-4-(benzo[d]thiazole-7-yl)-1-hydroxybuta-3-in-2-yl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 34. 1 H 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)2.26-2.3 3(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,1H) 3.96-4.04(m,1H)4.48-4.64(m,5H)4.65(s,2H)4.80-4.86(m,2H)5.0 3-5.10(m,1H)5.32-5.45(m,1H)5.71-5.78(m,1H)6.69-6.80(m,2H)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) + .

[0241] Example 93: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((hexahydro-1H-cyclopenta[c]furan-5-yl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0242] Example 94: (2S,4R)-1-((2S)-2-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclobutyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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) + .

[0243] Example 95: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxy-3-methylbutyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H NMR(400MHz,CD3OD)δ8.46(s,1H),7.94-7.89(m,1H),7.64-7.54(m,6H),7.4 9(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),5.4Hz,1H),5.77-5.74(m,1H),5.37(d,J=10.1Hz,1H),5.05(d,J= 7.2Hz,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) + .

[0244] Example 96: (2S,4R)-1-((2S)-2-(4-(((2-((2-Oxaspiro[3.5]nonane-7-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H 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) + .

[0245] Example 97: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-7-(7-chloro-6-fluoro-5-methyl-1H-indazole-4-yl)-6-cyclopropyl-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide This compound was prepared in the same manner as in Example 32. [ka] 1 H 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) + .

[0246] Example 98: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-4-(2-chloro-3-fluorophenyl)-1-hydroxybuta-3-in-2-yl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 34. 1H NMR(400MHz,CD3OD)δ8.44-8.34(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) + .

[0247] Example 99: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6,7-difluoro-5-methyl-1H-indazole-4-yl)-2-(((1R,4S)-4-methoxycyclohexyl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0248] Example 100: (2S,4R)-1-((2S)-2-(4-(((2-((2-Oxaspiro[3.3]heptan-6-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1H NMR(400MHz,CD3OD)δ8.48-8.38(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) + .

[0249] Example 101: (2S,4R)-1-((2S)-2-(4-(((2-((6-Oxaspiro[3.4]octan-2-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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) + .

[0250] Example 102: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1S,3R)-3-methoxycyclobutoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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) + .

[0251] Example 103: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6,7-difluoro-5-methyl-1H-indazole-4-yl)-2-(((1S,4R)-4-methoxycyclohexyl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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) + .

[0252] Example 104: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((hexahydro-1H-cyclopenta[c]furan-5-yl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H NMR(400MHz,CD3OD)δ8.50-8.34(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), 1.40-1.32(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) + .

[0253] Example 105: (2S,4R)-1-((2S)-2-(4-(((2-((7-Oxaspiro[3.5]nonan-2-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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) + .

[0254] Example 106: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclobutyl-7-(6,7-difluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0255] Example 107: (2S,4R)-1-((2S)-2-(4-(4-(((6-Cyclopropyl-4-(1,4-Diazepan-1-yl)-7-(6-Fluoro-5-methyl-1H-Indazole-4-yl)-2-((S)-2-Methoxypropoxy)Quinazolin-8-yl)Oxy)Methyl)Phenyl)-1H-1,2,3-Triazole-1-yl)-3-Methylbutanoyl)-N-((R)-1-(4-(1-Ethyl-1H-Pyrazole-5-yl)Phenyl)-2-Hydroxyethyl)-4-Hydroxypyrrolidine-2-Carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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) + .

[0256] Example 108: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-4-(4-chloropyridine-3-yl)-1-hydroxybuta-3-in-2-yl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 34. 1H NMR(500MHz,CD3OD)δ8.67-8.57(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) + .

[0257] Example 109: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3S)-3-methoxycyclobutoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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) + .

[0258] Example 110: (2S,4R)-1-((2S)-2-(4-(((2-((2-Oxaspiro[3.5]nonane-7-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6,7-difluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-(((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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(br d,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) + .

[0259] Example 111: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-4-(2-aminobenzo[d]thiazole-6-yl)-1-hydroxybuta-3-in-2-yl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 34. 1 H 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) + .

[0260] Example 112: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-(3-methoxypyrrolidine-1-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1H NMR(400MHz,CD3OD)δ8.40(s,1H),7.54-7.46(m,5H),7.44-7.38(m,4H),7.25(s,1H),6.79(br d,J=7.9Hz,2H),6.30(d,J=1.8Hz,1H),5.35(d,J=10.4Hz,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=7.2Hz,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=1.3Hz,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=7.2Hz,3H),1.16(d,J=6.6Hz,3H),0.82-0.82(m,1H),0.82(d,J=6.7Hz,3H),0.55(br d,J=7.6Hz,3H)。MS(ES-APIポジティブ):1113.5(M+1) + 。

[0261] Example 113: (2S,4R)-1-((2S)-2-(4-(((2-((7-Oxaspiro[3.5]nonan-2-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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),5.9Hz,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) + .

[0262] Example 114: (2S,4R)-1-((2S)-2-(4-(((2-((6-Oxaspiro[3.4]octan-2-yl)oxy)-4-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-6-Cyclopropyl-7-(6-Fluoro-5-methyl-1H-indazole-4-yl)Quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-Triazole-1-yl)-3-Methylbutanoyl)-N-((1R,2S)-1-(4-(1-Ethyl-1H-pyrazole-5-yl)phenyl)-2-Hydroxypropyl)-4-Hydroxypyrrolidine-2-Carboxamide [ka] This compound was prepared by the same method as in Example 84. 1H 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) + .

[0263] Example 115: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((hexahydro-1H-cyclopenta[c]furan-5-yl)oxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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) + .

[0264] Example 116: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-1-hydroxy-4-(2-methyl-2H-indazole-4-yl)buta-3-in-2-yl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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) + .

[0265] Example 117: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-1-hydroxy-4-(2-methylbenzo[d]thiazole-4-yl)buta-3-in-2-yl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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) + .

[0266] Example 118: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-1-hydroxy-4-(thiazolo[4,5-c]pyridine-7-yl)buta-3-in-2-yl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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) + .

[0267] Example 119: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-2-(3,3-difluoro-2-methoxypropoxy)-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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),4.6 7-4.56(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(br d,J=12.0Hz,1H),2.20(dd,J=8.0,13.1Hz,1H),2.14(d,J=2.3Hz,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) + .

[0268] Example 120: (2S,4R)-1-((2S)-2-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclobutyl-7-(6,7-difluoro-5-methyl-1H-indazole-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H NMR(400MHz,CD3OD)δ8.90-8.85(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(br s,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) + .

[0269] Example 121: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-(((1R,4S)-4-methoxycyclohexyl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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) + .

[0270] Example 122: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-2-(3,3-difluoro-2-methoxypropoxy)-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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) + .

[0271] Example 123: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(((R)-1-hydroxy-4-phenylbuto-3-in-2-yl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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) + .

[0272] Example 124: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-(4-methoxypiperidine-1-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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(br s,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(br d,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) + .

[0273] Example 125: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-(3-(methoxymethyl)pyrrolidine-1-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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(br s,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) + .

[0274] Example 126: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-(3-methoxyazetidine-1-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1H 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) + .

[0275] Example 127: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((4-methoxycyclohexyl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1H 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) + .

[0276] Example 128: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclobutyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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) + .

[0277] Example 129: (2S,4R)-1-((2S)-2-(4-(((2-((2-Oxaspiro[3.3]heptan-6-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0278] Example 130: (2S,4R)-1-((2S)-2-(4-(((2-((2-Oxaspiro[3.5]nonane-7-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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ポジティブ):1168.6(M+1) + 。

[0279] Example 131: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3S)-3-methoxycyclobutoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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) + .

[0280] Example 132: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((hexahydro-1H-cyclopenta[c]furan-5-yl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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(br s,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ポジティブ):1157.4(M+1) + 。

[0281] Example 133: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-1-hydroxy-4-(1H-indazole-4-yl)buta-3-in-2-yl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 34. 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ポジティブ):1072.5(M+1) + 。

[0282] Example 134: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-1-hydroxy-4-(1-methyl-1H-indazole-4-yl)buta-3-in-2-yl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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) + .

[0283] Example 135: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1S,3R)-3-methoxycyclobutoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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,4 H),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=2.3 Hz, 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) + .

[0284] Example 136: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclobutyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3S)-3-methoxycyclobutoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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) + .

[0285] Example 137: (2S,4R)-1-((2S)-2-(4-(((2-((2-Oxaspiro[3.5]nonane-7-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclobutyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-(((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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ポジティブ):1168.5(M+1) + 。

[0286] Example 138: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-2-cyclopropyl-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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(br d,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) + .

[0287] Example 139: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)butyl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H NMR(400MHz,CD3OD)δ8.89-8.85(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) + .

[0288] Example 140: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-1-hydroxy-4-(1-methyl-1H-benzo[d]imidazole-4-yl)buta-3-in-2-yl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 34. 1 H 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) + .

[0289] Example 141: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-4-(3,5-difluorophenyl)-1-hydroxybuta-3-in-2-yl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 34. 1 H 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) + .

[0290] Example 142: (2S,4R)-1-((2S)-2-(4-((6-cyclobutyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H NMR(400MHz,CD3OD)δ8.90-8.84(m,1H),8.46-8.41(m,1H),7.87-7.82(m,1H),7.56-7.51 (m,2H),7.48-7.44(m,4H),7.40(s,1H),7.32-7.26(m,1H),6.83-6.77(m,2H),5.39-5.32 (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) + .

[0291] Example 143: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H 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) + .

[0292] Example 144: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H 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) + .

[0293] Example 145: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6,7-difluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H 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) + .

[0294] Example 146: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6,7-difluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H 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,1H) ,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=6.6 Hz,3H),0.88-0.83(m,3H),0.82-0.67(m,4H);MS(ES-API positive):1136.6(M+1) + .

[0295] Example 147: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3S)-3-methoxycyclobutoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(5-(1-ethyl-1H-pyrazole-5-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H NMR(400MHz,CD3OD)δ8.54-8.30(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) + .

[0296] Example 148: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(pentafluoro-16-sulfanyl)phenyl)propyl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H 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) + .

[0297] Example 149: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(5-(1-ethyl-1H-pyrazole-5-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H NMR(400MHz,CD3OD)δ0.58-0.74(m,4H)0.79-0.86(m,3H)1.17(d,J=6.56Hz ,3H)1.23-1.30(m,7H)1.31-1.43(m,4H)1.43-1.50(m,1H)1.95-2.08(m,4H) 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)3.85-3.97(m,2 H)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 )6.66Hz,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) + .

[0298] Example 150: (2S,4R)-1-((2S)-2-(4-(((2-((2-Oxaspiro[3.3]heptan-6-yl)oxy)-4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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) + .

[0299] Example 151: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-(((1S,3S)-3-methoxycyclopentyl)oxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H 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) + .

[0300] Example 152: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(5-(1-ethyl-1H-pyrazole-5-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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) + .

[0301] Example 153: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-((S)-7-methyl-1,4-diazepan-1-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide

change

[0302] Example 154: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-((R)-7-methyl-1,4-diazepan-1-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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(r s,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,1H),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ポジティブ):1118.6(M+1) + 。

[0303] Example 155: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-4-(6-hydroxy-6-methyl-1,4-diazepan-1-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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),1.2 5-1.21(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) + .

[0304] Example 156: (2S,4R)-1-((2S)-2-(4-(4-(((6-Cyclopropyl-4-(1,4-Diazepan-1-yl)-7-(6-Fluoro-5-methyl-1H-Indazole-4-yl)-2-((1r,3r)-3-Methoxycyclobutoxy)Quinazolin-8-yl)Oxy)Methyl)Phenyl)-1H-1,2,3-Triazole-1-yl)-3-Methylbutanoyl)-N-((1R,2S)-1-(4-(1-Ethyl-1H-Pyrazole-5-yl)Phenyl)-2-Hydroxypropyl)-4-Hydroxypyrrolidine-2-Carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H 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) + .

[0305] Example 157: (2S,4R)-1-((2S)-2-(4-(4-(((6-Cyclopropyl-4-(1,4-Diazepan-1-yl)-7-(6-Fluoro-5-methyl-1H-Indazole-4-yl)-2-((S)-2-Methoxypropoxy)Quinazolin-8-yl)Oxy)Methyl)Phenyl)-1H-1,2,3-Triazole-1-yl)-3-Methylbutanoyl)-4-Hydroxy-N-((1R,2S)-2-Hydroxy-1-(4-(4-Methylthiazole-5-yl)Phenyl)Propyl)Pyrrolidine-2-Carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H 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) + .

[0306] Example 158: (2S,4R)-1-((2S)-2-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-(2,3,6,7-tetrahydro-1H-azepine-1-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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),4.60 (t,J=8.34Hz,1H),5.07(t,J=6.14Hz,1H),5.22-5.29(m,1H),5.36(d,J=10.37Hz,1H) ,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) + .

[0307] Example 159: (2S,4R)-1-((2S)-2-(4-((6-Cyclobutyl-7-(6-Fluoro-5-methyl-1H-Indazole-4-yl)-2-((S)-2-Methoxypropoxy)-4-(Methyl((S)-Pyrrolidine-3-yl)amino)Quinazoline-8-yl)Oxy)Methyl)Phenyl)-1H-1,2,3-Triazole-1-yl)-3-Methylbutanoyl)-4-Hydroxy-N-((1R,2S)-2-Hydroxy-1-(4-(4-Methylthiazole-5-yl)phenyl)Propyl)Pyrrolidine-2-Carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H 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) + .

[0308] Example 160: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-(((1R,3S)-3-methoxycyclobutoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(5-(1-ethyl-1H-pyrazole-5-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H 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) + .

[0309] Example 161: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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 0.18-2.09 (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) + .

[0310] Example 162: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-4-(2-ethyl-2H-indazole-4-yl)-1-hydroxybuta-3-in-2-yl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 34. 1 H 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)+ .

[0311] Example 163: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-2-((1R,3R)-3-methoxycyclobutoxy)-7-(6-fluoro-5-methyl-1H-indazole-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-4-(1-ethyl-1H-indazole-4-yl)-1-hydroxybuta-3-in-2-yl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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) + .

[0312] Example 164: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(5-(1-ethyl-1H-pyrazole-5-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H 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) + .

[0313] Example 165: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3S)-3-methoxycyclobutoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0314] Example 166: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3S)-3-methoxycyclobutoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0315] Example 167: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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) + .

[0316] Example 168: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3S)-3-methoxycyclobutoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-4-(2-ethyl-2H-indazole-7-yl)-1-hydroxybuta-3-in-2-yl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 34. 1 H 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) + .

[0317] Example 169: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(5-(1-ethyl-1H-pyrazole-5-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H 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) +.

[0318] Example 170: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3S)-3-methoxycyclobutoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1H NMR(400MHz,CD3OD)δ8.45-8.40(m,1H),7.56-7.49(m,5H),7.47(d,J=2.4 Hz,2H),7.43-7.40(m,2H),7.29(d,J=9.8Hz,1H),6.79(d,J=8.2Hz,2H),6. 31(d,J=1.9Hz,1H),5.9Hz,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) + .

[0319] Example 171: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3S)-3-methoxycyclobutoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H NMR(400MHz,CD3OD)δ8.89-8.84(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) + .

[0320] Example 172: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3S)-3-methoxycyclobutoxy)quinazolin-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-4-(1-ethyl-1H-indazole-7-yl)-1-hydroxybuta-3-in-2-yl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 34. 1 H 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) + .

[0321] Example 173: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1r,3S)-3-methoxycyclobutoxy)-4-(methyl(((S)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(5-(1-ethyl-1H-pyrazole-5-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H 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 0.03 (m, 3H), 1.99 (ddd, J=4.6, 8.8, 13.2Hz, 1H), 1.52-1.41 (m, 1H), 1.38-1.33 (m, 3H), 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) + .

[0322] Example 174: (2S,4R)-1-((2S)-2-(4-(((4-(4-cyanopiperidine-1-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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) + .

[0323] Example 175: (2S,4R)-1-((2S)-2-(4-((6-cyclobutyl-7-(6,7-difluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide This compound was prepared by the same method as in Example 84. [ka] 1 H NMR(400MHz,CD3OD)δ8.88(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) + .

[0324] Example 176: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-1-hydroxy-4-(2-(methylamino)benzo[d]thiazole-6-yl)buta-3-in-2-yl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 34. 1H NMR(400MHz,CD3OD)δ8.44-8.39(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) + .

[0325] Example 177: (2S,4R)-1-((2S)-2-(4-((((4-(azepan-1-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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) + .

[0326] Example 178: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-((R)-7-methyl-1,4-diazepan-1-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0327] Example 179: (2S,4R)-1-((2S)-2-(4-(4-(((6-Cyclopropyl-4-(1,4-Diazepan-1-yl)-7-(6-Fluoro-5-methyl-1H-Indazole-4-yl)-2-((S)-2-Methoxypropoxy)Quinazolin-8-yl)Oxy)Methyl)Phenyl)-1H-1,2,3-Triazole-1-yl)-3-Methylbutanoyl)-4-Hydroxy-N-((R)-2-Hydroxy-1-(4-(4-Methylthiazole-5-yl)Phenyl)Ethyl)Pyrrolidine-2-Carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H 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) + .

[0328] Example 180: (2S,4R)-1-((2S)-2-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-(1,4-oxazepan-4-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1H NMR(400MHz,CD3OD)δ8.44-8.39(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,1 H),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),2.29- 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) + .

[0329] Example 181: (2S,4R)-1-((2S)-2-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-(2,3,6,7-tetrahydro-1H-azepine-1-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0330] Example 182: (2S,4R)-1-((2S)-2-(4-(4-(((4-(4-cyanoazepan-1-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0331] Example 183: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-((S)-7-methyl-1,4-diazepan-1-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as 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) + .

[0332] Example 184: (2S,4R)-1-((2S)-2-(4-(4-(((6-Cyclopropyl-4-(1,4-Diazepan-1-yl)-7-(6-Fluoro-5-methyl-1H-Indazole-4-yl)-2-((S)-2-Methoxypropoxy)Quinazolin-8-yl)Oxy)Methyl)Phenyl)-1H-1,2,3-Triazole-1-yl)-3-Methylbutanoyl)-N-((1R,2S)-1-(4-(1-Ethyl-1H-Pyrazole-5-yl)Phenyl)-2-Hydroxypropyl)-4-Hydroxypyrrolidine-2-Carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H 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,3H) ),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=2.1H z,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) + .

[0333] Example 185: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-1-hydroxy-4-(2-methyl-2H-pyrazolo[3,4-c]pyridine-4-yl)buta-3-in-2-yl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 34. 1 H 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) + .

[0334] Example 186: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((R)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(5-(1-ethyl-1H-pyrazole-5-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H 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) + .

[0335] Example 187: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((R)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H 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) + .

[0336] Example 188: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-1-hydroxy-4-(6-methyl-1H-indazole-4-yl)buta-3-in-2-yl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as 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) + .

[0337] Example 189: (2S,4R)-1-((2S)-2-(4-(((6-Cyclopropyl-7-(6-Fluoro-5-methyl-1H-Indazole-4-yl)-2-((S)-2-Methoxypropoxy)-4-((R)-7-Methyl-1,4-Diazepan-1-yl)Quinazolin-8-yl)Oxy)Methyl)Phenyl)-1H-1,2,3-Triazole-1-yl)-3-Methylbutanoyl)-4-Hydroxy-N-((R)-2-Hydroxy-1-(4-(4-Methylthiazole-5-yl)Phenyl)Ethyl)Pyrrolidine-2-Carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1H NMR(400MHz,CD3OD)δ0.53-0.74(m,4H)0.77-0.91(m,3H)1.17(d,J=6.56Hz ,3H)1.22-1.30(m,3H)1.40-1.49(m,1H)1.49-1.69(m,3H)1.81-1.95(m,1H )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(d,J=8.23Hz,2H)7.27(d,J=9.66Hz,1H)7.36-7.71(m,8H)8.41(s,1H)8.88(s,1H);MS(ES-API positive):1121.5(M+1) + .

[0338] Example 190: (2S,4R)-1-((2S)-2-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-((R)-7-methyl-1,4-diazepan-1-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1H NMR(400MHz,CD3OD)δ8.91-8.84(m,1H),8.40(s,1H),7.54-7.41(m,8H),7.30-7. 24(m,1H),6.78(d,J=8.2Hz,2H),5.39-5.27(m,2H),4.85(s,1H),4.83-4.81(m,1H) ),4.81-4.72(m,2H),4.60(s,1H),4.50-4.45(m,1H),4.40(dd,J=2.9,5.1Hz,3H) ,4.14-4.07(m,1H),3.96-3.89(m,1H),3.89-3.83(m,1H),3.82-3.74(m,1H),3.59 -3.51(m,1H),3.43(s,3H),3.39-3.34(m,1H),3.24-3.18(m,1H),3.14-3.07(m,1 H),2.65-2.61(m,1H),2.52-2.47(m,3H),2.42-2.34(m,1H),2.22-2.13(m,1H),2. 09(d,J=2.3Hz,3H),1.99-1.83(m,2H),1.54(d,J=6.3Hz,3H),1.49-1.42(m,1H),1 .29-1.22(m,6H),1.17(d,J=6.6Hz,3H),0.83(d,J=6.6Hz,3H),0.71-0.54(m,4H). MS(ES-API positive):1135.5(M+1) + .

[0339] Example 191: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-1-hydroxy-4-(2-methyl-2H-pyrazolo[3,4-b]pyridine-4-yl)buta-3-in-2-yl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 34. 1 H NMR(400MHz,CD3OD)δ8.55(d,J=4.4Hz,1H),8.41(d,J=17.4Hz,2H),7.53-7.50(m,3H),7.39(s,1H),7.27(d,J=9.3Hz,1H),7.20(d,J=4.6Hz,1H),6. 6Hz,1H),6.78(d,J=8.2Hz,2H),5.35(d,J=10.4Hz,1H),5.27(d,J=11.3Hz ,1H),5.21(s,1H),5.06(s,1H),4.61(s,1H),4.56-4.48(m,2H),4.39(d,J= 4.7Hz,2H),4.31(s,1H),4.27(s,2H),4.00-3.93(m,3H),3.90(s,1H),3.8 6-3.83(m,3H),3.45-3.43(m,2H),3.42-3.40(m,4H),3.16(td,J=1.6,3.1 Hz,3H),2.13-2.11(m,1H),2.08(d,J=2.3Hz,3H),1.92(s,1H),1.44(s,1H) ),1.25-1.23(m,3H),1.16(d,J=6.7Hz,3H),0.83(d,J=6.6Hz,3H),0.67(br s,1H),0.63-0.60(m,3H). MS (ES-API positive):1087.6(M+1) + .

[0340] Example 192: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl((R)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(5-(1-ethyl-1H-pyrazole-5-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H NMR(500MHz,CD3OD)δ8.44(s,1H),7.58-7.53(m,3H),7.50(s,2H),7.33-7.24(m,3H),6.83(d,J=8.1Hz,2H),6.32(d,J=1.8Hz,1H),5. 38(d,J=10.2Hz,1H),5.29(d,J=11.6Hz,1H),5.20-4.97(m,2H),5.06-4.95(m,2H),4.91-4.87(m,1H),4.61(t,J=8.3Hz,1H),4.53(br s,1H),4.47-4.39(m,2H),4.20(q,J=7.3Hz,2H),4.10-3.88(m,4H),3.87-3.78(m,1H),3.44(s,3H),3.36(s, 4H),3.31-3.20(m,4H),3.19-3.11(m,1H),3.10-3.01(m,1H),2.70-2.64(m,1H),2.40-2.30(m,1H),2.26(br dd,J=7.7,13.2Hz,1H),2.21-2.13(m,1H),2.10-2.05(m,4H),1.52-1.43(m,1H),1.37(t,J=7.1Hz,3H),1.29-1.24(m,3H),1.19(d,J=6.6Hz,3H),0.88-0.81(m,3H),0.78-0.70(m,1H),0.69-0.61(m,3H);MS(ES-API positive):1130.7(M+1) + .

[0341] Example 193: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3S)-3-methoxycyclobutoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(6-(1-ethyl-1H-pyrazole-5-yl)pyridine-3-yl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H NMR(400MHz,CD3OD)δ8.66(d,J=1.8Hz,1H),8.41(s,1H),7.89(dd,J=2.2,8.3Hz,1H),7. 69(d,J=8.3Hz,1H),7.55-7.49(m,4H),7.40(s,1H),7.31-7.25(m,1H),6.77(d,J=8.3Hz ,2H),6.67(d,J=2.0Hz,1H),5.44(t,J=6.2Hz,1H),5.34(d,J=10.1Hz,1H),5.28(d,J=11 .4Hz,1H),5.20(s,1H),4.82-4.77(m,4H),4.66-4.53(m,4H),4.50-4.44(m,1H),4.31(br d,J=9.1Hz,1H),4.21-4.09(m,2H),3.95-3.81(m,4H),3.26(s,4H),3.18-3.10(m,2H),2.68- 2.61(m,1H),2.53-2.46(m,4H),2.22-2.13(m,1H),2.08(d,J=2.3Hz,4H),1.3Hz,4H),1.93(br d,J=3.8Hz,1H),1.49-1.42(m,1H),1.39-1.33(m,3H),1.17(d,J=6.6Hz,3H),0.87-0.80(m,3H),0.71-0.65(m,1H),0.64-0.57(m,3H);MS(ES-API positive):1129.6(M+1) + .

[0342] Example 194: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3S)-3-methoxycyclobutoxy)-4-(methyl((S)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(5-(4-methylthiazole-5-yl)bicyclo[4.2.0]octa-1(6),2,4-triene-2-yl)propyl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H NMR(400MHz,CD3OD)δ8.97-8.79(m,1H),8.46-8.36(m,1H),7.59-7.50(m,2H),7.50-7.43(m,2H),7.36-7.20(m,3H),6.79(d ,J=8.2Hz,2H),5.52-5.39(m,1H),5.35(d,J=10.4Hz,1H),5.31-5.23(m,1H),5.07-4.95(m,1H),4.92-4.88(m,1H),4.85(br s,2H),4.60(t,J=8.3Hz,1H),4.53-4.38(m,1H),4.26-4.08(m,2H),4.00-3.82(m,2H) ),3.45-3.33(m,2H),3.30-3.15(m,9H),3.12-2.96(m,2H),2.72-2.57(m,1H),2.55-2 .44(m,7H),2.36-2.22(m,1H),2.22-2.09(m,2H),2.08-1.95(m,4H),1.52-1.40(m,1H ),1.27(d,J=6.4Hz,3H),1.16(d,J=6.6Hz,3H),0.88-0.78(m,3H),0.76-0.57(m,4H). MS(ES-API positive):1159.5(M+1) + .

[0343] Example 195: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3S)-3-methoxycyclobutoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)-3-fluorophenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H NMR(400MHz,CD3OD)δ8.44-8.40(m,1H),7.60-7.49(m,4H),7.42-7.24(m,5H),6.77(d,J=8.2Hz,2H),6.36-6.30(m,1H),5.44(t,J=6.1Hz,1H),5 .35(d,J=10.4Hz,1H),5.28(d,J=11.3Hz,1H),5.20(s,1H),4.79(d,J=11 .3Hz,1H),4.60(d,J=8.3Hz,2H),4.49(s,1H),4.36-4.29(m,1H),4.21-4 .01(m,4H),3.99-3.79(m,4H),3.30-3.22(m,4H),3.18-3.10(m,1H),2. 69-2.59(m,1H),2.50(d,J=3.8Hz,4H),2.23-2.14(m,1H),2.13-2.06(m, 4H),2.00-1.87(m,2H),1.49-1.40(m,1H),1.35-1.32(m,3H),1.29-1.25 (m,3H),1.17(d,J=6.6Hz,3H),0.84(d,J=6.6Hz,3H),0.73-0.56(m,4H). MS(ES-API positive):1146.8(M+1) + .

[0344] Example 196: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3S)-3-methoxycyclobutoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)-2,6-difluorophenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H NMR(400MHz,CD3OD)δ8.44-8.37(m,1H),7.56-7.49(m,4H),7.40(s,1H),7.28(d,J=9.8Hz,1H),7.09(d,J=8.5Hz,2H),6.76(d,J=8.2Hz,2H) ,6.39(d,J=1.9Hz,1H),5.49-5.40(m,1H),5.37-5.31(m,1H),5.30-5. 23(m,2H),5.20(s,1H),4.81-4.77(m,2H),4.60-4.56(m,1H),4.46(br s,1H),4.31(br d,J=9.8Hz,1H),4.24-4.15(m,4H),3.97-3.88(m,2H),3.88-3.78(m,2H),3.26(s,3H),3.17-3.11(m,1H),2.68-2.59(m,1H),2.50(br d,J=3.6Hz,4H),2.15-2.03(m,5H),1.95-1.86(m,2H),1.49-1.44(m,1H),1 .42-1.34(m,6H),1.21-1.14(m,3H),0.86-0.80(m,3H),0.69-0.57(m,4H). MS(ES-API positive):1164.5(M+1) + .

[0345] Example 197: (2S,4R)-1-((2S)-2-(4-(((4-(((1S,4S,5S)-2-azabicyclo[2.1.1]hexane-5-yl)(methyl)amino)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H NMR(400MHz,CD3OD)δ0.59-0.75(m,4H)0.79-0.88(m,3H)1.17(d,J=6.68H z,3H)1.22-1.26(m,3H)1.31-1.38(m,3H)1.42-1.56(m,2H)1.99-2.09(m, 4H)2.17-2.29(m,1H)2.46-2.53(m,1H)2.57-2.66(m,1H)3.03(d,J=8.70H z,2H)3.23(d,J=8.58Hz,1H)3.42(d,J=14.31Hz,6H)3.79-3.88(m,3H)3.89 -3.95(m,3H)4.17(q,J=7.07Hz,2H)4.36-4.43(m,2H)4.50(s,1H)4.60(t, J=8.28Hz,1H)4.90-4.97(m,1H)5.07(t,J=6.14Hz,1H)5.24-5.33(m,1H)5 .33-5.49(m,1H)6.31(d,J=1.91Hz,1H)6.82(d,J=8.11Hz,2H)7.26-7.32(m,1H)7.35-7.58(m,9H)8.25-8.54(m,1H);MS(ES-API positive):1116.5(M+1) + .

[0346] Example 198: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3S)-3-methoxycyclobutoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)-2-fluorophenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H NMR(400MHz,CD3OD)δ8.41(s,1H),7.64-7.46(m,5H),7.40(s,1H),7.32-7.15(m,3H),6.76(d,J=8.2Hz,2H),6.3 6(d,J=2.0Hz,1H),5.50-5.39(m,1H),5.35(d,J=10.4Hz,1H),5.28(d,J=11.4Hz,1H),5.25-5.17(m,2H),4.79(br d,J=11.3Hz,1H),4.59(t,J=8.3Hz,1H),4.48(br s,1H),4.31(br d,J=7.7Hz,1H),4.25-4.10(m,4H),3.98-3.75(m,4H),3.29-3.22(m,4H),3.14(br s,1H),2.72-2.59(m,1H),2.55-2.42(m,4H),2.22-2.02(m,5H),2.02-1.85(m,2H),1.50-1.40(m,1H) ),1.39-1.32(m,3H),1.27(d,J=6.3Hz,3H),1.22-1.11(m,3H),0.87-0.77(m,3H),0.74-0.50(m,4H). MS(ES-API positive):1146.5(M+1) + .

[0347] Example 199: (2S,4R)-1-((2S)-2-(4-(4-(((6-Cyclopropyl-4-(1,4-Diazepan-1-yl)-7-(6-Fluoro-5-methyl-1H-Indazole-4-yl)-2-((1r,3r)-3-Methoxycyclobutoxy)Quinazolin-8-yl)Oxy)Methyl)Phenyl)-1H-1,2,3-Triazole-1-yl)-3-Methylbutanoyl)-4-Hydroxy-N-((R)-2-Hydroxy-1-(4-(4-Methylthiazole-5-yl)Phenyl)Ethyl)Pyrrolidine-2-Carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H NMR(400MHz,CD3OD)δ0.58-0.64(m,3H)0.65-0.73(m,1H)0.83(d,J=6.56Hz,3H)1.17(d,J=6.56Hz,3H)1.41-1.49(m,1H)2.01-2.07(m,4 H)2.13-2.26(m,3H)2.40-2.55(m,8H)2.61-2.66(m,1H)3.00(d,J=5.01Hz,2H)3.26(s,4H)3.85(d,J=6.20Hz,2H)3.91-3.97(m,1H)4.4. 03-4.10(m,4H)4.14-4.21(m,1H)4.50(s,1H)4.60(t,J=8.29Hz,1H)4.78-4.84(m,2H)5.06(t,J=6.02Hz,1H)5.20-5.29(m,1H)5.35(d,J =10.25Hz,1H)5.44(quin,J=6.02Hz,1H)6.77(d,J=8.11Hz,2H)7.24-7.30(m,1H)7.45-7.50(m,6H)7.54(s,2H)8.41(s,1H)8.88(s,1H). MS(ES-API positive):1119.4(M+1) + .

[0348] Example 200: (2S,4R)-1-((2S)-2-(4-(4-(((4-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3S)-3-methoxycyclobutoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(5-(1-ethyl-1H-pyrazole-5-yl)pyridine-2-yl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H NMR(400MHz,CD3OD)δ8.69-8.48(m,1H),8.45-8.31(m,1H),7.93-7.74(m,1H),7.60-7.43(m,5H),7.39(br d,J=5.8Hz,1H),7.32-7.23(m,1H),6.81-6.67(m,2H),6.48-6.28(m,1 H),5.42(td,J=5.5,6.8Hz,1H),5.38-5.30(m,1H),5.30-5.23(m,1H), 5.22-5.16(m,1H),5.04-4.97(m,1H),4.66-4.56(m,2H),4.52-4.44(m , 1H), 4.35-4.27(m, 1H), 4.24-4.08(m, 4H), 3.97-3.77(m, 4H), 3.25(br s, 3H), 3.16-3.11(m, 1H), 2.68-2.58(m, 1H), 2.54-2.42(m, 4H), 2.19(br dd, J=4.5,12.6Hz,1H),2.12-1.98(m,5H),1.94-1.87(m,1H),1.51-1.23(m,8H),1.1 9-1.10(m,3H),0.87-0.76(m,3H),0.68-0.53(m,4H);MS(ES-API positive):1129.5(M+1) + .

[0349] Example 201: (2S,4R)-1-((2S)-2-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-((R)-7-methyl-1,4-diazepan-1-yl)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxypropyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H NMR(500MHz,CD3ODδ8.43-8.38(m,1H),7.56-7.45(m,7H),7.42(d,J=8.2Hz,2H),7.24(s ,1H),6.78(d,J=8.1Hz,2H),6.31(d,J=1.8Hz,1H),5.38-5.27(m,2H),4.89-4.86(m,2H), 4.80-4.74(m,1H),4.64-4.57(m,1H),4.50-4.45(m,1H),4.45-4.36(m,3H),4.21-4.15( m,2H),4.15-4.08(m,1H),3.97-3.90(m,1H),3.90-3.84(m,1H),3.83-3.78(m,1H),3.59- 3.53(m,1H),3.43(s,3H),3.40-3.33(m,2H),3.24-3.16(m,1H),3.15-3.08(m,1H),2.64 -2.59(m,1H),2.43-2.34(m,1H),2.22-2.13(m,1H),2.13-2.06(m,3H),2.01-1.83(m,2H) ,1.57-1.50(m,3H),1.47(s,1H),1.33(s,3H),1.25(d,J=6.3Hz,6H),1.19-1.15(m,3H),0.87-0.80(m,3H),0.71-0.65(m,1H),0.65-0.54(m,3H). MS (ES-API positive):1132.6(M+1) + .

[0350] Example 202: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3R)-3-methoxycyclobutoxy)-4-(methyl((R)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H NMR(400MHz,CD3OD)δ8.87(d,J=0.8Hz,1H),8.41(s,1H),7.57-7.41(m,8H),7.28(d,J=9.8Hz,1H),6.79(d,J=7.9Hz,2H),5.50-5.41(m,1H),5 .34(d,J=10.7Hz,1H),5.27(t,J=11.0Hz,1H),5.05-4.96(m,1H),4.86 (m,3H),4.60(t,J=8.0Hz,1H),4.48(s,1H),4.23-4.05(m,2H),3.99-3. 82(m,2H),3.35(m,2H),3.25(d,J=1.3Hz,5H),3.11-2.97(m,2H),2.64 (m,J=9.1Hz,1H),2.55-2.43(m,7H),2.30(m,1H),2.14(m,2H),2.05(s, 3H),1.97(m,J=4.4,8.7Hz,1H),1.50-1.42(m,1H),1.25(d,J=5.8Hz,3H),1.17(d,J=6.6Hz,3H),0.83(d,J=6.1Hz,3H),0.65(m,J=3.5Hz,4H). MS(ES-API positive):1133.6(M+1) + .

[0351] Example 203: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3R)-3-methoxycyclobutoxy)-4-(methyl((R)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((R)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H NMR(400MHz,CD3OD)δ8.87-8.92(m,1H),8.44(s,1H),7.57(d,2H),7.47-7.51(m,6H),7.29-7.33(m,1H),6.8 1(d,2H),5.45-5.51(m,1H),5.38(d,1H),5.29(d,1H),5.08(m,1H),4.99-5.05(m,1H),4.62(m,1H),4.52(br s,1H),4.17-4.21(m,1H),3.94-3.99(m,1H),3.85-3.93(m,3H),3.39(br d,1H),3.34(br s,4H),3.27(s,3H),3.01-3.18(m,3H),2.65-2.70(m,1H),2.48-2.55(m,8H),2.32-2.39(m,1H),2.26(br m,1H),2.14(br m,1H),2.07(d,3H),2.00-2.06(m,1H),1.45-1.52(m,1H),1.19(d,3H),0.85(d,3H),0.61-0.75(m,4H). MS(ES-API positive):1119.5(M+1) + .

[0352] Example 204: (2S,4R)-1-((2S)-2-(4-(4-(((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1r,3R)-3-methoxycyclobutoxy)-4-(methyl(((R)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-(((R)-1-(5-(1-ethyl-1H-pyrazole-5-yl)bicyclo[4.2.0]octa-1(6),2,4-trien-2-yl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1H NMR(400MHz,CD3OD)δ8.43-8.40(m,1H),7.57-7.51(m,3H),7.49-7.46(m,2H),7.31-7.25(m,2H),7.24-7.22(m,1H) ,6.82-6.77(m,2H),6.31-6.27(m,1H),5.49-5.43(m,1H),5.39-5.32(m,1H),5.27(dd,J=6.9,11.4Hz,1H),5.07(br t,J=6.1Hz,2H),4.92-4.88(m,1H),4.59(t,J=8.3Hz,1H),4.51(br s,1H),4.22-4.15(m,3H),3.97-3.92(m,1H),3.89(d,J=6.1Hz,3H),3.39-3.33(m,2H),3.30-3. 28(m,1H),3.27-3.18(m,7H),3.17-3.09(m,1H),3.04-2.97(m,1H),2.68-2.61(m,1H),2.49(br dd,J=3.0,5.7Hz,5H),2.57-2.41(m,1H),2.35-2.19(m,2H),2.11-2.03(m,5H),1.50-1.44(m,1H),1.37-1.33(m,3 H),1.17(d,J=6.6Hz,3H),0.85-0.81(m,3H),0.73-0.68(m,1H),0.67-0.60(m,3H);MS(ES-API positive):1142.7(M+1) + .

[0353] Example 205: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((1R,3R)-3-methoxycyclobutoxy)-4-(methyl((R)-pyrrolidine-3-yl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H NMR(400MHz,CD3OD)δ8.46-8.39(m,1H),7.63-7.36(m,9H),7.29(d,J=9.5Hz,1H) ,6.79(d,J=8.2Hz,2H),6.33-6.26(m,1H),5.50-5.42(m,1H),5.36(d,J=10.3Hz,1 H),5.27(d,J=11.4Hz,1H),5.07(t,J=6.0Hz,1H),5.01(t,J=7.9Hz,1H),4.90(s,1 H),4.60(t,J=8.4Hz,1H),4.50(d,J=1.4Hz,1H),4.17(q,J=7.0Hz,3H),4.08-3.72 (m,4H),3.40-3.34(m,1H),3.33(s,3H),3.25(s,3H),3.22-3.16(m,1H),3.14-3.0 0(m,2H),2.66(s,1H),2.50(d,J=2.3Hz,4H),2.38-2.28(m,1H),2.27-2.19(m,1H) ,2.14(s,1H),2.09-1.96(m,4H),1.51-1.41(m,1H),1.37-1.28(m,3H),1.17(d,J=6.6Hz,3H),0.87-0.77(m,3H),0.76-0.57(m,4H);MS(ES-API positive):1116.5(M+1) + .

[0354] Example 206: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-2-((S)-2-methoxypropoxy)-4-(methyl(((S)-pyrrolidine-3-yl)methyl)amino)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazole-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1 H NMR(400MHz,CD3OD)δ8.42(s,1H),7.66-7.35(m,9H),7.28(br d,J=9.5Hz,1H),6.81(br d,J=8.0Hz,2H),6.30(d,J=1.7Hz,1H),5.36(d,J=10.1Hz,1H),5.26(d,J=11.4Hz,1H),5.07(t,J=6.0Hz,1H),4.60(t,J=8. 2Hz,1H),4.50(s,1H),4.40(d,J=4.5Hz,2H),4.16(q,J=7.1Hz,2H),4.07-3.73(m,8H),3.52(s,3H),3.41(s,3H),3.19-3.0 7(m,2H),2.99(m,J=7.2Hz,1H),2.88-2.72(m,2H),2.69-2.59(m,1H),2.28-2.19(m,1H),2.06(m,J=1.9Hz,5H),1.60(m,J= 7.0,12.9Hz,1H),1.51-1.43(m,1H),1.34(t,J=7.2Hz,3H),1.28-1.10(m,6H),0.83(d,J=6.6Hz,3H),0.63(m,J=5.1Hz,4H). MS(ES-API positive):1118.5(M+1) + .

[0355] Example 207: (2S,4R)-1-((2S)-2-(4-(4-(((6-Cyclopropyl-4-(1,4-Diazepan-1-yl)-7-(6-Fluoro-5-methyl-1H-Indazole-4-yl)-2-(((S)-Tetrahydrofuran-2-yl)Methoxy)Quinazolin-8-yl)Oxy)Methyl)Phenyl)-1H-1,2,3-Triazole-1-yl)-3-Methylbutanoyl)-N-((R)-1-(4-(1-Ethyl-1H-Pyrazole-5-yl)Phenyl)-2-Hydroxyethyl)-4-Hydroxypyrrolidine-2-Carboxamide [ka] This compound was prepared in the same manner as in Example 32. 1H NMR(400MHz,CD3OD)δ8.44-8.39(m,1H),7.56-7.52(m,3H),7.51-7.46(m,4H),7.45-7.41(m,2H),7.28(d,J=9.9Hz,1H ),6.82(d,J=8.1Hz,2H),6.33-6.28(m,1H),5.36(d,J=10.3Hz,1H),5.27-5.22(m,1H),5.08(t,J=6.0Hz,1H),4.60(br t,J=8.3Hz,2H),4.50(br d,J=1.2Hz,1H),4.42(dd,J=2.0,5.1Hz,2H),4.36-4.30(m,1H),4.17(q,J=7.0Hz,2H),4.12-4.05(m,4H),3.95-3.8 9(m,2H),3.86(d,J=6.2Hz,2H),3.82-3.76(m,1H),3.27-3.22(m,3H),3.04-2.98(m,2H),2.70-2.61(m,1H),2.24(br dd,J=7.9,13.0Hz,1H),2.20-2.14(m,2H),2.09-2.05(m,4H),2.03-1.87(m,3H),1.82-1.74(m,1H),1. 51-1.43(m,1H),1.35(t,J=7.2Hz,3H),1.17(d,J=6.6Hz,3H),0.84(d,J=6.7Hz,3H),0.72-0.60(m,4H). MS(ES-API positive):1116.5(M+1) + .

[0356] Example 208: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-4-(methyl((S)-pyrrolidine-3-yl)amino)-2-(((R)-tetrahydrofuran-2-yl)methoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((1R,2S)-2-hydroxy-1-(4-(4-methylthiazole-5-yl)phenyl)propyl)pyrrolidine-2-carboxamide [ka] This compound was prepared by the same method as in Example 84. 1 H NMR(400MHz,CD3OD)δ0.59-0.73(m,4H),0.83(d,J=6.56Hz,3H),1.17(d,J=6.68Hz,3H),1.25(d,J=6.44Hz ,3H),1.41-1.52(m,1H),1.71-1.80(m,1H),1.88-1.99(m,3H),2.02-2.09(m,4H),2.10-2.21(m,2H),2.23 -2.35(m,1H),2.45-2.52(m,3H),2.62-2.69(m,1H),2.99-3.24(m,4H),3.34(s,3H),3.75-3.81(m,1H),3. 82-3.98(m,3H),4.06-4.15(m,1H),4.30-4.44(m,3H),4.44-4.49(m,1H),4.59(t,J=8.29Hz,1H),4.85(br s,2H),4.91(br s,1H),4.94-5.03(m,1H),5.26(d,J=11.44Hz,1H),5.35(d,J=10.25Hz,1H),6.84(d,J=7.99Hz,2H),7.28(br d,J=9.54Hz,1H),7.43-7.50(m,6H),7.55(d,J=8.11Hz,2H),8.42(s,1H),8.85-8.91(m,1H). MS(ES-API positive):1133.5(M+1) + .

[0357] Example 209: (2S,4R)-1-((2S)-2-(4-((6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazole-4-yl)-4-(methyl((S)-pyrrolidine-3-yl)amino)-2-(((R)-tetrahydrofuran-2-yl)methoxy)quinazoline-8-yl)oxy)methyl)phenyl)-1H-1,2,3-triazole-1-yl)-3-methylbutanoyl)-N-((1R,2S)-1-(5-(1-ethyl-1H-pyrazole-5-yl)bi...

Claims

1. The compound of formula (I), or a pharmaceutically acceptable salt thereof, tautomer, or stereoisomer. 【Chemistry 1】 (In the formula, X is N or CR ３ It is; G is CR １４ R １５ or O; J is CR ５ａ R ５ｂ Or O, but G and J are not both O at the same time; G is CR １４ R １５ and J is CR ５ａ R ５ｂ In the case where, optionally, the carbon atoms of G and J (each of R １４ and R １５ , as well as R ５ａ and R ５ｂ to which they are attached) form a cycloalkylene or cycloalkenylene of C １４ or R １５ , and / or R ５ａ or R ５ｂ together with C ３ -C ６ ; Between G and J 【Chemistry 2】 (Dashed lines) indicate single or double bonds between G and J; L stands for alkynylene, allylene, heteroarylene, C ３ -C ８ Monocyclic or bicyclic cycloalkylene, or C ３ -C ８ It is a heterocycloalkylene and has one or more R ９ It is arbitrarily replaced by; K is, 【Transformation 3】 It is; Q is an alkylylene, arylene, heteroarylene, monocyclic or bicyclic cycloalkylene, or heterocycloalkylene, which is optionally substituted with one or more halo, alkyl, haloalkyl, alkoxyalkyl, hydroxy, hydroxyalkyl, -O-alkyl, or cycloalkyl groups; R １ C １ -C ６ Alkyl, alkoxyalkyl, haloalkyl, monocyclic or bicyclic cycloalkyl or heterocyclyl, each of which has one or more R １０ It is arbitrarily replaced by; R ２ This includes saturated or unsaturated heterocyclyl, bridging bicyclic heterocyclyl, condensed bicyclic heterocyclyl, spirocyclic heterocyclyl, or -NR １６ R １６’ Here, the heterocyclyl is one or more R １１ The heterocyclyl is optionally substituted with, where the heterocyclyl comprises 1 to 3 ring-forming heteroatoms, each of which is independently oxygen, sulfur, or nitrogen; R ３ H, Halo, C １ -C ６ Alkyl or haloalkyl, or C ３ -C ８ It is a cycloalkyl or heterocyclyl, where C １ -C ６ Alkyl or haloalkyl, or C ３ -C ８ The cycloalkyl or heterocyclyl is one or more R １３ It is arbitrarily replaced by; R ４ is H, aryl, heteroaryl, condensed aryl, condensed heteroaryl, aryl-condensed spiroheterocyclyl, or heteroaryl-condensed spiroheterocyclyl, each of which is one or more R １２ The heteroaryl or heterocyclyl is optionally substituted with -CH in the condensed aryl, the condensed heteroaryl, the aryl-condensed spiroheterocyclyl, or the heteroaryl-condensed spiroheterocyclyl. ２ - The group is arbitrarily substituted with -C (=O)-; R ５ａ and R ５ｂ These are, independently, H, alkyl, halo, haloalkyl, hydroxyl, hydroxyalkyl, -O-alkyl, alkoxyalkyl, and -NR １４ R １５ , -alkamino or -alkaminoalkyl; or R ５ａ and R ５ｂ They, together with the atoms to which they are bonded, form a cycloalkyl group; R ６ C １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl, or C ４ -C ８ It is a heterocycline; where the cycloalkyl or the heterocycloalkyl is optionally substituted with alkyl, halo, or haloalkyl; R ７ａ and R ７ｂ These are H and C, which are independent of each other. １ -C ６ Alkyl, halo, haloalkyl, hydroxyl, hydroxyalkyl, -O-alkyl, alkoxyalkyl, -NR １４ R １５ -Alkamino, -Alkaminoalkyl, -Alkylene-C(=O)-NR １４ R １５ , C ３ -C ８ Cycloalkyl, or C ４ -C ８ It is heterocycloalkyl; or R ７ａ and R ７ｂ They, together with the atoms to which they are bonded, form a cycloalkyl group; R ８ Here, H, halo, alkyl, monocyclic or bicyclic aryl or heteroaryl is defined as halo, alkyl, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, -O-alkyl, -SF ５ , -NR １４ R １５ , or optionally substituted with one or more substituents independently selected from alkoxyalkyl groups; R ９ 、R １０ 、R １１ and R １２ are each independently H, halo, -CN, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxyalkyl, -NR １４ R １５ 、-NH-C(O)-R １６ 、-O-alkyl, -SO ２－ R[[ID=1十七]] １５ 、C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ８ cycloalkyl, haloalkoxy, cycloalkyl, -alkylene-cycloalkyl, heterocyclyl, -alkylene-heterocyclyl, aryl, or heteroaryl; or two of R ９ 、R １０ 、R １１ and R １２ together with the atom to which they are both attached form a cycloalkyl or heterocyclyl; and each of the aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally further substituted with alkyl, halo, or haloalkyl; R １３ is H, halo, alkyl, haloalkyl, haloalkoxy, -CN, oxo, -NR １４ R １５ , hydroxy, hydroxyalkyl, -O-alkyl, alkoxyalkyl, cycloalkyl or heterocyclyl; R １４ and R １５ Each of these is independently either H or alkyl; R １６ and R １６’ Each of these is independently H, alkyl, cycloalkyl, or heterocyclyl, and each of these is one or more R １１ (It is arbitrarily replaced.)

2. R ２ The compound according to claim 1, wherein the following is true. 【Chemistry 4】 (In the formula, Y is NH, -CH(CN)-, CH ２ , or O; and each R ２ This can be any one or more R １１ (Further replaced by...)

3. The compound according to claim 1 or 2, wherein L is a crosslinked bicyclic cycloalkylene, an aryl condensed cycloalkylene, or an arylene.

4. L, 【Transformation 5】 The compound according to any one of claims 1 to 3.

5. K 【Transformation 6】 The compound according to any one of claims 1 to 4.

6. Q is, 【Transformation 7】 The compound according to any one of claims 1 to 5, wherein Q is optionally substituted with one or more alkyl, halo, or haloalkyl groups.

7. R ４ However, H, 【Transformation 8】 And; and, R ４ａ , R ４ｂ , R ４ｃ , and R ４ｄ The compound according to any one of claims 1 to 6, wherein each is independently H, alkyl, halo, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, -O-alkyl, alkoxyalkyl, -CN, alkynyl, cycloalkyl, heterocyclyl, or hydroxyalkalkynyl.

8. R ６ However, C １ -C ６ Alkyl, C ３ -C ６ A compound according to any one of claims 1 to 7, wherein the compound is a cycloalkyl, oxetanyl, or azetidinyl.

9. R ８ but, 【Chemistry 9】 And; and, R ８ However, each is independent of halo, alkyl, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, -O-alkyl, -SF ５ The compound according to any one of claims 1 to 8, which is optionally substituted with one or more substituents that are amino or alkoxyalkyl.

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

11. The compound according to claim 1, wherein G is O.

12. J is CH ２ The compound according to claim 1.

13. The compound according to claim 1, wherein the compound is of formula (II). 【Chemistry 10】 (In the formula, L is, 【Chemistry 11】 And L is one or more R ９ (It is arbitrarily replaced.)

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

15. R ３ However, H, F, trifluoromethyl, Ｃ１－６ Alkyl, or C ３－５ The compound according to claim 14, wherein it is a cycloalkyl compound.

16. The compound according to claim 1, wherein the compound is of formula (III). 【Chemistry 12】 (In the formula, L is, 【Chemistry 13】 And L is one or more R ９ (It is arbitrarily replaced.)

17. R ４ but, 【Chemistry 14】 And, R ４ａ , R ４ｂ , R ４ｃ and R ４ｄ The compound according to claim 1 or 16, wherein each is independently H, alkyl, halo, haloalkyl, hydroxyl, hydroxyalkyl, haloalkoxy, -O-alkyl, alkoxyalkyl, -CN, alkynyl, cycloalkyl, heterocyclyl, or hydroxyalkalkynyl.

18. The compound according to claim 1, wherein the compound is of formula (IV). 【Chemistry 15】 (In the formula, L is, 【Chemistry 16】 And L is one or more R ９ It is arbitrarily replaced by; also, R ４ａ , R ４ｂ , R ４ｃ and R ４ｄ These are, independently, H, alkyl, halo, and haloalkyl, respectively.

19. The compound according to claim 18, wherein the halo is -F or -Cl.

20. R ６ C １ -C ６ The compound according to claim 1 or 18, wherein it is alkyl.

21. The compound according to claim 1, wherein the compound is of formula (V). 【Chemistry 17】 (In the formula, L is, [Chemistry 18] And L is one or more R ９ It is arbitrarily replaced by; R ４ｂ , R ４ｃ and R ４ｄ These are, independently, H, alkyl, halo, and haloalkyl, respectively.

22. The compound according to any one of claims 1 to 21, wherein the compound is selected from the following. 【Chemistry 19-1】 【Chemistry 19-2】 【Chemistry 19-3】 【Chemistry 19-4】 【Chemistry 19-5】 【Chemistry 19-6】 【Chemistry 19-7】 【Chemistry 19-8】 【Chemistry 19-9】 【Chemistry 19-10】 【Chemistry 19-11】 [Chemistry 19-12] [Chemistry 19-13] [Chemistry 19-14] 【Chemistry 19-15】 [Chemistry 19-16] [Chemistry 19-17] [Chemistry 19-18] 【Chemistry 19-19】 [Chemistry 19-20] [Chemistry 19-21] [Chemistry 19-22]

23. The compound according to any one of claims 1 to 22, wherein the compound degrades or inhibits the KRAS protein having the G12D mutation.

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

25. The pharmaceutical composition according to claim 24, further comprising a second therapeutic agent.

26. A method for treating a disorder mediated by the KRAS(G12D) mutation in a subject requiring treatment, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 23, or a pharmaceutical composition according to claim 24 or 25.

27. The method according to claim 26, wherein the disorder mediated by the KRAS(G12D) mutation is a cancer characterized by the presence of the KRAS(G12D) mutation.

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

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